Hepatitis C

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0100371 acute hepatitis C virus infection Not Yet Curated

MONDO:0100371 names the acute phase of the infection this entry curates, not a separate disease. Under design decisions §3e a phase of one infection is never its own entry, and the entry it belongs to enumerates its phases in progression: -- which this entry now does, with "Acute infection" and "Chronic infection" phases carrying the content of the former Acute_Hepatitis_C_Virus_Infection entry. The mapping is recorded as a narrowMatch so the MONDO concept is retired from the curation queue rather than lost.

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Mechanistic Hypotheses

2

Host-virus response balance determines clearance or persistence

canonical_acute_hcv_clearance_persistence_model CANONICAL

Evidence balance 1 support

Productive hepatocyte infection generates viremia and innate antiviral activation while HCV simultaneously suppresses interferon induction. Adaptive immune responses can accompany clearance, but ongoing immune responses and viral escape can coexist with persistence. Hepatocellular injury is immune-associated, although the contribution of individual cell populations is not fully resolved.

Pathograph links

HCV attachment and hepatocyte entry -> HCV Polyprotein Translation INDIRECT KNOWN INTERMEDIATES Productive hepatocyte entry and genome release permit translation of the HCV polyprotein. Intermediates: Endosomal fusion and release of the positive-sense viral RNA genome

HCV Polyprotein Translation -> HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein DIRECT The viral NS3/4A serine protease cleaves defined sites in the nonstructural region of the HCV polyprotein.

HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein -> HCV genome replication and early viremia INDIRECT KNOWN INTERMEDIATES NS3/4A-dependent processing releases nonstructural proteins required for HCV genome replication. Intermediates: Release of processed HCV nonstructural proteins; Assembly of the HCV replication complex

HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein -> NS3/4A-mediated innate immune evasion INDIRECT KNOWN INTERMEDIATES Processed active NS3/4A also cleaves the host innate-sensing adaptors MAVS and TRIF, suppressing interferon induction. Intermediates: Release and assembly of the active NS3/4A protease complex

HCV genome replication and early viremia -> Interferon-driven innate and NK-cell activation INDIRECT KNOWN INTERMEDIATES Newly acquired HCV infection is accompanied by a transient type-I-interferon-imprinted activated NK-cell population. Intermediates: Viral RNA sensing and type I interferon induction

HCV genome replication and early viremia -> Immune-associated hepatocellular injury UNKNOWN HCV viremia is associated with inflammatory immune activation and hepatocellular injury, but the exact direction and cell-specific causal contribution remain unresolved.

Interferon-driven innate and NK-cell activation -> HCV-specific adaptive immune response UNKNOWN Early interferon-associated innate activation precedes the later adaptive response associated with control or persistence, but the cited temporal pattern does not establish that NK-cell activation causes the adaptive response.

NS3/4A-mediated innate immune evasion -> Persistent HCV viremia UNKNOWN Suppressed interferon induction and escape from immune recognition are proposed contributors to failure of viral clearance, but their specific causal contribution to persistence is not isolated by the cited review.

HCV-specific adaptive immune response -> Spontaneous viral clearance UNKNOWN Early multispecific T-cell responses and low viral diversity are associated with untreated clearance, without establishing that the measured response is independently causal.

HCV-specific adaptive immune response -> Immune-associated hepatocellular injury UNKNOWN Activated immune-cell populations track with biochemical hepatitis, but their causal contribution to hepatocyte killing remains unresolved.

HCV-specific adaptive immune response -> Persistent HCV viremia INDIRECT KNOWN INTERMEDIATES Adaptive responses can remain ongoing yet fail to clear immune-escape variants. Intermediates: Incomplete effector control; Viral escape from antibody and T-cell recognition

IFNL3 rs12979860 host-clearance modifier -> Spontaneous viral clearance UNKNOWN rs12979860 C/C is associated with spontaneous HCV clearance, while the molecular intermediates and causal mechanism remain unresolved.

Immune-associated hepatocellular injury -> Elevated Transaminases DIRECT Hepatocellular injury is reflected by increased circulating ALT and other hepatic transaminases.

Immune-associated hepatocellular injury -> Jaundice INDIRECT KNOWN INTERMEDIATES Clinically apparent acute hepatitis can impair bilirubin handling and present with jaundice. Intermediates: Hepatocellular dysfunction and impaired bilirubin handling

Immune-associated hepatocellular injury -> Nausea INDIRECT UNKNOWN INTERMEDIATES Symptomatic acute hepatitis can include nausea through incompletely resolved systemic and gastrointestinal intermediates.

Immune-associated hepatocellular injury -> Fatigue INDIRECT UNKNOWN INTERMEDIATES Symptomatic acute hepatitis can include fatigue through incompletely resolved systemic inflammatory intermediates.

Immune-associated hepatocellular injury -> Anorexia INDIRECT UNKNOWN INTERMEDIATES Symptomatic acute hepatitis can include loss of appetite through incompletely resolved systemic and gastrointestinal intermediates.

Persistent HCV viremia -> Chronic hepatitis C virus infection DIRECT Viremia persisting beyond six months meets the definition of chronic HCV infection.

Chronic hepatitis C virus infection -> Chronic Inflammation and Fibrosis INDIRECT KNOWN INTERMEDIATES Persistent infection is the substrate for chronic hepatic inflammation and progressive fibrosis; about 30% of persistently infected people develop chronic liver disease. Intermediates: Sustained intrahepatic immune infiltration

Show evidence (1 reference)

PMID:25443342 SUPPORT Other

"Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses."

This review supports the canonical coordination of innate and adaptive responses in acute-HCV outcome.

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Discussions and Knowledge Gaps

3

Does the liver-enriched PD-1-high ICOS-high Tfh1-like CD4 response observed in HCV-infected chimpanzees mark or mechanistically assist viral control in humans with acute HCV?

HUMAN MODEL MISMATCH OPEN human_validation_of_tfh1_helper_axis

Attached to

pathophysiology#HCV-specific adaptive immune response pathophysiology#Spontaneous viral clearance

The chimpanzee study temporally links the population to viral control, seroconversion, and hepatitis and shows enrichment in liver, but the source does not establish the same population or a causal helper function in humans. Human longitudinal sampling with matched blood and liver-proximal material is needed before promoting this refinement to the canonical model.

Show evidence (1 reference)

PMID:40956619 SUPPORT Model Organism

"HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication."

This is the model-organism observation whose human generalizability remains open.

Which immune-cell populations directly cause hepatocyte injury during acute HCV, and which are biomarkers or bystanders of the same inflammatory state?

KNOWLEDGE GAP OPEN cell_specific_cause_of_acute_hcv_liver_injury

Attached to

pathophysiology#Immune-associated hepatocellular injury phenotypes#Elevated Transaminases

Human iNKT activation correlates with ALT, but the study explicitly cannot determine whether iNKT cells kill hepatocytes or respond to injury-related drivers. The pathograph therefore retains UNKNOWN causal directness rather than encoding a specific effector population as established.

Show evidence (1 reference)

PMID:34905514 SUPPORT Human Clinical

"Given the correlative nature of our study, we cannot distinguish whether iNKT cell activation contributes to hepatocyte killing or whether ALT elevation"

The authors directly identify the unresolved causal direction captured by this discussion.

Which early virologic and immune measurements robustly predict spontaneous clearance across populations, coinfection states, and HCV genotypes?

KNOWLEDGE GAP OPEN generalizable_predictors_of_spontaneous_clearance

Attached to

pathophysiology#HCV-specific adaptive immune response pathophysiology#Spontaneous viral clearance progression#Spontaneous viral clearance

Rapid viral-load decline and strong T-cell responses predicted clearance in an HIV-positive male cohort, while clearance proportions vary across cohorts. External validation is needed before these associations can be treated as universal decision rules.

Show evidence (1 reference)

PMID:21139063 SUPPORT Human Clinical

"Spontaneous clearance of acute HCV in HIV-positive men can be predicted by a rapid decline in viral load, high CD4 count, elevated bilirubin and ALT, and is associated with low viral diversity and strong T cell responses."

This directly supports candidate predictors while the cohort restriction motivates the generalizability gap.

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Pathophysiology

15

HCV attachment and hepatocyte entry

HCV first attaches to cell-surface proteoglycans, SR-BI, and CD81, then uses the tight-junction proteins claudin-1 and occludin and clathrin-mediated endocytosis to enter human liver cells.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

symbiont entry into host cell GO:0046718 ↑ INCREASED

liver UBERON:0002107

Downstream

HCV Polyprotein Translation Productive hepatocyte entry and genome release permit translation of the HCV polyprotein.

Show evidence (1 reference)

PMID:31427285 SUPPORT Other

"The virus initially attaches to surface proteoglycans, lipid receptors such as the scavenger receptor BI (SR-BI), and to the tetraspanin CD81. After lateral translocation of virions to tight junctions, claudin-1 (CLDN1) and occludin (OCLN) are essential for entry."

This review directly supports the host-factor sequence in the entry node.

HCV Polyprotein Translation

The positive-sense HCV RNA genome is translated as a single long polyprotein in infected hepatocytes. Host and viral proteases subsequently process this precursor into structural and nonstructural proteins.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

Viral Gene Expression GO:0019080 ↑ INCREASED

liver UBERON:0002107

Downstream

HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein The viral NS3/4A serine protease cleaves defined sites in the nonstructural region of the HCV polyprotein.

Show evidence (1 reference)

PMID:22558217 SUPPORT In Vitro

"The hepatitis C virus (HCV) genome encodes a long polyprotein, which is processed by host cell and viral proteases to the individual structural and non-structural (NS) proteins."

The primary cleavage-assay study establishes the HCV polyprotein precursor and its processing into individual viral proteins.

HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein

HCV NS3/4A is a virus-encoded serine protease complex that cleaves four defined junctions in the nonstructural region of the HCV polyprotein. This processing is essential for viral replication and produces active viral proteins, including NS3/4A itself. The active protease can also cleave host innate-sensing adaptors, a distinct downstream immune-evasion effect.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

Viral Protein Processing GO:0019082 ↑ INCREASED

Peptidase Activity GO:0008233

liver UBERON:0002107

Downstream

HCV genome replication and early viremia NS3/4A-dependent processing releases nonstructural proteins required for HCV genome replication.

NS3/4A-mediated innate immune evasion Processed active NS3/4A also cleaves the host innate-sensing adaptors MAVS and TRIF, suppressing interferon induction.

Show evidence (2 references)

PMID:22558217 SUPPORT In Vitro

"NS3/4A cleaves the polyprotein sequence at four specific regions."

The primary cleavage-assay study directly establishes four specific NS3/4A-dependent polyprotein cleavage regions.

PMID:22558217 SUPPORT In Vitro

"NS3/4A is essential for viral replication and has been considered an attractive drug target."

The study directly links NS3/4A activity to viral replication and its therapeutic vulnerability.

HCV genome replication and early viremia

Processed HCV nonstructural proteins assemble the replication complex that synthesizes viral RNA in infected hepatocytes, producing the circulating HCV RNA that marks productive infection. HCV replicates primarily in hepatocytes and evades clearance through high mutation rates and quasispecies diversity. In one tertiary-center cohort of newly acquired infection, RNA was detectable at presentation in 26 of 30 patients; this cohort proportion is not assigned as a universal frequency.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

Viral RNA Genome Replication GO:0039694 ↑ INCREASED

liver UBERON:0002107

Computational models

Aston2018 HCV Within-Host Viral-Dynamics Model KINETIC MATLAB for publication fitting; COPASI for the BioModels model and fitted variants The model explicitly couples healthy-hepatocyte infection, infected-cell loss, virion production, and viral clearance, and fits the viral-load state to human treatment-response profiles.

Downstream

Interferon-driven innate and NK-cell activation Newly acquired HCV infection is accompanied by a transient type-I-interferon-imprinted activated NK-cell population.

Immune-associated hepatocellular injury HCV viremia is associated with inflammatory immune activation and hepatocellular injury, but the exact direction and cell-specific causal contribution remain unresolved.

Show evidence (1 reference)

PMID:23481134 SUPPORT Human Clinical

"HCV-ribonucleic acid (RNA) was detectable at presentation in 26 (86.7%) patients."

This cohort of newly acquired infection directly documents early detectable viremia.

Interferon-driven innate and NK-cell activation

During acute HCV, a highly activated NK-cell subset shows a strong type I interferon imprint and largely returns toward baseline after viral clearance.

Host-virus response balance determines clearance or persistence

natural killer cell CL:0000623

natural killer cell activation GO:0030101 ↑ INCREASED type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED

Downstream

HCV-specific adaptive immune response Early interferon-associated innate activation precedes the later adaptive response associated with control or persistence, but the cited temporal pattern does not establish that NK-cell activation causes the adaptive response.

Show evidence (1 reference)

PMID:41453396 SUPPORT Human Clinical

"Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C that is largely restored upon viral clearance."

This directly supports the human innate-activation node and its resolution after clearance.

NS3/4A-mediated innate immune evasion

HCV NS3/4A protease cleaves and inactivates MAVS and TRIF, blunting pathogen-sensing pathways that induce interferons. Escape from adaptive immunity additionally involves viral escape mutations that reduce antibody and T-cell recognition, and exhaustion of HCV-specific T cells during persistent infection.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

MAVS hgnc:29233

symbiont-mediated suppression of host type I interferon-mediated signaling pathway GO:0039502 ↑ INCREASED type I interferon-mediated signaling pathway GO:0060337 ↓ DECREASED

Downstream

Persistent HCV viremia Suppressed interferon induction and escape from immune recognition are proposed contributors to failure of viral clearance, but their specific causal contribution to persistence is not isolated by the cited review.

Show evidence (3 references)

PMID:25443342 SUPPORT In Vitro

"the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1..."

This review directly supports the stated NS3/4A mechanism.

PMID:25443342 SUPPORT Other

"Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells."

This directly supports adaptive immune escape as an additional persistence mechanism.

PMID:16127453 SUPPORT In Vitro

"'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection"

In-vitro siRNA-knockdown study demonstrates the RIG-I/IPS-1(MAVS) interferon-induction pathway that HCV NS3/4A disrupts to evade interferon signaling; general virology, not HCV-specific.

HCV-specific adaptive immune response

Virus-specific T-cell responses emerge after the early innate response. Strong multispecific responses are associated with spontaneous clearance, whereas the recent liver-enriched Tfh1-like helper-cell refinement is based on chimpanzee data and remains unconfirmed in humans.

Host-virus response balance determines clearance or persistence Intrahepatic Tfh1-like CD4 response as a helper axis for HCV control

T cell CL:0000084

T cell activation GO:0042110 ↑ INCREASED

Downstream

Spontaneous viral clearance Early multispecific T-cell responses and low viral diversity are associated with untreated clearance, without establishing that the measured response is independently causal.

Immune-associated hepatocellular injury Activated immune-cell populations track with biochemical hepatitis, but their causal contribution to hepatocyte killing remains unresolved.

Persistent HCV viremia Adaptive responses can remain ongoing yet fail to clear immune-escape variants.

Show evidence (2 references)

PMID:21139063 SUPPORT Human Clinical

"Evolution to spontaneous clearance occurred in patients with low viral diversity in the presence of an early multispecific T cell response."

This human cohort supports an association between early multispecific T-cell responses and clearance.

PMID:40956619 SUPPORT Model Organism

"circulating CD4+ T cells with high programmed cell death 1 (PD-1) and ICOS coexpression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees."

This supports the emerging Tfh1-like refinement in the chimpanzee model, not direct human confirmation.

IFNL3 rs12979860 host-clearance modifier

The rs12979860 C/C genotype near IFNL3 (formerly IL28B) is associated with a higher probability of untreated HCV clearance in both European- and African-ancestry cohorts. The associated locus is established, but its precise functional mechanism remains unresolved.

Host-virus response balance determines clearance or persistence

IFNL3 hgnc:18365

Downstream

Spontaneous viral clearance rs12979860 C/C is associated with spontaneous HCV clearance, while the molecular intermediates and causal mechanism remain unresolved.

Show evidence (1 reference)

PMID:19759533 SUPPORT Human Clinical

"We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry."

This multi-cohort human genetic study directly supports the rs12979860-clearance association.

Immune-associated hepatocellular injury

Hepatocellular injury releases alanine aminotransferase and may produce symptomatic hepatitis. Injury reflects both direct cytopathic effects of viral replication and immune-mediated hepatocyte destruction. Human iNKT-cell activation correlates with ALT, but available data do not determine whether those cells cause injury or respond to the same inflammatory drivers.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Elevated Transaminases Hepatocellular injury is reflected by increased circulating ALT and other hepatic transaminases.

Jaundice Clinically apparent acute hepatitis can impair bilirubin handling and present with jaundice.

Nausea Symptomatic acute hepatitis can include nausea through incompletely resolved systemic and gastrointestinal intermediates.

Fatigue Symptomatic acute hepatitis can include fatigue through incompletely resolved systemic inflammatory intermediates.

Anorexia Symptomatic acute hepatitis can include loss of appetite through incompletely resolved systemic and gastrointestinal intermediates.

Show evidence (1 reference)

PMID:34905514 SUPPORT Human Clinical

"We next analyzed the activation status of iNKT cells in the context of liver damage, which is defined by serum levels of alanine transaminase (ALT)."

This human study operationalizes acute-HCV liver damage using ALT and supports the immune-associated injury node.

Spontaneous viral clearance

Some newly acquired infections lose detectable viremia without antiviral therapy. Clearance proportions vary by population and ascertainment; a small tertiary-center cohort observed clearance in 9 of 30 patients.

response to virus GO:0009615 ↑ INCREASED

Show evidence (1 reference)

PMID:23481134 SUPPORT Human Clinical

"Totally, 9 patients (30%) experienced spontaneous viral eradication."

This directly documents a spontaneous-clearance outcome in acute HCV.

Persistent HCV viremia

When host responses do not eradicate HCV, viremia persists despite ongoing innate and adaptive responses and can progress to chronic infection.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

viral genome replication GO:0019079 ↑ INCREASED

Downstream

Chronic hepatitis C virus infection Viremia persisting beyond six months meets the definition of chronic HCV infection.

Show evidence (1 reference)

PMID:25443342 SUPPORT Other

"However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response."

This directly supports the persistent-viremia state.

Chronic hepatitis C virus infection

Chronic HCV is the natural-history outcome in which viremia persists for more than six months after acquisition. It is the state from which the hepatic and extrahepatic complications of hepatitis C develop.

Host-virus response balance determines clearance or persistence

hepatocyte CL:0000182

viral process GO:0016032 ↑ INCREASED

Downstream

Chronic Inflammation and Fibrosis Persistent infection is the substrate for chronic hepatic inflammation and progressive fibrosis; about 30% of persistently infected people develop chronic liver disease.

Cryoglobulin Immune Complex Deposition Sustained HCV antigenaemia during chronic infection drives the cryoprecipitable immune complexes behind the extrahepatic manifestations.

Show evidence (1 reference)

PMID:39599853 SUPPORT Human Clinical

"approximately 50-70% of individuals with recently acquired hepatitis C will develop a chronic infection, defined as the persistence of viremia for a period exceeding six months."

This directly supports the chronic outcome and its definition.

Chronic Inflammation and Fibrosis

Persistent HCV infection induces chronic hepatic inflammation with infiltration of lymphocytes and activation of hepatic stellate cells. This leads to progressive fibrosis through excessive collagen deposition, ultimately resulting in cirrhosis.

hepatic stellate cell CL:0000632 T cell CL:0000084

chronic inflammatory response GO:0002544 hepatic stellate cell activation GO:0035733 collagen biosynthetic process GO:0032964

Downstream

Cirrhosis Persistent stellate-cell activation and collagen deposition scar the liver until bridging fibrosis and nodular regeneration produce cirrhosis.

Hepatocellular Carcinoma Development Cirrhosis is the dominant substrate for hepatocarcinogenesis, with the highest cumulative risk in HCV-infected patients.

Show evidence (1 reference)

PMID:26569658 SUPPORT

"patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"

Study specifically targets HCV patients with decompensated cirrhosis, confirming progression of chronic inflammation to advanced liver damage.

Hepatocellular Carcinoma Development

Chronic inflammation, oxidative stress, and direct viral effects on cell signaling pathways contribute to hepatocarcinogenesis. Cirrhosis is the major risk factor, but HCC can occur in non-cirrhotic livers.

hepatocyte CL:0000182

Downstream

Hepatocellular Carcinoma Hepatocarcinogenesis in the chronically infected liver presents as hepatocellular carcinoma.

Show evidence (2 references)

PMID:22537432 SUPPORT Human Clinical

"The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)"

Epidemiologic review establishing cirrhosis as the dominant HCC risk factor, with the highest cumulative HCC risk among HCV-infected patients.

PMID:19759533 SUPPORT Human Clinical

"Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"

Documents the natural-history progression from persistent HCV infection to cirrhosis and hepatocellular carcinoma.

Cryoglobulin Immune Complex Deposition

Chronic HCV antigenaemia drives production of cryoprecipitable immunoglobulin complexes that deposit in small vessels and glomerular capillary walls. This single immune-complex mechanism accounts for the cryoglobulinemia-spectrum extrahepatic manifestations, which affect skin and kidney rather than liver.

immune complex formation GO:0097281 ↑ INCREASED

Downstream

Mixed Cryoglobulinemia Cryoprecipitable immune complexes are the defining constituent of the mixed cryoglobulinemia syndrome.

Leukocytoclastic Vasculitis Immune complexes deposited in dermal small vessels produce the cutaneous leukocytoclastic vasculitis.

Membranoproliferative Glomerulonephritis Immune complexes deposited in glomerular capillary walls produce membranoproliferative glomerulonephritis.

Show evidence (1 reference)

PMID:22919404 SUPPORT Other

"Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney."

Histomorphologic review states that immune complex deposition in small vessels and glomerular capillaries is the mechanism producing the cutaneous and renal manifestations, establishing this node as their shared upstream cause.

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Pathograph

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Phenotypes

14

Blood 1

B-Cell Non-Hodgkin Lymphoma B-cell lymphoma HP:0012191

HPO has no combined "B-cell non-Hodgkin lymphoma" term. HP:0012191 B-cell lymphoma is a descendant of HP:0012539 Non-Hodgkin lymphoma, so the narrower lineage term is bound here and the non-Hodgkin sense is entailed.

Show evidence (1 reference)

PMID:22919404 SUPPORT Other

"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."

Review of HCV extrahepatic manifestations lists B-cell non-Hodgkin lymphomas among the HCV-associated entities.

Cardiovascular 2

Leukocytoclastic Vasculitis HP:0034786

Show evidence (1 reference)

PMID:22919404 SUPPORT Other

"immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"

Review of HCV extrahepatic pathology identifies immune-complex-mediated leukocytoclastic vasculitis in the skin as a morphologic manifestation of HCV-associated cryoglobulinemia.

Sicca Syndrome Keratoconjunctivitis sicca HP:0001097

Show evidence (2 references)

PMID:22919404 SUPPORT Other

"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."

Review of HCV extrahepatic manifestations lists sicca syndrome among the HCV-associated entities.

PMID:16510035 SUPPORT Other

"Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."

Confirms sicca syndrome as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.

Digestive 6

Jaundice OCCASIONAL HP:0000952

Show evidence (2 references)

PMID:18657711 SUPPORT Human Clinical

"Symptomatic acute hepatitis C occurs in only about 15% of patients who are infected with hepatitis C virus (HCV)."

Acute HCV is symptomatic in only about 15% of infections, bounding jaundice within the HPO occasional frequency band and contradicting the previous FREQUENT assignment.

PMID:19124916 SUPPORT Human Clinical

"Out of 4 symptomatics 3 were with jaundice."

This small cohort directly documents jaundice in symptomatic acute/recent HCV without supporting a population frequency.

Nausea HP:0002018

Show evidence (1 reference)

PMID:29642211 SUPPORT Human Clinical

"a 26 year-old Chinese female acquired a tattoo and developed fatigue, nausea, and anorexia."

Case-level evidence supports possible presentation but not frequency.

Anorexia HP:0002039

Show evidence (1 reference)

PMID:29642211 SUPPORT Human Clinical

"a 26 year-old Chinese female acquired a tattoo and developed fatigue, nausea, and anorexia."

Case-level evidence supports possible presentation but not frequency.

Hepatomegaly FREQUENT HP:0002240

Cirrhosis FREQUENT HP:0001394

Show evidence (2 references)

PMID:26569658 SUPPORT

"patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"

Study specifically targets HCV patients with cirrhosis, confirming cirrhosis as a major complication.

PMID:24725239 SUPPORT

"Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis"

Large HCV trial confirms cirrhosis prevalence among chronic HCV patients.

Hepatocellular Carcinoma OCCASIONAL HP:0001402

Show evidence (1 reference)

PMID:22537432 SUPPORT Human Clinical

"most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections"

Establishes chronic HCV infection as a leading cause of hepatocellular carcinoma.

Genitourinary 1

Membranoproliferative Glomerulonephritis HP:0000793

Show evidence (1 reference)

PMID:22919404 SUPPORT Other

"immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"

Review of HCV extrahepatic pathology identifies immune-complex-mediated membranoproliferative glomerulonephritis in the kidney as the renal manifestation of HCV-associated cryoglobulinemia.

Immune 1

Mixed Cryoglobulinemia HP:0100778

Show evidence (1 reference)

PMID:16510035 SUPPORT Other

"The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications."

Review of HCV extrahepatic manifestations identifies mixed cryoglobulinemia as the most prevalent and most strongly HCV-associated extrahepatic syndrome.

Integument 1

Porphyria Cutanea Tarda Cutaneous photosensitivity HP:0000992

No HPO term exists for porphyria cutanea tarda itself (confirmed via OAK search of sqlite:obo:hp); bound to the closest broader phenotype, Cutaneous photosensitivity, with a more specific preferred_term, following the same pattern used for SSPE in Measles.yaml. MONDO:0015104 is the disease-level term for porphyria cutanea tarda.

Show evidence (2 references)

PMID:22919404 SUPPORT Other

"Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."

Review of HCV extrahepatic manifestations lists porphyria cutanea tarda among the HCV-associated entities beyond the cryoglobulinemia spectrum.

PMID:16510035 SUPPORT Other

"Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."

Confirms porphyria cutanea tarda as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.

Metabolism 1

Elevated Transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:19124916 SUPPORT Human Clinical

"Among 12 asymptomatics: 8 had elevated ALT"

This cohort directly documents ALT elevation even among asymptomatic acute/recent infections.

Constitutional 1

Fatigue VERY_FREQUENT HP:0012378

Show evidence (2 references)

PMID:16510035 SUPPORT Other

"Although nonspecific, fatigue and arthralgias are very common in those with chronic hepatitis C."

Review of HCV extrahepatic manifestations establishes fatigue as a very common symptom of chronic hepatitis C (not a treatment adverse event).

PMID:29642211 SUPPORT Human Clinical

"a 26 year-old Chinese female acquired a tattoo and developed fatigue, nausea, and anorexia."

Case-level evidence supports fatigue in the acute phase but not its frequency there.

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Genetic Associations

1

IFNL3 (IL28B) rs12979860 clearance modifier (The rs12979860 C/C genotype near IFNL3 (formerly IL28B) is associated with an increased probability of spontaneous HCV clearance and with response to interferon-based therapy; it is not necessary or sufficient for clearance, and its precise functional mechanism remains unresolved.)

Gene: IFNL3 hgnc:18365 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (2 references)

PMID:19759533 SUPPORT Human Clinical

"We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry."

This multi-cohort human genetic study establishes rs12979860 as a modifier of spontaneous HCV clearance.

PMID:19684573 SUPPORT Human Clinical

"a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment"

Landmark GWAS linking the IL28B polymorphism to response to interferon-based HCV therapy.

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Medical Actions

5

Direct-Acting Antivirals (DAAs)

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Oral medications targeting viral proteins (NS3/4A protease, NS5A, NS5B polymerase) with cure rates exceeding 95%. Regimens include sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and others.

Mechanism Target:

INHIBITS HCV genome replication and early viremia — DAAs inhibit HCV nonstructural proteins required for viral replication, eliminating the upstream driver of hepatic infection.

Show evidence (1 reference)

PMID:26569658 SUPPORT Human Clinical

"the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir"

Phase 3 HCV trial names the viral replication proteins inhibited by a direct-acting antiviral regimen, supporting the treatment-to-replication target edge.

Show evidence (3 references)

PMID:24725239 SUPPORT

"Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection."

Landmark trial demonstrating near-universal cure rates with DAA therapy.

PMID:26569658 SUPPORT

"Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis."

Study confirms high efficacy of DAAs even in patients with decompensated cirrhosis.

PMID:36891719 SUPPORT Other

"More and more direct antiviral agents, especially pan genotypic agents including those developed and produced by domestic enterprises, have been included in the national basic medical insurance directory."

The 2022 hepatitis C prevention-and-treatment guideline reflects expanding availability of pangenotypic direct-acting antiviral agents as standard therapy.

Immediate direct-acting antiviral treatment after confirmed acute HCV viremia

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Published AASLD-IDSA guidance recommends initiating direct-acting antiviral treatment after acute HCV with quantifiable RNA is diagnosed rather than waiting for possible spontaneous resolution.

Show evidence (1 reference)

DOI:10.1002/hep.31060 SUPPORT Other

"After the initial diagnosis of acute HCV with viremia (defined as quantifiable RNA), HCV treatment should be initiated without awaiting spontaneous resolution."

The published AASLD-IDSA guidance directly supports the test-and-treat timing recommendation.

Eight-week glecaprevir/pibrentasvir therapy

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Agent: glecaprevir NCIT:C170029 pibrentasvir NCIT:C166601

Platform: Small molecule

An eight-week oral glecaprevir/pibrentasvir direct-acting antiviral regimen produced high sustained virologic response rates in a completed single-arm phase IIIb study of adults with acute HCV. Glecaprevir is the regimen's NS3/4A protease inhibitor, whereas pibrentasvir inhibits NS5A. The absence of a randomized untreated comparator and geography-specific regulatory status should be considered when applying the result.

Mechanism Target:

INHIBITS HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein — The glecaprevir component directly inhibits HCV NS3/4A protease and therefore blocks NS3/4A-dependent nonstructural-polyprotein processing. Pibrentasvir acts through NS5A and is not represented by this protease-target edge.

Show evidence (2 references)

PMID:29084747 SUPPORT In Vitro

"Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity."

The primary biochemical study directly identifies glecaprevir as an HCV NS3/4A protease inhibitor.

PMID:29084747 SUPPORT In Vitro

"It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6 in vitro"

The biochemical assay directly demonstrates glecaprevir inhibition of purified HCV NS3/4A proteases across genotypes.

INHIBITS HCV genome replication and early viremia — Direct-acting antiviral treatment suppresses acute HCV replication and enables virologic eradication.

Show evidence (1 reference)

PMID:41297677 SUPPORT Human Clinical

"An 8-week glecaprevir/pibrentasvir regimen was efficacious and well-tolerated in patients with acute HCV."

This directly supports regimen efficacy against acute infection; the molecular target detail is intentionally kept at the viral-replication level.

INHIBITS Persistent HCV viremia — Achieving sustained virologic response removes persistent viremia and prevents progression to chronic infection.

Show evidence (1 reference)

PMID:41297677 SUPPORT Human Clinical

"SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population (n = 286), and 100% in the mITT-VF population (n = 275)."

Sustained virologic response directly supports inhibition and eradication of persistent viremia in the study population.

Show evidence (2 references)

PMID:41297677 SUPPORT Human Clinical

"Overall, 286 adults were enrolled and treated; 14.3% were recent/current users of injection drugs, 49.7% were HCV/HIV coinfected, and 64.2% had HCV genotype 1."

This establishes the treated acute-HCV study population and its important clinical contexts.

PMID:41297677 SUPPORT Human Clinical

"SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population (n = 286), and 100% in the mITT-VF population (n = 275)."

This directly supports the high sustained virologic response achieved with the regimen.

Liver Transplantation

Action: Liver Transplantation NCIT:C15271

Treatment option for decompensated cirrhosis or hepatocellular carcinoma. Direct-acting antiviral therapy post-transplant prevents graft reinfection.

Hepatocellular Carcinoma Surveillance

Action: surveillance for malignancies Ontology label: Cancer Screening NCIT:C15406

Regular ultrasound and AFP monitoring in cirrhotic patients for early detection of hepatocellular carcinoma.

Show evidence (1 reference)

PMID:15042359 SUPPORT Human Clinical

"biannual screening reduced HCC mortality by 37%"

Landmark randomized controlled trial demonstrating that biannual AFP plus ultrasound surveillance reduces HCC mortality in at-risk chronic-hepatitis patients.

🌍

Environmental Factors

5

Blood-exposure risk contexts

Injection drug use and unsafe medical procedures increase the opportunity for blood-borne HCV acquisition; HIV coinfection identifies an important clinical risk context but is not itself a transmission route.

Show evidence (1 reference)

PMID:36800699 SUPPORT Human Clinical

"People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection."

The source directly identifies these risk contexts while allowing HIV status to be distinguished from a route of transmission.

Mechanism Target:

TRIGGERS HCV attachment and hepatocyte entry — Hepatitis C is efficiently transmitted percutaneously, so unsafe injection and unsterile medical procedures put virus directly into blood, from which it reaches and attaches to hepatocytes.

Show evidence (1 reference)

PMID:36800699 SUPPORT Human Clinical

"People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection."

Identifies unsafe medical procedures and injection drug use among the contexts with the highest reported infection, the percutaneous blood-exposure routes this link describes.

Injection Drug Use

Major route of HCV transmission through sharing of needles and drug preparation equipment

Show evidence (2 references)

PMID:24923487 SUPPORT Human Clinical

"The highest detected risk was intravenous drug users (IDUs) (OR = 9.6)"

Meta-analysis of HCV risk factors: injecting drug use carries the single largest odds ratio of any exposure assessed, which is what makes it the major transmission route rather than merely one of several.

PMID:39066277 SUPPORT Human Clinical

"injection drug use has become the major route of HCV transmission, especially in high-income countries, and it is emerging even in rural areas"

Historical worldwide review of HCV transmission modes identifies injection drug use as the current major transmission route.

Unsafe Medical Practices

Transmission through contaminated medical equipment, blood transfusions (pre-1992), and organ transplants

Show evidence (2 references)

PMID:18657711 SUPPORT Human Clinical

"unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries"

States the iatrogenic transmission route this annotation records, and notes the geographic split: transfusion-related transmission has declined in developed countries while unsafe medical practice continues to drive it elsewhere.

PMID:25516637 SUPPORT Human Clinical

"the more important risk is represented by unsafe practices regarding injections, notably with the improper use of multidose vials used for multiple patients"

Review of health care-associated HCV infection identifies unsafe injection practices, including improper multidose-vial use, as the leading contamination route.

Occupational Exposure

Healthcare workers at risk through needlestick injuries

Show evidence (2 references)

PMID:15018469 SUPPORT Human Clinical

"Of 4,403 exposed HCW, 14 seroconverted (0.31%; 95% CI 0.15-0.48)"

Quantifies the per-exposure risk in 4,403 exposed healthcare workers. The same study found the risk concentrated in hollow-bore blood-filled needle injuries (0.74%) and raised sixfold by deep injury, so the annotation's needlestick framing is the right one.

PMID:16231252 SUPPORT Human Clinical

"All case patients were exposed to HCV-infected fluids through percutaneous injuries"

European case-control study of HCV seroconversion in health care workers confirms percutaneous (needlestick) injury as the occupational exposure route.

Tattoos and Body Piercing

Both are established HCV risk factors; non-sterile equipment is the presumed route but is not itself evidenced by the cited studies

Show evidence (2 references)

PMID:20678951 SUPPORT Human Clinical

"The pooled odds ratio (OR) and 95% confidence interval (CI) of the association of tattooing and hepatitis C from all studies was 2.74"

Meta-analysis of 83 studies; the association is strongest in non-injection drug users (OR 5.74), which matters because it separates tattooing from confounding by injecting. It covers the tattooing half of this exposure only -- piercing is evidenced by the item below -- and it measures association rather than the sterility mechanism the note names.

PMID:24923487 SUPPORT Human Clinical

"Other significant risk factors included poor education, older age, sharing sharp or blunt objects, MSM, tattooing, hijama, body piercing, minor operations and medical procedures"

Covers the body-piercing half of this exposure, which the tattooing meta-analysis above does not. The source lists piercing among significant risk factors without a per-factor odds ratio, so it establishes that piercing is a risk factor without quantifying it.

🔬

Biochemical Markers

4

HCV RNA (Detected during active infection)

Context: Qualitative or quantitative HCV RNA establishes current infection and quantitative levels guide treatment monitoring, but a single positive result does not by itself establish recent acquisition.

Pathograph Readouts

Readout Of HCV genome replication and early viremia Present Absent Diagnostic

Detectable circulating HCV RNA reports active viremia.

Show evidence (1 reference)

PMID:23481134 SUPPORT Human Clinical

"HCV-ribonucleic acid (RNA) was detectable at presentation in 26 (86.7%) patients."

This directly supports HCV RNA as a viremia readout in newly acquired infection.

Show evidence (1 reference)

PMID:30927209 SUPPORT Human Clinical

"Tests for HCV RNA are valuable in distinguishing between active and resolved infection, but the presence of HCV RNA does not distinguish between acute and chronic hepatitis C"

This directly supports the use and limitation of HCV RNA as a biomarker.

Anti-HCV Antibodies (Negative before seroconversion or positive after seroconversion)

Context: Anti-HCV may be absent early and, once present, cannot distinguish active, resolved, acute, or chronic infection without RNA results and longitudinal context.

Show evidence (1 reference)

PMID:30927209 SUPPORT Human Clinical

"Anti-HCV antibodies are usually used to exclude acute hepatitis C in a patient with acute liver injury, but it does not distinguish between acute, chronic or resolved hepatitis."

This directly supports the interpretive limitation of anti-HCV antibody.

Alanine aminotransferase (Increased or fluctuating during hepatocellular injury)

Context: Serum ALT reports hepatocellular injury. It is not specific for HCV, can be elevated in clinically silent infection, and may be normal in some chronic infections.

Pathograph Readouts

Readout Of Immune-associated hepatocellular injury Positive Diagnostic

ALT is a biochemical readout of liver injury, not proof of a particular immune effector mechanism.

Show evidence (1 reference)

PMID:34905514 SUPPORT Human Clinical

"We next analyzed the activation status of iNKT cells in the context of liver damage, which is defined by serum levels of alanine transaminase (ALT)."

This directly identifies ALT as the study's liver-damage readout.

Show evidence (1 reference)

PMID:19124916 SUPPORT Human Clinical

"Among 12 asymptomatics: 8 had elevated ALT"

This directly documents ALT elevation in asymptomatic acute/recent infection.

Elevated Bilirubin (Elevated)

Context: Indicates impaired hepatic function, especially in acute infection or decompensated cirrhosis

🔬

Diagnosis

4

Combined HCV RNA and anti-HCV testing with evidence of recent acquisition

Acute infection is best supported by HCV RNA during the antibody-negative window, documented anti-HCV seroconversion, de novo RNA detection, or RNA loss during untreated recovery. RNA or antibody at one time point cannot by itself reliably distinguish acute from chronic infection.

diagnostic procedure NCIT:C18020

anti-HCV LOINC:16128-1 HCV RNA LOINC:104721-6

Results: Current HCV RNA plus a documented recent negative result, seroconversion, or compatible longitudinal course supports acute HCV.

Show evidence (1 reference)

PMID:30927209 SUPPORT Human Clinical

"Thus, reliable diagnosis of acute hepatitis C usually requires testing at two time points demonstrating seroconversion to anti-HCV reactivity, de novo development of HCV RNA, or loss of HCV RNA during recovery."

This directly supports longitudinal antibody/RNA evidence for recent infection.

Serial HCV RNA assessment

Repeat HCV RNA assessment is important when timing is uncertain because untreated viremia may fluctuate and a transient decline does not establish spontaneous clearance.

diagnostic procedure NCIT:C18020

HCV RNA LOINC:104721-6

Results: Persistent, recurrent, or cleared RNA across serial measurements resolves uncertainty that remains after a single result.

Show evidence (1 reference)

PMID:21139063 SUPPORT Human Clinical

"The latter group included a significant proportion of 'fluctuating' progressors (37.5%), in whom a fall followed by a rise (>1 log₁₀) in viraemia was observed."

This directly supports serial rather than single-point interpretation of viremia, with the cohort context stated in progression.

Anti-HCV screening with reflex HCV RNA testing

Hepatitis C testing begins with an antibody (anti-HCV) assay. A nonreactive result in an immunocompetent person without hepatitis C risks needs no further testing. A reactive result indicates current infection, past resolved infection or a false positive, and is followed by nucleic acid testing for HCV RNA: detected RNA indicates current infection, and RNA not detected indicates resolved infection or a false-positive antibody result. CDC encourages reflex RNA testing on the same specimen in the laboratory.

laboratory testing NCIT:C25294

anti-HCV LOINC:16128-1 HCV RNA LOINC:104721-6

Results: Anti-HCV reactive with HCV RNA detected establishes current infection; anti-HCV reactive with HCV RNA not detected indicates no current infection.

Anti-HCV binds the method-less serum presence code. A Monarch KG search found no method-less HCV RNA code for serum or plasma, so the RNA step binds the quantitative code whose method is the generic molecular genetics method; the step itself asks only whether RNA is detected. No band is recorded: both steps of the sequence are read as detected or not detected, and the CDC recommendations cited here define no quantitative RNA threshold for diagnosis.

Show evidence (3 references)

PMID:32271723 SUPPORT Other

"Hepatitis C testing should be initiated with a U.S. Food and Drug Administration (FDA)-approved anti-HCV test. Persons who test anti-HCV positive are either currently infected or had past infection that has resolved naturally or with treatment. Immunocompetent persons without hepatitis C risks..."

The CDC recommendations make the antibody test the first step and state what a negative and a positive antibody result mean.

PMID:32271723 SUPPORT Other

"Persons testing anti-HCV positive should have follow-up testing with an FDA-approved nucleic acid test (NAT) for detection of HCV RNA. NAT for HCV RNA detection determines viremia and current HCV infection. Persons who test anti-HCV positive but HCV RNA negative do not have current HCV..."

States the RNA step after a positive antibody result, its interpretation, and the reflex-testing recommendation.

PMID:23657112 SUPPORT Other

"A nonreactive HCV antibody result indicates no HCV antibody detected. A reactive result indicates one of the following: 1) current HCV infection, 2) past HCV infection that has resolved, or 3) false positivity. A reactive result should be followed by NAT for HCV RNA. If HCV RNA is detected, that..."

The CDC testing guidance gives the interpretation of each antibody and RNA outcome.

Combined HCV antibody and antigen immunoassay

A fourth-generation antibody/antigen assay can shorten the diagnostic window but does not eliminate the need for nucleic-acid testing.

serology testing NCIT:C25294

Results: Antibody/antigen reactivity is an early-detection adjunct and should be interpreted with HCV RNA testing.

Show evidence (1 reference)

PMID:39283072 SUPPORT Human Clinical

"Fourth generation HCV Duo Ab/Ag assay demonstrated comparable performance to SOC testing and shortens the diagnostic window but does not eliminate the need for NAAT in all patients."

This diagnostic study directly supports the stated adjunctive role and limitation.

📈

Progression

4

Acute infection

Duration: Up to six months from acquisition, before persistent viremia is classified as chronic

Acute infection begins with recent HCV acquisition and detectable viremia. The six-month boundary is a clinical definition of chronicity rather than a claim that every untreated infection remains biologically unchanged until that time. The phase is predominantly asymptomatic and so is rarely diagnosed while it lasts; a minority present with clinically apparent hepatitis, which may include jaundice, nausea, fatigue, anorexia, and elevated transaminases. Diagnosis requires evidence that acquisition was recent, because anti-HCV and HCV RNA at a single time point do not separate this phase from chronic infection.

Show evidence (2 references)

PMID:39599853 SUPPORT Human Clinical

"approximately 50-70% of individuals with recently acquired hepatitis C will develop a chronic infection, defined as the persistence of viremia for a period exceeding six months."

This defines the recent-infection phase and the six-month chronicity boundary.

PMID:23481134 SUPPORT Human Clinical

"Acute hepatitis C is rarely diagnosed due to its predominantly asymptomatic course."

This directly supports clinically silent presentation as a major feature of the acute phase.

Spontaneous viral clearance

Clearance can occur without antiviral treatment, ending the infection at the acute phase. The observed proportion varies by cohort; one tertiary-center series reported clearance in 9 of 30 patients and should not be treated as a universal population frequency.

Show evidence (1 reference)

PMID:23481134 SUPPORT Human Clinical

"Totally, 9 patients (30%) experienced spontaneous viral eradication."

This cohort directly documents untreated spontaneous clearance while the note limits generalization of its frequency.

Fluctuating viremia during unresolved infection

Serial viral loads can fall and then rise. The quantified 37.5% fluctuation estimate came from an HIV-1-positive male cohort and is retained only as evidence that a single decline does not establish clearance.

Show evidence (1 reference)

PMID:21139063 SUPPORT Human Clinical

"The latter group included a significant proportion of 'fluctuating' progressors (37.5%), in whom a fall followed by a rise (>1 log₁₀) in viraemia was observed."

This cohort directly demonstrates fluctuating viremia among patients who progressed.

Chronic infection

Duration: More than six months of persistent viremia

Failure to clear HCV leads to persistent viremia and classification as chronic hepatitis C. Reported persistence is 50-70% of recently acquired infections in one review and 70-80% in another. This is the phase in which progressive hepatic inflammation and fibrosis, cirrhosis, hepatocellular carcinoma, and the immune-complex extrahepatic syndromes arise, typically over decades.

Show evidence (2 references)

PMID:39599853 SUPPORT Human Clinical

"approximately 50-70% of individuals with recently acquired hepatitis C will develop a chronic infection, defined as the persistence of viremia for a period exceeding six months."

This directly supports both the outcome frequency range and definition of chronicity.

PMID:19759533 SUPPORT Human Clinical

"Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"

Gives the second reported persistence range and the downstream chronic-liver-disease outcome that defines this phase.

📊

Prevalence

2

Global (all ages)

Annual Incidence Unknown

The Global Burden of Disease 2019 analysis estimated 6.2 million new HCV infections worldwide in 2019. This is an incidence estimate for newly acquired infection, not the prevalence of symptomatic acute hepatitis.

Show evidence (1 reference)

PMID:36935711 SUPPORT Human Clinical

"It was estimated that 6.2 million new HCV infections, 0.54 million HCV-related deaths, and 15.3 million DALYs worldwide in 2019, with an increase of 25.4, 59.1, and 43.6%, respectively, from 1990"

This GBD analysis quantifies global incident HCV infection in 2019.

Global women of reproductive age (15-49 years)

Annual Incidence Unknown

In a GBD analysis restricted to reproductive-age women, global acute-HCV incidence increased by 46.45% from 1990 through 2019; this is a trend rather than an individual-level risk estimate.

Show evidence (1 reference)

PMID:38638097 SUPPORT Human Clinical

"Over the 30 years, global incidences of AHC and HCV-related cirrhosis in reproductive-age women increased by 46.45 and 72.74%, respectively."

This directly supports the acute-HCV incidence trend in the specified population.

🦠

Infectious Agent

1

Hepatitis C virus

Hepacivirus hominis is the enveloped, positive-sense single-stranded RNA virus whose productive entry into human liver cells initiates hepatitis C.

Hepacivirus hominis NCBITaxon:3052230

Show evidence (1 reference)

PMID:31427285 SUPPORT Other

"Numerous host factors including proteins, lipids, and glycans promote productive uptake of HCV particles into human liver cells."

This review directly identifies HCV particles as the agent productively entering human liver cells.

↔️

Transmission

4

Percutaneous and parenteral blood exposure

The dominant route. Injection drug use, non-sterile injections, and unsafe medical procedures put infected blood directly into the recipient's circulation. Injection drug use is the major route in high-income countries; unsafe injection and medical practice continue to drive transmission where sterile technique is not assured.

Show evidence (3 references)

PMID:39066277 SUPPORT Human Clinical

"The major modes of transmission for HCV include unscreened blood and blood products, injection drug use, non-sterile injections, and unsafe medical procedures in healthcare settings."

This historical worldwide review names the parenteral routes that make up this transmission entry.

PMID:36800699 SUPPORT Human Clinical

"People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection."

This review identifies major human exposure contexts for newly acquired HCV.

PMID:23481134 SUPPORT Human Clinical

"The source of infection was mainly injection drug use in 17/30 (56.7) and medical procedures 6/30 (20%)."

This cohort of newly acquired infections documents injection drug use and medical procedures as the observed acquisition sources.

Transfusion of unscreened blood and blood products

Historically a major route, now largely closed in high-income countries by donor screening. Transfusion and other iatrogenic exposure remain important where blood is not reliably screened.

Show evidence (2 references)

PMID:39066277 SUPPORT Human Clinical

"Until the late 1980s, blood and blood-derived products were not screened for HCV, resulting in a transmission rate of approximately one case in every 50 blood units, even in high-income countries"

Quantifies the pre-screening transfusion route and dates the point at which donor screening closed it.

PMID:18657711 SUPPORT Human Clinical

"unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries"

States the geographic split this entry records: transfusion-related transmission has declined where blood is screened and continues where it is not.

Sexual transmission

A less efficient route than blood exposure, concentrated in men who have sex with men and in people with HIV coinfection rather than distributed across the general population.

Show evidence (2 references)

PMID:39066277 SUPPORT Human Clinical

"Emerging high-risk groups include men who have sex with men (MSM), individuals exposed to tattoo practices, and newborns of HCV-infected pregnant women."

Identifies men who have sex with men as the population in which sexual transmission is an emerging route.

PMID:24923487 SUPPORT Human Clinical

"Attention and urgent intervention should be given to the sexual route of transmission, as well as that through minor operations and medical procedures."

This worldwide risk-factor meta-analysis identifies the sexual route as one requiring intervention, establishing it as a real if secondary route.

Vertical (mother-to-child) transmission

Transmission from mother to child around delivery, restricted to viremic mothers and increased by HIV coinfection. Neither mode of delivery nor feeding method changes the risk in monoinfected women.

Show evidence (2 references)

PMID:39066277 SUPPORT Human Clinical

"only anti-HCV-positive women with viremia face the risk of mother-to-child transmission (MTCT) of HCV, which is further heightened by HIV coinfection"

States that the vertical route requires maternal viremia and is amplified by HIV coinfection.

PMID:39066277 SUPPORT Human Clinical

"The mode of delivery and type of feeding do not significantly affect vertical transmission in monoinfected women"

Supports the stated limits of the vertical route in women without HIV coinfection.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hepatitis C:

Drug-induced liver injury Not Yet Curated MONDO:0005359

Overlapping Features Drug-induced liver injury can closely mimic the hepatocellular presentation of acute HCV. Medication and supplement exposure, dechallenge, and formal causality assessment are interpreted alongside both anti-HCV and HCV RNA.

Distinguishing Features

A compatible drug or supplement exposure and improvement after withdrawal favor drug-induced injury.
HCV RNA during an antibody-negative window or longitudinal seroconversion favors acute HCV.

Show evidence (1 reference)

PMID:30927209 SUPPORT Human Clinical

"These findings indicate that patients presenting with acute hepatocellular injury, even with features suggestive of DILI, should be tested for both anti-HCV and HCV RNA to reliably exclude acute HCV infection."

This prospective DILI-network analysis directly supports distinguishing acute HCV from DILI using both tests.

Other viral, autoimmune, and biliary causes of acute hepatocellular injury

Overlapping Features Hepatitis A, B, and E, autoimmune hepatitis, and biliary disease can produce an overlapping acute-hepatitis presentation and require cause-specific testing when HCV timing is uncertain.

Distinguishing Features

Cause-specific viral testing distinguishes hepatitis A, B, or E.
Autoimmune evaluation and biliary imaging are guided by the presentation.
Longitudinal anti-HCV and HCV RNA results establish or weaken recent-HCV timing.

Show evidence (1 reference)

PMID:30927209 SUPPORT Human Clinical

"These assessments could include testing for hepatitis A, B, C, E, infectious mononucleosis, iron overload, and autoimmune conditions, as well as imaging for biliary tract disease10."

This human diagnostic cohort directly supports the listed alternative-cause workup.

📊

Related Datasets

8

Hepatitis C Virus-induced Differential Transcriptional Traits in Host Cells After Persistent Infection Elimination by Direct-Acting Antivirals In Cell Culture geo:GSE267834

Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct acting antiviral (DAA) drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection.

human BULK RNA SEQ n=28

PMID:38988177

Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection geo:GSE119117

Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq to characterize immune function in peripheral blood before, during, and after acute HCV infection resulting in spontaneous resolution.

human BULK RNA SEQ n=53

PMID:30222771

Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Gene expression analysis during acute hepatitis C virus infection associates dendritic cell activation with viral clearance geo:GSE65123

Background and Aims: Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses our goal was to analyze gene expression in DC from patients during acute HCV infection. Methods: By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from those who become chronically infected (ANR), as well as in HCV chronically infected patients (CHR) and healthy seronegative individuals (CTRL).

human MICROARRAY n=56

PMID:26447929

Identified by GEO DataSets index search for Acute Hepatitis C Virus Infection (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

The human liver circadian transcriptome and its carcinogenic perturbation by hepatitis C virus infection (RNA-Seq I) geo:GSE200809

Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome.

human BULK RNA SEQ n=6

PMID:39209804

Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort ega:EGAS00001000096

The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus ega:EGAS00001002324

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.

human

PMID:28394351

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) dbgap:phs000430

Reprinted from http://www.haltctrial.org/ Purpose The H epatitis C A ntiviral L ong-term T reatment against C irrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.

Site specific glycan analysis of hepatitis C virus E1E2 glycoprotein complex massive:MSV000088553

Dataset for N-linked glycosylation analysis contained within "Structure of the hepatitis C virus E1E2 glycoprotein complex"

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.

🔬

Clinical Trials

1

NCT04903626 PHASE_III COMPLETED

Completed multicenter, single-arm phase IIIb study of eight weeks of oral glecaprevir/pibrentasvir in adults with acute HCV. The publication reports 286 treated adults and 96.2% ITT SVR12 (95% CI 93.2%-97.8%).

Show evidence (2 references)

clinicaltrials:NCT04903626 SUPPORT Human Clinical

"Participants will receive oral tablets of GLE/PIB once daily (QD) for 8 weeks and will be followed for 12 weeks after the end of treatment."

The registry directly establishes the regimen and follow-up schedule.

PMID:41297677 SUPPORT Human Clinical

"SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population (n = 286), and 100% in the mITT-VF population (n = 275)."

The peer-reviewed phase IIIb report supplies the completed efficacy result.

🧮

Computational Models

1

Aston2018 HCV Within-Host Viral-Dynamics Model SBML Level 2 Version 4 (main PVR parameterization); COPASI CPS scenario variants; SED-ML Level 1 Version 4 / COMBINE OMEX MATLAB for publication fitting; COPASI for the BioModels model and fitted variants KINETIC

Deterministic three-state ordinary differential-equation model of healthy hepatocytes, infected hepatocytes, and circulating HCV viral load in a well-mixed liver compartment. It represents hepatocyte regeneration and death, infection, virion production and clearance, and treatment-adjusted infection and virion-production rates.

Repository ↗ PMID:29652855

Variable	Model ID	Unit
Healthy hepatocyte concentration Latent model-scaled concentration of uninfected hepatocytes; it was not observed in the fitted clinical viral-load datasets.	`T`	IU/mL
Infected hepatocyte concentration Latent model-scaled concentration of infected hepatocytes inferred from viral-load fitting rather than measured in the clinical datasets.	`I`	IU/mL
HCV viral load Observable model state fitted to treatment-period HCV RNA measurements.	`V`	IU/mL
Stem-cell hepatocyte generation rate Rate parameter for generation of healthy hepatocytes in proportion to infected hepatocytes.	`s`	1/day
Treatment-adjusted infection rate SBML parameter for the treatment-adjusted rate at which virions infect healthy hepatocytes.	`beta`	mL/IU/day
Treatment-adjusted virion-production rate Rate of virion production by infected hepatocytes after the modeled treatment effect.	`pstar`	1/day

Pathograph links

HCV genome replication and early viremia partially recapitulates fidelity: moderate The model explicitly couples healthy-hepatocyte infection, infected-cell loss, virion production, and viral clearance, and fits the viral-load state to human treatment-response profiles.

Limitations: The model is deterministic and well mixed, with only healthy hepatocytes, infected hepatocytes, and virions. Hepatocyte states are latent and were not measured in the fitted datasets; aggregate death-rate terms replace immune-mediated injury. Viral genotype and evolution, interferon signaling, immune-cell responses, inflammation, fibrosis, and cancer are absent. Four treatment profiles were fitted in-sample without held-out or prospective validation, and substantially different parameter sets can produce similar fits.

Readouts

HCV viral-load trajectory

Time course of state V, fitted on the logarithmic scale to viral-load measurements obtained during treatment.

Interpretation: Captures partial-response, breakthrough, null-response, and triphasic profile shapes but is not a prospectively validated individual treatment prediction.

Show evidence (1 reference)

PMID:29652855 SUPPORT Computational

"We fitted our model to the data during treatment only. The data together with the fitted curve V(t) and the predicted curves T(t) and I(t) from the model for each case are shown in Figure 12."

Identifies viral load as the fitted observable and healthy and infected hepatocyte concentrations as latent model predictions.

Show evidence (1 reference)

PMID:29652855 SUPPORT Computational

"We have proposed a new mathematical model of HCV infection, which involves the same three variables (concentrations of healthy and infected hepatocytes and of virions) as the earlier models of Neumann and Dahari, but which has a significantly different structure to the steady state solutions."

Establishes that the model directly represents hepatocyte infection states and circulating virus while differing in its dynamical structure.

Findings

The same three-state ODE structure was fitted to partial virologic response, breakthrough, null-response, and triphasic treatment-period viral-load profiles.

Show evidence (2 references)

PMID:29652855 SUPPORT Computational

"We considered various datasets that show partial virologic response (PVR), breakthrough, null response and triphasic behaviour."

Names the four response profiles selected for model fitting.

PMID:29652855 SUPPORT Computational

"We fitted our model to the data during treatment only. The data together with the fitted curve V(t) and the predicted curves T(t) and I(t) from the model for each case are shown in Figure 12."

Confirms that the one model structure was fitted to each selected treatment-period profile.

With stem-cell hepatocyte generation set to zero, the model has uninfected, infected, and pure-infection steady-state branches; adding stem-cell generation unfolds the pure-infection bifurcation into one valid infected branch with a limit point.

Show evidence (1 reference)

PMID:29652855 SUPPORT Computational

"In the case S=0 (no generation of hepatocytes from stem cells), we showed that there is a pure infection branch of solutions, and an infected steady state branch was found analytically that connects the uninfected and pure infection branches. When S>0, the bifurcation between the pure infected..."

Summarizes the model's analytically derived steady-state structure.

Notes

BioModels entry BIOMD0000000713 (internal submission MODEL1808280002) is manually curated; this record pins public revision 9 at https://www.biomodels.org/services/download/get-files/MODEL1808280002/9/MODEL1808280002.9.omex. The revision-9 COMBINE archive retrieved for curator testing was 83,278 bytes with SHA-256 5ca8ec25248d053f4dc52374658df7fc403ea1c4fa4a9141ca93bd0b600712c8, and its main PVR.xml file has SHA-256 b8d62ff28623b18ba31fd59a39a3f5bbd799a0fef9601a5a0f435d5c722cf3b3. BioModels distributes the model under CC0; the archive itself contains no separate license file. PVR.cps, Breakthrough.cps, NullResponse.cps, and Triphasic.cps are distinct parameter and initial-condition variants of the same three-species, nine-reaction structure. Under Python 3.13.9 with COPASI 4.46.300 and basiCO 0.86, all four CPS files loaded and simulated; the PVR SBML and CPS trajectories agreed to a maximum relative difference below 1.03e-7 under matched LSODA settings and reproduced the archived Figure 12(a) result. The standardized workflow is incomplete: every SED-ML file references PVR.xml without model changes, so the named Breakthrough, NullResponse, and Triphasic SED-ML files do not encode their corresponding CPS parameterizations; Breakthrough.sedml and NullResponse.sedml are byte-identical. The stored Triphasic CPS time-course settings are internally inconsistent (19 steps of 3.333333333 days with a declared duration of 60 days), and current COPASI runs to 63.333 days unless the step size is forced to 60/19. BioSimulators archive validation completes with unit/modeling warnings, but the standardized COPASI archive runner hung after task start in the curator environment while direct COPASI execution succeeded. libSBML reports no parse errors, with 17 unit/modeling-practice warnings including eight parameters without declared units. The archive hash is a retrieval snapshot because BioModels can regenerate container packaging; the revision and main-file hash are the stronger content pins. The original MATLAB fit estimated ten parameters and initial values by least squares on log viral load. Raw fitting data and fitting code are not deposited, COPASI parameter-estimation and validation sets are empty, and the paper warns that substantially different parameters give similar fits. The clinical profiles predate modern direct-acting antiviral regimens; direct-acting antiviral effects are discussed as parameter hypotheses rather than validated against DAA-treated cohorts. The model does not justify links to Chronic Inflammation and Fibrosis, Immune Evasion, or Hepatocellular Carcinoma Development.

Show evidence (1 reference)

PMID:29652855 SUPPORT Computational

"A new model for HCV infection is proposed, based on various dynamical processes that occur during the infection that are described in the literature."

Identifies the disease-specific computational model and its literature-derived dynamical basis.

{ }

Source YAML

click to show

name: Hepatitis C
creation_date: '2026-01-09T05:44:55Z'
category: Infectious Disease
description: >
  Hepatitis C is a liver infection caused by the hepatitis C virus (HCV). It is primarily
  transmitted through blood-to-blood contact, including injection drug use, unsafe medical
  practices, and transfusion of unscreened blood and blood products before donor screening;
  sexual and mother-to-child transmission occur less often. The entry covers the whole
  course of one infection. The acute phase, within six months of acquisition, is often
  clinically silent and can end in spontaneous clearance; the majority of infections
  instead persist as chronic hepatitis C, in which continuing viremia drives progressive
  hepatic fibrosis, cirrhosis, hepatocellular carcinoma, and immune-complex extrahepatic
  disease. Direct-acting antiviral therapies cure more than 95% of treated infections and
  are recommended once acute infection with quantifiable viremia is diagnosed, without
  waiting for possible spontaneous resolution.
disease_term:
  preferred_term: hepatitis C virus infection
  term:
    id: MONDO:0005231
    label: hepatitis C virus infection
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100371
      label: acute hepatitis C virus infection
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0100371 names the acute phase of the infection this entry curates, not a
      separate disease. Under design decisions §3e a phase of one infection is never its
      own entry, and the entry it belongs to enumerates its phases in progression: --
      which this entry now does, with "Acute infection" and "Chronic infection" phases
      carrying the content of the former Acute_Hepatitis_C_Virus_Infection entry. The
      mapping is recorded as a narrowMatch so the MONDO concept is retired from the
      curation queue rather than lost.
parents:
- Viral Hepatitis
- Liver Disease
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:39599853
      reference_title: "Acute Hepatitis C: Current Status and Future Perspectives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hepatitis C virus (HCV) infection continues to represent a
        significant public health threat and is a leading cause of liver
        cirrhosis, liver cancer, and liver-related mortality.
      explanation: HCV is the infectious cause of hepatitis C.
  - classification_value: GASTROINTESTINAL
    evidence:
    - reference: PMID:31427285
      reference_title: "Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Numerous host factors including proteins, lipids, and glycans promote
        productive uptake of HCV particles into human liver cells.
      explanation: HCV productively invades liver cells, placing the disease in the liver and gastrointestinal chapter.
infectious_agent:
- name: Hepatitis C virus
  infectious_agent_term:
    preferred_term: Hepacivirus hominis
    term:
      id: NCBITaxon:3052230
      label: Hepacivirus hominis
  description: >-
    Hepacivirus hominis is the enveloped, positive-sense single-stranded RNA virus whose
    productive entry into human liver cells initiates hepatitis C.
  evidence:
  - reference: PMID:31427285
    reference_title: "Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Numerous host factors including proteins, lipids, and glycans promote
      productive uptake of HCV particles into human liver cells.
    explanation: This review directly identifies HCV particles as the agent productively entering human liver cells.
transmission:
- name: Percutaneous and parenteral blood exposure
  description: >-
    The dominant route. Injection drug use, non-sterile injections, and unsafe medical
    procedures put infected blood directly into the recipient's circulation. Injection
    drug use is the major route in high-income countries; unsafe injection and medical
    practice continue to drive transmission where sterile technique is not assured.
  evidence:
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major modes of transmission for HCV include unscreened blood and blood
      products, injection drug use, non-sterile injections, and unsafe medical procedures
      in healthcare settings.
    explanation: This historical worldwide review names the parenteral routes that make up this transmission entry.
  - reference: PMID:36800699
    reference_title: "Acute hepatitis C virus infection: clinical update and remaining challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      People who have received unsafe medical procedures, used injection drugs,
      and lived with human immunodeficiency virus are reported to be most
      susceptible to acute HCV infection.
    explanation: This review identifies major human exposure contexts for newly acquired HCV.
  - reference: PMID:23481134
    reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The source of infection was mainly injection drug use in 17/30 (56.7) and
      medical procedures 6/30 (20%).
    explanation: This cohort of newly acquired infections documents injection drug use and medical procedures as the observed acquisition sources.
- name: Transfusion of unscreened blood and blood products
  description: >-
    Historically a major route, now largely closed in high-income countries by donor
    screening. Transfusion and other iatrogenic exposure remain important where blood is
    not reliably screened.
  evidence:
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Until the late 1980s, blood and blood-derived products were not screened for HCV,
      resulting in a transmission rate of approximately one case in every 50 blood units,
      even in high-income countries
    explanation: Quantifies the pre-screening transfusion route and dates the point at which donor screening closed it.
  - reference: PMID:18657711
    reference_title: "Acute hepatitis C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      unsafe blood products and medical practices continue to increase transmission of
      HCV in many developing countries
    explanation: "States the geographic split this entry records: transfusion-related transmission has declined where blood is screened and continues where it is not."
- name: Sexual transmission
  description: >-
    A less efficient route than blood exposure, concentrated in men who have sex with men
    and in people with HIV coinfection rather than distributed across the general
    population.
  evidence:
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Emerging high-risk groups include men who have sex with men (MSM), individuals
      exposed to tattoo practices, and newborns of HCV-infected pregnant women.
    explanation: Identifies men who have sex with men as the population in which sexual transmission is an emerging route.
  - reference: PMID:24923487
    reference_title: "A comprehensive hepatitis C virus risk factors meta-analysis (1989-2013): do they differ in Egypt?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Attention and urgent intervention should be given to the sexual route of
      transmission, as well as that through minor operations and medical procedures.
    explanation: This worldwide risk-factor meta-analysis identifies the sexual route as one requiring intervention, establishing it as a real if secondary route.
- name: Vertical (mother-to-child) transmission
  description: >-
    Transmission from mother to child around delivery, restricted to viremic mothers and
    increased by HIV coinfection. Neither mode of delivery nor feeding method changes the
    risk in monoinfected women.
  evidence:
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      only anti-HCV-positive women with viremia face the risk of mother-to-child
      transmission (MTCT) of HCV, which is further heightened by HIV coinfection
    explanation: States that the vertical route requires maternal viremia and is amplified by HIV coinfection.
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mode of delivery and type of feeding do not significantly affect vertical
      transmission in monoinfected women
    explanation: Supports the stated limits of the vertical route in women without HIV coinfection.
environmental:
- name: Blood-exposure risk contexts
  exposure_term:
    preferred_term: blood exposure
    term:
      id: ECTO:7000110
      label: exposure to blood
  influences_mechanisms:
  - target: HCV attachment and hepatocyte entry
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hepatitis C is efficiently transmitted percutaneously, so unsafe
      injection and unsterile medical procedures put virus directly into
      blood, from which it reaches and attaches to hepatocytes.
    evidence:
    - reference: PMID:36800699
      reference_title: "Acute hepatitis C virus infection: clinical update and remaining challenges."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection."
      explanation: >-
        Identifies unsafe medical procedures and injection drug use among the
        contexts with the highest reported infection, the percutaneous
        blood-exposure routes this link describes.
  description: >-
    Injection drug use and unsafe medical procedures increase the opportunity
    for blood-borne HCV acquisition; HIV coinfection identifies an important
    clinical risk context but is not itself a transmission route.
  evidence:
  - reference: PMID:36800699
    reference_title: "Acute hepatitis C virus infection: clinical update and remaining challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      People who have received unsafe medical procedures, used injection drugs,
      and lived with human immunodeficiency virus are reported to be most
      susceptible to acute HCV infection.
    explanation: The source directly identifies these risk contexts while allowing HIV status to be distinguished from a route of transmission.
- name: Injection Drug Use
  exposure_term:
    preferred_term: injection drug use
    term:
      id: ECTO:6000007
      label: exposure to substance abuse
  notes: Major route of HCV transmission through sharing of needles and drug preparation equipment
  evidence:
  - reference: PMID:24923487
    reference_title: "A comprehensive hepatitis C virus risk factors meta-analysis (1989-2013): do they differ in Egypt?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The highest detected risk was intravenous drug users (IDUs) (OR = 9.6)"
    explanation: "Meta-analysis of HCV risk factors: injecting drug use carries the single largest odds ratio of any exposure assessed, which is what makes it the major transmission route rather than merely one of several."
  - reference: PMID:39066277
    reference_title: "Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "injection drug use has become the major route of HCV transmission, especially in high-income countries, and it is emerging even in rural areas"
    explanation: Historical worldwide review of HCV transmission modes identifies injection drug use as the current major transmission route.
- name: Unsafe Medical Practices
  notes: Transmission through contaminated medical equipment, blood transfusions (pre-1992), and organ transplants
  evidence:
  - reference: PMID:18657711
    reference_title: "Acute hepatitis C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries"
    explanation: "States the iatrogenic transmission route this annotation records, and notes the geographic split: transfusion-related transmission has declined in developed countries while unsafe medical practice continues to drive it elsewhere."
  - reference: PMID:25516637
    reference_title: "Health care-associated hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the more important risk is represented by unsafe practices regarding injections, notably with the improper use of multidose vials used for multiple patients"
    explanation: Review of health care-associated HCV infection identifies unsafe injection practices, including improper multidose-vial use, as the leading contamination route.
- name: Occupational Exposure
  notes: Healthcare workers at risk through needlestick injuries
  evidence:
  - reference: PMID:15018469
    reference_title: "Risk of hepatitis C virus transmission following percutaneous exposure in healthcare workers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 4,403 exposed HCW, 14 seroconverted (0.31%; 95% CI 0.15-0.48)"
    explanation: "Quantifies the per-exposure risk in 4,403 exposed healthcare workers. The same study found the risk concentrated in hollow-bore blood-filled needle injuries (0.74%) and raised sixfold by deep injury, so the annotation's needlestick framing is the right one."
  - reference: PMID:16231252
    reference_title: "Risk factors for hepatitis C virus transmission to health care workers after occupational exposure: a European case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All case patients were exposed to HCV-infected fluids through percutaneous injuries"
    explanation: European case-control study of HCV seroconversion in health care workers confirms percutaneous (needlestick) injury as the occupational exposure route.
- name: Tattoos and Body Piercing
  notes: Both are established HCV risk factors; non-sterile equipment is the presumed route but is not itself evidenced by the cited studies
  evidence:
  - reference: PMID:20678951
    reference_title: "Tattooing and the risk of transmission of hepatitis C: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled odds ratio (OR) and 95% confidence interval (CI) of the association of tattooing and hepatitis C from all studies was 2.74"
    explanation: "Meta-analysis of 83 studies; the association is strongest in non-injection drug users (OR 5.74), which matters because it separates tattooing from confounding by injecting. It covers the tattooing half of this exposure only -- piercing is evidenced by the item below -- and it measures association rather than the sterility mechanism the note names."
  - reference: PMID:24923487
    reference_title: "A comprehensive hepatitis C virus risk factors meta-analysis (1989-2013): do they differ in Egypt?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other significant risk factors included poor education, older age, sharing sharp or blunt objects, MSM, tattooing, hijama, body piercing, minor operations and medical procedures"
    explanation: "Covers the body-piercing half of this exposure, which the tattooing meta-analysis above does not. The source lists piercing among significant risk factors without a per-factor odds ratio, so it establishes that piercing is a risk factor without quantifying it."
prevalence:
- population: Global (all ages)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: UNKNOWN
  notes: >-
    The Global Burden of Disease 2019 analysis estimated 6.2 million new HCV
    infections worldwide in 2019. This is an incidence estimate for newly
    acquired infection, not the prevalence of symptomatic acute hepatitis.
  evidence:
  - reference: PMID:36935711
    reference_title: "The burden of hepatitis C virus in the world, China, India, and the United States from 1990 to 2019."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was estimated that 6.2 million new HCV infections, 0.54 million
      HCV-related deaths, and 15.3 million DALYs worldwide in 2019, with an
      increase of 25.4, 59.1, and 43.6%, respectively, from 1990
    explanation: This GBD analysis quantifies global incident HCV infection in 2019.
- population: Global women of reproductive age (15-49 years)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: UNKNOWN
  notes: >-
    In a GBD analysis restricted to reproductive-age women, global acute-HCV
    incidence increased by 46.45% from 1990 through 2019; this is a trend rather
    than an individual-level risk estimate.
  evidence:
  - reference: PMID:38638097
    reference_title: "Epidemiology of acute hepatitis C and hepatitis C virus-related cirrhosis in reproductive-age women, 1990-2019: An analysis of the Global Burden of Disease study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the 30 years, global incidences of AHC and HCV-related cirrhosis in
      reproductive-age women increased by 46.45 and 72.74%, respectively.
    explanation: This directly supports the acute-HCV incidence trend in the specified population.
progression:
- phase: Acute infection
  duration: Up to six months from acquisition, before persistent viremia is classified as chronic
  duration_days: "180"
  notes: >-
    Acute infection begins with recent HCV acquisition and detectable viremia. The
    six-month boundary is a clinical definition of chronicity rather than a claim that
    every untreated infection remains biologically unchanged until that time. The phase
    is predominantly asymptomatic and so is rarely diagnosed while it lasts; a minority
    present with clinically apparent hepatitis, which may include jaundice, nausea,
    fatigue, anorexia, and elevated transaminases. Diagnosis requires evidence that
    acquisition was recent, because anti-HCV and HCV RNA at a single time point do not
    separate this phase from chronic infection.
  evidence:
  - reference: PMID:39599853
    reference_title: "Acute Hepatitis C: Current Status and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 50-70% of individuals with recently acquired hepatitis C
      will develop a chronic infection, defined as the persistence of viremia
      for a period exceeding six months.
    explanation: This defines the recent-infection phase and the six-month chronicity boundary.
  - reference: PMID:23481134
    reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Acute hepatitis C is rarely diagnosed due to its predominantly asymptomatic course.
    explanation: This directly supports clinically silent presentation as a major feature of the acute phase.
- phase: Spontaneous viral clearance
  notes: >-
    Clearance can occur without antiviral treatment, ending the infection at the acute
    phase. The observed proportion varies by cohort; one tertiary-center series reported
    clearance in 9 of 30 patients and should not be treated as a universal population
    frequency.
  evidence:
  - reference: PMID:23481134
    reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Totally, 9 patients (30%) experienced spontaneous viral eradication.
    explanation: This cohort directly documents untreated spontaneous clearance while the note limits generalization of its frequency.
- phase: Fluctuating viremia during unresolved infection
  notes: >-
    Serial viral loads can fall and then rise. The quantified 37.5% fluctuation
    estimate came from an HIV-1-positive male cohort and is retained only as
    evidence that a single decline does not establish clearance.
  evidence:
  - reference: PMID:21139063
    reference_title: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter group included a significant proportion of 'fluctuating'
      progressors (37.5%), in whom a fall followed by a rise (>1 log₁₀) in
      viraemia was observed.
    explanation: This cohort directly demonstrates fluctuating viremia among patients who progressed.
- phase: Chronic infection
  duration: More than six months of persistent viremia
  notes: >-
    Failure to clear HCV leads to persistent viremia and classification as chronic
    hepatitis C. Reported persistence is 50-70% of recently acquired infections in one
    review and 70-80% in another. This is the phase in which progressive hepatic
    inflammation and fibrosis, cirrhosis, hepatocellular carcinoma, and the
    immune-complex extrahepatic syndromes arise, typically over decades.
  evidence:
  - reference: PMID:39599853
    reference_title: "Acute Hepatitis C: Current Status and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 50-70% of individuals with recently acquired hepatitis C
      will develop a chronic infection, defined as the persistence of viremia
      for a period exceeding six months.
    explanation: This directly supports both the outcome frequency range and definition of chronicity.
  - reference: PMID:19759533
    reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
    explanation: Gives the second reported persistence range and the downstream chronic-liver-disease outcome that defines this phase.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_acute_hcv_clearance_persistence_model
  hypothesis_label: Host-virus response balance determines clearance or persistence
  status: CANONICAL
  description: >-
    Productive hepatocyte infection generates viremia and innate antiviral
    activation while HCV simultaneously suppresses interferon induction.
    Adaptive immune responses can accompany clearance, but ongoing immune
    responses and viral escape can coexist with persistence. Hepatocellular
    injury is immune-associated, although the contribution of individual cell
    populations is not fully resolved.
  evidence:
  - reference: PMID:25443342
    reference_title: Innate and adaptive immune responses in HCV infections.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Elimination of HCV during acute infection correlates with a rapid
      induction of innate, especially interferon (IFN) induced genes, and a
      delayed induction of adaptive immune responses.
    explanation: This review supports the canonical coordination of innate and adaptive responses in acute-HCV outcome.
- hypothesis_group_id: intrahepatic_tfh1_helper_refinement
  hypothesis_label: Intrahepatic Tfh1-like CD4 response as a helper axis for HCV control
  status: EMERGING
  description: >-
    A recent chimpanzee study proposes that liver-enriched HCV-specific
    PD-1-high ICOS-high Tfh1-like CD4 cells help B-cell and CD8-cell responses
    at the site of replication. This refines the general adaptive-response node
    but is not asserted as a confirmed human mechanism.
  evidence:
  - reference: PMID:40956619
    reference_title: "A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver,
      suggesting the potential for B and CD8+ T cell help at the site of virus
      replication.
    explanation: The chimpanzee study directly supports the proposed helper-cell refinement while not establishing it in humans.
pathophysiology:
- name: HCV attachment and hepatocyte entry
  description: >-
    HCV first attaches to cell-surface proteoglycans, SR-BI, and CD81, then uses
    the tight-junction proteins claudin-1 and occludin and clathrin-mediated
    endocytosis to enter human liver cells.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: symbiont entry into host cell
    modifier: INCREASED
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  evidence:
  - reference: PMID:31427285
    reference_title: "Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The virus initially attaches to surface proteoglycans, lipid receptors
      such as the scavenger receptor BI (SR-BI), and to the tetraspanin CD81.
      After lateral translocation of virions to tight junctions, claudin-1
      (CLDN1) and occludin (OCLN) are essential for entry.
    explanation: This review directly supports the host-factor sequence in the entry node.
  downstream:
  - target: HCV Polyprotein Translation
    description: >-
      Productive hepatocyte entry and genome release permit translation of the
      HCV polyprotein.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Endosomal fusion and release of the positive-sense viral RNA genome
    evidence:
    - reference: PMID:31427285
      reference_title: "Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Numerous host factors including proteins, lipids, and glycans promote
        productive uptake of HCV particles into human liver cells.
      explanation: >-
        Productive uptake supports the entry side of the edge; polyprotein
        translation after genome release is independently evidenced at the
        target node.
- name: HCV Polyprotein Translation
  biological_scale: MOLECULAR
  conforms_to: "viral_protease_inhibition#Synthesis of the Viral Polyprotein Precursor"
  role: trigger
  description: >-
    The positive-sense HCV RNA genome is translated as a single long
    polyprotein in infected hepatocytes. Host and viral proteases subsequently
    process this precursor into structural and nonstructural proteins.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: Viral Gene Expression
    term:
      id: GO:0019080
      label: viral gene expression
    modifier: INCREASED
  evidence:
  - reference: PMID:22558217
    reference_title: "New details of HCV NS3/4A proteinase functionality revealed by a high-throughput cleavage assay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The hepatitis C virus (HCV) genome encodes a long polyprotein, which is
      processed by host cell and viral proteases to the individual structural
      and non-structural (NS) proteins.
    explanation: >-
      The primary cleavage-assay study establishes the HCV polyprotein
      precursor and its processing into individual viral proteins.
  downstream:
  - target: HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein
    description: >-
      The viral NS3/4A serine protease cleaves defined sites in the
      nonstructural region of the HCV polyprotein.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: DIRECT
- name: HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein
  biological_scale: MOLECULAR
  conforms_to: "viral_protease_inhibition#Virus-Encoded Protease-Dependent Polyprotein Processing"
  role: therapeutic_vulnerability
  description: >-
    HCV NS3/4A is a virus-encoded serine protease complex that cleaves four
    defined junctions in the nonstructural region of the HCV polyprotein. This
    processing is essential for viral replication and produces active viral
    proteins, including NS3/4A itself. The active protease can also cleave host
    innate-sensing adaptors, a distinct downstream immune-evasion effect.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: Viral Protein Processing
    term:
      id: GO:0019082
      label: viral protein processing
    modifier: INCREASED
  molecular_functions:
  - preferred_term: Peptidase Activity
    term:
      id: GO:0008233
      label: peptidase activity
  evidence:
  - reference: PMID:22558217
    reference_title: "New details of HCV NS3/4A proteinase functionality revealed by a high-throughput cleavage assay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NS3/4A cleaves the polyprotein sequence at four specific regions.
    explanation: >-
      The primary cleavage-assay study directly establishes four specific
      NS3/4A-dependent polyprotein cleavage regions.
  - reference: PMID:22558217
    reference_title: "New details of HCV NS3/4A proteinase functionality revealed by a high-throughput cleavage assay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NS3/4A is essential for viral replication and has been considered an
      attractive drug target.
    explanation: >-
      The study directly links NS3/4A activity to viral replication and its
      therapeutic vulnerability.
  downstream:
  - target: HCV genome replication and early viremia
    description: >-
      NS3/4A-dependent processing releases nonstructural proteins required for
      HCV genome replication.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Release of processed HCV nonstructural proteins
    - Assembly of the HCV replication complex
    evidence:
    - reference: PMID:22558217
      reference_title: "New details of HCV NS3/4A proteinase functionality revealed by a high-throughput cleavage assay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        NS3/4A is essential for viral replication and has been considered an
        attractive drug target.
      explanation: >-
        The primary cleavage study directly links NS3/4A processing activity
        to the viral-replication output represented by this edge.
  - target: NS3/4A-mediated innate immune evasion
    description: >-
      Processed active NS3/4A also cleaves the host innate-sensing adaptors MAVS
      and TRIF, suppressing interferon induction.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Release and assembly of the active NS3/4A protease complex
    evidence:
    - reference: PMID:25443342
      reference_title: Innate and adaptive immune responses in HCV infections.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the HCV NS3/4A protease can efficiently cleave and inactivate two
        important signalling molecules in the sensory pathways that react to
        HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs,
        i.e., the mitochondrial anti-viral signalling protein (MAVS) and the
        Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF).
      explanation: >-
        The review directly supports cleavage of MAVS and TRIF by active
        NS3/4A; release of that protease from the polyprotein is the stated
        intermediate.
    - reference: PMID:16177806
      reference_title: "Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production."
      explanation: In-vitro work showed that the HCV NS3/4A protease inactivates the Cardif/MAVS adaptor in the RIG-I pathway, supporting the NS3/4A immune-evasion edge.
- name: HCV genome replication and early viremia
  biological_scale: CELLULAR
  conforms_to: "viral_protease_inhibition#Replication-Complex Formation and Viral RNA Replication"
  role: effector
  description: >-
    Processed HCV nonstructural proteins assemble the replication complex that
    synthesizes viral RNA in infected hepatocytes, producing the circulating
    HCV RNA that marks productive infection. HCV replicates primarily in
    hepatocytes and evades clearance through high mutation rates and
    quasispecies diversity. In one tertiary-center cohort of newly acquired
    infection, RNA was detectable at presentation in 26 of 30 patients; this
    cohort proportion is not assigned as a universal frequency.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: Viral RNA Genome Replication
    modifier: INCREASED
    term:
      id: GO:0039694
      label: viral RNA genome replication
  evidence:
  - reference: PMID:23481134
    reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HCV-ribonucleic acid (RNA) was detectable at presentation in 26 (86.7%) patients.
    explanation: This cohort of newly acquired infection directly documents early detectable viremia.
  downstream:
  - target: Interferon-driven innate and NK-cell activation
    description: Newly acquired HCV infection is accompanied by a transient type-I-interferon-imprinted activated NK-cell population.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Viral RNA sensing and type I interferon induction
    evidence:
    - reference: PMID:41453396
      reference_title: Transient Interferon-Driven Natural Killer Cell Activation in Acute Hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At the transcriptomic level, we identified a subset of highly activated
        NK cells with a robust type I interferon imprint.
      explanation: Longitudinal human data directly support interferon-imprinted NK-cell activation during acute HCV.
  - target: Immune-associated hepatocellular injury
    description: >-
      HCV viremia is associated with inflammatory immune activation and
      hepatocellular injury, but the exact direction and cell-specific causal
      contribution remain unresolved.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:34905514
      reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Given the correlative nature of our study, we cannot distinguish whether
        iNKT cell activation contributes to hepatocyte killing or whether ALT
        elevation
      explanation: Human data support immune activation accompanying injury while explicitly requiring UNKNOWN causal directness.
- name: Interferon-driven innate and NK-cell activation
  description: >-
    During acute HCV, a highly activated NK-cell subset shows a strong type I
    interferon imprint and largely returns toward baseline after viral
    clearance.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell activation
    modifier: INCREASED
    term:
      id: GO:0030101
      label: natural killer cell activation
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:41453396
    reference_title: Transient Interferon-Driven Natural Killer Cell Activation in Acute Hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, these data suggest an interferon-driven rise of an activated
      NK cell population during acute hepatitis C that is largely restored upon
      viral clearance.
    explanation: This directly supports the human innate-activation node and its resolution after clearance.
  downstream:
  - target: HCV-specific adaptive immune response
    description: >-
      Early interferon-associated innate activation precedes the later adaptive
      response associated with control or persistence, but the cited temporal
      pattern does not establish that NK-cell activation causes the adaptive
      response.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:25443342
      reference_title: Innate and adaptive immune responses in HCV infections.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Elimination of HCV during acute infection correlates with a rapid
        induction of innate, especially interferon (IFN) induced genes, and a
        delayed induction of adaptive immune responses.
      explanation: The review supports temporal ordering of the responses but does not establish a causal NK-cell-to-adaptive-response link.
- name: NS3/4A-mediated innate immune evasion
  description: >-
    HCV NS3/4A protease cleaves and inactivates MAVS and TRIF, blunting
    pathogen-sensing pathways that induce interferons. Escape from adaptive
    immunity additionally involves viral escape mutations that reduce antibody
    and T-cell recognition, and exhaustion of HCV-specific T cells during
    persistent infection.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  genes:
  - preferred_term: MAVS
    term:
      id: hgnc:29233
      label: MAVS
  biological_processes:
  - preferred_term: symbiont-mediated suppression of host type I interferon-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0039502
      label: symbiont-mediated suppression of host type I interferon-mediated signaling pathway
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:25443342
    reference_title: Innate and adaptive immune responses in HCV infections.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the HCV NS3/4A protease can efficiently cleave and inactivate two
      important signalling molecules in the sensory pathways that react to HCV
      pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the
      mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1
      receptor-domain-containing adaptor-inducing IFN-β (TRIF).
    explanation: This review directly supports the stated NS3/4A mechanism.
  - reference: PMID:25443342
    reference_title: Innate and adaptive immune responses in HCV infections.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Escape from adaptive immune responses can be achieved by emergence of
      viral escape mutations that avoid recognition by antibodies and T cells.
    explanation: This directly supports adaptive immune escape as an additional persistence mechanism.
  - reference: PMID:16127453
    reference_title: "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection"
    explanation: In-vitro siRNA-knockdown study demonstrates the RIG-I/IPS-1(MAVS) interferon-induction pathway that HCV NS3/4A disrupts to evade interferon signaling; general virology, not HCV-specific.
  downstream:
  - target: Persistent HCV viremia
    description: >-
      Suppressed interferon induction and escape from immune recognition are
      proposed contributors to failure of viral clearance, but their specific
      causal contribution to persistence is not isolated by the cited review.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:25443342
      reference_title: Innate and adaptive immune responses in HCV infections.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        However, the majority of patients is unable to clear the virus and
        develops viral persistence in face of an ongoing innate and adaptive
        immune response.
      explanation: This supports persistence despite ongoing antiviral immunity but only partially supports attribution to the modeled evasion mechanisms.
- name: HCV-specific adaptive immune response
  description: >-
    Virus-specific T-cell responses emerge after the early innate response.
    Strong multispecific responses are associated with spontaneous clearance,
    whereas the recent liver-enriched Tfh1-like helper-cell refinement is based
    on chimpanzee data and remains unconfirmed in humans.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell activation
    modifier: INCREASED
    term:
      id: GO:0042110
      label: T cell activation
  evidence:
  - reference: PMID:21139063
    reference_title: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evolution to spontaneous clearance occurred in patients with low viral
      diversity in the presence of an early multispecific T cell response.
    explanation: This human cohort supports an association between early multispecific T-cell responses and clearance.
  - reference: PMID:40956619
    reference_title: "A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      circulating CD4+ T cells with high programmed cell death 1 (PD-1) and ICOS
      coexpression were temporally associated with onset of virus control,
      seroconversion, and hepatitis in HCV-infected chimpanzees.
    explanation: This supports the emerging Tfh1-like refinement in the chimpanzee model, not direct human confirmation.
  downstream:
  - target: Spontaneous viral clearance
    description: >-
      Early multispecific T-cell responses and low viral diversity are
      associated with untreated clearance, without establishing that the
      measured response is independently causal.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    - intrahepatic_tfh1_helper_refinement
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:21139063
      reference_title: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Evolution to spontaneous clearance occurred in patients with low viral
        diversity in the presence of an early multispecific T cell response.
      explanation: This directly supports the human association, while the edge description avoids asserting that association alone proves sufficiency.
  - target: Immune-associated hepatocellular injury
    description: Activated immune-cell populations track with biochemical hepatitis, but their causal contribution to hepatocyte killing remains unresolved.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    - intrahepatic_tfh1_helper_refinement
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:34905514
      reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        activated CD38+ or CD69+ iNKT cells strongly correlated with alanine
        transaminase levels with particularly pronounced correlations in
        spontaneously resolving patients.
      explanation: Human data support an immune-activation/injury association but do not establish the causal direction.
  - target: Persistent HCV viremia
    description: Adaptive responses can remain ongoing yet fail to clear immune-escape variants.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Incomplete effector control
    - Viral escape from antibody and T-cell recognition
    evidence:
    - reference: PMID:25443342
      reference_title: Innate and adaptive immune responses in HCV infections.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        However, the majority of patients is unable to clear the virus and
        develops viral persistence in face of an ongoing innate and adaptive
        immune response.
      explanation: This directly supports persistence despite ongoing adaptive immunity.
- name: IFNL3 rs12979860 host-clearance modifier
  role: susceptibility
  description: >-
    The rs12979860 C/C genotype near IFNL3 (formerly IL28B) is associated with
    a higher probability of untreated HCV clearance in both European- and
    African-ancestry cohorts. The associated locus is established, but its
    precise functional mechanism remains unresolved.
  genes:
  - preferred_term: IFNL3
    term:
      id: hgnc:18365
      label: IFNL3
  evidence:
  - reference: PMID:19759533
    reference_title: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that the C/C genotype strongly enhances resolution of HCV
      infection among individuals of both European and African ancestry.
    explanation: This multi-cohort human genetic study directly supports the rs12979860-clearance association.
  downstream:
  - target: Spontaneous viral clearance
    description: >-
      rs12979860 C/C is associated with spontaneous HCV clearance, while the
      molecular intermediates and causal mechanism remain unresolved.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:19759533
      reference_title: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We show that the C/C genotype strongly enhances resolution of HCV
        infection among individuals of both European and African ancestry.
      explanation: The association supports a host-genetic modifier edge without claiming a resolved causal mechanism.
- name: Immune-associated hepatocellular injury
  description: >-
    Hepatocellular injury releases alanine aminotransferase and may produce
    symptomatic hepatitis. Injury reflects both direct cytopathic effects of
    viral replication and immune-mediated hepatocyte destruction. Human
    iNKT-cell activation correlates with ALT, but available data do not
    determine whether those cells cause injury or respond to the same
    inflammatory drivers.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:34905514
    reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We next analyzed the activation status of iNKT cells in the context of
      liver damage, which is defined by serum levels of alanine transaminase
      (ALT).
    explanation: This human study operationalizes acute-HCV liver damage using ALT and supports the immune-associated injury node.
  downstream:
  - target: Elevated Transaminases
    description: Hepatocellular injury is reflected by increased circulating ALT and other hepatic transaminases.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34905514
      reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We next analyzed the activation status of iNKT cells in the context of
        liver damage, which is defined by serum levels of alanine transaminase
        (ALT).
      explanation: The study directly treats serum ALT as the biochemical readout of liver damage.
    - reference: PMID:18657711
      reference_title: "Acute hepatitis C."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinically, acute hepatitis C can increase concentrations of alanine aminotransferase to ten times the upper limit of normal"
      explanation: Review of acute HCV states that infection can raise ALT concentrations, supporting the hepatocyte-injury to transaminase edge.
  - target: Jaundice
    description: Clinically apparent acute hepatitis can impair bilirubin handling and present with jaundice.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatocellular dysfunction and impaired bilirubin handling
    evidence:
    - reference: PMID:19124916
      reference_title: "Acute/recent HCV infection. Clinical course, viral replication kunetic and disease outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Out of 4 symptomatics 3 were with jaundice.
      explanation: The cohort directly documents jaundice in symptomatic acute/recent HCV.
    - reference: PMID:18657711
      reference_title: "Acute hepatitis C."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptomatic patients with jaundice have a higher likelihood of spontaneous viral clearance than do asymptomatic patients"
      explanation: Review of acute HCV describes jaundice in the symptomatic acute-infection presentation, the clinical context modeled by this edge.
  - target: Nausea
    description: Symptomatic acute hepatitis can include nausea through incompletely resolved systemic and gastrointestinal intermediates.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29642211
      reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a 26 year-old Chinese female acquired a tattoo and developed fatigue,
        nausea, and anorexia.
      explanation: This case supports nausea as a possible symptomatic manifestation but does not establish its intermediate mechanism or frequency.
  - target: Fatigue
    description: Symptomatic acute hepatitis can include fatigue through incompletely resolved systemic inflammatory intermediates.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29642211
      reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a 26 year-old Chinese female acquired a tattoo and developed fatigue,
        nausea, and anorexia.
      explanation: This case supports fatigue as a possible manifestation but does not establish its intermediate mechanism or frequency.
  - target: Anorexia
    description: Symptomatic acute hepatitis can include loss of appetite through incompletely resolved systemic and gastrointestinal intermediates.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29642211
      reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a 26 year-old Chinese female acquired a tattoo and developed fatigue,
        nausea, and anorexia.
      explanation: This case supports anorexia as a possible manifestation but does not establish its intermediate mechanism or frequency.
- name: Spontaneous viral clearance
  description: >-
    Some newly acquired infections lose detectable viremia without antiviral
    therapy. Clearance proportions vary by population and ascertainment; a small
    tertiary-center cohort observed clearance in 9 of 30 patients.
  biological_processes:
  - preferred_term: response to virus
    modifier: INCREASED
    term:
      id: GO:0009615
      label: response to virus
  evidence:
  - reference: PMID:23481134
    reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Totally, 9 patients (30%) experienced spontaneous viral eradication.
    explanation: This directly documents a spontaneous-clearance outcome in acute HCV.
- name: Persistent HCV viremia
  description: >-
    When host responses do not eradicate HCV, viremia persists despite ongoing
    innate and adaptive responses and can progress to chronic infection.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: viral genome replication
    modifier: INCREASED
    term:
      id: GO:0019079
      label: viral genome replication
  evidence:
  - reference: PMID:25443342
    reference_title: Innate and adaptive immune responses in HCV infections.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, the majority of patients is unable to clear the virus and
      develops viral persistence in face of an ongoing innate and adaptive
      immune response.
    explanation: This directly supports the persistent-viremia state.
  downstream:
  - target: Chronic hepatitis C virus infection
    description: Viremia persisting beyond six months meets the definition of chronic HCV infection.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39599853
      reference_title: "Acute Hepatitis C: Current Status and Future Perspectives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        approximately 50-70% of individuals with recently acquired hepatitis C
        will develop a chronic infection, defined as the persistence of viremia
        for a period exceeding six months.
      explanation: This directly defines chronic infection as persistent viremia beyond six months.
- name: Chronic hepatitis C virus infection
  description: >-
    Chronic HCV is the natural-history outcome in which viremia persists for
    more than six months after acquisition. It is the state from which the
    hepatic and extrahepatic complications of hepatitis C develop.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: viral process
    modifier: INCREASED
    term:
      id: GO:0016032
      label: viral process
  evidence:
  - reference: PMID:39599853
    reference_title: "Acute Hepatitis C: Current Status and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 50-70% of individuals with recently acquired hepatitis C
      will develop a chronic infection, defined as the persistence of viremia
      for a period exceeding six months.
    explanation: This directly supports the chronic outcome and its definition.
  downstream:
  - target: Chronic Inflammation and Fibrosis
    description: >-
      Persistent infection is the substrate for chronic hepatic inflammation and
      progressive fibrosis; about 30% of persistently infected people develop
      chronic liver disease.
    hypothesis_groups:
    - canonical_acute_hcv_clearance_persistence_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Sustained intrahepatic immune infiltration
    evidence:
    - reference: PMID:19759533
      reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
      explanation: Directly links persistent infection to the chronic liver disease this edge draws.
  - target: Cryoglobulin Immune Complex Deposition
    description: >-
      Sustained HCV antigenaemia during chronic infection drives the
      cryoprecipitable immune complexes behind the extrahepatic manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic B-cell stimulation and cryoprecipitable immunoglobulin production
    evidence:
    - reference: PMID:16510035
      reference_title: "Extrahepatic manifestations of hepatitis C virus."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications."
      explanation: Establishes mixed cryoglobulinemia as the extrahepatic syndrome most strongly associated with HCV infection; the attribution to the chronic phase specifically rests on the antigenaemia description at the target node rather than on this sentence.
- name: Chronic Inflammation and Fibrosis
  description: >
    Persistent HCV infection induces chronic hepatic inflammation with infiltration
    of lymphocytes and activation of hepatic stellate cells. This leads to progressive
    fibrosis through excessive collagen deposition, ultimately resulting in cirrhosis.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: chronic inflammatory response
    term:
      id: GO:0002544
      label: chronic inflammatory response
  - preferred_term: hepatic stellate cell activation
    term:
      id: GO:0035733
      label: hepatic stellate cell activation
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  evidence:
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
    explanation: Study specifically targets HCV patients with decompensated cirrhosis, confirming progression of chronic inflammation to advanced liver damage.
  downstream:
  - target: Cirrhosis
    description: >-
      Persistent stellate-cell activation and collagen deposition scar the liver
      until bridging fibrosis and nodular regeneration produce cirrhosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19759533
      reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
      explanation: Names cirrhosis as an outcome of the chronic liver disease this node describes.
    - reference: PMID:22537432
      reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HCV increases the risk for HCC by inducing fibrosis and, eventually, cirrhosis"
      explanation: Viral-hepatitis epidemiology review places cirrhosis downstream of HCV-induced fibrosis.
  - target: Hepatocellular Carcinoma Development
    description: >-
      Cirrhosis is the dominant substrate for hepatocarcinogenesis, with the
      highest cumulative risk in HCV-infected patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Regenerative nodule formation and accumulated genomic damage
    evidence:
    - reference: PMID:22537432
      reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)"
      explanation: Quantifies the cirrhosis-to-HCC step and identifies HCV as the etiology with the highest risk.
    - reference: PMID:22537432
      reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "most cases of HCV-related HCC occur among patients with advanced fibrosis or cirrhosis"
      explanation: Viral-hepatitis epidemiology review links advanced HCV fibrosis or cirrhosis to most HCV-related hepatocellular carcinoma.
- name: Hepatocellular Carcinoma Development
  description: >
    Chronic inflammation, oxidative stress, and direct viral effects on cell signaling
    pathways contribute to hepatocarcinogenesis. Cirrhosis is the major risk factor,
    but HCC can occur in non-cirrhotic livers.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:22537432
    reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)"
    explanation: Epidemiologic review establishing cirrhosis as the dominant HCC risk factor, with the highest cumulative HCC risk among HCV-infected patients.
  - reference: PMID:19759533
    reference_title: "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma"
    explanation: Documents the natural-history progression from persistent HCV infection to cirrhosis and hepatocellular carcinoma.
  downstream:
  - target: Hepatocellular Carcinoma
    description: Hepatocarcinogenesis in the chronically infected liver presents as hepatocellular carcinoma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22537432
      reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections"
      explanation: Attributes the majority of hepatocellular carcinoma to chronic HBV or HCV infection.
    - reference: PMID:22537432
      reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1%–4%"
      explanation: Viral-hepatitis epidemiology review quantifies hepatocellular carcinoma incidence after HCV-related cirrhosis is established.
- name: Cryoglobulin Immune Complex Deposition
  description: >
    Chronic HCV antigenaemia drives production of cryoprecipitable
    immunoglobulin complexes that deposit in small vessels and glomerular
    capillary walls. This single immune-complex mechanism accounts for the
    cryoglobulinemia-spectrum extrahepatic manifestations, which affect skin
    and kidney rather than liver.
  biological_processes:
  - preferred_term: immune complex formation
    term:
      id: GO:0097281
      label: immune complex formation
    modifier: INCREASED
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney."
    explanation: Histomorphologic review states that immune complex deposition in small vessels and glomerular capillaries is the mechanism producing the cutaneous and renal manifestations, establishing this node as their shared upstream cause.
  downstream:
  - target: Mixed Cryoglobulinemia
    description: Cryoprecipitable immune complexes are the defining constituent of the mixed cryoglobulinemia syndrome.
    causal_link_type: DIRECT
  - target: Leukocytoclastic Vasculitis
    description: Immune complexes deposited in dermal small vessels produce the cutaneous leukocytoclastic vasculitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22919404
      reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin"
      explanation: States the small-vessel deposition to cutaneous leukocytoclastic vasculitis link directly.
  - target: Membranoproliferative Glomerulonephritis
    description: Immune complexes deposited in glomerular capillary walls produce membranoproliferative glomerulonephritis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22919404
      reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
      explanation: States the glomerular capillary deposition to membranoproliferative glomerulonephritis link directly.
phenotypes:
- name: Fatigue
  category: Constitutional
  frequency: VERY_FREQUENT
  description: >-
    Chronic fatigue is the most common symptom of chronic infection, often persisting
    even after viral clearance. It is also one of the symptoms reported in clinically
    apparent acute hepatitis.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although nonspecific, fatigue and arthralgias are very common in those with chronic hepatitis C."
    explanation: Review of HCV extrahepatic manifestations establishes fatigue as a very common symptom of chronic hepatitis C (not a treatment adverse event).
  - reference: PMID:29642211
    reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 26 year-old Chinese female acquired a tattoo and developed fatigue,
      nausea, and anorexia.
    explanation: Case-level evidence supports fatigue in the acute phase but not its frequency there.
- name: Jaundice
  category: Hepatic
  frequency: OCCASIONAL
  description: >-
    Yellow discoloration of skin and sclera due to elevated bilirubin, occurring in a
    subset of clinically apparent acute presentations and more common in the acute than
    the chronic phase.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:18657711
    reference_title: "Acute hepatitis C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic acute hepatitis C occurs in only about 15% of patients who are infected with hepatitis C virus (HCV)."
    explanation: Acute HCV is symptomatic in only about 15% of infections, bounding jaundice within the HPO occasional frequency band and contradicting the previous FREQUENT assignment.
  - reference: PMID:19124916
    reference_title: "Acute/recent HCV infection. Clinical course, viral replication kunetic and disease outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Out of 4 symptomatics 3 were with jaundice.
    explanation: This small cohort directly documents jaundice in symptomatic acute/recent HCV without supporting a population frequency.
- name: Nausea
  category: Gastrointestinal
  description: Nausea is a possible symptom of clinically apparent acute hepatitis C.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:29642211
    reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 26 year-old Chinese female acquired a tattoo and developed fatigue,
      nausea, and anorexia.
    explanation: Case-level evidence supports possible presentation but not frequency.
- name: Anorexia
  category: Gastrointestinal
  description: Loss of appetite is a possible symptom of clinically apparent acute hepatitis C.
  phenotype_term:
    preferred_term: Anorexia
    term:
      id: HP:0002039
      label: Anorexia
  evidence:
  - reference: PMID:29642211
    reference_title: A case report of sofosbuvir and daclatasvirto treat a patient with acute hepatitis C virus genotype 2 monoinfection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 26 year-old Chinese female acquired a tattoo and developed fatigue,
      nausea, and anorexia.
    explanation: Case-level evidence supports possible presentation but not frequency.
- name: Hepatomegaly
  category: Hepatic
  frequency: FREQUENT
  description: Enlarged liver due to inflammation and/or fatty infiltration.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- name: Elevated Transaminases
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >-
    Elevated ALT and AST indicating hepatocyte injury. Levels may fluctuate in chronic
    infection and are raised even in clinically silent acute infection.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:19124916
    reference_title: "Acute/recent HCV infection. Clinical course, viral replication kunetic and disease outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 12 asymptomatics: 8 had elevated ALT"
    explanation: This cohort directly documents ALT elevation even among asymptomatic acute/recent infections.
  reports_on:
  - target: Immune-associated hepatocellular injury
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Serum ALT and AST measure hepatocyte injury from HCV replication and immune-mediated destruction, but do not identify the responsible immune-cell population.
    evidence:
    - reference: PMID:34905514
      reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We next analyzed the activation status of iNKT cells in the context of
        liver damage, which is defined by serum levels of alanine transaminase
        (ALT).
      explanation: The human study directly uses ALT as a readout of liver damage.
- name: Cirrhosis
  category: Hepatic
  frequency: FREQUENT
  description: End-stage liver fibrosis developing in 15-30% of chronically infected patients over 20-30 years.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis"
    explanation: Study specifically targets HCV patients with cirrhosis, confirming cirrhosis as a major complication.
  - reference: PMID:24725239
    reference_title: "Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection."
    supports: SUPPORT
    snippet: "Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis"
    explanation: Large HCV trial confirms cirrhosis prevalence among chronic HCV patients.
- name: Hepatocellular Carcinoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: Primary liver cancer developing in 1-5% of cirrhotic patients annually.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:22537432
    reference_title: "Epidemiology of viral hepatitis and hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections"
    explanation: Establishes chronic HCV infection as a leading cause of hepatocellular carcinoma.
- name: Mixed Cryoglobulinemia
  category: Immunologic
  description: >
    Immune-complex syndrome with skin, neurologic, renal, and rheumatologic
    complications; the most prevalent and most strongly HCV-associated
    extrahepatic manifestation.
  phenotype_term:
    preferred_term: Cryoglobulinemia
    term:
      id: HP:0100778
      label: Cryoglobulinemia
  evidence:
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications."
    explanation: Review of HCV extrahepatic manifestations identifies mixed cryoglobulinemia as the most prevalent and most strongly HCV-associated extrahepatic syndrome.
- name: Leukocytoclastic Vasculitis
  category: Dermatologic
  description: >
    Cutaneous small-vessel vasculitis from immune-complex deposition, the
    dermatologic manifestation of HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: Leukocytoclastic vasculitis
    term:
      id: HP:0034786
      label: Leukocytoclastic vasculitis
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
    explanation: Review of HCV extrahepatic pathology identifies immune-complex-mediated leukocytoclastic vasculitis in the skin as a morphologic manifestation of HCV-associated cryoglobulinemia.
- name: Membranoproliferative Glomerulonephritis
  category: Renal
  description: >
    Immune-complex glomerulonephritis, the classic renal manifestation of
    HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: Membranoproliferative glomerulonephritis
    term:
      id: HP:0000793
      label: Membranoproliferative glomerulonephritis
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney"
    explanation: Review of HCV extrahepatic pathology identifies immune-complex-mediated membranoproliferative glomerulonephritis in the kidney as the renal manifestation of HCV-associated cryoglobulinemia.
- name: Porphyria Cutanea Tarda
  category: Dermatologic
  description: >
    Cutaneous porphyria presenting with photosensitivity and skin fragility;
    an HCV-associated extrahepatic entity with a less definite (non-cryoglobulin)
    relationship to infection than cryoglobulinemia.
  phenotype_term:
    preferred_term: Porphyria cutanea tarda
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  notes: >-
    No HPO term exists for porphyria cutanea tarda itself (confirmed via OAK
    search of sqlite:obo:hp); bound to the closest broader phenotype,
    Cutaneous photosensitivity, with a more specific preferred_term, following
    the same pattern used for SSPE in Measles.yaml. MONDO:0015104 is the
    disease-level term for porphyria cutanea tarda.
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists porphyria cutanea tarda among the HCV-associated entities beyond the cryoglobulinemia spectrum.
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
    explanation: Confirms porphyria cutanea tarda as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
- name: Sicca Syndrome
  category: Immunologic
  description: >
    Sjogren-like sicca complex reported as an HCV-associated extrahepatic
    manifestation, distinct from classic autoimmune Sjogren syndrome.
  phenotype_term:
    preferred_term: Keratoconjunctivitis sicca
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists sicca syndrome among the HCV-associated entities.
  - reference: PMID:16510035
    reference_title: "Extrahepatic manifestations of hepatitis C virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes."
    explanation: Confirms sicca syndrome as one of the non-cryoglobulin HCV-associated extrahepatic syndromes with a less definite relationship to infection.
- name: B-Cell Non-Hodgkin Lymphoma
  category: Neoplastic
  description: >
    Lymphoproliferative outcome at the far end of the same chronic B-cell
    stimulation continuum as HCV-associated mixed cryoglobulinemia.
  phenotype_term:
    preferred_term: B-cell non-Hodgkin lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  notes: >-
    HPO has no combined "B-cell non-Hodgkin lymphoma" term. HP:0012191 B-cell
    lymphoma is a descendant of HP:0012539 Non-Hodgkin lymphoma, so the
    narrower lineage term is bound here and the non-Hodgkin sense is entailed.
  evidence:
  - reference: PMID:22919404
    reference_title: "Morphologic features of extrahepatic manifestations of hepatitis C virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis."
    explanation: Review of HCV extrahepatic manifestations lists B-cell non-Hodgkin lymphomas among the HCV-associated entities.
biochemical:
- name: HCV RNA
  presence: Detected during active infection
  loinc_term:
    id: LOINC:104721-6
    label: Hepatitis C virus RNA [Units/volume] in Serum or Plasma by Molecular genetics method
  notes: >-
    A Monarch KG search found no method-less quantitative HCV RNA code for serum or plasma, and no LOINC Part for HCV RNA, so loinc_term binds the
    quantitative code in international units per volume whose method is the
    generic molecular genetics method rather than a specific amplification or
    probe method.
  context: >-
    Qualitative or quantitative HCV RNA establishes current infection and
    quantitative levels guide treatment monitoring, but a single positive result
    does not by itself establish recent acquisition.
  readouts:
  - target: HCV genome replication and early viremia
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: Detectable circulating HCV RNA reports active viremia.
    evidence:
    - reference: PMID:23481134
      reference_title: "Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: HCV-ribonucleic acid (RNA) was detectable at presentation in 26 (86.7%) patients.
      explanation: This directly supports HCV RNA as a viremia readout in newly acquired infection.
  evidence:
  - reference: PMID:30927209
    reference_title: Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tests for HCV RNA are valuable in distinguishing between active and
      resolved infection, but the presence of HCV RNA does not distinguish
      between acute and chronic hepatitis C
    explanation: This directly supports the use and limitation of HCV RNA as a biomarker.
- name: Anti-HCV Antibodies
  presence: Negative before seroconversion or positive after seroconversion
  loinc_term:
    id: LOINC:16128-1
    label: Hepatitis C virus Ab [Presence] in Serum
  notes: >-
    A Monarch KG search found no LOINC Part for HCV antibody, so loinc_term binds
    the method-less serum presence code.
  context: >-
    Anti-HCV may be absent early and, once present, cannot distinguish active,
    resolved, acute, or chronic infection without RNA results and longitudinal
    context.
  evidence:
  - reference: PMID:30927209
    reference_title: Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-HCV antibodies are usually used to exclude acute hepatitis C in a
      patient with acute liver injury, but it does not distinguish between
      acute, chronic or resolved hepatitis.
    explanation: This directly supports the interpretive limitation of anti-HCV antibody.
- name: Alanine aminotransferase
  presence: Increased or fluctuating during hepatocellular injury
  context: >-
    Serum ALT reports hepatocellular injury. It is not specific for HCV, can be
    elevated in clinically silent infection, and may be normal in some chronic
    infections.
  readouts:
  - target: Immune-associated hepatocellular injury
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: ALT is a biochemical readout of liver injury, not proof of a particular immune effector mechanism.
    evidence:
    - reference: PMID:34905514
      reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We next analyzed the activation status of iNKT cells in the context of
        liver damage, which is defined by serum levels of alanine transaminase
        (ALT).
      explanation: This directly identifies ALT as the study's liver-damage readout.
  evidence:
  - reference: PMID:19124916
    reference_title: "Acute/recent HCV infection. Clinical course, viral replication kunetic and disease outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 12 asymptomatics: 8 had elevated ALT"
    explanation: This directly documents ALT elevation in asymptomatic acute/recent infection.
- name: Elevated Bilirubin
  presence: Elevated
  context: Indicates impaired hepatic function, especially in acute infection or decompensated cirrhosis
genetic:
- name: IFNL3 (IL28B) rs12979860 clearance modifier
  gene_term:
    preferred_term: IFNL3
    term:
      id: hgnc:18365
      label: IFNL3
  association: >-
    The rs12979860 C/C genotype near IFNL3 (formerly IL28B) is associated with an
    increased probability of spontaneous HCV clearance and with response to
    interferon-based therapy; it is not necessary or sufficient for clearance, and its
    precise functional mechanism remains unresolved.
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19759533
    reference_title: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that the C/C genotype strongly enhances resolution of HCV
      infection among individuals of both European and African ancestry.
    explanation: This multi-cohort human genetic study establishes rs12979860 as a modifier of spontaneous HCV clearance.
  - reference: PMID:19684573
    reference_title: "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment"
    explanation: Landmark GWAS linking the IL28B polymorphism to response to interferon-based HCV therapy.
diagnosis:
- name: Combined HCV RNA and anti-HCV testing with evidence of recent acquisition
  description: >-
    Acute infection is best supported by HCV RNA during the antibody-negative
    window, documented anti-HCV seroconversion, de novo RNA detection, or RNA
    loss during untreated recovery. RNA or antibody at one time point cannot by
    itself reliably distinguish acute from chronic infection.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Current HCV RNA plus a documented recent negative result, seroconversion, or
    compatible longitudinal course supports acute HCV.
  measurements:
  - preferred_term: anti-HCV
    term:
      id: LOINC:16128-1
      label: Hepatitis C virus Ab [Presence] in Serum
  - preferred_term: HCV RNA
    term:
      id: LOINC:104721-6
      label: Hepatitis C virus RNA [Units/volume] in Serum or Plasma by Molecular genetics method
  evidence:
  - reference: PMID:30927209
    reference_title: Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, reliable diagnosis of acute hepatitis C usually requires testing at
      two time points demonstrating seroconversion to anti-HCV reactivity, de
      novo development of HCV RNA, or loss of HCV RNA during recovery.
    explanation: This directly supports longitudinal antibody/RNA evidence for recent infection.
- name: Serial HCV RNA assessment
  description: >-
    Repeat HCV RNA assessment is important when timing is uncertain because
    untreated viremia may fluctuate and a transient decline does not establish
    spontaneous clearance.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Persistent, recurrent, or cleared RNA across serial measurements resolves
    uncertainty that remains after a single result.
  measurements:
  - preferred_term: HCV RNA
    term:
      id: LOINC:104721-6
      label: Hepatitis C virus RNA [Units/volume] in Serum or Plasma by Molecular genetics method
  evidence:
  - reference: PMID:21139063
    reference_title: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter group included a significant proportion of 'fluctuating'
      progressors (37.5%), in whom a fall followed by a rise (>1 log₁₀) in
      viraemia was observed.
    explanation: This directly supports serial rather than single-point interpretation of viremia, with the cohort context stated in progression.
- name: Anti-HCV screening with reflex HCV RNA testing
  description: >-
    Hepatitis C testing begins with an antibody (anti-HCV) assay. A nonreactive
    result in an immunocompetent person without hepatitis C risks needs no
    further testing. A reactive result indicates current infection, past
    resolved infection or a false positive, and is followed by nucleic acid
    testing for HCV RNA: detected RNA indicates current infection, and RNA not
    detected indicates resolved infection or a false-positive antibody result.
    CDC encourages reflex RNA testing on the same specimen in the laboratory.
  diagnosis_term:
    preferred_term: laboratory testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Anti-HCV reactive with HCV RNA detected establishes current infection;
    anti-HCV reactive with HCV RNA not detected indicates no current infection.
  measurements:
  - preferred_term: anti-HCV
    term:
      id: LOINC:16128-1
      label: Hepatitis C virus Ab [Presence] in Serum
  - preferred_term: HCV RNA
    term:
      id: LOINC:104721-6
      label: Hepatitis C virus RNA [Units/volume] in Serum or Plasma by Molecular genetics method
  notes: >-
    Anti-HCV binds the method-less serum presence code. A Monarch KG search found no method-less HCV RNA code for serum or plasma, so the RNA step binds the
    quantitative code whose method is the generic molecular genetics method;
    the step itself asks only whether RNA is detected. No band is recorded:
    both steps of the sequence are read as detected or not detected, and the
    CDC recommendations cited here define no quantitative RNA threshold for
    diagnosis.
  evidence:
  - reference: PMID:32271723
    reference_title: "CDC Recommendations for Hepatitis C Screening Among Adults - United States, 2020."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hepatitis C testing should be initiated with a U.S. Food and Drug
      Administration (FDA)-approved anti-HCV test. Persons who test anti-HCV
      positive are either currently infected or had past infection that has
      resolved naturally or with treatment. Immunocompetent persons without
      hepatitis C risks who test anti-HCV negative are not infected and require
      no further testing.
    explanation: The CDC recommendations make the antibody test the first step and state what a negative and a positive antibody result mean.
  - reference: PMID:32271723
    reference_title: "CDC Recommendations for Hepatitis C Screening Among Adults - United States, 2020."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Persons testing anti-HCV positive should have follow-up testing with an
      FDA-approved nucleic acid test (NAT) for detection of HCV RNA. NAT for HCV
      RNA detection determines viremia and current HCV infection. Persons who
      test anti-HCV positive but HCV RNA negative do not have current HCV
      infection. CDC encourages use of reflex HCV RNA testing, in which
      specimens testing anti-HCV positive undergo HCV RNA testing immediately
      and automatically in the laboratory, using the same sample from which the
      anti-HCV test was conducted.
    explanation: States the RNA step after a positive antibody result, its interpretation, and the reflex-testing recommendation.
  - reference: PMID:23657112
    reference_title: "Testing for HCV infection: an update of guidance for clinicians and laboratorians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A nonreactive HCV antibody result indicates no HCV antibody detected. A
      reactive result indicates one of the following: 1) current HCV infection,
      2) past HCV infection that has resolved, or 3) false positivity. A
      reactive result should be followed by NAT for HCV RNA. If HCV RNA is
      detected, that indicates current HCV infection. If HCV RNA is not
      detected, that indicates either past, resolved HCV infection, or false
      HCV antibody positivity.
    explanation: The CDC testing guidance gives the interpretation of each antibody and RNA outcome.
- name: Combined HCV antibody and antigen immunoassay
  description: >-
    A fourth-generation antibody/antigen assay can shorten the diagnostic window
    but does not eliminate the need for nucleic-acid testing.
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: Antibody/antigen reactivity is an early-detection adjunct and should be interpreted with HCV RNA testing.
  evidence:
  - reference: PMID:39283072
    reference_title: Comparison of a dual antibody and antigen HCV immunoassay to standard of care algorithmic testing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fourth generation HCV Duo Ab/Ag assay demonstrated comparable performance
      to SOC testing and shortens the diagnostic window but does not eliminate
      the need for NAAT in all patients.
    explanation: This diagnostic study directly supports the stated adjunctive role and limitation.
differential_diagnoses:
- name: Drug-induced liver injury
  disease_term:
    preferred_term: drug-induced liver injury
    term:
      id: MONDO:0005359
      label: drug-induced liver injury
  description: >-
    Drug-induced liver injury can closely mimic the hepatocellular presentation
    of acute HCV. Medication and supplement exposure, dechallenge, and formal
    causality assessment are interpreted alongside both anti-HCV and HCV RNA.
  distinguishing_features:
  - A compatible drug or supplement exposure and improvement after withdrawal favor drug-induced injury.
  - HCV RNA during an antibody-negative window or longitudinal seroconversion favors acute HCV.
  evidence:
  - reference: PMID:30927209
    reference_title: Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that patients presenting with acute
      hepatocellular injury, even with features suggestive of DILI, should be
      tested for both anti-HCV and HCV RNA to reliably exclude acute HCV
      infection.
    explanation: This prospective DILI-network analysis directly supports distinguishing acute HCV from DILI using both tests.
- name: Other viral, autoimmune, and biliary causes of acute hepatocellular injury
  description: >-
    Hepatitis A, B, and E, autoimmune hepatitis, and biliary disease can produce
    an overlapping acute-hepatitis presentation and require cause-specific
    testing when HCV timing is uncertain.
  distinguishing_features:
  - Cause-specific viral testing distinguishes hepatitis A, B, or E.
  - Autoimmune evaluation and biliary imaging are guided by the presentation.
  - Longitudinal anti-HCV and HCV RNA results establish or weaken recent-HCV timing.
  evidence:
  - reference: PMID:30927209
    reference_title: Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These assessments could include testing for hepatitis A, B, C, E,
      infectious mononucleosis, iron overload, and autoimmune conditions, as
      well as imaging for biliary tract disease10.
    explanation: This human diagnostic cohort directly supports the listed alternative-cause workup.
treatments:
- name: Direct-Acting Antivirals (DAAs)
  description: >
    Oral medications targeting viral proteins (NS3/4A protease, NS5A, NS5B polymerase)
    with cure rates exceeding 95%. Regimens include sofosbuvir/velpatasvir,
    glecaprevir/pibrentasvir, and others.
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  target_mechanisms:
  - target: HCV genome replication and early viremia
    treatment_effect: INHIBITS
    description: >-
      DAAs inhibit HCV nonstructural proteins required for viral replication,
      eliminating the upstream driver of hepatic infection.
    evidence:
    - reference: PMID:26569658
      reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir"
      explanation: Phase 3 HCV trial names the viral replication proteins inhibited by a direct-acting antiviral regimen, supporting the treatment-to-replication target edge.
  evidence:
  - reference: PMID:24725239
    reference_title: "Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection."
    supports: SUPPORT
    snippet: "Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection."
    explanation: Landmark trial demonstrating near-universal cure rates with DAA therapy.  # codespell:ignore-line
  - reference: PMID:26569658
    reference_title: "Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis."
    supports: SUPPORT
    snippet: "Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis."
    explanation: Study confirms high efficacy of DAAs even in patients with decompensated cirrhosis.
  - reference: PMID:36891719
    reference_title: "Guideline for the prevention and treatment of hepatitis C (2022 version)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More and more direct antiviral agents, especially pan genotypic agents including those developed and produced by domestic enterprises, have been included in the national basic medical insurance directory."
    explanation: The 2022 hepatitis C prevention-and-treatment guideline reflects expanding availability of pangenotypic direct-acting antiviral agents as standard therapy.
- name: Immediate direct-acting antiviral treatment after confirmed acute HCV viremia
  description: >-
    Published AASLD-IDSA guidance recommends initiating direct-acting antiviral
    treatment after acute HCV with quantifiable RNA is diagnosed rather than
    waiting for possible spontaneous resolution.
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  evidence:
  - reference: DOI:10.1002/hep.31060
    reference_title: "Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      After the initial diagnosis of acute HCV with viremia (defined as
      quantifiable RNA), HCV treatment should be initiated without awaiting
      spontaneous resolution.
    explanation: The published AASLD-IDSA guidance directly supports the test-and-treat timing recommendation.
  notes: >-
    This entry captures treatment timing rather than a specific drug regimen.
    Regimen choice, contraindications, interactions, and jurisdiction-specific
    availability require consultation of current guidance.
- name: Eight-week glecaprevir/pibrentasvir therapy
  description: >-
    An eight-week oral glecaprevir/pibrentasvir direct-acting antiviral regimen
    produced high sustained virologic response rates in a completed single-arm
    phase IIIb study of adults with acute HCV. Glecaprevir is the regimen's
    NS3/4A protease inhibitor, whereas pibrentasvir inhibits NS5A. The absence
    of a randomized untreated comparator and geography-specific regulatory
    status should be considered when applying the result.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: glecaprevir
      term:
        id: NCIT:C170029
        label: Glecaprevir
    - preferred_term: pibrentasvir
      term:
        id: NCIT:C166601
        label: Pibrentasvir
  target_mechanisms:
  - target: HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein
    treatment_effect: INHIBITS
    description: >-
      The glecaprevir component directly inhibits HCV NS3/4A protease and
      therefore blocks NS3/4A-dependent nonstructural-polyprotein processing.
      Pibrentasvir acts through NS5A and is not represented by this
      protease-target edge.
    evidence:
    - reference: PMID:29084747
      reference_title: "In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV)
        NS3/4A protease inhibitor (PI) with pangenotypic activity.
      explanation: >-
        The primary biochemical study directly identifies glecaprevir as an HCV
        NS3/4A protease inhibitor.
    - reference: PMID:29084747
      reference_title: "In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        It inhibited the enzymatic activity of purified NS3/4A proteases from
        HCV genotypes 1 to 6 in vitro
      explanation: >-
        The biochemical assay directly demonstrates glecaprevir inhibition of
        purified HCV NS3/4A proteases across genotypes.
  - target: HCV genome replication and early viremia
    treatment_effect: INHIBITS
    description: Direct-acting antiviral treatment suppresses acute HCV replication and enables virologic eradication.
    evidence:
    - reference: PMID:41297677
      reference_title: A single-arm phase IIIb study of 8-week glecaprevir/pibrentasvir treatment in adults with acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An 8-week glecaprevir/pibrentasvir regimen was efficacious and
        well-tolerated in patients with acute HCV.
      explanation: This directly supports regimen efficacy against acute infection; the molecular target detail is intentionally kept at the viral-replication level.
  - target: Persistent HCV viremia
    treatment_effect: INHIBITS
    description: Achieving sustained virologic response removes persistent viremia and prevents progression to chronic infection.
    evidence:
    - reference: PMID:41297677
      reference_title: A single-arm phase IIIb study of 8-week glecaprevir/pibrentasvir treatment in adults with acute hepatitis C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population
        (n = 286), and 100% in the mITT-VF population (n = 275).
      explanation: Sustained virologic response directly supports inhibition and eradication of persistent viremia in the study population.
  evidence:
  - reference: PMID:41297677
    reference_title: A single-arm phase IIIb study of 8-week glecaprevir/pibrentasvir treatment in adults with acute hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 286 adults were enrolled and treated; 14.3% were recent/current
      users of injection drugs, 49.7% were HCV/HIV coinfected, and 64.2% had HCV
      genotype 1.
    explanation: This establishes the treated acute-HCV study population and its important clinical contexts.
  - reference: PMID:41297677
    reference_title: A single-arm phase IIIb study of 8-week glecaprevir/pibrentasvir treatment in adults with acute hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population
      (n = 286), and 100% in the mITT-VF population (n = 275).
    explanation: This directly supports the high sustained virologic response achieved with the regimen.
  notes: >-
    This entry represents the regimen directly studied in acute HCV. Treatment
    selection, contraindications, interactions, and regulatory availability
    require current jurisdiction-specific guidance.
- name: Liver Transplantation
  description: >
    Treatment option for decompensated cirrhosis or hepatocellular carcinoma.
    Direct-acting antiviral therapy post-transplant prevents graft reinfection.
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
- name: Hepatocellular Carcinoma Surveillance
  description: >
    Regular ultrasound and AFP monitoring in cirrhotic patients for early
    detection of hepatocellular carcinoma.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:15042359
    reference_title: "Randomized controlled trial of screening for hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biannual screening reduced HCC mortality by 37%"
    explanation: Landmark randomized controlled trial demonstrating that biannual AFP plus ultrasound surveillance reduces HCC mortality in at-risk chronic-hepatitis patients.
computational_models:
- name: Aston2018 HCV Within-Host Viral-Dynamics Model
  description: >-
    Deterministic three-state ordinary differential-equation model of healthy
    hepatocytes, infected hepatocytes, and circulating HCV viral load in a
    well-mixed liver compartment. It represents hepatocyte regeneration and
    death, infection, virion production and clearance, and treatment-adjusted
    infection and virion-production rates.
  model_type: KINETIC
  repository_url: https://www.ebi.ac.uk/biomodels/BIOMD0000000713
  model_id: BIOMD0000000713
  model_software: MATLAB for publication fitting; COPASI for the BioModels model and fitted variants
  model_format: SBML Level 2 Version 4 (main PVR parameterization); COPASI CPS scenario variants; SED-ML Level 1 Version 4 / COMBINE OMEX
  publication: PMID:29652855
  variables:
  - name: Healthy hepatocyte concentration
    dataset_identifier: T
    description: >-
      Latent model-scaled concentration of uninfected hepatocytes; it was not
      observed in the fitted clinical viral-load datasets.
    unit: IU/mL
  - name: Infected hepatocyte concentration
    dataset_identifier: I
    description: >-
      Latent model-scaled concentration of infected hepatocytes inferred from
      viral-load fitting rather than measured in the clinical datasets.
    unit: IU/mL
  - name: HCV viral load
    dataset_identifier: V
    description: Observable model state fitted to treatment-period HCV RNA measurements.
    unit: IU/mL
  - name: Stem-cell hepatocyte generation rate
    dataset_identifier: s
    description: Rate parameter for generation of healthy hepatocytes in proportion to infected hepatocytes.
    unit: 1/day
  - name: Treatment-adjusted infection rate
    dataset_identifier: beta
    description: SBML parameter for the treatment-adjusted rate at which virions infect healthy hepatocytes.
    unit: mL/IU/day
  - name: Treatment-adjusted virion-production rate
    dataset_identifier: pstar
    description: Rate of virion production by infected hepatocytes after the modeled treatment effect.
    unit: 1/day
  modeled_mechanisms:
  - target: HCV genome replication and early viremia
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      The model explicitly couples healthy-hepatocyte infection, infected-cell
      loss, virion production, and viral clearance, and fits the viral-load state
      to human treatment-response profiles.
    fidelity: MODERATE
    limitations: >-
      The model is deterministic and well mixed, with only healthy hepatocytes,
      infected hepatocytes, and virions. Hepatocyte states are latent and were
      not measured in the fitted datasets; aggregate death-rate terms replace
      immune-mediated injury. Viral genotype and evolution, interferon signaling,
      immune-cell responses, inflammation, fibrosis, and cancer are absent. Four
      treatment profiles were fitted in-sample without held-out or prospective
      validation, and substantially different parameter sets can produce similar
      fits.
    readouts:
    - name: HCV viral-load trajectory
      target: HCV genome replication and early viremia
      description: >-
        Time course of state V, fitted on the logarithmic scale to viral-load
        measurements obtained during treatment.
      interpretation: >-
        Captures partial-response, breakthrough, null-response, and triphasic
        profile shapes but is not a prospectively validated individual treatment
        prediction.
      evidence:
      - reference: PMID:29652855
        reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          We fitted our model to the data during treatment only. The data together
          with the fitted curve V(t) and the predicted curves T(t) and I(t) from
          the model for each case are shown in Figure 12.
        explanation: >-
          Identifies viral load as the fitted observable and healthy and infected
          hepatocyte concentrations as latent model predictions.
    evidence:
    - reference: PMID:29652855
      reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We have proposed a new mathematical model of HCV infection, which involves
        the same three variables (concentrations of healthy and infected hepatocytes
        and of virions) as the earlier models of Neumann and Dahari, but which has
        a significantly different structure to the steady state solutions.
      explanation: >-
        Establishes that the model directly represents hepatocyte infection states
        and circulating virus while differing in its dynamical structure.
  evidence:
  - reference: PMID:29652855
    reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      A new model for HCV infection is proposed, based on various dynamical
      processes that occur during the infection that are described in the
      literature.
    explanation: Identifies the disease-specific computational model and its literature-derived dynamical basis.
  findings:
  - statement: >-
      The same three-state ODE structure was fitted to partial virologic response,
      breakthrough, null-response, and triphasic treatment-period viral-load
      profiles.
    evidence:
    - reference: PMID:29652855
      reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We considered various datasets that show partial virologic response (PVR),
        breakthrough, null response and triphasic behaviour.
      explanation: Names the four response profiles selected for model fitting.
    - reference: PMID:29652855
      reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We fitted our model to the data during treatment only. The data together
        with the fitted curve V(t) and the predicted curves T(t) and I(t) from
        the model for each case are shown in Figure 12.
      explanation: Confirms that the one model structure was fitted to each selected treatment-period profile.
  - statement: >-
      With stem-cell hepatocyte generation set to zero, the model has uninfected,
      infected, and pure-infection steady-state branches; adding stem-cell
      generation unfolds the pure-infection bifurcation into one valid infected
      branch with a limit point.
    evidence:
    - reference: PMID:29652855
      reference_title: "A New Model for the Dynamics of Hepatitis C Infection: Derivation, Analysis and Implications."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        In the case S=0 (no generation of hepatocytes from stem cells), we showed
        that there is a pure infection branch of solutions, and an infected steady
        state branch was found analytically that connects the uninfected and pure
        infection branches. When S>0, the bifurcation between the pure infected and
        infected branches unfolds, generating a single valid branch of infected
        solutions on which there is a limit point (see Figure 7).
      explanation: Summarizes the model's analytically derived steady-state structure.
  notes: >-
    BioModels entry BIOMD0000000713 (internal submission MODEL1808280002) is
    manually curated; this record pins public revision 9 at
    https://www.biomodels.org/services/download/get-files/MODEL1808280002/9/MODEL1808280002.9.omex.
    The revision-9 COMBINE archive retrieved for curator testing was 83,278 bytes with SHA-256
    5ca8ec25248d053f4dc52374658df7fc403ea1c4fa4a9141ca93bd0b600712c8,
    and its main PVR.xml file has SHA-256
    b8d62ff28623b18ba31fd59a39a3f5bbd799a0fef9601a5a0f435d5c722cf3b3.
    BioModels distributes the model under CC0; the archive itself contains no
    separate license file. PVR.cps, Breakthrough.cps, NullResponse.cps, and
    Triphasic.cps are distinct parameter and initial-condition variants of the
    same three-species, nine-reaction structure. Under Python 3.13.9 with COPASI
    4.46.300 and basiCO 0.86, all four CPS files loaded and simulated; the PVR
    SBML and CPS trajectories agreed to a maximum relative difference below
    1.03e-7 under matched LSODA settings and reproduced the archived Figure 12(a)
    result. The standardized
    workflow is incomplete: every SED-ML file references PVR.xml without model
    changes, so the named Breakthrough, NullResponse, and Triphasic SED-ML files
    do not encode their corresponding CPS parameterizations; Breakthrough.sedml
    and NullResponse.sedml are byte-identical. The stored Triphasic CPS time-course
    settings are internally inconsistent (19 steps of 3.333333333 days with a
    declared duration of 60 days), and current COPASI runs to 63.333 days unless
    the step size is forced to 60/19. BioSimulators archive validation completes
    with unit/modeling warnings, but the standardized COPASI archive runner hung
    after task start in the curator environment while direct COPASI execution
    succeeded. libSBML reports no parse errors, with 17 unit/modeling-practice
    warnings including eight parameters without declared units. The archive hash
    is a retrieval snapshot because BioModels can
    regenerate container packaging; the revision and main-file hash are the
    stronger content pins. The original MATLAB fit estimated ten parameters and
    initial values by least squares on log viral load. Raw fitting data and fitting
    code are not deposited, COPASI parameter-estimation and validation sets are
    empty, and the paper warns that substantially different parameters give
    similar fits. The clinical profiles predate modern direct-acting antiviral
    regimens; direct-acting antiviral effects are discussed as parameter hypotheses rather than
    validated against DAA-treated cohorts. The model does not justify links to
    Chronic Inflammation and Fibrosis, Immune Evasion, or Hepatocellular Carcinoma
    Development.

clinical_trials:
- name: NCT04903626
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Completed multicenter, single-arm phase IIIb study of eight weeks of oral
    glecaprevir/pibrentasvir in adults with acute HCV. The publication reports
    286 treated adults and 96.2% ITT SVR12 (95% CI 93.2%-97.8%).
  evidence:
  - reference: clinicaltrials:NCT04903626
    reference_title: "A Multicenter, Single-Arm Prospective Study to Evaluate Safety and Efficacy of GLE/PIB 8-Week Treatment in Adults and Adolescents With Acute Hepatitis C Virus (HCV) Infection"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants will receive oral tablets of GLE/PIB once daily (QD) for 8
      weeks and will be followed for 12 weeks after the end of treatment.
    explanation: The registry directly establishes the regimen and follow-up schedule.
  - reference: PMID:41297677
    reference_title: A single-arm phase IIIb study of 8-week glecaprevir/pibrentasvir treatment in adults with acute hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SVR12 was achieved by 96.2% (95% CI 93.2%-97.8%) in the ITT population
      (n = 286), and 100% in the mITT-VF population (n = 275).
    explanation: The peer-reviewed phase IIIb report supplies the completed efficacy result.
discussions:
- discussion_id: human_validation_of_tfh1_helper_axis
  prompt: >-
    Does the liver-enriched PD-1-high ICOS-high Tfh1-like CD4 response observed
    in HCV-infected chimpanzees mark or mechanistically assist viral control in
    humans with acute HCV?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#HCV-specific adaptive immune response
  - pathophysiology#Spontaneous viral clearance
  rationale: >-
    The chimpanzee study temporally links the population to viral control,
    seroconversion, and hepatitis and shows enrichment in liver, but the source
    does not establish the same population or a causal helper function in
    humans. Human longitudinal sampling with matched blood and liver-proximal
    material is needed before promoting this refinement to the canonical model.
  evidence:
  - reference: PMID:40956619
    reference_title: "A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver,
      suggesting the potential for B and CD8+ T cell help at the site of virus
      replication.
    explanation: This is the model-organism observation whose human generalizability remains open.
- discussion_id: cell_specific_cause_of_acute_hcv_liver_injury
  prompt: >-
    Which immune-cell populations directly cause hepatocyte injury during acute
    HCV, and which are biomarkers or bystanders of the same inflammatory state?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Immune-associated hepatocellular injury
  - phenotypes#Elevated Transaminases
  rationale: >-
    Human iNKT activation correlates with ALT, but the study explicitly cannot
    determine whether iNKT cells kill hepatocytes or respond to injury-related
    drivers. The pathograph therefore retains UNKNOWN causal directness rather
    than encoding a specific effector population as established.
  evidence:
  - reference: PMID:34905514
    reference_title: Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the correlative nature of our study, we cannot distinguish whether
      iNKT cell activation contributes to hepatocyte killing or whether ALT
      elevation
    explanation: The authors directly identify the unresolved causal direction captured by this discussion.
- discussion_id: generalizable_predictors_of_spontaneous_clearance
  prompt: >-
    Which early virologic and immune measurements robustly predict spontaneous
    clearance across populations, coinfection states, and HCV genotypes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#HCV-specific adaptive immune response
  - pathophysiology#Spontaneous viral clearance
  - progression#Spontaneous viral clearance
  rationale: >-
    Rapid viral-load decline and strong T-cell responses predicted clearance in
    an HIV-positive male cohort, while clearance proportions vary across
    cohorts. External validation is needed before these associations can be
    treated as universal decision rules.
  evidence:
  - reference: PMID:21139063
    reference_title: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spontaneous clearance of acute HCV in HIV-positive men can be predicted by
      a rapid decline in viral load, high CD4 count, elevated bilirubin and ALT,
      and is associated with low viral diversity and strong T cell responses.
    explanation: This directly supports candidate predictors while the cohort restriction motivates the generalizability gap.
datasets:
- accession: geo:GSE267834
  title: Hepatitis C Virus-induced Differential Transcriptional Traits in Host Cells After Persistent Infection Elimination by Direct-Acting Antivirals In Cell Culture
  description: Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct acting antiviral (DAA) drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection.  # codespell:ignore-line
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 28
  publication: PMID:38988177
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE119117
  title: Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection
  description: Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq to characterize immune function in peripheral blood before, during, and after acute HCV infection resulting in spontaneous resolution.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 53
  publication: PMID:30222771
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE65123
  title: Gene expression analysis during acute hepatitis C virus infection associates dendritic cell activation with viral clearance
  description: 'Background and Aims: Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses our goal was to analyze gene expression in DC from patients during acute HCV infection. Methods: By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from those who become chronically infected (ANR), as well as in HCV chronically infected patients (CHR) and healthy seronegative individuals (CTRL).'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 56
  publication: PMID:26447929
  notes: Identified by GEO DataSets index search for Acute Hepatitis C Virus Infection (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE200809
  title: The human liver circadian transcriptome and its carcinogenic perturbation by hepatitis C virus infection (RNA-Seq I)
  description: Chronic liver disease and cancer are global health challenges. The role of the circadian clock (CC) as a regulator of physiology and disease is well established in animal models. However, in human liver the identity of circadian genes and their epigenetic regulation is unknown. Here, we unraveled the circadian transcriptome and epigenome of human hepatocytes using a human liver chimeric mouse model. We identified genes coding for transcription factors, chromatin modifiers, and critical enzymes which are expressed rhythmically in human hepatocytes, and which differ from the mouse liver circadian transcriptome.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:39209804
  notes: Identified by GEO DataSets index search for Hepatitis C (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001000096
  title: Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort
  description: The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001002324
  title: Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus
  description: Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28394351
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Hepatitis C"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: dbgap:phs000430
  title: Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)
  description: Reprinted from http://www.haltctrial.org/    Purpose    The  H epatitis C  A ntiviral  L ong-term  T reatment against  C irrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
- accession: massive:MSV000088553
  title: Site specific glycan analysis of hepatitis C virus E1E2 glycoprotein complex
  description: Dataset for N-linked glycosylation analysis contained within "Structure of the hepatitis C virus E1E2 glycoprotein complex"
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Hepatitis C"). Retrieved 2026-08-02.
notes: >-
  The separate entry Acute_Hepatitis_C_Virus_Infection (MONDO:0100371) was merged into
  this entry under design decisions §3e (issue 10115): a phase of one infection is never
  its own entry, and the entry it belongs to lists its phases in progression:. Its
  pathophysiology, phenotypes, biochemical markers, diagnosis, differential diagnoses,
  treatments, clinical trial, discussions, mechanistic hypotheses, prevalence, transmission
  and datasets were folded in here; its acute-phase and chronic-phase progression entries
  became this entry's Acute infection and Chronic infection phases; and MONDO:0100371 is
  carried as a skos:narrowMatch mapping so the concept stays retired from the curation
  queue rather than being lost. The two former has_subtypes rows, Acute Hepatitis C and
  Chronic Hepatitis C, were phases rather than organism strata, so their content moved to
  progression: as well and the has_subtypes block was removed. The merged entry's synonyms
  (Acute HCV infection, Recently acquired hepatitis C virus infection) name that phase
  rather than this disease and were not carried over.

📚

References & Deep Research

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Re-review: Acute Hepatitis C Virus Infection · 2026-07-20T21:28:38Z · View source

Comprehensive evidence re-review rebuilt the entry around a connected exposure-to-entry-to-viremia-to-host-response-to-clearance-or-chronicity pathograph. Added infectious-agent and transmission context, longitudinal natural history, biomarkers, diagnosis and differential guidance, an evidence-backed 8-week glecaprevir/pibrentasvir regimen and completed phase IIIb result, current human immune-response evidence, model-system caveats, and explicit knowledge gaps. Removed the inherited broad deep-research bibliography in favor of claim-level evidence.

Review response: fix evidence_source tags and boilerplate snippets (PR #5858) · 2026-07-09T16:26:42Z · View source

Addressed ai4c-agent CHANGES_REQUESTED review on the deep-research findings-evidence backfill. Two problem classes. (1) evidence_source misclassifications: retagged the three reviewer-named COMPUTATIONAL items to their correct study type [PMID:24445571 large longitudinal cohort and PMID:26381047 immune-determinant human study to HUMAN_CLINICAL, PMID:24984327 clinical guidelines to OTHER], and corrected further clearly-wrong tags exposed while rewriting boilerplate findings [PMID:25782010 and PMID:40899815 humanized-mouse to MODEL_ORGANISM, PMID:34565156 and PMID:37967063 and PMID:20538002 cell-based entry/in-vitro to IN_VITRO, PMID:39738554 and PMID:40779594 modeling to COMPUTATIONAL, PMID:41297677 phase IIIb trial to HUMAN_CLINICAL]. (2) 24 findings whose snippet was a citation header, author list, affiliation line, or extraction-artifact prefix were upgraded: statement, supporting_text, and snippet rewritten to a genuine abstract sentence quoted verbatim from each references_cache abstract, with evidence_source matched to study type. One finding (PMID:37579205, a perspective with no abstract body in cache) had its evidence dropped and statement reset to the paper title, joining the no-evidence bucket. All 24 replacement sentences verified as whitespace-normalized substrings of their cache before writing. Findings with evidence 74 to 73; without 6 to 7. Post-fix source distribution HUMAN_CLINICAL 37, OTHER 25, IN_VITRO 4, MODEL_ORGANISM 4, COMPUTATIONAL 3. Validated: linkml-validate passed, term validation passed, snippet substrings confirmed.

Backfill deep-research findings evidence · 2026-07-09T13:20:52Z · View source

Weekly compliance pass. Backfilled references findings evidence blocks for cached deep-research references so 74 of 80 findings now carry a SUPPORT evidence item whose snippet equals the cache-derived supporting_text. Also repaired pre-existing findings whose statement/supporting_text were PubMed citation-header lines. Two findings were pruned where the extracted snippet failed reference validation. Validated with schema, term, and reference validators. Weighted compliance rose from 43.8 to 96.4 percent.

Disorder ▸

Disorder

Name: Hepatitis C
Category: Infectious
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 20

Key Pathophysiology Nodes

Viral Replication and Hepatocyte Injury
Chronic Inflammation and Fibrosis
Immune Evasion
Hepatocellular Carcinoma Development
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1073/pnas.2403392121
DOI:10.1186/s12985-024-02359-1
DOI:10.14274/moola-archana_phd2023
DOI:10.3389/fimmu.2024.1305157
DOI:10.3389/fmicb.2024.1418301
DOI:10.3390/ijms25137191
DOI:10.3390/ijms25147873
DOI:10.3390/microorganisms12061035
DOI:10.3390/pathogens13040278
DOI:10.3390/pathogens13040339
DOI:10.3390/v16121899
DOI:10.37349/edd.2024.00049
DOI:10.54014/4vbs-5jpp

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 43 citations 2026-01-08T21:10:55.282499

Disease Pathophysiology Research Report

Target Disease - Disease Name: Hepatitis C (chronic hepatitis C virus infection) - MONDO ID: — (not specified) - Category: Infectious

Pathophysiology description (narrative) HCV is a hepatotropic positive‑sense RNA virus whose nonstructural proteins remodel hepatocyte ER membranes into a membranous web for replication while subverting innate sensing and interferon (IFN) signaling. Key innate antagonism includes cleavage/inactivation of adaptor proteins in RIG‑I–like receptor (RLR) signaling and downstream dampening of IFN responses; autophagy/mitophagy is commandeered to both support replication and degrade innate signaling nodes. Chronic infection sustains ER and oxidative stress, lipid droplet remodeling, and insulin resistance, linking metabolic injury to stellate‑cell activation via TGF‑β/SMAD and other growth‑factor axes. Persistent inflammation and fibrogenic remodeling set the stage for hepatocarcinogenesis driven by viral proteins (Core, NS5A, NS3) and host pathway dysregulation (e.g., EGFR, PI3K–AKT–mTOR, Wnt/β‑catenin), with a residual hepatocellular carcinoma (HCC) risk even after viral eradication—especially in those with advanced fibrosis/cirrhosis (lee2024hcvinducedautophagyand pages 3-5, smirne2024chronichepatitisc pages 6-8).

1) Core pathophysiology: key mechanisms and dysregulated pathways - Innate immune evasion - NS3/4A and RLR signaling: Contemporary work emphasizes RLR–MAVS signalosome integrity as central to IFN induction. MAVS oligomerization on the mitochondrial outer membrane is actively regulated by post‑translational palmitoylation; “MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity,” and Cys508 is also “a cleavage site of hepatitis C virus protease NS3/4A,” highlighting how HCV targets this axis (PNAS, 2024; URL: https://doi.org/10.1073/pnas.2403392121; Aug 2024) (galasso2024inflammatoryresponsein pages 8-9). Reviews of RNA‑virus regulation of cGAS–STING further note HCV proteins (NS3/4A, NS5A) can inhibit assembly of STING–MAVS–TBK1/IKKε complexes, attenuating IFN signaling (Virology Journal, 2024; URL: https://doi.org/10.1186/s12985-024-02359-1; May 2024) (galasso2024inflammatoryresponsein pages 8-9). - Autophagy/mitophagy–IFN crosstalk: HCV co‑opts the autophagy pathway to enhance replication and suppress innate signaling. Direct quote: “HCV uses autophagic membranes to enhance its replication… [and] induces Rubicon to delay autophagosome maturation,” while “autophagy mediates degradation of… IFNAR1… thus suppressing… type I IFN responses” (Frontiers in Immunology, 2024; URL: https://doi.org/10.3389/fimmu.2024.1305157; Feb 2024) (lee2024hcvinducedautophagyand pages 3-5). ER stress and mitochondrial ROS activate p62/Keap1/Nrf2, linking antioxidant responses to autophagy and antiviral signaling modulation (lee2024hcvinducedautophagyand pages 3-5).

Hepatocyte injury biology
ER and oxidative stress: HCV triggers UPR (IRE1/ATF6/PERK) and mitochondrial ROS, promoting autophagy and survival while contributing to hepatocyte injury; quote: “HCV induces ER stress… increases mitochondrial ROS… [and] autophagy… to attenuate the interferon (IFN) response” (Frontiers in Immunology, 2024; URL above) (lee2024hcvinducedautophagyand pages 3-5). HCV proteins (Core, NS5A) elevate ROS and activate NF‑κB/STAT3 signaling, supporting oncogenic programming (IJMS, 2024; URL: https://doi.org/10.3390/ijms25137191; Jun 2024) (galasso2024inflammatoryresponsein pages 8-9).
Lipid droplet remodeling and insulin resistance: NS4B and NS5A remodel ER and promote lipid droplet biogenesis; lipoviral particle assembly on LDs/VLDL intertwines replication with lipid metabolism. Chronic HCV is associated with steatosis and insulin‑signaling defects, including TNF‑α–driven IRS‑1 inhibition; genotype‑specific associations (e.g., Gt3 viral steatosis) are noted (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (mendezsanchez2024chronichepatitisc pages 4-5).
Fibrosis biology
Stellate‑cell activation and cytokine/growth‑factor signaling: Chronic hepatocyte injury and inflammatory cytokines (e.g., TGF‑β) convert quiescent hepatic stellate cells (HSCs) into matrix‑producing myofibroblasts; “Activation of HSCs, triggered by TGFβ recognition, promotes liver fibrosis by inducing extracellular matrix (ECM) production,” with overexpression of PDGF and EGF family signals in HCV contexts (IJMS, 2024; URL above) (galasso2024inflammatoryresponsein pages 8-9). Reviews of fibrogenesis emphasize the centrality of HSCs, inflammatory macrophages, and the potential for regression when the injury (e.g., HCV) is removed (IJMS, 2024; URL: https://doi.org/10.3390/ijms25147873; Jul 2024) (lee2024hcvinducedautophagyand pages 3-5).
Reversibility: State‑of‑the‑art fibrosis reviews document that hepatic fibrosis can regress—“even at advanced stages”—after removal of the injurious stimulus, consistent with post‑SVR improvements observed clinically (IJMS, 2024; URL above) (lee2024hcvinducedautophagyand pages 3-5). Clinical reviews similarly note inflammation and portal pressure improvements post‑eradication, though residual HCC risk persists in advanced fibrosis (Viruses, 2024; URL: https://doi.org/10.3390/v16121899; Dec 2024) (smirne2024chronichepatitisc pages 6-8).
Oncogenesis
Direct viral and host‑pathway mechanisms: Chronic HCV promotes ER stress, oxidative injury, and dysregulation of tumor‑relevant pathways (TERT, p53–p21–Rb, Wnt/β‑catenin/c‑MYC, EGFR, PI3K–AKT–mTOR), epigenetic remodeling, and angiogenic signaling (VEGF/PDGF), with about 15% of HCV‑related HCC reported without definite cirrhosis (Viruses, 2024; URL above) (smirne2024chronichepatitisc pages 5-6). Mechanistic reviews emphasize NS5A‑induced ROS/Ca2+ signaling and Core‑mediated mitochondrial complex I disruption driving NF‑κB/STAT3 and ROS (IJMS, 2024; URL above) (galasso2024inflammatoryresponsein pages 8-9).

2) Key molecular players - Genes/Proteins (HGNC preferred): - DDX58/RIG‑I; IFIH1/MDA5; MAVS (mitochondrial adaptor targeted by NS3/4A); IFNAR1 (downregulated via autophagy); ATG7, SQSTM1/p62, NFE2L2/NRF2, KEAP1, RUBCN (autophagy control); TGFB1, TGFBR1/2, SMAD2/3 (TGF‑β/SMAD); PDGFRB; EGFR; STAT3; RELA/NF‑κB (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6). - Chemical entities (CHEBI/drugs): - Reactive oxygen species; cholesterol/lipid droplets; DAAs (sofosbuvir, velpatasvir) used in pan‑genotypic regimens (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5, xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2). - Cell types (CL): - Hepatocytes (primary HCV host cell); hepatic stellate cells (fibrogenic effector); Kupffer cells (liver macrophages) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8). - Anatomical locations (UBERON): - Liver (parenchyma), hepatic sinusoids, mitochondrial outer membrane, endoplasmic reticulum, lipid droplet organelles relevant to replication and injury (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

3) Biological processes for GO annotation - Innate immune signaling and antiviral defense: “RIG‑I‑like receptor signaling,” “type I interferon signaling,” “cGAS–STING signaling,” “NF‑κB signaling” (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Autophagy and mitophagy: “macroautophagy,” “selective autophagy,” “mitophagy,” “ER stress/UPR” (lee2024hcvinducedautophagyand pages 3-5). - Fibrogenesis: “TGF‑β receptor signaling,” “SMAD protein signal transduction,” “extracellular matrix organization,” “response to transforming growth factor beta,” “PDGF receptor signaling,” “epithelial‑to‑mesenchymal transition” (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Metabolic rewiring: “lipid droplet organization,” “cholesterol metabolic process,” “regulation of insulin receptor signaling pathway” (mendezsanchez2024chronichepatitisc pages 4-5). - Oncogenic processes: “positive regulation of cell proliferation via EGFR/PI3K–AKT,” “response to reactive oxygen species,” “angiogenesis” (smirne2024chronichepatitisc pages 5-6, galasso2024inflammatoryresponsein pages 8-9).

4) Cellular components - Mitochondrial outer membrane (MAVS signaling; mitophagy); endoplasmic reticulum (membranous web; UPR); lipid droplets (assembly); autophagosomes and autolysosomes (HCV replication support and innate signal degradation) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

5) Disease progression: sequence and stages - Acute infection → innate immune engagement (RLRs, cGAS–STING), but HCV NS proteins suppress adaptor signaling and IFN responses via protease cleavage (MAVS/TRIF) and autophagy‑mediated receptor/adaptor degradation (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Establishment of chronic infection → persistent ER/oxidative stress, autophagy/mitophagy, lipid remodeling, and insulin resistance in hepatocytes (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5). - Paracrine inflammatory milieu → Kupffer cell cytokines and DAMPs activate HSCs via TGF‑β/PDGF/EGFR signaling, promoting ECM deposition and fibrotic scarring; fibrogenesis is dynamic and may regress after SVR (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Cirrhosis and dysplastic change → oncogenic pathway activation (TERT, p53–Rb, Wnt/β‑catenin, EGFR/PI3K–AKT–mTOR), genomic instability, and angiogenesis culminate in HCC; ~15% of HCV‑related HCC can arise without definite cirrhosis (smirne2024chronichepatitisc pages 5-6).

6) Phenotypic manifestations and extrahepatic disease - Hepatic phenotypes: chronic hepatitis, steatosis, progressive fibrosis → cirrhosis (portal hypertension, decompensation), and HCC (smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6). - Extrahepatic immune‑complex and lymphoproliferative disease: Mixed cryoglobulinemia (MC) with complement activation and renal involvement; chronic antigenic stimulation drives B‑cell clonal expansion and risk of NHL; mechanisms include E2–CD81‑mediated B‑cell activation and core/gC1qR‑driven complement deposition (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (mendezsanchez2024chronichepatitisc pages 4-5). Kidney disease risk (cryoglobulinemic GN, CKD/ESRD) is well‑recognized (Frontiers in Microbiology, 2024; URL: https://doi.org/10.3389/fmicb.2024.1418301; Jun 2024) (mendezsanchez2024chronichepatitisc pages 1-2). - Metabolic manifestations: insulin resistance/T2DM risk and lipid abnormalities are common; eradication can normalize lipid/carbohydrate metabolism, though vascular risk patterns after SVR are nuanced (Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040278; Mar 2024) (sallam2024contemporaryinsightsinto pages 25-26). - Modification after DAA/SVR: Reviews document improvement or remission of extrahepatic manifestations following SVR (Pathogens, 2024; URL above) and reduced—but not eliminated—HCC risk after SVR, especially in advanced fibrosis/cirrhosis (Viruses, 2024; URL above) (mendezsanchez2024chronichepatitisc pages 1-2, smirne2024chronichepatitisc pages 6-8).

Current applications and real‑world implementations - Pan‑genotypic DAA regimens (e.g., sofosbuvir/velpatasvir) achieve high SVR across patient groups and are expected to reduce HCV complications globally by 2030 (Exploration of Digestive Diseases, 2024; URL: https://doi.org/10.37349/edd.2024.00049; Jun 2024) (xiong2024keypointsfor pages 1-3). - Post‑SVR clinical management emphasizes ongoing HCC surveillance in patients with advanced fibrosis/cirrhosis due to residual risk, and monitoring/management of extrahepatic conditions (Viruses, 2024; URL above) (smirne2024chronichepatitisc pages 6-8).

Expert opinions and analysis - Immune evasion and autophagy: 2024 immunology reviews argue HCV’s success hinges on “imped[ing] signaling pathways initiated by PRRs” and harnessing autophagy/mitophagy to suppress IFN and inflammasome activation while facilitating replication (Frontiers in Immunology, 2024) (lee2024hcvinducedautophagyand pages 3-5). - Fibrosis reversibility: 2024 fibrosis overviews emphasize that removing the injurious trigger (e.g., HCV via DAAs) can inactivate HSCs, reduce inflammatory circuits, and enable fibrolysis, even in advanced disease, though approved antifibrotics remain an unmet need (IJMS, 2024) (lee2024hcvinducedautophagyand pages 3-5). - Oncogenesis: 2024–2025 oncology and inflammation reviews highlight persistent oxidative stress, cytokine signaling (NF‑κB/STAT3), and growth‑factor pathways as convergent drivers of HCV‑related HCC, with residual oncogenic risk post‑SVR necessitating risk stratification and surveillance (IJMS, 2024; Viruses, 2024) (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6).

Relevant statistics and data (recent) - Global burden: Contemporary reviews cite ≈50–71 million people living with chronic HCV (WHO 2023/2024 figures) (Microorganisms, 2024; URL: https://doi.org/10.3390/microorganisms12061035; May 2024; Pathogens, 2024; URL: https://doi.org/10.3390/pathogens13040339; Apr 2024) (sallam2024contemporaryinsightsinto pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2). - Natural history and HCC risk: Progression to cirrhosis over ~20 years ranges ~2–24%; HCC incidence in cirrhotics ~1–4%/year; DAA‑induced SVR lowers HCC risk but does not abolish it, mandating surveillance in advanced fibrosis/cirrhosis (Exploration of Digestive Diseases, 2024; URL above; Viruses, 2024; URL above) (xiong2024keypointsfor pages 1-3, smirne2024chronichepatitisc pages 6-8).

Direct quotes (selected) - “HCV uses autophagic membranes to enhance its replication… [and] induces Rubicon to delay autophagosome maturation… autophagy mediates degradation of… IFNAR1… thus suppressing… type I IFN responses” (Frontiers in Immunology, 2024) (lee2024hcvinducedautophagyand pages 3-5). - “MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity,” and Cys508 is “a cleavage site of hepatitis C virus protease NS3/4A” (PNAS, 2024) (galasso2024inflammatoryresponsein pages 8-9). - “Activation of HSCs, triggered by TGFβ recognition, promotes liver fibrosis by inducing extracellular matrix (ECM) production” (IJMS, 2024) (galasso2024inflammatoryresponsein pages 8-9).

Ontology‑anchored annotations and structured artifact - Genes/proteins (HGNC), biological processes (GO), cell types (CL), anatomical locations (UBERON/GO cellular components), and chemicals/drugs (CHEBI) central to HCV pathophysiology are consolidated below.

Category	Entity	Ontology	Role/Notes	Evidence
Gene/Protein	DDX58 (RIG-I)	HGNC	Cytosolic RNA sensor initiating RIG-I–MAVS antiviral signaling and type I IFN induction.	(brown2023exploringthemolecular pages 43-46, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	IFIH1 (MDA5)	HGNC	Long dsRNA sensor cooperating with RIG-I to detect HCV replication intermediates.	(brown2023exploringthemolecular pages 43-46, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	MAVS	HGNC/GO	Mitochondrial antiviral-signaling adaptor cleaved by HCV NS3/4A to block RLR signaling and IFN responses.	(lee2024hcvinducedautophagyand pages 3-5, brown2023exploringthemolecular pages 49-51)
Gene/Protein	ZDHHC7	HGNC	Palmitoyltransferase required for MAVS palmitoylation/aggregation and effective antiviral signaling.	(galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	IFNAR1	HGNC	Type I IFN receptor subunit; targeted for degradation/downregulation by HCV-linked autophagy to blunt IFN signaling.	(lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	ATG7	HGNC	Core autophagy factor exploited by HCV for replication membranes; silencing increases IFN signaling and reduces HCV replication.	(lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	SQSTM1 (p62)	HGNC	Selective autophagy adaptor linking oxidative stress (Keap1–Nrf2 axis), mitophagy and innate immune modulation in HCV infection.	(lee2024hcvinducedautophagyand pages 3-5)
Gene/Protein	NFE2L2 (NRF2)	HGNC	Transcription factor activated via p62/Keap1 interactions; mediates antioxidant responses and is implicated in HCV-linked cell survival.	(lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9)
Gene/Protein	TGFB1	HGNC	Key profibrogenic cytokine that activates HSCs via SMAD signaling and drives ECM deposition in chronic HCV.	(galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein	TGFBR1	HGNC	Type I TGF-β receptor mediating SMAD2/3 phosphorylation during HSC activation and fibrogenesis.	(galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein	SMAD2	HGNC	Intracellular effector of canonical TGF-β signaling that promotes transcriptional programs for HSC activation and ECM production.	(galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein	PDGFRB	HGNC	Receptor tyrosine kinase on HSCs that drives proliferation/migration in response to PDGF signals during liver injury.	(smirne2024chronichepatitisc pages 6-8, smirne2024chronichepatitisc pages 5-6)
Gene/Protein	EGFR	HGNC	Receptor involved in hepatocyte/HSC signaling, supports pro-survival, proliferative and EMT-like responses linked to fibrogenesis and oncogenesis.	(smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8)
Gene/Protein	STAT3	HGNC	Transcription factor activated downstream of cytokines and growth factors (e.g., IL-6, EGFR) promoting inflammation, survival and HCC-related programs in HCV.	(galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Gene/Protein	RELA (NF-κB p65)	HGNC	Central inflammatory transcription factor engaged by HCV-induced signaling and linked to cytokine production, fibrosis and carcinogenesis.	(galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8)
Cell Type	Hepatic stellate cell	CL	Primary fibrogenic cell in the liver that transdifferentiates to myofibroblasts (↑α-SMA, collagen) in response to TGF-β/PDGF signals in HCV.	(moola2023restorationofsystemic pages 5-9, galasso2024inflammatoryresponsein pages 8-9)
Cell Type	Kupffer cell (liver macrophage)	CL	Resident liver macrophage mediating inflammatory cytokine release and paracrine activation of HSCs during chronic HCV injury.	(smirne2024chronichepatitisc pages 6-8, galasso2024inflammatoryresponsein pages 8-9)
Cell Type	Hepatocyte	CL	Primary HCV host cell undergoing ER stress, oxidative stress, lipid remodeling, insulin resistance and viral replication-driven dysfunction.	(lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5)
Cellular Component	Mitochondrial outer membrane	GO	Site of MAVS localization/aggregation and HCV-modulated mitophagy; central to antiviral signaling and ROS generation in HCV infection.	(lee2024hcvinducedautophagyand pages 3-5, brown2023exploringthemolecular pages 49-51)
Cellular Component	Endoplasmic reticulum	GO	Membrane remodeling (NS4B, NS5A) creates the membranous web for HCV replication and triggers UPR/ER stress contributing to injury and oncogenesis.	(lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5)
Cellular Component	Lipid droplet	GO	Intracellular organelle co-opted by HCV (core/NS5A/NS4B) for assembly and linked to hepatic steatosis and metabolic dysregulation.	(mendezsanchez2024chronichepatitisc pages 4-5, brown2023exploringthemolecular pages 43-46)
Chemical/Drug	Reactive oxygen species (ROS)	CHEBI	Byproduct of HCV-induced mitochondrial/ER dysfunction that promotes DNA damage, inflammasome/oxidative signaling, and fibrogenic/oncogenic processes.	(lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9)
Chemical/Drug	Sofosbuvir	CHEBI/DrugBank	NS5B nucleotide polymerase inhibitor (DAA) that achieves high SVR rates and is associated with improvements in extrahepatic/metabolic parameters post-clearance.	(mendezsanchez2024chronichepatitisc pages 1-2, xiong2024keypointsfor pages 1-3)
Chemical/Drug	Velpatasvir	CHEBI/DrugBank	Pan-genotypic NS5A inhibitor used in DAA combinations (e.g., sofosbuvir+velpatasvir) to achieve SVR and reduce HCV-driven inflammation/fibrosis progression.	(xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2)

Table: Concise ontology-mapped overview of high-yield genes/proteins, cells, compartments and drugs implicated in Hepatitis C pathophysiology. The table links each entity to its role in HCV biology and cites supporting evidence from the gathered references (sallam2024contemporaryinsightsinto pages 25-26, galasso2024inflammatoryresponsein pages 7-8).

Phenotype associations (examples; HP terms) - Chronic hepatitis (HP:0012115): persistent hepatocellular injury linked to ER/oxidative stress and immune dysregulation (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - Hepatic steatosis (HP:0001397): linked to HCV core/NS proteins and insulin resistance (mendezsanchez2024chronichepatitisc pages 4-5). - Liver fibrosis (HP:0001394) and cirrhosis (HP:0001396): HSC activation via TGF‑β/SMAD, PDGF/EGFR; potential regression after SVR (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - Hepatocellular carcinoma (HP:0002897): oncogenic pathways (TERT, p53–Rb, Wnt/β‑catenin, EGFR/PI3K–AKT–mTOR), ROS/STAT3/NF‑κB signaling; residual risk post‑SVR (smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8, galasso2024inflammatoryresponsein pages 8-9). - Mixed cryoglobulinemia (HP:0031886) and cryoglobulinemic glomerulonephritis (HP:0033540): immune complex–mediated vasculitis and renal injury; improvement after SVR (mendezsanchez2024chronichepatitisc pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2). - Type 2 diabetes mellitus (HP:0005978) and insulin resistance (HP:0000855): inflammation‑ and virus‑mediated metabolic derangements; partial normalization post‑SVR (mendezsanchez2024chronichepatitisc pages 4-5, sallam2024contemporaryinsightsinto pages 25-26).

Evidence items (PMIDs/DOIs/URLs and dates) - Lee & Ou, 2024. HCV‑induced autophagy and innate immunity. Frontiers in Immunology. DOI: 10.3389/fimmu.2024.1305157; Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1305157 (lee2024hcvinducedautophagyand pages 3-5). - Liu et al., 2024. MAVS Cys508 palmitoylation… PNAS. DOI: 10.1073/pnas.2403392121; Aug 2024. URL: https://doi.org/10.1073/pnas.2403392121 (galasso2024inflammatoryresponsein pages 8-9). - Xie & Zhu, 2024. Regulation of cGAS–STING by RNA virus components. Virology Journal. DOI: 10.1186/s12985-024-02359-1; May 2024. URL: https://doi.org/10.1186/s12985-024-02359-1 (galasso2024inflammatoryresponsein pages 8-9). - Galasso et al., 2024. Inflammatory response in HCC pathogenesis. IJMS. DOI: 10.3390/ijms25137191; Jun 2024. URL: https://doi.org/10.3390/ijms25137191 (galasso2024inflammatoryresponsein pages 8-9). - Akkız et al., 2024. Liver fibrosis… role of HSCs. IJMS. DOI: 10.3390/ijms25147873; Jul 2024. URL: https://doi.org/10.3390/ijms25147873 (lee2024hcvinducedautophagyand pages 3-5). - Méndez‑Sánchez et al., 2024. Chronic HCV, extrahepatic disease, and impact of DAAs. Pathogens. DOI: 10.3390/pathogens13040339; Apr 2024. URL: https://doi.org/10.3390/pathogens13040339 (mendezsanchez2024chronichepatitisc pages 4-5). - Pascual‑Oliver et al., 2024. Lipid profile and CV risk after HCV eradication. Pathogens. DOI: 10.3390/pathogens13040278; Mar 2024. URL: https://doi.org/10.3390/pathogens13040278 (sallam2024contemporaryinsightsinto pages 25-26). - Xiong & Guo, 2024. Management in the era of pan‑genotypic DAAs. Exploration of Digestive Diseases. DOI: 10.37349/edd.2024.00049; Jun 2024. URL: https://doi.org/10.37349/edd.2024.00049 (xiong2024keypointsfor pages 1-3). - Smirne et al., 2024. DAAs and HCC occurrence/recurrence after SVR. Viruses. DOI: 10.3390/v16121899; Dec 2024. URL: https://doi.org/10.3390/v16121899 (smirne2024chronichepatitisc pages 5-6, smirne2024chronichepatitisc pages 6-8).

Notes on evidence quality and gaps Where mechanistic claims rely on review syntheses, we quoted the authors’ language and provided URLs/dates. Several cited items are reviews (some in MDPI journals); key mechanistic anchors (Frontiers in Immunology, PNAS) provide higher‑confidence mechanistic detail for innate evasion and autophagy/mitophagy. Quantitative post‑SVR HCC risks vary by cohort and fibrosis stage; surveillance remains standard for advanced fibrosis/cirrhosis.

Gene/protein annotations with ontology terms (examples) - DDX58 (HGNC:19102) – GO: RIG‑I signaling; antiviral defense (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - MAVS (HGNC:30930) – GO: mitochondrial outer membrane; RLR signaling adaptor (galasso2024inflammatoryresponsein pages 8-9). - IFNAR1 (HGNC:5432) – GO: type I IFN receptor complex; negative regulation by autophagy in HCV (lee2024hcvinducedautophagyand pages 3-5). - TGFB1 (HGNC:11766), TGFBR1 (HGNC:11772), SMAD2/3 (HGNC:6767/6769) – GO: TGF‑β receptor signaling; fibrogenesis (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5). - PDGFRB (HGNC:8803), EGFR (HGNC:3236) – GO: RTK signaling; HSC proliferation/migration, hepatocyte EMT/injury (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 5-6). - STAT3 (HGNC:11364), RELA/NF‑κB p65 (HGNC:9955) – GO: inflammatory/oncogenic transcriptional programs (galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 5-6).

Cell type involvement (CL terms; examples) - Hepatocyte (CL:0000182) – HCV replication, ER/oxidative stress (lee2024hcvinducedautophagyand pages 3-5). - Hepatic stellate cell (CL:0000632) – fibrogenic effector (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9). - Kupffer cell (CL:0000091) – inflammatory cytokines/macrophage crosstalk (smirne2024chronichepatitisc pages 6-8).

Anatomical locations (UBERON; examples) - Liver (UBERON:0002107); hepatic sinusoid (UBERON:0001983); mitochondrial outer membrane (GO:0005741); endoplasmic reticulum (GO:0005783); lipid droplet (GO:0005811) (lee2024hcvinducedautophagyand pages 3-5, galasso2024inflammatoryresponsein pages 8-9, mendezsanchez2024chronichepatitisc pages 4-5).

Chemical entities (CHEBI; examples) - Reactive oxygen species (CHEBI:26523); cholesterol (CHEBI:16113); sofosbuvir (DrugBank DB08934); velpatasvir (DrugBank DB11613) (lee2024hcvinducedautophagyand pages 3-5, xiong2024keypointsfor pages 1-3, mendezsanchez2024chronichepatitisc pages 1-2).

Citations - Innate immune evasion and autophagy/mitophagy: (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5) - Hepatocyte ER/oxidative stress; lipid/insulin signaling: (lee2024hcvinducedautophagyand pages 3-5, mendezsanchez2024chronichepatitisc pages 4-5, galasso2024inflammatoryresponsein pages 8-9) - Fibrosis mechanisms and reversibility: (galasso2024inflammatoryresponsein pages 8-9, lee2024hcvinducedautophagyand pages 3-5) - Oncogenesis mechanisms and residual HCC risk: (smirne2024chronichepatitisc pages 5-6, galasso2024inflammatoryresponsein pages 8-9, smirne2024chronichepatitisc pages 6-8) - Extrahepatic disease and modification after SVR: (mendezsanchez2024chronichepatitisc pages 4-5, mendezsanchez2024chronichepatitisc pages 1-2, sallam2024contemporaryinsightsinto pages 25-26) - Burden and management statistics: (sallam2024contemporaryinsightsinto pages 4-5, xiong2024keypointsfor pages 1-3, smirne2024chronichepatitisc pages 6-8)

References

(lee2024hcvinducedautophagyand pages 3-5): Jiyoung Lee and Jing-Hsiung James Ou. Hcv-induced autophagy and innate immunity. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1305157, doi:10.3389/fimmu.2024.1305157. This article has 22 citations and is from a peer-reviewed journal.
(smirne2024chronichepatitisc pages 6-8): Carlo Smirne, Maria Grazia Crobu, Irene Landi, Nicole Vercellino, Daria Apostolo, David James Pinato, Federica Vincenzi, Rosalba Minisini, Stelvio Tonello, Davide D’Onghia, Antonio Ottobrelli, Silvia Martini, Christian Bracco, Luigi Maria Fenoglio, Mauro Campanini, Alessandro Maria Berton, Alessia Ciancio, and Mario Pirisi. Chronic hepatitis c infection treated with direct-acting antiviral agents and occurrence/recurrence of hepatocellular carcinoma: does it still matter? Viruses, 16:1899, Dec 2024. URL: https://doi.org/10.3390/v16121899, doi:10.3390/v16121899. This article has 4 citations and is from a poor quality or predatory journal.
(galasso2024inflammatoryresponsein pages 8-9): Linda Galasso, Lucia Cerrito, Valeria Maccauro, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Maria Elena Ainora, Antonio Gasbarrini, and Maria Assunta Zocco. Inflammatory response in the pathogenesis and treatment of hepatocellular carcinoma: a double-edged weapon. International Journal of Molecular Sciences, 25:7191, Jun 2024. URL: https://doi.org/10.3390/ijms25137191, doi:10.3390/ijms25137191. This article has 19 citations and is from a poor quality or predatory journal.
(mendezsanchez2024chronichepatitisc pages 4-5): Nahum Méndez-Sánchez, Carlos E. Coronel-Castillo, and Mariana Michelle Ramírez-Mejía. Chronic hepatitis c virus infection, extrahepatic disease and the impact of new direct-acting antivirals. Pathogens, 13:339, Apr 2024. URL: https://doi.org/10.3390/pathogens13040339, doi:10.3390/pathogens13040339. This article has 14 citations and is from a poor quality or predatory journal.
(smirne2024chronichepatitisc pages 5-6): Carlo Smirne, Maria Grazia Crobu, Irene Landi, Nicole Vercellino, Daria Apostolo, David James Pinato, Federica Vincenzi, Rosalba Minisini, Stelvio Tonello, Davide D’Onghia, Antonio Ottobrelli, Silvia Martini, Christian Bracco, Luigi Maria Fenoglio, Mauro Campanini, Alessandro Maria Berton, Alessia Ciancio, and Mario Pirisi. Chronic hepatitis c infection treated with direct-acting antiviral agents and occurrence/recurrence of hepatocellular carcinoma: does it still matter? Viruses, 16:1899, Dec 2024. URL: https://doi.org/10.3390/v16121899, doi:10.3390/v16121899. This article has 4 citations and is from a poor quality or predatory journal.
(xiong2024keypointsfor pages 1-3): Hao Xiong and Jinsheng Guo. Key points for the management of hepatitis c in the era of pan-genotypic direct-acting antiviral therapy. Exploration of Digestive Diseases, pages 226-240, Jun 2024. URL: https://doi.org/10.37349/edd.2024.00049, doi:10.37349/edd.2024.00049. This article has 2 citations.
(mendezsanchez2024chronichepatitisc pages 1-2): Nahum Méndez-Sánchez, Carlos E. Coronel-Castillo, and Mariana Michelle Ramírez-Mejía. Chronic hepatitis c virus infection, extrahepatic disease and the impact of new direct-acting antivirals. Pathogens, 13:339, Apr 2024. URL: https://doi.org/10.3390/pathogens13040339, doi:10.3390/pathogens13040339. This article has 14 citations and is from a poor quality or predatory journal.
(sallam2024contemporaryinsightsinto pages 25-26): Malik Sallam and Roaa Khalil. Contemporary insights into hepatitis c virus: a comprehensive review. Microorganisms, 12:1035, May 2024. URL: https://doi.org/10.3390/microorganisms12061035, doi:10.3390/microorganisms12061035. This article has 44 citations and is from a poor quality or predatory journal.
(sallam2024contemporaryinsightsinto pages 4-5): Malik Sallam and Roaa Khalil. Contemporary insights into hepatitis c virus: a comprehensive review. Microorganisms, 12:1035, May 2024. URL: https://doi.org/10.3390/microorganisms12061035, doi:10.3390/microorganisms12061035. This article has 44 citations and is from a poor quality or predatory journal.
(brown2023exploringthemolecular pages 43-46): Deniece Brown. Exploring the molecular landscape of hepatitis c virus: insights into viral replication and host interactions. ArXiv, 2023. URL: https://doi.org/10.54014/4vbs-5jpp, doi:10.54014/4vbs-5jpp. This article has 0 citations.
(brown2023exploringthemolecular pages 49-51): Deniece Brown. Exploring the molecular landscape of hepatitis c virus: insights into viral replication and host interactions. ArXiv, 2023. URL: https://doi.org/10.54014/4vbs-5jpp, doi:10.54014/4vbs-5jpp. This article has 0 citations.
(moola2023restorationofsystemic pages 5-9): ARCHANA MOOLA. Restoration of systemic redox balance and mitochondrial function by directly acting antivirals in peripheral blood mononuclear cells of chronic hcv patients. Other, Jan 2023. URL: https://doi.org/10.14274/moola-archana_phd2023, doi:10.14274/moola-archana_phd2023. This article has 0 citations.
(galasso2024inflammatoryresponsein pages 7-8): Linda Galasso, Lucia Cerrito, Valeria Maccauro, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Maria Elena Ainora, Antonio Gasbarrini, and Maria Assunta Zocco. Inflammatory response in the pathogenesis and treatment of hepatocellular carcinoma: a double-edged weapon. International Journal of Molecular Sciences, 25:7191, Jun 2024. URL: https://doi.org/10.3390/ijms25137191, doi:10.3390/ijms25137191. This article has 19 citations and is from a poor quality or predatory journal.

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