Hepatitis C virus

Hepatitis C virus (HCV) is a small, enveloped, positive-sense RNA virus in the family Flaviviridae that establishes chronic infection in around three-quarters of those exposed and is a leading global cause of cirrhosis and hepatocellular carcinoma. Around 50 million people are living with chronic hepatitis C worldwide. The virus was molecularly cloned in 1989, ending a fifteen-year quest to identify the agent of “non-A non-B hepatitis”; the discovery work was recognised with the 2020 Nobel Prize in Physiology or Medicine. HCV is the only major chronic viral infection of humans for which a single short course of oral therapy now reliably achieves cure: pan-genotypic direct-acting antiviral (DAA) regimens cure over 95 per cent of patients in 8 to 12 weeks, and have placed elimination on the public-health agenda. There is no vaccine, and there is unlikely to be one in the near term, because the envelope glycoproteins mutate continuously under immune pressure and the virus circulates as a swarm of quasispecies. The clinical burden is concentrated in people who inject drugs, recipients of unscreened blood products before universal screening, and populations with unsafe medical injection practices, with sub-Saharan Africa, Eastern Europe, and parts of Asia carrying the largest share of undiagnosed infections.

Discovery and historical significance

For most of the 1970s and 1980s, “non-A non-B hepatitis (NANBH)” was a frustrating clinical entity: an agent of post-transfusion chronic hepatitis that could be transmitted in blood, that produced cirrhosis and hepatocellular carcinoma over decades, and that could not be identified despite intensive effort. Harvey J. Alter at the US National Institutes of Health led the pivotal prospective cohort studies in transfusion recipients that established NANBH as a distinct entity, separable from hepatitis A and hepatitis B, and demonstrated its capacity to chronic chronicity.

The molecular breakthrough came in 1989. Michael Houghton and colleagues at Chiron Corporation (with Qui-Lim Choo, George Kuo, and Daniel Bradley) screened a complementary DNA library constructed from infected chimpanzee plasma against antibodies in serum from a chronic NANBH patient. They identified a single positive clone, designated 5-1-1, which proved to encode part of the NS4 region of a previously unknown positive-strand RNA virus. The discovery was reported in Science in April 1989 and named hepatitis C virus.

Charles M. Rice at Washington University (later Rockefeller University) then established that the cloned HCV genome was functionally infectious: a series of full-length HCV cDNA constructs produced viable infection in chimpanzees, definitively attributing NANBH to HCV. Rice’s later development of the subgenomic replicon system (with Volker Lohmann) and the JFH-1 cell-culture system (with Takaji Wakita) made HCV biology laboratory-tractable for the first time. This work underwrote the decade-long direct-acting antiviral drug development programme that transformed HCV from an incurable chronic infection to a curable one.

Alter, Houghton, and Rice were awarded the 2020 Nobel Prize in Physiology or Medicine “for the discovery of hepatitis C virus”, recognised for the discovery, the establishment of HCV as an infectious agent, and the development of the tools that enabled the DAA era.

The first DAAs licensed (boceprevir, telaprevir; 2011) targeted the NS3/4A protease but required combination with pegylated interferon and ribavirin. Sofosbuvir (NS5B nucleotide polymerase inhibitor; 2013) was the first all-oral interferon-free regimen anchor; pan-genotypic combinations (sofosbuvir / velpatasvir, glecaprevir / pibrentasvir) followed between 2016 and 2017. The WHO 2016 Global Health Sector Strategy on Viral Hepatitis set the goal of HCV elimination by 2030.

Classification, structure, and genome

Classification

HCV is the species Hepacivirus hominis in the genus Hepacivirus, family Flaviviridae. The family also contains the genus Flavivirus (dengue, yellow fever, Japanese encephalitis, West Nile, Zika) and the genus Pestivirus (bovine viral diarrhoea virus and related animal viruses). Hepaciviruses share the family-level features of enveloped positive-strand RNA virions with a single polyprotein open reading frame and an internal ribosome entry site, but differ from the classical flaviviruses in cell tropism, lipoprotein association, and use of NS3/4A rather than a separate NS2B/3 protease.

Eight major HCV genotypes are recognised (1 to 8), with around 30 to 35 per cent nucleotide divergence between genotypes and 20 to 25 per cent between subtypes within a genotype. The eighth genotype was characterised only in 2018 from a Punjabi Indian cohort. Genotype distribution is geographically structured: genotype 1 dominates in Europe, the Americas, and Australia; genotype 3 in South Asia; genotype 4 in Egypt and North Africa; genotype 6 in South-East Asia; and genotype 5 in southern Africa, where subtype 5a was first identified. Within a single infected host the virus also exists as a quasispecies swarm of closely related variants, dominated by sequence variation in the hypervariable region 1 (HVR1) of E2.

Genotype is clinically relevant for treatment selection in some jurisdictions, although pan-genotypic DAA regimens have reduced the role of routine pre-treatment genotyping in 2026. Genotype 3 is associated with more rapid fibrosis progression and a higher post-cure hepatocellular carcinoma risk than other genotypes.

Related viruses in the genus. The genus Hepacivirus contains other recognised species in horses (equine hepacivirus, the closest known relative of HCV), dogs (canine hepacivirus), rodents, bats, and several non-human primates. The hepaciviruses of horses and rodents are now used as small-animal models of HCV biology. The related pegivirus lineage (formerly GB virus C) infects humans but appears apathogenic.

Virion structure

The HCV virion is an enveloped particle of 55 to 65 nm diameter. Inside the envelope sits an icosahedral nucleocapsid of core (C) protein dimers surrounding a single copy of the positive-strand RNA genome. The envelope, derived from the endoplasmic reticulum membrane, carries the E1 and E2 glycoproteins as a heterodimeric and ultimately trimeric spike complex.

The defining biophysical feature of the circulating HCV particle is its association with host apolipoproteins and triglycerides. The virion is secreted by the hepatocyte through the very-low-density lipoprotein (VLDL) export pathway, acquiring apoB, apoE, and a triglyceride core during egress. The resulting “lipo-viro-particle” has a buoyant density of 1.06 to 1.10 g/mL, far lower than a conventional flavivirus virion, and uses host lipoprotein receptors (low-density lipoprotein receptor and scavenger receptor B1) for attachment to the next hepatocyte. This lipoprotein masquerade underpins several of the most distinctive features of HCV biology: hepatotropism, masking of envelope antigens from neutralising antibodies, and use of host lipid pathways for both entry and exit.

A second class of particle is also released: non-infectious core-only particles lacking envelope, which appear to be a by-product of assembly.

Genome organisation

The HCV genome is a single positive-strand RNA molecule of around 9.6 kilobases, with a single open reading frame flanked by structured 5’ and 3’ untranslated regions.

• The 5’ untranslated region (5’ UTR) contains the internal ribosome entry site (IRES), a structured RNA element that recruits the 40S ribosomal subunit directly to the start codon without requiring a 5’ cap or the usual cap-binding initiation complex. The 5’ UTR also binds the liver-specific microRNA miR-122, which stabilises the viral genome and is a potential host-directed drug target.
• The single open reading frame encodes a polyprotein of around 3,000 amino acids that is co- and post-translationally cleaved into ten mature proteins.
• The 3’ untranslated region contains a poly(U/UC) tract and a conserved X-tail required for replication.

The ten mature proteins fall into structural and non-structural groups. The structural proteins are core (C), the nucleocapsid component, and the envelope glycoproteins E1 and E2. The viroporin p7 sits between the structural and non-structural regions and is required for assembly. The non-structural proteins are NS2 (a cysteine protease that cleaves the NS2/NS3 junction), NS3 (a multifunctional protein with an N-terminal serine protease domain that uses NS4A as a cofactor and a C-terminal RNA helicase), NS4A (the NS3 protease cofactor), NS4B (induces the membranous replication compartment), NS5A (a phosphoprotein required for replication and assembly), and NS5B (the RNA-dependent RNA polymerase).

Replication cycle

The HCV replication cycle is entirely cytoplasmic, with no DNA intermediate and no integration into the host genome. The cycle has six broad phases.

Entry. Attachment is multi-step. The lipo-viro-particle first tethers to heparan sulfate proteoglycans and the low-density lipoprotein receptor (LDLR) on the basolateral surface of the hepatocyte, primarily through host apolipoproteins. High-affinity binding follows through scavenger receptor B1 (SR-B1), the tetraspanin CD81, and the tight-junction proteins claudin-1 and occludin. The Niemann-Pick C1-like 1 cholesterol receptor is an additional entry factor. Clathrin-mediated endocytosis carries the particle into the endosome, where pH-dependent fusion delivers the RNA genome into the cytoplasm.

Translation. The genome serves directly as messenger RNA. The IRES recruits the 40S ribosomal subunit at the start codon, and the whole open reading frame is translated into the single polyprotein on rough endoplasmic reticulum membranes. The polyprotein is cleaved during and after translation by three proteases acting in concert. Host signal peptidase cleaves the structural junctions (core / E1, E1 / E2, E2 / p7, p7 / NS2). NS2 autoprotease (with the N-terminal portion of NS3) cleaves the NS2 / NS3 junction. NS3/4A serine protease cleaves all four downstream non-structural junctions (NS3 / NS4A, NS4A / NS4B, NS4B / NS5A, NS5A / NS5B).

RNA replication. NS4B induces a network of endoplasmic reticulum-derived double-membrane vesicles, the membranous web, that contains the replication complex. Within the membranous web, NS5B uses the positive-strand genome as template to synthesise a negative-strand RNA intermediate, then uses that negative strand as template to make many new positive-strand progeny genomes. NS5B has no proofreading function and the mutation rate is around 10⁻⁴ per nucleotide per replication cycle, generating the quasispecies swarm that characterises chronic HCV infection.

Assembly. New positive-strand genomes are packaged by core protein into nucleocapsids at the surface of cytoplasmic lipid droplets, which serve as an organising platform. NS5A and p7 are required for assembly; NS2 coordinates the linkage between assembly sites and the membranous web.

Maturation and egress. Nucleocapsids bud into the endoplasmic reticulum, acquiring the host membrane with embedded E1 and E2. The enveloped particles enter the VLDL secretion pathway and acquire apoB, apoE, and a triglyceride core during transit through the Golgi. Mature lipo-viro-particles are secreted by exocytosis at the basolateral surface.

The lipo-viro-particle is therefore a Trojan horse: it leaves the hepatocyte disguised as a lipoprotein, and uses lipoprotein receptors to enter the next cell.

Pathogenesis

HCV is not directly cytopathic; infected hepatocytes are otherwise viable. Liver injury is driven by the host inflammatory response to chronic infection and by repeated cycles of immune-mediated hepatocyte killing and regeneration. Five mechanisms dominate pathogenesis and explain both the high chronicity rate and the extrahepatic disease spectrum.

Innate immune evasion by NS3/4A. The NS3/4A serine protease is required for cleavage of the viral non-structural polyprotein junctions, but its substrate specificity also extends to two critical host adaptors in type I interferon induction. MAVS (mitochondrial antiviral signalling protein) couples RIG-I sensing of cytoplasmic viral RNA to IRF3 activation; cleavage of MAVS by NS3/4A abolishes RIG-I-driven interferon induction. TRIF (TIR-domain-containing adapter inducing IFN-β) couples endosomal TLR3 sensing of double-stranded RNA to the same IRF3 output; cleavage of TRIF by NS3/4A abolishes the TLR3 arm as well. The infected hepatocyte therefore cannot mount a competent type I interferon response. The same enzyme that is required for viral replication is also the principal innate immune evader, which makes NS3/4A an especially attractive drug target.

Quasispecies escape and HVR1 evolution. The hypervariable region 1 (HVR1) of E2 contains the principal neutralising antibody epitope. Under sustained antibody pressure HVR1 evolves rapidly, with new variants outrunning the maturing antibody response. The neutralising antibody response in chronic infection is therefore always at least one step behind the circulating quasispecies.

T cell exhaustion. Persistent antigen exposure in chronic HCV infection drives CD8+ T cells into an exhausted phenotype with upregulated inhibitory receptors (PD-1, Tim-3, Lag-3), reduced cytokine production, and impaired cytotoxicity. Exhaustion is reversed only partially by DAA cure.

Chronic B cell stimulation. E2 binds CD81 on B lymphocytes, providing a sustained survival and proliferation signal that supports progressive polyclonal, then oligoclonal, then monoclonal B cell expansion. The expanded B cells secrete rheumatoid-factor-like IgM that complexes with polyclonal IgG to form type II mixed cryoglobulins; these deposit in small and medium vessels, glomeruli, and the dermoepidermal junction, producing the dominant extrahepatic syndromes. The same chronic B cell drive underwrites the eventual emergence of B cell non-Hodgkin lymphoma in a small proportion of patients.

Indirect oncogenesis. HCV does not integrate into the host genome and does not encode a classical viral oncogene. Hepatocellular carcinoma in chronic HCV arises through decades of inflammation, regeneration, and cumulative genetic and epigenetic damage in the cirrhotic liver. Direct contributions from core protein (interaction with retinoblastoma protein, mitochondrial dysfunction) and NS5A (interaction with p53) have been described, but the cirrhotic background is the dominant prerequisite.

Epidemiology

Around 50 million people are living with chronic hepatitis C globally, with around 290,000 deaths per year from cirrhosis and hepatocellular carcinoma. The number has fallen from a 2015 estimate of 71 million through a combination of DAA-mediated cure, mortality, and refined prevalence estimates.

Geographic distribution. Genotype distribution is geographically structured (see Classification above for the breakdown). Anti-HCV antibody prevalence varies from below 1 per cent in most European and North American adult populations to over 5 per cent in Egypt (historically driven by schistosomiasis-control parenteral antimony treatment in the mid-twentieth century), with intermediate prevalence in central Asia, parts of southern Europe, and sub-Saharan Africa.

Transmission routes.

• People who inject drugs (PWID) are the dominant transmission population in most high-income and many middle-income settings. HCV transmission efficiency through shared injecting equipment is high, and incidence in PWID without harm reduction is several per cent per year.
• Unsafe medical injections and dental procedures are responsible for a large share of historical and ongoing HCV transmission in low- and middle-income countries.
• Unscreened blood and blood products were the dominant transmission route in many countries until anti-HCV screening was introduced (1990s in most high-income countries; later in many LMICs).
• Sexual transmission is inefficient in conventional heterosexual partnerships but is well-documented in HIV- positive men who have sex with men, particularly with practices that involve mucosal trauma.
• Vertical transmission occurs at 2 to 4 per cent from HIV-negative mothers and 10 to 25 per cent from HIV co-infected mothers.
• Occupational exposure through needlestick injury is the principal residual route in healthcare workers; transmission risk per percutaneous exposure is around 1.8 per cent.

Key populations. PWID, MSM living with HIV, prison populations, recipients of unscreened blood products before universal screening, migrants from high-prevalence regions, and healthcare workers.

WHO elimination targets. The 2016 Global Health Sector Strategy on Viral Hepatitis sets a 90 per cent reduction in new infections and a 65 per cent reduction in mortality by 2030 relative to 2015. Macro-elimination in microcosms has been demonstrated in prison cohorts in Australia and in PWID services in Reykjavík, Tayside, and other settings.

Natural history

Around 75 to 85 per cent of acute infections become chronic. Spontaneous clearance is more likely in symptomatic acute infections (the immune response is competent enough to clear), in women, in younger patients, and in carriers of the favourable IFNL3/IFNL4 genotype (formerly IL28B), a host genetic determinant of interferon-λ signalling that strongly predicts spontaneous and treatment-induced clearance.

Chronic infection is most often asymptomatic, with persistently or fluctuating mildly elevated transaminases. Fibrosis progresses at a variable rate; 15 to 30 per cent of chronic infections progress to cirrhosis over 20 to 30 years. Co-factors that accelerate progression include HIV co-infection (relative risk for cirrhosis around 2 to 4), alcohol use, hepatic steatosis (genotype 3 contributes directly), male sex, older age at acquisition, and HBV co-infection.

Once cirrhosis is established, the annual incidence of hepatocellular carcinoma is 1 to 4 per cent, and hepatic decompensation occurs at around 4 per cent per year. DAA-mediated cure reduces the HCC risk but does not eliminate it in patients who are already cirrhotic at the time of treatment.

Clinical presentations and complications

Acute hepatitis C

Acute hepatitis C is subclinical in 70 to 80 per cent of cases; only 20 to 30 per cent develop jaundice. Symptoms, when they occur, follow a 6 to 8 week incubation period and include malaise, nausea, right-upper-quadrant discomfort, and jaundice. ALT rises 10 to 20 times the upper limit of normal. Fulminant hepatic failure is rare. Symptomatic acute infection is paradoxically more likely to clear spontaneously than asymptomatic infection.

Chronic hepatitis C

Chronic hepatitis C is most often asymptomatic until late complications appear. Non-specific symptoms of fatigue, arthralgia, and depression are reported but are not specific or sensitive. Transaminases fluctuate around 1 to 3 times the upper limit of normal, and a normal ALT does not exclude significant fibrosis. Fibrosis assessment by transient elastography (FibroScan), shear-wave elastography, or serological scores (FIB-4, APRI) has largely replaced liver biopsy in 2026.

Extrahepatic manifestations

Extrahepatic disease is a defining feature of chronic HCV and is driven principally by chronic B cell stimulation and cryoglobulin formation:

• Mixed cryoglobulinaemic vasculitis: palpable purpura, arthralgia, peripheral neuropathy, and renal disease.
• Membranoproliferative glomerulonephritis: immune-complex glomerular disease with proteinuria, haematuria, and progressive renal impairment.
• B cell non-Hodgkin lymphoma: most often a marginal zone lymphoma. A late consequence of progressive B cell clonal expansion.
• Porphyria cutanea tarda: photosensitive bullous skin disease on sun-exposed surfaces.
• Other recognised associations include lichen planus, Sjögren-like sicca syndrome, autoimmune thyroiditis, and an increased risk of type 2 diabetes mellitus.

DAA cure produces meaningful regression of most extrahepatic manifestations, which is one of the strongest arguments for universal HCV treatment regardless of fibrosis stage.

Hepatocellular carcinoma

HCV-driven hepatocellular carcinoma almost always arises on a cirrhotic background. Surveillance with six-monthly liver ultrasound (with or without serum alpha-fetoprotein) is recommended lifelong in cirrhotic patients, including after DAA-mediated cure.

Diagnosis

The diagnostic cascade has two essential layers and one optional alternative.

Anti-HCV antibody screening

Third-generation enzyme immunoassay or chemiluminescent assays detect antibody against multiple HCV antigens (core, NS3, NS4, NS5). Sensitivity is above 99 per cent. The window period from infection to detectable antibody is 6 to 12 weeks. A positive antibody alone identifies exposure, not active infection, and cannot distinguish current from past (spontaneously cleared or treatment-cured) infection. Antibody persists for life in most patients.

Confirmation of active infection

Confirmation of active viraemia is by HCV RNA polymerase chain reaction, the preferred test. HCV RNA is detectable from around 2 weeks after infection (well before antibody appears) and is reported quantitatively in IU/mL. The South African NDoH 2019 Viral Hepatitis Guideline requires HCV RNA confirmation of every anti-HCV-positive sample before treatment. Where nucleic acid testing is not available, HCV core antigen is an acceptable alternative, with sensitivity above an HCV RNA threshold of around 500 to 3,000 IU/mL (genotype- dependent).

Modern diagnostic workflows use reflex RNA testing: laboratories automatically perform HCV RNA on every anti-HCV-positive screening sample, eliminating the need for a follow-up clinic visit. Point-of-care anti-HCV (oral fluid or fingerprick) and point-of-care HCV RNA (under one hour, low volume) enable same-day “test and treat” pathways in hard-to- reach populations.

Additional virological tests

• Genotyping is used selectively in 2026: most patients start a pan-genotypic DAA regimen without prior genotype testing. Genotype is investigated when the standard regimen fails or in retreatment workups.
• Resistance-associated substitution (RAS) testing is reserved for treatment-experienced patients facing retreatment, particularly for NS5A resistance, which can compromise the pan-genotypic regimens.
• Liver fibrosis assessment by transient elastography, shear-wave elastography, or non-invasive scores (FIB-4, APRI) is performed before treatment and guides post-cure surveillance intensity.

Pre-treatment co-infection screening

Before initiation of DAA therapy, every patient should be screened for HBV (HBsAg, anti-HBc total, anti-HBs) and HIV (fourth-generation antigen / antibody assay). The HBV screen identifies patients at risk of reactivation during HCV suppression by DAAs, and the HIV screen identifies the co-infected patients who need integrated HIV care alongside HCV cure.

Management

The DAA revolution

Therapy for chronic hepatitis C was transformed between 2011 and 2014 by the licensure of direct-acting antivirals (DAAs) targeting NS3/4A protease, NS5A, and NS5B polymerase. The combination of high cure rates, short oral regimens, and favourable tolerability has made HCV the only major chronic viral infection of humans that can be reliably cured with a single short course of oral therapy.

Pan-genotypic first-line regimens

Three pan-genotypic fixed-dose combinations dominate 2026 clinical practice:

Regimen	Components	Duration	Notes
Sofosbuvir / velpatasvir	NS5B nucleotide polymerase inhibitor + NS5A inhibitor	12 weeks	First-line in most jurisdictions, including the SA NDoH 2019 Guideline; usable in decompensated cirrhosis with ribavirin
Glecaprevir / pibrentasvir	NS3/4A protease inhibitor + NS5A inhibitor	8 weeks (treatment-naive, non-cirrhotic) or 12 weeks (cirrhotic or treatment-experienced)	Avoid in decompensated cirrhosis (NS3/4A protease inhibitors are contraindicated)
Sofosbuvir / velpatasvir / voxilaprevir	Adds a second-generation protease inhibitor	12 weeks	Retreatment after DAA failure

A low-cost alternative is sofosbuvir plus daclatasvir for 12 weeks (24 weeks in cirrhotic or treatment-experienced patients), recommended by the World Health Organization and available as a generic at under USD 50 per course.

Sustained virological response (SVR12)

Sustained virological response 12 weeks after end of treatment (SVR12) is defined as undetectable HCV RNA 12 weeks after the last dose, and is accepted as the regulatory endpoint for HCV cure. SVR12 is equivalent to virological cure: the lifetime late-relapse rate is well below 1 per cent across large cohorts, and most “recurrences” in the post-DAA era are actually reinfections in ongoing-risk populations. Pan-genotypic regimens achieve SVR12 in over 95 per cent of patients across all genotypes.

Special populations

• HBV co-infection. HBsAg-positive patients require HBV antiviral cover (tenofovir or entecavir) before or with HCV DAA initiation, continued at least 12 months after HCV DAA completion, to prevent HBV reactivation as HCV suppression lifts the HCV-mediated inhibition of HBV. Anti-HBc-positive HBsAg-negative patients are monitored with HBV DNA and ALT during DAA therapy.
• HIV co-infection. Pan-genotypic DAAs are co-administered with most modern ART regimens, with attention to drug-drug interactions (especially sofosbuvir with tenofovir alafenamide, and protease inhibitors with NS3/4A inhibitors).
• Decompensated cirrhosis. Sofosbuvir / velpatasvir with ribavirin is preferred; NS3/4A protease inhibitors are contraindicated.
• Renal impairment. Glecaprevir / pibrentasvir and sofosbuvir / velpatasvir are both safe across the full range of renal function in 2026, including dialysis.
• Pregnancy. DAAs are not currently licensed in pregnancy; treatment is deferred until after delivery.
• Paediatrics. Pan-genotypic DAAs are licensed from age 3 in weight-based dosing.

Post-cure follow-up

Surveillance after SVR12 is required in three domains:

• Hepatocellular carcinoma surveillance with six-monthly liver ultrasound (with or without alpha-fetoprotein) continues lifelong in cirrhotic patients. Non-cirrhotic patients at SVR generally do not require HCC surveillance.
• Reinfection surveillance with annual HCV RNA (not antibody, which persists for life) in patients with ongoing exposure risk.
• Portal hypertension surveillance can be de-escalated post-SVR if liver stiffness drops below 12 kPa and platelets rise above 150 × 10⁹/L (the Baveno VII criteria).

Prevention and public health

Vaccination

There is no licensed HCV vaccine, and one is unlikely in the short term. The barriers are intrinsic to HCV biology: hypervariability of the E2 hypervariable region 1, quasispecies escape under immune pressure, masking of envelope epitopes by the lipo-viro-particle’s apolipoprotein coat, and difficulty inducing T cell responses of the breadth and durability that appear to correlate with spontaneous clearance. The most advanced clinical candidate (a chimpanzee adenoviral vector prime / modified vaccinia Ankara boost, encoding the non-structural region) reduced peak viraemia but did not prevent chronic infection in a phase II PWID trial.

Infection prevention and control

Standard precautions for blood and body-fluid exposure prevent healthcare-associated HCV transmission. Safe injection practices (single-use injecting equipment, decontamination of dental and surgical instruments) and elimination of unsafe medical practices remain the highest-yield interventions in LMIC settings.

Post-exposure prophylaxis

There is no post-exposure prophylactic regimen for HCV. Management of a healthcare worker exposed to an HCV-positive source patient is surveillance-based: baseline anti-HCV at exposure, anti-HCV at 12 weeks, and HCV RNA at 4 to 6 weeks. Acute infection identified at seroconversion is treated promptly with a standard DAA regimen, which functions as treatment in lieu of prophylaxis.

Treatment as prevention

Each cured patient is removed from the transmission reservoir. This is the rationale for universal treatment (rather than fibrosis-stage-gated selection) under WHO elimination targets. Treatment-as-prevention works particularly in concentrated epidemics (PWID, MSM with HIV) where the cure of a relatively small population produces large reductions in onward transmission.

Harm reduction

For people who inject drugs, harm reduction is the principal HCV elimination lever. The evidence-based package includes needle and syringe programmes, opioid agonist therapy, drug consumption rooms, peer support, and integration with HCV testing and DAA delivery. Modelling shows that combined harm reduction at high coverage plus universal DAA access can drive HCV elimination in PWID populations within a decade.

Surveillance and notification

Acute hepatitis C is notifiable in most jurisdictions worldwide. The WHO 2016 strategy targets include defined diagnostic and treatment coverage indicators (90 per cent diagnostic, 80 per cent treatment by 2030). National HCV registries support cascade-of-care monitoring and elimination verification.

Elimination and eradication

The World Health Organization 2016 Global Health Sector Strategy on Viral Hepatitis set targets of a 90 per cent reduction in new infections and a 65 per cent reduction in mortality by 2030, relative to 2015, alongside diagnostic and treatment coverage targets of 90 per cent and 80 per cent respectively. Modelling indicates that elimination is technically feasible with a combination of harm reduction, screening, and rapid linkage to DAA therapy, but progress has been uneven across regions and the COVID-19 pandemic disrupted service delivery in 2020 to 2022.

The four operational pillars of HCV elimination are:

• Test: simplified diagnostic algorithms (reflex RNA, point- of-care testing, dried blood spot) to identify the undiagnosed.
• Link: simplified care models, decentralisation, task shifting to primary care, and integration with HIV, drug treatment, and antenatal services.
• Treat: pan-genotypic DAA regimens without genotype testing or fibrosis-stage gatekeeping.
• Prevent: harm reduction at the scale required to outpace reinfection in ongoing-risk populations.

Macro-elimination in microcosms has been demonstrated in prison cohorts in Australia and in PWID services in Reykjavík, Tayside, and other settings, showing that elimination is biologically and operationally achievable when political will, funding, and DAA price are aligned.

South African context

South Africa carries an estimated 400,000 chronic HCV infections, with an adult anti-HCV prevalence of around 1 per cent and a higher RNA-positive prevalence in defined key populations: around 55 per cent in PWID, around 20 per cent in men who have sex with men with HIV, and around 1 per cent in the general adult population. The national HCV epidemic has several distinguishing features that shape clinical practice.

Genotype distribution. Genotype 5 (subtype 5a) was first identified in South Africa and remains largely confined to southern Africa. In the general population genotypes 1 and 5 co-dominate, with genotype 4 rising in prevalence. In PWID cohorts genotype 1a (around 73 per cent) and 3a (around 15 per cent) dominate, and genotype 5 has not yet been detected in the surveyed PWID populations.

HIV co-epidemic. South Africa has the largest HIV epidemic in the world, and HIV-HCV co-infection is concentrated in PWID and MSM populations. HIV co-infection accelerates HCV fibrosis progression around two- to four-fold and increases vertical HCV transmission risk to 10 to 25 per cent.

SA NDoH 2019 Viral Hepatitis Guideline. This first-edition national guideline sets the operational framework:

• Test and treat as the dominant pathway: anti-HCV screening at primary care for the defined risk groups, with reflex HCV RNA confirmation.
• First-line treatment with sofosbuvir / velpatasvir for 12 weeks across all genotypes (with ribavirin in decompensated cirrhosis).
• HBV and HIV co-infection screening mandatory before DAA initiation; tenofovir-based HBV cover for HBsAg-positive patients during DAA therapy and for at least 12 months after.
• No universal antenatal HCV screening; testing is risk-based.
• Infant follow-up of HCV-positive mothers by HCV RNA at 2 to 6 months or anti-HCV at 18 months (to allow clearance of passively transferred maternal antibody).
• Hepatocellular carcinoma surveillance by six-monthly ultrasound in cirrhotic patients, continued lifelong after SVR.

Key populations and service delivery. PWID-focused services remain the principal HCV elimination lever in South Africa. Opioid agonist therapy is available but at limited scale; needle and syringe programmes operate in several major centres but coverage is uneven. Decentralised PWID-friendly HCV services in TB Hivcare and similar programmes have shown that treatment is feasible and effective in this population, with SVR12 rates comparable to clinical-trial cohorts when retention is supported.

Notification. Viral hepatitis (including hepatitis C) is a Category 2 Notifiable Medical Condition in South Africa, reported to the Department of Health (typically via the NICD NMC App) within seven days of diagnosis.

References and recommended reading

• Whitehouse CA, Williams JV, Cook AG (eds). Richman DD, Whitley RJ, Hayden FG (founders). Clinical Virology, 4th edition. Chapter 54: Hepatitis C virus. ASM Press, 2016.
• Knipe DM, Howley PM, Cohen JI, Damania B, Enquist LW, Freed EO, Karbiener M, Lamb RA, Layne SP, Mettenleiter TC, Pellett PE, Racaniello VR, Rall GF, Roizman B (eds). Fields Virology, 7th edition: Volume 1 – Principles (chapter on Replication strategies). Wolters Kluwer, 2023.
• South African National Department of Health. National Guidelines for the Management of Viral Hepatitis, first edition. Pretoria: NDoH, 2019. Section on hepatitis C.
• Martinello M, Solomon SS, Terrault NA, Dore GJ. Hepatitis C. The Lancet 2023; 402(10407): 1085 to 1096.
• World Health Organization. Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022 to 2030. Geneva: WHO; 2022.