Hepatitis C

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Hepatitis C virus is an enveloped RNA virus with substantial genetic diversity. Transmission requires infected blood to enter another person's circulation. Current UK case finding therefore includes people who inject drugs, prison populations, recipients of blood or medical care in higher-prevalence settings, people with occupational exposure and anyone with unexplained liver disease.

Anti-HCV remains reactive after spontaneous clearance or successful treatment and sometimes reflects false reactivity. Diagnosis of active infection therefore depends on HCV RNA or an appropriately validated core-antigen pathway. Reflex RNA testing and rapid linkage reduce loss between screening and cure.

Modern direct-acting antivirals cure most infection with short oral regimens. The infectious-disease priorities are finding viraemia, preventing blood exposure, checking coinfection and interactions, supporting adherence and verifying cure. Detailed portal-hypertension management and continuing cancer surveillance for advanced fibrosis remain hepatology responsibilities.

Treatment is also prevention because sustained virological response removes circulating virus. Reinfection remains possible after cure, making sterile injecting equipment, opioid-substitution access, condom discussion for blood-associated sexual risk and repeat RNA testing essential.

Key points

HCV is blood-borne; injecting equipment is the principal UK route, while needlestick, unscreened historical blood, tattooing and sexual blood exposure also matter.
Antibody shows exposure, not current infection. Detectable HCV RNA confirms active viraemia and is the result that triggers treatment linkage.
A negative antibody test can miss very recent acquisition or immune suppression; request HCV RNA when clinical or exposure suspicion remains high.
Most acute infections are asymptomatic, yet chronic infection can silently progress to fibrosis, cirrhosis and hepatocellular carcinoma.
All people with active HCV should be offered specialist assessment for curative direct-acting antiviral therapy without stigma or an abstinence prerequisite.
Common pangenotypic adult regimens include glecaprevir 300 mg plus pibrentasvir 120 mg once daily with food for eight weeks in suitable compensated treatment-naive disease, or sofosbuvir 400 mg plus velpatasvir 100 mg once daily for 12 weeks.
Protease-inhibitor regimens such as glecaprevir-pibrentasvir are unsuitable in decompensated cirrhosis; treatment duration and choice change with liver stage, prior therapy, genotype and interactions.
Confirm cure with an undetectable HCV RNA at least 12 weeks after treatment, then continue harm reduction because cure does not create immunity.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Injecting exposure

Shared needles, syringes, filters, spoons, water or other preparation equipment transfer small quantities of infected blood efficiently.

Healthcare blood exposure

Needlestick injury, unscreened historical transfusion and inadequately sterilised medical or cosmetic equipment can inoculate HCV directly.

Sexual blood exposure

Transmission through sex is less efficient but rises with mucosal trauma, ulceration, chemsex injecting, concurrent STIs and HIV.

Perinatal transmission

Maternal viraemia can transmit HCV around birth, with risk increased by HIV coinfection and prolonged exposure to maternal blood.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Error-prone replication
An RNA polymerase lacking proofreading creates viral quasispecies that evade immune clearance and previously complicated genotype-specific treatment.
2
Immune hepatocyte injury
Innate and adaptive responses against infected hepatocytes produce inflammation, while incomplete clearance permits continuing viral replication.
3
Fibrotic remodelling
Chronic inflammatory signalling activates hepatic stellate cells and collagen deposition, progressing from portal fibrosis to cirrhosis and portal hypertension.
4
Extrahepatic immune activation
Persistent antigen drives B-cell and immune-complex phenomena, causing cryoglobulinaemia, vasculitis, renal disease and selected lymphoproliferative disorders.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Usually silent infection

Most acute and many chronic infections cause no specific symptoms, so risk-based testing finds disease that examination cannot.

Acute hepatitis pattern

Fatigue, nausea, right-upper-quadrant discomfort, dark urine and jaundice can occur weeks after exposure but are uncommon.

Chronic liver phenotype

Fatigue, thrombocytopenia, splenomegaly, spider naevi or abnormal aminotransferases can reveal established fibrosis after years of infection.

Decompensated cirrhosisRed flag

Ascites, variceal bleeding, encephalopathy, jaundice and renal dysfunction signal advanced disease and constrain antiviral selection.

Cryoglobulinaemic vasculitis

Palpable purpura, neuropathy, arthralgia and glomerulonephritis can result from HCV-driven mixed cryoglobulin immune complexes.

Recent high-risk exposure

Sharing injecting equipment or a percutaneous blood injury warrants RNA-based follow-up even when the first antibody result is negative.

Red flags requiring action

Haematemesis, melaena, hypotension or syncope in known or possible cirrhosis requires immediate variceal-bleeding management and endoscopy planning.
New confusion, fever, ascites, jaundice, oliguria or rising INR suggests decompensation, spontaneous bacterial peritonitis or acute-on-chronic liver failure.
A new focal liver lesion, weight loss or rising alpha-fetoprotein in chronic HCV needs urgent hepatocellular-carcinoma assessment.
HCV RNA positivity during pregnancy requires coordinated hepatology and maternity review, infant testing planning and avoidance of unsupported antiviral prescribing.
Needlestick or blood exposure needs prompt baseline assessment and follow-up RNA testing; no vaccine or immunoglobulin can prevent HCV.
Direct-acting antiviral treatment with severe bradycardia, jaundice, drug toxicity or virological rebound requires immediate specialist and interaction review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Anti-HCV antibodyFirst step
Why
Screen for previous exposure in people beyond the antibody window period.
Interpretation and limitations
Reactive antibody requires RNA testing and does not distinguish current from cleared infection; a negative result can miss recent acquisition or impaired antibody production.
02
Quantitative HCV RNA
Why
Confirm active infection, establish baseline viraemia and document treatment response.
Interpretation and limitations
Detectable RNA means current infection; undetectable RNA with reactive antibody means no current viraemia but may represent spontaneous clearance, cure or a false-reactive screen.
03
Early-exposure RNA testing
Why
Detect infection before seroconversion after a recent blood exposure.
Interpretation and limitations
RNA becomes detectable earlier than antibody; follow the occupational or sexual-health schedule because one early negative result does not close the exposure episode.
04
Liver stage assessment
Why
Identify fibrosis, cirrhosis and decompensation that alter regimen and follow-up.
Interpretation and limitations
Combine FBC, ALT, bilirubin, albumin, INR, renal function, non-invasive scores and elastography; thrombocytopenia or high stiffness raises concern for portal hypertension.
05
Coinfection and immunity screen
Why
Find conditions affecting treatment safety and prevention.
Interpretation and limitations
Test HBV and HIV, assess HAV and HBV immunity, and manage active or resolved HBV because direct-acting antiviral therapy can permit HBV reactivation.
06
Medication interaction review
Why
Prevent loss of antiviral exposure or serious toxicity.
Interpretation and limitations
Check every prescribed, non-prescribed and recreational substance with a validated interaction resource; strong enzyme inducers, acid suppression and amiodarone are notable regimen-specific concerns.
07
Post-treatment HCV RNA
Why
Demonstrate sustained virological response and identify failure or reinfection.
Interpretation and limitations
Undetectable RNA at least 12 weeks after completing therapy defines cure; later detectable RNA needs specialist distinction between relapse and reinfection.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Resolved HCV

Reactive antibody with repeatedly undetectable RNA indicates no current viraemia after spontaneous clearance or previous successful treatment.

Other chronic hepatitis

HBV, autoimmune hepatitis, alcohol-related disease and metabolic steatotic liver disease can produce the same enzyme and fibrosis pattern.

Acute drug injury

A medication, supplement or toxin timeline may better explain abrupt hepatitis, although concurrent HCV infection still requires RNA classification.

Cryoglobulinaemic mimics

Autoimmune vasculitis, endocarditis and haematological disease can cause purpura, neuropathy, low complement and renal inflammation without active HCV.

False-reactive antibody

Low-prevalence screening and immune phenomena occasionally produce reactive anti-HCV without RNA or evidence of previous true infection.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01FINDTest beyond symptomsFirst stepA person has a past or current blood exposure, belongs to a higher-prevalence group or has unexplained liver disease.

1Ask non-judgementally about injecting and equipment sharing, prison, tattoos, transfusion era and country, healthcare exposure, sexual blood exposure and previous testing or treatment.
2Request anti-HCV with laboratory reflex RNA testing whenever possible, or request RNA directly if exposure is recent or antibody formation may be impaired.
3Test HBV and HIV, assess HAV and HBV vaccination needs and obtain baseline liver, renal and pregnancy information in the same episode.
4Communicate both antibody and RNA results explicitly so a reactive antibody is neither mistaken for active disease nor falsely described as immunity.

02LINKMove viraemia to treatmentHCV RNA is detectable on a current sample.

1Refer directly into the local hepatitis C operational delivery network or specialist pathway and assign ownership for contact after the result.
2Assess fibrosis, cirrhosis, previous DAA exposure, HBV or HIV coinfection, renal function, pregnancy potential and every medicine or supplement interaction.
3Select a pangenotypic regimen and duration from the current commissioned pathway; active drug use or unstable housing should trigger support, not exclusion.
4Provide adherence planning, harm-reduction access and a dated end-of-treatment and sustained-response RNA plan before the first tablets are supplied.

03TREATUse a safe curative regimenBaseline assessment confirms a direct-acting antiviral treatment plan.

1Use glecaprevir-pibrentasvir for a suitable compensated patient or sofosbuvir-velpatasvir according to prior treatment, cirrhosis, renal status and commissioning criteria.
2Avoid NS3/4A protease inhibitors in current or previous decompensated cirrhosis and refer complex or previously treated infection for expert regimen design.
3Resolve strong inducer, acid-suppressant, statin, anticoagulant, antiepileptic, antiretroviral and amiodarone interactions before treatment begins.
4Review adherence and toxicity during therapy, but do not use a falling ALT as a substitute for the planned post-treatment RNA cure test.

04EXPOSUREFollow a blood contactA needlestick, mucosal splash or other significant exposure to potentially HCV-infected blood occurs.

1Clean the site, document route and time, assess the source when lawful and send exposed-person baseline HCV, HBV and HIV tests through occupational health.
2Explain that HCV has no vaccine or immunoglobulin and that routine antiviral post-exposure prophylaxis is not recommended.
3Use the current occupational schedule for early HCV RNA and later antibody or RNA testing rather than relying on symptoms.
4Refer immediately if RNA becomes detectable so curative therapy can be offered and onward blood exposure prevented.

05AFTERCAREConfirm cure and prevent reinfectionThe antiviral course is complete or sustained virological response has been documented.

1Check HCV RNA at least 12 weeks after treatment completion and investigate any detectable result for adherence, interaction, relapse or reinfection.
2Continue cirrhosis care and hepatocellular-carcinoma surveillance in people with advanced fibrosis despite cure because structural risk does not disappear immediately.
3Offer sterile injecting equipment, opioid-substitution treatment, sexual-health care and repeat RNA testing when ongoing exposure continues.
4Explain that anti-HCV will usually stay positive and provides no protection, preventing future clinicians from mislabelling reinfection or immunity.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

A first-line short pangenotypic curative regimen for selected adults without decompensated liver disease, modified by previous treatment and specialist pathway.

Glecaprevir with pibrentasvir

Give glecaprevir 300 mg plus pibrentasvir 120 mg orally once daily as three 100 mg/40 mg tablets with food for eight weeks in suitable treatment-naive compensated infection.

Contraindicated in decompensated or significant hepatic impairment; check strong inducers, statins, anticoagulants and antiretrovirals, and review HBV reactivation risk before treatment.

A first-line pangenotypic curative option across broad HCV groups, with specialist modification for decompensation, prior failure and ribavirin need.

Sofosbuvir with velpatasvir

Give one 400 mg/100 mg tablet orally once daily with or without food for 12 weeks in the standard specialist-selected adult regimen.

Avoid potent P-gp or enzyme inducers, manage acid-reducing medicines carefully and avoid amiodarone unless no alternative because profound symptomatic bradycardia can occur.

Occasional adjunct for selected decompensated, genotype-specific or previous-treatment-failure pathways rather than routine uncomplicated infection.

Ribavirin in selected complex HCV

Use only the specialist weight- and renal-adjusted oral regimen alongside a defined direct-acting antiviral course; there is no safe universal dose for unsupervised prescribing.

Causes haemolytic anaemia and is highly teratogenic; require contraception for exposed reproductive partners, avoid pregnancy and monitor FBC and renal function closely.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cirrhosis

Progressive fibrosis distorts hepatic architecture, causing portal hypertension, thrombocytopenia, ascites, varices, encephalopathy and reduced synthetic reserve.

Hepatocellular carcinoma

Chronic inflammation and cirrhosis increase primary liver-cancer risk, which falls but does not vanish after curative treatment.

Mixed cryoglobulinaemia

Circulating immune complexes precipitate in small vessels, producing palpable purpura, arthralgia, peripheral neuropathy and membranoproliferative glomerulonephritis.

Lymphoproliferative disease

Chronic B-cell stimulation is associated with selected non-Hodgkin lymphomas and may improve after successful viral eradication.

Reinfection

Continued blood exposure after cure can establish a genetically new infection, returning liver and transmission risks despite persistent antibody positivity.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Before treatment, document HCV RNA, fibrosis stage, liver synthetic function, renal function, HBV and HIV status, pregnancy considerations and interaction review.
During therapy, check adherence, newly started medicines and symptom-led laboratory tests; complex cirrhosis or ribavirin requires more intensive monitoring.
Confirm sustained virological response with HCV RNA at least 12 weeks after the final dose and communicate cure clearly to the patient and primary care.
Investigate detectable RNA after therapy for missed doses, drug interactions, resistance, relapse or reinfection through the specialist network.
Continue variceal and hepatocellular-carcinoma surveillance after cure when cirrhosis or qualifying advanced fibrosis was present before treatment.
Use periodic HCV RNA, not repeat antibody, to detect reinfection in people with ongoing injecting or other blood exposure.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Antibody is historical

Anti-HCV records immune exposure and usually remains positive after cure, while RNA answers whether virus is currently circulating.

Reflex testing retains patients

Running RNA automatically after a reactive screen reduces repeat visits and prevents loss before diagnosis is completed.

Cure prevents transmission

Sustained virological response removes viraemia, benefitting the individual while reducing onward infection within exposed networks.

Cure is not immunity

HCV genetic diversity and incomplete protective immunity allow reinfection, so prevention and repeat RNA testing remain necessary.

Cirrhosis outlives virus

Portal-hypertension and cancer risks can persist after viral eradication, requiring continued hepatology follow-up in advanced disease.

Scope boundary

Case finding, cure linkage and reinfection prevention are emphasised here; detailed decompensated-cirrhosis care sits in hepatology.

11Common pitfallsFrequent interpretation and management errors.

01
Do not tell a patient that reactive anti-HCV proves active infection; always locate or obtain an RNA result.
02
Do not reassure after a negative antibody test taken soon after exposure when RNA testing and scheduled follow-up are required.
03
Do not withhold curative therapy solely because a person currently injects drugs, drinks alcohol or has unstable housing; add support instead.
04
Do not prescribe glecaprevir-pibrentasvir in decompensated cirrhosis or without a complete interaction assessment.
05
Do not declare cure from symptom resolution, normal ALT or end-of-treatment RNA; obtain the sustained-response RNA at the correct interval.
06
Do not stop surveillance automatically after cure when cirrhosis or advanced fibrosis continues to confer cancer and portal-hypertension risk.