Hepatitis C diagnosis and curative therapy

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

Hepatitis C is a blood-borne RNA virus. In the UK, risk is concentrated among people who have injected drugs or shared equipment, received blood before effective screening, had medical or cosmetic procedures with inadequate infection control, or experienced certain sexual and occupational exposures. Many people have no symptoms until fibrosis is advanced, so testing should be offered without judgement and through accessible routes. Anti-HCV is the screening marker: it may take weeks to appear and usually remains detectable for life. Reflex HCV RNA testing converts a reactive antibody result into a clinically useful answer before the person is lost to follow-up.

Detectable HCV RNA confirms current infection. Undetectable RNA with reactive antibody may mean spontaneous clearance, successful prior treatment or occasionally intermittent early viraemia; repeat testing depends on exposure timing and ongoing risk. Baseline assessment includes liver panel, FBC, INR where relevant, renal function and non-invasive fibrosis staging. Look for cirrhosis and previous decompensation because these change regimen safety, duration, follow-up and transplant involvement. Test for HBV and HIV: clearing HCV can alter HBV control, and coinfection affects the full treatment plan.

Direct-acting antivirals inhibit viral proteins and are delivered through specialist or operational delivery network pathways. Pangenotypic combinations simplify care, but no regimen is universal. Previous DAA exposure, genotype in selected retreatment cases, cirrhosis, decompensation, renal impairment, pregnancy and interactions influence selection. Protease-inhibitor regimens are unsuitable in decompensated liver disease. After completion, undetectable RNA at twelve weeks establishes sustained virological response in common UK practice. People without advanced fibrosis may leave liver follow-up after cure if no other disease remains; those with cirrhosis continue six-monthly HCC surveillance and portal-hypertension care because structural risk persists.

Key points

Anti-HCV indicates exposure, not necessarily current infection; confirm active viraemia with HCV RNA or an accepted core-antigen pathway.
Antibody commonly remains positive after spontaneous clearance or cure, so it cannot diagnose relapse, reinfection or sustained virological response.
A negative antibody result can miss very recent infection or infection in severe immunosuppression; request RNA when clinical risk persists.
Before treatment, stage fibrosis or cirrhosis and assess decompensation, renal function, HBV and HIV status, pregnancy possibility and the complete medicine list.
Modern oral direct-acting antiviral combinations cure more than 95% of treated people, commonly after an eight- to twelve-week specialist-selected course.
Use an interaction checker and current SmPC because acid suppression, anticonvulsants, rifamycins, statins, anticoagulants and herbal products can alter safety or efficacy.
Sustained virological response is an undetectable RNA result at the protocol-defined post-treatment point, usually twelve weeks after completion.
Cure does not confer immunity; provide harm-reduction support and repeat RNA testing for ongoing exposure, while continuing HCC surveillance after cirrhosis.

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

Injecting-equipment exposure

Sharing needles, syringes or other drug-preparation equipment is a major route because small quantities of infected blood can transmit HCV.

Healthcare and blood exposure

Unscreened transfusion, inadequately sterilised medical or cosmetic procedures and occupational needlestick injuries can expose a person to infected blood.

Sexual and perinatal transmission

Sexual transmission is less efficient but increases with blood exposure and selected practices; an infected mother can also transmit HCV during pregnancy or birth.

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

1
Hepatocyte viral replication
HCV is an RNA virus that replicates mainly within hepatocytes, generating genetically variable viral populations that can evade immune clearance.
2
Persistent inflammatory injury
Failure to clear infection permits ongoing immune-mediated hepatocyte injury, even when symptoms are absent and aminotransferase concentrations fluctuate.
3
Fibrosis and malignant transformation
Repeated inflammation activates hepatic stellate cells, leading to fibrosis, cirrhosis, portal hypertension and an increased risk of hepatocellular carcinoma.
4
Systemic immune effects
Chronic antigen stimulation can form immune complexes and drive cryoglobulinaemic vasculitis, glomerular disease and selected lymphoproliferative disorders.

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

Asymptomatic risk

Previous injecting, sharing drug equipment, unscreened blood exposure or medical care in a higher-prevalence setting may be the only clue; normal ALT does not exclude infection.

Acute infection

Recent exposure can cause malaise, jaundice and a fluctuating ALT, but most acute infections are not recognised clinically. RNA becomes detectable before antibody.

Chronic liver disease

Fatigue, thrombocytopenia, spider naevi, splenomegaly or incidental fibrosis may reveal longstanding infection, yet symptom severity correlates poorly with viral load.

Decompensated cirrhosisRed flag

Ascites, encephalopathy, jaundice or variceal bleeding demands transplant-linked specialist care and excludes protease-inhibitor treatment without relying on a compensated-looking clinic letter.

Extrahepatic manifestations

Mixed cryoglobulinaemic vasculitis, glomerulonephritis, porphyria cutanea tarda and selected lymphoproliferative disease can be HCV-related and may strengthen urgency for treatment.

Reinfection after cure

New RNA positivity after sustained response can reflect reinfection when exposure continues; avoid framing it as personal failure and re-engage treatment and prevention promptly.

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 or current exposure to hepatitis C virus.
Interpretation and limitations
A reactive result needs HCV RNA confirmation and remains reactive after cure. A non-reactive result may be too early after exposure or falsely negative in immunosuppression, prompting RNA when risk is recent or strong.
02
Quantitative HCV RNA
Why
Confirm current infection, establish baseline viraemia and document treatment response or reinfection.
Interpretation and limitations
Detectable RNA means active infection. Viral-load magnitude does not reliably grade fibrosis; undetectable RNA at the defined post-treatment time establishes cure, while antibody remains unhelpful for this purpose.
03
Non-invasive fibrosis assessment
Why
Identify advanced fibrosis or cirrhosis that changes regimen and long-term surveillance.
Interpretation and limitations
Use elastography or a validated serum score with clinical and imaging findings. Acute inflammation can elevate liver stiffness; decompensation is diagnosed clinically and cannot be reduced to one score.
04
FBC, liver profile, INR and renal function
Why
Assess treatment safety, hepatic reserve, portal-hypertension clues and relevant comorbidity.
Interpretation and limitations
Low platelets may signal portal hypertension; low albumin or raised INR suggests impaired reserve. Renal impairment affects selected regimens and interacting medicines but does not justify leaving HCV untreated without specialist review.
05
HBV and HIV screen
Why
Detect coinfection that changes antiviral coordination and monitoring.
Interpretation and limitations
Check HBsAg, anti-HBc and anti-HBs before DAA therapy and plan HBV prophylaxis or monitoring by risk. A positive HIV test requires a coordinated complete antiretroviral plan.
06
Pregnancy test and interaction reconciliation
Why
Prevent avoidable fetal exposure and serious pharmacokinetic interactions before prescribing.
Interpretation and limitations
Review every prescribed, over-the-counter, recreational and herbal product using the current regimen resources. Ribavirin requires strict prolonged pregnancy prevention for all exposed partners under its SmPC.

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

Cleared previous infection

A reactive antibody with undetectable RNA may reflect spontaneous clearance or successful treatment because anti-HCV usually remains positive after virus disappears.

Very recent infection

RNA can become detectable before antibody after a new exposure, so a negative antibody result does not exclude infection during the window period.

False-reactive screening result

A reactive antibody in a low-risk setting may not represent genuine infection; RNA testing determines whether current viraemia is present.

Alternative chronic liver disease

Alcohol, metabolic steatotic disease, hepatitis B, autoimmune disease and medicines can cause abnormal liver tests or fibrosis independently of HCV.

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

01ConfirmTurn screening into diagnosisFirst stepAnti-HCV is reactive, exposure was recent, or immunosuppression makes antibody testing unreliable.

1Arrange reflex or prompt HCV RNA, explain that antibody alone does not mean current infection, and repeat RNA when timing or fluctuating early viraemia leaves uncertainty.
2If RNA is detectable, notify and refer through the local HCV operational pathway while assessing urgent liver failure or decompensation and offering partner or contact advice proportionately.
3If RNA is undetectable, distinguish prior cure or spontaneous clearance from very recent exposure and agree whether repeat RNA is required by ongoing risk.

02TreatChoose a curative regimenCurrent HCV infection is confirmed and baseline liver, renal and medicine assessments are available.

1Stage fibrosis, identify decompensation and previous DAA treatment, check HBV, HIV and pregnancy status, and reconcile medicines using an authoritative interaction resource.
2Let the specialist service select the current commissioned DAA combination and duration, explicitly avoiding protease inhibitors in decompensated cirrhosis and planning transplant timing where relevant.
3Support simple once-daily or with-food instructions, missed-dose advice and uninterrupted supply, addressing housing, substance use and mental health barriers without withholding curative treatment.

03ProveConfirm cure and protect itThe patient completes the direct-acting antiviral course or has a new exposure after treatment.

1Obtain HCV RNA at the service's sustained-response point, commonly twelve weeks after treatment, and explain why antibody testing cannot demonstrate cure.
2Continue six-monthly HCC surveillance and cirrhosis care after cure when advanced disease was present, while managing alcohol, metabolic and other liver injury.
3For ongoing blood exposure risk, provide sterile equipment and harm-reduction support and repeat RNA at the agreed interval because reinfection remains curable and should prompt re-engagement.

Key medicines and prescribing safety1 treatment · regimens, roles and cautions

Pangenotypic direct-acting antiviral combination used to cure selected chronic HCV infection across multiple clinical pathways.

Glecaprevir 100 mg with pibrentasvir 40 mg tablets

Adults take three tablets together once daily with food when this specialist-selected regimen is appropriate; treatment duration depends on cirrhosis, previous therapy and the current commissioned pathway.

Do not use in severe hepatic impairment and it is not recommended in moderate hepatic impairment; identify any prior decompensation. Check strong transporter or enzyme interactions, statins, anticonvulsants, rifamycins, HIV medicines and ethinylestradiol-containing products against the current SmPC.

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

Cirrhosis and portal hypertension

Progressive hepatic fibrosis can produce splenomegaly, thrombocytopenia, varices and ascites after years of clinically silent infection.

Hepatic decompensation

Advanced liver disease can cause jaundice, ascites, variceal bleeding, encephalopathy, infection susceptibility and acute kidney injury.

Hepatocellular carcinoma

Established cirrhosis retains a continuing liver-cancer risk after virological cure, so structural disease still determines surveillance needs.

Cryoglobulinaemic disease

Immune complexes can cause purpura, arthralgia, neuropathy and membranoproliferative glomerulonephritis, sometimes with little overt hepatic illness.

Lymphoid and metabolic effects

Chronic HCV is associated with selected B-cell lymphomas, porphyria cutanea tarda and disturbances of glucose metabolism.

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

Confirm adherence and tolerability during the course using a proportionate schedule, with extra liver and renal tests for cirrhosis, comorbidity or interaction risk.
Monitor INR closely when a vitamin K antagonist is used because improving liver function during DAA treatment can change anticoagulant control.
For diabetes, warn that glucose control can improve rapidly after treatment and arrange closer monitoring to prevent hypoglycaemia from unchanged medicines.
Apply the agreed HBV DNA and ALT monitoring or prophylaxis plan throughout and after DAA treatment for HBsAg- or anti-HBc-positive people.
Document sustained virological response with HCV RNA, not antibody, and arrange repeat RNA for ongoing exposure or suspected reinfection.
Continue HCC ultrasound every six months and portal-hypertension follow-up after cure when cirrhosis remains, despite normalised liver tests.

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

Antibody remembers exposure

Anti-HCV usually persists after the virus has gone, which is why RNA—not repeated antibody—is the test for active infection, treatment response and reinfection.

Viral load is not fibrosis

A high RNA value confirms abundant viraemia but does not map directly to scarring severity; non-invasive staging and clinical evidence answer that question.

Cure changes pharmacology

Improving hepatic inflammation can alter warfarin and glucose control even without a direct drug interaction, so seemingly unrelated medicines may need closer monitoring.

Cirrhosis survives cure

Fibrosis may regress after sustained response, but established cirrhosis retains sufficient HCC and portal-hypertension risk to require continuing specialist surveillance.

Reinfection is not relapse by default

New viraemia after documented cure may be a new acquisition; sequence and timing can help specialists distinguish it, but either outcome needs prompt care rather than stigma.

11Common pitfallsFrequent interpretation and management errors.

01
Telling a patient they have current hepatitis C from a reactive antibody result without arranging RNA.
02
Using anti-HCV after treatment to decide whether cure has occurred.
03
Starting a DAA before establishing cirrhosis, prior decompensation, HBV status, pregnancy possibility and interaction risk.
04
Giving glecaprevir-containing therapy to decompensated cirrhosis without the specialist liver pathway.
05
Discharging a cured cirrhotic patient from HCC and portal-hypertension surveillance.
06
Withholding curative therapy because of ongoing injecting risk instead of coupling treatment with harm reduction and RNA retesting.