What is the recommended evaluation and management, including antiviral therapy and surveillance, for a patient with chronic hepatitis C–related liver disease?

Management of Hepatitis C-Related Chronic Liver Disease

All patients with chronic hepatitis C should be offered direct-acting antiviral (DAA) therapy immediately, regardless of fibrosis stage, as modern regimens achieve cure rates exceeding 95% and prevent progression to cirrhosis, hepatocellular carcinoma, and death. 1, 2

Initial Diagnostic Confirmation

• Confirm active HCV infection by testing HCV RNA using a sensitive molecular method with detection limit <15 IU/mL on the same blood sample as the positive anti-HCV antibody test 3, 4
• Quantify baseline HCV RNA levels expressed in IU/mL using real-time PCR assays 3
• Determine HCV genotype (1-6) prior to treatment initiation, as this guides ribavirin dosing in older regimens, though pangenotypic DAAs have largely eliminated this requirement 3
• For genotype 1, subtyping (1a vs 1b) provides information on resistance barriers and response rates in certain treatment scenarios 3

Pre-Treatment Assessment of Disease Severity

Identifying patients with cirrhosis is critical because they require hepatocellular carcinoma surveillance every 6 months indefinitely, even after achieving sustained virological response. 3, 2

Fibrosis Assessment Strategy

• Use non-invasive methods as first-line assessment rather than liver biopsy for most patients 3, 2
• Transient elastography (liver stiffness measurement): LSM <8 kPa suggests minimal fibrosis; LSM ≥10 kPa indicates advanced fibrosis/cirrhosis 2
• FIB-4 score: <1.45 suggests minimal fibrosis; >3.25 indicates advanced fibrosis/cirrhosis 2
• Serum biomarker panels (APRI, AST/ALT ratio, Forns Index) can detect significant fibrosis (METAVIR F2-F4) 3
• Combining transient elastography with serum biomarkers improves diagnostic accuracy and reduces need for liver biopsy 3
• Liver biopsy remains the reference standard when non-invasive tests are contradictory, when assessing mixed etiologies (HBV coinfection, metabolic syndrome, alcohol), or in obese patients where elastography performance is reduced 3
• Perform disease severity evaluation regardless of ALT levels, as significant fibrosis can progress even with repeatedly normal ALT 3

Additional Pre-Treatment Evaluation

• Test for HBV (HBsAg, anti-HBc, anti-HBs) and HIV, as coinfection alters management and increases mortality risk 3, 4
• Assess and quantify alcohol consumption; provide specific counseling for complete abstinence, as alcohol accelerates fibrosis progression and increases HCC risk 3, 4
• Evaluate for metabolic comorbidities including diabetes, obesity (BMI ≥25 kg/m²), and metabolic syndrome, which accelerate fibrosis progression 3, 2
• Screen for autoimmune diseases, genetic hemochromatosis, and drug-induced hepatotoxicity 3
• Assess renal function (serum creatinine, eGFR), as severe renal impairment (eGFR <30 mL/min) contraindicates sofosbuvir-containing regimens 1
• Vaccinate against hepatitis A and B if not immune 4

Treatment Recommendations

First-Line Pangenotypic DAA Regimens

Sofosbuvir/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8 weeks (no cirrhosis) or 12 weeks (compensated cirrhosis) are the preferred first-line options, achieving SVR rates of 95-100% across all genotypes. 1, 5

Treatment Priority Groups (Treat Immediately Regardless of Fibrosis Stage)

• Patients with significant fibrosis (METAVIR F3-F4) or any degree of cirrhosis 3, 1
• Clinically significant extrahepatic manifestations: symptomatic cryoglobulinemia, HCV-related nephropathy, vasculitis, non-Hodgkin B-cell lymphoma 3, 1
• HIV or HBV coinfection 1
• Active injection drug users (to prevent transmission) 1
• Men who have sex with men engaging in high-risk sexual practices 1
• Women of childbearing age planning pregnancy 1
• Hemodialysis patients 1
• Liver or other solid organ transplant recipients or candidates 1
• Incarcerated individuals 1

Special Population Considerations

Decompensated Cirrhosis (Child-Pugh B/C):

• Avoid all protease inhibitor-containing regimens due to risk of hepatic decompensation 3, 1
• Use sofosbuvir/velpatasvir for 12 weeks plus ribavirin (starting 600 mg daily) 1
• Patients with MELD score ≥18-20 who are transplant candidates should generally be transplanted first and treated post-transplantation 1
• Monitor closely, as clinical trials reported 5% mortality from variceal bleeding during treatment 1

Severe Renal Impairment (eGFR <30 mL/min or dialysis):

• Avoid sofosbuvir-containing regimens when feasible 1
• For genotype 1a: grazoprevir/elbasvir for 12 weeks 1
• For genotype 1b: grazoprevir/elbasvir for 12 weeks without ribavirin 1
• Initiate ribavirin at 200 mg/day only if hemoglobin >10 g/dL; monitor frequently and discontinue if hemoglobin falls below 8.5 g/dL 1

Compensated Cirrhosis (Child-Pugh A):

• Glecaprevir/pibrentasvir for 12 weeks 1
• Sofosbuvir/velpatasvir for 12 weeks 1
• Require surveillance for esophageal varices and HCC 3

No Cirrhosis (Treatment-Naïve):

• Glecaprevir/pibrentasvir for 8 weeks (shortest effective regimen) 1, 5
• Sofosbuvir/velpatasvir for 12 weeks 1, 5

Treatment Contraindications

• Limited life expectancy due to non-hepatic causes 3, 1
• Uncontrolled depression, psychosis, or epilepsy (for interferon-containing regimens only; not applicable to modern DAAs) 3
• Pregnancy or unwillingness to use adequate contraception (for ribavirin-containing regimens) 3
• Severe concurrent medical disease: poorly controlled hypertension, heart failure, diabetes, chronic obstructive pulmonary disease (for interferon-containing regimens) 3

Treatment Endpoint and Definition of Cure

• Sustained virological response (SVR) is defined as undetectable HCV RNA (<15 IU/mL) at 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion 3
• SVR12 and SVR24 have 99% concordance and both are accepted regulatory endpoints 3
• SVR corresponds to definitive cure in >99% of cases with long-term follow-up 3, 4

Post-Treatment Surveillance and Follow-Up

Patients Who Achieve SVR Without Cirrhosis

• Patients with minimal fibrosis (LSM <8 kPa or FIB-4 <1.45) and no other liver disease cofactors can be discharged to primary care after confirming SVR 2
• Monitor for persistent cofactors (metabolic dysfunction-associated steatotic liver disease, harmful alcohol intake) that require ongoing specialized follow-up 2

Patients Who Achieve SVR With Advanced Fibrosis or Cirrhosis

Continue hepatocellular carcinoma surveillance with abdominal ultrasound every 6 months indefinitely, as HCV eradication reduces but does not eliminate HCC risk. 3, 2

• Perform laboratory testing (platelet count, ALT, bilirubin, albumin) every 6-12 months 2
• Continue screening for esophageal varices per standard cirrhosis protocols 3
• SVR reduces rates of hepatic decompensation and will reduce (but not abolish) HCC risk 3
• Some patients retain residual risk of progressive liver damage, decompensation, and death despite viral clearance 6

Monitoring for Persistent Liver Injury Post-SVR

• Persistently elevated liver enzymes after viral clearance indicate ongoing inflammation from other causes (alcohol, metabolic syndrome, autoimmune disease) or residual HCV-related inflammatory changes 2
• Reassess for alternative or concurrent liver disease etiologies if biochemical abnormalities persist 2

Common Pitfalls to Avoid

• Do not defer treatment in patients with active substance use—they should be prioritized to prevent disease progression and onward transmission 1
• Do not use IL28B genotyping to defer therapy in patients most in need of treatment (those with significant fibrosis), as its predictive value is low and only relevant for interferon-based regimens 3
• Do not assume normal ALT levels indicate absence of significant fibrosis—disease severity evaluation must be performed regardless of ALT patterns 3
• Do not use protease inhibitors in decompensated cirrhosis due to risk of further hepatic decompensation 3, 1
• Do not use sofosbuvir in severe renal impairment (eGFR <30 mL/min) unless no alternative exists, and monitor renal function closely 1
• Do not discontinue HCC surveillance after SVR in patients with cirrhosis or advanced fibrosis—the risk is reduced but persists indefinitely 3, 2