What is the best medication to treat Hepatitis C (Hep C)?

Best Medication to Treat Hepatitis C

Sofosbuvir/velpatasvir for 12 weeks is the preferred first-line treatment for chronic hepatitis C across all genotypes (1-6), regardless of treatment history or presence of compensated cirrhosis. 1

Pangenotypic First-Line Regimens

The American Association for the Study of Liver Diseases recommends sofosbuvir/velpatasvir as the preferred pangenotypic regimen because it achieves 95-98% sustained virologic response (SVR) rates across all genotypes without requiring genotype-specific adjustments 1. This single-tablet, once-daily regimen simplifies treatment and eliminates the need for genotype testing in resource-limited settings.

Alternative pangenotypic options include:

• Glecaprevir/pibrentasvir: 8 weeks for non-cirrhotic patients, 12 weeks for compensated cirrhosis 1, 2
• Ledipasvir/sofosbuvir: Highly effective for genotypes 1,4,5, and 6 1, 3

Genotype-Specific Considerations

Genotype 1 (Most Common in North America/Europe)

For treatment-naive patients without cirrhosis:

• Ledipasvir/sofosbuvir for 8 weeks if HCV RNA <6 million IU/mL 3, 4
• Ledipasvir/sofosbuvir for 12 weeks for all others 5
• Glecaprevir/pibrentasvir for 8 weeks 5, 2

For treatment-naive patients with compensated cirrhosis:

• Ledipasvir/sofosbuvir for 12 weeks 5
• Glecaprevir/pibrentasvir for 12 weeks 5, 2
• Sofosbuvir/velpatasvir for 12 weeks 5

For treatment-experienced patients:

• If prior NS5A inhibitor failure: Glecaprevir/pibrentasvir for 16 weeks 5, 2
• If prior NS3/4A protease inhibitor failure: Ledipasvir/sofosbuvir for 12 weeks 5

Genotype 2

Sofosbuvir plus ribavirin for 12 weeks in non-cirrhotic patients, 16 weeks in cirrhotic patients 1, 6. However, sofosbuvir/velpatasvir for 12 weeks is preferred as it avoids ribavirin-related side effects 1.

Genotype 3

For treatment-naive patients:

• Sofosbuvir/velpatasvir for 12 weeks (non-cirrhotic) 5, 1
• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks (cirrhotic) 5, 1
• Glecaprevir/pibrentasvir for 8 weeks (non-cirrhotic) or 12 weeks (cirrhotic) 5

For treatment-experienced patients:

• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks 5, 1
• Glecaprevir/pibrentasvir for 16 weeks 5

Genotypes 4,5, and 6

All three genotypes respond well to:

• Sofosbuvir/velpatasvir for 12 weeks (highest quality evidence with 100% SVR in GT4 and GT6) 5
• Ledipasvir/sofosbuvir for 12 weeks 5
• Glecaprevir/pibrentasvir for 8 weeks (non-cirrhotic) or 12 weeks (cirrhotic) 5

Special Populations

Decompensated Cirrhosis (Child-Pugh B or C)

Ledipasvir/sofosbuvir plus ribavirin for 12 weeks is the recommended regimen 5, 7. This combination achieved 86-89% SVR12 in patients with decompensated cirrhosis 7. Interferon-free regimens are the only safe options in this population 5.

Post-Liver Transplant

Ledipasvir/sofosbuvir plus ribavirin for 12 weeks achieved 96-98% SVR12 in transplant recipients without cirrhosis or with compensated cirrhosis 7. For patients with moderate hepatic impairment post-transplant, SVR12 rates were 85-88% 7.

HIV/HCV Coinfection

The same regimens and durations as HCV monoinfection are recommended, with sofosbuvir/velpatasvir achieving 92-95% SVR rates 1. Comprehensive medication reconciliation is critical to identify drug-drug interactions with antiretroviral therapy 1.

Treatment Duration Algorithm

Non-cirrhotic, treatment-naive:

• 8 weeks: Glecaprevir/pibrentasvir (all genotypes) 5, 2 OR ledipasvir/sofosbuvir (GT1 with HCV RNA <6 million IU/mL) 3, 4
• 12 weeks: Sofosbuvir/velpatasvir (all genotypes) 1

Compensated cirrhosis, treatment-naive:

• 12 weeks for all regimens 5, 1

Treatment-experienced with prior DAA failure:

• 16 weeks: Glecaprevir/pibrentasvir 5, 2

Critical Pre-Treatment Assessment

Mandatory testing before initiating therapy:

• HCV genotype and viral load determination 1
• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) to assess HBV reactivation risk 2, 4
• Assessment for cirrhosis using FIB-4 score, transient elastography, or other non-invasive methods 1
• Comprehensive medication reconciliation for drug-drug interactions 1

Monitoring and Follow-Up

During treatment:

• No routine HCV RNA monitoring is required during therapy for most patients 1

Post-treatment:

• HCV RNA at 12 weeks post-treatment to confirm SVR12 (undetectable HCV RNA = virological cure) 1, 3
• Hepatic function panel to assess normalization of liver enzymes 1

Common Pitfalls and Warnings

Hepatitis B reactivation: All patients must be tested for current or prior HBV infection before starting HCV treatment, as HBV reactivation can cause fulminant hepatitis, liver failure, and death 2, 4, 6. Monitor HCV/HBV coinfected patients during and after HCV treatment 2.

Proton pump inhibitor interactions: Concurrent PPI use was associated with lower SVR rates in real-world studies 8. Ledipasvir absorption is pH-dependent; if PPIs are necessary, take ledipasvir/sofosbuvir 4 hours before the PPI 4.

Ribavirin considerations: When ribavirin is required, use weight-based dosing (1000 mg if <75 kg, 1200 mg if ≥75 kg) 5. Ribavirin requires dose reduction in renal impairment (CrCl ≤50 mL/min) 1. Pregnancy must be avoided during and for 6 months after ribavirin-containing regimens 4, 6.

Amiodarone interaction: Concurrent use of amiodarone with sofosbuvir-containing regimens can cause severe bradycardia, potentially requiring pacemaker placement or resulting in death 6. Avoid this combination or provide intensive cardiac monitoring 6.

African Americans with advanced fibrosis: Real-world data showed lower SVR rates (83%) with 8-week ledipasvir/sofosbuvir in African Americans with stage 3 fibrosis 9. Use 12-week regimens in this population 9.

Underutilization of 8-week regimens: Despite eligibility, only 44% of qualifying patients received 8-week ledipasvir/sofosbuvir in real-world practice, with equivalent outcomes to 12-week therapy 8. Expanded use of 8-week treatment for eligible patients is supported by real-world data 8.