What are the recommended first-line treatment regimens for Hepatitis C Virus (HCV) infection?

First-Line Treatment for Hepatitis C Virus (HCV) Infection

The recommended first-line treatment for chronic HCV infection is a pangenotypic direct-acting antiviral (DAA) regimen: either sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks or glecaprevir/pibrentasvir (300 mg/120 mg) once daily for 8 weeks in patients without cirrhosis. 1, 2

Treatment Regimens by Patient Population

For Treatment-Naïve Patients Without Cirrhosis

All HCV genotypes (1-6):

• Sofosbuvir/velpatasvir: 12 weeks without ribavirin 3, 4
• Glecaprevir/pibrentasvir: 8 weeks 1, 5

Both regimens achieve SVR rates exceeding 95-99% across all genotypes 1, 6. These are single-tablet, once-daily regimens that should be taken with food 4, 5.

For Treatment-Naïve Patients With Compensated Cirrhosis (Child-Pugh A)

All HCV genotypes (1-6):

• Sofosbuvir/velpatasvir: 12 weeks without ribavirin 3, 4
• Glecaprevir/pibrentasvir: 8 weeks 1, 5

The SVR12 rates remain high (93-98%) even in cirrhotic patients 3, 6.

For Treatment-Experienced Patients

Genotype 1,2,4,5, or 6 (previously treated with peginterferon/ribavirin/sofosbuvir only):

• Sofosbuvir/velpatasvir: 12 weeks without ribavirin 3, 4
• Glecaprevir/pibrentasvir: 8 weeks (no cirrhosis) or 12 weeks (compensated cirrhosis) 5

Genotype 3 (previously treated with peginterferon/ribavirin/sofosbuvir only):

• Sofosbuvir/velpatasvir: 12 weeks WITH ribavirin if no NS5A resistance testing performed 3
• Glecaprevir/pibrentasvir: 16 weeks 5

Prior NS5A inhibitor failure (Genotype 1):

• Glecaprevir/pibrentasvir: 16 weeks 5

Prior NS3/4A protease inhibitor failure (Genotype 1):

• Glecaprevir/pibrentasvir: 12 weeks 5

Genotype-Specific Considerations

Genotype 3 Infection

This is the most challenging genotype to treat. 3

• Treatment-naïve without cirrhosis: Sofosbuvir/velpatasvir 12 weeks without ribavirin achieves 98% SVR 3
• Treatment-experienced or cirrhotic patients: Add weight-based ribavirin (1000 mg if <75 kg, 1200 mg if ≥75 kg) for 12 weeks if NS5A RAS Y93H is present 3
• Alternative: Sofosbuvir/daclatasvir 24 weeks with ribavirin for cirrhotic patients 3

Important caveat: Sofosbuvir/ledipasvir is NOT recommended for genotype 3 due to insufficient NS5A potency 3. In Asian populations with genotype 3b and cirrhosis, SVR rates may be lower (50%) even with sofosbuvir/velpatasvir 7.

Genotype 1 Infection

Multiple highly effective options exist:

• Sofosbuvir/velpatasvir: 12 weeks (98-99% SVR) 3, 6
• Sofosbuvir/ledipasvir: 12 weeks 3
• Ombitasvir/paritaprevir/ritonavir + dasabuvir:
  • Genotype 1b: 12 weeks without ribavirin 3
  • Genotype 1a without cirrhosis: 12 weeks with ribavirin 3
  • Genotype 1a with cirrhosis: 24 weeks with ribavirin 3

Genotype 2 Infection

• Sofosbuvir/velpatasvir: 12 weeks without ribavirin (99% SVR) 3
• Alternative: Sofosbuvir/daclatasvir 12 weeks without ribavirin 3

Special Populations

HIV/HCV Coinfection

Use the same HCV treatment regimens as in HCV monoinfection 1, 2. However, carefully evaluate drug-drug interactions with antiretroviral therapy 2:

• Daclatasvir dose adjustments: 30 mg with ritonavir/cobicistat-boosted regimens; 90 mg with efavirenz 2
• Sofosbuvir/velpatasvir achieved 95% SVR12 in HIV-coinfected patients 8

Decompensated Cirrhosis (Child-Pugh B or C)

Sofosbuvir/velpatasvir PLUS weight-based ribavirin for 12 weeks 2, 4. This is the only recommended regimen for decompensated cirrhosis, achieving 85-100% SVR 9.

Critical warning: Glecaprevir/pibrentasvir is contraindicated in Child-Pugh B or C cirrhosis 5.

Liver or Kidney Transplant Recipients

• Sofosbuvir/velpatasvir: 12 weeks for treatment-naïve and treatment-experienced recipients without cirrhosis or with compensated cirrhosis 4
• Glecaprevir/pibrentasvir: 12 weeks 5

Pediatric Patients (≥3 Years)

Weight-based dosing is required:

• Sofosbuvir/velpatasvir: 150 mg/37.5 mg (<17 kg), 200 mg/50 mg (17-30 kg), 400 mg/100 mg (≥30 kg) once daily for 12 weeks 4
• Glecaprevir/pibrentasvir: Oral pellets for <45 kg; tablets for ≥45 kg, duration 8 weeks 5

Critical Pre-Treatment Testing

Before initiating any DAA therapy, test ALL patients for:

• Hepatitis B surface antigen (HBsAg) 4, 5
• Hepatitis B core antibody (anti-HBc) 4, 5

HBV reactivation has resulted in fulminant hepatitis, hepatic failure, and death in HCV/HBV coinfected patients receiving DAAs without HBV treatment 5.

Monitoring and Follow-Up

• Measure HCV RNA at baseline, weeks 4 and 12 during treatment, end of treatment, and 12 weeks post-treatment 2
• SVR is defined as undetectable HCV RNA (<15 IU/mL) at 12 weeks after treatment completion 2, 7
• For patients with cirrhosis who achieve SVR, continue hepatocellular carcinoma surveillance with ultrasound every 6 months indefinitely 1, 2

Common Pitfalls to Avoid

1. Do not use sofosbuvir/ledipasvir for genotype 3 - it lacks sufficient potency 3
2. Do not use glecaprevir/pibrentasvir in decompensated cirrhosis - it is contraindicated 5
3. Always check for HBV coinfection before starting treatment - reactivation can be fatal 4, 5
4. For genotype 3 with cirrhosis or treatment experience, add ribavirin unless NS5A resistance testing shows no Y93H mutation 3
5. Evaluate all drug-drug interactions, particularly with HIV antiretrovirals, before initiating therapy 2
6. Administer all DAA regimens with food to optimize absorption and tolerability 4, 5

Safety Profile

Both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are extremely well tolerated 10, 9, 6. The most common adverse events are:

• Fatigue (25%) 8
• Headache (13%) 8
• Nausea 9
• Upper respiratory tract infection 7, 8

Discontinuation rates due to adverse events are <1% 6. Serious adverse events are rare (1-2%) and typically unrelated to treatment 7, 8.