What are the recommended first-line treatment regimens for hepatitis C?

Hepatitis C Treatment Guidelines

First-Line Treatment Recommendations

The current standard of care for hepatitis C is pangenotypic direct-acting antiviral (DAA) therapy with either sofosbuvir/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis status. 1, 2, 3

Pangenotypic Regimens (All Genotypes 1-6)

Sofosbuvir/Velpatasvir

• Treatment-naïve patients without cirrhosis: 12 weeks without ribavirin 4, 1
• Treatment-naïve patients with compensated cirrhosis: 12 weeks without ribavirin 4, 1
• Treatment-experienced patients without cirrhosis (genotypes 1,2,4,5,6): 12 weeks without ribavirin 4
• Treatment-experienced patients without cirrhosis (genotype 3): 12 weeks with ribavirin 4, 1
• Decompensated cirrhosis: 12 weeks with ribavirin 3

Glecaprevir/Pibrentasvir

• Treatment-naïve patients without cirrhosis: 8 weeks 1, 2, 3, 5
• Treatment-naïve patients with compensated cirrhosis: 8 weeks 5
• Treatment-experienced patients without cirrhosis (genotypes 1,2,4,5,6 who received peginterferon/ribavirin/sofosbuvir only): 8 weeks 5
• Treatment-experienced patients with compensated cirrhosis (genotypes 1,2,4,5,6 who received peginterferon/ribavirin/sofosbuvir only): 12 weeks 5
• Treatment-experienced patients (genotype 3 who received peginterferon/ribavirin/sofosbuvir only): 16 weeks regardless of cirrhosis 5
• NS5A inhibitor-experienced patients (genotype 1): 16 weeks regardless of cirrhosis 5
• NS3/4A protease inhibitor-experienced patients (genotype 1): 12 weeks regardless of cirrhosis 5

Genotype-Specific Regimens

Genotype 1a

Without Cirrhosis:

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin (can shorten to 8 weeks if treatment-naïve and HCV RNA <6 million IU/mL) 4
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for 12 weeks 4
• Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4

With Compensated Cirrhosis:

• Treatment-naïve: Ledipasvir/sofosbuvir for 12 weeks without ribavirin 4, 6
• Treatment-experienced: Ledipasvir/sofosbuvir for 12 weeks with ribavirin OR 24 weeks without ribavirin 4
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for 24 weeks 4

Genotype 1b

Without Cirrhosis:

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin (can shorten to 8 weeks if treatment-naïve and HCV RNA <6 million IU/mL) 4
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir for 12 weeks without ribavirin 4
• Daclatasvir plus asunaprevir for 24 weeks (must test for NS5A resistance-associated variants L31F/I/M/V and/or Y93H; do not use if present) 4

With Compensated Cirrhosis:

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin for both treatment-naïve and treatment-experienced patients 4, 6
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir for 12 weeks without ribavirin 4

Genotype 2

• Without cirrhosis: Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4
• With cirrhosis: Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4
• Alternative: Sofosbuvir plus ribavirin for 12 weeks (non-cirrhotic) or 16 weeks (cirrhotic) 4, 3

Genotype 3

Without Cirrhosis:

• Treatment-naïve: Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4
• Treatment-experienced: Sofosbuvir plus daclatasvir for 24 weeks without ribavirin 4
• Alternative: Sofosbuvir plus ribavirin for 24 weeks 4

With Compensated Cirrhosis:

• Treatment-naïve: Sofosbuvir plus daclatasvir for 12 weeks, with consideration for adding ribavirin or extending to 24 weeks 4
• Treatment-experienced: Sofosbuvir plus daclatasvir for 24 weeks with or without ribavirin 4
• Alternative: Peginterferon plus sofosbuvir plus ribavirin for 12 weeks 4

Genotype 4

Without Cirrhosis:

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin 4
• Paritaprevir/ritonavir/ombitasvir with ribavirin for 12 weeks 4
• Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4

With Compensated Cirrhosis:

• Treatment-naïve: Ledipasvir/sofosbuvir for 12 weeks without ribavirin 4
• Treatment-experienced: Ledipasvir/sofosbuvir for 12 weeks with ribavirin 4

Genotypes 5 and 6

• Ledipasvir/sofosbuvir for 12 weeks without ribavirin (treatment-naïve) 4
• Ledipasvir/sofosbuvir for 12 weeks with ribavirin (treatment-experienced) 4
• Sofosbuvir plus daclatasvir for 12 weeks without ribavirin 4

Treatment Duration Considerations

8-Week Regimens

The 8-week duration with ledipasvir/sofosbuvir should be used cautiously and only in treatment-naïve patients without cirrhosis with baseline HCV RNA <6 million IU/mL 4. Exercise particular caution in patients with F3 fibrosis, as relapse rates are higher with shorter treatment duration 4. Real-world data confirms comparable efficacy to 12-week regimens when selection criteria are strictly followed 7.

12-Week Regimens

This is the standard duration for most patients with compensated cirrhosis and represents the backbone of treatment for treatment-naïve patients 4.

24-Week Regimens

Extended duration should be considered for:

• Treatment-experienced patients with compensated cirrhosis who cannot receive ribavirin 4
• Treatment-experienced patients with negative predictors of response (platelet count <75 × 10³/μL) 4
• Genotype 3 treatment-experienced patients with cirrhosis 4

Special Populations

HIV Coinfection

Use the same HCV treatment regimens as in HCV-monoinfected patients, but carefully evaluate for drug-drug interactions with antiretroviral therapy 4, 1.

Liver or Kidney Transplant Recipients

Glecaprevir/pibrentasvir for 12 weeks is recommended, with extension to 16 weeks for genotype 1 NS5A inhibitor-experienced patients or genotype 3 peginterferon/ribavirin/sofosbuvir-experienced patients 5.

Decompensated Cirrhosis

Sofosbuvir/velpatasvir plus ribavirin for 12 weeks is the preferred regimen 3. Ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks is an alternative, with SVR rates of 87-89% in Child-Pugh B and C patients 4.

Pre-Treatment Assessment

Required Testing

• HCV genotype determination 3
• HCV RNA viral load 3
• Assessment for cirrhosis using FIB-4 score, transient elastography, or other non-invasive methods 3
• Hepatitis B surface antigen (HBsAg) and anti-HBc testing 5
• Medication reconciliation for drug-drug interactions 3

Resistance Testing Considerations

For genotype 1a treatment-experienced patients receiving ledipasvir/sofosbuvir, if reliable NS5A resistance testing is available, those with high-level resistance mutations (M28A/G/T, Q30E/G/H/K/R, L31M/V, P32L/S, H58D, Y93C/H/N/S) should receive ribavirin for 12 weeks, while those without these mutations can be treated without ribavirin 4.

For genotype 1b patients considering daclatasvir plus asunaprevir, mandatory testing for NS5A resistance-associated variants L31F/I/M/V and/or Y93H is required; do not use this regimen if these variants are present 4.

Monitoring

During Treatment

No routine laboratory monitoring is required for most patients during treatment with modern DAA regimens 3.

Post-Treatment

• HCV RNA testing at 12 weeks post-treatment to confirm sustained virologic response (SVR12) 1, 3
• Hepatic function panel to assess normalization of liver enzymes 3
• Continue hepatocellular carcinoma surveillance with ultrasound every 6 months in patients with cirrhosis, even after achieving SVR 1

Common Pitfalls and Caveats

Drug-Drug Interactions

Carefully evaluate all concomitant medications before initiating DAA therapy, particularly in patients on multiple medications or antiretroviral therapy 1, 3. This is the most common preventable cause of treatment failure or adverse events.

Q80K Polymorphism in Genotype 1a

Patients with genotype 1a who have the NS3 Q80K polymorphism have significantly lower SVR rates (58% vs 84%) with sofosbuvir plus simeprevir 4. Use alternative regimens in these patients 1.

Treatment Duration Errors

Do not arbitrarily shorten treatment duration below guideline recommendations. The 8-week ledipasvir/sofosbuvir regimen is only appropriate for carefully selected treatment-naïve patients without cirrhosis and with HCV RNA <6 million IU/mL 4. Real-world data shows higher relapse rates when these criteria are not strictly followed 8.

Ribavirin in Cirrhotic Patients

Treatment-experienced patients with compensated cirrhosis have lower SVR rates with 12 weeks of ledipasvir/sofosbuvir without ribavirin (90%) compared to regimens with ribavirin or extended duration 6. Either add ribavirin or extend treatment to 24 weeks in this population 4, 6.

Genotype 3 Complexity

Genotype 3 is more difficult to treat than other genotypes, particularly in cirrhotic and treatment-experienced patients 4. Do not use 12-week regimens without ribavirin in treatment-experienced cirrhotic genotype 3 patients; extend to 24 weeks 4.