What is the recommended treatment regimen for a patient with Hepatitis C (HCV) genotype 1, using Direct-Acting Antivirals (DAAs)?

Treatment of Hepatitis C Genotype 1 with Direct-Acting Antivirals

For HCV genotype 1 infection, initiate treatment with sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks, which achieves 98% sustained virologic response (SVR) rates regardless of cirrhosis status. 1, 2, 3

First-Line Pangenotypic Regimens

The American Association for the Study of Liver Diseases recommends pangenotypic DAA regimens as the standard of care for all HCV genotype 1 patients 1, 2:

• Sofosbuvir/velpatasvir 400mg/100mg: One tablet once daily for 12 weeks, taken with or without food 1, 4
• Glecaprevir/pibrentasvir: Three tablets (300mg/120mg total) once daily with food for 8 weeks in patients without cirrhosis, or 12 weeks in patients with compensated cirrhosis (Child-Pugh A) 1, 2, 5

Both regimens achieve SVR rates exceeding 95-98% across all patient populations 1, 2. Sofosbuvir/velpatasvir is preferred as it maintains the same 12-week duration regardless of cirrhosis status, simplifying treatment decisions 3, 4.

Treatment Duration by Cirrhosis Status

Treatment-naive patients without cirrhosis:

• Sofosbuvir/velpatasvir: 12 weeks 1, 4
• Glecaprevir/pibrentasvir: 8 weeks 1, 5

Treatment-naive patients with compensated cirrhosis (Child-Pugh A):

• Sofosbuvir/velpatasvir: 12 weeks 1, 4
• Glecaprevir/pibrentasvir: 12 weeks (extended from 8 weeks) 1, 5

Patients with decompensated cirrhosis (Child-Pugh B or C):

• Sofosbuvir/velpatasvir plus weight-based ribavirin for 12 weeks 1, 4
• Ribavirin dosing: 1,000mg daily if <75kg, 1,200mg daily if ≥75kg, divided twice daily with food 4

Alternative Genotype-Specific Regimens

If pangenotypic regimens are unavailable, genotype-specific options for genotype 1a include 2, 3:

• Ledipasvir/sofosbuvir 90mg/400mg: Once daily for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis) 2, 3
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin: For 12 weeks in genotype 1a 2

For genotype 1b, ledipasvir/sofosbuvir for 12 weeks or paritaprevir/ritonavir/ombitasvir plus dasabuvir (without ribavirin) for 12 weeks are effective 2.

Pre-Treatment Requirements

Before initiating DAA therapy, complete the following assessments 1, 2, 3:

• HCV RNA quantitative testing to confirm active viremia 1, 3
• HCV genotype and subtype determination (distinguishing 1a from 1b affects certain regimen selections) 1, 2, 3
• Hepatitis B screening: Measure HBsAg and anti-HBc in all patients, as HBV reactivation can occur during DAA therapy 4, 5
• Fibrosis staging using non-invasive methods (FibroScan, APRI, FIB-4) or liver biopsy if uncertainty exists 1, 3
• Comprehensive drug-drug interaction screening before prescribing 1, 2

Critical Drug-Drug Interactions

Absolute contraindications that significantly reduce DAA efficacy include 1, 2, 3:

• P-glycoprotein (P-gp) inducers: rifampin, St. John's wort 1, 3
• Moderate-to-strong CYP3A4 inducers: carbamazepine, phenytoin, phenobarbital 1, 3
• Efavirenz-containing antiretroviral regimens 1

Important interactions requiring dose adjustments:

• Ledipasvir/sofosbuvir with proton pump inhibitors 2
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir with salmeterol and CYP3A4 substrates 2

Carefully evaluate all concomitant medications before initiating therapy 1, 2.

Monitoring Protocol

During treatment 1, 2:

• Measure HCV RNA at baseline, weeks 4 and 12, and end of treatment 1, 2
• Monitor for adverse events (generally mild with DAA-only regimens; more common with ribavirin-containing regimens) 3

Post-treatment 1, 2:

• SVR12 (undetectable HCV RNA 12 weeks after treatment completion) is the primary measure of cure, achieved in >99% of patients who reach this endpoint 1, 2
• For cirrhotic patients, continue hepatocellular carcinoma surveillance with ultrasound every 6 months even after achieving SVR 2

Special Populations

HIV/HCV coinfection:

• Use the same HCV treatment regimens as HCV mono-infected patients 1, 2
• Verify antiretroviral drug interactions before prescribing 1, 2

Kidney transplant recipients with GFR ≥30 mL/min/1.73m²:

• Sofosbuvir/ledipasvir for 12-24 weeks or sofosbuvir/daclatasvir for 12-24 weeks 6

Patients with chronic kidney disease (CKD G4-G5ND):

• Glecaprevir/pibrentasvir for 8 weeks or grazoprevir/elbasvir for 12 weeks (genotypes 1a, 1b, 4 only) 6

Common Pitfalls and Caveats

Cirrhosis status determines treatment duration: Glecaprevir/pibrentasvir requires 8 weeks without cirrhosis but 12 weeks with compensated cirrhosis, while sofosbuvir/velpatasvir remains 12 weeks regardless 1, 2, 5.

Protease inhibitors are contraindicated in decompensated cirrhosis: Drugs ending in "-previr" (simeprevir, paritaprevir, grazoprevir) cannot be used in Child-Pugh B or C cirrhosis 6.

HBV reactivation risk: All patients must be screened for current or prior HBV infection before starting DAA therapy, as reactivation can result in fulminant hepatitis, hepatic failure, and death 4, 5.

Treatment prioritization should focus on patients with advanced fibrosis (≥F3), any cirrhosis, pre- and post-liver transplant status, severe extrahepatic manifestations, hepatocellular carcinoma, and active injection drug users 2.

Expected Outcomes

With modern DAA regimens, expect 1, 2, 3:

• SVR rates exceeding 95-98% in most patient populations 1, 2, 3
• Improvement in liver histology and decreased risk of cirrhotic complications 3
• Reduced occurrence of hepatocellular carcinoma 6
• Improved survival rates 6
• Resolution of extrahepatic manifestations 1

The infection is cured in more than 99% of patients who achieve SVR12 6, 1.