What is the recommended treatment regimen for a patient with active Hepatitis C (HCV) infection, considering their viral genotype and potential presence of liver cirrhosis?

Treatment of Active Hepatitis C Infection

All patients with confirmed active HCV infection should be treated with a pangenotypic direct-acting antiviral (DAA) regimen, specifically sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis status. 1, 2, 3

Preferred First-Line Regimen

Sofosbuvir/velpatasvir is the preferred pangenotypic option, administered as a single tablet (400mg/100mg) once daily for 12 weeks, achieving 98% sustained virological response (SVR) rates across all genotypes (1-6) regardless of treatment history. 1, 3

Alternative First-Line Regimen

Glecaprevir/pibrentasvir serves as an equally effective alternative with treatment duration stratified by cirrhosis status: 1, 2, 3

• 8 weeks for patients without cirrhosis 1, 2, 4
• 12 weeks for patients with compensated cirrhosis (Child-Pugh A) 1, 2, 4

Pre-Treatment Assessment Requirements

Before initiating DAA therapy, you must obtain: 1, 2, 3

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

Genotype-Specific Considerations (When Pangenotypic Regimens Unavailable)

If pangenotypic regimens are not accessible, genotype-specific treatment follows these algorithms:

Genotype 1a (Treatment-Naive)

• Ledipasvir/sofosbuvir 90mg/400mg daily for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis) 6, 2
• Critical caveat: In cirrhotic patients with the NS3 Q80K polymorphism, sofosbuvir/simeprevir has reduced efficacy; use ledipasvir/sofosbuvir instead 6, 2

Genotype 1b (Treatment-Naive)

• Ledipasvir/sofosbuvir 90mg/400mg daily for 12 weeks 6, 2
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir for 12 weeks 6, 2

Genotype 2 (Treatment-Naive)

• Sofosbuvir/velpatasvir for 12 weeks without ribavirin 6, 2
• Sofosbuvir 400mg plus weight-based ribavirin (1000mg if <75kg, 1200mg if ≥75kg) for 12 weeks, extended to 16 weeks if cirrhosis present 6, 2

Genotype 3 (Treatment-Naive)

Genotype 3 is the most difficult to treat with available DAAs. 6

• Treatment-naive without cirrhosis: Sofosbuvir/velpatasvir for 12 weeks without ribavirin 6, 2
• Treatment-experienced or with cirrhosis: Sofosbuvir/velpatasvir plus weight-based ribavirin for 12 weeks 6, 2
• Do not use ledipasvir/sofosbuvir for genotype 3, as ledipasvir has considerably less potency against this genotype 6

Genotypes 4,5, and 6

• Sofosbuvir/velpatasvir for 12 weeks without ribavirin 6, 2
• For genotype 4: Ledipasvir/sofosbuvir for 12 weeks or paritaprevir/ritonavir/ombitasvir plus weight-based ribavirin for 12 weeks 6

Treatment Modifications for Cirrhosis

For compensated cirrhosis (Child-Pugh A): 1, 2

• Use the same pangenotypic regimens as non-cirrhotic patients 1
• Extend glecaprevir/pibrentasvir duration to 12 weeks 1, 2, 4
• Monitor closely for side effects, which are increased compared to non-cirrhotic patients 1
• Exercise special care when albumin <3.5 g/dL or platelets <100,000 1

For decompensated cirrhosis (Child-Pugh B or C): 2, 4

• Glecaprevir/pibrentasvir is contraindicated in moderate or severe hepatic impairment 4
• Use sofosbuvir/velpatasvir plus ribavirin for 12 weeks 2

Special Populations

HIV/HCV Coinfection

Use the same HCV treatment regimens as HCV mono-infected patients with identical expected virological outcomes, but verify antiretroviral drug interactions before prescribing. 1, 3

Liver or Kidney Transplant Recipients

Treat for 12 weeks with standard regimens; extend to 16 weeks for genotype 1a patients who are NS5A inhibitor-experienced or genotype 3 patients who are treatment-experienced. 4

Patients with Renal Impairment

Follow standard dosing recommendations regardless of renal function degree. 4

Critical Drug-Drug Interactions

Absolute contraindications that significantly decrease DAA concentrations and reduce efficacy: 1, 3, 4

• P-glycoprotein (P-gp) inducers 1
• Moderate-to-strong CYP3A4 inducers (carbamazepine, rifampin) 4
• Efavirenz-containing antiretroviral regimens 4
• St. John's wort 4

Specific interactions to verify: 6

• Ledipasvir/sofosbuvir has potential interaction with proton pump inhibitors 6
• Paritaprevir/ritonavir/ombitasvir has substantial interaction with salmeterol and other CYP3A4 substrates 6
• Atazanavir is contraindicated with glecaprevir/pibrentasvir 4

Monitoring Protocol

During treatment: 1, 3

• HCV RNA at baseline 1, 3
• HCV RNA at weeks 4 and 12 during treatment 1
• HCV RNA at end of treatment 1, 3

Post-treatment: 1, 3

• HCV RNA at 12 weeks post-treatment (SVR12) is the primary measure of cure, achieved in >99% of patients who reach this endpoint 1, 3
• SVR12 represents viral eradication and is associated with resolution of liver disease in non-cirrhotic patients 1

For patients with cirrhosis: 3

• Continue hepatocellular carcinoma (HCC) surveillance with ultrasound every 6 months indefinitely, even after achieving SVR 3

Treatment Prioritization

Immediate treatment priority should be given to: 1

• Patients with advanced fibrosis (≥F3) or any cirrhosis 1
• Pre- and post-liver transplant patients 1
• Patients with severe extrahepatic manifestations (symptomatic vasculitis, HCV immune complex nephropathy) 1
• Patients with hepatocellular carcinoma 1

Do not defer treatment in patients with minimal or no fibrosis (F0-F2), although timing may be more flexible. 1

Common Pitfalls and Caveats

HBV reactivation risk: Hepatitis B virus reactivation has been reported during DAA therapy, in some cases resulting in fulminant hepatitis, hepatic failure, and death. 4, 5 Test all patients for HBsAg and anti-HBc before initiating HCV treatment, monitor HCV/HBV coinfected patients during and after treatment, and initiate appropriate HBV management as clinically indicated. 4, 5

Resistance-associated substitutions (RAS): 7

• Effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del 7
• Baseline RAS identification is recommended for HCV genotype 1a 7

Genotype subtyping: Genotype 1 HCV infection that cannot be subtyped should be treated as genotype 1a infection, as genotype 1a tends to have higher relapse rates than 1b with certain regimens. 6, 3

Hepatic decompensation monitoring: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C). 4 Monitor for clinical and laboratory evidence of hepatic decompensation and discontinue treatment if it develops. 4

Expected Outcomes

With modern DAA regimens, expected outcomes include: 1

• SVR rates exceeding 95% in most patient populations 1
• Improvement in liver histology 1
• Decreased risk of cirrhotic complications 1
• Reduced occurrence of hepatocellular carcinoma 1
• Improved survival rates 1
• Resolution of extrahepatic manifestations 1