What is the recommended initial treatment for a patient with a Hepatitis C (HCV) PCR positive result?

Management of Hepatitis C PCR Positive Result

All patients with chronic HCV infection confirmed by positive HCV PCR should be treated immediately 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

Pre-Treatment Assessment Requirements

Before initiating DAA therapy, the following mandatory testing must be completed:

• HCV RNA quantitative testing to confirm active viremia 1, 2
• HCV genotype and subtype determination (though modern pangenotypic regimens eliminate genotype-specific treatment decisions) 1, 2
• Hepatitis B testing - measure both HBsAg and anti-HBc to identify current or prior HBV infection, as HBV reactivation during DAA therapy can result in fulminant hepatitis, hepatic failure, and death 3, 4, 5, 6
• Fibrosis staging assessment to determine cirrhosis status and guide treatment duration 1, 2
• Comprehensive drug-drug interaction screening with all concurrent medications, particularly P-glycoprotein inducers and moderate-to-strong CYP inducers which are absolute contraindications 1, 7, 8

First-Line Treatment Selection

Sofosbuvir/velpatasvir is the preferred pangenotypic regimen, achieving 98% SVR rates across all genotypes with a simple once-daily dosing schedule 1, 2:

• Dosing: Single tablet containing 400mg sofosbuvir/100mg velpatasvir once daily with or without food 1, 3
• Duration: 12 weeks for patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) 1, 2, 3

Glecaprevir/pibrentasvir is an equally effective alternative 1, 2:

• Dosing: Three tablets (total 300mg glecaprevir/120mg pibrentasvir) once daily with food 2, 4
• Duration: 8 weeks for patients without cirrhosis; 12 weeks for compensated cirrhosis (Child-Pugh A) 1, 2, 4

Treatment Modifications by Clinical Scenario

Decompensated Cirrhosis (Child-Pugh B or C)

• Sofosbuvir/velpatasvir plus weight-based ribavirin for 12 weeks is the recommended regimen 1, 2, 3
• Ribavirin dosing: 1,000 mg daily for patients <75 kg; 1,200 mg daily for patients ≥75 kg, divided twice daily with food 3

Liver Transplant Recipients

• Sofosbuvir/velpatasvir plus ribavirin for 12 weeks applies to both pre- and post-transplant settings 1
• For patients awaiting transplant, treatment can continue up to 48 weeks or until transplantation to prevent post-transplant reinfection 5

HIV/HCV Coinfection

• Use identical HCV treatment regimens as HCV mono-infected patients with the same expected virological outcomes 1
• Screen for drug-drug interactions with antiretroviral medications 1, 2

Treatment Prioritization

Immediate treatment priority should be given to:

• Patients with advanced fibrosis (≥F3) or any degree of cirrhosis 1, 9
• Pre- and post-liver transplant patients 1
• Patients with severe extrahepatic manifestations 1
• Patients with hepatocellular carcinoma 1
• Individuals at high risk of HCV transmission (people who inject drugs, men who have sex with men with high-risk practices, women of childbearing age wishing to conceive, hemodialysis patients) 9

Critical Drug-Drug Interactions and Contraindications

Absolute contraindications include concomitant use of:

• P-glycoprotein (P-gp) inducers 1
• Moderate-to-strong CYP inducers (e.g., carbamazepine, phenytoin, phenobarbital, rifampin, St. John's wort) which significantly decrease DAA concentrations and reduce efficacy 1, 7

Common pitfall: First-generation anticonvulsants (carbamazepine, phenytoin, phenobarbital) are contraindicated with DAAs due to enzyme induction, though limited case series suggest some patients may still achieve SVR if coadministration cannot be avoided 7. However, every effort must be made to switch to alternative anticonvulsants before initiating DAA therapy 7.

Monitoring Protocol

HCV RNA monitoring schedule:

• Baseline (pre-treatment) 1, 2
• Week 4 during treatment 1
• Week 12 during treatment (end of treatment for most regimens) 1
• Week 12 post-treatment (SVR12) - this is the primary endpoint defining cure 1, 2, 9

HBV monitoring in coinfected patients:

• Monitor for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up 3, 4, 5, 6
• Initiate HBV antiviral therapy as clinically indicated if reactivation occurs 3, 4, 5

Expected Outcomes and Definition of Cure

SVR12 (undetectable HCV RNA 12 weeks after treatment completion) represents cure and is achieved in >95-99% of patients with modern DAA regimens 1, 2, 9, 10:

• Prevents cirrhosis complications, hepatocellular carcinoma, extrahepatic manifestations, and death 1, 9
• Improves liver histology and quality of life 1, 2, 9
• Reduces risk of cirrhotic complications and hepatocellular carcinoma 1, 2

Critical caveat: Patients with established cirrhosis (F4) or advanced fibrosis (F3) remain at reduced but ongoing risk for hepatocellular carcinoma even after achieving SVR and require continued HCC surveillance with ultrasound every 6 months indefinitely 9.

Special Considerations

The evidence provided includes outdated guidelines from 2011-2013 discussing interferon-based regimens and first-generation protease inhibitors (telaprevir, boceprevir) 11. These regimens are obsolete and should not be used - modern pangenotypic DAA regimens are interferon-free, ribavirin-free (except in decompensated cirrhosis), significantly more effective, and far better tolerated 1, 2, 10.