Which Hepatitis C Virus (HCV) genotype is typically treated with triple agent therapy including pegylated interferon (peg-IFN), ribavirin (RBV), and a protease inhibitor (PI)?

Genotype 1 HCV is Treated with Triple Agent Therapy Including Pegylated Interferon, Ribavirin, and a Protease Inhibitor

The correct answer is D. Genotype 1, as this specific HCV genotype is the primary indication for triple therapy with pegylated interferon, ribavirin, and a protease inhibitor based on current treatment guidelines. 1

Evidence for Genotype 1 Treatment with Triple Therapy

• According to the 2014 EASL recommendations, six treatment options are available for patients infected with HCV genotype 1, including both interferon/ribavirin-containing and interferon-free regimens 1
• In settings where newer direct-acting antivirals (DAAs) are not available, the triple combination of pegylated interferon-α, ribavirin, and either telaprevir or boceprevir remains an acceptable treatment option for genotype 1 1
• Triple therapy regimens with protease inhibitors achieved higher SVR rates (65-75%) than pegylated interferon-α/ribavirin dual therapy (40-50%) in genotype 1 patients 1

Treatment Approach for Genotype 1

• The standard therapeutic approach for genotype 1 HCV infection involves triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV), and NS3/NS4 protease inhibitors such as boceprevir or telaprevir 2
• First-generation protease inhibitors (telaprevir and boceprevir) must be administered in combination with pegylated interferon-α and ribavirin specifically for genotype 1 infection 1
• In clinical studies, this triple therapy demonstrated a significant increase in sustained virological response rates from 38-44% to 63-75% for treatment-naïve genotype 1 patients compared to dual therapy 3

Evidence Against Other Genotypes

• For genotype 2 and 3 infections, dual therapy with pegylated interferon-α and ribavirin was historically the standard treatment with SVR rates up to about 80% (higher for genotype 2 than genotype 3), making triple therapy unnecessary 1, 4
• For genotype 4 infections, intermediate SVR rates were achieved with dual therapy, similar to or slightly better than genotype 1 1
• The NEUTRINO trial specifically evaluated sofosbuvir plus pegylated interferon-α and ribavirin in genotype 1 and 4 patients, but protease inhibitor-based triple therapy was primarily developed for and indicated in genotype 1 4

Clinical Considerations and Pitfalls

• When using protease inhibitor-based triple therapy for genotype 1, it's important to note that subtype 1a may have lower response rates than 1b, particularly when Q80K substitution is present 1
• Cirrhosis status significantly impacts SVR rates with triple therapy - patients with cirrhosis had lower SVR rates (60-80%) compared to non-cirrhotics (84-92%) 1
• Drug-drug interactions are a major concern with protease inhibitor-based regimens, particularly in HIV co-infected patients receiving antiretroviral therapy 1

Modern Treatment Evolution

• While triple therapy with protease inhibitors was the standard of care for genotype 1 in 2011-2014, newer DAAs have since emerged that offer interferon-free regimens with higher efficacy and better tolerability 1
• The combination of sofosbuvir and simeprevir or sofosbuvir and daclatasvir (with or without ribavirin) has become more attractive for genotype 1 treatment in recent years 1
• Despite these advances, in regions with limited access to newer DAAs, triple therapy with pegylated interferon, ribavirin, and a protease inhibitor remains an acceptable option specifically for genotype 1 1, 5