Faculty Bibliography

Mericitabine (RG7128), an orally administered prodrug of PSI-6130, is the most clinically advanced nucleoside analogue inhibitor of the RNA-dependent RNA polymerase (RdRp) of HCV. This review describes what has been learnt so far about the resistance profile of mericitabine. A serine to threonine substitution at position 282 (S282T) of the RdRp that reduces its replication capacity to approximately 15% of wild-type is the only variant that has been consistently generated in serial in vitro passage experiments. To date, no evidence of genotypic resistance to mericitabine has been detected by population or clonal sequence analysis in any baseline or on-treatment samples collected from >600 patients enrolled in Phase I/II trials of mericitabine administered as monotherapy, in combination with pegylated interferon/ribavirin, or in combination with the protease inhibitor, danoprevir, for 14 days in the proof-of-concept study of interferon-free therapy.

Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naive patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens.

Direct-acting antiviral agents in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve sustained virologic response rate and reduce duration of therapy among both treatment-naive and treatment-experienced patients with genotype 1 chronic hepatitis C. One of the most important considerations with both boceprevir and telaprevir is the potential development of resistant variants with therapy. Patients with poor intrinsic responsiveness to interferon, and those with incomplete virological suppression on protease inhibitor therapy, appear to be at higher risk for resistance. In this article we will define antiviral resistance and review the data on both in vitro and in vivo resistance to protease inhibitors, concentrating on data on boceprevir and telaprevir. We will also explore the significance of resistant variants present at the baseline, as well as the fate of the resistant variants and the ways to minimize the development of resistance to protease inhibitors.

UNLABELLED: In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of >/= 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a >/= 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. CONCLUSION: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels >/= 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level >/= 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.

Background: Patients in P/R control arms of BOC Phase II/III studies who did not achieve SVR could receive BOC + P/R in PROVIDE. This interim analysis examines preliminary efficacy and safety of BOC + P/R in patients who failed prior P/R treatment. Methods: BOC (800 mg TID) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/ day) BID for up to 44 weeks. If > 2 weeks had elapsed since end of treatment (EOT) in the previous study, P/R was given for 4 weeks before adding BOC. Analyses included patients who received >=1 BOC dose. Denominators for on-treatment response included patients who reached the specific time point or discontinued, while those for SVR included all who reached end of follow-up, discontinued, or failed treatment. Results: 67% of 168 enrolled patients were male, 84% Caucasian, mean age 52 years, mean body mass index (BMI) 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% HCV subtype 1a. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of partial responders/ relapsers; 78% (38/49) of prior null responders and 24% (26/107) of partial responders/relapsers had <1 log10 decline in HCV RNA after P/R lead in. Overall SVR was 47% in patients with <1 log10 decline with 36% SVR rates in prior null versus 65% partial responders/relapsers. 68% of patients with >=1 log decline achieved SVR (55% prior null; 70% prior partial responders/relapsers) and 7% discontinued due to adverse events. (Table Presented) Conclusions: BOC + P/R achieved high SVR rates regardless of prior response to P/R. Degree of interferon responsiveness after P/R lead in correlated with prior response and could help predict SVR for prior null responders. The safety profile was comparable to that previously reported for BOC + P/R

For a decade, standard therapy for patients with genotype 1 chronic HCV (HCV G1) consisted of pegylated interferon (Peg-IFN) alfa-2a or Peg-IFN alfa-2b, combined with ribavirin. Despite the improved efficacy of this therapy over others, the overall sustained virologic response rate in patients with HCV G1 was still low. This article discusses phase I, II, and III trials examining telaprevir's role in treating patients with HCV. We have now entered an era of combination therapy utilizing direct acting anti-virals, the start of which was marked by the FDA approval of HCV protease inhibitors.