alexa Predictors of Response to Grazoprevir Elbasvir Among HCV Genotype 1 (GT1)-Infected Patients: Integrated Analysis of Phase 2-3 Trials
Microbiology

Microbiology

Journal of Antivirals & Antiretrovirals

Author(s): Stefan Zeuzem

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Purpose: In phase 2-3 trials, 95% of GT1-infected patients (±cirrhosis, HIV coinfection, prior treatment, end-stage renal disease) who received grazoprevir 100 mg + elbasvir 50 mg (GZR/EBR) ± ribavirin (RBV) achieved a sustained virologic response 12 weeks after end of therapy (SVR12); 3% experienced virologic failure. This analysis assessed potential predictors of response to therapy. Methods: Analyses were performed on 2 pooled datasets of 1408 GT1-infected patients enrolled in phase 2/3 trials of GZR/EBR ± RBV: (1) treatment-naive patients (TN; N=801), and (2) patients who previously failed peginterferon + RBV ± first-generation protease inhibitor (TE; N=607). Demographic factors and presence of resistance-associated variants (RAVs) that were fit (ie, >25% of the overall baseline viral load) were considered. Univariate logistic regression models were fitted one variable at a time in assessing the potential association with SVR12. Multivariable logistic regression (MVLR) models with forward selection were then applied to identify significant (ie, P < 0.1) independent predictors of SVR12. Results: In the MVLR, among TN patients, age, sex, cirrhosis, HIV coinfection, baseline NS3 RAVs, and use of RBV did not impact SVR12 rates. Among TN GT1a-infected patients, baseline HCV RNA level and baseline NS5A RAVs conferring >5-fold shift in the potency of EBR in vitro (termed NS5A >5× RAVs) were identified as significant predictors of SVR12. Baseline HCV RNA had a significant impact only when NS5A >5× RAVs were present, representing 5.3% of the GT1a population. No significant predictors were identified among GT1b-infected patients. Among TE patients, no significant predictors were identified for GT1b-infected patients or in GT1a-infected patients with prior relapse. Among GT1a-infected patients with prior on-treatment failure, female patients and noncirrhotics had higher SVR12 rates, and the addition of RBV and/or longer treatment durations had a positive impact on SVR12. The most prevalent (>1%) NS5A >5× RAVs in both TN and TE patients were L31M and Y93H. Baseline NS5A >5× RAVs, which were detected in 8% of TE GT1a-infected patients had a significant negative impact on SVR12; this impact was confined to the 12-wk treatment duration, as no patient treated for 16 or 18 weeks with RBV experienced virologic failure. Conclusion: GZR/EBR ± RBV is highly effective among GT1-infected patients. Among GT1a-infected patients, presence of fit NS5A >5× RAVs at baseline impacts efficacy. These RAVs are uncommon (<10%), and the impact is limited to TN patients with high viral load and TE patients with prior on-treatment failure who receive 12 weeks of GZR/EBR±RBV. Code of conduct/disclaimer available in G

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This article was published in AASLD and referenced in Journal of Antivirals & Antiretrovirals

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