Caring Ambassadors Program Hepatitis C Literature Review

Post-Treatment Resistance Analysis of Hepatitis C Virus from Phase 2 and 3 Clinical Trials of Ledipasvir/ Sofosbuvir. Wyles D1, Dvory-Sobol H2, Svarovskaia Doehle ES3, et al. J Hepatol. 2016 Dec 3. pii: S0168-8278(16)30699-7. doi: 10.1016/j.jhep.2016.11.022. [Epub ahead of print] BACKGROUND & AIMS: Ledipasvir/sofosbuvir combination treatment in phase 3 clinical trials, resulted in sustained viral suppression in 94%-99% of patients. Characterization of drug resistance in treatment failures may help inform retreatment options. METHODS: We performed NS5A and NS5B deep sequencing of HCV from patients infected with genotype (GT) 1 who participated in ledipasvir/sofosbuvir phase 2 and 3 clinical trials. RESULTS: Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cutoff). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24 weeks, respectively. The common substitutions detected at failure were Q30R/H, Y93H/N and/or L31M in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had 2 or more NS5A RASs and the majority of patients harbored NS5A RASs conferring 100-1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase 2 study with a known ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. CONCLUSIONS: In GT1 HCV-infected patients treated with ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. LAY SUMMARY: Clinical studies have shown that combination treatment with ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for selection of optimal retreatment strategies for these patients.