Re-treatment of Chronic Hepatitis C Virus Genotype 1 Infection After Relapse

Abstract

Background The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined. Objective To assess the safety and efficacy of sofosbuvir and ledipasvir in chronic HCV GT-1 infected subjects who relapsed following sofosbuvir/ribavirin therapy. Design Phase 2a, open-label study (ClinicalTrials.gov, number NCT01805882). Setting Single U.S site. Subjects Fourteen HCV, GT-1 subjects who relapsed following treatment with 24 weeks of sofosbuvir/ribavirin were treated with 12 weeks of sofosbuvir/ledipasvir. Measurments HCV RNA concentration and population sequencing to detect NS5B S282T mutations. Results All 14 subjects treated with sofosbuvir/ledipasvir for 12 weeks achieved a sustained virologic response, including seven with advanced liver disease (HAI-fibrosis 3-4) and one with a detectable NS5B S282T mutation post sofosbuvir/ribavirin therapy. Sofosbuvir/ledipasvir was well tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a subject with baseline renal insufficiency, hypercholesterolemia and hypophosphatemia (n=2)) occurred. There were no grade 4 events or treatment discontinuations. Limitations Small sample size. Conclusions The fixed-dose combination of sofosbuvir/ledipasvir was efficacious in a small cohort of subjects with HCV GT-1 infections who relapse following sofosbuvir/ribavirin therapy, even in the setting of advanced liver disease. Larger studies are needed to confirm these preliminary efficacy results. Primary Funding Source National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program and a Collaborative Research And Development Agreement between NIAID and Gilead Sciences, Inc.

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

“…The reason for virologic failure in the patients without S282T development is not completely clear, but the most likely explanation is persistence of a wild‐type virus that was not completely eradiated by the treatment. Moreover, several studies have demonstrated that virologic failures of an SOF‐based regimen can be successfully retreated with another SOF‐based regimen 19, 20. In the current study, eight of nine patients who failed SOF or LDV/SOF with treatment‐emergent S282T achieved SVR following retreatment with a second course of SOF‐based regimen, with either a second or third DAA or longer treatment duration.…”

“…Even the failure to detect RASs after treatment failure does not rule out the possibility that RASs may have emerged at the time of treatment failure before being replaced by wild type because of their relatively poor replication fitness. Two recent studies have demonstrated that previous virologic failure with SOF‐based treatment does not prevent successful retreatment with another SOF‐based regimen 19, 20. In both studies, all patients with HCV GT1 infection who had relapsed after SOF+RBV with or without pegylated interferon achieved SVR following 12 weeks LDV/SOF with or without RBV.…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…Moreover, it provides better sustained virological response in relapsing cases from RBV/SOF combination. [17] While it is only currently available as a combination with Sof. Ledipasvir several studies have shown its value as a combination therapy with other DAA therapies, other than SOF.…”

Management of Hepatitis C Infection with Direct Action Antiviral Drugs (DAA)

“…In other small nonrandomized (SPARE Study) of patients with genotype1 (most 1a) who failed 24 weeks of SOF plus RBV and were retreated with 12 weeks of sofosbuvir e ledipasvir. All reached SVR after completion of therapy [60].…”