clinicaltrials.gov Identifier:NCT01878799.

Background Direct acting anti-HCV drugs have demonstrated a high cure rate and favorable tolerability. The development of shorter courses of therapy may improve affordability and adherence. Sofosbuvir and ledipasvir together with ribavirin have yielded high efficacy when administered for 8, but not for 6 weeks. We hypothesized that addition of a third potent directly acting antiviral to sofosbuvir and ledipasvir would allow for shortened durations of therapy. Methods In this single center, open-label cohort, phase 2 atrial, sixty HCV GT-1 treatment naïve patients were sequentially enrolled onto three arms and treated with 12 weeks of sofosbuvir and ledipasvir (an NS5B nucleotide polymerase inhibitor and an NS5A inhibitor, respectively) (n=20); or 6 weeks with sofosbuvir, ledipasvir, and GS-9669 (a non-nucleoside NS5B inhibitor) (n=20) or 6 weeks with sofosbuvir, ledipasvir and GS-9451 (an NS3/4A protease inhibitor) (n=20). Patients and investigators were unmasked to treatment assignment. The primary efficacy analysis was SVR12 (HCV RNA less than the level of quantitation 12 weeks after treatment completion). Findings All subjects treated with sofosbuvir and ledipasvir for 12 weeks achieved SVR12 (95%CI: 83–100%). Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir and GS-9669 achieved SVR12, with 1 patient relapsing 2 weeks after completion of therapy. Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir, and GS-9451 for 6 weeks achieved SVR12, one patient was lost to follow up after achieving SVR4. There were no discontinuations of treatment due to adverse events. Interpretation In this small proof of concept study, two different three drug regimens administered for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Funding NIAID, National Cancer Institute and Clinical Center Intramural Program. Clinical Trials.gov number NCT01805882. The study was also supported in part by the German Research Foundation (DFG) by the clinical research unit KFO 129 and a Collaborative Research and Development Agreement between NIH and Gilead Sciences.

Background Chronic hepatitis C (HCV) genotype 4 (GT-4) represents up to 13% of HCV infections globally, concentrated in resource limited countries in the Middle East and Africa. In patients with HCV GT-1, the combination of ledipasvir and sofosbuvir has shown high cure rates with excellent tolerability but has not been examined for HCV GT-4. We evaluated, the efficacy, safety and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir in patients infected with HCV GT-4. Methods In this single center, open-label cohort, phase 2a trial, twenty-one HCV GT-4 treatment naïve or interferon treatment-experienced patients (HIV negative) were sequentially enrolled and treated with 12 weeks of ledipasvir (aNS5A inhibitor and nucleotide polymerase inhibitor, respectively) and sofosbuvir (n=21). The primary efficacy endpoint was SVR12 (HCV RNA less than the level of quantification 12 weeks after treatment completion). Findings Twenty of 21 patients treated with a two drug combination (ledipasvir and sofosbuvir) for 12 weeks achieved SVR12 (95%CI: 76-100%), including seven patients with cirrhosis. One patient was identified as non-adherent to study medications and withdrew from the study, but is included in the intention to treat analysis. There were no discontinuations of treatment due to adverse events and no grade 3 or 4 adverse events related to study medications. Interpretation In this small proof of concept study, ledipasvir and sofosbuvir for 12 weeks in HCV GT-4 patients was well tolerated and resulted in 100% SVR on all patients who took 12 weeks of study drugs regardless of previous treatment status and underlying liver fibrosis. This is the first report of a single pill, all oral interferon and ribavirin free therapy for patients with HCV GT-4. Funding NIAID, National Cancer Institute and Clinical Center Intramural Program. Clinical Trials.gov number NCT01805882. The study was also supported in part a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success.

Background As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.MethodsMedication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.ResultsOverall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.ConclusionsAdherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.Electronic supplementary materialThe online version of this article (doi:10.1007/s12072-015-9680-7) contains supplementary material, which is available to authorized users.