Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

TLDR

Phase 2 studies showed that the all‑oral ledipasvir‑sofosbuvir combination achieved high sustained virologic response rates in treatment‑naïve HCV genotype 1 patients, prompting a phase 3 open‑label trial. The phase 3 study aimed to confirm the efficacy and safety of ledipasvir‑sofosbuvir, with or without ribavirin, in previously untreated chronic HCV genotype 1 infection. Patients were randomized 1:1:1:1 to receive 12 weeks or 24 weeks of ledipasvir‑sofosbuvir alone or plus ribavirin, with sustained virologic response at 12 weeks post‑therapy as the primary endpoint. Sustained virologic response rates were 99 % (12 weeks combo), 97 % (12 weeks combo + ribavirin), 98 % (24 weeks combo), and 99 % (24 weeks combo + ribavirin), with no discontinuations due to adverse events and fatigue, headache, insomnia, and nausea as the most common side effects. The trial was funded by Gilead Sciences (ClinicalTrials.gov NCT01701401).

Abstract

In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection.We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea.Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).