Fixed-dose ledipasvir-sofosbuvir (LDV-SOF) plus weight-based ribavirin (RBV) may offer an alternative treatment in patients with genotype 3 (GT3) hepatitis C virus (HCV). The findings of a phase 2 open-label study were published in Clinical Infectious Diseases.1
Jordan J. Feld, MD, from the Toronto Centre for Liver Disease at the University of Toronto, Ontario, Canada, and colleagues investigated the efficacy and safety of LDV-SOF plus RBV in patients with difficult-to-treat GT3 HCV, the most common genotype in South Asian populations, which represents one-third of the global HCV population (ClinicalTrials.gov identifier: NCT02413593).
The 12-week study recruited 111 treatment-naïve patients with GT3 (mean age: 48; 61% men) from 15 sites across Canada who were given coformulated 90 mg ledipasvir and 400 mg sofosbuvir plus RBV based on the patients’ weight. Most of the patients (95%) had GT3a, 3% had GT3b, and 3% had an indeterminant subtype; 35% of patients had cirrhosis.
Overall, the sustained virologic response at 12 weeks after treatment (SVR12) was 89% (95% CI, 82%-94%). Patients with cirrhosis vs patients without cirrhosis had a SVR12 rate of 79% and 94%, respectively.
The most common adverse events included fatigue (51%), headache (36%), and nausea (23%). The one patient who discontinued treatment died of liver cancer 22 days after stopping therapy.
Of the 12 patients who did not achieve SVR12, 8 had a virologic relapse. Two of the patients who relapsed had resistance-associated variants Y93H at baseline, but not at virologic failure. The remaining 6 patients who relapsed had no NS5A or NS5B resistance-associated substitutions.
Subsequent trials have demonstrated more robust results in patients with GT3 HCV, most notably the pangenotypic NS5A inhibitor velpatasvir in combination with sofosbuvir, which led to a 98% SVR12 rate in patients without cirrhosis and 93% in patients with cirrhosis.2
“The results from this study were informative, partially because they were somewhat surprising,” noted Dr Feld in an email interview with Infectious Disease Advisor. “Ledipasvir has very little activity against genotype 3 HCV in vitro, yet when combined with sofosbuvir and ribavirin, it clearly added benefit, with 12 weeks of therapy leading to high rates of cure, particularly in non-cirrhotic patients.”
“This may suggest that our assays that evaluate the mechanism of action and thus resistance to antiviral agents may be incomplete. Clearly this agent is more active than the laboratory tests would suggest, something that we will have to take into account for HCV, as well as other pathogens, as new in vitro tools are developed,” Dr Feld concluded.
- The study was a single-arm, open-label trial, had no control group, and recruited only treatment-naïve patients.
The researchers received financial support from Gilead Sciences.
- Feld JJ, Ramji A, Shafran SD, et al. Ledipasvir-sofosbuvir plus ribavirin in treatment-naive patients with hepatitis C virus genotype 3 infection: an open-label study [published online May 23, 2017]. Clin Infect Dis. doi:10.1093/cid/cix289
- Foster GR, Afdhal N, Roberts SK, et al; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608-2017. doi:10.1056/NEJMoa1512612