Glecaprevir and Pibrentasvir Helps HCV Patients with Treatment Failure
DECEMBER 05, 2019
Anna Lok, MD
A team of investigators, led by Anna S. Lok, MD, Division of Gastroenterology and Hepatology, University of Michigan, performed a randomized, phase 3B, open-label, pragmatic trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin (RBV), in 177 patients with HCV genotype 1 (GT1) infection with treatment failure after sofosbuvir and an NS5A inhibitor.
To be included in the study, patients must be at least 18 years old with HCV genotype 1 and documented treatment failure to a regimen comprising an NS5A inhibitor—ledipasvir, velpatasvir, or daclatasvir—with sofosbuvir and/or RBV taken for at least 4 weeks with no documented noncompliance.
Patients without cirrhosis was randomly assigned to groups that received treatment for either 12 weeks (n=78) or 16 weeks (n=49). A third and fourth group of patients, with cirrhosis received G/P treatment with ribavirin for 12 weeks (n=21) or just G/P for 16 weeks (n=29).
Of the 177 patients from 30 US centers, 81% were men and 79% had HCV genotype 1a infections.
The primary endpoint of the study was a sustained virologic response 12 weeks following treatment. Samples collected at baseline, as well as at the time of treatment failure, were sequenced for resistance-associated substitutions (RASs) in NS3 and NS5A.
The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in the first group, 3 (6.1%) in second group, 3 (6.1%) in the third group (6.1%), and 1 (3.4%) in the fourth group.
The majority of patients had baseline resistance-associated substitutions in NS5A.
Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure. While G/P was well-tolerated, ribavirin increased adverse events and did not increase efficacy.
“In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis,” the authors wrote.
In recent years, direct-acting antivirals (DAAs) have improved treatment for hepatitis C. There are currently 3 classes of DAAs targeting different nonstructural proteins of HCV—NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors.
While several protease inhibitors and NS5A inhibitors have been approved by the US Food and Drug Administration (FDA), sofosbuvir is the only approved nucleoside polymerase inhibitor.
Sofosbuvir is often used in combination with an NS5A inhibitor, such as ledipasvir, velpatasvir, or daclatasvir, for treatment of chronic genotype 1 HCV.
Despite the low failure rate, the absolute number of GT1 HCV patients who failed to achieve SVR after treatment with sofosbuvir plus NS5A inhibitor regimens worldwide is increasing due to the widespread adoption of DAA treatment.
“In summary, our study provided additional safety and efficacy data in support of the use of 16-week G/P in HCV GT1 patients (with or without compensated cirrhosis) who failed prior treatment with sofosbuvir and NS5A inhibitor,” the authors wrote. “We found that baseline NS5A RASs were present in 76% of patients, yet only 7% experienced treatment failure.”
The investigators also did not find a link between individual NS5A RAS and reduced SVR12, or a statistically significant difference in SVR12 rates between patients with or without baseline NS5A RASs. This shows that testing for RAS prior to re-treatment is not beneficial.
The study, "Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy," was published online in Gastroenterology.