Data found the combination of glecaprevir and pibrentasvir is highly effective and well tolerated in patients with chronic hepatitis C virus (HCV) genotype-1 infections who have prior treatment experience with sofosbuvir/NS5A inhibitor.
The data comes from a study by researchers at Johns Hopkins Hospital, University of Michigan, Medical University of South Carolina, University of Pennsylvania, Bon Secours Mercy Health, Liver Institute of Virginia, University of Minnesota, Emory University School of Medicine, Orlando Immunology Centre, New York University, University of Florida, University of North Carolina at Chapel Hill, and Abbvie Inc, presented at The Liver Meeting® – held by the American Association for the Study of Liver Diseases.
Although most patients with HCV genotype 1 infection can be cured of the infection with first-line direct-acting antiviral therapies, those who do not respond have few retreatment options, presenting a challenge to clinicians.
To address this, researchers from multiple centres in the US took part in a randomised, controlled trial of a fixed-dose combination of once-daily 300 milligrams of glecaprevir (an NS3/4A protease inhibitor) and 120 milligrams of pibrentasvir (an NS5A inhibitor, also known as G/P).
“The G/P regimen given for 16 weeks was approved by the US Food and Drug Administration for retreatment of HCV GT1-infected patients who failed a prior NS5Ai-containing regimen without prior exposure to a protease inhibitor, explains Dr Mark Sulkowski, who is a professor of medicine at Johns Hopkins and the principle investigator of the study at the Hopkins site. “However, due the relatively small number of patients included in the registration trial, the AASLD/IDSA guidelines panel recommended this regimen as an alternative treatment option leading to uncertainty regarding the use this regimen in clinical practice for the re-treatment of persons with HCV genotype 1 infection who failed prior treatment with an NS5Ai-containing regimen,” he explains of what prompted the study.
One hundred seventeen patients participated in the study, which evaluated the G/P regimen for 16 weeks in compensated cirrhotic and non-cirrhotic patients with HCV genotype 1 infection who had previously failed on the combination of an NS5Ai with sofosbuvir. The patients were predominately male (82%) who ranged in age from 60-64 years, and the study included patients with HIV infection as well as patients who had undergone prior liver transplantation.
Patients who did not have cirrhosis were randomly assigned to receive G/P for either 12 or 16 weeks at a 2:1 ratio, and patients with cirrhosis were randomly assigned to receive G/P with ribavirin for 12 weeks or G/P alone for 16 weeks at a 1:1 ratio.
Patients were grouped by HCV genotype 1 subtype (1a and 1b), and the researchers monitored them to see if/when they achieved sustained virologic response (as marked by having no detectible HCV virus in their blood for 12 or more weeks after the last dose of treatment).
As of October 2018, sustained virologic outcomes data was available for 172 of the 177 study participants. Of those 172, 157 achieved sustained virologic response.
Among 126 patients without cirrhosis (data on one patient is still pending), 91% have reached sustained virologic response. Within this group, 78 patients received G/P for 12 weeks (a 90% sustained virologic response rate), and 48 patients received G/P for 16 weeks (a 94% sustained virologic response rate).
Among 46 patients with cirrhosis (data on four patients is still pending), 91% have reached sustained virologic response. Ninety-six percent of patients in this group who were randomized to 16 weeks of G/P achieved sustained virologic response.
Overall, the researchers found G/P was well-tolerated among study participants with fatigue, headache and nausea reported in 17%, 19% and 9% of participants, respectively. The addition of ribavirin was associated with more side effects. Eleven serious adverse events have been observed among nine participants in the study, including one death due to hepatocellular carcinoma; none of these events were classified as treatment-related. Complete safety, efficacy and resistance associated substitution data will be presented at the Liver Meeting.
Background: The fixed dose combination of once daily 300mg glecaprevir, an HCV NS3/4A protease inhibitor (PI), and 120mg pibrentasvir (G/P), an NS5A inhibitor (NS5Ai), was approved by FDA for HCV genotype 1 (GT1) infected patients who failed a prior NS5Ai-containing regimen without prior exposure to a PI. The aims of this study are: 1) to evaluate the FDA labelled G/P regimen given for 16 weeks in GT1 infected patients who were prior NS5Ai+SOF±RBV failures and 2) to explore 12-week durations of G/P in non-cirrhotic subjects and subjects with compensated cirrhosis and addition of RBV.
Methods: NS5Ai+SOF±RBV-experienced, HCV GT1 subjects were randomized and dosed as follows: 127 non-cirrhotic (NC) subjects in a 2:1 ratio to Arm A- G/P 12 weeks (NC-12), N=78 and Arm B- G/P 16 weeks (NC-16), N=49 and 50 subjects with compensated cirrhosis (CC) in a 1:1 ratio to ±, N= 21 and Arm D-GP 16 weeks (CC-16), N=29. Randomization was stratified by GT1 subtype (1b or non-1b). All baseline and any viral failure samples are deep sequenced for NS3 and NS5A resistance. Primary endpoint is sustained virologic response 12 weeks post-treatment (SVR12).
Results: 217 subjects screened with 177 dosed. Screen failure was primarily due to decompensated cirrhosis. The population is mostly male (81%) and infected with GT1a (80%); 44% are Black race. Of 177 dosed, 147(83%) have reached Post-treatment Week (PTW) 4 and 132(75%) have reached PTW 12 to date. For the 132 with PTW 12 data available, SVR12 rates are 92% in NC-12, 96% in NC-16, 86% in CC-12+R, and 100% in CC-16, respectively (Table 1). Overall, 9 participants failed treatment: 5 in NC-12 (4 relapse, 1 breakthrough), 1 in NC-16 (relapse) and 3 in CC-12+R (all breakthroughs, which led to discontinuation of this arm). There are no discontinuations due to adverse events (AEs); the most frequently reported AEs are fatigue (25%), headache (22%) and nausea (10%). Eleven serious AEs (SAE) have been observed among 8 participants, including one resulting in death (hepatocellular carcinoma); none were classified as treatment related.
Conclusion: Patients who failed direct acting antiviral HCV therapy represent a challenging population with few retreatment options. In this ongoing large study, G/P 16 weeks in patients with GT1 infection and prior NS5Ai +SOF ±RBV failure has been well tolerated and demonstrated high SVR12 rates, to date. Final efficacy and safety data will be presented.
Mark S Sulkowski, Anna S Lok, Ira R Willner, K Rajender Reddy, Mitchell L Shiffman, Mohamed A Hassan, Brian L Pearlman, Federico Hinestrosa, Ira M Jacobson, Giuseppe Joseph Morelli, Joy A Peter, Monika Vainorius, Larry Michael, Michael W Fried, Gary P Wang, Yiran B Hu, Jens Kort, David R Nelson