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VIDEO: Sofosbuvir with velpatasvir beat other HCV GT3 regimens

 

Key clinical point. Regimens containing sofosbuvir and velpatasvir were more effective than were other direct-acting antiviral combinations for treating genotype 3 hepatitis C virus infection, regardless of cirrhosis status.

Major finding: For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin for 12 weeks yielded the highest estimated likelihood of sustained viral response (99%). For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%).

Data source: A systematic review and meta-analysis of 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies.

Disclosures: Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.

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Study offers insight into HCV GT3 treatment difficulty

The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.

One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.

On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.  

Dr. Norman Sussman
The results were uniformly excellent – 94%-99% SVR, substantially higher than reported in clinical trials. The analysis also showed that sofosbuvir plus velpatasvir was superior to sofosbuvir plus daclatasvir or sofosbuvir plus interferon plus ribavirin. This result conforms to in vitro data that show good inhibitory activity of velpatasvir against the NS5A replication complex inhibitor in genotype 3 replicons. The study also showed that the addition of ribavirin improved SVR in all groups, all durations of treatment, and with all drug combinations – not bad for a weak antiviral agent with an unknown mode of action.

The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress.  Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.

Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.


 

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

 

Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).

“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.

Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
 

 

For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.

For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.

Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.

Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.

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