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Where Direct Acting Agents Fail, a New Retreatment Strategy May Win


For patients infected with hepatitis C virus who do not respond to direct-acting antiviral agents, results of a new study could mean a much brighter future.

©Tsvetkov Maxim/Shutterstock.com

Once-daily treatment with a direct-acting antiviral regimen including an NS5A inhibitor is highly effective in patients with chronic HCV infection and a history of NS5A inhibitor treatment failure, a recently published, open-label study has confirmed.

Treatment with sofosbuvir, velpatasvir, and voxilaprevir resulted in a 97% rate of sustained virologic response 12 weeks after the end of treatment (SVR12) in a cohort of patients who previously had not responded to an NS5A inhibitor, investigators reported in The Lancet Gastroenterology & Hepatology.1

The study included 147 patients who had initially received placebo in POLARIS-1,2 the previously reported phase 3 trial that evaluated 12 weeks of treatment with the combination of sofosbuvir (an NS5B inhibitor), velpatasvir (an NS5A inhibitor), and voxilaprevir (an NS3/4A protease inhibitor).

These latest results “add to the confidence of the regimen by considerably increasing the number of patients treated with it,” POLARIS-1 investigator Marc Bourlière, MD (Hospital Saint Joseph, Marseilles), and co-authors said. 

POLARIS-1 plus ...

In the primary POLARIS-1 study results, this regimen resulted in SVR for 96% of patients who previously received an NS5A inhibitor. Combining those results with new data from the current substudy, 396 of 410 patients (97%) were considered cured, according to study authors.

“To date,” the authors wrote, “POLARIS-1 is the only phase 3 registration study dedicated to enrollment of patients who were previously treated with NS5A inhibitors, and there have been few data for retreatment of these patients from other clinical development programs.”

In the more recently reported substudy, 113 patients (77%) had HCV genotype 1a, while 30 had genotype 1b and 2 had genotype 6. One-third of patients had compensated cirrhosis. Ninety-one patients (62%) had previously received the NS5A inhibitor ledipasvir, while 27 received daclatasvir and 24 received ombitasvir.

Most patients (89%) had baseline NS5A or NS3 resistance-associated substitutions, but investigators noted those had “no discernible impact” on SVR rates, which remained high in subset analyses. Likewise, the regimen produced high SVR rates regardless of cirrhosis status or previous treatment regimen.

These results confirm that sofosbuvir-velpatasvir-voxilaprevir is effective in patients who do not respond to direct-acting antiviral treatment, according to Imam Waked, MB, BCh, MSc, MD, of the National Liver Institute in Egypt.

The regimen is a treatment of choice for HCV patients when NS5A or NS3 direct-acting antiviral therapy fails, Dr Waked wrote in an editorial discussing the POLARIS-1 substudy results. The combination is recommended in clinical practice guidelines from the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, and from the European Association for the Study of the Liver.

Dr Waked also wrote, “Since sofosbuvir-velpatasvir-voxilaprevir results in a very high SVR rate in patients who have not responded to all types of direct-acting antiviral therapy, regardless of genotype and of the presence of NS3 or NS5A resistance-associated substitutions, its use as a first-line treatment in untreated patients is appealing.”

However, its use as first-line therapy for 12 weeks still needs to be evaluated, Waked added, citing the POLARIS-2 study, which did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks.


1. Bourlière M, Gordon SC, Schiff ER, et al. Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1. Lancet Gastroenterol Hepatol. 2018; pii: S2468-1253(18)30118-3. doi: 10.1016/S2468-1253(18)30118-3. [Epub ahead of print]

2. Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376:2134-2146. 


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