Investigational Hepatitis C Drugs Show Promising Results

Newer hepatitis C (HCV) drugs have shown very good sustained viral response (SVR) rates and little risk of resistance-associated substitutions, David L. Wyles, M.D., of Denver Health Medical Center reported in an International Antiviral Society-USA (IAS-USA) webinar. He summarized studies on various direct-acting antiviral agents (DAAs) from the recent International Liver Congress (EASL) in Amsterdam.

A triple combination of sofosbuvir (SOF, Sovaldi), velpatasvir (VEL) and voxilaprevir (VOX) is likely to be approved by the U.S. Federal Drug Administration late this summer, Wyles projected. The phase 3 POLARIS studies found it to work well across the various HCV genotypes, even among people who had been previously treated with a DAA. Two of its components, SOF and VEL, have already been approved in a combination pill (Epclusa). While VEL interacts with some antiretroviral regimens taken by people living with HIV, the addition of VOX has little effect on that interaction profile. A study of volunteers who do not live with HCV or HIV found that the triple-drug combination interacts with statins, atazanavir (Reyataz)/ritonavir (Norvir) and to some extent boosted anti-HIV regimens. However, it is unclear whether these results can be applied to people co-infected with HCV and HIV, Wyles cautioned.

Glecaprevir/pibrentasvir (G/P) is another investigational DAA that is relatively far along the development pipeline. The EXPEDITION and ENDURANCE phase 2/3 trials found slightly higher virologic failure rates among participants in the eight-week arm compared with 12 weeks of treatment, but "whether that's significant enough to warrant that extra four weeks is a matter of debate," Wyles said. One of the EXPEDITION trials tested an eight-week course of treatment in people living with HCV and HIV. Participants were on a wide variety of HIV treatment regimens, and SVR rates were excellent. This dual-drug combination may become the first eight-week HCV regimen approved for those co-infected with HIV and HCV, Wyles hypothesized.

Most virologic failure in the TARGET analysis of all-oral DAA data occurred among participants who abandoned treatment early. Other groups that achieved SVR less often than the average included those with cirrhosis and people who took the early DAA combination of SOF and simprevir (SMV). The latter may be due to shorter courses of treatment that were common with the earlier DAAs, Wyles suspected. A modeling study predicted that in Europe 47,000 people would not have achieved SVR on their first round of DAA drugs by 2020. Most of those needing re-treatment for HCV were expected to have cirrhosis and/or to have been exposed to NS5A inhibitors.

Another triple-drug combination, grazoprevir/ruzasvir/uprifosbuvir, was evaluated in people who had already developed resistance to some DAAs. The trial included two arms: 16 weeks of the base drug with ribavirin (RBV, Rebetol) added and 24 weeks without RBV. Everyone achieved SVR, independent of baseline resistance. Wyles wondered whether a 16-week regimen without RBV might be enough.

Earlier reports had shown an increased risk of hepatocellular carcinoma (HCC) after taking DAAs. However, once data were adjusted for cofounding factors, the RESIST study found no such risk among those who achieved SVR. These factors included older age and more severe liver disease among people treated with DAAs compared with those who took interferon-based medications. Wyles emphasized that successful treatment of HCV "will dramatically decrease the risk of HCC" even if the newer drugs might slightly increase that risk in some.

HCV treatment among intravenous drug users was studied in the SIMPLIFY trial. Ninety-four percent of participants achieved SVR after 12 weeks of SOF/VEL, with most of the treatment failures attributable to loss to follow up. Reinfection rates may become a concern in this group, though.

People co-infected with HBV and HCV could see their HBV flare up during HCV treatment. A trial of 12 weeks lopinavir (LPV)/SOF among that group showed that to be the case only for participants who had high HBV levels before starting HCV therapy. Good results were achieved in the two patients treated concurrently for both forms of hepatitis.

Other issues addressed at EASL included extrahepatic manifestations of HCV, treatment of people who are on a waiting list for a liver transplant and the longer-term impact of DAAs on liver fibrosis.