Wednesday, June 15, 2016

New Combination Therapy May Be Effective Against Chronic HCV Infection

New Combination Therapy May Be Effective Against Chronic HCV Infection
By Will Boggs MD
June 14, 2016

NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Various combinations of direct-acting antiviral agents (DAAs) provide sustained virologic responses in most patients infected with HCV, but there are ongoing efforts to optimize and shorten regimens.

Dr. Edward J. Gane from Auckland City Hospital in New Zealand and colleagues evaluated the efficacy and safety of short-duration regimens (four, six, or eight weeks) of SOF/VEL plus GS-9857 in a broad range of patients with genotype 1 (n=120) and 3 (n=41) HCV infections, including 63 treatment-naïve patients and 98 previously-treated patients.

Sustained viral response at 12 weeks (SVR12) was achieved by 27% of treatment-naïve patients with genotype 1 infection without cirrhosis after four weeks of treatment and by 93% after six, the team reports in Gastroenterology, online May 27.

SVR12 was 87% among treatment-naïve patients with cirrhosis after six weeks of treatment, while it was 67% among DAA-experienced patients with and without cirrhosis. In patients who had received other previous treatment and did or did not have cirrhosis, SVR12 with eight weeks of therapy ranged from 89% to 100%.

Among patients with genotype 3 infection, SVR12 was achieved by 83% of treatment-naïve patients with cirrhosis after six weeks of treatment and by 100% of previously treated patients with or without cirrhosis after eight weeks of treatment.

Of the 30 patients who did not achieve SVR12, 28 had virologic relapse after completing treatment, one withdrew consent four weeks after the treatment ended (at which time the patient had undetectable HCV RNA), and one never attained HCV RNA below 15 IU/mL on treatment.

Relapse rates were 73% among patients who received only four weeks of treatment, 19% among those who received six weeks of treatment, and 4% among those who received eight weeks of treatment.

SVR12 rates were also high among patients who had resistance-associated substitutions at baseline (84%-86%, depending on the threshold), and no treatment-emergent resistance-associated substitutions were detected in 26 of 28 patients who relapsed.

Common adverse events included headache, nausea, fatigue, and diarrhea, most of which were mild in severity. No patient discontinued treatment due to an adverse event.

"These results suggest that 8 weeks is the threshold of treatment duration with combination DAAs for the easier-to-treat patient population, not 4 or 6 weeks as suggested by recent viral kinetic models," the researchers note. "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

"SOF/VEL/GS-9857 is now coformulated as a single tablet which is being evaluated in the larger Phase III program, which includes different patient populations, including DAA-experienced patients," they add. "This group of DAA-experienced patients is growing and currently represents an unmet medical need."

Dr. Assy Nimer from Ziv Medical Center in Haifa, Israel, who has studied various aspects of HCV infection and its treatment, told Reuters Health by email, "The most interesting or surprising results is the low rate of SVR at week 4 in naïve HCV genotype 1 patients without cirrhosis, indicating that the combination of three potent DAA is not effective for 4 weeks but is highly effective for 8 weeks of treatment."

"The best treatment duration of the new DAA combination would be between 8 and 12 weeks," he concluded, adding that "this type of new medications will likely be effective in minimizing resistance-associated variants (RAV), which persist for years."

Gilead Sciences supported the trial, employed several authors, and had various relationships with the rest, including Dr. Gane.

Dr. Gane did not respond to a request for comments.

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