HCV: 4 Weeks Too Short for Treatment With New Drugs

Veronica Hackethal, MD

November 24, 2015

Four weeks of triple or quadruple combination therapy using new drugs for hepatitis C virus (HCV) results in only limited cure rates in patients with early-stage liver fibrosis, according to a study published online November 23 in the Annals of Internal Medicine.

"In this proof-of-concept study involving treatment-naive noncirrhotic patients with chronic HCV genotype 1 infection, 4 weeks of treatment with ledipasvir, sofosbuvir, and GS-9451 with or without GS-9669 was well-tolerated; however, only 30% (15 of 50) of patients achieved [a sustained viral response at 12 weeks]," write Anita Kohli, MD, from the University of Maryland, Baltimore, and colleagues "Thus, a treatment duration of 4 weeks with 3 or 4 potent [direct-acting antivirals] is not sufficient to cure HCV infection in most patients."

Current treatment regimens for HCV require 12 or more weeks of therapy. Shorter-term regimens have the potential to simplify therapy, increase adherence, reduce toxicity, and increase cost-effectiveness.

A previous study with the investigational drugs GS-9451 (a protease inhibitor) and GS-9669 (a nonnucleoside polymerase inhibitor), combined with ledipasvir and sofosbuvir, showed a sustained viral response rate of 95% (39 of 40 patients) in just 6 weeks.

To try to abbreviate therapy further, Dr Kohli and colleagues designed the current trial. The open-label nonrandomized phase 2a trial took place at the National Institutes of Health Clinical Center in Bethesda, Maryland, from January 2014 to May 2015. It included mostly African Americans (76%; 38/50), who are disproportionately affected by the HCV epidemic. Participants had not been previously treated and had early-stage liver fibrosis. Most were male (72%; 36/50) and had HCV 1a genotype (68%; 34/50).

Researchers divided participants sequentially into two groups. Twenty-five participants received a triple drug regimen of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks. The second group of 25 participants received the four-drug regimen of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. Dosages included ledipasvir 400 mg and sofosbuvir 90 mg as a single combination tablet taken once daily, GS-9451 80 mg once daily, and GS-9669 250 mg once daily. All but one patient completed the trial.

Among participants in the triple-drug group, 10 patients (40%; 95% confidence interval [CI], 21% - 61%) reached a sustained viral response at 12 weeks, defined as unquantifiable HCV RNA levels at week 12, as did five patients (20%; 95% CI, 7% - 41%) in the four-drug group.

At baseline, 10 participants had HCV variants that increased resistance to at least one of the antivirals in the study. All these participants experienced viral relapse.

Adverse events, mostly mild, occurred among 48% (12/25) of patients in the triple-drug group and 72% (18/25) in the four-drug group. None of the patients discontinued therapy because of adverse events.

Lower baseline viral load, younger age, HCV genotype 1b, and absence of resistance mutations were linked to increased likelihood of a sustained viral response at 12 weeks. This subgroup may achieve acceptable response rates using a 4-week regimen, the authors suggest, and the possibility warrants further investigation.

"Our data suggest that for most patients, a treatment duration longer than 4 weeks is required to achieve [a sustained viral response]," they conclude. "However, some patients are capable of achieving [a sustained viral response] with 4 weeks of therapy, which could be attributable to the presence of several favorable factors, such as early fibrosis, low viral burden, and absence of [resistance-associated variables]."

The nonrandomized nature of the study and small sample size could have limited the study.

One or more coauthors reports research agreements, grants, personal fees, and/or stock ownership in one or more of the following: National Institutes of Health, Gilead Sciences, Merck, Pfizer, Johnson & Johnson, and Bristol-Myers Squibb. Two coauthors were employees of Gilead Sciences.

Ann Intern Med. Published online November 24, 2015. Abstract


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