Vaniprevir boosts interferon/ribavirin response rate for prior non-responders with cirrhosis

The next-generation HCV protease inhibitor vaniprevir (MK-7009) increased post-treatment sustained response rates for previously treated genotype 1 chronic hepatitis C patients with liver cirrhosis when added to pegylated interferon plus ribavirin, researchers reported at the 48^th International Liver Congress (EASL 2013) last month in Amsterdam.

The advent of direct-acting antivirals (DAAs) has changed the treatment paradigm for chronic hepatitis C, but many people with advanced liver damage cannot wait for the forthcoming interferon-free regimens.

Adding a DAA to pegylated interferon/ribavirin can shorten treatment duration and improve cure rates, but the currently approved HCV protease inhibitors – boceprevir (Victrelis) and telaprevir (IncivoorIncivek) – have complex dosing regimens and come with their own side-effects.

Maribel Rodriguez-Torres from Fundación de Investigación in Puerto Rico and colleagues evaluated vaniprevir, Merck's HCV NS3/4A protease inhibitor, as an add-on to interferon-based therapy in a phase 2b study that enrolled a hard-to-treat population of genotype 1 prior non-responders.

The study first enrolled a cohort of non-cirrhotic patients (n=211), followed by people with compensated cirrhosis (n=74). In both groups about two-thirds were men, most were white and the median age was in the early 50s.

Looking at the known predictors of response in this population prior to starting the study treatment, 25% of non-cirrhotics and 35% of cirrhotics were prior null responders (meaning little or no response to prior interferon), the most difficult group to re-treat. Almost all participants in both groups had high baseline HCV RNA levels; 42% of non-cirrhotics and 47% of cirrhotics had harder-to-treat HCV subtype 1a. Most patients (80 and 72%, respectively) had unfavourable IL28B non-CC gene variants associated with poor interferon responsiveness.

Participants were randomly allocated to five treatment arms:

• Vaniprevir 600mg twice-daily + pegylated interferon/ribavirin for 24 weeks.

• Vaniprevir 600mg twice-daily for 24 weeks + pegylated interferon/ribavirin for 48 weeks.

• Vaniprevir 600mg twice-daily + pegylated interferon/ribavirin for 48 weeks.

• Vaniprevir 300mg twice-daily + pegylated interferon/ribavirin for 48 weeks.

• Pegylated interferon/ribavirin + placebo for 48 weeks (control arm).

All patients received 180mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000 to 1200mg/day weight-based ribavirin. Follow-up continued through to week 72, or 24 weeks past the end of treatment, to determine sustained virological response (SVR24).

As previously reported and described in an article in press in the Journal of Hepatology, SVR24 rates for the non-cirrhotic participants receiving the vaniprevir-containing regimens were 71, 84, 78 and 67%, respectively, compared with just 19% in the control arm. The combined rate for all vaniprevir 600mg twice-daily arms was also 78%, which was used as a basis for comparison.

At the International Liver Congress, Edward Gane from Auckland City Hospital (substituting for Rodriguez-Torres) reported findings from participants with cirrhosis.

Overall, the cirrhotic cohort had somewhat lower response rates than people without cirrhosis: 60, 69, 77 and 53% in the vaniprevir arms, respectively, compared with 14% in the standard therapy arm. Response patterns were similar for both cohorts, with the lower vaniprevir dose being less effective than the higher dose, and the short duration working less well than a longer course of triple therapy or at least pegylated/ribavirin.

HCV subtype played an important role in response to vaniprevir. Among cirrhotic patients with easier-to-treat HCV subtype 1b, 83% in the combined vaniprevir 600mg arms and 60% in the 300mg arm achieved SVR24. For those with subtype 1a, the corresponding rates were 50 and 44%.

As is typical in re-treatment studies, prior relapsers had the highest sustained response rate (83% for all vaniprevir arms combined vs 29% for control arm), followed by those with previous partial response or breakthrough during therapy (62% for vaniprevir vs 0% for control) and finally prior null responders (42% for vaniprevir vs 0% for control).

A total of 18 vaniprevir recipients experienced virological failure, including four partial responses, six viral breakthroughs on treatment and eight relapses. A few were found to have resistance-associated variants at baseline, but all had resistance mutations – often more than one – following treatment failure, with changes at positions D168 or R155K being most frequent.

Vaniprevir was general safe and well tolerated. Two people (4%) taking 600mg vaniprevir, one (7%) taking 300mg vaniprevir and one (7%) in the control arm experienced serious adverse events, with two in the 600mg arm discontinuing treatment for this reason. No one experienced liver decompensation.

Gastrointestinal side effects were common and occurred more often in the combined 600mg vaniprevir arms (56% nausea, 31% vomiting, 49% diarrhoea) than in the lower dose (47, 20, 13%) or placebo (29, 14, 29%) arms, though all cases were mild to moderate. Rash occurred in 20% of 600mg vaniprevir recipients, 13% of 300mg recipients and 14% of control patients.No one developed severe (grade 3 or 4) anaemia.

"In genotype 1 cirrhotic prior non-responders to [pegylated interferon/ribavirin], vaniprevir + [pegylated interferon/ribavirin] demonstrated significant improvement in SVR compared to [pegylated interferon/ribavirin]," the researchers concluded.

Gane noted that a phase 3 trial of 300mg twice-daily vaniprevir plus pegylated interferon/ribavirin is nearly completed in Japan, where most chronic hepatitis C patients have the more responsive subtype 1b.

While this study demonstrated reasonably good sustained response rates for such a difficult-to-treat population, a regimen that requires twice-daily dosing and a 48-week duration of pegylated interferon/ribavirin may be a hard sell when competing against more convenient and shorter DAA combinations.