Daclatasvir plus interferon-based therapy cures more genotype 2/3 hepatitis C patients

Adding the HCV NS5A inhibitor daclatasvir to pegylated interferon and ribavirin for 12 or 16 weeks led to higher response rates for previously untreated people with genotype 2 or 3 hepatitis C, according to results from the COMMAND study reported last month at the 48^th International Liver Congress (EASL 2013) in Amsterdam. People with genotype 3, however, did not respond as well as those with genotype 2.

HCV protease inhibitors have changed the treatment paradigm for chronic hepatitis C genotype 1 but these are not active against genotypes 2 and 3. Agents active against genotypes 2 and 3 are still in development.

Gregory Dore from the University of New South Wales and colleagues evaluated the safety and effectiveness of adding daclatasvir (formerly BMS-790062) to pegylated interferon and ribavirin for people with HCV genotypes 2 or 3, traditionally considered 'easier to treat'. People with genotypes 2 and 3 already have a relatively high rate of response to a 24-week course of pegylated interferon/ribavirin, but including a DAA could allow for shorter treatment duration.

The COMMAND GT2/3 trial enrolled 151 treatment-naive chronic hepatitis C patients, 71 with genotype 2 and 80 with genotype 3. About half of the genotype 2 participants were men, their median age was approximately 53 years, 32% had the favourable IL28B CC gene pattern, and only one was known to have liver cirrhosis. Among genotype 3 participants, about 70% were men, the median age was about 45 years, 41% had the CC variant and nearly one-quarter had cirrhosis.

Participants were randomly assigned to receive triple therapy using 60mg once-daily daclatasvir, pegylated interferon alfa-2a (Pegasys) and 800mg/day fixed-dose ribavirin for either 12 or 16 weeks or, alternatively, the same doses of pegylated interferon and ribavirin for 24 weeks (the standard interferon-based regimen for genotypes 2/3). Using a response-guided therapy algorithm, people in the daclatasvir arms who did not experience protocol-defined response at weeks 4 and 10 stopped daclatasvir at week 12 and continued on pegylated interferon/ribavirin alone through to week 24.

About 90% of daclatasvir recipients completed treatment, compared with 82% in the standard therapy control arm, who were more likely to stop early due to lack of efficacy.

A number of studies presented at the Congress showed divergent sustained response rates for people with HCV genotypes 2 and 3, suggesting, in the opinion of many researchers, that they should not continue to be "lumped together" as a single, presumed easy-to-treat population. Dore reported the COMMAND efficacy findings broken out by genotype, and here too, genotype 2 responded better.

Looking first at genotype 2 patients, at week 4 of treatment 88% in the daclatasvir 12-week arm and 74% in the daclatasvir 16-week arm achieved rapid virological response (RVR), compared with just 42% in the standard therapy arm. At the end of treatment 96, 91 and 92%, respectively, had undetectable HCV RNA.

After two participants relapsed post-treatment, a modified intent-to-treat analysis showed that 88 and 83% in the 12-week and 16-week daclatasvir arms, and 71% in the control arm, achieved sustained virological response at 12 weeks after finishing therapy (SVR12). Corresponding SVR24 rates were 83, 83 and 63%. Dore noted that, when participants with missing post-treatment data were excluded, SVR24 rates rose to 95, 100 and 83%.

Turning to genotype 3 patients, response rates were similar during treatment, but a higher number of relapsers led to lower sustained response. At week 4 of treatment, 85% in the daclatasvir 12-week arm, 74% in the 16-week arm and 37% in the standard therapy arm reached RVR. End-of-treatment response rates were 96, 89 and 78%.

There were six post-treatment relapses in both daclatasvir arms and three in the control arm. In the modified intent-to-treat analysis, SVR12 rates were 69, 78 and 52%, respectively, while SVR24 rates were 69, 67 and 59%. After excluding people with missing data, observed SVR24 rates were just 72, 69 and 70%, or essentially the same in all arms.

Nearly 85% of daclatasvir recipients with both genotypes achieved protocol-defined response and were eligible to stop all treatment at week 12 or 16 with no interferon/ribavirin tail. Within this group, 81 and 94% of genotype 2 patients achieved SVR24 with the 12- and 16-week regimens, respectively. Among genotype 3 patients, the rate was 73% with either duration. Only one to three participants in each genotype/duration arm failed to experience good early response and received extended interferon/ribavirin. Their SVR24 rates were 100 and 40% for genotype 2, and 50 and 40% for genotype 3.

Responses according to IL28B genotype were surprising in two ways.

In almost all studies of interferon-based HCV treatment conducted to date, patients with the CC genotype have shown a better response to treatment. Yet when responses were compared between CC and CT/TT populations in the COMMAND study there was almost no difference in response to the 12-week regimen (80% vs 83%) in genotype 2 patients and a better response to the 12-week regimen in genotype 3 CT/TT patients (81% vs 50% for CC patients). The same did not hold true for the 16-week regimen. Responses in the CC patients were better (100 vs 75% for genotype 2 and 75% vs 64% for genotype 3).

In this study, patients with the CT or TT genotype associated with poorer interferon response did better on the 12-week treatment course. This effect was more pronounced for genotype 3 than genotype 2. On the other hand, patients with the CC genotype did better on the 16-week treatment course.

Why these differences arose is unclear, and because the numbers in each group are small, it would be premature to draw any firm conclusions.

Further analysis showed that among people with genotype 3, the presence of resistance-association viral mutations at baseline raised the risk of relapse (50 vs 19%), as did presence of cirrhosis (36 vs 21%), but IL28B non-CC gene variants and high baseline viral load did not.

Adding daclatasvir to interferon-based therapy was generally safe and well tolerated. Four people taking the 12-week daclatasvir regimen, none taking the 16-week regimen and two taking standard therapy experienced serious adverse events. Four, three, and two, respectively, stopped treatment early due to adverse events. About one-quarter of participants in all arms reported rash and itching, and neutropenia was also common (20, 24 and 31% in the three arms).

The researchers concluded that daclatasvir triple therapy for 12 or 16 weeks "achieved numerically higher SVR24 rates" than standard interferon/ribavirin for 24 weeks. While end-of-treatment responses were similar in genotype 2 and 3 participants taking daclatasvir, "relapse was more frequent in genotype 3".

There was "no indication of additional benefit" of continuing daclatasvir for 16 versus 12 weeks, Dore added, and "no clear data" to show that extending treatment duration for patients with rapid response would improve outcomes.