Daclatasvir works well against hepatitis C either with interferon or in all-oral regimen

A short 12- or 16-week triple regimen of daclatasvir plus pegylated interferon/ribavirin cured more people than a 24-week course of pegylated interferon/ribavirin alone, whilst an interferon-free regimen containing daclatasvir, asunaprevir and BMS-791325 produced sustained response rates of around 90%, researchers reported at the IDWeek 2013 conference last week in San Francisco.

The advent of direct-acting antiviral agents has brought about a new era of treatment for hepatitis C virus (HCV). These agents will first be used as add-ons to interferon-based therapy, and later in all-oral regimens that enable patients to avoid the difficult side-effects of interferon.

Daclatasvir + pegylated interferon/ribavirin

Stephen Shafran from the University of Alberta and fellow investigators with the COMMAND GT 2/3 study evaluated the safety and efficacy of 12 or 16 weeks of 60mg once-daily daclatasvir (an HCV NS5A inhibitor, formerly BMS-790052) plus pegylated interferon alfa-2a (Pegasys) and 800mg ribavirin in treatment-naive hepatitis C patients with HCV genotypes 2 or 3.

People who did not experience adequate early response stopped daclatasvir and continued on pegylated interferon/ribavirin through to 24 weeks. The control group received the standard of care for these genotypes, pegylated interferon/ribavirin alone for 24 weeks.

The analysis included 151 treatment-naive chronic hepatitis C patients, 47% with genotype 2 and 53% with genotype 3. The genotype 2 group was just over half men with a median age of approximately 53 years; about 30% had the favourable IL28B CC gene variant and only one person had liver cirrhosis. The genotype 3 group included about 70% men with a median age of about 45 years; about 41% had the CC variant and nearly one-quarter had cirrhosis.

Most people (83%) with either genotype 2 or 3 experienced protocol-defined early response and were eligible for shorter therapy. People taking the triple regimen for 12 or 16 weeks were less likely to stop treatment early for any reason than those on standard therapy (10, 12 and 18%, respectively).

HCV genotypes 2 and 3 have traditionally been considered 'easier-to-treat' relative to genotypes 1 and 4, but recent studies have shown that genotype 3 is harder to cure. This study reported efficacy results for the two genotypes separately.

Amongst people with genotype 2, rates of sustained virological response (SVR), or undetectable HCV RNA at 12 weeks after completing therapy (SVR12), were 88% in the 12-week daclatasvir arm and 83% in the 16-week arm, compared with 71% in the standard therapy arm (modified intent-to-treat, missing=failure analysis).

After 12 more weeks of post-treatment follow-up, SVR24 rates were 83% in both daclatasvir arms and 63% in the standard therapy arm. SVR24 rates were 80, 100 and 83%, respectively, for genotype 2 patients with the IL28B CC variant compared with 85, 75 and 56% for those with non-CC variants.

Amongst genotype 3 patients, 69% in the 12-week daclatasvir arm and 78% in the 16-week arm achieved SVR12, compared with 52% in the standard therapy arm. Corresponding SVR24 rates were 69, 67 and 59%, respectively. SVR24 rates for IL28B CC patients were 50, 75 and 64%, compared with 81, 64 and 56% for those with non-CC variants.

SVR24 was traditionally considered the criteria for a cure for hepatitis C. Regulatory authorities in the US and Europe now accept SVR12, but these findings show that relapses may still occur between 12 and 24 weeks of post-treatment follow-up.

Genotype 3 patients were more likely to experience virological failure – mostly post-treatment relapses – than those with genotype 2. Relapse was associated with baseline drug-resistance mutations and cirrhosis, but not with IL28B status.

Daclatasvir plus interferon/ribavirin 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 people, respectively, stopped due to adverse events. About one-quarter of participants in all arms reported rash and itching. Neutropenia was also common (20, 24 and 31%, respectively) but anaemia was uncommon (8, 6 and 10%).

The researchers concluded that daclatasvir triple therapy for 12 or 16 weeks "achieved numerically higher SVR24 rates" than pegylated interferon/ribavirin. Genotype 2 patients had higher response rates than genotype 3 patients with all three regimens.

End-of-treatment responses were similar for genotype 2 and 3 patients taking daclatasvir, but relapse was more frequent for genotype 3, they added. Within genotype groups, however, SVR24 rates were statistically similar with 12 or 16 weeks of treatment.

Daclatasvir interferon-free regimen

Gregory Everson from the University of Colorado in Denver presented interim findings from a phase 2a trial of all-oral daclatasvir-containing regimens for previously untreated people with HCV genotype 1.

This study included 66 chronic hepatitis C patients, 74% with harder-to-treat HCV subtype 1a, the rest with 1b. About 60% were men and the median age was 50 years. Nearly one-third had the favourable IL28B CC variant. People with liver cirrhosis were excluded.

Participants were randomly assigned to receive regimens containing 60mg once-daily daclatasvir, 200mg twice-daily asunaprevir (an HCV protease inhibitor, formerly BMS-650032) and either 75mg or 150mg twice-daily BMS-791325 (a non-nucleoside polymerase inhibitor), taken for either 12 or 24 weeks.

Sustained virological response rates were high with all combinations. SVR12 rates were 94% for the groups taking 75mg BMS-791325 for 24 or 12 weeks or 150mg for 24 weeks, and 88% for the 150mg 12-week group. Participants taking the 75mg dose had longer follow-up and reached the 24-weeks post-treatment endpoint. SVR24 rates were 88% for patients treated for 24 weeks and 94% for those treated for 12 weeks. Follow-up is ongoing for the 150mg arms.

Three people with virological breakthrough on treatment and one with post-treatment relapse underwent treatment intensification by adding pegylated interferon and ribavirin, and all reached and maintained undetectable HCV RNA.

Again, the three-drug regimen was generally safe and well tolerated, regardless of BMS-791325 dose or treatment duration. There was one serious adverse event (kidney stones), but no participants discontinued treatment early due to adverse events. The most commonly reported side-effects were headache (27% in all treatment arms combined), asthenia or weakness (17%), diarrhoea (17%) and nausea (14%), which occurred at similar rates across arms; abdominal pain was more common with the higher BMS-791325 dose (0 vs 20%). No serious changes in liver enzymes, bilirubin or blood cell counts were observed.

"The all-oral, interferon-free, ribavirin-free, ritonavir-free combination" of daclatasvir, asunaprevir and BMS-791325 at 75mg or 150mg [twice-daily] was generally well tolerated" and "achieved high rates of SVR in treatment-naive [genotype 1]-infected patients", the investigators concluded.

There were no clear differences according to BMS-791325 dose, treatment duration or IL28B status. The researchers did not separately analyse people with HCV 1a and 1b, but three-quarters of participants had subtype 1a, which responds less well to some medications.

Bristol-Myers Squibb has said that it plans to soon begin testing daclatasvir, asunaprevir and BMS-791325 in a fixed-dose coformulation.