IDWeek 2013: Daclatasvir Is Effective Against HCV 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, while an interferon-free regimen containing daclatasvir, asunaprevir, and BMS-791325 produced sustained response rates of around 90%, researchers reported at the Second IDWeek 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(study AI444-031) evaluated the safety and efficacy of 12 or 16 weeks of 60mg once-daily daclatasvir (HCV NS5A inhibitor, formerly BMS-790052) plus pegylated interferon alfa-2a (Pegasys) and 800 mg/day fixed-dose ribavirin in 151 treatment-naive hepatitis C patients with HCV genotypes 2 or 3. People who did not experience protocol-defined response at weeks 4 and 10 stopped daclatasvir and continued on pegylated interferon/ribavirin through 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 favorable IL28B CC gene variant and only 1 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 in both groups were white.

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 than genotype 2. This study reported efficacy results for the genotypes separately.

Results

• 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%); more people stopped the standard regimen due to poor efficacy (0%, 2% and 6%).
• Among genotype 2 patients, rates of sustained virological response, 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 in a modified intent-to-treat 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.
• Among 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 genotype 3 IL28B CC patients were 50%, 75%, and 64%, compared with 81%, 64%, and 56% for those with non-CC variants.
• 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.
• 4 people taking the 12-week daclatasvir regimen, none taking the 16-week regimen, and 2 taking standard therapy experienced serious adverse events.
• 4, 3, and 2 people, respectively, discontinued early 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 anemia 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 regimens.

End-of-treatment response rates 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.

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

Daclatasvir Interferon-free Regimen

Gregory Everson from the University of Colorado at Denver presented interim findings from a Phase 2a trial (AI443-014) 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, about 80% were white, and the median age was 50 years. Nearly one-third had the favorable IL28B CC variant. People with liver cirrhosis were excluded.

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

Results

• Sustained response rates were high with all combinations.
• SVR12 rates were 94% for the groups taking 75 mg BMS-791325 for 24 or 12 weeks or 150 mg for 24 weeks, and 88% for the 150 mg 12-week group.
• Participants taking the 75 mg dose had longer follow-up and reached the 24-week post-treatment endpoint; SVR24 rates were 88% and 94%, respectively, for those receiving 24 and 12 weeks of treatment (follow-up is ongoing for the 150 mg arms).
• 3 people with virological breakthrough on treatment and 1 with post-treatment relapse underwent treatment intensification with pegylated interferon/ribavirin, and all reached and maintained undetectable HCV RNA.
• Again, the 3-drug regimen was generally safe and well-tolerated regardless of BMS-791325 dose or treatment duration.
• There was 1 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%), diarrhea (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 75 mg or 150 mg [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 analyze 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.

10/8/13

References

G Dore, E Lawitz, C Hezode, S Shafran, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with hepatitis C virus genotype 2 or 3 infection: COMMAND GT 2/3 study. 2nd ID Week Conference (IDWeek 2013). San Francisco. October 2-6, 2013. Abstract 1827.

G Everson, K Sims, M Rodriguez-Torres, et al. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. 2nd ID Week Conference (IDWeek 2013). San Francisco. October 2-6, 2013. Abstract 1828.