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Daclatasvir + Asunaprevir Works Well for HCV 1b, but 1a Requires Interferon

An all-oral combination of Bristol-Myers Squibb's daclatasvir plus asunaprevir cured nearly 80% of patients with genotype 1b hepatitis C virus (HCV), but people with harder-to-treat HCV subtype 1a needed to add pegylated interferon and ribavirin to achieve high sustained response rates, researchers reported in the March 2014 Journal of Hepatology.

Direct-acting agents that target different steps of the HCV lifecycle have begun to revolutionize treatment for chronic hepatitis C, but many patients and providers are waiting for all-oral regimens without the difficult side effects of interferon.

Anna Lok from the University of Michigan at Ann Arbor and colleagues conducted a Phase 2 study to evaluate the HCV NS5A inhibitor daclatasvir (formerly BMS-790052) plus the NS3 protease inhibitor asunaprevir (formerly BMS-650032), taken with or without pegylated interferon and ribavirin.

The study included 101 participants, a majority of whom were men and most of whom were white. They were considered especially hard to treat, being null responders to prior interferon-based therapy (<2 log reduction in HCV RNA after at least 12weeks of treatment) and 99% having unfavorable non-CC IL28B gene variants associated with poor interferon responsiveness.

All participants in this open-label study received 60 mg once-daily daclatasvir. In addition, 38 genotype 1b patients received 200 mg asunaprevir once-daily or twice-daily. Another 18 genotype 1a and 4 genotype 1b patients received triple therapy with twice-daily asunaprevir and ribavirin. Also, 36 genotype 1a and 5 genotype 1b patients received asunaprevir once-daily or twice-daily in a quadruple regimen with both pegylated interferon and ribavirin. All treatment lasted for 24 weeks.

Results

• All regimens substantially reduced HCV RNA levels after starting treatment, but some patients had viral breakthrough or relapsed.
• Sustained virological response rates at 12 weeks post-treatment (SVR12) were as follows:

o   Daclatasvir + asunaprevir once-daily: 65%;

o   Daclatasvir + asunaprevir twice-daily: 78%;

o   Daclatasvir + asunaprevir once-daily + pegylated interferon/ribavirin: 95%;

o   Daclatasvir + asunaprevir twice-daily + pegylated interferon/ribavirin: 95%.

• In the triple therapy arm, most of the genotype 1a patients experienced viral breakthrough during treatment and did not achieve SVR.
• The combination regimens were generally safe and well-tolerated, though the expected side effects were seen among people taking interferon and ribavirin.
• The most common adverse events were headache, diarrhea, and asthenia (weakness).
• Grade 3-4  elevations were infrequent and not treatment-limiting.

Based on these findings, the study authors concluded, "In genotype 1 null responders, daclatasvir plus twice-daily asunaprevir dual therapy is effective for most genotype 1b patients, and daclatasvir, asunaprevir, and [pegylated interferon/ribavirin] quad therapy is effective for nearly all genotype 1a and 1b patients."

However, "neither dual nor triple therapy is effective for genotype 1a patients," they continued. They therefore recommended that, "Interferon-free regimens including daclatasvir and twice-daily asunaprevir for genotype 1 null responders should be tailored to subtype."

Daclatasvir and asunaprevir were among the first next-generation direct-acting antivirals to enter the development pipeline. The cure rates in this study are much higher than those of pegylated interferon/ribavirin alone or triple therapy with pegylated interferon/ribavirin plus the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek), especially for such a difficult-to-treat population.

However, newer agents have since been shown to be even more effective, with response rates in the 90%-100% range for interferon-free regimens such as Gilead Science's sofosbuvir (Sovaldi) plus ledipasvir and AbbVie's "3D" regimen.

Bristol-Myers Squibb has requested approval of daclatasvir in Japan, where most hepatitis C patients have subtype 1b. A 3-drug regimen of daclatasvir, asunaprevir, and the non-nucleoside polymerase inhibitor BMS-791325 cured most people with HCV subtypes 1a or 1b. Daclatasvir has also demonstrated very high response rates in combination with sofosbuvir.

2/20/14

Reference

AS Lok, DF Gardiner, C Hézode, et al. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. Journal of Hepatology 60(3):490-499. March 2014.