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DDW 2015: Sofosbuvir + Daclatasvir for 12 Weeks Cures Most HIV/HCV Coinfected Patients

Nearly all HIV/HCV coinfected patients treated for 12 weeks with an interferon- and ribavirin-free regimen of sofosbuvir (Sovaldi) and daclatasvir (Daklinza) achieved sustained virological response, but the cure rate fell to 76% for those treated for only 8 weeks, according to results from the ALLY-2 trial presented at Digestive Disease Week 2015 this month in Washington, DC.

The development of oral direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus (HCV) lifecycle has revolutionized treatment, offering therapy that is shorter, better tolerated, and more effective than interferon-based therapy. Unlike interferon, DAAs appear to work as well for HIV-positive people with hepatitis C, who tend to experience more rapid liver disease progression.

Kenneth Sherman from the University of Cincinnati presented findings from the Phase 3 ALLY-2 trial, which evaluated Gilead Sciences' nucleotide polymerase inhibitor sofosbuvir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir without ribavirin.

Daclatasvir is available in Europe and Japan and is currently awaiting U.S. Food and Drug Administration approval. Gilead's Harvoni coformulation contains sofosbuvir plus its own NS5A inhibitor, ledipasvir. Unlike ledipasvir, which is active against genotype 1, daclatasvir is more pangenotypic, meaning it works against multiple HCV genotypes.

ALLY-2 enrolled 203 chronic hepatitis C patients, of whom 151 were previously untreated and 52 were non-responders to prior therapy. Nearly 90% were men, about 60% were white, about 35% were black, and the median age was approximately 55 years. Most (83%) had HCV genotype 1, with a majority of these having harder-to-treat subtype 1a, while 9% had genotype 2, 6% had genotype 3 (now considered hardest to treat), and 2% had genotype 4. Just under 10% of treatment-naive patients and 29% of treatment-experienced patients had liver cirrhosis.

Participants could either be on antiretroviral therapy (ART) with undetectable HIV RNA and a CD4 count of at least 100 cells/mm³, or not yet on ART with at least 350 cells/mm³. The median baseline CD4 count was 565 cells/mm³. Almost all were on ART, with halftaking HIV protease inhibitors, 25% taking NNRTIs, and 25% taking other regimens, primarily integrase inhibitors.

All participants in this open-label study received 400 mg sofosbuvir plus daclatasvir once-daily. The standard 60 mg daclatasvir dose was adjusted down to 30 mg when taken with ritonavir-boosted protease inhibitors, or up to 90 mg when used with most NNRTIs to account for drug-drug interactions. Previously untreated patients were randomly assigned to 8 or 12 weeks of treatment, while all treatment-experienced patients were treated for 12 weeks.

Results

• 96% of genotype 1 treatment-naive patients and 98% of treatment-experienced patients treated for 12 weeks achieved sustained virological response, or undetectable HCV RNA 12 weeks after completing treatment (SVR12).
• The sustained response rate fell to just 76%, however, for genotype 1 treatment-naive people treated for 8 weeks.
• Response rates were similar when looking at all genotypes combined, and everyone with genotype 2, 3, or 4 treated for 12 weeks achieved SVR12.
• There was 1 relapse in both 12-week arms and 10 in the 8-week arm; both of the 12-week relapsers had HCV subtype 1a.
• People with cirrhosis had somewhat lower cure rates than non-cirrhotics in both the 8-week arm (60% vs 77%) and the 12-week arms (91% vs 99%).
• Treatment was generally safe and well-tolerated, with no treatment-related serious adverse events or adverse events leading to treatment discontinuation.
• Most patients maintained undetectable HIV RNA and stable CD4 counts (1 was lost to follow-up and 1 experienced HIV rebound after completing hepatitis C treatment).

"Treatment of HIV/HCV coinfected patients with daclatasvir + sofosbuvir once-daily for 12 weeks resulted in an overall 97% SVR12, and was well-tolerated," the researchers concluded. "Daclatasvir + sofosbuvir was effective in patients with cirrhosis, in other demographic and disease categories, and across a broad range of combination ART regimens without compromising HIV virologic control."

These findings support current U.S. hepatitis C treatment guidelines and recently updated European guidelines recommending that HIV-positive and HIV-negative people should be treated the same for hepatitis C, with the exception of taking into account potential interactions with antiretroviral drugs.

5/28/15

Reference

D Wyles, PJ Ruane, M Sulkowski, et al (K Sherman presenting). Daclatasvir plus Sofosbuvir for Treatment of HCV Genotypes 1-4 in HIV-HCV Coinfection: The ALLY-2 Study. Digestive Disease Week 2015. Washington, DC, May 16-19, 2015. Abstract 901d.