Nearly all trial participants with HIV and hepatitis C virus (HCV) co-infection, who were treated for 12 weeks with an interferon- and ribavirin-free regimen of sofosbuvir (Sovaldi) and daclatasvir (Daklinza), achieved sustained virological response, but the HCV 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 last 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 revolutionised 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 than those with HCV alone.
Kenneth Sherman of 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 pangenotypic – meaning it works against multiple HCV genotypes – unlike ledipasvir, the NS5A inhibitor in Gilead's Harvoni coformulation.
ALLY-2 enrolled 203 people with chronic hepatitis C, 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 participants and 29% of treatment-experienced participants had liver cirrhosis.
Participants could either be on antiretroviral treatment (ART) with undetectable HIV viral load or not yet on ART with a CD4 cell count of at least 350 cells/mm3. Almost all were on ART, with half taking HIV protease inhibitors, 25% taking NNRTIs and 25% taking other regimens, primarily integrase inhibitors; the median baseline CD4 count was 565 cells/mm3.
All participants in this open-label study received 400mg sofosbuvir plus daclatasvir once daily. The standard 60mg daclatasvir dose was adjusted down to 30mg when taken with ritonavir-boosted protease inhibitors or up to 90mg when used with most NNRTIs to account for drug-drug interactions. Previously untreated participants were randomly assigned to 8 or 12 weeks of treatment, while all treatment-experienced participants were treated for 12 weeks.
Sherman reported that 96% of people with genotype 1 who were treatment-naive and 98% of treatment-experienced participants 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 participants treated for only 8 weeks.
Response rates were similar when looking at all genotypes combined. Everyone with genotype 2, 3 or 4 who was treated for 12 weeks achieved SVR12.
People with cirrhosis had somewhat lower cure rates than people who did not have cirrhosis in both the 8-week arm (60% vs 77%) and in the 12-week arms (91% vs 99%).
There was one relapse in both 12-week arms and ten relapses in the 8-week arm. Both people who experienced relapse in the 12-week study arms had hard-to-treat HCV subtype 1a.
Treatment was generally safe and well-tolerated, with no treatment-related serious adverse events or adverse events leading to treatment discontinuation. Most participants maintained undetectable HIV RNA and stable CD4 counts (one was lost to follow-up and one 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 recently updated EASL European hepatitis C treatment guidelines and current US 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.
Wyles D et al. (Sherman K presenting) Daclatasvir plus sofosbuvir for treatment of HCV genotypes 1-4 in HIV-HCV coinfection: the ALLY-2 study. Digestive Disease Week, Washington, DC, abstract 901d, 2015.