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.