An oral regimen of three direct-acting antivirals plus
ribavirin taken for 12 weeks demonstrated a sustained virological response rate
of 94% for people with both HIV and genotype 1 hepatitis C co-infection in the
TURQUOISE-I study, delegates heard on Monday at
the 20th International AIDS Conference (AIDS
2014) in Melbourne, Australia.
People with HIV and hepatitis C virus (HCV)
co-infection generally experience more rapid liver disease progression than
people with hepatitis C alone and do not respond as well to interferon-based
therapy. Direct-acting antivirals that target different steps of the HCV
lifecycle offer the prospect of shorter treatment, fewer side-effects and
higher cure rates for people with HIV and HCV co-infection as well as people
with HCV mono-infection.
Mark Sulkowski from Johns Hopkins University School of
Medicine and colleagues conducted the phase 3 TURQUOISE-I trial to evaluate the
safety and efficacy of AbbVie's 3D direct-acting antiviral regimen for people
with HIV and HCV co-infection.
The 3D regimen consists of the HCV protease inhibitor
ABT-450, a 100mg boosting dose of ritonavir and the NS5A inhibitor ombitasvir
(formerly ABT-267) in a once-daily fixed-dose co-formulation, taken with the twice-daily
non-nucleoside HCV polymerase inhibitor dasabuvir (ABT-333) and 1000-1200
mg/day weight-based ribavirin.
Prior to testing in people with co-infection, extensive drug-drug
interaction studies in healthy volunteers showed that the AbbVie drugs have no clinically
meaningful interactions with tenofovir or emtricitabine (the drugs in Truvada), atazanavir (Reyataz) or raltegravir (Isentress). The ritonavir in the ABT-450
co-formulation also acts as a booster for atazanavir.
TURQUOISE-I will be conducted in two parts. Part 1 included
63 people with HIV and genotype 1 HCV co-infection. More than 90% were men, a
majority were white and the mean age was 51 years. The study enrolled both
previously untreated people (about 67%) and prior relapsers (6%), partial
responders (11%) and null responders (16%). About 90% had harder-to-treat HCV subtype
1a, about 25% had the favourable IL28B CC gene variant, and 19% had liver
cirrhosis at baseline. They had undetectable HIV viral load on a stable
antiretroviral regimen containing either atazanavir or raltegravir (45% and
55%, respectively), and the mean CD4 cell count was approximately 630 cells/mm3.
Participants in this open-label study were randomly assigned
to take the 3D regimen plus ribavirin for either 12 or 24 weeks. The primary
endpoint was sustained virological response, or undetectable HCV RNA at 12
weeks after completing treatment (SVR12). All participants in the 12-week arm
and about two-thirds in the 24-week arm had reached this endpoint.
The SVR12 rate
was 94% for participants in the 12-week arm. In the 24-week arm, the SVR4 rate –
which is too soon to consider a cure – was 97%. Among the 20 people in this arm
who had reached 12 weeks of post-treatment follow-up, the SVR12 rate was 95%
and none had relapsed.
experienced virological failure – one relapse and one viral breakthrough while
on treatment. Sulkowski noted that both were prior null responders with
cirrhosis who had HCV subtype 1a and the least favourable IL28B TT gene
variant. Both had resistance-associated viral variants at the time of treatment
failure that were not present at baseline.
The 3D regimen
plus ribavirin was generally safe and well-tolerated. None of the participants experienced
serious adverse events or discontinued treatment early for this reason. The
most common side-effects were fatigue (58% in the 12-week arm and 38% in the
24-week arm), insomnia (16% and 22%, respectively), nausea (16% and 19%) and
headache (19% and 13%). Most adverse events were mild or moderate.
laboratory abnormalities, 35% in the 12-week arm and 19% in the 24-week arm
experienced bilirubin elevations. Four people in the 12-week arm and three in
the 24-week arm developed low haemoglobin, but no one progressed to severe
anaemia. Six people reduced their ribavirin dose due to anaemia, but all went
on to achieve SVR12.
experienced episodes of low-level HIV viral load during treatment, but all
regained undetectable HIV RNA while remaining on the same antiretroviral
regimen. There were no notable changes in CD4 count.
concluded that the 3D regimen plus ribavirin was effective and well-tolerated,
and that these results are "highly consistent" with those previously
observed in people with HCV mono-infection taking the same combination.
Part 2 of the
TURQUOISE-I trial – which will test the 3D regimen plus ribavirin in people
with HIV and HCV co-infection taking the ritonavir-boosted HIV protease
inhibitor darunavir (Prezista) – will
start later this year.
In response to a
question, Sulkowski agreed that people with easier-to-treat HCV subtype 1b
probably do not need to include ribavirin with the 3D regimen and most people
probably need only 12 weeks of treatment. The biggest concern, he said, is the
group of hard-to-treat prior non-responders with subtype 1a and cirrhosis.
Among the six people like this in the trial, four achieved SVR12 and two
experienced treatment failure.