The hepatitis C protease inhibitor faldaprevir plus pegylated interferon
and ribavirin improved 4-week sustained response rates for HIV-positive people with genotype 1 hepatitis C co-infection in the STARTVerso4 trial, according to
a poster presented at The Liver Meeting 2013, the 64th annual meeting of the American
Association for the Study of Liver Diseases (AASLD), last week in Washington,
People with HIV and hepatitis C virus (HCV) co-infection experience more rapid liver
disease progression and do not respond as well to interferon-based therapy as people with HCV alone. New direct-acting antiviral agents have the potential
to improve response rates for people with co-infection, but this population
faces concerns regarding toxicities and drug-drug interactions with
antiretroviral therapy (ART). While these new drugs will eventually
be combined in all-oral regimens, they will initially be used as add-ons to
pegylated interferon/ribavirin; some people with co-infection who have advanced liver
disease cannot wait for interferon-free therapy.
Jürgen Rockstroh from the University of Bonn and colleagues evaluated Boehringer Ingelheim's faldaprevir (formerly
BI 201335) plus pegylated interferon/ribavirin for people with HIV and HCV co-infection who had either never previously taken treatment for hepatitis C or had relapsed after a
prior course of interferon-based therapy. Faldaprevir has previously
demonstrated good efficacy and tolerability in HIV-negative people, both in combination with pegylated interferon/ribavirin and in interferon-free regimens.
The phase 3 STARTVerso4 trial (NCT01399619) enrolled 308 people with co-infection in Europe,
North America and Brazil. Most (81%) were men, 83% were white and the average
age was 47 years. About one-third had the favourable IL28B CC gene variant, 79%
had harder-to-treat HCV subtype 1a, 14% had advanced liver fibrosis (stage F3)
and 15% had compensated cirrhosis (stage F4). Just over three-quarters were HCV
treatment-naive while 22% were prior relapsers; this study did not include prior
null responders, the most difficult-to-treat group.
Participants were either on stable antiretroviral
therapy (ART) or had a high enough CD4 cell count that they did not yet need HIV
treatment. At baseline, 96% were on ART and the mean CD4 count was 537 cells/mm3.
They were limited to using antiretrovirals shown not to have clinically
relevant interactions with faldaprevir, though in some cases dose adjustments
were needed. Nearly half took raltegravir (Isentress),
27% took efavirenz (Sustiva) and 22%
took either ritonavir-boosted atazanavir (Reyataz)
or darunavir (Prezista).
All participants in this open-label study received
once-daily faldaprevir in combination with pegylated interferon alfa-2a (Pegasys)
plus weight-based ribavirin. Those taking boosted atazanavir or darunavir used
120mg faldaprevir while those taking efavirenz used 240mg. Participant who were
ART-naive or taking raltegravir were randomly assigned to receive either 120mg
Everyone receiving 120mg
faldaprevir stayed on triple therapy for 24 weeks. Those taking 240mg were
randomly assigned to take faldaprevir triple therapy for 12 or 24 weeks.
According to a response-guided therapy algorithm, people who experienced 'early
treatment success' (HCV RNA <25 IU/ml at week 4 and undetectable at week 8)
were randomised to either stop all drugs at 24 weeks or continue on pegylated
interferon/ribavirin alone through week 48, as did all patients without early
Overall, 74% of patients
achieved sustained virological response, or continued undetectable HCV RNA, 4
weeks after completing therapy (SVR4). People with SVR4 are not yet considered
cured as relapse may still occur after this point; regulatory agencies in
Europe and the US consider sustained response at post-treatment week 12 (SVR12)
indicative of a cure.
Response rates were
statistically comparable regardless of faldaprevir dose or treatment duration. SVR4 rates ranged from 72% for people treated with
120mg faldaprevir for 24 weeks, to 79% for those treated with 240mg for 12
weeks, to 84% for those treated with 240mg for 24 weeks. Among randomised
participants 80% achieved early treatment success, and for these individuals
the SVR4 rate reached 88%.
Unlike some other
direct-acting antivirals, SVR4 rates were similar for people with HCV subtype
1a and 1b (74 vs 77%). People with and without cirrhosis also had similar early
sustained response rates (76 vs 74%). SVR4 rates did not differ significantly
according to ART regimen (ranging from 67% for people taking darunavir to 80% for
those taking raltegravir) or being ART-naive (73%).
However, prior treatment
status did appear to have an effect: 71% of people who had not taken treatment before
achieved SVR4 compared with 87% of prior relapsers. IL28B status also had an
impact, with SVR4 rates of 89% for people with the favourable CC pattern and
67% for those with the CT or TT variants.
Faldaprevir triple therapy
was generally safe and well-tolerated, with a safety profile comparable to that observed for people with HCV alone (mono-infection) in other studies. Adverse events were similar across treatment regimens.
experienced side-effects typical of interferon. One in ten experienced serious
adverse events, 44% had grade 3 or higher laboratory abnormalities and 7%
discontinued treatment for this reason. The most common side-effects were
nausea (37%), fatigue (34%), diarrhoea (27%) and headache (25%), while the most
common lab abnormality was elevated bilirubin (19%). One person taking 120mg faldaprevir experienced HIV
this large, phase III study in patients co-infected with HIV and HCV
genotype-1, faldaprevir + pegylated interferon/ribavirin was well tolerated and
efficacious and did not have any impact on HIV RNA suppression by ART",
the researchers concluded.
SVR4 results are encouraging given the difficult-to-treat population (79%
genotype-1a, 15% cirrhosis, 82% high baseline HCV RNA, 66% IL28B non-CC), and
suggest that faldaprevir + pegylated interferon/ribavirin may become an
important option for the treatment of chronic HCV genotype-1 infection in
patients co-infected with HIV with or without concomitant ART", they