Faldaprevir plus pegylated interferon/ribavirin leads to early sustained response in people with HIV and HCV co-infection

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, DC.

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 or 240mg.

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 treatment success.

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.

Most participants 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 viral rebound.

"In 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.

"These 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 added.