experimental hepatitis C virus (HCV) protease inhibitor telaprevir,
used with pegylated interferon plus ribavirin, produced good
virological response in the first study of HIV/HCV co-infected
individuals, according to interim data presented on Wednesday at
the 18th Conference on Retroviruses and Opportunistic Infections
(CROI), taking place this week in Boston.
in combination with pegylated
interferon/ribavirin has demonstrated good efficacy in Phase 3
studies of treatment-naive and treatment-experienced patients with
chronic hepatitis C alone. But HIV-positive people co-infected with
HCV tend to respond less well to standard hepatitis C treatment and
are eagerly awaiting new therapeutic options.
Sulkowski from Johns Hopkins University reported interim results from
Study 110, the first clinical trial of telaprevir combination therapy
in HIV/HCV co-infected patients with previously untreated chronic
- rapid virological response (RVR)
An undetectable hepatitis C RNA viral load within 4 weeks of starting treatment. An extended rapid virological response (eRVR) is when viral load is undetectable within 4 weeks and remains undetectable until at least week 12.
A of the study included 13 co-infected participants who had CD4 T-cell
counts of at least 500 cells/mm3
and were not yet taking antiretroviral therapy (ART).
B included 46 people with CD4 counts of at least 300 cells/mm3
who were on ART consisting of either efavirenz (Sustiva
also in the Atripla
co-formulation) or atazanavir (Reyataz)
plus tenofovir and either emtricitabine (Emtriva)
or lamivudine (Epivir).
All patients on ART had suppressed HIV viral load below 50
the groups most participants were men, with an average age of 46
years. More than half the patients in Part A were black
population that does not respond as well to interferon-based therapy
– but this fell to less than one-third in Part B. Most had high HCV
viral load, another predictor of poor treatment response, but only
about 10% had bridging liver fibrosis or cirrhosis.
both parts of the study, participants were randomly assigned to
telaprevir or placebo arms.
the active drug arm, patients took telaprevir with 180 mcg per week
of pegylated interferon alfa 2a (Pegasys)
plus either 800 mg per day or weight-based ribavirin for 12 weeks,
followed by pegylated interferon/ribavirin alone through to week 48.
Participants in the control arm received standard-of-care therapy
consisting of the same doses of pegylated interferon and ribavirin
for 48 weeks, along with a placebo during the first 12 weeks.
discussed in another presentation on Tuesday, telaprevir has modest
drug-drug interactions with some antiretroviral drugs. Based on
pharmacokinetic studies in healthy volunteers, atazanavir and
efavirenz were judged to be the most suitable HIV drugs for use with
slightly reduces blood levels of atazanavir, but no dose adjustment
was considered necessary.
in Study 110 using atazanavir-based ART received 750 mg telaprevir
three times daily, the same dose used in monotherapy studies. Since
efavirenz more strongly lowers telaprevir concentrations,
participants using efavirenz-based ART received a higher telaprevir
dose of 1125mg three times daily.
in an intention-to-treat analysis of rapid virological response (RVR)
at week 4, 70% of participants taking telaprevir achieved
undetectable HCV viral load, compared with just 5% in the placebo
down the telaprevir arm according to type of HIV treatment, 71% of
patients not on ART, 75% taking efavirenz-based ART and 64% taking
atazanavir-based ART had undetectable HCV RNA.
pattern was similar when looking at complete early virological
response rates among participants followed through week 12. Overall
response rates were 68% in the telaprevir group, compared with 14% in
the placebo group. Broken down by ART type, response rates were 71%,
75% and 57%, respectively.
people taking telaprevir in Part B experienced HCV breakthrough, one
using atazanavir at week 4 and one using efavirenz at week 8. An
additional four patients discontinued treatment due to pre-defined
non-response stopping rules.
was generally well tolerated. Nausea and itching were the most common
side-effects that occurred significantly more often in the telaprevir
arm than in the standard-therapy arm. There were three serious
adverse events amongst telaprevir recipients and two drug
discontinuations due to adverse events (one jaundice and one anaemia,
both in atazanavir recipients).
11% of telaprevir recipients developed moderate skin rash (compared
with less than 1% in the standard-therapy arm), there were no cases
of severe rash, as have been reported in HCV monoinfection studies.
at pharmacokinetics, the researchers found that median telaprevir
trough, or lowest, concentrations were similar with and without ART.
Antiretroviral drug trough concentrations fell by less than 20% when
telaprevir was added, and there were no cases of HIV viral rebound.
HIV RNA levels in Part B decreased by about one log in both the
telaprevir and standard-therapy arms, consistent with what has been
reported previously during treatment with pegylated
interferon/ribavirin. There were no significant CD4 cell count
rapid and early response rates were somewhat lower among atazanavir
recipients compared with efavirenz recipients, Sulkowski said it was
not possible to make comparisons between ART groups given the small
numbers in this study.
researchers concluded that, in this interim analysis, "substantially
more patients receiving a telaprevir-based regimen achieved
undetectable HCV RNA at weeks 4 and 12". Safety and tolerability
profiles were consistent with those previously seen in studies of HCV
monoinfection, with no new or unexpected adverse events in this
a press conference following his presentation, Sulkowski concurred
with a statement by Joseph Eron that he would only feel
comfortable giving telaprevir in combination with atazanavir or
efavirenz. Given significant
interactions between telaprevir and boosted lopinavir (Kaletra),
and fosamprenavir (Lexiva),
telaprevir is not currently being evaluated in people taking these
will continue for six months after the end of therapy to
determine rates of sustained virological response, considered a cure
for hepatitis C. In studies of monoinfected patients, rapid and early
virological response strongly predicted sustained response.