Adding the hepatitis C virus
(HCV) protease inhibitor faldaprevir (formerly BI 201335) to pegylated interferon and
ribavirin led to a higher early response rate and the potential for shorter
treatment for HIV/HCV co-infected people, according to a presentation last week
at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI
2013) in Atlanta.
Direct-acting antiviral agents that target
different steps of the HCV lifecycle have ushered in a new era of treatment.
While interferon-free, all-oral regimens are on the horizon, many people with
chronic hepatitis C have advancing liver disease and cannot wait. Although HIV-positive
people with hepatitis C experience more rapid liver disease progression, they
will have to wait longer for approval of interferon-free combinations, as new agents
are typically approved for HCV monoinfected people first.
Douglas Dieterich from
Mt Sinai School of Medicine in New York presented findings from the STARTVerso 4
trial, looking at the safety and efficacy of faldaprevir plus pegylated
interferon/ribavirin in co-infected individuals with HCV genotype 1.
This open-label phase
III study enrolled 308 HIV/HCV co-infected people who were either never before
treated for hepatitis C (78%) or relapsed after prior interferon-based therapy
About 80% of
participants were men, a similar proportion was white, and the average age was
47 years. Nearly 80% had harder-to-treat HCV sub-type 1a, 17% had compensated liver
cirrhosis (stage F4 or FibroScan cut-off of >13kPa) and about 80% had high
baseline HCV viral load.
At study entry they
had well-controlled HIV, with a mean CD4 cell count of approximately 450
cells/mm3. Nearly 25% were taking antiretroviral regimens containing
efavirenz (Sustiva or Stocrin), about 20% were taking ritonavir-boosted
atazanavir (Reyataz) or darunavir (Prezista), 47% were taking raltegravir (Isentress) or other anti-HIV drugs, and 4%
were not on antiretroviral therapy.
treated with once-daily faldaprevir in combination with 180mcg once-weekly
pegylated interferon alfa-2a (Pegasys)
plus weight-based ribavirin. Faldaprevir doses were adjusted according to which
antiretrovirals were used, based on data from drug-drug interaction studies.
Three separate phase I trials, described at the same
session by Jens Kort from Boehringer
Ingelheim, tested pharmacokinetic interactions between faldaprevir and darunavir/ritonavir,
efavirenz, and tenofovir (Viread,
also in several coformulations) in healthy HIV-negative volunteers; a study of
atazanavir is underway.
The studies showed no
clinically relevant effect of faldaprevir on these medications. This is
important because interactions that lower antiretroviral drug levels in the
body could lead to loss of HIV control. Conversely, faldaprevir levels
increased by approximately 130% when
taken with boosted darunavir, but fell by approximately
35% when taken with efavirenz.
4 participants taking efavirenz received 240mg faldaprevir, people taking
boosted atazanavir or darunavir got 120mg and those on raltegravir or maraviroc
(Selzentry or Celsentri) were randomised to one of the two doses.
Everyone assigned to 120mg
faldaprevir stayed on triple therapy for 24 weeks, whilst those taking 240mg
were randomly assigned to do so for 12 or 24 weeks. Using a response-guided
therapy algorithm, people with "early treatment success" (defined as unquantifiable
HCV RNA at week 4 and undetectable at week 8) were re-randomised at week 24 to
either stop treatment or continue pegylated interferon/ribavirin alone through
week 48; everyone without early success took the longer course.
interim data from 12 weeks on treatment. Faldaprevir dose assignments for the
randomised group remained blinded.
At week 4, 60% of
previously untreated participants and 74% of prior relapsers had HCV RNA below
the level of detection, rising to 82 and 91%, respectively, at week 12. Rates
for the relapsers were similar to those seen in the SILEN-C1 study of HCV
mono-infected people, at 76 and 93%. Most participants – 77% of
treatment-naives and 88% of relapsers – had early success
and were eligible for randomisation to shorter treatment.
None of the
participants on antiretroviral therapy saw an HIV RNA increase indicating loss
of viral suppression.
Triple therapy was
generally safe and well tolerated. The most common side-effects were nausea
(37%), fatigue (33%) diarrhoea (27%), headache (23%) and weakness (22%) – rates similar to
those seen with pegylated interferon/ribavirin alone. About one-tenth
experienced serious adverse events and there were three deaths, though none were
considered related to study medications. At the time of the interim analysis 18
participants had withdrawn early due to adverse events.
side-effects that have proven problematic with other HCV drugs, 18% of
participants developed anaemia, 16% had neutropenia and 18% reported skin rash.
Faldaprevir was "much less toxic"
than the approved HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo
or Incivek), Dieterich said.
compare well with early response rates in mono-infected patients," the
researchers concluded. "Adverse events were comparable to those with
faldaprevir and [pegylated interferon/ribavirin] in HCV mono-infected
presented data at a later conference session showing good results for another
HCV protease inhibitor – simeprevir (formerly TMC435) – combined with pegylated interferon/ribavirin
for HIV/HCV co-infected patients (see related news report).
At a press conference
discussing hepatitis C research, Dieterich said the combined findings were
"very encouraging", showing that co-infected people have outcomes
"about equal" to those of HCV monoinfected individuals.
The two next-generation HCV
protease inhibitors "represent a significant advance" over telaprevir
and boceprevir, Dieterich said, as they are both once-daily and easy to take,
with dramatically fewer side-effects and higher success rates.
"We don’t know when interferon-free
regimens will be on the market, and in the meantime we're still stuck seeing patients
every day, and some are really sick and need to be treated now," he
continued. These new compounds are "easier and far superior" and can be
used until interferon-free treatment is available.
Moderator David Thomas of
Johns Hopkins University predicted that, while the approval of interferon-free
combinations is not expected this year, the first components are likely to become available. Comparing
the hepatitis C drug development process to HIV, he said, "It's as if
we're going from Crixivan to Atripla in a year and a half."