Adding the new hepatitis C
virus (HCV) protease inhibitor simeprevir (formerly TMC435) to pegylated interferon and
ribavirin cures about three-quarters of HIV/HCV co-infected people, most of
them with a shortened course of therapy, researchers reported last week at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI
2013) in Atlanta.
Direct-acting antiviral agents have brought
about a new era of treatment for chronic hepatitis C. While interferon-free
regimens are on the horizon, many patients 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
interferon-free combos, as new agents are typically approved for HCV
mono-infected people first.
from Mt Sinai School of Medicine in New York presented findings from the TMC435-C212
study, evaluating the safety and efficacy of the HCV NS3/4A protease inhibitor
simeprevir plus pegylated interferon/ribavirin in co-infected individuals with
HCV genotype 1.
single-arm, phase III study included 106 HIV/HCV co-infected people, most of
them on antiretroviral therapy (ART), who could either have no previous
hepatitis C treatment or be prior non-responders.
Most (85%) were men,
82% were white, the median age was 48 years and about one-quarter had the
favourable IL28B CC gene pattern. Just over 80% had difficult-to-treat HCV
sub-type 1a, 12% had advanced liver fibrosis (stage F3) and 9% had cirrhosis
Looking at HIV-related
characteristics, they had a median CD4 cell count of 629 cells/mm3
(561 cells/mm3 for those on ART, 677 cells/mm3 for those
untreated). Almost all people on ART had HIV RNA <200 copies/mL, as did 23%
of those not on HIV therapy. Nearly everyone on treatment was using NRTIs, 87% were on
raltegravir (Isentress), 15% were on
rilpivirine (Edurant) and 3% each
were using maraviroc (Selzentry or Celsentri) and enfuvirtide (T-20, Fuzeon).
received 150mg once-daily simeprevir in combination with pegylated interferon
alfa-2a (Pegasys) plus weigh-adjusted
ribavirin. Treatment-naive people and those who relapsed after prior
interferon-based therapy received the triple regimen for 12 weeks, then
continued on pegylated interferon/ribavirin alone through week 24.
At that point, using
a response-guided therapy algorithm, early responders (defined as HCV RNA <25
IU/mL at week 4 and undetectable at week 12) stopped all study drugs, while the
rest continued on pegylated interferon/ribavirin alone for an additional 24
weeks. Prior partial responders, null responders and everyone with cirrhosis
(regardless of prior response) received the full 48-week regimen.
Dieterich presented data
from an interim analysis of 100 patients who completed 24 weeks of treatment or
discontinued prior to that point; within this group, 71 had reached 28 weeks
and 27 had reached 36 weeks.
At week 4, the
overall rapid virological response (RVR) rate was 66%. Prior naives, relapsers
and partial responders all had good early response (71, 93 and 80%,
respectively), but the RVR rate for null responders was only 37%.
preliminary sustained response rates, calculated for patients eligible for
response-guided therapy, 86% overall had undetectable HCV RNA 4 weeks after
completion of treatment (SVR4) and 77% were still undetectable at 12 weeks
post-treatment (SVR12). Corresponding rates were 84% SVR4 and 75% SVR12 for
treatment-naive patients, and 90% SVR4 and 80% SVR12 for prior relapsers.
A large majority
(88%) of eligible participants met the response-guided therapy criteria and
finished treatment at week 24. For this group, the SVR4 rate was 85% and SVR12
Overall, 15% of
patients experienced on-treatment failure and ended therapy based on
non-response stopping rules. Failure rates ranged from 0% for prior relapsers,
to 9% for naives to 36% for prior null responders. In addition, 13% overall
(10% of naives and 18% of prior relapsers) relapsed during post-treatment
follow-up. All relapses occurred among people with HCV sub-type 1a. Prior null
responders were still being followed, but 64% had not experienced treatment
failure at the interim analysis.
None of the
participants on antiretroviral therapy saw an increase in HIV RNA indicating
loss of viral suppression. Absolute CD4 cell counts fell during treatment with
interferon – a typical finding – but CD4
percentages rose or remained stable.
Triple therapy with
simeprevir was generally safe and well tolerated. Serious adverse events were
reported by 5% of patients, and 4% discontinued treatment for this reason. The
most common side-effects were fatigue (41%), headache (27%) and nausea (26%),
typical of pegylated interferon/ribavirin. Just over one-quarter developed
neutropenia, 21% had anaemia, 20% reported itching and 17% developed skin rash.
In addition, 49 people experienced bilirubin increases, mostly
mild to moderate, that were not associated with liver enzyme elevations.
pegylated interferon/ribavirin "led to high virologic response in
co-infected patients, regardless of prior response", the investigators
concluded. "Simeprevir was well tolerated, with a safety profile similar
to HCV mono-infected patients."
presented data at an earlier conference session that showed good early response
rates using another HCV protease inhibitor, faldaprevir (formerly BI 201335) 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.
These next-generation HCV
protease inhibitors "represent a significant advance" over boceprevir
(Victrelis) and telaprevir (Incivo or Incivek), Dieterich said, as they are once daily, easier to take, and
have dramatically reduced 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."