Dieterich of Icahn School of Medicine at Mount Sinai in New York presented late-breaking
findings from the C212 study evaluating triple therapy with simeprevir for
HIV/HCV co-infected patients. Co-infected people experience more rapid liver
disease progression and do not respond as well to interferon-based therapy as
HIV-negative people with hepatitis C alone, so there is an urgent need for
(formerly TMC435) is a once-daily HCV NS3/4A protease inhibitor discovered by
Medivir and being developed by Janssen. Prior studies in treatment-naive and
previously relapsed HCV mono-infected patients showed response rates around
80%. It is currently under review by
European and US regulatory authorities, with US approval expected by the end of
phase 3, open-label trial evaluated the safety and efficacy of simeprevir in
106 HIV-positive people with genotype 1 chronic hepatitis C. Most (85%) were
men, 82% were white, 14% were black and the median age was 48 years.
90% were on antiretroviral therapy (ART), almost all with undetectable HIV
viral load, and the median CD4 cell count was 429 cells/mm3.
Simeprevir is metabolised by the CYP3A4 enzyme and preclinical studies showed
it can interact with certain antiretrovirals. In this study, patients were not
permitted to use HIV protease inhibitors or efavirenz (Sustiva). Most (87%) were on raltegravir (Isentress) and almost all took nucleoside/nucleotide reverse
to hepatitis C factors, just over 80% had HCV subtype 1a, which is harder to
treat than 1b. Just over one-quarter had the favourable IL28B 'CC' gene variant
associate with good interferon responsiveness. Fibrosis was absent to moderate
(METAVIR score F0-F2) in 42% whilst 21% had advanced fibrosis or cirrhosis
participants received 150mg once-daily simeprevir plus pegylated interferon
alfa-2a (Pegasys) and ribavirin for
12 weeks. People never before treated for hepatitis C and those who had relapsed
after a prior course of interferon and who did not have cirrhosis were eligible
for response-guided therapy (RGT). Those with good response at weeks 4 and 12
continued on pegylated interferon/ribavirin alone for 12 more weeks whilst the
rest did so for 36 more weeks. More difficult to treat patients – prior
partial responders, null responders and people with cirrhosis – all stayed on
pegylated interferon/ribavirin through to week 48.
reported results from the primary analysis, with all participants either
reaching 12 weeks of post-treatment follow-up or dropping out prematurely.
Sustained virological response (SVR) or continued undetectable HCV RNA at 12 weeks
after completing treatment (SVR12) is considered a cure.
Overall, 66% of participants experienced rapid
virological response (RVR), or undetectable HCV RNA at week 4, and 84% were
undetectable at the end of treatment.
The overall SVR12 rate was 74%. By prior treatment
status, this broke down to 79% for treatment-naive individuals, 87% for prior
relapsers, 70% for prior partial responders and 57% for prior null responders – the most difficult-to-treat group. For comparison, historical rates seen in
prior co-infection studies using pegylated interferon/ribavirin alone were 29%
for treatment-naive people and just 5% for null responders.
eligible participants (89%) met the RGT criteria and were able to stop all
treatment at week 24. Within this group, the SVR12 rate was 87%.
with HCV subtype 1b were more likely to achieve SVR12 than those with 1a (89
vs 71%), with an even lower rate (67%) for 1a patients with the Q80K NS3
resistance mutation at baseline.
with advanced fibrosis or cirrhosis did not respond as well as those with
mild-to-moderate liver disease, with overall SVR12 rates of 80 and 64%,
respectively. The difference appeared particularly striking for treatment-naive
people (89 vs 57%), but Dieterich noted that patient numbers were small in the
breakdown according to prior treatment status.
was asked to show some back-up slides, revealing that response was better for
people with low baseline HCV RNA levels (<800,000 IU/ml) compared to those
with higher viral load: 93 vs 70%, respectively; among null responders the
corresponding figures were 100 and 54%, but again numbers were small.
status also had an effect, with 96% of those with the favourable 'CC' variant,
68% with the intermediate 'CT' variant and 61% with the least favourable 'TT'
variant achieving SVR12. Finally, people on ART responded better than those
with untreated HIV: 75 vs 62%, respectively.
at treatment failure, 17% overall experience HCV virological failure whilst
still on treatment, ranging from 0% for prior relapsers to 39% for null
responders. Post-treatment relapse was uncommon at 9% overall; two prior
relapsers (13%) relapsed again, as did two prior null responders (7%). All but
one relapse occurred amongst people with genotype 1a. Most of these patients
who underwent resistance testing (79%) had
emergent resistance mutations, mostly R155K alone.
In addition, two individuals (2%) experienced loss
of HIV viral suppression, but this happened 12 weeks after completion of
hepatitis C treatment and is not thought to be related.
triple therapy was generally safe and well tolerated, with adverse events
similar to those seen in HCV mono-infected people in other studies. Overall adverse
events were common, as is typical for regimens containing interferon and
ribavirin. There were six serious adverse events, of which four led to
simeprevir discontinuation. The most common side-effects were fatigue (41%),
headache (28%), nausea (26%), neutropenia (28%), anaemia (21%), itching (20%)
and rash (17%).
once daily plus pegylated interferon/ribavirin for 12 weeks "led to high rates of SVR12 in HCV genotype 1/HIV-1 patients
regardless of prior HCV treatment response", the researchers concluded.
"SVR12 rates were high, regardless of baseline METAVIR fibrosis score or
HCV genotype 1 subtype."
findings, Dieterich said, support the trend that "SVR rates for
HIV-positive people seem similar to [those for] HIV-negative people in the new
world of direct acting antiretrovirals." He added that it is good to
finally have "true antivirals" for hepatitis C, as HIV clinicians have
had for a long time.
Noting that people on antiretroviral therapy responded better, Dieterich
said that even if co-infected patients don't need ART according to CD4 count,
"I want them on it during hepatitis C treatment because we want as many
good-quality CD4 cells as possible."