However the headline outcomes of these trials conceal a
number of caveats, notes Tracy Swan of New
York’s Treatment Action Group
In the Hepatitis C
Treatment Pipeline Report published last month, she highlighted a host of
unanswered questions that should give clinicians pause for thought when
considering how to treat patients with hepatitis C using the new drugs. These
issues are likely to be just as relevant in HIV/HCV coinfected people as in the
much larger HCV-monoinfected population.
In particular she points to the lower rate of response in
patients who failed to respond to first-line treatment with pegylated
interferon. These patients were much less likely to achieve a sustained
virological response in trials of telaprevir and boceprevir, although the
responses were still better than those seen in the control groups receiving
In the case of the REALIZE study of telaprevir, for example,
just 31% of prior null responders had a successful response to telaprevir,
compared to 83% of those who experienced a virological relapse after completing
treatment successfully. Among those null responders with cirrhosis – the people
with a more urgent need for successful treatment – the cure rate was just 14%
in the telaprevir group.
Cure rates were similarly lower among patients with
cirrhosis who had a partial response to prior therapy (defined as a reduction
in HCV viral load of at least 2 log at week 12 without achieving undetectable
viral load before therapy was completed). 34% of this group achieved a
sustained virological response compared to 59% of non-responders in the study
as a whole.
These findings suggest that patients with advanced liver
disease will need to weigh up carefully the risks and benefits of attempting
another course of pegylated interferon and ribavirin in combination with a new
HCV protease inhibitor. Would it be better to wait for further drugs, or is the
severity of liver disease such that a further attempt at a cure would be
These issues may be more pressing for patients with HIV/HCV
coinfection, where liver disease may be more rapidly progressive, particularly
if HIV is uncontrolled by treatment.
There is also uncertainty about just how long patients need
to take the new drugs, a question that has a crucial bearing on the cost of new
hepatitis C treatments – and the convenience and tolerability of these drugs.
On the up side, trials of both protease inhibitors reinforced the concept of 'response-guided therapy' to hepatitis C treatment, by establishing a series of
time points at which protease inhibitor treatment or all treatment could be
stopped if HCV was undetectable.
In the case of telaprevir, there is evidence to suggest that treatment with pegylated interferon and ribavirin can be shortened to 24 weeks if HCV is
undetectable after 12 weeks of telaprevir treatment. With boceprevir, treatment should carry on until week 24, but
hepatitis C treatment can stop completely at this point if HCV RNA was
undetectable at weeks 8 and 24.
However, a further complexity of boceprevir treatment is the
four-week lead-in phase of pegylated interferon and ribavirin, designed to
reduce viral load and so minimise the risk of resistance to boceprevir. What
should happen if a patient fails to show some signs of virological response
after this four-week lead-in phase? Is the patient fundamentally unresponsive
to interferon, and thus likely to fail treatment completely?
The REALIZE study of telaprevir in treatment-experienced
patients showed that a four-week lead-in phase did not improve response rates.
In a possible re-run of history from the HIV field, some
experts are concerned that premature use of new agents in patients with a poor
chance of response could leave them with resistance to new agents that may
affect their response to subsequent innovations in hepatitis C treatment.
Professor Heiner Wedemeyer, Secretary General of the European
Association for the Study of the Liver, told a press conference at last week’s
Congress: “Studies show that care must be taken in the prescription and use of
the new compounds. What we want to avoid is a rapid spread of HCV resistance
within the patient population, which could drastically lower the effectiveness
of the new drugs.”
Evidence from the SPRINT-2 study of boceprevir showed that
patients in the poor-responder category had a high risk of developing drug
resistance. This in turn could compromise their response to future experimental
treatment. (See Clinical
Care Options summary of this study – registration required.)
However there is also evidence
that resistance mutations to telaprevir may fade over time, possibly allowing
that drug or other HCV protease inhibitors to be used again. A lot more
evidence will be needed on this question to convince liver experts that re-use
or sequencing of HCV protease inhibitors would be possible in the case of
Other protease inhibitors are being developed. Tibotec presented
preliminary results from a phase IIb study of TMC-435, studied in
combination with pegylated interferon and ribavirin. Week 24 virological
response data showed a much less marked gap in response rates between
relapsers, prior partial responders and null responders. At week 24, 92 to 96% of
protease inhibitor recipients in the prior relapser group had undetectable HCV
RNA, as did 70 to 87% of null responders, according to dosing and treatment
To make a meaningful comparison with boceprevir or
telaprevir a further 24 weeks of follow-up data will be needed in order to
assess whether these patients achieve a sustained virological response.
Roche’s HCV protease inhibitor also showed
strong preliminary results in a study of previous null responders, at least in
patients infected with HCV genotype 1b. Danoprevir is boosted with ritonavir in
the same way as HIV protease inhibitors, and administered alongside pegylated
interferon and ribavirin. By week 12 88% of those with genotype 1b receiving
danoprevir had achieved a rapid virologic response (undetectable HCV RNA by
week 4). In comparison a high rate of viral breakthrough occurred within weeks
of viral suppression in the genotype 1a group. (See Clinical
Care Options summary of this study – registration required.)