The advent of direct-acting antiviral agents can rightly be described as
a revolution in treatment for chronic hepatitis C, but potential challenges
remain – including drug interactions and cost, Heiner Wedemeyer told
participants during a Thursday plenary session at the 14th European
AIDS Conference in Brussels.
hepatitis C has traditionally been difficult to treat. Until recently, the
standard of care was dual therapy with pegylated interferon (Pegasys or PegIntron) and ribavirin, which lasts up to a year – perhaps even
longer for people with HIV and hepatitis C virus (HCV) co-infection – has notorious side-effects, and offers
only a modest cure rate, especially for people with unfavourable factors such
as advanced liver fibrosis.
development of direct-acting antivirals (DAAs) has been described by many as
revolutionary. Looking at the dictionary definition of 'revolution', Wedemeyer,
from Hannover Medical School, Germany, agreed that the new therapies offer "a
radical and profound change in relationships and technological
conditions", "a fundamental departure from any historic pattern"
and "a challenge to the established order".
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
first approved DAAs, the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo or Incivek), must be used with pegylated interferon/ribavirin.
Although they can shorten treatment duration and improve sustained virological
response (SVR, considered a cure) rates, they add side-effects, regimen complexity and
potential for drug-drug interactions.
next-generation HCV drugs now in the pipeline are better tolerated, more
convenient and raise cure rates even further – often into the 90 to 100%
range for people with favourable response predictors. As add-ons, they improve
the efficacy of interferon-based therapy, but the real revolution will be
all-oral, interferon-free regimens.
only will new treatments be more effective, Wedemeyer explained, but all-oral
regimens will "dramatically increase" the number of treatable
patients, many of whom cannot tolerate interferon. Ultimately "we should be able to treat almost all
patients", and hopefully, if this becomes widely known, general
practitioners will be more likely to screen for HCV and offer treatment, he
effective therapies will not only raise the likelihood of sustained virological
response, but studies have shown that SVR is associated with reduced risk of
progression to advanced liver disease, liver cancer and mortality. New therapies
"will not only cure HCV but will save lives", Wedemeyer emphasised.
treatment with sustained response – which essentially eliminates infectious
virus – also prevents HCV transmission and is expected to lower hepatitis C
incidence, especially among people who inject drugs.
briefly ran through the history of development of hepatitis C DAAs, which over
the past couple of years has led to publication of ground-breaking new findings
every couple of months, starting with the first report of SVR with two DAAs
(daclatasvir and asunaprevir) in the February 2012 New England Journal of Medicine. New therapies have increased
treatment response rates for people with HIV/HCV co-infection as well as people with HCV mono-infection.
showed a list of DAAs and how they interfere with different steps of the HCV
protease inhibitors – ending in 'previr' – include the approved drugs
boceprevir and telaprevir as well as simeprevir (submitted for European and US
approval), asunaprevir, danoprevir, faldaprevir, sovaprevir, ABT-450 and
polymerase inhibitors – ending in 'buvir' – may be nucleoside/nucleotide
analogues such as sofosbuvir (also submitted for approval), mericitabine and
ALS-2200 (VX-135), or non-nucleoside such as deleobuvir, setrobuvir, ABT-072,
ABT-333, BMS-791325 and VX-222.
inhibitors – ending in 'asvir' – include daclatasvir, ledipasvir and ABT-267.
Other types of novel
therapies undergoing testing include the microRNA blocker miravirsen, the HCV
therapeutic vaccine candidate TG4040 and cyclophilin inhibitors.
Is one class better
than other? "Each class has good and bad drugs in terms of potency,
resistance and side-effects, which makes things a little more
complicated," Wedermeyer explained. The large number of trials and
multiple regimens under study adds to the confusion.
As with antiretroviral
therapy for HIV, interferon-free hepatitis C regimens will need to combine
agents from different classes to provide adequate potency and prevent
development of drug resistance.
Whilst several DAA
combinations look very promising in phase 2 trials – and with some phase 3
data now being reported – challenges remain, Wedemeyer cautioned. These
largely involve factors that lead to poorer response for certain groups of patients.
ribavirin for 12 weeks, for example, offers excellent SVR rates for previously
treated patients with HCV genotype 2 and mild liver fibrosis, but this falls to
just 19% for people with genotype 3 and cirrhosis. However, adding four more
weeks of therapy boosts the latter cure rate to 61%. Sofosbuvir has also
consistently shown better outcomes in women compared with men, he said, but
"no one has explained to me why".
problems with the new DAAs, Wedemeyer suggested that pill burden is unlikely to
be a major barrier as most of the leading candidates are once daily. Unlike
boceprevir and telaprevir, newer DAAs are generally well-tolerated and
side-effects are "so far not a major issue". Resistance may be an
issue in the short term, but in the long term probably not, he added.
Patients' IL28B status – which affects interferon responsiveness – "may still play a role"
with weaker interferon-free DAA combinations, Wedemeyer predicted. Looking at viral
factors, genotype 2 has proven easier to treat than genotype 3 and subtype 1b
is easier than 1a.
Drug interactions could
be a problem, especially for people with advanced fibrosis or cirrhosis. For
this reason, Wedemeyer stressed, "we need drug-drug interaction studies
not only in healthy volunteers but also in patients with advanced liver
Finally, cost may prove
to be a barrier and limit the number of people who have access to treatment.
"I've never seen a new treatment that's cheaper than the previous
one," Wedemeyer cautioned. "We have to advocate to be able to treat
as many patients as possible."