The hepatitis C protease inhibitor faldaprevir added to pegylated interferon and ribavirin cured
hepatitis C in nearly three-quarters of people with genotype 1 hepatitis C virus (HCV) and HIV co-infection in the
STARTVerso4 trial, equaling response rates for people with hepatitis C alone,
according to a report at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) this week in Boston.
Direct-acting antivirals have revolutionised treatment for chronic
hepatitis C. These drugs were initially tested as add-ons to the previous
standard of care, pegylated interferon plus ribavirin. Although interferon-free
combinations are now becoming available, regimens containing single
direct-acting drugs plus interferon may remain an option for some patients.
Douglas Dieterich from Mt. Sinai Icahn School
of Medicine presented data from the open-label phase 3 STARTVerso4
trial, which evaluated Boehringer Ingelheim's faldaprevir (formerly BI
201335) plus pegylated interferon and ribavirin for people with HIV and HCV co-infection who were
previously untreated for hepatitis C or relapsed after a prior course of
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.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
"Faldaprevir was highly efficacious and well-tolerated in difficult-to-treat patients co-infected with HIV and HCV genotype 1."
People with HIV and HCV co-infection experience more rapid liver disease
progression, on average, and do not respond as well to interferon as those with
HCV alone. But direct-acting drugs may help reduce this disparity.
enrolled 308 people with HIV and HCV genotype 1, mostly in Europe and
North America. Most were men, 83% were white, 14% were black and the
age was 47 years. About 80% had the harder-to-treat HCV subtype 1a,
the favourable IL28B CC gene variant and 15% had liver cirrhosis. More
three-quarters were hepatitis C treatment-naive and 22% were prior
relapsers; this study did not include the most difficult-to-treat
group, prior null responders.
were either on stable antiretroviral therapy (ART) or had a high enough
CD4 cell count that they did not yet need HIV treatment. At baseline,
95% were on
ART, most had undetectable HIV viral load and the mean CD4 count was
approximately 540 cells/mm3. Patients used antiretrovirals that
either did not have clinically relevant interactions with faldaprevir or
interactions that could be managed with dose adjustments. Nearly half took
raltegravir (Isentress), 27% took
efavirenz (Sustiva) and 22% took
either ritonavir-boosted atazanavir (Reyataz)
or darunavir (Prezista).
All participants were
treated with once-daily faldaprevir plus pegylated interferon alfa-2a (Pegasys)
and weight-based ribavirin. Participants taking HIV protease inhibitors received
120mg faldaprevir for 24 weeks, those taking efavirenz took 240mg faldaprevir
for either 12 or 24 weeks, and those taking raltegravir or not on ART were
randomised to one of these doses.
Duration of pegylated interferon/ribavirin was
determined using response-guided therapy. People with 'early treatment success'
(HCV RNA <25 IU/mL at week 4 and undetectable at week 8) were re-randomised
to either stop all drugs at week 24 or continue pegylated interferon/ribavirin
alone through week 48. All patients without early treatment success received
the longer course.
primary study endpoint was sustained virological response (SVR), or continued
undetectable HCV RNA at 12 weeks after the end of treatment (SVR12).
Overall SVR12 rates were 71% for people
treated with 120mg faldaprevir for 24 weeks and 72% for all those treated with
240mg faldaprevir. Among participants
who had early treatment success, 87% and 85%, respectively, went on to achieve
Participants' interferon responsiveness
influenced treatment outcomes. Prior relapsers responded significantly better
than treatment-naive patients, with SVR12 rates of 83% and 69%, respectively.
IL28B status also had a significant effect, with SVR12 rates or 88% and 64%,
respectively, for CC and non-CC genetic variants.
But other factors traditionally associated
with poor response had little or no effect with this regimen. People with liver
cirrhosis responded as well as people who did not have cirrhosis, with SVR12 rates of 73% and 72%,
respectively. Dieterich noted that people with cirrhosis have consistently done
well in faldaprevir studies.
HCV subtype had little effect, with SVR12
rates of 76% for people with 1b and 71% for those with 1a. Presence of the Q80K
resistance mutation also did not seem to affect outcomes in this co-infected
population, with SVR12 rates of 75% for those with and 71% for those without
the mutation at baseline. Response rates did not differ significantly between
people with early treatment success who continued pegylated
interferon/ribavirin for 24 weeks or 48 weeks.
Faldaprevir combination therapy was
generally safe and well tolerated, with most side-effects being typical of
interferon-based therapy. One-tenth of participants experienced serious adverse
events and 7% had adverse events leading to hepatitis C treatment
The most common side-effects were nausea
(37%), fatigue (34%), diarrhoea (27%), headache (25%) and weakness (23%). The
most common laboratory abnormality was elevated bilirubin (19%).
Photosensitivity, or increased sensitivity to sunburn, was uncommon.
"Faldaprevir was highly efficacious and
well-tolerated in difficult-to-treat patients co-infected with HIV and HCV
the researchers concluded. "Among
patients with [early treatment success], 24 weeks total duration
of therapy was possible without compromising SVR12 rates."
They added that the safety
profile of faldaprevir in people with HIV and HCV co-infection "was similar to that
observed in HCV genotype 1 mono-infected patients."
improved treatment response rates compared with pegylated interferon/ribavirin
alone, other researchers at CROI reported that various interferon-free regimens
yielded higher SVR rates in the 90% to 100% range with fewer side-effects.
Faldaprevir has demonstrated good
efficacy and tolerability in all-oral
regimens for HCV mono-infected people.
is hard to consider using any drug now with interferon, but I know in many
parts of the world that will still be the case for many years to come," Dieterich
Reviewing results from this
and other hepatitis C trials at a CROI opening press conference on Monday,
Dieterich noted that direct-acting agents can overcome many of the factors
traditionally associated with poor treatment response, including HIV co-infection,
race/ethnicity and liver cirrhosis. "All the old
predictors of response are gone when you have a potent two-three drug
combination," he said.