Real-world experience in the French early-access CUPIC
cohort shows that hepatitis C patients with advanced liver damage can achieve good
response to interferon-based triple-therapy including boceprevir (Victrelis) or telaprevir (Incivo), researchers reported at The Liver Meeting 2012, the 63rd Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) last month in Boston.
Over years or decades people with chronic hepatitis C
can develop serious liver disease, including cirrhosis or hepatocellular carcinoma.
Whilst people with advanced liver damage are most urgently in need of
treatment, they do not respond as well to interferon-based therapy, the current standard treatment for hepatitis C.
Pivotal trials of new drugs typically do not include
the most difficult-to-treat patient groups, both because pharmaceutical
companies want their candidates to perform as well as possible and because
people with advanced disease are most likely to experience safety problems.
Such individuals may be able to access new treatments
through early- and expanded-access programmes that run alongside controlled
clinical trials, however. In France early access is available through the
Temporary Authorisation for Use, or ATU, programme as drugs are awaiting
CUPIC (ANRS CO20), run under the auspices of the National Agency for Research on AIDS and Viral Hepatitis, is a
multicentre observational study in the ATU setting of compassionate use of HCV
protease inhibitors for people with cirrhosis who were non-responders to
prior interferon-based therapy.
Christophe Hézode from Hôpital Henri
Mondor in Paris presented findings from a 16-week analysis of nearly 500 CUPIC
participants who were treated with boceprevir or telaprevir plus pegylated
interferon and ribavirin.
The phase 3 SPRINT-2 and RESPOND-2 trials showed that
people receiving triple therapy with boceprevir had more anaemia and dysgeusia
(odd taste sensations) than those on pegylated interferon/ribavirin alone. The
ADVANCE, ILLUMINATE, and REALIZE trials likewise showed that telaprevir
recipients were more likely to experience anaemia, rash and pruritus (itching).
However, Hézode noted, these studies included only a small number of people
with liver cirrhosis –
115 total in the boceprevir trials and 247 in the telaprevir trials.
Between February 2011 and April 2012 a total of 674
treatment-experienced hepatitis C patients with cirrhosis were enrolled in the
CUPIC cohort at 56 sites throughout France. The present analysis included 497
A majority of participants (68%) were men and the average
age was 57 years. About half had HCV subtype 1b, 30 to 40% had harder-to-treat
subtype 1a and the rest had other genotypes. About two-thirds had high baseline
HCV viral load (>800,000 IU/mL). At baseline they had normal haemoglobin
levels and platelet counts. Participants had compensated cirrhosis; most had
Child-Pugh class A liver function (the least severe level) and MELD scores
Although only 2% of boceprevir recipients experienced
rapid virological response at week 4, 38% went on to do so by week 8, 55% at
week 12 and 58% at week 16 in an intent-to-treat analysis. In a per-protocol or
as-treated analysis, the corresponding rates were 3, 42, 64 and 77%,
Telaprevir proved more effective overall. The rapid
response rate at week 4 was 55%, rising to 80% by week 8 and 79% at week 12,
but falling back to 67% at week 16 in an
intent-to-treat analysis. In the per-protocol analysis response rates remained
high at 58, 92, 93 and 92%, respectively.
Among boceprevir recipients, 33% experienced serious
adverse events, 26% stopped treatment early and 7% did so due to adverse
events. One patient died, six experienced hepatic decompensation, and five had
serious (grade 3/4) infections. None developed severe rash or kidney failure.
Looking at haematological side-effects, 23% developed
grade 2 anaemia (haemoglobin 8.0-9.0 g/dL), 4% developed grade 3/4 anaemia
(<8.0 g/dL), 46% used erythropoietin, 6% received blood transfusions and 11%
had ribavirin dose reductions. In addition, 1% developed grade 3 and 3%
developed grade 4 thrombocytopenia (low platelet count), whilst 5% developed
grade 3 and 2% developed grade 4 neutropenia (low white blood cell count).
Telaprevir was less well tolerated overall. Amongst
telaprevir recipients 45% experienced serious adverse events, 23% stopped
treatment early and 15% did so for this reason. Five patients died, six
experienced hepatic decompensation, 19 had serious infections, 14 (5%)
developed severe rash and five experienced kidney failure.
Turning to haematological events, 19% developed grade
2 anaemia, 12% developed grade 3/4 anaemia, 54% used erythropoietin, 16%
received transfusions and 13% had ribavirin dose reductions. About 10%
developed grade 3 and 3% developed grade 4 thrombocytopenia, but only 2%
developed grade 3 and fewer than 1% developed grade 4 neutropenia.
In a multivariate analysis, low platelet level
(<100,000/mm3) and low serum albumin (<35 g/L) at baseline
were significant predictors of severe complications, including death, severe
infection, or decompensation (odds ratios of 3.1 and 6.3, respectively). Female
sex, being age 65 or older, and low haemoglobin at baseline predicted severe anaemia
or need for blood transfusion.
"In this large cohort of compensated cirrhotic
patients, the safety profile of telaprevir or boceprevir in triple combination
was poor as compared with phase 3 trials" – with increased rates of serious adverse events and
more difficult management of anaemia –
"but associated with high rates of on-treatment virologic response",
the CUPIC researchers concluded.
The risk/benefit ratio should be assessed for
treatment-experienced cirrhotic individuals with low platelet or serum albumin
levels and "these patients should be treated on a case-by-case basis due
to high risk to develop severe complications", they added. Cirrhotic
treatment-experienced patients without predictors of severe complications
"should be treated but cautiously and carefully monitored".