Chronic hepatitis C patients treated with boceprevir (Victrelis) plus pegylated interferon and
ribavirin can effectively manage drug-induced anaemia by either ribavirin dose
reduction or addition of erythropoietin (EPO) without compromising treatment
effectiveness, researchers reported on Sunday at The Liver Meeting 2012, the 63rd Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD) in Boston.
Approval of the first
direct-acting antiviral agents for hepatitis C virus (HCV) – Merck's
boceprevir and Janssen/Vertex's telaprevir (Incivo) – ushered in a new era of more effective treatment. But these new drugs must
still be used with pegylated interferon and ribavirin, adding to the already
difficult side-effects of standard therapy.
Ribavirin often causes anaemia
due to destruction of red blood cells. Boceprevir and interferon alfa
can also cause anaemia, presenting a potential problem when the three drugs are
used in combination.
Lowering the standard dose of
ribavirin can improve anaemia; because it plays a role in preventing
post-treatment viral relapse, however, there is concern that inadequate doses
may compromise sustained response.
Another approach uses EPO, a
hormone that stimulates red blood cell production. But EPO has its own side-effects
and adds to the total cost of treatment. Adverse events are especially a
concern for people with more advanced liver disease, who are less able to
Eric Lawitz, from Alamo Medical Research in Texas, and
colleagues conducted the anaemia management study to evaluate these two
management strategies in genotype 1, chronic hepatitis C patients, with or
without liver cirrhosis, treated with standard therapy consisting of
boceprevir, pegylated interferon and ribavirin.
This retrospective analysis
enrolled 687 participants. Fewer than half were men, the average age was
approximately 50 years and about 20% were of African descent. A majority (about
55%) had HCV subtype 1a, 33% had 1b and the rest were not subtyped.
Participants were stratified
according to whether they had compensated liver cirrhosis (n=60) or no cirrhosis
(n=604). They had normal levels of haemoglobin – the protein in red blood
cells that carries oxygen – at study entry,12 to15 g/dL for
women and 13 to 15 g/dL for men.
After a four-week lead-in of 1.5 mcg/kg/week pegylated
interferon alfa-2b plus 600 to 1400 mg/day ribavirin, all participants added 800
mg boceprevir three times daily for 24 or 44 weeks.
Participants with haemoglobin levels of 10 g/dL or
less were randomly assigned to either undergo ribavirin dose reduction in
increments of 200 mg (n=249) or take EPO starting with 40,000 units/week
(n=251). People with haemoglobin levels below normal but above 10 g/dL were
treated but not randomised (n=187).
If the randomised anaemia management strategy was not
adequate and haemoglobin remained at 8.5 g/dL or less, participants could add
the second strategy or receive blood transfusions if needed. If haemoglobin
fell to 7.5 g/dL or less, all study drugs were discontinued.
Anaemia was quite common in the study: about 80% of people
with cirrhosis and about 70% of those without cirrhosis met criteria for
randomised anaemia management. Yet whilst the likelihood of developing anaemia
was similar, people with cirrhosis tended to have larger haemoglobin drops.
Virological suppression rates were similar for
participants with and without cirrhosis: 68 vs 76% for end-of-treatment
response and 55 vs 64% for sustained virological response (SVR; continued
undetectable HCV RNA after the end of therapy); relapse rates were 18 and 11%,
Amongst patients with cirrhosis, SVR rates were
statistically similar with ribavirin dose reduction and use of EPO, 57 and 64%
respectively. This was also the case for non-cirrhotic patients, with SVR rates
of 72 and 73% respectively.
However, people with cirrhosis were significantly more
likely than non-cirrhotics to add a second anaemia management strategy (44 vs
26%). Adding a second management strategy improved the likelihood of SVR, from
52 to 71% for people with cirrhosis and from 70 to 80% for non-cirrhotics.
SVR rates were notably higher if HCV RNA was
undetectable when the first anaemia management strategy was initiated (84 vs
45% for cirrhotics; 86 vs 58% for non-cirrhotics).
Turning to adverse events, almost all participants
with or without cirrhosis experienced treatment-emergent side-effects.
Interestingly, most side-effects occurred with similar frequency in cirrhotic
and non-cirrhotic groups. The exceptions were anaemia, diarrhoea, headache and
neutropenia, all of which were more common amongst people with cirrhosis.
Rates of serious adverse events (20 vs 12%), drug
discontinuation due to side-effects (17 vs 16%) and blood transfusions (3 vs
2%) were also similar.
However, participants with cirrhosis had higher rates
of neutropenia (low white blood cells) and thrombocytopenia (low platelets).
"SVR rates are comparable in cirrhotic patients when
anaemia is managed by ribavirin dose reduction or EPO," the researchers
concluded. "Patients with cirrhosis were more likely to receive secondary
interventions for the management of anaemia."
Although overall sustained response rates were similar
for both management strategies, Merck noted in a press release that people
whose ribavirin dose fell below half of the total assigned dose did not do as
Based on these findings, the investigators recommended
that ribavirin dose reduction should be considered as the initial management
strategy for people who develop anaemia during hepatitis C treatment.