- Category: HCV Treatment
- Published on Tuesday, 13 November 2012 00:00
- Written by Liz Highleyman
Chronic hepatitis C patients being treated with boceprevir (Victrelis) plus pegylated interferon and ribavirin can effectively manage drug-induced anemia, either by ribavirin dose reduction or addition of erythropoietin (EPO), without compromising treatment effectiveness, according to a presentation at theAmerican Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this week in Boston.
Last year's approval of the first direct-acting anti-HCV agents -- Merck's boceprevir (Victrelis) and Vertex's telaprevir (Incivek) -- ushered in a new era of more effective treatment. These drugs must still be used with pegylated interferon and ribavirin, however, adding to already difficult side effects of standard therapy.
Ribavirin often causes anemia due to destruction of red blood cells. Boceprevir, as well as interferon alfa, can also cause anemia, presenting a potential problem with the 3 drugs are used in combination.
Lowering the standard dose of ribavirin can improve anemia risk, but because it plays a role in preventing post-treatment viral relapse, there is concern that inadequate doses could compromise sustained response. Another approach is using EPO (brand names include Epogen and Procrit), a hormone that stimulates red blood cell production; EPO has its own side effects, however, and adds to the total cost of treatment.
Eric Lawitz from Alamo Medical Research in San Antonio and colleagues designed the Anemia Management Study to evaluate these 2 management strategies in genotype 1 chronic hepatitis C patients with or without liver cirrhosis undergoing treatment with standard therapy consisting of boceprevir, pegylated interferon, and ribavirin.
This retrospective analysis included 687 participants. Less than half were men, unlike most U.S. hepatitis C treatment trials. The average age was approximately 50 years, and about 20% were African American. 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 (60 patients) or no cirrhosis (604 patients). At baseline they had normal levels of hemoglobin, the protein in red blood cells that transports oxygen 12-15 g/dL for women, 13-15 g/dL for men). Lawitz noted that on the whole the group was "pretty healthy" for a cirrhotic population.
After a 4-week lead-in of 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 600-1400 mg/day ribavirin, all participants added 800 mg 3-times-daily boceprevir for 24 or 44 weeks.Participants with hemoglobin levels of 10 g/dL or less were randomly assigned either to start ribavirin dose reduction in increments of 200 mg (n=249) or to initiate EPO starting at 40,000 units/week (n=251). People with hemoglobin levels below normal but above 10 g/dL were treated but not randomized (n=187).
If the randomized strategy was not adequate and hemoglobin remained at 8.5 g/dL or less, participants could add the second strategy or receive blood transfusions if necessary. If hemoglobin fell to 7.5 g/dL or less, all study drugs were stopped.
- Anemia was common overall, with about 80% of patients with cirrhosis and about 70% without cirrhosis meeting criteria for randomized anemia management.
- While the likelihood of developing anemia was similar in both groups, people with cirrhosis tended to have more severe hemoglobin declines.
- Virological suppression rates were similar for participants with cirrhosis and non-cirrhotics:
o End-of-treatment response: 68% vs 76%, respectively;
o Sustained virological response (SVR), or continued undetectable HCV RNA after completing therapy: 55% vs 64%, respectively;
o Relapse: 18% vs 11%, respectively.
- Among patients with cirrhosis, SVR rates were statistically similar with ribavirin dose reduction and EPO, at 57% and 64%, respectively.
- This was also the case for non-cirrhotic patients, at 72% and 73%, respectively.
- However, people with cirrhosis were significantly more likely than non-cirrhotics to add a second anemia management strategy, 44% vs 26%, respectively.
- Adding a second management strategy improved the likelihood of SVR:
o From 52% to 71% for people with cirrhosis;
o From 70% to 80% for non-cirrhotics.
- SVR rates were higher if HCV RNA was undetectable when the first anemia 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 some treatment-emergent side effects.
- Most side effects occurred with similar frequency in the groups with and without cirrhosis, with the exceptions of anemia, diarrhea, headache, and neutropenia -- all of which were all more common among people with cirrhosis.
- Rates of serious adverse events (20% vs 12%), drug discontinuation due to adverse events (17% vs 16%), and blood transfusions (3% vs 2%) were also similar.
- However, participants with cirrhosis had higher rates of neutropenia (low white blood cell count) and thrombocytopenia (low platelet count).
"SVR rates are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or EPO," the study investigators concluded. "Patients with cirrhosis were more likely to receive secondary interventions for the management of anemia."
Yet while overall sustained response rates were similar with both management strategies, Merck noted in a press release coinciding with the presentation that people whose ribavirin doses fell below half of the total assigned dose did not respond as well.
Based on these findings, the researchers recommended that "[r]ribavirin dose reduction should be considered as the initial management strategy" for people who develop anemia during hepatitis C treatment."
E Lawitz, S Zeuzem, LM Nyberg, et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/ribavirin (P/RBV) in Treatment-Naïve Chronic HCV Genotype 1 Patients with Compensated Cirrhosis: Sustained Virologic Response (SVR) and Safety Subanalyses from the Anemia Management Study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 50.
Merck. Merck Reports New Phase III Analyses on Anemia Management Strategies Used With VICTRELIS (boceprevir) Combination Therapy, Including Cirrhotic Patients. Press release. November 10, 2012.