ITPA Deficiency Cuts Anemia Risk, Even on Boceprevir

Elsevier Global Medical News

MAY 2 0 1 2 • G I & H E PATOLOGY NEWS
May Newsletter

BY SUSAN LONDON
Elsevier Global Medical News

ITPA Deficiency Cuts Anemia Risk, Even on Boceprevir
SAN FRANCISCO – Patients who have chronic hepatitis C and a deficiency of inosine triphosphatase are less likely to develop anemia on ribavirin containing herapy, whether or not they receive additional boceprevir therapy,findings from a retrospective study suggest.

The study included data on 908 patients participating in a pair of randomized trials that tested the addition of boceprevir to peginterferon and ribavirin.

Lead author Dr. Mark S. Sulkowski of the Johns Hopkins University in Baltimore reported the results in a poster session at the annual meeting of the American Association for the Study of Liver Diseases.

“The clinical implications are that if you had a patient whom you knew was deficient [in inosine triphosphatase], you would anticipate less [risk of] anemia and the ability to give more ribavirin,” he commented. “And perhaps you would treat them differently. That’s speculation,as this test is not commercially available.”

About one-third of the patients had low activity of inosine triphosphatase (ITPA), an enzyme that degrades inosine triphosphate. Inosine triphosphate protects red blood cells from ribavirin-induced hemolysis (Gastroenterology 2011; 140:1314-21).

“The data show it’s all due to the impact of ITPA activity deficiency on ribavirin anemia,” Dr. Sulkowski noted in an interview. On average, anemia develops in 55% of patients with normal ITPA activity and in 41% of those with low ITPA activity, a pattern that was consistent across treatment arms.

“Since this is a multifactorial anemia – interferon bone marrow suppression,boceprevir likely through an impact on bone marrow, and ribavirin hemolysis – it’s [affecting] only one of the components,” he said.

This is not the first study to show that ITPA deficiency protects against ribavirin- induced anemia. The new finding here is that the same is seen in patients also receiving boceprevir – which typically improves SVR rates when added to interferon and ribavirin, but also leads to an additional drop in hemoglobin.

Patients with low ITPA activity were less likely to need a ribavirin dose reduction or to receive erythropoietin. Also, they tended to have a higher rate of sustained virologic response.

The findings also point to several possible areas of future research and clinical application, according to Dr. Sulkowski.

“One of them is that with any combination of hepatitis C treatment that includes ribavirin, this is likely to play a role: people who are deficient or have low ITPA activity will have less hemolytic anemia and therefore tolerate ribavirin a bit better,” he said.

“The other is that if you could find a way pharmacologically to make people deficient in ITPA, assuming it’s safe – and we think it’s safe because these one-third of patients are fine, this is a natural variant then you could potentially make ribavirin a bit safer by coadministering that drug,” he added.

In the study, the investigators analyzed data from two randomized boceprevir trials among patients with chronic hepatitis C having viral genotype 1: the SPRINT-2 trial in treatment-naive patients and the RESPOND-2 trial in patients who had had a failure of previous therapy.Both trials had a 4-week lead-in period during which all patients received only peginterferon plus ribavirin. Thereafter,patients were assigned to continue peginterferon plus ribavirin alone, or with the addition of boceprevir for a shorter or longer duration, with treatment ending by 48 weeks.

Study results were based on a total of 650 patients from the SPRINT-2 trial and 258 patients from the RESPOND-2 trial who had samples for ITPA assessment.

Overall, 32% had low ITPA activity. Patients were less likely to develop anemia during the lead-in period if they had low ITPA activity (12%) than if they had normal ITPA activity (48%). In addition, within each treatment arm, patients were less likely to develop anemia at any time during treatment if they had low ITPA activity. Anemia occurred in 41% of those with low ITPA activity and in 55% of those with normal activity.

Ribavirin dose was reduced or erythropoietin was given to 38% of patients with low ITPA activity and to 49% of patients with normal ITPA activity.
Finally, within each treatment arm, patients with low ITPA activity tended to be more likely to have a sustained virologic response. A sustained virologic response was seen in 65% of patients with low ITPA activity and 59% with normal ITPA activity.

Dr. Sulkowski reported that he is an advisor to or reviewer for Pfizer, and is a consultant to and receives grant or research support from Roche, Merck, Abbott, Vertex,Tibotec, Boehringer Ingelheim Pharmaceuticals,Gilead, Bristol-Myers Squibb,and Pharmasset.

http://www.gastro.org/journals-publications/gi-hepatology-news/GI_-_Hepatology_News_-_May_2012.pdf