763 Evidence Suggesting Mitochondrial Toxicity in HIV/HCV Co-infected Patients Receiving Ribavirin and Didanosine R. Fleischer*1, D. Boxwell1, K. E. Sherman2 1FDA, Rockville, MD and 2Univ of Cincinnati, OH
Background: Several cases suggestive of Mitochondrial Toxicity (MT) (e.g., pancreatitis, lactic acidosis with liver failure and/or hepatic steatosis) in HIV/HCV co-infected patients (pts) treated with ribavirin (RBV) and didanosine (ddI) have been reported. These events may be related to RBV’s promotion of the conversion of ddI to its active metabolite, ddATP. It is not clear whether individual reports represent rare associations or an important pattern of drug toxicity.
Methods: The FDA Adverse Event Reporting System was searched for reports of any adverse events associated with concomitant use of RBV and ddI or any other nucleoside reverse transcriptase inhibitor (NRTI).
Results: We identified 65 unduplicated reports of any adverse events in pts receiving a combination of RBV and NRTIs. Of the 65 pts, 39 were receiving ddI and 26 were receiving other NRTIs. A total of 26 pts (23 on ddI and 3 on other NRTIs) reported 53 events suggestive of MT:
The frequency of events suggestive of MT was 59% (23/39) among pts receiving ddI and 11% (3/26) among pts receiving other NRTIs. Among pts who received RBV and ddI and experienced events suggestive of MT, the mean duration of ddI therapy was approximately 18 months, and the mean duration of RBV therapy was approximately five months. Three pts who received RBV and ddI died: two from liver failure and one from lactic acidosis/multi-organ failure. In this series, there did not appear to be an association with gender or body weight and the occurrence of MT.
Conclusions: In this data set, concomitant use of ddI and RBV appeared to be associated with an approximately 5-fold increased likelihood of events suggestive of MT compared to use of RBV with other NRTIs. RBV and ddI should be co-administered with caution, and ddI should be suspended if signs or symptoms suggestive of MT develop.
