In their in-vitro evaluation of the antiviral triple combination of didanosine, IFN-α, and ribavirin, Klein et al. [1] reported that this triple combination was synergistic against HIV-1 and that ribavirin potentiated the activity of didanosine. No cytotoxicity was observed with didanosine or IFN-α at the maximal doses tested (12.5 μmol/l didanosine and > 250 U/ml IFN-α). Although these results suggest a possible clinical strategy for the treatment of individuals with HIV who are also chronically infected with hepatitis C virus, the authors recognized that the safety of the combination of didanosine and ribavirin warranted consideration because this combination may enhance didanosine-related toxicity.
It is important that clinicians are aware of data from the US Food and Drug Administration adverse event reporting system that was presented at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA in 2003 [2]. There were 31 reports of adverse events suggestive of mitochondrial toxicity associated with the combination of ribavirin and nucleoside analogue reverse transcriptase inhibitors, with a higher frequency among patients receiving didanosine. In this data set, the concomitant use of didanosine and ribavirin was associated with a relative risk of mitochondrial toxicity of 5.023 (95% confidence interval 1.971, 12.801). The prescribing information for VIDEX® and VIDEX® EC has been revised to reflect these data.
Ribavirin, a guanosine nucleoside analogue, may potentiate the efficacy of didanosine by inhibiting inosine monophosphate (IMP) dehydrogenase, subsequently increasing the IMP pool. IMP is thought to be the phosphate donor for the conversion to the active forms of the drug [3]. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'–triphosphate) is increased when didanosine is co-administered with ribavirin. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, have been reported in patients receiving both didanosine and ribavirin. A clinician considering the co-administration of didanosine and ribavirin should consult the prescribing information for VIDEX and VIDEX EC concerning the potential increased risk for didanosine-related toxicities [4,5].
References
1. Klein MB, Campeol N, Lalonde RG, Brenner B, Wainberg MA.
Didanosine, interferon-alfa and ribavirin: a highly synergistic combination with potential activity against HIV-1 and hepatitis C virus.AIDS 2003,
17:1001–1008.
2. Boxwell D, Fleischer R, Sherman KE.
Evidence suggestive of mitochondrial toxicity (MT) in HIV/HCV co-infected patients receiving ribavirin and didanosine. In:
10th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA, 10–14 February 2003 [Poster 763].
3. Balzarini J, Lee CK, Herdewijn P, DeClercq E.
Mechanism of the potentiating effect of ribavirin on the activity of 2',3'-dideoxyinosine against human immunodeficiency virus.J Biol Chem 1991,
266:21509–21514.
4. Package inserts.
VIDEX® (didanosine) and VIDEX® EC (didanosine) delayed-release capsules. Bristol-Myers Squibb Company, Princeton, NJ; February 2003.
5. Summary of product characteristics.
VIDEX® gastro-resistant capsules. Bristol-Myers Squibb Company, Princeton, NJ; April 2003.
