Portal de Periódicos da CAPES

Mitochondrial toxic effects and ribavirin

2001; Elsevier BV; Volume: 357; Issue: 9270 Linguagem: Inglês

10.1016/s0140-6736(00)04920-5

1474-547X

Thomas N. Kakuda, Kees Brinkman,

HIV-related health complications and treatments

Alain Lafeuillade and colleagues (Jan 27, p 280)1Lafeuillade A Hittinger G Chadapaud S Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection.Lancet. 2001; 357: 280-281Summary Full Text Full Text PDF PubMed Scopus (304) Google Scholar report on 15 patients who developed raised lactate and pyruvate concentrations while taking ribavirin and highly active antiretroviral therapy. Because ribavirin can potentially inhibit mitochondrial DNA polymerase, they conclude that ribavirin elicits mitochondrial toxic effects. However, there may be other explanations for their observations. Two patients were being treated with didanosine and had been for several years when ribavirin was started. Ribavirin is a 5′-monophosphate dehydrogenase inhibitor that stimulates the activation of didanosine in vitro. Concentrations of the active anabolite, 2′,3′-dideoxyadenosine- triphosphate (ddATP), is around two-fold greater in cells exposed to didanosine with ribavirin than in those exposed to didanosine alone. The increase in ddATP formation is accompanied by an increase in anti-HIV activity.2Hartman NR Ahluwalia GS Cooney DA et al.Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-human immunodeficiency virus nucleosides 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine.Mol Pharmacol. 1991; 40: 118-124PubMed Google Scholar Drugs that can potentiate the anti-HIV activity of nucleoside analogues can also increase their toxic effects. Adverse effects related to didanosine, such as peripheral neuropathy pancreatitis, and hepatic steatosis with lactic acidosis, are reported more frequently with concomitant use of hydroxyurea.3Brinkman K Kakuda TN Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?.Curr Opin Infect Dis. 2000; 13: 5-11Crossref PubMed Scopus (128) Google Scholar Thus the hyper-lactataemia seen by Lafeuillade and colleagues might have been related to didanosine-induced mitochondrial toxic effects resulting from ribavirin potentiation. Little is known about the clinical interaction between didanosine and ribavirin. In a study of 600 mg oral ribavirin daily and 200 mg didanosine twice daily in 19 HIV-1-positive patients treated for up to 20 weeks, adverse effects did not increase significantly in frequency. Plasma pharmacokinetics of didanosine were relatively unchanged in the presence of ribavirin, although intracellular ddATP was not measured.4Japour AJ Lertora JJ Meehan PM et al.A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease: AIDS Clinical Trials Group 231 Protocol Team.JAcquir Immune Defic Syndr Hum Retrovirol. 1996; 13: 235-246Crossref PubMed Scopus (50) Google Scholar Lactate or pyruvate concentrations were not monitored in that study. Mitochondrial toxic effects should be recognised as an effect of nucleoside analogues, but can also be a feature of viral disease. Hepatitis C virus and HIV can cause disruption of the mitochondria.3Brinkman K Kakuda TN Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?.Curr Opin Infect Dis. 2000; 13: 5-11Crossref PubMed Scopus (128) Google Scholar5Genini D Sheeter D Rought S et al.HIV induces lymphocyte apoptosis by a p53-initiated mitochondrial-mediated mechanism.FASEBJ. 2001; 15: 5-6PubMed Google Scholar Clinicians need to be aware of mitochondrial toxic effects associated with nucleoside analogues as well as the (intracellular) drug and disease interactions that might affect them.3Brinkman K Kakuda TN Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?.Curr Opin Infect Dis. 2000; 13: 5-11Crossref PubMed Scopus (128) Google Scholar