Mitochondrial Toxicity and NRTIs

"Mitochondrial toxicity is a feature of all NRTIs, except possibly 3TC. Also nucleotides (like Adefovir) are capable of this toxicity. This mechanism has been shown in in vitro studies, in which the gradation of toxicity appears to be more or less: ddC>d4T>ddI=AZT. These are in vitro data; no clinical evaluation in this respect has been done and it is very unlikely they will be performed ever so, since there are no real test sofar. Clinically, all NRTI toxicities have a striking similarity with the clinical features of patients suffering from heriditary mitochondrial dysfunction, which seems to confirm that the in vitro observed mitochondrial toxicity of NRTIs really occurs in vivo. Only for AZT this has been proven definitely (AZT induced myopathy; Dalakas et al. NEJM 1990), but I assume the prove for the other NRTIs will follow shortly (further reading: AIDS 1998:12;1735-1744).

During the workshop I have also demonstrated that lipodystrophy can be caused by mitochondrial dysfunction and I therefore proposed that the the mitochondrial toxicity of NRTIs might be an important factor in the pathogenesis of HAART related lipodystrophy. At present, I think it is to early to say that one NRTI is more toxic than the other in this respect, and I furthermore don't believe, that the role of NRTIs will be more prominent than the role of PIs in inducing lipodystrophy. I think, both groups of drugs play a complementary role in this process. Again: formal proof is lacking and further research has to be done."

Kees Brinkman
K.Brinkman@OLVG.nl

dept of Internal Medicine
Onze Lieve Vrouwe Gasthuis (OLVG)
PO box 95500
1090 HM Amsterdam
The Netherlands