An inherited mutation in human mitochondria found in around 10-15% of Caucasians places these individuals at five-fold higher risk of developing peripheral neuropathy after exposure to d4T/ddI (stavudine and didanosine) according to an analysis of a large international study that compared ddT/ddI-based combination therapy with AZT/3TC (zitovudine/ lamivudine) -containing regimens.
The study provides another genetic predictor of a severe drug-related toxicity in HIV-positive people, and is likely to stimulate further studies to determine whether genetic predictors of peripheral neuropathy also exist among people of African origin.
The study looked at mitochondrial haplotypes in 509 people who participated in the ACTG 384 study and who had DNA available for analysis. One hundred and forty-seven developed peripheral neuropathy during the study, of whom 73% were receiving d4T/ddI at the time (p<0.001).
Peripheral neuropathy was more common in people who had had very low CD4 cell counts in the past (the nadir CD4 cell count), or high viral load at baseline. It was also common in older people. No difference was observed by race or sex.
In order to analyse genetic determinants, the researchers looked at polymorphisms (natural variations or mutations) in mitochondria (bodies within cells that generate energy for cellular processes). They hypothesised that some genetic patterns in mitochondria might make carriers more susceptible to the effects of nucleoside analogue drugs on mitochondrial DNA polymerase gamma, since inhibition of this polymerase by nucleoside analogues is thought to contribute to a wide range of drug-related toxicities in people treated with this class of drugs.
In order to obtain coherent results the researchers looked only at Caucasians, because the number of different polymorphisms in the mitochondrial DNA of people of European origin is much smaller than in Africa. Whilst Europeans belong to one of nine haplogroups, Africans may belong to one of more than 100 haplogroups. This difference is believed to be due to human migration patterns over many millennia.
Among white participants, peripheral neuropathy was diagnosed in 70 individuals, of whom 48 were taking d4T/ddI. In this subset, individuals who developed peripheral neuropathy were 5.4 times more likely to carry haplotype group T (p=0.009), compared to an odds ratio of 2.8 when all white participants were analysed. Multivariate analysis showed that belonging to haplotype group T carried a similar level of risk as treatment with d4T/ddI for the development of peripheral neuropathy.
The authors are uncertain why this particular haplogroup should be associated with an increased risk of peripheral neuropathy, since it is not associated with any other sort of illness or type of mitochondrial dysfunction, but they point out that other forms of disease associated with a mitochondrial polymorphism probably require an additional risk factor, and they suggest that the combination of the `T` haplogroup with nucleoside analogues that have a greater inhibitory effect on mitochondrial DNA polymerase gamma might lead to toxicity.
They also note that with the continuing widespread use of d4T in developing countries, especially Africa, it will be important to characterise the haplogroups associated with drug-related peripheral neuropathy in Africans.