The first report of an association between a gene variant and tenofovir-induced kidney damage has come from French researchers.
Tenofovir (Viread) is one of the most widely used antiretroviral drugs and now forms a component of many first-line antiretroviral combinations. Although clinical trials have shown it to be a generally safe drug there have been several reported cases of kidney problems associated with its use. These range from mild reversible renal insufficiency to more severe renal failure. There have been suggestions that because of the large variation in the likelihood and severity of the problem, there might be a genetic influence. The new study in the December 1st edition of the Journal of Infectious Diseases is the first to confirm this.
The researchers studied the DNA of 13 HIV-infected patients who received tenofovir and suffered renal proximal tubulopathy (rPT) - i.e. damage of the kidney tubules. DNA from 17 HIV-infected patients who took tenofovir with no associated problems was used as a comparison. They looked specifically at two genes which encode proteins found in kidney membranes involved in excreting tenofovir into the urine - ABCC2 and ABCC4.
A single nucleotide change in the ABCC2 gene sequence (guanine to adenine at position 1249) was found to increase the likelihood of rPT more than six fold (odds ratio 6.11 95% CI 1.19 to 31.15).
The researchers also found a characteristic DNA sequence - or haplotype - that was found in 40% of those with rPT and 13.7% of those who did not (p
No association between ABCC4 sequences and tenofovir-induced rPT were seen in this study.
Nucleotide changes in genes do not always affect the final expression of the protein. But the changes in ABCC2 genes seen here do alter the final amino acid sequence of the tubule membrane protein. This has led the researchers to speculate that the changes, or polymorphisms, could be the reason for the drug-associated kidney problems. But they admit their results should be interpreted with caution. A small number of patients were studied - all of whom were French Caucasians - and the results need to be replicated in larger, more ethnically varied population, they say.
But the hope is that eventually the results could lead to tests which could be used to screen out people who might have problems with specific drugs.
Other genetic factors have been identified which are associated with toxicities with NNRTIs and protease inhibitors.
Izzedine H et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis194;1481-1491, 2006.