Research increasingly indicates that individual genetic variations play a role in the toxicity of antiretroviral therapy.

As reported in the December 1, 2006 Journal of Infectious Diseases, French researchers conducted a study to explore whether variations in the genes encoding the multidrug-resistance protein 2 (MRP 2) and MRP4 transporters predict proximal renal tubulopathy, a form of kidney toxicity that develops in a small proportion of patients taking tenofovir DF (Viread), especially those with pre-existing kidney disease or other risk factors.

The investigators performed mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) using genomic DNA from 13 HIV positive individuals with tenofovir-induced proximal renal tubulopathy, along with 17 HIV positive control subjects who took tenofovir but did not develop tubulopathy. Both genes encode proteins involved in excretion of tenofovir by the kidneys.

Results

• 6 single-nucleotide polymorphisms (SNPs) were identified in ABCC2.

• A significant association between the 1249 G-A SNP and tenofovir-induced tubulopathy was observed (OR 6.11; 95% CI 1.19-31.15; P < 0.02).

• ABCC2 haplotypes were significantly associated with the onset of tenofovir-induced renal tubulopathy.

• The CATC sequence appeared to be a predisposing haplotype, as it was found in 40.9% of the patients with renal tubulopathy compared with 13.7% of control subjects (P < 0.01).

• The CGAC sequence seemed to be a protective haplotype, as it was not observed in the patients with tubulopathy, but was present in 20.2% of the control subjects (P < 0.01).

• No association was observed between ABCC4 polymorphisms and tenofovir-induced renal tubulopathy in the present study.

Conclusion

In conclusion, the authors wrote, "ABCC2 haplotypes are associated with [proximal renal tubulopathy] induced by tenofovir DF in HIV-1-infected patients."

1/19/07

Reference
H Izzedine, J S Hulot, E Villard, and others. Association between ABCC2 Gene Haplotypes and Tenofovir-Induced Proximal Tubulopathy. Journal of Infectious Diseases 194(11): 1481-1491. December 1, 2006.