Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy

Background: Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous. Polymorphisms in chemokine receptor genes modulate the natural history of HIV-1 infection. In comparison with subjects with other genotypes, the prognosis for HIV-1-infected CCR5-Delta 32 heterozygotes is more favorable and that for CCR5 promoter allele 59029A homozygotes is less favorable. Methods: HIV-1-infected adults with a CD4+ lymphocyte count greater than or equal to 200 cells x 10(6)/l and a plasma HIV RNA level greater than or equal to 1000 copies/ml were treated with indinavir, zidovudine and lamivudine for 6 months. HIV RNA levels were measured at 4-week intervals. Genotyping for chemokine receptor gene polymorphisms (CCR5-Delta 32, CCR5 59029A/G, CCR2-64l) was performed. We examined whether the time to first HIV RNA < 200 copies/ml, frequency of viral suppression failure (HIV RNA greater than or equal to 200 copies/ mi between weeks 16 and 28 of therapy), or reduction from the pre-treatment HIV RNA level differed by genotype. Results: Time to first HIV RNA < 200 copies/ml was not predicted by genotype. Among 272 Caucasian patients, viral suppression failure was more common among patients with the CCR5 +/+ / CCR2+/+ \ CCR5-59029 A/A genotype (28%) than among all other subjects combined (relative risk, 2.0; P = 0.06). After 24 weeks of therapy, genotype groups differed in the reduction of the HIV RNA level from baseline (P = 0.02); patients with the CCR5 +/+ / CCR2+/+ \ CCR5-59029 A/A genotype had a mean reduction of 2.12 log(10) copies/ml compared to 2.64 log(10) copies/ml among all other groups combined. Conclusion: Polymorphisms in chemokine receptor genes may explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy. (C) 2000 Lippincott Williams & Wilkins.