<em>ABCB1</em> Variation and Treatment Response in AIDS Patients: Initial Results of the Henan Cohort

<div><p>HIV/AIDS has the highest mortality among infectious diseases in China. In ongoing efforts to alleviate this crisis, the national government has placed great emphasis on efforts in Henan province where HIV-infected former plasma donors in the 1990s contributed to AIDS becoming a public health crisis. Concomitant with a national initiative focusing the use of phamacogenetics for the better prediction of treatment response, we studied genetic variants with known pharmacokinetic phenotypes in a set of 298 HAART-treated (highly active antiretroviral therapy) patients infected with HIV from the Henan cohort. We measured the association of response to treatment, assessed as changes in CD4+ T cell counts after antiretroviral therapy, of five polymorphisms in four genes (<em>CYP2B6</em>, <em>ABCB1</em>/<em>MDR1</em>, <em>ABCG2,</em> and <em>ABCC4</em>) in which variation has been suggested to affect the pharmacokinetics of drugs commonly employed to treat HIV/AIDS. We show that genotyping for <em>ABCB1</em> variations (rs1045642 and rs2032582) may help predict HIV treatment response. We found variations in this gene have a significant association with outcome as measured by CD4+ T cell counts in a discovery subset (N = 197; odds ratio (OR) = 1.58; 95% CI 1.02–2.45), these results were confirmed in a validation subset of the cohort (N = 78; OR = 2.81; 95% CI 1.32–5.96). Exploratory analysis suggests that this effect may be specific to NVP (nevirapine) or 3TC (lamivudine) response. This publication represents the first genetic analysis in a continuing effort to study and assist the patients in a very large, unique, and historically significant HIV-AIDS cohort. Genotyping of AIDS patients for <em>ABCB1</em> variation may help predict outcome and potentially could help guide treatment strategies.</p> </div

Flow chart of study participant selection.

<p>Flow chart of study participant selection.</p

Association analysis of SNPs and therapeutic response.

<p><i>ABCB1*: ABCB1</i> 3435T>C + <i>ABCB1</i> 2677T>G.</p

Demographic characteristics of the Henan cohort (N = 298).

<p>Demographic characteristics of the Henan cohort (N = 298).</p

Distribution of candidate SNPs in studied subjects (N = 298).

<p>Distribution of candidate SNPs in studied subjects (N = 298).</p

HAART Regimens.

<p>HAART Regimens.</p

Multivariate analysis.

<p><i>ABCB1*: ABCB1</i> 3435T>C+<i>ABCB1</i> 2677T>G.</p

Analysis of Social and Genetic Factors Influencing Heterosexual Transmission of HIV within Serodiscordant Couples in the Henan Cohort

<div><p>There is considerable variability between individuals in susceptibility to infection by human immunodeficiency virus (HIV). Many social, clinical and genetic factors are known to contribute to the likelihood of HIV transmission, but there is little consensus on the relative importance and potential interaction of these factors. Additionally, recent studies of several variants in chemokine receptors have identified alleles that may be predictive of HIV transmission and disease progression; however the strengths and directions of the associations of these genetic markers with HIV transmission have markedly varied between studies. To better identify factors that predict HIV transmission in a Chinese population, 180 cohabiting serodiscordant couples were enrolled for study by the Henan Center for Disease Prevention and Control, and transmission and progression of HIV infection were regularly measured. We found that anti-retroviral therapy, education level, and condom use were the most significant factors in determining likelihood of HIV transmission in this study. We also assessed ten variants in three genes (<i>CXCL12</i>, <i>CCR2</i>, and <i>CCR5</i>) that have been shown to influence HIV transmission. We found two tightly linked variants in <i>CCR2</i> and <i>CCR5</i>, rs1799864 and rs1800024, have a significant positive association with transmission as recessive models (OR>10, <i>P</i> value=0.011). Mixed effects models showed that these genetic variants both retained significance when assessed with either treatment or condom use. These markers of transmission susceptibility may therefore serve to help stratify individuals by risk for HIV transmission.</p></div

Distribution of selected SNPs.

<p>^a one sample failed to genotype.</p><p>^b two samples failed to genotype.</p><p>Distribution of selected SNPs.</p

Linkage disequilibrium analysis of the <i>CCR2</i> and <i>CCR</i>5 alleles included in this study.

<p>Linkage disequilibrium analysis of the <i>CCR2</i> and <i>CCR</i>5 alleles included in this study.</p