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African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.

ABSTRACT: INTRODUCTION:In a North American, HIV-positive, highly active antiretroviral therapy (HAART)-treated, adherent cohort of self-identified white and black patients, we previously observed that chemokine (C-C motif) receptor 5 (CCR5) -2459G>A genotype had a strong association with time to achieve virologic success (TVLS) in black but not in white patients. METHODS:Using 128 genome-wide ancestry informative markers, we performed a quantitative assessment of ancestry in these patients (n = 310) to determine (1) whether CCR5 -2459G>A genotype is still associated with TVLS of HAART when ancestry, not self-identified race, is considered and (2) whether this association is influenced by varying African ancestry. RESULTS:We found that the interaction between CCR5 -2459G>A genotype and African ancestry (? 0.125 vs. ? 0.425 and <0.71 vs. ? 0.71) was significantly associated with TVLS (GG compared with AA, P = 0.044 and 0.018, respectively). Furthermore, the association between CCR5 -2459G>A genotype and TVLS was stronger in patients with African ancestry ? 0.71 than in patients with African ancestry ? 0.452, in both Kaplan-Meier (log-rank P = 0.039 and 0.057, respectively, for AA, GA, and GG) and Cox proportional hazards regression (relative hazard for GG compared with AA 2.59 [95% confidence interval: 1.27 to 5.22; P = 0.01] and 2.26 [95% confidence interval: 1.18 to 4.32; P = 0.01], respectively) analyses. CONCLUSIONS:We observed that the association between CCR5 -2459G>A genotype and TVLS of HAART increased with stronger African ancestry. Understanding the genomic mechanisms by which African ancestry influences this association is critical and requires further studies.

SUBMITTER: Cheruvu VK

PROVIDER: S-EPMC3996453 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.

Cheruvu Vinay K VK Igo Robert P RP Jurevic Richard J RJ Serre David D Zimmerman Peter A PA Rodriguez Benigno B Mehlotra Rajeev K RK

Journal of acquired immune deficiency syndromes (1999) 20140501 1

<h4>Introduction</h4>In a North American, HIV-positive, highly active antiretroviral therapy (HAART)-treated, adherent cohort of self-identified white and black patients, we previously observed that chemokine (C-C motif) receptor 5 (CCR5) -2459G>A genotype had a strong association with time to achieve virologic success (TVLS) in black but not in white patients.<h4>Methods</h4>Using 128 genome-wide ancestry informative markers, we performed a quantitative assessment of ancestry in these patients ...[more]

PMID: 24714069

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Project description:INTRODUCTION:Directly observed therapy of highly active antiretroviral therapy (DOT-HAART) is a feasible adherence intervention. Prospective DOT-HAART studies have shown mixed results, and optimal target groups have yet to be defined. We performed a meta-analysis and systematic review to assess the effect of DOT-HAART on adherence and virologic and immunologic response. METHODS:We performed a comprehensive search through August 2009 to identify peer-reviewed controlled studies that involved outpatient DOT-HAART among adults and reported at least 1 outcome assessed in this meta-analysis. Random-effects meta-analyses were performed; differences in effect on virologic suppression were examined using stratified meta-analyses and meta-regression on several study characteristics. RESULTS:Seventeen studies met inclusion criteria. Compared with control groups, DOT-HAART recipients were more likely to achieve an undetectable viral load (random effects risk ratio 1.24, 95% confidence interval (CI): 1.08 to 1.41), a greater increase in CD4 cell count (random effects weighted mean difference 43 cells/microL, 95% CI: 12 to 74 cells/microL), and HAART adherence of > or =95% (random effects risk ratio 1.17, 95% CI: 1.03 to 1.32). Results varied with respect to virologic response. DOT-HAART did not have a significant effect on virologic suppression when restricted to randomized controlled studies. Post-treatment effect was not observed in a limited number of studies. CONCLUSIONS:DOT-HAART had a significant effect on virologic, immunologic, and adherence outcomes, although its efficacy was not supported when restricting analysis to randomized controlled trials. DOT-HAART shows greatest treatment effect when targeting individuals with greater risk of nonadherence and when delivering the intervention that maximizes participant convenience and provides enhanced adherence support. Further investigation is needed to assess the postintervention effect and cost-effectiveness of DOT-HAART.

Project description:INTRODUCTION:The 2016 WHO consolidated guidelines on the use of antiretroviral drugs defines HIV virologic failure for low and middle income countries (LMIC) as plasma HIV-RNA ? 1000 copies/mL. We evaluated virologic failure and predictors in four African countries. MATERIALS AND METHODS:We included HIV-infected participants on a WHO recommended antiretroviral therapy (ART) regimen and enrolled in the African Cohort Study between January 2013 and October 2017. Studied outcomes were virologic failure (plasma HIV-RNA ? 1000 copies/mL at the most recent visit), viraemia (plasma HIV-RNA ? 50 copies/mL at the most recent visit); and persistent viraemia (plasma HIV-RNA ? 50 copies/mL at two consecutive visits). Generalized linear models were used to estimate relative risks with their 95% confidence intervals. RESULTS:2054 participants were included in this analysis. Viraemia, persistent viraemia and virologic failure were observed in 396 (19.3%), 160 (7.8%) and 184 (9%) participants respectively. Of the participants with persistent viraemia, only 57.5% (92/160) had confirmed virologic failure. In the multivariate analysis, attending clinical care site other than the Uganda sitebeing on 2nd line ART (aRR 1.8, 95% CI 1·28-2·66); other ART combinations not first line and not second line (aRR 3.8, 95% CI 1.18-11.9), a history of fever in the past week (aRR 3.7, 95% CI 1.69-8.05), low CD4 count (aRR 6.9, 95% CI 4.7-10.2) and missing any day of ART (aRR 1·8, 95% CI 1·27-2.57) increased the risk of virologic failure. Being on 2nd line therapy, the site where one receives care and CD4 count < 500 predicted viraemia, persistent viraemia and virologic failure. CONCLUSION:In conclusion, these findings demonstrate that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART. The findings also show that being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virologic failure that should trigger intensified adherence counselling especially in the absence of reliable or readily available viral load monitoring. Finally, clinical care sites are different calling for further analyses to elucidate on the unique features of these sites.

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African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.

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African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.

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