Association of pol Diversity with Antiretroviral Treatment Outcomes among HIV-Infected African Children

Abstract

BackgroundIn HIV-infected children, viral diversity tends to increase with age in the absence of antiretroviral treatment (ART). We measured HIV diversity in African children (ages 6–36 months) enrolled in a randomized clinical trial comparing two ART regimens (Cohort I of the P1060 trial). Children in this cohort were exposed to single dose nevirapine (sdNVP) at birth.MethodsHIV diversity was measured retrospectively using a high resolution melting (HRM) diversity assay. Samples were obtained from 139 children at the enrollment visit prior to ART initiation. Six regions of the HIV genome were analyzed: two in gag, one in pol, and three in env. A single numeric HRM score that reflects HIV diversity was generated for each region; composite HRM scores were also calculated (mean and median for all six regions).ResultsIn multivariable median regression models using backwards selection that started with demographic and clinical variables, older age was associated with higher HRM scores (higher HIV diversity) in pol (P = 0.005) and with higher mean (P = 0.014) and median (P<0.001) HRM scores. In multivariable models adjusted for age, pre-treatment HIV viral load, pre-treatment CD4%, and randomized treatment regimen, higher HRM scores in pol were associated with shorter time to virologic suppression (P = 0.016) and longer time to study endpoints (virologic failure [VF], VF/death, and VF/off study treatment; P<0.001 for all measures).ConclusionsIn this cohort of sdNVP-exposed, ART-naïve African children, higher levels of HIV diversity in the HIV pol region prior to ART initiation were associated with better treatment outcomes.

Analysis of HIV Diversity in HIV-Infected Black Men Who Have Sex with Men (HPTN 061)

“…There was no association between HIV diversity and viral load among men who were HIV infected at study enrollment, and lower HIV gag diversity was only weakly associated with higher CD4 cell count after adjusting for other factors. These findings are consistent with other studies that reported no association of HIV diversity with viral load [13,20,21] or CD4 cell count [11,17]. We did find that HIV pol diversified more over 12 months among men who had higher CD4 cell counts and lower HIV viral loads at study enrollment.…”

“…Prolonged exposure to non-suppressive ART has been significantly associated with decreases in HIV diversity in pol in adults [32] and in gag , pol , and env in children [19]. Lower gag diversity was also associated with self-reported prior maternal ARV drug use in a cohort of African children [20]. These findings suggest that the selective pressure exerted by ARV drugs may influence HIV diversity in regions other than pol .…”

“…An association between higher gag diversity and lower CD4 cell count was observed in one study [6], but not others [11,17]. Similarly, some studies have reported an association of higher gag or env diversity with higher viral load [4,6,7,24], while others have reported no association [13,20,21]. HIV diversity can also be affected by ARV drug use and is associated with clinical outcomes.…”

“…Lower HRM scores were observed in children who experienced prolonged exposure to non-suppressive ART (i.e., genetic bottlenecking) [19]. In a cohort of African children, higher HRM scores in pol were associated with better ART outcomes, including shorter time to virologic suppression and longer time to virologic failure [20]. In contrast, higher HRM scores in gag and pol were associated with decreased 5-year survival in children who did not receive ART [21].…”

Genetic Consequences of Antiviral Therapy on HIV-1

“…In contrast, the survival strains may present drug resistance mutations [ 33 ] that often increase genetic diversity of the protein-coding genes of the target proteins [ 12 , 34 , 35 ]. Wu et al [ 36 ] found that patients treated with several PIs presented 3 times more protease mutations than untreated patients.…”