Viral Reservoir in Early-Treated Human Immunodeficiency Virus-Infected Children and Markers for Sustained Viral Suppression

Abstract

Background The impact of very early infant treatment on HIV reservoir, and markers for treatment success, require study. Methods The Early Infant Treatment Study (EIT) enrolled 40 children living with HIV started on antiretroviral treatment (ART) at <7 days of age and 23 who had started treatment between 30-365 days to serve as controls. Quantitative HIV DNA was evaluated every 1-3 months in PBMCs. 84-week repeat qualitative whole blood DNA PCR and dual enzyme EIA were performed. Results Median quantitative cell-associated DNA after at least 84 weeks was significantly lower among the first 27 EIT children tested than among 10 controls (40.8 vs. 981.4 copies/million cells; p<0.001) and correlated with pre-ART DNA. Median DNA after 84 weeks did not differ significantly by negative or positive serostatus at 84 weeks (p=0.94), and appeared unaffected by periods of unsuppressed plasma RNA from 24-84 weeks (p=0.70). However, negative 84-week serostatus was 67% predictive for sustained RNA suppression and positive serostatus was 100% predictive for viremia. Loss of qualitative DNA positivity at 84 weeks was 73% predictive for sustained suppression and persistent positivity was 77% predictive for viremia. Conclusions Lower viral reservoir was associated with starting ART at <1 week. Negative serostatus and qualitative DNA were useful markers of sustained viral suppression from 24-84 weeks.

HIV-1 Persistence in Children during Suppressive ART

“…A study of 20 children from the CHER cohort who had viremia well-suppressed on ART for 7-8 years also found significantly lower DNA and RNA loads in those who initiated treatment within two months of birth compared with those who initiated later [53]. These findings are mirrored by others [60][61][62][63][64][65][66][67] and highlight the role of early ART in limiting the size of the HIV reservoir. This finding is well-illustrated by a recent study in children showing a positive correlation between HIV RNA area under the viral load curve in the first year of life and HIV DNA levels at one year of age [68].…”

Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure

“…Regardless of the mode of transmission earlier ART is generally associated with a smaller reservoir during viremia suppression (210,214,(225)(226)(227)(228)(229)(230)(231)(232)(233)(234)(235)(236)(237), although starting ART within 14 days of life may not lead to significantly greater HIV DNA persistence compared to within 48 hours of life (238). ART initiation within 8 days has also been associated with a faster HIV DNA decay compared to ART started at 5 months (239).…”

“…A smaller reservoir size as measured by total HIV DNA in PBMCs was not correlated with maintained viral suppression whereas a longer time to initial viral suppression was, implicating immunologic contributions to aviremia, although this finding may have been influenced by ART nonadherence. In children in the EIT study who started on ART at < 7 days of life, sustained HIV RNA suppression was associated with negative HIV serostatus and negative qualitative HIV DNA PCR at ~20 months ( 225 ). HIV seronegativity has also been described in other studies of early or very early ART and has been proposed as an estimate for reservoir size ( 227 , 228 , 241 – 244 ).…”

Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis

“…Among the 20 selected studies that focus on cART-treated children ( Table 1 ), the frequency of seronegativity was reported in 11 studies in which early-treated children were included with a median age of 2.2 months (IQR: 1.7–2.7, N = 583) when cART started ( 4 , 14 – 16 , 20 – 22 , 26 , 29 , 32 , 33 ) and in 4 studies that deferred-treated children were included with a median age of 55.7 months (IQR: 37.4–86.4, N = 587) ( 18 , 23 – 25 ). In addition, 5 studies included both early-treated and deferred-treated children and separately reported the frequency of seronegativity in the two groups ( 17 , 19 , 27 , 28 , 31 ).…”

“…It has been reported that the intensity of anti-HIV-1 antibody response correlated well with the size of the HIV-1 reservoir since maturation and maintenance of antibody response depend on continuous stimulation of HIV-1 antigens ( 17 , 19 , 27 , 28 , 33 , 39 , 57 – 64 ). However, inconsistent results existed ( 21 , 23 , 32 , 38 ). In this systematic review, we adapted a meta-analysis to analyze HIV-1 seroreversion caused by cART and to explore the possibility of anti-HIV-1 levels as an alternative biomarker for HIV-1 reservoir size.…”