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Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children.

ABSTRACT: BACKGROUND:Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING:We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age. METHODS:Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS:At ART initiation, children were aged median [IQR] 2.3 [1.2-4.1] months, CD4% 37 [24-45] %, CD8% 28 [18-36] %, log10 plasma viral load (VL) 5.4 [4.4-5.9] copies per milliliter. Time to viral suppression was 7.98 [4.6-19.3] months. After suppression, 13 (25%) children had suboptimal response [?2 consecutive VL 50-400 followed by VL <50] and/or experienced periods of virological failure [?2 consecutive VL ?400 followed by VL <50]. Median total HIV-1 DNA was 43 [6195] copies/10 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, P = 0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, P = 0.0022) and the absence of viral failure/suboptimal response (AC 0.34 for those with fail/suboptimal response, P = 0.0483) were associated with lower total HIV-1 DNA. CONCLUSIONS:Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1-infected children minimize the size of viral reservoir.

SUBMITTER: Tagarro A

PROVIDER: S-EPMC6173292 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children.

Tagarro Alfredo A Chan Man M Zangari Paola P Ferns Bridget B Foster Caroline C De Rossi Anita A Nastouli Eleni E Muñoz-Fernández María A MA Gibb Diana D Rossi Paolo P Giaquinto Carlo C Babiker Abdel A Fortuny Claudia C Freguja Riccardo R Cotugno Nicola N Judd Ali A Noguera-Julian Antoni A Navarro María Luisa ML Mellado María José MJ Klein Nigel N Palma Paolo P Rojo Pablo P

Journal of acquired immune deficiency syndromes (1999) 20181001 2

<h4>Background</h4>Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size.<h4>Setting</h4>We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age.<h4>Methods</h4>Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV ...[more]

PMID: 30211778

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Project description:BackgroundExisting studies have suggested decreased adherence and rebound in mortality in perinatally HIV-infected adolescents receiving antiretroviral therapy (ART) as compared to adults and young children.MethodsWe used both quantitative and qualitative approaches to identify factors influencing adherence among perinatally infected adolescents in Thailand. We analyzed data from 568 pairs of perinatally infected adolescents (aged 12-19) and their primary caregivers in the Teens Living With Antiretrovirals (TEEWA) study, a cross-sectional survey conducted in 2010-2012. We also conducted 12 in-depth interviews in 2014 with infected adolescents or their primary caregivers to elicit experiences of living with long-term ART.ResultsFrom the quantitative analysis, a total of 275 (48.4%) adolescents had evidence of suboptimal adherence based on this composite outcome: adolescents self-reported missing doses in the past 7 days, caregiver rating of overall adherence as suboptimal, or latest HIV-RNA viral load ≥1000 copies/ml. In multivariate logistic regression analysis, younger age, having grandparents or extended family members as the primary caregiver, caregiver-assessed poor intellectual ability, having a boy/girlfriend, frequent online chatting, self-reported unhappiness and easiness in asking doctors questions were significantly associated with suboptimal adherence. From the in-depth interviews, tensed relationships with caregivers, forgetfulness due to busy schedules, and fear of disclosing HIV status to others, especially boy/girlfriends, were important contributors to suboptimal adherence. Social and emotional support and counseling from peer group was consistently reported as a strong adherence-promoting factor.ConclusionOur findings highlight unique barriers of ART adherence among the perinatally infected adolescents. Future interventions should be targeted at helping adolescents to improve interpersonal relationships and build adaptive skills in recognizing and addressing challenging situations related to ART taking.

Project description:HIV establishes a persistent viral reservoir in the brain despite viral suppression in blood to undetectable levels on antiretroviral therapy (ART). The brain viral reservoir in virally suppressed HIV+ individuals is not well-characterized. In this study, intact, defective, and total HIV proviral genomes were measured in frontal lobe white matter from 28 virally suppressed individuals on ART using the intact proviral DNA assay (IPDA). HIV gag DNA/RNA levels were measured using single-copy assays and expression of 78 genes related to inflammation and white matter integrity was measured using the NanoString platform. Intact proviral DNA was detected in brain tissues of 18 of 28 (64%) individuals on suppressive ART. The median proviral genome copy numbers in brain tissue as measured by the IPDA were: intact, 10 (IQR 1-92); 3' defective, 509 (225-858); 5' defective, 519 (273-906); and total proviruses, 1063 (501-2074) copies/106 cells. Intact proviral genomes accounted for less than 10% (median 8.3%) of total proviral genomes in the brain, while 3' and 5' defective genomes accounted for 44% and 49%, respectively. There was no significant difference in median copy number of intact, defective, or total proviruses between groups stratified by neurocognitive impairment (NCI) vs. no NCI. In contrast, there was an increasing trend in intact proviruses in brains with vs. without neuroinflammatory pathology (56 vs. 5 copies/106 cells, p = 0.1), but no significant differences in defective or total proviruses. Genes related to inflammation, stress responses, and white matter integrity were differentially expressed in brain tissues with >5 vs. +5 intact proviruses/106 cells. These findings suggest that intact HIV proviral genomes persist in the brain at levels comparable to those reported in blood and lymphoid tissues and increase CNS inflammation/immune activation despite suppressive ART, indicating the importance of targeting the CNS reservoir to achieve HIV cure.

Dataset Information

Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children.

Publications

Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children.

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