Background: Improved understanding of HIV-1 proviral DNA latent reservoir formation and impact of ART-strategies on reservoir size can inform treatment strategies in paediatric HIV.
Methods: HIV-1 proviral DNA was measured from a substudy of 118 children from the Children with HIV Early Antiretroviral Therapy (CHER) trial where HIV-infected infants <12 weeks with CD4% ≥25% were randomised to early limited ART for 40 or 96 weeks or deferred ART. For Infants on deferred ART or following ART interruption after 40/96 weeks ART was started/re-started for clinical progression (CDC severe stage B/C disease) or CD4% <20%. HIV-1 proviral DNA was measured by quantitative PCR using DNA extracted from 384 cryopreserved PBMC samples taken 12-weekly from 40 to 252 weeks after a minimum of 24 weeks of ART. The effects on proviral DNA decline of early versus deferred ART and ART-interruption were investigated. Predictive factors for reservoir decline were explored including ART duration, enrolment CD4 and CD4 at 96 weeks, HIV serostatus and quantitative HIV-antibody at 84 weeks, baseline CMV viraemia, immunological phenotypes, enrolment viral load, viral load 9-12 months prior to proviral DNA measurement and total weeks continuous suppression below 400 copies/ml. The profiles of 5 children with undetectable proviral DNA measurements were also described.
Results: After a minimum 24 weeks of ART, 73 children starting early ART showed a trend towards less HIV-1 proviral DNA compared with 45 children on deferred ART: median 27 [IQR 8 – 51] versus 100 [48 – 202] copies of provirus per 105 PBMCs, p=0.08). Overall, reduced reservoir size and probability of developing an undetectable reservoir were strongly associated with earlier ART-initiation and longer continuous virological suppression (p-values all <0.0001). However patterns of decline varied despite continuous ART and apparent virological suppression. ART-interruption only modestly increased levels of proviral DNA (p=0.03). HIV serostatus did not correlate with reservoir size (p=0.92) but higher CMV DNA levels at enrolment were associated with an increased HIV reservoir (p=0.02). Four children with undetectable proviral DNA underwent ART-interruption as per CHER randomisation and exhibited HIV-1 viral resurgence.
Conclusions: These findings inform the interplay between clinical, immunological or virological factors involved in reservoir dynamics, and support the view that early-initiation of ART and sustained virological suppression are key to reservoir reduction.