Predictors of HIV reservoir size and decay dynamics in early-treated paediatric infection: a prospective, multicentre longitudinal cohort study

Background Early antiretroviral therapy (ART) after perinatal HIV infection can restrict reservoir size and diversity, offering potential for remission. We evaluated HIV-1 DNA dynamics up to four years of age and predictors of reservoir size in early-treated African children. Methods In this prospective, multicentre cohort study, infants with perinatal HIV from South Africa, Mozambique, and Mali who initiated ART before 6 months of age and within 3 months of diagnosis were enrolled. Children were followed at 2, 6, 12, and 24 weeks, then biannually for 4 years. Total HIV-1 DNA in PBMCs was quantified longitudinally by droplet digital PCR in 207 children. The main outcomes were HIV-1 DNA reservoir size at year 3 (log 10 copies/million PBMC) and longitudinal HIV-1 DNA decay. Multivariable models were developed to identify predictors of reservoir size using generalised additive regression models, and decay dynamics were evaluated using mixed-effects Poisson models including random intercepts and viral load slopes. Findings Of 207 children, 155 (75%) had >12 months of follow-up. HIV was diagnosed at a median age of 31 days (IQR: 0, 47) and ART started at 33 days (IQR: 23.5, 69.5). Nineteen of 155 (12.3%) had undetectable HIV-1 DNA at year 4. Median decay rate was −0.020 log10 copies/million cells/month (−0.212/year). Smaller reservoirs at year 3 were associated with lower pre-ART viral load (β = 0.26, 95% CI: 0.09, 0.43) and faster first-year HIV-1 DNA decay rate (β = 1.09, 95% CI: 0.02, 2.19), with trends toward smaller reservoirs among females (β = −0.41, 95% CI: −0.87, 0.04) and larger reservoirs among children whose mothers reported social challenges (β = 0.42, 95% CI: −0.04, 0.87). Faster decay correlated with longer time on ART, lower serial viral loads, sustained viral suppression >12 months, earlier ART initiation, and region (Mali). Maternal health issues correlated with slower decay. Eleven "excellent controllers" maintained durable viral suppression, immunological control, and undetectable total HIV-1 DNA at last follow-up. Interpretation Early virological parameters may help identify children likely to develop smaller HIV reservoirs. Early ART is key to faster reservoir reduction. Maternal health issues influence reservoir decay, reflecting a parental legacy effect. Sex differences should be further explored to understand mechanisms of reservoir control. Children with sustained virological suppression, preserved immune status, and undetectable total HIV-1 DNA may represent candidates with favourable characteristics for HIV remission strategies, as these factors have been associated with a reduced burden of persistent HIV infection and have been observed in rare cases of post-treatment control.