Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”. Dynamics of HIV-1 DNA in Children Over Long-term Sustained Viral Suppression: Impact of the Time of Infection at Viral Control on Reservoir Size M. Moragas, M. Distefano, D. Mecikovsky, S. Arazi Caillaud, R. Bologna, P. Aulicino, A. Mangano. Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”.

Conflict of Interest No conflicts of interest to declare.

Aims To determine the decay of viral reservoirs throughout sustained virological suppression in perinatally infected children. How the time to achieve effective ART response affects the persistence of HIV-1.

Design and Methodology A retrospective study including 37 HIV-1 perinatally infected children born between 1990-2008. At least sustained viral suppression during 4 years. Total HIV-DNA was quantified by semi-nested real time PCR, and analyzed longitudinally by linear mixed-effect model. 2-LTR circles were detected by hemi-nested real time PCR and followed over VS by logistic regression.

Infant Characteristics Value Subjects, No. 37 Sex, No. (%), Female 19 (51.4) ACTG 076 prophylaxis regimen, No. (%)   None 24 (64.9) Partial 5 (13.5) Complete Unknown 3 (8.1) Age at ART initiation, median (IQR), yrs 2.4 (0.8-5.1) First ART regimen, No. (%) 2 NRTIs + NNRTI 16 (43.2) 2 NRTs + PI 21 (56.8) Age at VS, median (IQR), yrs 5.3 (3.8-10.8) ART regimen at VS, No. (%) 23 (62.2) 14 (37.8) pVL at pre-VS, median (IQR), log10 copies/mL 5.89 (5.03-6.25)

Total HIV-DNA and 2-LTRs have a strong decay during the first two years of VS  Variable Values in PBMCs No. of children 37 Intercept Estimated (95% CI) 2.44 (2.17 to 2.70) First slope (0-2 yrs) Estimated ( 95% CI) -0.26 (-0.43 to -0.09) P-value .0028 Second slope (2-4 yrs) -0.06 (-0.15 to 0.55) .2578 Level of CA-HIV-DNA (log10 cpm) At 0 yrs of VS, mean (95% PI) 2.55 (2.18 to 2.93) At 2 yrs of VS, mean (95% PI) 2.03 (1.79 to 2.27) At 4 yrs of VS, mean (95% PI) 1.98 (1.66 to 2.30) Piecewise linear mixed-effect model. 2-LTRs circles - At VS: 82.9% (29/35) - At 2 yrs. of VS: 37.5% (9/24) At 4 yrs. of VS: 28.1% (9/32) Significant decay (P=.0009) 2-LTRs = CA-HIV-DNA 2.48 (IQR: 1.68 to 3.01) vs. 1.89 (IQR: 0.78 to 2.39) log10 cpm (P<.005).

Decay of total HIV-DNA according to the age at VS  Variable Time of Infection at VS ≤1.5 yrs >1.5-4 yrs >4 yrs P-value No. of children 4 6 27 NA Intercept Estimated (95% CI) 2.44 (2.18 to 2.70) 2.44 (2.18 to2.70) First slope (0-2 yrs) Estimated ( 95% CI) -0.51 (-0.94 to -0.07) -0.35 (-0.83 to 0.14) -0.21 (-0.39 to -0.02) .1645 .0235 .1583 .0287 Second slope (2-4 yrs) -0.001 (-1.50 to 1.50) -0.11 (-1.64 to 1.44) -0.07 (-0.63 to 0.49) .7346 .3477 .6495 .4798 Level of CA-HIV-DNA (log10 cpm) At 0 yrs of VS, mean (95% PI) 2.73 (2.01 to 3.45) 2.58 (1.86 to 3.30) 2.52 (2.13 to 2.90) .5941 At 2 yrs of VS, mean (95% PI) 1.72 (1.24 to 2.20) 1.89 (1.40 to 2.37) 2.11 (1.85 to 2.37) .1614 At 4 yrs of VS, mean (95% PI) 1.56 (0.75 to 2.37) 1.83 (0.94 to 2.73) 2.08(1.73 to 2.43) .1942

Discussion These data highlight the difficulty to eliminate the circulating reservoirs from peripheral blood, reinforcing the clinical benefit of very early effective therapy in perinatally infected children. Peripheral blood HIV-1 reservoir size decayed markedly during the first two years of VS. Children with VS before 18 months tended to have a higher decay rate. After two years of VS peripheral blood HIV-1 reservoirs decay very slowly and independently of the time to achieve VS.

Acknowledgement