Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy

Abstract

Background: Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children.

Methods: This retrospective study included 23 perinatally HIV-1-infected children who initiated very early treatment within 12 weeks after birth (n = 14), or early treatment between week 12 and 1 year (n = 9). We measured the proviral reservoir (CD4(+) T-cell-associated HIV-1 DNA) in blood samples collected beyond the first year of sustained virologic suppression.

Results: There is a strong positive correlation between the time to initiation of cART and the size of the proviral reservoir. Children who initiated cART within the first 12 weeks of life showed a proviral reservoir 6-fold smaller than children initiating cART beyond this time (P < .01). Rapid virologic control after initiation of cART also limits the size of the viral reservoir. However, patients who underwent transient treatment interruptions showed a dramatic increase in the size of the viral reservoir after discontinuation.

Conclusions: Initiation of cART during the first 12 weeks of life in perinatally HIV-1-infected children limits the size of the viral reservoir. Treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir.

Keywords: HIV-1; early antiretroviral therapy; vertical infection; viral reservoir.

Figure 1.

Association between human immunodeficiency virus type 1 (HIV-1) DNA copies/10⁶ CD4⁺ T cells and age at initiation of treatment (A and B) or time to virologic control after initiation of treatment (C and D). Median (interquartile range) levels are shown. The non-parametric Spearman correlation coefficient (ρ) and the associated 2-tailed P value (A and C) and 2-tailed P value of grouped comparisons (Mann–Whitney test) (B and D) are shown. Abbreviations: ET, early treatment; VET, very early treatment.

Figure 2.

Influence of age at initiation of treatment and time to virologic control after initiation of treatment on proviral reservoir size and humoral profiles. A, Three-dimensional graph shows raw data (black circles) with the predicted multiple model (red plane). B, Bubble size represents human immunodeficiency virus type 1 (HIV-1) reservoir size (HIV-1 DNA copies/10⁶ CD4⁺ T cells). Measurements in infants who had fully seroconverted are in blue. Patients with negative or indeterminate results in the Inno-Lia assay are indicated in light or dark orange, respectively. Abbreviations: cART, combination antiretroviral therapy; ET, early treatment; VET, very early treatment.

Figure 3.

Reservoir size dynamics over time. A, Values of total human immunodeficiency virus type 1 (HIV-1) DNA from longitudinal samples are represented as mean ± standard error of the mean from patients who discontinued combination antiretroviral therapy (cART) (pink symbols) or did not discontinue cART (green symbols) after timepoint 0. The slope and P values were calculated using the linear mixed model. B, Longitudinal follow-up of Pt03. Plasma viral load (green) and CD4⁺ T-cell count (dark grey) were measured from birth to 6 years of age. Total HIV-1 DNA levels (red) were measured in 4 samples, 1 of which was taken before the 3-week discontinuation of treatment (light grey line). After reinitiation of cART, reservoir size was measured repeatedly over the following 3 years. Abbreviations: 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; NVP, nevirapine.