Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection (original) (raw)
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HIV-1 DNA Decay Dynamics with Early, Long-term Virologic Control of Perinatal Infection
Clinical Infectious Diseases, 2017
Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. Results. In the first 2 years following VS, HIV-1 DNA levels decreased by-0.25 (95% confidence interval [CI],-.36 to-.13) log 10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and-0.15 log 10 copies/ million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by-0.05 (95% CI,-.06 to-.03) log 10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. Conclusions. Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.
HIV ‐1 DNA decay is faster in children who initiate ART shortly after birth than later
Journal of the International AIDS Society
Introduction: There is limited data in children on whether persistence of HIV-1 infected cells is affected by age at initiating antiretroviral therapy (ART), its duration or any subsequent ART interruption. We therefore investigated the effects of both age of ART initiation and duration of ART interruption on HIV-1 DNA decay in children. Methods: We investigated HIV-1 DNA decay in three groups of children on ART: Group-1 (n = 7) started uninterrupted ART within eight days of life; Group-2 (n = 8) started uninterrupted ART at a median of five months of age; and Group-3 (n = 23) started ART at a median age of 1.8 months for either 40 or 96 weeks, then interrupted ART (median of seven months), and restarted ART based on CD4 count and clinical criteria. Total HIV-1 DNA was assayed using a sensitive HIV-1 subtype C-adapted quantitative PCR for integrase. The duration of ART was square root transformed to fit the observed slowing of HIV-1 DNA decay rate. For each group, point estimates for decay rates were determined after six months of continuous suppressive ART in groups 1 and 2 or six months after restarting ART in Group-3. Groups-2 and 3 were combined using a mixed effect regression model to investigate covariates of HIV-1 DNA decay rate. Results and Discussion: At six months of continuous suppressive ART, the HIV-1 DNA t½ (95% CI) was shorter in Group-1 (n = 7): 2.7 months (2.1 to 3.8), than 9.2 months (7.4 to 12.1) in Group-2 (n = 8); and 9.6 months (7.6 to 12.6) in Group-3 (n = 23) (p < 0.01). In multivariable analyses, HIV-1 DNA before treatment (p < 0.001) and the change in HIV-1 DNA during interruption (p < 0.01) were independent predictors of slower HIV-1 DNA decay. Conclusions: These data suggest that ART initiation within the first week of life can reduce the persistence of long-lived infected cells. Delaying ART is associated with slower decay of infected cells.
Journal of the International AIDS Society, 2017
Background: The dynamics of HIV-1 DNA reservoir in perinatally infected children throughout long-term sustained viral suppression (VS) – and how they are affected by the time of infection at VS – have not been defined. Improved understanding of HIV-1 dynamics is necessary for therapeutic interventions that aim to achieve sustained antiretroviral therapy-free HIV-1 remission. Methods: This study included 37 perinatally HIV-1 infected children on suppressive antiretroviral therapy. Children were grouped according to the timing of antiretroviral therapy (ART) initiation (≤0.5 or >0.5 years) and the time to achieve VS (≤1.5, between >1.5 and 4, and >4 years). Decay of cell-associated HIV-1 DNA (CA-HIV-1 DNA) level -quantified by semi-nested real time PCR- and 2-long terminal repeats (2-LTR) circles frequency -detected by hemi-nested real time PCR- were analysed over 4 years of VS using piecewise linear mixed-effects model with two splines and logistic regression, respectively. Results: CA-HIV-1 DNA in peripheral blood mononuclear cells (PBMC) had a high decay during the first two years of VS [−0.26 (95% CI: −0.43 to −0.09) log10 copies per one million (cpm) PBMC/ year], followed by a slow decay and reaching a plateau between 2 and 4 years of VS [−0.06 (95% CI: −0.15 to 0.55) log10 cpm PBMC/ year]. The level of CA-HIV-1 DNA in PBMCs highly correlated with those estimated in CD4+ T cells (r = 0.97, p < 0.0001) and whole blood (r = 0.98, p < 0.0001). The initial decay according to time of infection at VS was −0.51 (95% CI: −0.94 to −0.07), −0.35 (95% CI: −0.83 to 0.14) and −0.21 (95% CI: −0.39 to −0.02) log10 cpm PBMC/ year for children who achieved VS by 1.5, >1.5–4 and >4 years of infection, respectively. The frequency of 2-LTR circles decayed significantly, from 82.9% at pre-VS to 37.5% and 28.1% at two and four years of VS, respectively (p = 0.0009). Conclusions: A marked decay of HIV-1 DNA occurs during the first two years of viral suppression – where the earlier the time of infection at viral suppression, the higher the rate of decay – and seems to set HIV-1 reservoir size. After two years, HIV-1 DNA decreases slowly and independently of the time to achieve effective viral control.
HIV-1 DNA Decay Dynamics in Blood During More Than a Decade of Suppressive Antiretroviral Therapy
Clinical Infectious Diseases, 2014
Background. Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. Methods. Blood mononuclear cells obtained during 7-12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. Results. Thirty participants were studied. HIV-1 DNA decreased significantly from years 0-1 and 1-4 of ART with median decay slopes of −0.86 (interquartile range, −1.05, −0.59) and −0.11 (−0.17, −0.06) log 10 (copies/10 6 CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4-7 (−0.02 [−0.06, 0.02]; P = .09) or after year 7 of ART (−0.006 [−0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10 6 CD4+ T-cells; range: 7-2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1-4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. Conclusions. Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1-4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.
The Journal of infectious diseases, 2014
Early initiation of combination antiretroviral therapy (cART) to human immunodeficiency virus type 1 (HIV-1)-infected infants controls HIV-1 replication and reduces mortality. Plasma viremia (lower limit of detection, <2 copies/mL), T-cell activation, HIV-1-specific immune responses, and the persistence of cells carrying replication-competent virus were quantified during long-term effective combination antiretroviral therapy (cART) in 4 perinatally HIV-1-infected youth who received treatment early (the ET group) and 4 who received treatment late (the LT group). Decay in peripheral blood mononuclear cell (PBMC) proviral DNA levels was also measured over time in the ET youth. Plasma viremia was not detected in any ET youth but was detected in all LT youth (median, 8 copies/mL; P = .03). PBMC proviral load was significantly lower in ET youth (median, 7 copies per million PBMCs) than in LT youth (median, 181 copies; P = .03). Replication-competent virus was recovered from all LT yout...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015
Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay. We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation. Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile ran...
PLOS ONE
Background The latent viral reservoir is the major obstacle to achieving HIV remission and necessitates lifelong antiretroviral therapy (ART) for HIV-infected individuals. Studies in adults and children have found that initiating ART soon after infection is associated with a reduction in the size of the HIV-1 reservoir. Here we quantified cell-associated HIV-1 DNA in early-treated but currently older HIV-infected children suppressed on ART. Methods The study participants comprised of a cohort of 146 early-treated children with HIV-1 RNA <50 copies/ml enrolled as part of a clinical trial in Johannesburg, South Africa. A stored buffy coat sample collected after a median 4.3 years on ART and where HIV-1 RNA was <50 copies/ml was tested for cell-associated HIV-1 DNA levels. An in-house, semi-nested real-time quantitative hydrolysis probe PCR assay to detect total HIV-1 subtype C proviral DNA was used. Children were followed prospectively for up to 3 years after this measurement to investigate subsequent HIV-1 RNA rebound/failure while remaining on ART. Age at ART initiation, HIV-1 RNA decline prior to HIV-1 DNA measurement and other factors were investigated. Results A gradient between age at ART initiation and later HIV-1 DNA levels was observed. When ART was started <2 months of age, the lowest levels of cell-associated HIV-1 DNA (median 1.4 log 10 copies/10 6 cells, interquartile range [IQR] 0.95-1.55) were observed
Kinetics of Cell-Associated HIV DNA During Viral Suppression in HIV-Infected Children
Topics in Antiviral Medicine, 2016
Background: Although the success of combined antiretroviral therapy (cART) to control viral replication, HIV erradication has not been yet achieved. One of the major known obstacles is the establishment of viral reservoirs very early after infection. The aim of this study was to determine the decay in the level of cell-associated HIV-DNA (CA-HIV-DNA) in children with sustained virological suppression (VS) for many years on cART. Methods: The research was conducted in an academic pediatric hospital including 37 HIV-infected children by vertical transmission with more than 2 years on VS, defined as plasma viral load below the limit of detection of the available assay. CA-HIV-DNA levels were quantified by a semi-nested real time PCR with Taqman probes targetting LTR-gag region in PBMCs. Samples were tested at pre-cART, at 2 and 4 years (± 6 months) on VS. Clinical, virological and inmunological data were collected. Mann-Whitney test and with Pearson´s or Sperman correlation coefficient were used for data analysis. Results: Of the 37 children, 14 started cART during the first year of infection (3-12 mo) and 23 children between 20-131 mo. Three time points (pre cART, 2 and 4 years on VS) were able to study in 23 children while in 14 only pre cART and at 4 years on VS could be performed. The median CA-HIV-DNA levels pre cART was 2.67 (IQR: 1.72- 3.07) log10/106 PBMCs and was significantly lower when compared to 2 and 4 years on VS with median levels of 1.96 (IQR:1.32-2.56) log10 (p<0.05) and 1.91 (IQR: 0.78-2.36) log10/106 PBMCs (p<0.005), respectively. However, no changes in CA-HIV-DNA levels between 2 and 4 years on VS was found. Moreover, initiation of therapy before or after 12 months of age did not modify CA-HIV-DNA levels. No correlation between clinical stage or CD4 counts and CA-HIV-DNA levels were found. Conclusions: CA-HIV-DNA levels is markedly reduced by therapy after 2 years of VS. However, once CA-HIV-DNA levels reaches a set point, it remains stable despite prolonged therapy and they could not been reduced by cART initiation between 3 -12 months of age. Collectively, these findings suggest that the strongest effect of cART on viral reservoirs is restricted to a very short period after infection, and extended ART prophylaxis may play a central role to limit the set point of CA-HIV-DNA levels.
Journal of the Pediatric Infectious Diseases Society, 2020
Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged <2 years, and remained suppressed (viral load [VL] <50 copies/mL) for >5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-...