Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection

Uprety, Priyanka; Patel, Kunjal; Karalius, Brad; Ziemniak, Carrie; Chen, Ya Hui; Brummel, Sean; Siminski, Suzanne; Dyke, Russell B. Van; Seage, George R.; Persaud, Deborah; Yogev, Ram; Sanders, Margaret Ann; Malee, Kathleen; Hunter, Scott J.; Shearer, William T.; Paul, Mary E.; Cooper, Norma; Harris, Lynnette; Purswani, Murli; Baig, Mahboobullah; Cintron, Anna; Puga, Ana María Méndez; Navarro, Sandra; Garvie, Patricia A.; Blood, James; Burchett, Sandra; Karthas, Nancy; Kammerer, Betsy; Wiznia, Andrew; Burey, Marlene; Nozyce, Molly; Dieudonne, Arry; Bettica, Linda; Chen, Janet S.; Bulkley, Maria Garcia; Ivey, Latreaca; Grant, Mitzie; Knapp, Katherine M.; Allison, Kim; Wilkins, Megan L.; Acevedo-Flores, Midnela; Rios, Heida; Olivera, Vivian; Silio, Margarita; Gabriel, Medea; Sirois, Patricia A.; Spector, Stephen A.; Norris, Kim; Nichols, Sharon L.; McFarland, Elizabeth J.; Darrow, Juliana; Barr, Emily; Harding, Paul A.; Scott, Gwendolyn B.; Alvarez, Grace; Cuadra, Anai

doi:10.1093/cid/cix192

Cited by 36 publications

(24 citation statements)

References 39 publications

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“…We found that for chronically HIV-1infected patients, total HIV-1 DNA decay after initiation of cART demonstrated a biphasic reduction within 96 weeks. Most decline happened in the rst six months and then began to plateau, which was consistent with other ndings in chronically HIV-1-infected patients [25,26]. Furthermore, 18.8% of chronic patients achieved < 100 total HIV-1 DNA copies/10 6 PBMCs after 96 weeks of cART; in comparison, with prolonged treatment as long as the median duration of 13 years, it was reported that 28% of such patients could achieve ~ 150 total HIV-1 DNA copies/10 6 PBMCs [18].…”

Section: Discussionsupporting

confidence: 91%

Therapeutic Prediction of HIV-1 DNA Decay: A Multicenter Longitudinal Cohort Study

Yue

Cui³

et al. 2020

Preprint

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Background: Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions.Methods: Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, and 288 weeks after combined antiretroviral therapy (cART) initiation in 607 treatment-naïve patients with chronic HIV-1 infection were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART.Results: The total HIV-1 DNA rapidly decreased from baseline [mean = 3.04 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (mean = 2.51 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (<100 copies/106 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P < 0.001] and higher baseline CD4+ T cell count (RR = 1.72, per 100 cells/μL, P < 0.001) were significantly associated with a low total HIV-1 DNA count at week 96. In an independent cohort of 117 patients, this model achieved a sensitivity of 75.00% and specificity of 69.52%.Conclusions: The derived model based on baseline total HIV-1 DNA and CD4+ T cell count provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

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Section: Discussionsupporting

confidence: 91%

Therapeutic Prediction of HIV-1 DNA Decay: A Multicenter Longitudinal Cohort Study

Yue

Cui³

et al. 2020

Preprint

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“…In addition, since we measured HIV-1 DNA after more than 4 years of ART the size of the viral reservoir may have stabilized. Generally, the most marked declines in HIV-1 DNA levels are within the first two years of treatment [ 13 ]. Associations between pre-treatment characteristics including CD4 T cell count and HIV-1 RNA quantity were consistent with expectations that pre-treatment disease severity would predict a larger persisting viral reservoir.…”

Section: Discussionmentioning

confidence: 99%

Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children

et al. 2018

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BackgroundThe latent viral reservoir is the major obstacle to achieving HIV remission and necessitates life-long 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.MethodsThe 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.ResultsA 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 log10copies/106 cells, interquartile range [IQR] 0.95–1.55) were observed compared to ART started at 2–4 months (median 1.68, IQR 1.26–1.97) or 5–14 months of age (median1.98, IQR 1.69–2.25). A low CD4 T-cell count pre-treatment predicted higher levels of HIV-1 DNA on later testing. The probability of HIV-1 RNA rebound >50 copies/ml whilst on ART within 3 years after the DNA measurement was 2.07 (95% CI: 1.352–3.167) times greater if the HIV-1 DNA level was above the median of 55 copies/106 cells.ConclusionsCell-associated HIV-1 DNA levels measured after more than 4 years on ART were lower the younger the age of the child when ART was initiated. This marker of the size of the viral reservoir also predicted subsequent viral rebound/treatment failure while ART was sustained. The results provide additional evidence of the benefits of prompt diagnosis and early ART initiation in newborns and infants.

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“…Although the NGS analysis of cell‐associated DNA at baseline detected more DRMs compared with Sanger sequencing of the cell‐free RNA, their prevalence did not differ significantly between nonresponders and responders. The observed loss of DRMs contained in cell‐associated DNA at baseline during the course of ART was expected considering the rapid clearance of the short‐lived infected CD4 T cells during ART initiation . These findings point to the limited utility of NGS analysis of the cell‐associated DNA before ART initiation to predict the imminent virological failure .…”

Section: Discussionmentioning

confidence: 94%

Viral evolution in the cell‐associated HIV‐1 DNA during early ART can lead to drug resistance and virological failure in children

Gopalan

D'Souza

Rajnala

et al. 2019

Journal of Medical Virology

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Using cell‐associated DNA and cell‐free RNA of human immunodeficiency virus type‐1 (HIV‐1), we investigated the role of drug‐resistant viral variants that emerged during early antiretroviral therapy (ART) in determining virological outcome. This case‐control study compared virologic nonresponder children (two viral loads [VLs] ≥ 200 copies/mL within 2 years of ART) and responder children (two VLs < 200 copies/mL after six months of ART) infected with HIV‐1 initiated on nonnucleoside reverse‐transcriptase inhibitor (NNRTI)‐based ART. The partial reverse‐transcriptase gene of HIV‐1 in cell‐associated DNA was genotyped using next‐generation sequencing (NGS; Illumina; threshold 0.5%; at baseline and month six of ART) and in cell‐free RNA (concurrently and at virological failure; VL > 1000 copies/mL at ≥ 12 months of ART) using the Sanger method. Among 30 nonresponders and 37 responders, baseline differences were insignificant while adherence, VL, and drug resistance mutations (DRMs) observed at month six differed significantly ( P ≥ 0.05). At month six, NGS estimated a higher number of DRMs compared with Sanger (50% vs 33%; P = 0.001). Among the nonresponders carrying a resistant virus (86.6%) at virological failure, 26% harbored clinically relevant low‐frequency DRMs in the cell‐associated DNA at month six (0.5%‐20%; K103N, G190A, Y181C, and M184I). Plasma VL of > 3 log 10copies/mL (AOR, 30.4; 95% CI, 3.3‐281; P = 0.003) and treatment‐relevant DRMs detected in the cell‐associated DNA at month six (AOR, 24.2; 95% CI, 2.6‐221; P = 0.005) were independently associated with increased risk for early virological failure. Our findings suggest that treatment‐relevant DRMs acquired in cell‐associated DNA during the first six months of ART can predict virological failure in children initiated on NNRTI‐based ART.

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Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection

Abstract: 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.

Cited by 36 publications

References 39 publications

Therapeutic Prediction of HIV-1 DNA Decay: A Multicenter Longitudinal Cohort Study

Therapeutic Prediction of HIV-1 DNA Decay: A Multicenter Longitudinal Cohort Study

Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children

Viral evolution in the cell‐associated HIV‐1 DNA during early ART can lead to drug resistance and virological failure in children

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