Interruption of Antiretroviral Treatment in HIV‐Infected Patients with Preserved Immune Function Is Associated with a Low Rate of Clinical Progression: A Prospective Study by AIDS Clinical Trials Group 5170

Skiest, Daniel J.; Su, Zhaohui; Havlir, Diane V.; Robertson, Kevin; Coombs, Robert W.; Cain, Pat; Peterson, Tianna; Krambrink, Amy; Jahed, Nasreen C.; McMahon, Deborah; Margolis, David M.

doi:10.1086/512681

Cited by 65 publications

(85 citation statements)

References 40 publications

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“…However, ART alone is unable to eradicate infected cells, and without lifelong treatment, HIV plasma viremia almost invariably rebounds (2,3). One study of individuals undergoing multiple short ATIs detected generally homogeneous populations of rebounding virus with different lineages present at different ATI cycles, suggesting stochastic reactivation of monoclonal or small oligoclonal populations of latently infected cells (4).…”

Section: Importancementioning

confidence: 99%

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Kearney

Wiegand

Shao

et al. 2016

J Virol

126

131

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Understanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2-to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIVinfected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission. IMPORTANCEAntiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.)

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Section: Importancementioning

confidence: 99%

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Kearney

Wiegand

Shao

et al. 2016

J Virol

126

131

View full text Add to dashboard Cite

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“…Participants in 6 ACTG ATI studies (ACTG 371 [18], A5024 [19], A5068 [20], A5170 [21], A5187 [22], and A5197 [23]) were included if they were on suppressive ART, received no immunologic interventions (e.g., therapeutic vaccination, IL-2), and had HIV-1 RNA <50 copies/mL at the time of ATI. For participants of ACTG 371, A5024, A5068, and A5197, viral loads were measured at ATI weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16.…”

Section: Study Populationmentioning

confidence: 99%

The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption

2016

Aids

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Objectives-Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics.Design-A pooled analysis of participants from 6 AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound.Methods-Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI PBMC samples, and residual plasma viremia (RV) was measured using the single-copy assay.Results-Participants who initiated ART during acute/early HIV infection and those on an NNRTI-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronictreated: median <92 vs. 156 HIV-1 RNA copies/10 6 CD4+ cells, P<0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 wks vs. 5-8 wks vs. >8 wks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 6 CD4+ cells, Kruskal-Wallis P<0.01). The proportion of participants with detectable RV prior to ATI was significantly higher among those with shorter time to viral rebound.Conclusions-Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission.

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“…8,9 There are conflicting results as to whether these patients can safely discontinue ART. [10][11][12] Studies have shown that cognitive deficits are associated with ongoing viral replication in the CNS and that neurocognitive functioning improves in patients who initiate ART. [13][14][15][16][17][18] This recovery of function suggests that the underlying mechanism includes an alteration of neuronal function prior to actual cell death.…”

mentioning

confidence: 99%

“…11 In step 1, eligible subjects elected to stop antiretroviral therapy; in step 2, patients from step 1 reinitiated antiretroviral therapy. This study design provided a Class III level of evidence.…”

mentioning

confidence: 99%

Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort

et al. 2010

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Objective: Prior studies have shown improved neurocognition with initiation of antiretroviral treatment (ART) in HIV. We hypothesized that stopping ART would be associated with poorer neurocognitive function. Methods:Neurocognitive function was assessed as part of ACTG 5170, a multicenter, prospective observational study of HIV-infected subjects who elected to discontinue ART. Eligible subjects had CD4 count Ͼ350 cells/mm 3 , had HIV RNA viral load Ͻ55,000 cp/mL, and were on ART (Ն2 drugs) for Ն6 months. Subjects stopped ART at study entry and were followed for 96 weeks with a neurocognitive examination.Results: A total of 167 subjects enrolled with a median nadir CD4 of 436 cells/mm 3 and 4.5 median years on ART. Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (all p Ͻ 0.001). In the 46 subjects who restarted ART prior to week 96, no significant changes in neurocognitive function were observed. Conclusion: Subjects with preserved immune function found that neurocognition improved signif-icantly following antiretroviral treatment (ART) discontinuation. The balance between the neurocognitive cost of untreated HIV viremia and the possible toxicities of ART require consideration. Classification of evidence:This study provides Class III evidence that discontinuing ART is associ- -1266GLOSSARY ACTG ϭ AIDS Clinical Trials Group; ART ϭ antiretroviral treatment; EFV ϭ efavirenz; HAART ϭ highly active antiretroviral therapy; HAD ϭ HIV-associated dementia; NP ϭ neuropsychological summary score; TI ϭ treatment interruption; VL ϭ viral load.

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Interruption of Antiretroviral Treatment in HIV‐Infected Patients with Preserved Immune Function Is Associated with a Low Rate of Clinical Progression: A Prospective Study by AIDS Clinical Trials Group 5170

Abstract: Disease progression after TI was low in this cohort. A higher nadir in CD4(+) cell count, a lower HIV load before ART, and an HIV load < or =50 copies/mL at the time of TI predicted a longer time to the primary end point.

Cited by 65 publications

References 40 publications

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption

Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort

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