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Meta-Analysis
. 2024 Aug;27(8):e26349.
doi: 10.1002/jia2.26349.

The impact of analytical treatment interruptions and trial interventions on time to viral re-suppression in people living with HIV restarting ART in cure-related clinical studies: a systematic review and meta-analysis

Ming Jie Lee #  1   2 , Miles Eason #  3 , Antonella Castagna  4 , Galli Laura  5 , Marie-Angelique De Scheerder  6 , James Riley  7 , Pablo Tebas  7 , Jesper Gunst  8   9 , Ole Søgaard  8 , Eric Florence  10   11 , Eugene Kroon  12 , Mark De Souza  12 , Beatriz Mothe  13 , Marina Caskey  14 , Sarah Fidler  1
Affiliations
Meta-Analysis

The impact of analytical treatment interruptions and trial interventions on time to viral re-suppression in people living with HIV restarting ART in cure-related clinical studies: a systematic review and meta-analysis

Ming Jie Lee et al. J Int AIDS Soc. 2024 Aug.

Abstract

Introduction: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart.

Methods: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re-suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI-only groups. Random-effects proportional meta-analysis and multivariable Cox proportional hazards analysis were performed using R.

Results: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI-only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow-up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40-0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46-0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89-0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59-0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16-2.59).

Discussion: When designing studies involving ATIs, information on time to viral re-suppression after restarting ART is important to share with participants, and should be regularly monitored and reported, to assess the impact and safety of specific trial interventions in ATI studies.

Conclusions: The majority of participants achieved viral suppression after restarting ART in ATI studies. ART regimens containing integrase inhibitors and frequent VL monitoring should be offered for people restarting ART after ATI studies to ensure rapid re-suppression.

Keywords: ATI; HIV; HIV cure; antiretroviral therapy; treatment interruption; viral suppression.

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Conflict of interest statement

MJL is supported by the UK Medical Research Council Clinical Research Training Fellowship (MR/W024454/1), and has received speakers’ fees, conference from Viiv Healthcare, Gilead Sciences, and consultancy fees from Thriva Limited, external to the submitted work. EF has received grants and support for attending meetings from Viiv Healthcare and Gilead. BM has received stock options and consulting fees from AELIX Therapeutics SL, consulting fees from AbbviE, and speakers’ fees from Gilead, Janssen and Viiv Healthcare, outside the submitted work; and also participates on the data safety monitoring board for Leyden Labs. JLR is funded by the following NIH grants (NIH U19AI117950, NIH UM1AI164570) and has received stock options, royalties or licenses from Kite Pharma, BlueWhale Bio, and consulting fees from Scietemex Consulting, all external to the submitted work. JDG is supported by the Lundbeck Foundation (R381–2021–1405). All other authors have declared no conflicts of interests.

Figures

Figure 1
Figure 1
Flow chart of the study selection process.
Figure 2
Figure 2
Kaplan−Meier plot of the proportion of participants with undetectable plasma viral loads (<50 copies/ml) following ART restart after ATI (weeks). Kaplan−Meier survival plot of the proportion of participants with suppressed plasma viral load <50 copies/ml against time in weeks. The red line represents participants undergoing ATI‐only protocols, and the blue line represents participants who received an interventional study drug with ATI as part of their study protocol. The red and blue shaded areas represent the 95% confidence intervals of their respective lines. Large changes in proportions at weeks 4 and 12 reflect study protocols where monitoring was undertaken only at these times after restarting ART. The table below shows the numbers at risk at 4‐weekly intervals stratified by receipt of interventional study drug with ATI or ATI‐only protocols. Datapoints are censored past week 32. Abbreviations: ART, antiretroviral therapy; ATI, analytical treatment interruption; VL, viral load.
Figure 3
Figure 3
Forest plots of primary outcome events stratified by receipt of intervention with ATI or undergoing ATI‐only protocols. Studies are identified by the name of the first author, journal and year of publication. Primary outcome events were defined as participants who experienced viral suppression with plasma HIV viral load <50 copies/ml) by week 12 after restarting ART. Study weights (%) are from the random‐effects analysis and represented by individual box sizes. The dashed line represents the overall proportion of primary outcome events across all participants. Abbreviations: ATI, analytical treatment interruption; CI, confidence interval.
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