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Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis

By James Baxter, Sarah Langhorne, Ting Shi, Damien C. Tully, Christian Julian Villabona Arenas, Stephane Hue, Jan Albert, Andrew Leigh Brown, Katherine Elizabeth Atkins

Posted 18 Jul 2021
medRxiv DOI: 10.1101/2021.07.14.21259809

Background HIV-1 infections that are initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis, yet little is known about the routes of exposure through which multiple variant transmission is most likely, and whether methods of quantifying the number of founder variants differ in their accuracy. Methods We conducted a systematic review of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, EMBASE and Global Health databases for papers published between 1st January 1990 and 14th September 2020 (PROSPERO study CRD42020202672). Leveraging individual patient estimates from these studies, we performed a logistic meta-regression to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across nine transmission routes in a univariate analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the nine transmission routes. Findings We included 71 publications in our analysis, comprising 1664 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0.25 (95% CI: 0.21-0.30), with moderate heterogeneity (Q=137.1, p<.001, I2=65.3%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by transmission route. Relative to a baseline of male-to-female transmission , the probability for female-to-male multiple variant transmission was significantly lower at 0.10 (95% CI: 0.05-0.21), while the probability for people-who-inject-drugs (PWID) transmission was significantly higher at 0.29 (0.13-0.52). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0.16 (0.08-0.29)), post-partum mother-to-child (0.12 (0.02-0.51)), pre-partum mother-to-child (0.13 (0.05-0.32)), intrapartum mother-to-child (0.21 (0.08-0.44)) and men-who-have-sex-with-men (MSM) transmission (0.23 (0.03-0.7)). Interpretation We identified PWID transmissions are significantly more likely to result in an infection initiated by multiple founder variants, whilst female-to-male infections are significantly less likely. Quantifying how the routes of HIV infection impact the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine the clinical picture. Funding This study was supported by the MRC Precision Medicine Doctoral Training Programme (ref: 2259239) and a ERC Starting Grant awarded to KEA (award number 757688).

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