Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis
Authors: Baxter James , Langhorne Sarah , Shi Ting , Tully Damien C. , Villabona-Arenas Ch. Julián , Hué Stéphane , Albert Jan , Leigh Brown Andrew , Atkins Katherine E. 
Published: July 2021

SummaryBackgroundHIV-1 infections 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 transmission of multiple founder variants is most likely.MethodsWe 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 univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the nine transmission routes.FindingsWe included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI: 0·21-0·29), with moderate heterogeneity (Q = 132 · 3, p < 0 · 001, I2 = 64 · 2%). 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 predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI: 0·08-0·20), while the probabilities for people-who-inject-drugs (PWID) and men-who-have-sex-with-men (MSM) transmissions were significantly higher at 0·37 (0·24-0·53) and 0·30 (0·33-0·40), respectively. There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 (0·14-0·31)), post-partum mother-to-child (0·18 (0·03-0·57)), pre-partum mother-to-child (0·17 (0·08-0·33)), intrapartum mother-to-child (0·27 (0·14-0·40)).InterpretationWe identified PWID and MSM 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 clinical outcomes.FundingThis study was supported by the MRC Precision Medicine Doctoral Training Programme (ref: 2259239) and an ERC Starting Grant awarded to KEA (award number 757688). The funding sources played no role in study design, data collection, data analysis, data interpretation, or writing of the report.Panel: Research in contextEvidence before this studyMost HIV-1 infections are initiated by a single, genetically homogeneous founder variant. Infections initiated by multiple founders, however, are associated with a significantly faster decline of CD4+ T cells in untreated individuals, ultimately leading to an earlier onset of AIDS. Through our systematic search of MEDLINE, EMBASE and Global Health databases, we identified 82 studies that classify the founder variant multiplicity of early HIV infections. As these studies vary in the methodology used to calculate the number of founder variants, it is difficult to evaluate the multiplicity of founder variants across routes of exposure.Added value of this studyWe estimated the probability that an HIV infection is initiated by multiple founder variants across exposure routes, leveraging individual patient data from 70 of the identified studies. Our multivariable meta-regression adjusted for heterogeneity across study methodology and uncovered differences in the probability that an infection is initiated by multiple founder variants by exposure route. While overall, we estimated that 25% of infections are initiated by multiple founder variants, our analysis found that this probability for female-to-male transmission is significantly lower than for male-to-female transmission. By contrast, this probability was significantly higher among people-who-inject-drugs (PWID) and men-who-have-sex-with-men (MSM). There was no difference in the probability of multiple founder variant transmission for mother-to-child transmission when compared with male-to-female sexual transmission.Implications of all the available evidenceBecause HIV-1 infections initiated by multiple founders are associated with a poorer prognosis, determining whether the route of exposure affects the probability with which infections are initiated by multiple variants facilitates an improved understanding of how the evolution and epidemiology of HIV-1 determine clinical progression. Our results identify that PWID and MSM transmissions are significantly more likely to result in an infection initiated by multiple founder variants compared to male-to-female. This reiterates the need for focussed public health programmes that reduce the burden of HIV-1 in these risk groups.