Abstract
1.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 multiple variant transmission is most likely, and whether methods of quantifying the number of founder variants differ in their accuracy.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 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)).InterpretationWe 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.FundingThis study was supported by the MRC Precision Medicine Doctoral Training Programme (ref: 2259239) and a ERC Starting Grant awarded to KEA (award number 757688).2.Panel: Research in contextEvidence before this studyThe majority of 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 acute 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 studyUsing meta-regression, we estimated the probability of multiple founder infections across exposure routes by accounting for variability in methodology between 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 transmission route, with the probability for female-to-male transmission significantly lower than for male-to-female transmission. By contrast, the probability for transmission among people-who-inject-drugs (PWID) was significantly higher. There was no difference in the probability of multiple founder variant transmission for mother-to-child transmission or men-who-have-sex-with-men (MSM) when compared with male-to-female.Implications of all the available evidenceBecause HIV-1 infections initiated by multiple founders are associated with a poorer prognosis, determining whether the route of infection affects the probability of transmission of multiple variants will facilitate an improved understanding of how the evolution and epidemiology of HIV-1 determine clinical progression. Our results identify that PWID 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 this vulnerable risk group.
Publisher
Cold Spring Harbor Laboratory