Using phylodynamics to inform and evaluate HIV public health interventions across three distinct epidemics

Abstract

Over 40 years on, progress towards ending the HIV/AIDS pandemic is slowing rather than accelerating. HIV molecular epidemiology tools, including phylogenetic, phylodynamic, and phylogeographic analyses have proven increasingly useful in public health planning, including in advising public health authorities and evaluating interventions. In this thesis, I apply phylodynamic and phylogeographic analyses to assess the impact of HIV public health interventions and inform public health responses across three diverse settings: a generalised epidemic in sub-Saharan Africa, a national epidemic in Kazakhstan, and a localised outbreak in Glasgow, Scotland.

In the first study I used HIV sequences obtained from dried blood spots to detect HIV transmission clusters within a universal test-and-treat trial in East Africa. Using partial gag and pol HIV-1 consensus sequences collected between 2013 and 2017 from 745 trial participants, I identified putative transmission clusters arising after the start of the trial with Bayesian time-calibrated phylogenies. The identification of trial-incident, within-community transmissions revealed the role of unsuppressed individuals in sustaining the epidemic in both arms of a universal test-and-treat trial setting, highlighting the need to improve delivery and adherence to up-to-date therapy recommendations to halt HIV transmission.

In the second study I focused on the HIV epidemic in Kazakhstan, a middle-income country in Central Asia that is experiencing a rapidly growing HIV epidemic. I used 968 partial HIV-1 pol sequences collected between 2017 and 2020 from people living with HIV across all regions of Kazakhstan to characterise the epidemic. I quantified levels of drug resistance within the study sample, identified distinct frequencies of drug resistant mutations among the two main viral subtypes, A6 and CRF02_AG, and carried out phylodynamic and phylogeographic analyses to elucidate the evolutionary history of the HIV epidemic in Kazakhstan and infer the routes of introduction of the two HIV subtypes into the country. Phylodynamic analysis revealed similar growth dynamics for both subtypes despite differences in the timing of the introduction of each one. Phylogeographic analyses inferred differences in the introduction and spread of A6 and CRF02_AG into Kazakhstan, although uncertainty in the inferences was high and differed depending on the subsampling strategy employed, cautioning against the bias that can be introduced into phylogeographic analyses in this setting.

In the third study I evaluated the impact of the COVID-19 pandemic on continued transmission of HIV subtype C among people who inject drugs in Glasgow, Scotland. Using partial HIV- 1 pol consensus sequences collected between 2005 and 2022 from the 217 individuals phylogenetically linked to the outbreak, and a subset of near full-length genomes, I performed a phylodynamic analysis to reconstruct the HIV effective population size among individuals linked to the outbreak before and after (a) the introduction of targeted interventions to control the outbreak and (b) the introduction of COVID-19 lockdown measures in the UK. Additionally, I inferred a transmission tree from the phylogeny to estimate the number of unsampled cases linked to the outbreak. Finally, I performed a continuous phylogeographic analysis to quantify the spatiotemporal diffusion of the outbreak, which is presented in this thesis in an anonymised, discretised manner to avoid risks of deductive disclosure. These results were used to directly support the understanding of the HIV outbreak by public health authorities, informing a focused public health response.

Overall, this thesis provides three distinct examples of the use of molecular epidemiology tools applied to aiding HIV public health responses, highlighting differences in the state of the HIV/AIDS pandemic worldwide and the need for targeted public health interventions.