P20.04 LB
Background: Clinical trials of HIV pre-exposure prophylaxis (PrEP) have found little risk of HIV drug resistance after breakthrough infection, provided that the infection is detected and PrEP is discontinued in a timely manner. However, broad roll-out of PrEP in resource-limited settings cannot guarantee ideal monitoring for all patients. Also unknown is the transmissibility of PrEP-related drug resistance, which may differ from that of ART-related drug resistance due to transmitted founder virus dynamics.
Methods: We developed a mathematical model that links PrEP adherence to the dynamic populations of drug-sensitive and drug-resistant virus, distinguishing between replicating virus and the long-lived latent reservoir. The model was parameterized for tenofovir-based oral PrEP with viral fitness and resistance pattern data for K65R. Novel model structures were explored to study transmitter founder virus dynamics.
Results: The size and persistence of the modeled drug-resistant viral pool grew fastest during acute viremia, but continued to grow over the duration of undetected infection. After cessation of oral PrEP, the latent HIV reservoir harbored approximately double the proportion of K65R compared to the actively replicating pool. Host immunity, which influences viral load setpoint, modulated the proportion of K65R over an order of magnitude, as did patterns of adherence during PrEP use. Resistance acquired during early HIV infection could potentially elevate the transmissibility of resistance, which was seen when models assumed early establishment of a stable founder virus.
Conclusions: The need for early detection of breakthrough infections during PrEP is expected to be highly heterogeneous, with the greatest need among patients with pre-existing immune impairment. Importance of adherence-driven pharmacokinetics implies that other PrEP methods, such as microbicides, may yield very different resistance patterns. More research is needed to understand transmissibility of drug resistance acquired during PrEP.
