Extended-Release Pre-exposure Prophylaxis and Drug-Resistant HIV

Abstract

AbstractThe pharmacologic tail of long-acting cabotegravir (CAB-LA), an injectable pre-exposure prophylaxis (PrEP), allows for months-long intervals between injections, but it may facilitate the emergence of drug-resistant human immunodeficiency virus (HIV) strains during the acute infection stage. In this chapter, we present a within-host, mechanistic ordinary differential equation model of the HIV latency and infection cycle in CD4$${ }^+$$ + T-cells to investigate the impact of CAB-LA on drug-resistant mutations in both humans and macaques. We develop a pharmacokinetic/pharmacodynamic model for CAB-LA to correlate the inhibitory drug response with the drug concentration in plasma. After validating our model against experimental results, we conduct in silico trials. First, we separately administer CAB-LA to the in silico macaque and human patients before and after exposure to simian-human immunodeficiency virus (SHIV)/HIV, to observe SHIV and HIV infectivity dynamics, respectively. Although the model does not incorporate a mechanism for CAB-LA-induced HIV mutations, we analyze the outcomes when mutations occur naturally. Our findings suggest that CAB-LA may enhance the growth of drug-resistant strains over the wild-type strains during the acute stage. The in silico trials demonstrate that the effectiveness of CAB-LA against mutations and the fitness of the drug-resistant strain to infect T-cells determine the course of the mutated strain.