Modelling the evolution of HIV-1 virulence in response to imperfect therapy and prophylaxis

Average HIV-1 virulence appears to have evolved in different directions in different host populations since antiretro- viral therapy first became available, and models predict that HIV drugs can select for either higher or lower virulence, depending on how treatment is administered. However, HIV virulence evolution in response to ‘leaky’ therapy (treat- ment that imperfectly suppresses viral replication) and the use of preventive drugs (pre-exposure prophylaxis) has not been explored. Using adaptive dynamics, we show that higher virulence can evolve when antiretroviral therapy is im- perfectly effective, and that this evolution erodes some of the long-term clinical and epidemiological benefits of HIV treatment. The introduction of pre-exposure prophylaxis greatly reduces infection prevalence, but can further amplify virulence evolution when it, too, is leaky. Increasing the uptake rate of these imperfect interventions increases selection for higher virulence, and can lead to counterintuitive increases in infection prevalence in some scenarios. Although populations almost always fare better with access to interventions than without, untreated individuals could experi- ence particularly poor clinical outcomes when virulence evolves. These findings predict that antiretroviral drugs may have underappreciated evolutionary consequences, but that maximizing drug efficacy can prevent this evolutionary response. We suggest that HIV virulence evolution should be closely monitored as access to interventions continues to improve.