The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

Abstract

Vaginal microbicides, designed to prevent HIV infection in women, are one of the most promising biomedical interventions. Clinical trials of second-generation microbicides have begun; if shown to be effective, they could be licensed within 5–10 years. Because these microbicides contain antiretrovirals (ARVs), they could be highly effective. However, there is concern that, if used by HIV-positive women, ARV resistance may evolve. By analyzing a mathematical model, we find that adherence could have both beneficial and detrimental effects on trial outcomes. Most importantly, we show that planned trial designs could mask resistance risks and therefore enable high-risk microbicides to pass clinical testing. We then parameterize a transmission model using epidemiological, clinical, and behavioral data to predict the consequences of wide-scale usage of high-risk microbicides in a heterosexual population. Surprisingly, we show that reducing a participant's risk of resistance during a trial could lead to unexpectedly high rates of resistance afterward when microbicides are used in public health interventions. We also find that, paradoxically, although microbicides will be used by women to protect themselves against infection, they could provide greater benefit to men. More infections in men than in women will be prevented if there is a high probability that ARVs are systemically absorbed, microbicides are less than ∼50% effective, and/or adherence is less than ∼60%. Men will always benefit more than women in terms of infections prevented per resistant case; but this advantage decreases as the relative fitness of drug-resistant strains increases. Interventions that use ARV-based microbicides could have surprising consequences.

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

“…It is known that lipophilic compounds have higher tissue residence times and therefore lower systemic exposure (10). The lipophilicity of IQP-0528 could similarly limit its systemic exposure when administered vaginally and therefore could be advantageous for a prophylactic antiretroviral strategy where there is concern over generating resistant viral mutants in infected individuals exposed to the gel (39).…”

Predicting the unpredictable real-world impact of ARV-based microbicides

“…A number of findings in the article by Wilson et al (1), which uses a mathematical model to examine the public health impact of widespread introduction of antiretroviral (ARV)-based microbicides, have been labeled ''surprising.'' For example, Wilson et al (1) highlight the ''paradox'' of a vaginal microbicide potentially benefiting more men than women.…”

How Much Do We Know about Drug Resistance Due to PrEP Use? Analysis of Experts' Opinion and Its Influence on the Projected Public Health Impact

“…Reduced fitness of the drug-resistant HIV Resistance carriers may be less infectious than those infected with wild-type HIV as a result of the reduced replication capacity [24,26,30,34,35,56] of the resistant HIV, which in turn can reduce the viral load. It may result in lower viral concentration that affects the likelihood of transmission.…”

“…The use of ARV as PrEP by infected individuals leads to emergence of drug resistance (acquired drug resistance, ADR) because PrEP is not designed for treatment and is unlikely to exert complete HIV suppression [24,26,30,34,35,56]. The rate of resistance emergence may depend on the consistency of PrEP use (adherence) since it controls the ARV drug concentrations and from there the pressure on the HIV virus.…”