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 approximately 50% effective, and/or adherence is less than approximately 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.

Fig. 1.

Results from 10,000 Monte Carlo simulations of our clinical trial model using a high-risk microbicide. (A) Scatterplot of the cumulative percentage of infections prevented versus adherence. (B) Scatterplot of the percentage of infections that are resistant at the end of a 12-month trial versus adherence. Dots are color-coded according to the average time of acquiring resistance to the NNRTI contained in the microbicide (given that it is systemically absorbed): blue, <12 months; pink, between 12 and 24 months; yellow, >24 months. (C) Effect of increasing the frequency of testing on decreasing the median number of NNRTI-resistant cases that would develop during the trial and on increasing the number of tests (the red line shows the number of tests required if testing is carried out monthly).

Fig. 2.

Nonlinear response surfaces with interaction terms, constructed from data generated from our epidemic model of heterosexual transmission with high-risk NNRTI microbicides used in public health interventions. The black curve delimits the male advantage threshold (MAT), where the ratio (men to women) of the cumulative number of infections prevented (RNIP) is 1; above this curve, microbicides are more beneficial for men than for women (i.e., RNIP > 1). Response surfaces for the degree of benefit for men over women in terms of the RNIP, on a log₂ scale, are presented as a function of efficacy in protecting men against HIV infection versus efficacy in protecting women against HIV infection (A), efficacy in protecting men against HIV infection versus adherence (B), and adherence versus efficacy in protecting women against HIV infection (C). (D) Response surface for the ratio (men to women) of infections prevented per NNRTI-resistant case (on log₂ scale) as a function of the relative fitness of the NNRTI-resistant strain and efficacy of the microbicide in preventing HIV infection in women.