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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.

SUBMITTER: Wilson DP

PROVIDER: S-EPMC2447864 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCardiac involvement in HIV infected children has been frequently reported, but whether this is due to HIV infection itself or to antiretroviral treatment (ART) is unknown.MethodsThis cross sectional study involved 114 vertically-acquired HIV-infected (56 ART-naive, 58 ART-exposed) and 51 healthy children in Jakarta, Indonesia. Echocardiography was performed to measure dimensions of the left ventricle (LV) and systolic functions. We applied general linear modeling to evaluate the associations between HIV infection/treatment status and cardiac parameters with further adjustment for potential confounders or explanatory variables. Findings are presented as (adjusted) mean differences between each of the two HIV groups and healthy children, with 95% confidence intervals and p values.ResultsCompared to healthy children, ART-naïve HIV-infected children did not show significant differences in age-and-height adjusted cardiac dimensions apart from larger LV internal diameter (difference 2.0 mm, 95%CI 0.2 to 3.7), whereas ART exposed HIV infection showed thicker LV posterior walls (difference = 1.1 mm, 95%CI 0.5 to 1.6), larger LV internal diameter (difference = 1.7 mm, 95%CI 0.2 to 3.2) and higher LV mass (difference = 14.0 g, 7.4 to 20.5). With respect to systolic function, reduced LV ejection fraction was seen in both ART-naïve HIV infected (adjusted difference = -6.7%, -11.4 to -2.0) and, to a lesser extent, in ART-exposed HIV infected children (difference = -4.5%, -8.5 to -0.4). Inflammation level seemed to be involved in most associations in ART-exposed HIV-infected, but few, if any, for decreased function in the ART-naive ones, whereas lower hemoglobin appeared to partially mediate chamber dilation in both groups and reduced function, mainly in ART-exposed children.ConclusionsART-naive HIV infected children have a substantial decrease in cardiac systolic function, whereas the ART-exposed have thicker ventricular walls with larger internal diameter and higher mass, but less functional impairment.

Project description:UNLABELLED:Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based "universal" placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of Lactobacillus spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by Lactobacillus spp., particularly L. crispatus, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates. IMPORTANCE:Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low in vivo efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.

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

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