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      Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model

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          Abstract

          Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF 2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques ( N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d -1) for the two formulations over 30 days ranged as follows: TAF 2 0.35–0.40; ACV 0.56–0.70; EE 0.03–0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL -1 prior to IVR insertion and 0.075 ± 0.064 ng mL -1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF 2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg -1; ACV, 0.2 ng mg -1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women’s sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

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          Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies.

          To estimate the sex-specific effect of herpes simplex virus type 2 (HSV-2) on the acquisition of HIV infection. The increased number of longitudinal studies available since the last meta-analysis was published allows for the calculation of age- and sexual behaviour-adjusted relative risks (RR) separately for men and women. Systematic review and meta-analysis of longitudinal studies. PubMed, Embase and relevant conference abstracts were systematically searched to identify longitudinal studies in which the relative timing of HSV-2 infection and HIV infection could be established. Where necessary, authors were contacted for separate estimates in men and women, adjusted for age and a measure of sexual behaviour. Summary adjusted RR were calculated using random-effects meta-analyses where appropriate. Studies on recent HSV-2 incidence as a risk factor for HIV acquisition were also collated. Of 19 eligible studies identified, 18 adjusted for age and at least one measure of sexual behaviour after author contact. Among these, HSV-2 seropositivity was a statistically significant risk factor for HIV acquisition in general population studies of men [summary adjusted RR, 2.7; 95% confidence interval (CI), 1.9-3.9] and women (RR, 3.1; 95% CI, 1.7-5.6), and among men who have sex with men (RR, 1.7; 95% CI, 1.2-2.4). The effect in high-risk women showed significant heterogeneity, with no overall evidence of an association. Prevalent HSV-2 infection is associated with a three-fold increased risk of HIV acquisition among both men and women in the general population, suggesting that, in areas of high HSV-2 prevalence, a high proportion of HIV is attributable to HSV-2.
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            Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review.

            Information on age- and sex-specific prevalence of herpes simplex virus (HSV) types 2 and 1 infections is essential to optimize genital herpes control strategies, which increase in importance because accumulating data indicate that HSV-2 infection may increase acquisition and transmission of human immunodeficiency virus. This review summarizes data from peer-reviewed publications of type-specific HSV seroepidemiologic surveys. HSV-2 prevalence is, in general, highest in Africa and the Americas, lower in western and southern Europe than in northern Europe and North America, and lowest in Asia. HSV-2 and -1 prevalence, overall and by age, varies markedly by country, region within country, and population subgroup. Age-specific HSV-2 prevalence is usually higher in women than men and in populations with higher risk sexual behavior. HSV-2 prevalence has increased in the United States but national data from other countries are unavailable. HSV-1 infection is acquired during childhood and adolescence and is markedly more widespread than HSV-2 infection. Further studies are needed in many geographic areas.
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              Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

              The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Validation
                Role: Investigation
                Role: Data curationRole: InvestigationRole: MethodologyRole: SupervisionRole: Validation
                Role: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: Data curationRole: Methodology
                Role: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: MethodologyRole: Validation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 October 2017
                2017
                : 12
                : 10
                : e0185946
                Affiliations
                [1 ] Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [2 ] Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America
                [3 ] Libra Management Group, Decatur, Georgia, United States of America
                [4 ] Department of Medicine, Johns Hopkins University, Osler, Baltimore, Maryland, United States of America
                [5 ] Department of Pathology, Johns Hopkins University, Sheikh Zayed Tower, Baltimore, Maryland, United States of America
                [6 ] Wisconsin National Primate Research Center, University of Wisconsin-Madison, Capitol Court, Madison, Wisconsin, United States of America
                University of Pittsburgh, UNITED STATES
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Two authors (SE and JZ) are employees of Libra Management Group (Libra), an independent contractor that provides laboratory technicians to CDC. The contractor (Libra) has no role in the study design; collection, analysis, and interpretation of data; writing of the paper; and/or decision to submit for publication. This commercial affiliation (Libra) does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-1558-5649
                Article
                PONE-D-17-27119
                10.1371/journal.pone.0185946
                5628903
                28982161
                bb84320f-e464-4ae3-b41a-9184696100c9

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 19 July 2017
                : 21 September 2017
                Page count
                Figures: 8, Tables: 4, Pages: 22
                Funding
                This work was supported in part through institutional funds at the Oak Crest Institute of Science and the Centers for Disease Control and Prevention. Additional support was provided by the National Institute of Allergy and Infectious Diseases ( www.niaid.nih.gov) of the National Institutes of Health under Award Number U19AI113048. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Libra Management Group, a commercial company, is the employer of several authors of this manuscript (SE and JZ). The funder provided support in the form of salaries for authors (SE and JZ), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “author contributions” section.
                Categories
                Research Article
                Biology and life sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Primates
                Monkeys
                Old World monkeys
                Macaque
                Medicine and health sciences
                Public and occupational health
                Preventive medicine
                HIV prevention
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                Medicine and health sciences
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