Anti-Retroviral–Based HIV Pre-Exposure Prophylaxis for Women: Recent Advances and Next Steps

There is a daunting challenge to prevent human immunodeficiency virus (HIV) acquisition in women at high risk of acquiring HIV. Of the 37 million people globally living with HIV, more than half are women. Women account for nearly 60% of adults with HIV in sub-Saharan Africa, where unprotected heterosexual sex is the primary driver of the epidemic. While male condoms are effective, they are not always used, and this is not something women can control. Women urgently need prevention tools they can decide to use, independent of a husband or partner. Pre-exposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral (ARV) medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. We review recent advances in the development of new biomedical HIV prevention interventions with a highlight of findings from pivotal clinical trials, as well as a discussion on future generation strategies for women

Transient Increase in Herpes Simplex Virus Type 2 (HSV-2)-Associated Genital Ulcers Following Initiation of Antiretroviral Therapy in HIV/HSV-2-Coinfected Individuals

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected persons beginning antiretroviral therapy (ART) has been incompletely characterized for herpes simplex virus type 2 (HSV-2). METHODS: We evaluated genital ulcer disease (GUD) and HSV-2-associated GUD at quarterly visits or when spontaneously reported at monthly visits in 3381 HIV/HSV-2-coinfected individuals in a placebo-controlled trial of suppressive acyclovir therapy to prevent HIV transmission, 349 of whom initiated ART during the study. Incidence was calculated for months before and after ART initiation, and incidence rate ratios (IRRs) were calculated. RESULTS: GUD incidence increased from 15.0 episodes per 100 person-years before ART to 26.9 episodes per 100 person-years in the first full quarter after ART initiation (IRR, 1.83;P= .03), and the incidence of HSV-2-associated GUD increased from 8.1 to 19.0 episodes per 100 person-years (IRR, 2.20;P= .02). Subsequently, the incidence of GUD was similar to that before ART, although the numbers were small. Persons receiving suppressive acyclovir had fewer GUD episodes, but the IRR after beginning ART was similar in the acyclovir and placebo groups. CONCLUSIONS: Initiation of ART in HIV/HSV-2-coinfected persons is associated with a transient increase in GUD and HSV-2 GUD. Acyclovir reduces the incidence of GUD but does not prevent an increase in GUD incidence during the first quarter following initiation of ART

Circumcision of Male Children for Reduction of Future Risk for HIV: Acceptability among HIV Serodiscordant Couples in Kampala, Uganda

The ultimate success of medical male circumcision for HIV prevention may depend on targeting male infants and children as well as adults, in order to maximally reduce new HIV infections into the future.We conducted a cross-sectional study among heterosexual HIV serodiscordant couples (a population at high risk for HIV transmission) attending a research clinic in Kampala, Uganda on perceptions and attitudes about medical circumcision for male children for HIV prevention. Correlates of willingness to circumcise male children were assessed using generalized estimating equations methods.318 HIV serodiscordant couples were interviewed, 51.3% in which the female partner was HIV uninfected. Most couples were married and cohabiting, and almost 50% had at least one uncircumcised male child of ≤18 years of age. Overall, 90.2% of male partners and 94.6% of female partners expressed interest in medical circumcision for their male children for reduction of future risk for HIV infection, including 79.9% of men and 87.6% of women who had an uncircumcised male child. Among both men and women, those who were knowledgeable that circumcision reduces men's risk for HIV (adjusted prevalence ratio [APR] 1.34 and 1.14) and those who had discussed the HIV prevention effects of medical circumcision with their partner (APR 1.08 and 1.07) were significantly (p≤0.05) more likely to be interested in male child circumcision for HIV prevention. Among men, those who were circumcised (APR 1.09, p = 0.004) and those who were HIV seropositive (APR 1.09, p = 0.03) were also more likely to be interested in child circumcision for HIV prevention.A high proportion of men and women in Ugandan heterosexual HIV serodiscordant partnerships were willing to have their male children circumcised for eventual HIV prevention benefits. Engaging both parents may increase interest in medical male circumcision for HIV prevention

Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention: prospective studies in HIV-uninfected men and women

Thesis (Ph.D.)--University of Washington, 2016-06Antiretroviral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) alone or when co-formulated with emtricitabine (FTC), the same medication used for treatment of HIV infection, is a recommended and highly effective strategy to reduce the risk of sexual acquisition of HIV. The central objective of the studies described in this dissertation was to quantify the risk of potential off-target safety signals associated with TDF-based PrEP use in HIV-uninfected men and women with the overarching goal of providing the evidence base for clinical practice guidelines to accelerate population level delivery of PrEP to fight the global HIV epidemic. The specific aims include to: 1) determine whether TDF-based PrEP causes clinically significant decline in glomerular filtration rate (eGFR), a commonly used-measure of overall kidney function, in HIV-uninfected men and women; 2) determine whether TDF-based PrEP causes proximal tubular dysfunction when used as PrEP and whether proximal tubular dysfunction is associated with clinically relevant decline eGFR; 3) quantify infant exposure to tenofovir and emtricitabine via maternal breast milk when used as PrEP by lactating HIV-uninfected women; 4) determine whether open-label PrEP use for HIV prevention is associated with reduction in safer sex practices (i.e., sexual risk compensation); and 5) review and summarize the totality of empirical literature on the TDF-induced off-target effects when use as PrEP. Findings: Effect of TDF-based PrEP on eGFR: In a large randomized, placebo-controlled trial of daily oral TDF and FTC-TDF PrEP among 4640 heterosexual persons, with median per-protocol follow-up of 18 months and maximum follow-up of 36 months, PrEP resulted in a small but non-progressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (≥25%) eGFR decline. The decline quickly resolves within weeks after TDF discontinuation. Effect of FTC-TDF PrEP on proximal tubular dysfunction: In a randomized, placebo-controlled comparison among >1500 HIV-uninfected men and women, FTC-TDF PrEP was not associated with increased risk for proximal tubular dysfunction up to 24 months nor was proximal tubular dysfunction associated with clinically relevant decline in eGFR. Infant exposure to PrEP via breastfeeding: Among lactating women using FTC-TDF PrEP during early postpartum, the estimated infant doses received from breastfeeding and the resultant infant plasma concentrations for both tenofovir and emtricitabine are 12500- and >200-fold below the respective proposed pediatric doses used for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection and tenofovir was unquantifiable in a majority of infant plasma samples, suggesting that PrEP can be safely used during breastfeeding with minimal infant drug exposure. Sexual risk compensation: The transition from a double-blinded, placebo-controlled phase to one in which all participants were aware that they were receiving active, effective PrEP in the Partners PrEP Study, provided a natural experiment to assess behavioral risk compensation. PrEP given as part of a comprehensive HIV prevention package, did not result in substantial changes in risk-taking sexual behavior by heterosexual couples. Summary of current empirical literature: TDF-based PrEP is generally safe and well tolerated in HIV-uninfected men and women, and infant exposure via breastfeeding is minimal. The risk of the small, non-progressive, and reversible decline in eGFR and bone mineral density as well as the potential for selection of drug resistant viral mutation associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP’s substantial reduction in the risk of HIV infection. These data support the safety of TDF-based PrEP for prevention HIV combination with safer sex practices

Correlates of willingness to circumcise male children for reduction of future risk for HIV.

<p>*Row percentages displayed; APR adjusted prevalence ratios.</p>†<p>Addition of age, religion, education level, and place of residence did not substantially affect estimates from the multivariable models.</p

Preferred age for medical circumcision of male children stratified by the parent's gender.

<p>Preferred age for medical circumcision of male children stratified by the parent's gender.</p