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Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review.

ABSTRACT: Despite significant efforts, the rate of new HIV infections worldwide remains unacceptably high, highlighting the need for new HIV prevention strategies. HIV pre-exposure prophylaxis (PrEP) is a new approach that involves the ongoing use of antiretroviral medications by HIV-negative individuals to reduce the risk of HIV infection. The use of daily tenofovir/emtricitabine as oral PrEP was found to be effective in multiple placebo-controlled clinical trials and approved by the United States Food and Drug Administration. In addition, the Centers for Disease Control and Prevention in the United States and the World Health Organization have both released guidelines recommending the offer of oral PrEP to high-risk populations. The scale-up of PrEP is underway, but several implementation questions remain unanswered. Demonstration projects and open-label extensions of placebo-controlled trials are ongoing and hope to contribute to our understanding of PrEP use and delivery outside the randomized controlled trial setting. Evidence is beginning to emerge from these open-label studies and will be critical for guiding PrEP scale-up. Outside of such studies, PrEP uptake has been slow and several client- and provider-related barriers are limiting uptake. Maximizing the public health impact of PrEP will require rollout to be combined with interventions to promote uptake, support adherence, and prevent increases in risk behavior. Additional PrEP strategies are currently under investigation in placebo-controlled clinical trials and may be available in the future.

SUBMITTER: Wilton J

PROVIDER: S-EPMC4422285 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review.

Wilton James J Senn Heather H Sharma Malika M Tan Darrell Hs DH

HIV/AIDS (Auckland, N.Z.) 20150428

Despite significant efforts, the rate of new HIV infections worldwide remains unacceptably high, highlighting the need for new HIV prevention strategies. HIV pre-exposure prophylaxis (PrEP) is a new approach that involves the ongoing use of antiretroviral medications by HIV-negative individuals to reduce the risk of HIV infection. The use of daily tenofovir/emtricitabine as oral PrEP was found to be effective in multiple placebo-controlled clinical trials and approved by the United States Food a ...[more]

PMID: 25987851

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Project description:IntroductionGiven the synergistic relationship between HIV and sexually transmitted infections (STI), the integration of services has the potential to reduce the incidence of both HIV and STIs. We explored the extent to which STI testing has been offered within HIV pre-exposure prophylaxis (PrEP) programmes worldwide.MethodsWe conducted a systematic review of PrEP programmes implementing STI testing services in nine databases. We approached PrEP implementers for additional unpublished data and implementation details. Descriptive statistics were used to present the characteristics of STI testing within PrEP programmes. Content analysis of the input from PrEP implementers was conducted to summarize the barriers to and facilitators of STI testing.ResultsOf 9,161 citations, 91 studies conducted in 32 countries were included: 69% from high-income countries (HICs) and 64% from programmes targeting men who have sex with men (MSM) and transgender women (TGW) only. The majority of programmes (70%, 64/91) conducted STI testing before the initiation of PrEP. The most common STIs tested were gonorrhoea (86%, 78/91), chlamydia (84%, 76/91) and syphilis (84%, 76/91). The majority provided STI testing at three-month intervals (70%, 53/76, for syphilis; 70% 53/78, for chlamydia; 68%, 53/78, for gonorrhoea). Relative to low- and middle-income countries (LMICs), a higher proportion of PrEP programmes in HICs offered testing for gonorrhoea (92% vs. 71%, p < 0.05), chlamydia (92% vs. 64%, p < 0.01), syphilis (87% vs. 75%, p < 0.05), hepatitis A (18% vs. 4%, p < 0.05) and hepatitis C (43% vs. 21%, p < 0.05); offered testing for a higher number of STIs (mean 3.75 vs. 3.04, p < 0.05); and offered triple (throat, genital/urine and anorectal) anatomical site screening (54% vs. 18%, p < 0.001). Common implementation challenges included costs, access to STI diagnostics, programme logistics of integrating STI testing into PrEP delivery models and lack of capacity building for staff involved in PrEP provision.ConclusionsSignificant gaps and challenges remain in the provision of STI testing services within HIV PrEP programmes. We recommend more active integration of STI testing and management into PrEP programmes, supported by standardized practice guidelines, staff capacity building training and adequate funding. This could lead to improved sexual health and HIV outcomes in key populations.

Project description:Pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for preventing the transmission of HIV. Although only one formulation is currently approved for PrEP, research into both new compounds and new delivery systems for PrEP regimens offer intriguing challenges from the perspective of pharmacokinetic and pharmacodynamic modeling. This review aims to provide an overview the current modeling landscape for HIV PrEP, focused on PK/PD and QSP models relating to antiretroviral agents. Both current PrEP treatments and new compounds that show promise as PrEP agents are highlighted, as well as models of uncommon administration routes, predictions based on models of mechanism of action and viral dynamics, and issues related to adherence to therapy. The spread of human immunodeficiency virus (HIV) remains one of the foremost global health concerns. In the absence of a vaccine, other prophylactic strategies have been developed to prevent HIV transmission. One approach, known as pre-exposure prophylaxis (PrEP), allows HIV-negative individuals who are at high risk of exposure to the virus, be it through an HIV-positive sexual partner or through the shared use of drug injection equipment, to substantially reduce the risk of developing an HIV infection. PrEP is a relatively recent approach to combating the HIV epidemic, with the only currently approved treatment being Truvada, a daily oral antiretroviral (ARV) therapy initially indicated in the treatment of active HIV-1 infections, but approved for HIV PrEP in 2012. Although PrEP therapy has consistently demonstrated high efficacy in preventing HIV infection, this efficacy is dependent on patient adherence to the prescribed treatment regimen. This can present a significant problem in low- and middle-income countries, which may lack the infrastructure to provide sufficient access to PrEP medication to maintain daily dosing regimens. Furthermore, while the conventional approach has generally been to advocate for continuous administration akin to regimens used for viral suppression in infected patients, there has been some discussion of whether a better treatment paradigm might be to push for PrEP therapy primarily during those known periods of heightened exposure risk, while relying on post-exposure prophylaxis regimens to prevent infection after unanticipated exposures during low-risk periods. These considerations have led to a push for the development of long-duration and on-demand PrEP formulations, including subdermal and subcutaneous implants, slow-release intramuscular depot injections, vaginal and rectal antimicrobial gels, and intravaginal rings and dissolving films. PrEP therapy is a quickly evolving field, with a variety of antiretroviral compounds and formulations under investigation. This review aims to report on notable drugs and formulations from a pharmacokinetic/pharmacodynamic (PK/PD) modeling perspective. Given the nature of PrEP as a preventive therapy designed for long-term use, clinical trials for PrEP therapies can last for months or even years, particularly in the case of long-duration formulations. Furthermore, in contrast to antiretroviral trials in infected patients, pharmacodynamic endpoints in PrEP therapies are difficult to quantify, as the primary endpoint for efficacy is generally the rate of seroconversion. Computational modeling approaches offer flexible and powerful tools to provide insight into drug behavior in clinical settings, and can ultimately reduce the time, expense, and patient burden incurred in the development of PrEP therapies.

Project description:Women in Africa face disproportionate risk of human immunodeficiency virus (HIV) acquisition, accounting for more than half of new infections in Africa and similarly face a disproportionate burden of sexually transmitted infections (STIs). Very high STI prevalence is being observed globally, especially among people taking pre-exposure prophylaxis (PrEP) for HIV prevention. Doxycycline post-exposure prophylaxis (dPEP) has been proposed as an STI prevention strategy to reduce chlamydia, syphilis, and possibly gonorrhea, and trials are ongoing among cisgender men who have sex with men (MSM) and transgender women who are taking PrEP in high-income settings. We designed and describe here the first open-label trial to determine the effectiveness of dPEP to reduce STI incidence among cisgender women. We are conducting an open-label 1:1 randomized trial of dPEP versus standard of care (STI screening and treatment and risk-reduction counseling without dPEP) among 446 Kenyan women aged ≥ 18 and ≤ 30 years old women taking PrEP. Women are followed for 12 months, with quarterly STI testing, treatment, and adherence counseling. The primary trial outcome will be the combined incidence of Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, compared between the randomized groups. We will also assess dPEP acceptability, tolerability, safety, impact on sexual behavior, adherence, and occurrence of antimicrobial resistance (AMR) in N. gonorrhoeae and C. trachomatis isolates. Finally, we will estimate cost per incident STI case and complications averted accounting for nonadherence and benefits relative AMR or side effects. The results of this trial may have immediate implications for the global epidemic of STIs and sexual health. If effective, dPEP could put STI prevention into women's hands. While dPEP may be able to prevent STIs, it carries important risks that could counter its benefits; global debate about the balance of these potential risks and benefits requires data to inform policy and implementation and our study aims to fill this gap. ClinicalTrials.gov NCT04050540 .

Project description:Tenofovir diphosphate (TFV-DP) concentrations measured with dried blood spots (DBS) can be used to classify adherence to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). A TFV-DP of 700 fmol/punch was previously associated with high PrEP efficacy, and was estimated to represent ≥4 doses/week on average. However, interindividual variability in TFV-DP concentrations may lead to adherence misclassification and decrease the precision of adherence-efficacy relationships. The purpose of this analysis was to evaluate sources of TFV-DP variability to improve the precision of TFV-DP for adherence assessments by incorporating individual characteristics. Data and samples from a 36-week study of TFV-DP in DBS, collected biweekly, among 48 HIV-negative volunteers (25 Females/26 Caucasian/10 African American/14 Hispanic) receiving F/TDF at 33%, 67%, and 100% of daily dosing under directly observed therapy were used for analysis. The simplest pharmacokinetic model to describe TFV-DP accumulation with acceptable performance was a one-compartment constant input model. Covariates, including laboratory values and demographics were ranked in importance of their association with post hoc pharmacokinetic (PK) parameters using random forest analyses. Weight and platelet count were included in the final model and simulations were conducted to generate benchmarks for <2, 2-3, 4-5, and 6-7 doses/week. Based on these simulations, the previously established protective TFV-DP concentration of ≥700 fmol/punch was observed in those taking 2-3 (in individuals ≤110 kg) and ≥4 (in individuals >110 kg) doses/week, amounting to a much lower rate of misspecification (17% vs. 30%) with this individualized model versus previous interpretations. Incorporating body weight and platelet count improved the precision of TFV-DP concentrations for adherence assessments. Previous benchmarks were conservative, indicating that the pharmacological forgiveness of F/TDF may be higher than currently recognized and supports continued investigation of intermittent PrEP dosing regimens. Clinical Trial Registration number, NCT02022657.

Dataset Information

Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review.

Publications

Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review.

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