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The promises and challenges of pre-exposure prophylaxis as part of the emerging paradigm of combination HIV prevention.

ABSTRACT: Towards the end of the twentieth century, significant success was achieved in reducing incidence in several global HIV epidemics through ongoing prevention strategies. However, further progress in risk reduction was uncertain. For one thing, it was clear that social vulnerability had to be addressed, through research on interventions addressing health systems and other structural barriers. As soon as antiretroviral treatment became available, researchers started to conceive that antiretrovirals might play a role in decreasing either susceptibility in uninfected people or infectiousness among people living with HIV. In this paper we focus on the origin, present status, and potential contribution of pre-exposure prophylaxis (PrEP) within the combination HIV prevention framework.After a phase of controversy, PrEP efficacy trials took off. By 2015, daily oral PrEP, using tenofovir alone or in combination with emtricitabine, has been proven efficacious, though efficacy seems heavily contingent upon adherence to pill uptake. Initial demonstration projects after release of efficacy results have shown that PrEP can be implemented in real settings and adherence can be high, leading to high effectiveness. Despite its substantial potential, beliefs persist about unfeasibility in real-life settings due to stigma, cost, adherence, and potential risk compensation barriers.The strategic synergy of behavioural change communication, biomedical strategies (including PrEP), and structural programmes is providing the basis for the combination HIV prevention framework. If PrEP is to ever become a key component of that framework, several negative beliefs must be confronted based on emerging evidence; moreover, research gaps regarding PrEP implementation must be filled, and appropriate prioritization strategies must be set up. Those challenges are significant, proportional to the impact that PrEP implementation may have in the global response to HIV.

SUBMITTER: Caceres CF

PROVIDER: S-EPMC4509895 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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The promises and challenges of pre-exposure prophylaxis as part of the emerging paradigm of combination HIV prevention.

Cáceres Carlos F CF Koechlin Florence F Goicochea Pedro P Sow Papa-Salif PS O'Reilly Kevin R KR Mayer Kenneth H KH Godfrey-Faussett Peter P

Journal of the International AIDS Society 20150720 4 Suppl 3

<h4>Introduction</h4>Towards the end of the twentieth century, significant success was achieved in reducing incidence in several global HIV epidemics through ongoing prevention strategies. However, further progress in risk reduction was uncertain. For one thing, it was clear that social vulnerability had to be addressed, through research on interventions addressing health systems and other structural barriers. As soon as antiretroviral treatment became available, researchers started to conceive ...[more]

PMID: 26198341

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Project description:There are 34 million people living with human immunodeficiency virus (HIV) worldwide and each year this number increases. Until a vaccine is discovered, the prevention of new HIV infections remains an urgent priority. Several trials studying the use of oral and topical agents for the prevention of HIV infection have already been completed. Adherence has proved to be a major challenge in achieving product efficacy.To provide the clinical pharmacist with an understanding of the oral pre-exposure prophylaxis (PrEP) and topical microbicide product pipeline whilst emphasizing the critical importance of adherence to these drugs to avert HIV infection.PubMed/Medline and the web-based clinical trials registry (ClinTrials.gov) were searched using appropriate key words. For the time period 1992-2013--all phase II and phase III safety and effectiveness studies--testing agents for prevention of HIV infection were included in the review. Efficacy estimates, adherence estimates and reported challenges with adherence were extracted.Twenty-four phase II and III clinical trials were found during review. Of these, 20 trials have been completed, and six trials show effectiveness in preventing HIV infection. The majority of the successful trials were to oral PrEP and to date only one microbicide trial of a vaginal antiretroviral microbicide gel has showed effectiveness. Adherence to study product played a major role in trial outcomes and there are several reasons for non-adherence. These include high on-trial pregnancy rates, low trial retention rates, low participant perception of risk, participant characteristics such as age <25 years, single status, migratory partners and trial fatigue. Study product characteristics such as dosage form, dosing interval, as well as associated adverse events may also influence adherence.Moderate to high adherence is critical to demonstrate efficacy of drugs for HIV prevention. For topical agents, intermittent use associated with coitus is more effective than daily use, particularly if sex is infrequent or partners migrant. For oral agents, daily use is effective but the motivation to use the drug and high risk perception is important. In serodiscordant couples, early initiation of highly active antiretroviral therapy in the infected partner affords almost complete protection to the negative partner. Drugs need to be tailored to the population at risk and availability of multiple drug options are important.

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.

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The promises and challenges of pre-exposure prophylaxis as part of the emerging paradigm of combination HIV prevention.

Publications

The promises and challenges of pre-exposure prophylaxis as part of the emerging paradigm of combination HIV prevention.

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