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Harnessing nanostructured systems for improved treatment and prevention of HIV disease.

ABSTRACT: Combination antiretroviral therapy effectively controls human immunodeficiency virus (HIV) viral replication, delaying the progression to acquired immune deficiency syndrome and improving and extending quality of life of patients. However, the inability of antiretroviral therapeutics to target latent virus and their poor penetration of viral reserve tissues result in the need for continued treatment for the life of the patient. Side effects from long-term antiretroviral use and the development of drug resistance due to patient noncompliance are also continuing problems. Nanostructured systems of antiretroviral therapeutics have the potential to improve targeted delivery to viral reservoirs, reduce drug toxicity, and increase dosing intervals, thereby improving treatment outcomes and enhancing patient adherence. Despite these advantages, very few nanostructured antiretroviral delivery systems have made it to clinical trials due to challenges in preclinical and clinical development. In this context, we review the current challenges in HIV disease management, and the recent progress in leveraging the unique performance of nanostructured systems in therapeutic delivery for improved treatment and prevention of this incurable human disease.

SUBMITTER: Monroe M

PROVIDER: S-EPMC6063869 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Harnessing nanostructured systems for improved treatment and prevention of HIV disease.

Monroe Maya M Flexner Charles C Cui Honggang H

Bioengineering & translational medicine 20180501 2

Combination antiretroviral therapy effectively controls human immunodeficiency virus (HIV) viral replication, delaying the progression to acquired immune deficiency syndrome and improving and extending quality of life of patients. However, the inability of antiretroviral therapeutics to target latent virus and their poor penetration of viral reserve tissues result in the need for continued treatment for the life of the patient. Side effects from long-term antiretroviral use and the development o ...[more]

PMID: 30065966

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Project description:IntroductionEswatini achieved a 44% decrease in new HIV infections from 2014 to 2019 through substantial scale-up of testing and treatment. However, it still has one of the highest rates of HIV incidence in the world, with 14 infections per 1,000 adults 15-49 years estimated for 2017. The Government of Eswatini has called for an 85% reduction in new infections by 2023 over 2017 levels. To make further progress towards this target and to achieve maximum health gains, this study aims to model optimized investments of available HIV resources.MethodsThe Optima HIV model was applied to estimate the impact of efficiency strategies to accelerate prevention of HIV infections and HIV-related deaths. We estimated the number of infections and deaths that could be prevented by optimizing HIV investments. We optimize across HIV programs, then across service delivery modalities for voluntary medical male circumcision (VMMC), HIV testing, and antiretroviral refill, as well as switching to a lower cost antiretroviral regimen.FindingsUnder an optimized budget, prioritising HIV testing for the general population followed by key preventative interventions may result in approximately 1,000 more new infections (2% more) being averted by 2023. More infections could be averted with further optimization between service delivery modalities across the HIV cascade. Scaling-up index and self-testing could lead to 100,000 more people getting tested for HIV (25% more tests) with the same budget. By prioritizing Fast-Track, community-based, and facility-based antiretroviral refill options, an estimated 30,000 more people could receive treatment, 17% more than baseline or US$5.5 million could be saved, 4% of the total budget. Finally, switching non-pregnant HIV-positive adults to a Dolutegravir-based antiretroviral therapy regimen and concentrating delivery of VMMC to existing fixed facilities over mobile clinics, US$4.5 million (7% of total budget) and US$6.6 million (10% of total budget) could be saved, respectively.SignificanceWith a relatively short five-year timeframe, even under a substantially increased and optimized budget, Eswatini is unlikely to reach their ambitious national prevention target by 2023. However, by optimizing investment of the same budget towards highly cost-effective VMMC, testing, and treatment modalities, further reductions in HIV incidence and cost savings could be realized.

Project description:Obtaining the definitive data necessary to determine the safety and efficacy of using antiretroviral treatment (ART) to reduce the sexual transmission of HIV in heterosexual couples encountered an array of ethical challenges that threatened to compromise HIV Prevention Trials Network (HPTN) 052, the multinational clinical trial addressing this issue that has profound public health implications.To describe and analyze the major ethical challenges faced in HPTN 052.The ethical issues and modifications of HPTN 052 in response to these issues were cataloged by the principal investigator, the lead coordinator, and the ethicist working on the trial. The major ethical issues that were unique to the trial were then described and analyzed in light of the published literature as well as guidances and policies. The ethical challenges that must be addressed in many clinical trials, such as those related to obtaining informed consent and making provisions for ancillary care, are not described.When HPTN 052 was being designed, ethical questions emerged related to the relevance of the research question itself given data from observational research and a range of beliefs about the appropriate means of preventing and treating HIV infection and AIDS. Furthermore, ethical challenges were faced regarding site selection since there was a scientific need to conduct the research in settings where HIV incidence was high, but alternatives to study participation should be available. As in most HIV-prevention research, ethical questions surrounded the determination of the appropriate prevention package for all of those enrolled. During the course of the trial, guidance documents and policies emerged that were of direct relevance to the research questions, calling for a balancing of concerns for the research subjects and trial integrity. When the study results were made public, there was a need to ensure access to the treatment shown to be effective that in some cases differed from the guidelines used at the sites where the research was being conducted. In addition, questions were raised about whether there was an obligation to notify subjects about 'unlinked' transmissions of HIV, that is, infections acquired from someone other than the designated sexual partner enrolled in the study.The ethical issues described are limited to those discerned by the authors and not those of other stakeholders who may have identified additional issues or had a different perspective in analyzing them.Understanding the ethical challenges faced in HPTN 052 promises to inform the design and conduct of future complex, long-term clinical trials aimed at addressing critical scientific and public health questions, where data and practice patterns emerge over the course of the trial.

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Harnessing nanostructured systems for improved treatment and prevention of HIV disease.

Publications

Harnessing nanostructured systems for improved treatment and prevention of HIV disease.

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