Liposomes for HIV prophylaxis.
Ontology highlight
ABSTRACT:
SUBMITTER: Malavia NK
PROVIDER: S-EPMC3263404 | biostudies-literature | 2011 Nov
REPOSITORIES: biostudies-literature
Publications
Liposomes for HIV prophylaxis.
Malavia Nikita K NK Zurakowski David D Schroeder Avi A Princiotto Amy M AM Laury Anna R AR Barash Hila E HE Sodroski Joseph J Langer Robert R Madani Navid N Kohane Daniel S DS
Biomaterials 20110908 33
There are approximately 33.4 million adults living with HIV worldwide of which an estimated 15.7 million are women. Although there has been enormous progress in the therapy of HIV/AIDS, treatment is not curative. Prevention is therefore of paramount importance, but vaccine-based and microbicidal approaches are still in their infancy. Since women acquire the virus largely through sexual intercourse, we developed liposomal systems potentially suitable for intra-vaginal use to prevent HIV-1 infecti ...[more]
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Project description: Not available
| S-EPMC9833205 | biostudies-literature
Project description:HIV-testing algorithms for preexposure prophylaxis (PrEP) should be optimized to minimize the risk of drug resistance, the time off PrEP required to evaluate false-positive screening results, and costs and to expedite the start of therapy for those confirmed to be infected. HIV rapid tests (RTs) for anti-HIV antibodies provide results in less than 1 h and can be conducted by nonlicensed staff at the point of care. In many regions, Western blot (WB) testing is required to confirm reactive RT results. WB testing, however, causes delays in diagnosis and adds expense. The iPrEx study evaluated the safety and efficacy of daily oral emtricitabine-tenofovir disoproxil fumarate among HIV-seronegative men and transgender women who have sex with men: HIV infection was assessed with two RTs plus WB confirmation, followed by HIV-1 plasma viral load testing. During the iPrEx study, there were 51,260 HIV status evaluations among 2,499 volunteers using RTs: 142 (0.28%) had concordant positive results (100% were eventually confirmed) and 19 (0.04%) had discordant results among 14 participants; 11 were eventually determined to be HIV infected. A streamlined approach using only one RT to screen and a second RT to confirm (without WB) would have had nearly the same accuracy. Discrepant RT results are best evaluated with nucleic acid testing, which would also increase sensitivity.
| S-EPMC4290918 | biostudies-literature
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.
| S-EPMC7005100 | biostudies-literature
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| S-EPMC4216036 | biostudies-other
Project description:The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for HIV-1. By contrast, small molecule inhibitors of the HIV-1 enzymes reverse transcriptase, integrase, and protease have been developed that effectively block virus replication. Three different drug compounds are commonly prescribed for people living with HIV as once-daily oral tablets. Once-daily pills composed of two different reverse transcriptase inhibitors are moreover approved as preexposure prophylaxis (PrEP) treatment for virus naïve individuals who may partake in behaviors associated with increased risk of HIV-1 acquisition such as unprotected sex or injection drug use. Long-acting (LA) injectable HIV-1 enzyme inhibitors are at the same time being developed to sidestep adherence noncompliance issues that can arise from self-administered once-daily oral dosing regimens. Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors. In this Perspective, we examine bench to bedside aspects of CAB-LA treatment and development, starting from the biochemical basis of HIV-1 integration and pharmacological inhibition of integrase catalysis. We also review the results of recent clinical trials that evaluated CAB-LA, as well as the promises and challenges that surround its use for HIV/AIDS PrEP.
| S-EPMC8515172 | biostudies-literature
Project description:The review describes the evidence for HIV preexposure prophylaxis (PrEP) with daily combined tenofovir disoproxil fumarate and emtricitabine for adolescents and young adults. Current recommendations are described, as are the unique medical, socioeconomic, and legal considerations regarding the use of PrEP for youth.PrEP with daily oral tenofovir disoproxil fumarate-emtricitabine has been shown to help prevent new HIV infection among adults at substantial risk. Evidence suggests a protective benefit of PrEP for youth at risk for HIV, although low adherence is emerging as a barrier to effective use.Effective use of antiretrovirals for PrEP represents a seminal development in HIV prevention efforts. Improving access and adherence to PrEP for youth has the potential to substantially reduce the incidence of HIV in this population.
| S-EPMC5762125 | biostudies-other
Project description:There is increasing evidence that the use of antiretroviral agents (ARVs) can be a safe and effective means of preventing HIV infection. In fact, a combination of ARVs, tenofovir-emtricitabine, was recently approved by the US Food and Drug Administration (FDA) for use as "pre-exposure prophylaxis"(PrEP), and the US Centers for Disease Control and other regulatory authorities have issued guidance concerning PrEP use. Clinicians and policy makers are now faced with questions about the appropriateness of prescribing ARVs to healthy persons who are at risk of becoming infected with HIV, and those at risk of being infected must decide whether to use PrEP. In addition, researcher stakeholders must grapple with determining whether and how PrEP should be included in future HIV prevention research. In addressing such issues, it is important that their ethical dimensions are identified. When using PrEP, 2 broad ethical domains are of special relevance: well-being and justice. Ethical issues related to well-being include safety, parameters of use, risk behaviors, resistance, stigma, and diversion. Those related to justice include access and competing priorities. In research involving PrEP, ethical issues include determining the appropriate control arm and whether PrEP should be included as a part of the prevention package provided to all at risk participants. Although PrEP could play an important role in HIV prevention, understanding and addressing the related ethical issues is critical to its safe, effective, and appropriate use in practice and future research.
| S-EPMC3728665 | biostudies-other
Project description:BACKGROUND:Publicly funded HIV-testing sites can identify HIV preexposure prophylaxis (PrEP) candidates and provide PrEP linkage. SETTING:Harris Health System's HIV clinic, HIV-testing program, and HIV-prevention program (HPP) in Houston, TX, a high HIV-incidence city. METHODS:A prospective assessment of individuals aged 18 years and older recruited from walk-in HIV testing from December 2013 to April 2015 included risk assessment, HIV testing, and self-administered survey, with follow-up surveys at 6 and 12 months and medical record review. RESULTS:The mean age of our sample (n = 300) was 38.3 ± 11.7 years. Men constituted 63.1% of the sample and 53.7% were black non-Hispanic, 26.3% Hispanic, and 14.7% white non-Hispanic. Most were uninsured (63.5%). Only 27% always used condoms, although 67% perceived personal HIV risk. Of 300 participants, 64 (21.3%) linked to PrEP care and 49 (16.3%) took PrEP. In multivariable analysis, compared with heterosexual men, women [adjusted OR (aOR) 4.1, 95% CI: 1.5 to 11.1] and MSM (aOR 10.2, 95% CI: 3.4 to 31.0) were more likely to attend HPP and to take PrEP (aOR 3.0, 95% CI: 1.6 to 15.1 and 3.0, 95% CI: 1.1 to 8.3, respectively). Serodiscordance and PrEP interest correlated with program attendance (aOR 14.0, 95% CI: 6.1 to 32.3 and aOR 6.7, 95% CI: 1.8 to 25.4) and taking PrEP (aOR 13.1, 95% CI: 5.2 to 32.8 and 14.4, 95% CI: 1.8 to 166.9), respectively. CONCLUSIONS:Preexposure prophylaxis interest, being female or MSM, and serodiscordance correlated with PrEP linkage. Safety-net health systems can facilitate PrEP access in marginalized populations, but the PrEP initiation rates remain low.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity, where insulin resistance and hepatocyte fat deposition may progress to steatohepatitis (NASH) and fibrosis/ cirrhosis. NASH has no approved treatment. Consequent upon hepatic fat deposition, NF-κB activation in hepatic myeloid cells mediates inflammation and NASH progression. We delivered micro-doses of liposome-encapsulated lipophilic NF-κB inhibitors, curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol), to the pro-fibrogenic inflammatory liver macrophages and dendritic cells (DCs) in diet-induced NASH. After i.v. administration, liver was the primary organ targeted. MHC class-II+ hepatic DCs taking up liposomes in mice and human were F4/80+ and CD14+ respectively, were lipid-laden and expressed pro-inflammatory genes. Curcumin or calcitriol liposomes suppressed hepatic inflammation, fibrosis and fat accumulation, and reduced insulin resistance associated with suppression of immune activation, cell cycle and collagen deposition pathways in vivo. Thus, hepatic inflammatory DCs passively targeted with liposomes encapsulating lipophilic NF-κB inhibitors are beneficial in NASH.
2020-01-22 | GSE94592 | GEO
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.
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