"Fusion and binding inhibition" key target for HIV-1 treatment and pre-exposure prophylaxis: targets, drug delivery and nanotechnology approaches.
Ontology highlight
ABSTRACT:
SUBMITTER: Malik T
PROVIDER: S-EPMC8241151 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DD Systems (DDS) currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.
| S-EPMC4879940 | biostudies-literature
Project description:Rectal pre-exposure prophylaxis (PrEP) will be a critical component of HIV prevention products due to the prevalence of unprotected receptive anal intercourse among men who have sex with men and heterosexual couples. Given the biological considerations of this compartment and the complexity of HIV infection, design of a successful rectal microbicide product faces a number of challenges. Important information is being compiled to begin to address deficits in knowledge toward design of rectal PrEP products for men and women. Aspects of formulation development and preclinical and clinical evaluation of rectal products studied to date are summarized in this review. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.
| S-EPMC3896093 | 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
Project description:IntroductionPoor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing.Areas coveredThis review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS. Technological challenges, knowledge gaps, preclinical testing considerations, and future directions important in the context of clinical translation and implementation of LA HIV PrEP are discussed.Expert opinionThe HIV prevention field is evolving faster than ever and the bar for developing next-generation LA HIV prevention options continues to rise. The requirements for viable LA PrEP products to be implemented in resource-limited settings are challenging, necessitating proactive consideration and product modifications during the design and testing of promising new candidates. If successfully translated, next-generation LA PrEP that are safe, affordable, highly effective, and accepted by both end-users and key stakeholders will offer significant potential to curb the HIV pandemic.
| S-EPMC9639748 | biostudies-literature
Project description:BackgroundPre-exposure prophylaxis (PrEP) is an effective and cost-effective strategy for HIV prevention. Spain carried out an implementation study in order to assess the feasibility of implementing PrEP programmes within its heterogeneous health system.MethodsObservational longitudinal study conducted on four different types of health-care setting: a community centre (CC), a sexually transmitted infections clinic (STIC), a hospital-based HIV unit (HBHIVU) and a hospital-based STI unit (HBSTIU). We recruited gay, bisexual and other men who have sex with men (GBSM) and transgender women at risk of HIV infections, gave them PrEP and monitored clinical, behavioural PrEP-related and satisfaction information for 52 weeks. We collected perceptions on PrEP implementation feasibility from health-care professionals participating in the study.ResultsA total of 321 participants were recruited, with 99.1% being GBMSM. Overall retention was 87.2% and it was highest at the CC (92.6%). Condom use decreased during the study period, while STIs did not increase consistently. The percentage of people who did not miss any doses of PrEP during the previous week remained at over 93%. No HIV seroconversions occurred. We observed overall decreases in GHB (32.5% to 21.8%), cocaine (27.5% to 21.4%), MDMA (25.7% to 14.3%), speed (11.4% to 5.7%) and mephedrone use (10.7% to 5.0%). The overall participant satisfaction with PrEP was 98.6%. Health-care professionals' perceptions of PrEP feasibility were positive, except for the lack of personnel.ConclusionsPrEP implementation is feasible in four types of health-care settings. Local specificities have to be taken into consideration while implementing PrEP.
| S-EPMC7870089 | biostudies-literature
Project description:As pre-exposure prophylaxis (PrEP) effectiveness is strongly linked to adherence, we sought to determine if certain self-report measures could be used to inform objective PrEP adherence. We studied participants from the TAPIR study (a multicenter randomized study of daily text messages to support adherence to PrEP In At-Risk), a 48-week randomized controlled trial of HIV-uninfected men who have sex with men (MSM) randomized to receive text message to support adherence versus standard of care. Self-reported medication adherence was assessed using several validated measures modified for PrEP. Objective PrEP adherence was determined through dried blood spot (DBS) measurement of intracellular tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP). A summary of adherence was estimated using responses to the seven adherence items at weeks 12 and 48 using confirmatory factor analysis. Correlations between self-report questions and drug concentrations were estimated with Pearson's correlations for continuous outcomes and point-biserial correlations for dichotomous outcomes. Receiver operating characteristic (ROC) analyses were conducted to assess the performance of self-report measures in predicting protective or perfect TFV-DP concentrations. Of the 369 participants who completed week 12 or 48 visits, the mean age was 35 (standard deviation 9 years), with 79% White, 12% Black, and 29% Hispanic. Correlations between self-report measures of adherence (both individual items and the adherence factor) and quantifiable FTC-TP and continuous TFV-DP concentrations showed that all self-report measures were significantly associated with these objective measures. Compared to a summary measure of self-reported adherence, the 4-week percent taken question medication recall was the only self-report item similarly or more strongly associated with recent adherence and long-term protective and perfect adherence at weeks 12 and 48. ROC analysis also showed that 4-week percent taken question had a reasonable AUC (0.798 at week 12 and 0.758 at week 48) in predicting protective TFV-DP concentrations. All single-item self-report questions assessing PrEP adherence were significantly associated with biomarker quantification, with the 4-week percent taken question performing best. Therefore, in the absence of drug concentration measurements, a 4-week self-report percent taken question may be a good single-item measure of PrEP adherence.
| S-EPMC6624646 | biostudies-literature
Project description:BACKGROUND:Despite evidence supporting pre-exposure prophylaxis (PrEP) efficacy, there are concerns regarding the feasibility of widespread PrEP implementation among men who have sex with men (MSM). To inform the development of targeted PrEP delivery guidelines, sexual risk trajectories among HIV-negative MSM were characterized. METHODS:At semiannual visits from 2003 to 2011, HIV-negative MSM (N = 419) participating in the Multicenter AIDS Cohort Study provided data on sexual risk behaviors (SRBs) since their last visit. Based on their reported behaviors, participants were assigned a SRB score at each visit as follows: 0 = no insertive or receptive anal intercourse, 1 = no unprotected insertive or receptive anal intercourse, 2 = only unprotected insertive anal intercourse, 3 = unprotected receptive anal intercourse with 1 HIV-negative partner, 4 = condom serosorting, 5 = condom seropositioning, and 6 = no seroadaptive behaviors. Group-based trajectory modeling was used to examine SRB scores (<4 vs. ?4) and identify groups with distinct sexual risk trajectories. RESULTS:Three sexual risk trajectory groups were identified: low-risk (n = 264; 63.0%), moderate-risk (n = 96; 22.9%; mean duration of consecutive high-risk intervals ?1 year), and high-risk (n = 59; 14.1%; mean duration of consecutive high-risk intervals ?2 years). Compared to low-risk group membership, high-risk group membership was associated with younger age (in years) [adjusted odds ratio (AOR) = 0.92, 95% confidence interval (CI): 0.88 to 0.96], being White (AOR = 3.67, 95% CI: 1.48 to 9.11), earning an income ?$20,000 (AOR = 4.98, 95% CI: 2.13 to 11.64), distress/depression symptoms (Center for Epidemiologic Studies Depression Scale ? 16) (AOR = 2.36, 95% CI: 1.14 to 4.92), and substance use (AOR = 2.00, 95% CI: 1.01 to 3.97). CONCLUSIONS:Screening for the sociodemographic and behavioral factors described above may facilitate targeted PrEP delivery during high-risk periods among MSM.
| S-EPMC4026016 | biostudies-literature
Project description:BackgroundHIV pre-exposure prophylaxis (PrEP) delivery at private pharmacies is a promising new differentiated service delivery model that may address barriers to PrEP delivery at public health care facilities. We measured the fidelity of this model (ie, delivery as intended) in a pilot study in Kenya.SettingFive private, retail pharmacies in Kisumu and Thika Counties.MethodsTrained pharmacy providers delivered PrEP services, including identifying eligible clients, counseling on HIV risk, assessing PrEP safety, testing for HIV, and dispensing PrEP. Pharmacy clients completed surveys that assessed the fidelity of the services received after each visit. Standardized client actors (ie, mystery shoppers) were trained on 4 different case scripts, then made unannounced pharmacy visits, and then completed a 40-item checklist that assessed the fidelity and quality of service delivery components.ResultsFrom November 2020 to December 2021, 287 clients initiated and 159 (55%) refilled PrEP. At initiation, most clients were counseled on PrEP adherence (99%, 284 of 287) and potential side effects (97%, 279 of 287) and all received provider-assisted HIV self-testing before PrEP dispensing (findings consistent across refill visits). Nine standardized client actors completed 15 pharmacy visits. At each visit, most actors were asked about their behaviors associated with HIV risk (80%, 12/15) and all were counseled on PrEP safety and side effects. All actors reported that pharmacy providers treated them with respect.ConclusionsIn this first pilot study of pharmacy-delivered PrEP services in Africa, the fidelity of service delivery was high, suggesting that trained providers at private pharmacies can deliver quality PrEP services.
| S-EPMC10337311 | biostudies-literature
Project description:Introduction: Antiretroviral therapy (ART) has led to a significant reduction in HIV-1 morbidity and mortality. Many antiretroviral drugs (ARVs) are metabolized by cytochrome P450 (CYP) pathway, and the majority of these drugs are also either CYP inhibitors or inducers and few possess both activities. These CYP substrates, when used for HIV treatment in the conventional dosage form, have limitations such as low systemic bioavailability, potential drug-drug interactions, and short half-lives. Thus, an alternative mode of delivery is needed in contrast to conventional ARVs. Areas covered: In this review, we summarized the limitations of conventional ARVs in HIV treatment, especially for ARVs which are CYP substrates. We also discussed the preclinical and clinical studies using the nanotechnology strategy to overcome the limitations of these CYP substrates. The preclinical studies and clinical studies published from 2000 to February 2019 were discussed. Expert opinion: Since preclinical and clinical studies for prevention and treatment of HIV using nanotechnology approaches have shown considerable promise in recent years, nanotechnology could become an alternative strategy for daily oral therapy as a future treatment.
| S-EPMC7183141 | biostudies-literature
Project description:Pre-exposure prophylaxis (PrEP) against HIV infection with tenofovir/emtricitabine is proven to be effective yet uptake of this preventive measure has been difficult due to several barriers such as cost, access, and misinformation. Certain subpopulations are disproportionately affected by this problem. Several methods have been developed to close the gap in care. New antiretroviral treatment strategies are being investigated for safety and efficacy in preventing HIV infection.
| S-EPMC7395680 | biostudies-literature