Pre-clinical evaluation of antiproteases as potential candidates for HIV-1 pre-exposure prophylaxis.
Ontology highlight
ABSTRACT:
SUBMITTER: Herrera C
PROVIDER: S-EPMC9720403 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Pre-clinical evaluation of antiproteases as potential candidates for HIV-1 pre-exposure prophylaxis.
Herrera Carolina C Olejniczak Natalia N Noël-Romas Laura L Plummer Frank F Burgener Adam A
Frontiers in reproductive health 20221121
Previous studies on highly HIV-1-exposed, yet persistently seronegative women from the Punwami Sex Worker cohort in Kenya, have shed light on putative protective mechanisms, suggesting that mucosal immunological factors, such as antiproteases, could be mediating resistance to HIV-1 transmission in the female reproductive tract. Nine protease inhibitors were selected for this study: serpin B4, serpin A1, serpin A3, serpin C1, cystatin A, cystatin B, serpin B13, serpin B1 and α-2-macroglobulin-lik ...[more]
Similar Datasets
Project description:BackgroundHIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic-pharmacodynamic (PK-PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue.MethodsInner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1BaL at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV-diphosphate (TFV-DP) concentrations were measured in tissues, culture supernatants and dosing and washing solutions.ResultsDose-response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV-DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV-DP and p24 concentrations following HVT.ConclusionsPre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding.
| S-EPMC9227286 | 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:ObjectivesThe objective was to perform a survey-based service evaluation of our telephone PrEP clinic (Tele-PrEP), which was instituted during the COVID-19 pandemic, to inform future service delivery.MethodsWe administered parallel, web-based, anonymous surveys to PrEP-users who had a Tele-PrEP appointment between 13.11.2020 and 17.12.2020 and all healthcare professionals (HCPs) conducting Tele-PrEP clinics. We used descriptive statistics to summarise demographic and qualitative data, and thematically categorised free text responses using the Framework for a Systems Approach to Healthcare Delivery.Results62/117 (53%) PrEP-users and 8/9 (89%) HCPs completed the surveys. Tele-PrEP was rated 'excellent' or 'good' by 61/62 (98%) PrEP-users. All HCPs felt that Tele-PrEP allowed them to assess patients safely and confidently. 10/62 (16%) PrEP-users and 1 (11%) HCP expressed a preference for face-to-face care. Using the Framework for a Systems Approach to Healthcare Delivery we identified key areas important to respondents who highlighted the rapid changes as a result of COVID-19, which required an increase in dedicated resources. HCPs valued teamwork, support/supervision and convenience in achieving quality care for the patient, who in turn, valued convenient, holistic and individualised management to meet their sexual healthcare needs.ConclusionTele-PrEP is feasible and acceptable. While most respondents rated the service highly, others identified a need/preference for face-to-face appointments.
| S-EPMC9189322 | biostudies-literature
Project description:PurposeFew risk-forecasting models of allergic rhinitis (AR) exist that may aid AR pre-exposure prophylaxis (PrEP) in clinical practice. Therefore, this study aimed to develop and validate an effective clinical model for identifying candidates for AR PrEP using a routine medical questionnaire.MethodsThis study was conducted in 10 Chinese provinces with 13 medical centers (n = 877) between 2019 and 2021. Clinical characteristics and exposure history were collected via face-to-face interviews. Well-trained physicians diagnosed patients with AR based on skin prick test results and clinical performance. The least absolute shrinkage and selection operator model was used to identify potential risk factors for AR, and the logistic regression model was used to construct the risk-forecasting model. Predictive power and model reliability were assessed using area under the receiver operating characteristic curve and calibration curves, respectively.ResultsThis study diagnosed 625 patients with AR who had positive responses to at least one indoor or outdoor allergen and 460 to at least one outdoor pollen allergen. Two nomograms were established to identify two types of AR with various sensitization patterns. Both models had an area under curve of approximately 0.7 in the development and internal validation datasets. Additionally, our findings found good agreement for the calibration curves of both models.ConclusionEarly identification of candidates for AR PrEP using routine medical information may improve the deployment of limited resources and effective health management. Our models showed good performance in predicting AR; therefore, they can serve as potential automatic screening tools to identify AR PrEP candidates.
| S-EPMC10836286 | biostudies-literature
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:Tenofovir-based regimens as pre-exposure prophylaxis (PrEP) are highly effective at preventing HIV infection. The most common side-effect is gastrointestinal (GI) distress which may be associated with changes in the microbiome. Dysbiosis of the microbiome can have numerous health-related consequences. To understand the effect of PrEP on dysbiosis, we evaluated 27 individuals; 14 were taking PrEP for an average of 171 weeks. Sequencing of 16S rRNA was performed using self-collected rectal swabs. Mixed beta diversity testing demonstrated significant differences between PrEP and non-PrEP users with Bray-Curtis and unweighted UniFrac analyses (p = 0.05 and 0.049, respectively). At the genus level, there was a significant reduction in Finegoldia, along with a significant increase in Catenibacterium and Prevotella in PrEP users. Prevotella has been associated with inflammatory pathways, insulin resistance and cardiovascular disease, while Catenibacterium has been associated with morbid obesity and metabolic syndrome. Overall, these results suggest that PrEP may be associated with some degree of microbiome dysbiosis, which may contribute to GI symptoms. Long-term impact of these changes is unknown.
| S-EPMC8169604 | biostudies-literature
Project description:Little is known about the potential population-level impact of HIV pre-exposure prophylaxis (PrEP) use among cisgender male sex workers (MSWs), a high-risk subset of cisgender men who have sex with men (MSM). Using an agent-based model, we simulated HIV transmission among cisgender MSM in Rhode Island to determine the impacts of PrEP implementation where cisgender MSWs were equally ("standard expansion") or five times as likely ("focused expansion") to initiate PrEP compared to other cisgender MSM. Without PrEP, the model predicted 920 new HIV infections over a decade, or an average incidence of 0.39 per 100 person-years. In a focused expansion scenario where 15% of at-risk cisgender MSM used PrEP, the total number of new HIV infections was reduced by 58.1% at a cost of $57,180 per quality-adjusted life-year (QALY) gained. Focused expansion of PrEP use among cisgender MSWs may be an efficient and cost-effective strategy for reducing HIV incidence in the broader population of cisgender MSM.
| S-EPMC7101419 | biostudies-literature
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.
| S-EPMC8213008 | biostudies-literature
Project description:BackgroundHIV pre-exposure prophylaxis (PrEP) is effective but underused, in part because clinicians do not have the tools to identify PrEP candidates. We developed and validated an automated prediction algorithm that uses electronic health record (EHR) data to identify individuals at increased risk for HIV acquisition.MethodsWe used machine learning algorithms to predict incident HIV infections with 180 potential predictors of HIV risk drawn from EHR data from 2007-15 at Atrius Health, an ambulatory group practice in Massachusetts, USA. We included EHRs of all patients aged 15 years or older with at least one clinical encounter during 2007-15. We used ten-fold cross-validated area under the receiver operating characteristic curve (cv-AUC) with 95% CIs to assess the model's performance at identifying individuals with incident HIV and patients independently prescribed PrEP by clinicians. The best-performing model was validated prospectively with 2016 data from Atrius Health and externally with 2011-16 data from Fenway Health, a community health centre specialising in sexual health care in Boston (MA, USA). We calculated HIV risk scores (ie, probability of an incident HIV diagnosis) for every HIV-uninfected patient not on PrEP during 2007-15 at Atrius Health and assessed the distribution of scores for thresholds to determine possible candidates for PrEP in the three study cohorts.FindingsWe included 1 155 966 Atrius Health patients from 2007-15 (150 [<0·1%] patients with incident HIV) in our development cohort, 537 257 Atrius Health patients in 2016 (16 [<0·1%] with incident HIV) in our prospective validation cohort, and 33 404 Fenway Health patients from 2011-16 (423 [1·3%] with incident HIV) in our external validation cohort. The best-performing algorithm was obtained with least absolute shrinkage and selection operator (LASSO) and had a cv-AUC of 0·86 (95% CI 0·82-0·90) for identification of incident HIV infections in the development cohort, 0·91 (0·81-1·00) on prospective validation, and 0·77 (0·74-0·79) on external validation. The LASSO model successfully identified patients independently prescribed PrEP by clinicians at Atrius Health in 2016 (cv-AUC 0·93, 95% CI 0·90-0·96) or Fenway Health (0·79, 0·78-0·80). HIV risk scores increased steeply at the 98th percentile. Using this score as a threshold, we prospectively identified 9515 (1·8%) of 536 384 patients at Atrius Health in 2016 and 4385 (15·3%) of 28 702 Fenway Health patients as potential PrEP candidates.InterpretationAutomated algorithms can efficiently identify patients at increased risk for HIV acquisition. Integrating these models into EHRs to alert providers about patients who might benefit from PrEP could improve prescribing and prevent new HIV infections.FundingHarvard University Center for AIDS Research, Providence/Boston Center for AIDS Research, Rhode Island IDeA-CTR, the National Institute of Mental Health, and the US Centers for Disease Control and Prevention.
| S-EPMC7522919 | biostudies-literature
Project description:When taken consistently, pre-exposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) with once daily tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) has been shown to safely reduce the incidence of HIV infection in high-risk individuals by more than 90%. Yet, according to the Centers for Disease Control and Prevention, there were about 2.1 million new cases of HIV reported worldwide in 2015. Undoubtedly, there is significant room for improvement to prevent the transmission of HIV. Research to date has been heavily focused on the high-risk men who have sex with men (MSM) population, yet, many women worldwide remain at high risk of HIV transmission. PrEP offers women a protection method that is discrete, does not require partner consent, and may be compatible with both contraception or conception as desired. However, women often remain under-represented in HIV prevention literature and are reported to have lower real-world uptake in comparison to men. Furthermore, clinical trials that do focus on the female population demonstrate mixed efficacy results that highlight the adherence challenges in this population. It is essential to identify factors that contribute to PrEP non-adherence as well as barriers to preventative treatment. This review will discuss the clinical evidence behind PrEP in women, current barriers to use afflicting this population, pharmacotherapy considerations for the female patient, alternative and future agents, and the current real-world application of PrEP.
| S-EPMC5595773 | biostudies-other