Topical Inserts: A Versatile Delivery Form for HIV Prevention.
ABSTRACT: The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.
Project description:INTRODUCTION:The majority of new HIV infections occur through mucosal transmission. The availability of readily applicable and accessible platforms for anti-retroviral (ARV) delivery is critical for the prevention of HIV acquisition through sexual transmission in both women and men. There is a compelling need for developing new topical delivery systems that have advantages over the pills, gels and rings, which currently fail to guarantee protection against mucosal viral transmission in vulnerable populations due to lack of user compliance. The silk fibroin (SF) platform offers another option that may be better suited to individual circumstances and preferences to increase efficacy through user compliance. The objective of this study was to test safety and efficacy of SF for anti-HIV drug delivery to mucosal sites and for viral prevention. METHODS:We formulated a potent HIV inhibitor Griffithsin (Grft) in a mucoadhesive silk fibroin (SF) drug delivery platform and tested the application in a non-human primate model in vivo and a pre-clinical human cervical and colorectal tissue explant model. Both vaginal and rectal compartments were assessed in rhesus macaques (Mucaca mulatta) that received SF (n = 4), no SF (n = 7) and SF-Grft (n = 11). In this study, we evaluated the composition of local microbiota, inflammatory cytokine production, histopathological changes in the vaginal and rectal compartments and mucosal protection after ex vivo SHIV challenge. RESULTS:Effective Grft release and retention in mucosal tissues from the SF-Grft platform resulted in protection against HIV in human cervical and colorectal tissue as well as against SHIV challenge in both rhesus macaque vaginal and rectal tissues. Mucoadhesion of SF-Grft inserts did not cause any inflammatory responses or changes in local microbiota. CONCLUSIONS:We demonstrated that in vivo delivery of SF-Grft in rhesus macaques fully protects against SHIV challenge ex vivo after two hours of application and is safe to use in both the vaginal and rectal compartments. Our study provides support for the development of silk fibroin as a highly promising, user-friendly HIV prevention modality to address the global disparity in HIV infection.
Project description:With more than 7,000 new HIV infections daily worldwide, there is an urgent need for non-vaccine biomedical prevention (nBP) strategies that are safe, effective, and acceptable. Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) can be effective at preventing HIV infection. In contrast, other trials using the same ARVs failed to show consistent efficacy. Topical (vaginal and rectal) dosing is a promising regimen for HIV PrEP as it leads to low systematic drug exposure. A series of titration studies were carried out in bone marrow/liver/thymus (BLT) mice aimed at determining the adequate drug concentrations applied vaginally or rectally that offer protection against rectal or vaginal HIV challenge. The dose-response relationship of these agents was measured and showed that topical tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can offer 100% protection against rectal or vaginal HIV challenges. From the challenge data, EC50 values of 4.6 ?M for TDF and 0.6 ?M for FTC for HIV vaginal administration and 6.1 ?M TDF and 0.18 ?M for FTC for rectal administration were obtained. These findings suggest that the BLT mouse model is highly suitable for studying the dose-response relationship in single and combination ARV studies of vaginal or rectal HIV exposure. Application of this sensitive HIV infection model to more complex binary and ternary ARV combinations, particularly where agents have different mechanisms of action, should allow selection of optimal ARV combinations to be advanced into pre-clinical and clinical development as nBP products.
Project description:Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83?days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3?days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.
Project description:Background: The HIV/AIDS epidemic in Vietnam is concentrated in subgroups of the population, including men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) is a viable strategy for HIV prevention, but knowledge about and preferences for PrEP delivery among Vietnamese MSM are not well understood. Methods: In 2015, an online survey was conducted with recruitment via social networking websites for MSM and peer recruitment. A description of daily oral, long-acting injectable, and rectal microbicide formulations of PrEP was provided to participants. Participants were asked about their prior awareness of and interest in PrEP, and ranked their most preferred PrEP modality. Multivariable logistic regression models were used to assess factors associated with having heard of PrEP and preference for each PrEP modality. Results: Of 548 participants who answered demographic and PrEP-related questions, 26.8% had previously heard of PrEP and most (65.7%) endorsed rectal microbicides as their most preferred PrEP delivery modality. Commonly-cited perceived barriers to uptake of PrEP included concern about side-effects, perception about being HIV positive, and family or friends finding out about their sexual behaviour. In multivariable models, older participants less often endorsed rectal microbicides (adjusted odds ratio (AOR) 0.95 per year, 95% confidence interval (CI) 0.91-0.99) and more often endorsed long-acting injectables (AOR 1.08 per year, 95% CI 1.03 to 1.14) as their preferred PrEP modality. Participants who were willing to pay more for PrEP less often endorsed rectal microbicides (AOR 0.81, 95% CI 0.72-0.92) and more often endorsed long-acting injectables (AOR 1.17, 95% CI 1.01-1.35) and daily oral pills (AOR 1.16, 95% CI 1.00-1.35) as their preferred form of PrEP. Conclusions: A variety of PrEP modalities were acceptable to MSM in Vietnam, but low knowledge of PrEP may be a barrier to implementation.
Project description:New forms of HIV pre-exposure prophylaxis (PrEP) include long-acting injectables and topical microbicides, each with unique attributes that may appeal to distinct users. We used a discrete choice experiment to characterize preferences for new PrEP formulations among Toronto men who have sex with men. MSM undergoing anonymous HIV testing completed a discrete choice experiment with 12 choice sets by selecting their preferred option within each set. Each set included “usual methods to prevent HIV” (excluding PrEP) as one alternative and two hypothetical PrEP alternatives, which differed according formulation/dosing, side effects (none/mild), risk of drug resistance (none/low/moderate), and HIV prevention efficacy (50%, 65%, 80% or 99% risk reduction). We used mixed logistic regression to infer preferences for PrEP attributes and calculate the marginal rate of substitution between efficacy and other PrEP attributes. 306 men with median (interquartile range) age = 29 (25, 36) years participated, and reported 6 (3, 10) partners and 0 (0, 2) condomless receptive anal sex acts in the preceding six months. An on-demand pill was the most preferred formulation, followed by a monthly injection, daily pill, and on-demand rectal gel. Drug resistance was an important determinant of preferences if the risk was moderate, but not if it was low. The minimum efficacy required for an on-demand pill to be preferred over no PrEP was 32.6% (95%CI = 21.2–43.9%); for a daily pill, injections, and rectal gel, minimum efficacy was 57.9% (95%CI = 44.1–71.7%), 40.1% (27.0–53.2%), and 71.3% (60.5–82.1%), respectively. Attitudes towards PrEP formulations vary among men who have sex with men, with on-demand pills and monthly injections having the highest average preference scores. Understanding these preferences may help to predict uptake.
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.
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:<h4>Introduction</h4>Over one hundred implementation studies of HIV pre-exposure prophylaxis (PrEP) are completed, underway or planned. We synthesized evidence from these studies to inform mathematical modelling of the prevention cascade for oral and long-acting PrEP in the setting of western Kenya, one of the world's most heavily HIV-affected regions.<h4>Methods</h4>We incorporated steps of the PrEP prevention cascade - uptake, adherence, retention and re-engagement after discontinuation - into EMOD-HIV, an open-source transmission model calibrated to the demography and HIV epidemic patterns of western Kenya. Early PrEP implementation research from East Africa was used to parameterize prevention cascades for oral PrEP as currently implemented, delivery innovations for oral PrEP, and future long-acting PrEP. We compared infections averted by PrEP at the population level for different cascade assumptions and sub-populations on PrEP. Analyses were conducted over the 2020 to 2040 time horizon, with additional sensitivity analyses for the time horizon of analysis and the time when long-acting PrEP becomes available.<h4>Results</h4>The maximum impact of oral PrEP diminished by over 98% across all prevention cascades, with the exception of long-acting PrEP under optimistic assumptions about uptake and re-engagement after discontinuation. Long-acting PrEP had the highest population-level impact, even after accounting for possible delays in product availability, primarily because its effectiveness does not depend on drug adherence. Retention was the most significant cascade step reducing the potential impact of long-acting PrEP. These results were robust to assumptions about the sub-populations receiving PrEP, but were highly influenced by assumptions about re-initiation of PrEP after discontinuation, about which evidence was sparse.<h4>Conclusions</h4>Implementation challenges along the prevention cascade compound to diminish the population-level impact of oral PrEP. Long-acting PrEP is expected to be less impacted by user uptake and adherence, but it is instead dependent on product availability in the short term and retention in the long term. To maximize the impact of long-acting PrEP, ensuring timely product approval and rollout is critical. Research is needed on strategies to improve retention and patterns of PrEP re-initiation.
Project description:<h4>Introduction</h4>Antiretroviral-based pre-exposure prophylaxis (PrEP) is today an established, effective and safe method of HIV prevention used in multiple countries worldwide by a broad range of populations at risk of HIV infection. Biomedical innovations are critical in supporting the primary prevention of HIV; however, their potential can only be maximized if end-user challenges are recognized, described and used to develop next-generation models.<h4>Discussion</h4>First-generation PrEP, a daily oral pill, is highly efficacious, discreet and affords users the ability to commence and conclude treatment rapidly. However, consistent daily adherence and persistence is challenging, especially among younger populations, due in part to side effects, the risk of stock-outs and a lack of pill storage options. Second-generation PrEP, longer acting agents that require less frequent dosing, could overcome such challenges. Agents that have shown efficacy in clinical trials include a monthly vaginal ring and PrEP injectables to be administered every 8 weeks, while products in development include 6 monthly injectables, oral therapy that uses monthly rather than daily pills, implants and the potential for long-acting passive immunization.<h4>Conclusions</h4>Second-generation PrEP agents will have the potential to offer improved adherence and less frequent reminders once they have undergone further development and the delivery systems that will best support them have been established. In order to pursue global UNAIDS targets of reducing new HIV infections to fewer than 500,000 annually by 2025, and to ensure that all people have access to prevention options that meet their specific prevention needs, both early and next-generation PrEP options are needed.
Project description:PURPOSE OF REVIEW:Clinical trials have found that PrEP is highly effective in reducing risk of HIV acquisition across types of exposure, gender, PrEP regimens, and dosing schemes. Evidence is urgently needed to inform scale-up of PrEP to meet the ambitious WHO/UNAIDS prevention target of 3,000,000 individuals on PrEP by 2020. RECENT FINDINGS:Successful models of delivering HIV services at scale evolved from years of formal research and programmatic evidence. These efforts produced lessons-learned relevant for scaling-up PrEP delivery, including the importance of streamlining laboratory tests, expanding prescription and management authority, differentiating medication access points, and reducing stigma and barriers of parental consent for PrEP uptake. Further research is especially needed in areas differentiating PrEP from ART delivery, including repeat HIV testing to ensure HIV negative status and defining and measuring prevention-effective adherence. Evidence from 15 years of ART scale-up could immediately inform a public health approach to PrEP delivery.