Expanding the pipeline for multipurpose prevention technologies: compounds with potential activity to prevent or treat HIV and other STIs.

BACKGROUND: Continued high incidence of HIV and other STIs, paired with rising antibiotic resistance to a number of existing treatments, warrants the development of new pharmaceutical approaches for STI prevention. Multipurpose prevention technologies (MPTs) offer an innovative approach for expanding HIV/STI prevention. The majority of MPT product candidates currently in development include HIV prevention, while only half include compounds active against non-HIV STIs. METHODS: This narrative review focuses on compounds in preclinical development (in vitro and in vivo) through phase 3 clinical trials with activity against one or more of the following infections: HIV, HSV-1, HSV-2, Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, and Trichomonas vaginalis. Bacterial vaginosis is included due to its association with increased risk of STIs. The focus is on compounds with novel mechanisms of action and prophylactic and/or therapeutic potential. Articles published in PubMed between 2011 and 2021, NIH RePorter and conference abstracts and proceedings between 2020 and 2021 were searched. Excluded from the review are compounds that are already being used in MPT product candidates. MAIN RESULTS: There is a growing pipeline of compounds targeting viral STIs, many of which have successfully transitioned from preclinical to clinical stages of development. However, the product development pipeline remains limited for compounds that target bacterial STIs. CONCLUSIONS: The paucity of new pharmaceutical approaches for STI prevention, particularly non-HIV STIs, remains a public health gap. Future funding priorities should include STI prevention research. Despite limited attention to STI prevention in the development of MPTs, many research institutions worldwide are working on discoveries of new compounds, exploring new indications for existing drugs or on innovative drug delivery mechanisms. Our findings can be used to connect researchers across the globe to advance the development of compounds that have potential as active pharmaceutical ingredients in future MPTs.

Towards a roadmap to advance non-hormonal contraceptive multipurpose prevention technologies: strategic insights from key stakeholders†.

The development of non-hormonal contraceptives is critical to increase options for women. In combination with prevention against sexually transmitted infections, they can become an important component of multipurpose prevention technologies (MPTs) which address multiple reproductive health needs with a single product. Resulting from multiple rounds of expert consultations, this framework aims to guide the development of non-hormonal contraceptive MPTs. Key informant interviews with experts in family planning and HIV and STI prevention and MPT product developers and funders from around the globe were conducted, reviewed, and coded. Identified key themes were discussed by experts at the November 2019 Eunice Kennedy Shriver National Institute of Child Health and Human Development Contraceptive Development Meeting in Houston, Texas. Seven action strategies were identified to address key research gaps and priorities for advancing the field. They highlight the importance of identifying target populations, a systematic approach to collaborative research, and leveraging knowledge from other fields, including regulatory and patenting, manufacturing, and commercialization expertise. Employing expanded target product profiles and setting go/no-go decisions for non-hormonal MPTs will help to prioritize the most promising candidates in the drug development pipeline. Further, they call for optimizing investments and engagement of stakeholders from public and private sectors. These action strategies aim to facilitate collaboration and innovation amongst multidisciplinary MPT stakeholders. Paramount to success will be enhancing strategic alliances and reconciling the essential social-behavioral context and market forces that drive product use with the complexities of research and development, regulatory approval, and commercialization.

A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV.

OBJECTIVE: Multipurpose prevention technologies (MPTs) are an innovative class of products that deliver varied combinations of human immunodeficiency virus (HIV) prevention, other sexually transmitted infection (STI) prevention, and contraception. Combining separate strategies for different indications into singular prevention products can reduce the stigma around HIV and STI prevention, improve acceptability of and adherence to more convenient products, and be more cost-effective by addressing overlapping risks. METHODS: This article outlines a strategic action framework developed as an outcome of a series of expert meetings held between 2014 and 2016. The meetings focused on identifying opportunities and challenges for MPTs that combine hormonal contraception (HC) with antiretroviral drugs into single products. The framework aims to present an actionable strategy, by addressing key research gaps and outlining the key areas for progress, to guide current and future HC MPT development. RESULTS: We identified eight primary action areas for the development of impactful HC MPTs, and includes aspects from epidemiology, pharmacology, clinical trial design, regulatory requirements, manufacturing and commercialisation, behavioural science, and investment needs for research and development. CONCLUSION: Overall, the challenges involved with reconciling the critical social-behavioural context that will drive MPT product use and uptake with the complexities of research and development and regulatory approval are of paramount importance. To realise the potential of MPTs given their complexity and finite resources, researchers in the MPT field must be strategic about the way forward; increased support among policy-makers, advocates, funders and the pharmaceutical industry is critical.

The role of economic evaluations in advancing HIV multipurpose prevention technologies in early-stage development.

Product development is a high-risk undertaking, especially so when investments are prioritized for low- and middle-income countries (LMICs) where markets may be smaller, fragile, and resource-constrained. New HIV prevention technologies, such as the dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA), are being introduced to these markets with one indication, meeting different needs of groups such as adolescent girls and young women (AGYW) and female sex workers (FSWs) in settings with high HIV burden. However, limited supply and demand have made their uptake a challenge. Economic evaluations conducted before Phase III trials can help optimize the potential public health value proposition of products in early-stage research and development (R&D), targeting investments in the development pathway that result in products likely to be available and taken up. Public investors in the HIV prevention pipeline, in particular those focused on innovative presentations such as multipurpose prevention technologies (MPTs), can leverage early economic evaluations to understand the intrinsic uncertainty in market characterization. In this perspective piece, we reflect on the role of economic evaluations in early product development and on methodological considerations that are central to these analyses. We also discuss methods, in quantitative and qualitative research that can be deployed in early economic evaluations to address uncertainty, with examples applied to the development of future technologies for HIV prevention and MPTs.

Strategic actions to advance multipurpose prevention technologies in low- and middle-income countries.

Background: HIV, other sexually transmitted infections (STIs) and unintended pregnancies are critical and interlinked health risks for millions of women of reproductive age worldwide. Multipurpose prevention technologies (MPTs) offer an innovative approach for expanding combined pregnancy and/or disease prevention. So far, MPT development efforts have focused mostly on HIV prevention, but about half of product candidates comprise compounds active against non-HIV STIs as well. This review aims to provide a framework that promotes the efficient advancement of the most promising preclinical products through the development pathway and into the hands of end-users, with a focus on women in low- and middle-income countries (L/MICs). Methods: This mini review provides a summary of the current landscape of the MPT field. It comprises a landscape assessment of MPTs in development, complemented by a series of 28 in-depth, semi-structured key informant interviews (KIIs) with experts representing different L/MIC perspectives. Main results: We identified six primary action strategies to advance MPTs for L/MICs, including identification of key research gaps and priorities. For each action strategy, progress to date and key recommendations are included. Conclusions: To realize the life-saving potential of MPTs and maximize the momentum made to date, a strategic, collaborative and well-funded response to the gaps and next steps outlined in this paper is critical. A coordinated response can add rigor and efficiency to the development process, to successfully advance the most promising MPT products to the hands of end-users.

Lime juice as a candidate microbicide? An open-label safety trial of 10% and 20% lime juice used vaginally.

OBJECTIVE: Lime has a long history as a contraceptive and vaginal hygiene douche, and ongoing use in Africa is documented. We report on the first safety study on diluted lime juice to assess its potential as a candidate microbicide. METHODS: Twenty-five sexually abstinent women were randomly assigned to apply a 10% or 20% concentration of lime juice or 0% (water-only) through a soaked tampon once daily for 14 consecutive days. Tests for genital infections, measurement of inflammatory biomarkers, and a colposcopy were performed before and after treatment. RESULTS: No participant showed severe vaginal irritation. Two women developed a yeast infection after using lime juice. More than 70% of women in all groups reported side effects, most being singular, mild, and transient events. The users of 20% diluted lime juice experienced a significantly higher frequency of burning and dryness. Vaginal inflammatory biomarkers showed no significant change between preexposure and postexposure levels. The naturally low vaginal pH showed little change, and lactobacilli colonization did not decrease. CONCLUSIONS: Lime juice up to 20% concentration has an acceptable safety profile for vaginal use. However, as new in vitro research shows that the effectiveness of lime juice to prevent HIV transmission in concentrations lower than >or=50% is unlikely and concentrations of 50% have been shown to be toxic, women should be discouraged from commencing or continuing the vaginal use of lime juice.

Pesticide-related symptoms among farm workers in rural Honduras.

A survey of 96 families in a rural region of Honduras, conducted in 1998, showed that 80 of these predominantly (95 or 96) farming families used pesticides in their work or at home. Paraquat was used most often, and safety measures were very rarely taken in its use. Seventy-seven families stored pesticide containers in their homes, often within the reach of children. Every worker who used paraquat had at least one symptom potentially related to its use, and the prevalences of childhood disorders in the region are abnormally high compared with national averages.

Increasing the effectiveness of vaginal microbicides: a biophysical framework to rethink behavioral acceptability.

BACKGROUND: Microbicide candidates delivered via gel vehicles are intended to coat the vaginal epithelium after application. The coating process depends on intrinsic biophysical properties of the gel texture, which restricts the potential choices for an effective product: the gel first must be physically synthesizable, then acceptable to the user, and finally applied in a manner promoting timely adequate coating, so that the user adherence is optimized. We present a conceptual framework anchoring microbicide behavioral acceptability within the fulfillment of the product biophysical requirements. METHODS: We conducted a semi-qualitative/quantitative study targeting women aged 18-55 in Northern California to assess user preferences for microbicide gel attributes. Attributes included: (i) the wait time between application and intercourse, (ii) the gel texture and (iii) the trade-off between wait time and gel texture. Wait times were assessed using a mathematical model determining coating rates depending upon the gel's physical attributes. RESULTS: 71 women participated. Results suggest that women would independently prefer a gel spreading rapidly, in 2 to 15 minutes (P<0.0001), as well as one that is thick or slippery (P<0.02). Clearly, thick gels do not spread rapidly; hence the motivation to study the trade-off. When asked the same question 'constrained' by the biophysical reality, women indicated no significant preference for a particular gel thickness (and therefore waiting time) (P>0.10) for use with a steady partner, a preference for a watery gel spreading rapidly rather than one having intermediate properties for use with a casual partner (P = 0.024). CONCLUSIONS: Biophysical constraints alter women's preferences regarding acceptable microbicide attributes. Product developers should offer a range of formulations in order to address all preferences. We designed a conceptual framework to rethink behavioral acceptability in terms of biophysical requirements that can help improve adherence in microbicide use ultimately enhancing microbicide effectiveness.