Preparing for microbicide introduction, rollout, and sustained access.

Two topical vaginal microbicide candidates for HIV prevention are at an advanced stage of clinical testing, with efficacy results from three clinical trials expected within the next 2 years. Therefore, preparations for introducing and ensuring access to these products in the event that they are proven safe and effective now require increased attention. Microbicides are expected to fill an important global public health need for HIV prevention options for women. They have been developed almost exclusively with public and private funding through academic and nongovernmental institutions and minimal involvement of commercial pharmaceutical partners. Efficient and rapid introduction of a new public health technology requires a broad range of expertise and collaborations, some of which are new to the microbicide field as products are at last completing late-stage pivotal licensure studies. Strong leadership, political commitment, and considerable financial investments will be required to ensure successful distribution as well as uptake and continued access to this new product class. This paper highlights work conducted since 2000 by scientists, advocates, and public health officials to prepare for microbicide introduction, and discusses some of the needed actions to ensure that products will become readily accessible to the women who need them.

Preference between precoital and daily use of Duet® and BufferGel in Zimbabwe.

Duet® is a microbicide-delivery system and cervical barrier for use daily or precoitally. We conducted a crossover study among 80 Zimbabwean women to explore factors associated with use-regimen preference. Women were assigned in random order to 14 days of precoital and 14 days of daily Duet and BufferGel use. About 51 % of women preferred precoital use, 39 % preferred daily use, and 10 % liked both equally. Overall product adherence during sex was similar for both use-regimens. In multivariable analysis, diaphragm experience was associated with preference for precoital use (AOR 2.80, 95 % CI 1.01-7.76). Reasons for preferring precoital use included use only when needed, cleanliness, and discomfort with daily use. Daily use preference included convenience, discreetness, and being prepared for "sex-on-demand." Different personal and life circumstances may result in varying use-regimen preferences. Methods that can accommodate both coitally-related and daily use may be advantageous by providing more choice to users.

Preventive misconception as a motivation for participation and adherence in microbicide trials: evidence from female participants and male partners in Malawi and Zimbabwe.

This paper presents empirical data on motivation to join an HIV prevention trial of vaginal microbicide gels in Malawi and Zimbabwe, and participant assumption of a preventive misconception. Interviews were conducted with women participating in the trial and their male partners. Most of the female participants were able to adequately describe basic aspects of the trial design. HIV counseling and testing were primary reasons motivating women's participation, and male partners' support of the trial. 29% of women and 20% of men also provided indications of a preventive misconception, attributing gel use and trial participation to avoiding HIV infection.

Using integrated mixed methods to develop behavioral measures of factors associated with microbicide acceptability.

Our current understanding of factors associated with microbicide acceptability and consistent use typically has been derived from separate and distinct qualitative or quantitative studies. Specifically, rarely have investigators used mixed methods to both develop and validate behavioral measures. We utilized an integrated mixed methods design, including qualitative metasyntheses, cognitive interviews and expert reviews, psychometric evaluation, and confirmatory qualitative analyses of the correspondence between quantitative items and original qualitative data to develop and validate measures of factors associated with microbicide acceptability and use. We describe this methodology and use the development of the Relationship Context Scale to illustrate it. As a result of independent confirmatory analyses of qualitative passages corresponding to survey items, we demonstrated that items from the same subscales are frequently double coded within a particular textual passage, and thematically related, suggesting associations that resulted in a unique factor structure within the subscale. This integrated mixed method design was critical to the development of this psychometrically validated behavioral measure, and could serve as a model for future measure development.

Sexual pleasure, gender power and microbicide acceptability in Zimbabwe and Malawi.

Topical vaginal microbicides are being developed to reduce HIV infection in women for whom correct and consistent condom use is impossible or undesirable. Although microbicides have been heralded as a "women-initiated" method that requires no action of the male partner, gender norms for sexual relationships and sexual practices could impede acceptability and use. To facilitate development of microbicides and look ahead to their eventual introduction, it is necessary to understand couples' sexual dynamics, including power and pleasure. This article presents data from a study of microbicide acceptability ancillary to a microbicide clinical trial in Malawi and Zimbabwe. Female trial participants, male partners, health care professionals and community stakeholders were interviewed about norms for sexual decision-making, sexual pleasure, and associated intravaginal practices that ensure this pleasure. Even though acceptability of microbicides was found to be high, sexual intercourse is accompanied by issues of power and gender norms that place women, particularly those in stable union, at a disadvantage for enactment of risk reduction strategies. Although woman-initiated use is an important goal in development of microbicides, the need for men's cooperation or agreement must be addressed in strategies for future product introduction.

Tuberculosis Knowledge, Awareness, and Stigma Among African-Americans in Three Southeastern Counties in the USA: a Qualitative Study of Community Perspectives.

To inform strategies to address the tuberculosis (TB) excess among US-born African-Americans, we sought to understand the TB experience in the most highly affected southeastern communities. We conducted semi-structured interviews and focus groups in three communities with a TB excess-urban (Georgia and Tennessee) and rural (North Carolina). Participants from five groups provided diverse perspectives-African-Americans: patients with TB disease or latent TB infection (LTBI), or at high risk of contracting TB; and local community leaders and TB program staff. Few differences emerged between sites. Many participants demonstrated low levels of knowledge and awareness and held many misconceptions about TB. Patients expressed a preference for verbal communication of medical information. Patients reported fear of stigmatization and shunning, but few experienced discrimination. Patient trust for TB program staff was high, though community leaders often assumed the opposite. The findings will help guide interventions to improve knowledge and awareness regarding TB, including specific attention to the role of public and private health care providers in dispelling persistent misinformation about TB. The insight from these communities will help build the scientific foundation required to effectively eliminate health inequities.

Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa.

BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174.

Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy.

This paper reviews key issues found to affect acceptability and preferences for vaginal products to prevent HIV infection or HIV and pregnancy. We focus on the interplay between the biological and physico-chemical aspects of formulation and the social and behavioral issues that may affect use. The need for an HIV prevention product that women can use is driven by women's increased biological and social vulnerability to HIV infection, and thus social and behavioral research on microbicide acceptability has been conducted alongside, as well as separate from, the earliest product development efforts. Some acceptability and preference issues are specific to a product's dosage form, use-requirements, and/or use indications, while others pertain to any vaginal product used for prevention of HIV or pregnancy. Although most of the work cited here was published since 2010, it draws on a much longer trajectory of research.

Recent work on vaginal rings containing antiviral agents for HIV prevention.

PURPOSE OF REVIEW: In response to the need for strategies women can use to protect themselves from HIV infection, a new class of product commonly referred to as vaginal 'microbicides' has been under development for the past few decades. Several leading products currently in development contain antiviral agents delivered in a vaginal ring. RECENT FINDINGS: Research published over the past year reports advances in identification and continued formulation of specific antiviral agents that have potential for delivery in vaginal rings, including drug combinations for HIV, other sexually transmitted infections and contraception. Most products are antiretroviral reverse transcriptase inhibitors. Advances in vaginal ring design have also been reported; some of these are designed to release specific antiviral agents, while other designs could be used for multiple drugs. This review focuses both on antiviral agents and vaginal ring designs. SUMMARY: Over the past year, advances continued to be made in the development of vaginal rings to deliver antiviral agents for prevention of HIV. An array of antiviral agents and vaginal ring designs to deliver these products are at various stages in the product pipeline process. Results from the first efficacy trials of an antiretroviral-containing vaginal ring are expected soon and will inform the continued development of this important product class.

Community and research staff collaboration for development of materials to inform microbicide study participants in Africa.

INTRODUCTION: Clinical trials of new vaginal products require careful communication with participants about trial requirements. Most microbicide trials have been multi-site studies conducted among women in sub-Saharan Africa, where literacy levels and understanding of scientific methods differ from those designing and conducting the trials. Microbicide trials require women to insert objects in their vagina and ensure they are present in the vagina during sex. For many women, this is a novel behaviour. These behaviours take place within the context of clinical trial participation, which is an additional novelty. Research teams must develop informational materials to help participants understand the clinical trial and input from local research staff and community members can improve the content and format of these materials. METHODS: This paper discusses the development of illustrated materials developed for microbicide trial participants, presenting examples from two studies. In both studies, research staff and community advisory groups collaborated to review and revise materials. RESULTS: Collaborative efforts revealed insights about how to convey information about clinical trial participation and microbicide use. These insights highlighted realities of the local context, details that might be misunderstood, illustrations of a sensitive nature and concerns about blood testing. In particular, information about blood testing and product use instructions required careful consideration. Although the research team anticipated needing advice on how best to convey information on these topics to participants, some aspects of potential participant concerns about these topics were also new to the research team. Community advisors and local research staff suggested better ways to convey this information, and provided guidance on how to use the materials. CONCLUSIONS: The collaboration served to develop informational materials for microbicide trial participants. Furthermore, staff gained a better understanding of issues and concerns that could influence trial participation. A collaborative engagement process can provide important insights into local culture and knowledge beyond what is needed for development of clinical trial participant information materials. Research teams should be sensitive to this possibility, avail themselves of information and take appropriate action.

Development of dapivirine vaginal ring for HIV prevention.

In the continuing effort to develop effective HIV prevention methods for women, a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine is currently being tested in two safety and efficacy trials. This paper reviews dapivirine ring's pipeline development process, including efforts to determine safe and effective dosing levels as well as identify delivery platforms with the greatest likelihood of success for correct and consistent use. Dapivirine gel and other formulations were developed and tested in preclinical and clinical studies. Multiple vaginal ring prototypes were also tested, resulting in the current ring design as well as additional designs under consideration for future testing. Efficacy results from clinical trials are expected in 2015. Through ongoing consultations with national regulatory authorities, licensure requirements for dapivirine vaginal ring approval have been defined. 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.

Microbicide clinical trial adherence: insights for introduction.

After two decades of microbicide clinical trials it remains uncertain if vaginally- delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre-licensure implementation trials, Phase IV post-marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large-scale microbicide efficacy trials completed to-date, the paper identifies six broad areas of adherence lessons learned: (1) Adherence measurement in clinical trials, (2) Comprehension of use instructions/Instructions for use, (3) Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4) Partner influence on use, (5) Retention and continuation and (6) Generalizability of trial participants' adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post-marketing research, and microbicide introduction and delivery programs.

An acceptability and safety study of the Duet cervical barrier and gel delivery system in Zimbabwe.

BACKGROUND: Adherence problems with coitally dependent, female-initiated HIV prevention methods have contributed to several trials' failure to establish efficacy. Continuous use of a cervical barrier with once-daily cleaning and immediate reinsertion may simplify use for women and improve adherence. We assessed the acceptability and safety of precoital and continuous use of the Duet, a cervical barrier and gel delivery system, in Zimbabwean women. METHODS: Using a two-arm crossover design with a parallel observation group, we randomized 103 women in a 2:2:1 ratio: (1) to use the Duet continuously for 14 days, followed by a minimum of seven days of washout and then 14 days of precoital use; (2) to use the same Duet regimens in reverse order; or (3) for observation only. Women were aged 18 to 40 years; half were recruited from a pool of previous diaphragm study participants and the other half from the general community. Acceptability and adherence were assessed through an interviewer-administered questionnaire at each of two follow-up visits. Safety was monitored through pelvic speculum exams and report of adverse events. RESULTS: The proportion of women who reported consistent Duet use during sex was virtually identical during continuous and precoital regimens (88.6% vs. 88.9%). Partner refusal was the most common reason cited for non-use during sex in both use regimens. Not having the device handy was the most common reason cited for non-daily use (in the continuous regimen). Most women were "very comfortable" using it continuously (86.3%) and inserting it precoitally (92.8%). The most favoured Duet attribute was that it did not interfere with "natural" sex (55%). The least favoured Duet attribute was the concern that it might come out during sex (71.3%). No serious adverse events were reported during the study; 57 participants reported 90 adverse events classified as mild or moderate. There were no statistically significant differences in: (1) the proportion of women reporting adverse events; (2) the severity of events among those using the Duet and observational controls; or (3) event severity reported during each regimen use period. CONCLUSIONS: In this study, the Duet was found to be acceptable and safe when inserted precoitally or used continuously for 14 days. Assignment to use of the Duet continuously did not increase adherence to the Duet during sex. Future HIV prevention trials should evaluate use of the Duet (precoitally and continuously) with promising microbicide candidates.

Willingness to use microbicides is affected by the importance of product characteristics, use parameters, and protective properties.

BACKGROUND: Along with efficacy, a microbicide's acceptability will be integral to its impact on the pandemic. Understanding Product Characteristics that users find most acceptable and determining who will use which type of product are key to optimizing use effectiveness. OBJECTIVES: To evaluate psychometrically the Important Microbicide Characteristics (IMC) instrument and examine its relationship to willingness to use microbicides. RESULTS: Exploratory and confirmatory factor analyses revealed 2 IMC subscales (Cronbach's coefficient alpha: Product Characteristics subscale (alpha = 0.84) and Protective Properties subscale (alpha = 0.89)). Significant differences on Product Characteristics subscale scores were found for history of douching (P = 0.002) and employment status (P = 0.001). Whether a woman used a method to prevent pregnancy or sexually transmitted disease (STD) in the last 3 months (P < 0.001) and whether she used a condom during the last vaginal sex episode (P < 0.001) were significantly related to her rating of the importance of microbicides being contraceptive. Product Characteristics (r = 0.21) and Protective Properties (r = 0.27) subscale scores and whether a microbicide had contraceptive properties (r = 0.24) were all significantly associated (P < 0.001) with willingness to use microbicides. CONCLUSIONS: Formulation and use characteristics and product function(s) affect willingness to use microbicides and should continue to be addressed in product development. The IMC instrument serves as a template for future studies of candidate microbicides.

Women's Autonomy and Informed Consent in Microbicides Clinical Trials.

ACHIEVING RESPECT FOR PERSONS is problematic in settings with concepts of autonomy that differ from Western values. For international research, women's autonomy to consent to participation is an increasingly contentious issue. We present data from ancillary studies conducted in preparation for a clinical trial testing the safety and efficacy of topical microbicides, used to prevent HIV infection. These ancillary studies were conducted in seven countries, using qualitative research methods to collect data from female and male community members, and their health care professionals and community leaders. Our findings indicate that by working at the level of the community, couple and individual, researchers may be able to take steps to increase women's ability to make their own independent decisions about participating in research. This approach may, in turn, improve both the conduct and outcomes of research.

A model designed to enhance informed consent: experiences from the HIV prevention trials network.

HIV prevention research in developing countries has resulted in increased attention to and discussion of ethical issues, particularly the issue of the quality of informed consent. We present a conceptual framework for an enhanced informed consent process, drawing on experiences garnered from domestic and international studies conducted by the HIV Prevention Trials Network, funded by the National Institutes of Health. This framework guides the development of an informed consent process designed to help ensure initial and continued comprehension of research participation, with an emphasis on HIV prevention research. Attention is focused at the individual and community levels and on 3 study phases: preenrollment, enrollment, and postenrollment.

A framework for examining the sustained acceptability of microbicides.

The concept of acceptability involves a complex set of individual, couple and socio-cultural factors. Within a specific focus on microbicides, this article sets forth the relevant behavioral issues demanding attention as scientists and product developers strive to identify microbicides that will be used in a sustained, long-term fashion to prevent HIV/AIDS. The paper re-conceptualizes long-term acceptability within the ARRM framework, reviews the basic issues and research related to microbicide acceptability, discusses couple relationships (especially the nature of intimate relationships), and identifies related gender and power factors. The importance of the cultural context within various international settings pervades all of these issues. Finally, a set of challenges is discussed for those contemplating such research.