Vaginal Microbicides Research Articles

Evaluation of polymer combinations in vaginal mucoadhesive tablets for the extended release of acyclovir

Genital herpes, caused by herpes simplex virus type 2 (HSV-2), affects nearly 500 million people, mostly women. Since the main route of transmission is sexual contact, the development of an acyclovir extended-release vaginal microbicide would be a suitable tool for the prevention of virus transmission. In this work, we evaluated the potential of three polymers with different characteristics (chitosan, xanthan gum and ethyl cellulose) for obtaining acyclovir extended-release vaginal tablets. By combining the polymers, certain useful synergies were observed to modify their mucoadhesive capacity and control drug release. In the swelling studies, it observed that a polyelectrolyte complex with more moderate swelling and sustained gelation was formed between chitosan and xanthan gum exclusively in acidic medium (simulated vaginal fluid). This complex allowed prolonging the mucoadhesion of the tablets in ex vivo studies performed with vaginal mucosa, which would translate into better retention in the vagina after administration. In addition, the combination of chitosan and xanthan gum allowed obtaining a controlled release of acyclovir for 5 days, regardless of the pH of the medium, which would guarantee that drug release continues even in the presence of seminal fluid.

Nonlinear dynamics model of HIV/AIDS: Assessing the impacts of condoms, vaginal microbicides, and optimized treatment

HIV/AIDS remains one of the main global causes of morbidity and mortality. While antiretroviral drugs are still the only treatment for HIV patients, their accessibility and efficient delivery in resource-poor nations constitute a major concern, and no epidemiological model has considered this. Based on this, we create a model for HIV/AIDS that considers condoms and vaginal microbicides alongside saturated treatment. We consider the constant control case, in which theoretical results show that the delay factor in the antiretroviral therapy (ART) regimen can induce backward bifurcation, which consequently distorts the global effort to end HIV incidence. We use the Castillo-Chavez stability to ensure that the disease-free equilibrium is globally asymptotically stable whenever the associated reproduction number is less than one. Uncertainty and sensitivity analysis using the Latin hypercube sampling technique was also carried out on the parameters and state variables of the model equations, and the result shows that half of the most highly influential parameters are capable of reducing cases of HIV and AIDS. For time-dependent control cases, our findings suggest that, in countries with low income, directing resources to either condom use or vaginal microbicides is more effective than a regular intake of antiretrovirals alone. Furthermore, results without ART delay have shown to be more effective in HIV control than others where the inaccessibility of the therapy encouraged outbursts of AIDS cases. Thus, as reliable as antiretrovirals are in HIV/AIDS treatment, early administration and regular intake are key to their continued success.

Pilot PET study of vaginally administered bioadhesive nanoparticles in cynomolgus monkeys: Kinetics and safety evaluation

AbstractLong‐lasting vaginal dosage forms could improve the therapeutic efficacy of vaginal microbicides, but achieving long‐term delivery to the vaginal canal has been a significant challenge. To advance understanding of vaginal dosage retention and biodistribution, we describe a method of noninvasive imaging with 89Zr‐labeled bioadhesive nanoparticles (BNPs) in non‐human primates. We additionally examined the safety of repeated BNP application. BNPs administered vaginally to cynomolgus monkeys were still detected after 24 h (1.7% retention) and 120 h (0.1% retention). BNPs did not translocate to the uterus or into systemic circulation. Analysis of inflammatory biomarkers in the vaginal fluid and plasma suggest that BNPs are safe and biocompatible, even after multiple doses. BNPs are a promising delivery vehicle for vaginally administered therapeutics. Further studies using the non‐human primate imaging materials and methods developed here could help advance clinical translation of BNPs and other long‐lasting vaginal dosage forms.

Cholesterol-conjugated siRNAs silence gene expression in mucosal dendritic cells in cervicovaginal tissue in mice.

RNA interference (RNAi) provides a powerful way to investigate the role of genes in disease pathogenesis and modulate gene expression to treat disease. In 2018, the FDA approved patisiran, the first RNAi-based drug, hence paving the way for a novel class of RNAi therapeutics. Harnessing RNAi to inhibit vaginal HIV transmission requires effective gene silencing in immune cells, which remains difficult. Knockdown in accessible mucosal tissues may be easier than systemic gene silencing. Vaginally applied cholesterol-conjugated small interfering RNAs (chol-siRNAs) blocked herpes simplex virus transmission in mice without tissue damage or immunostimulation. To investigate using flow cytometry, confocal microscopy, and quantitative imaging if chol-siRNAs silence gene expression in vaginal immune cells in mice. Although chol-siRNAs and lipoplexed-siRNAs silence gene expression in dendritic cells (DCs) in vitro, most internalized siRNAs concentrate within multivesicular bodies, where they are inaccessible to the cellular RNAi machinery. When applied intravaginally in vivo, chol-siRNAs penetrate the vaginal mucosa, including the lamina propria, and are efficiently internalized by intraepithelial (IE) and lamina propria (LP) DCs, and CD11b+ CD45+ cells, but not by T cells. Chol-siRNAs induce partial gene silencing in IE and LP DCs throughout the genital mucosa in vivo but are inactive in F4/80+ CD11b+ macrophages and T cells. As mucosal DCs play an essential role for mucosal viral entry and dissemination, chol-siRNAs could be harnessed to target various host factors that are critical for viral uptake, DC migration and trans-infection of virions to T cells, hence allowing the development of a preventive vaginal HIV microbicide. Furthermore, chol-siRNAs could help elucidate the pathways of HIV transmission and understand the immunologic function of DCs in the genital tract.

“Male-supported, female-initiated”

HIV and AIDS remain one of the leading public health challenges in the world, with young women in sub-Saharan Africa bearing the brunt of HIV infection. Female vulnerability to HIV infection is exacerbated by socio-cultural, economic and biological dynamics. Vaginal microbicide, one of the first topical pre-exposure prophylaxis (PrEP) innovations for HIV prevention can offer new hope for women, but an understanding of the local cultural context and its influence on product acceptability is fundamental for effective HIV communication strategies. Critical health communication navigates through the complexities of cultural discourses to create awareness among women in dominant cultural settings. As a means of understanding the key determinants for effective HIV communication, this paper used thematic analysis of data from a study among female students at the University of KwaZulu-Natal regarding their preferences and the acceptability of two microbicide technologies: the tenofovir gel and the dapivirine ring. Keyfindings indicate that microbicides give women more options for self-protection and cater for diverse sexual encounters, and that their covert use empowers women to use the products even if male partners do not support this. However, women felt more empowered with “male-supported, female-initiated” HIV prevention options. The study suggests that in providing HIV preventionoptions to women, culturally appropriate messages must be considered. We suggested that topical PrEP must be communicated as a “male-supported, female-initiated” HIV prevention option in rural KwaZulu-Natal contexts.

Hidden heterogeneity: Uncovering patterns of adherence in microbicide trials for HIV prevention.

BackgroundInterpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals, microbicide trials collected adherence data via self-report, and trials typically reported trial population adherence as overall averages in primary results manuscripts. This study first sought to determine if different patterns of adherence from three trials of vaginal microbicide gels could be identified, using self-reported data and if so, how those patterns compare across trials. The second objective was to explore which individual-level factors were associated with different adherence patterns.MethodsData from the following three clinical trials of vaginal microbicides were used for this study: HIV Prevention Trials Network (HPTN) 035 testing PRO 2000 and Buffergel, the Microbicides Development Programme (MDP) 301 testing PRO 2000, and the Population Council’s Carraguard study, testing Carraguard gel. Latent Class Analysis (LCA) was used to identify longitudinal patterns of adherence using self-reported data about gel use. Multinomial multivariable logistic regression was used to estimate relative risk-ratios for factors which were independently associated with different latent adherence trajectories within each trial, and compared across trials.ResultsIncluded in this analysis are 2,282 women from HPTN 035 (age 17–56 years), 6238 women from MDP 301 (age 16–75 years), and 6039 women from Carraguard (age 16–73 years). Using LCA, 3–4 different patterns of gel adherence were identified in each trial; these patterns were similar across the trials. Factors associated with adherence patterns were identified in all trials. Older age was associated with the adherence trajectory that consistently reported gel use in three trials. Participant-reported negative reaction of partners to the gel was associated with trajectories that reported less consistent adherence in two trials. A greater number of baseline-reported sex partners or sex acts was associated with trajectories which reported less consistent adherence in some trials. Trial site location was associated with membership of trajectories in all trials.ConclusionLCA was able to identify patterns of microbicide gel adherence in clinical trials that used self-reported data. Key factors associated with patterns of adherence in this study were participant age, clinical trial site location, and partner reaction to the study gel. These findings, in particular, age and perceived partner reaction to the method, are consistent with results from other clinical trials and programmatic rollout of biomedical HIV prevention methods for women in Africa. This study contributes to the body of evidence that women need more support to navigate power dynamics within their relationships with men so that they can successfully use HIV prevention methods.

Safety of G2-S16 Polyanionic Carbosilane Dendrimer as Possible HIV-1 Vaginal Microbicide.

The UNAIDS objective for 2020 was 500,000 new HIV-1 infections per year; however, the latest annual reported data confirmed 1.7 million new HIV-1 infections in that year. Those data evidences the need for new prevention strategies and prophylactic treatments. This prevention crisis occurred in spite of the knowledge and availability of efficient prevention strategies. The G2-S16 is a microbicidal polyanionic carbosilane dendrimer currently being tested for topical vaginal application, which has been shown to be efficient in the prevention of HIV-1 infection. However, safety tests were lacked. For this purpose, we injected intravenously G2-S16 dendrimer to CD1 mice, thereby analyzing the hemogram, blood biochemical markers of systemic damage, accumulation in the organs and organ-tissue damage in heart, spleen, kidney, liver and brain. This work shows that even if the G2-S16 dendrimer penetrates the epithelial tissue, it does not cause vaginal irritation or tissue damage. Moreover, the i.v. injection of the G2-S16 dendrimer did not cause a damaging effect on the studied organs and it did not modify the hemogram or the biochemical plasma markers. In conclusion, the G2-S16 dendrimer has a very good safety profile, indicating that this molecule can be a very safe and efficient vaginal microbicide.

Eudragit® L100/chitosan composite thin bilayer films for intravaginal pH-responsive release of Tenofovir

The high rate of HIV new infections and AIDS-related deaths each year make prevention tools still necessary today. Different dosage forms – including films – for vaginal administration of antiretroviral drugs have been developed for this purpose. Six batches of Tenofovir-loaded films were formulated based on Eudragit® L100 (EL100) and chitosan, containing triethyl citrate and glycerol. In all the cases films structured in two layers – the upper layer mainly attributed to EL100 and the lower layer to chitosan – were revealed by SEM. A higher content in EL100 and plasticizers improves the mechanical properties and control over drug release in the vaginal medium without affecting mucoadhesion. The EL100-based layer acts as a structuring agent that controls Tenofovir release for days in the vaginal medium while it occurs in a few hours in the presence of seminal fluid. Bilayer films with the highest tested content of EL100 and plasticizers would be the most suitable as vaginal microbicides as they are easier to administer due to their excellent mechanical properties and they offer more comfortable posology and enhanced protection against HIV during intercourse due to their pH-responsive release of Tenofovir.

Assessment of risk compensation following use of the dapivirine vaginal ring in southwestern Uganda

ObjectivesParticipation in HIV prevention trials could trigger risk compensation among participants. We evaluated potential risk compensation following use of a vaginal ring microbicide by women in a phase III trial...

Baseline and time-updated factors in preclinical development of anionic dendrimers as successful anti-HIV-1 vaginal microbicides.

Although a wide variety of topical microbicides provide promising in vitro and in vivo efficacy, most of them failed to prevent sexual transmission of human immunodeficiency virus type 1 (HIV‐1) in human clinical trials. In vitro, ex vivo, and in vivo models must be optimized, considering the knowledge acquired from unsuccessful and successful clinical trials to improve the current gaps and the preclinical development protocols. To date, dendrimers are the only nanotool that has advanced to human clinical trials as topical microbicides to prevent HIV‐1 transmission. This fact demonstrates the importance and the potential of these molecules as microbicides. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV‐1 that disturb HIV‐1 entry. Herein, the most significant advancements in topical microbicide development, trying to mimic the real‐life conditions as closely as possible, are discussed. This review also provides the preclinical assays that anionic dendrimers have passed as microbicides because they can improve current antiviral treatments' efficacy.This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Nanomedicine for Infectious DiseaseToxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

Do vaginal microbicides reduce the risk of HIV acquisition in women?

Currently, no single HIV prevention method meets the needs of all people at risk of infection and a range of options are needed for individuals to protect themselves and to curb the HIV epidemic. Many people living with HIV or at risk for HIV infection in low and middle-income countries do not have access to prevention, treatment and care, and there is still no cure. Despite large preventive efforts, HIV acquisition rates remain unacceptably high and transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Widespread violence, many sociocultural and economic factors in these regions limit the ability of women to insist on safer sexual practices to decrease HIV transmission risks. The development of vaginal HIV microbicides, the use of which would be discretely controlled or initiated by women, has therefore attracted much interest as a strategy to help prevent HIV sexual transmission. In this commentary, we discuss the evolution of vaginal microbicies, the different types that have undergone clinical trials, the past challenges to future hopes, the products that are currently in use and implications for women who are at risk to HIV infection in sub-Saharan Africa.

Enzyme Responsive Vaginal Microbicide Gels Containing Maraviroc and Tenofovir Microspheres Designed for Acid Phosphatase-Triggered Release for Pre-Exposure Prophylaxis of HIV-1: A Comparative Analysis of a Bigel and Thermosensitive Gel.

The challenges encountered with conventional microbicide gels has necessitated the quest for alternative options. This study aimed to formulate and evaluate a bigel and thermosensitive gel, designed to combat the challenges of leakage and short-residence time in the vagina. Ionic-gelation technique was used to formulate maraviroc and tenofovir microspheres. The microspheres were incorporated into a thermosensitive gel and bigel, then evaluated. Enzyme degradation assay was used to assess the effect of the acid phosphatase enzyme on the release profile of maraviroc and tenofovir microspheres. HIV efficacy and cytotoxicity of the microspheres were assessed using HIV-1-BaL virus strain and HeLa cell lines, respectively. Maraviroc and tenofovir release kinetics followed zero-order and Higuchi model kinetics. However, under the influence of the enzyme, maraviroc release was governed by first-order model, while tenofovir followed a super case II transport-mechanism. The altered mode of release and drug transport mechanism suggests a triggered release. The assay of the microspheres suspension on the HeLa cells did not show signs of cytotoxicity. The thermosensitive gel and bigel elicited a progressive decline in HIV infectivity, until at concentrations of 1 μg/mL and 0.1 μg/mL, respectively. The candidate vaginal gels have the potential for a triggered release by the acid phosphatase enzyme present in the seminal fluid, thus, serving as a strategic point to prevent HIV transmission.

PIH34 Assessing the Understandability and Importance of Patient Reported Outcomes Impacting Adherence and Outcomes of a NON-Hormonal Vaginal Microbicide to Prevent and Protect Against Chlamydia Trachomatis (CT) and Neisseria Gonorrhoeae (GC)

Treatment satisfaction, particularly sexual satisfaction, with a microbicidal vaginal gel (EVO100) to prevent urogenital CT and GC can influence adherence to the regimen. This qualitative research assessed the understandability and importance of questions/instruments used to assess product and global sexual satisfaction in the Phase 2b clinical study EVO-003 (NCT03107377). Concept elicitation and cognitive debriefing interviews were carried out in women with previous experience using EVO100. The cognitive interview methods reflected a theoretical model of the survey response process that involved 4 stages: comprehension or interpretation, information retrieval, judgment formation, and response editing. The interviews explored the concepts of sexual satisfaction and understandability of the Female Sexual Function Index (FSFI) global sexual satisfaction and product satisfaction questions. Patients were also asked about the importance of a microbicide to protect against infection and understanding the impact on sexual satisfaction. Twenty-one participants were interviewed. Average age was 27.62 (range: 20-42) years. Seventeen (81.0%) participants were White, three (14.3%) were Black and one (4.8%) was Native American. Eleven (52.4%) of participants reported being Hispanic. All participants reported the FSFI global sexual satisfaction item was well understood. The recall period was acceptable, and participants could easily recall their experiences over the 4-weeks. The second standardized question reviewed during the interviews was global product satisfaction. All 21 participants reported the question was well understood and there were no recommendations for change. Participants reported product satisfaction and the impact of microbicide on sexual satisfaction were important and meaningful concepts to assess and would be tied to product use. Participants reported adherence with use of EVO100 was related to product satisfaction and the impact on global sexual satisfaction as well as efficacy. All participants indicated that this information was important to know for women considering a microbicidal vaginal gel like EVO100.

Understanding Women's Vaginal Douching Behaviors and Practices for Consideration in the Development of a Potential Future Vaginal Microbicide Douche for HIV Prevention: A Systematic Review of the Literature.

Despite clinicians consistently advising against vaginal douching, 29-92% of women worldwide report douching. This review documents women's douching practices, motivations for douching, and specific associations (or absence of associations) between vaginal douche use and vaginal outcomes thought to be associated with douching. Understanding women's existing douching behaviors and vaginal health outcomes is critical for developing a safe vaginal microbicide douche that can be used as HIV pre-exposure prophylaxis (PrEP). A vaginal douche as PrEP could help prevent new HIV infections, since emerging evidence shows some women discontinue oral PrEP. We performed a systematic review of the literature using the guidelines for Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). Articles included in the analysis (N = 48) were published 2009-2019 in English and focused on women's experiences with douching. Two trained independent reviewers assessed these articles for content on vaginal douching, including racial/ethnic focus of studies, study design, sampling, women's reasons for douching, contents of douche solutions, and associations between vaginal douching and vaginal health outcomes. Several studies focused on Black women (N = 12 studies) or had no racial/ethnic focus (N = 12). Just over half of all studies (N = 24) were cross-sectional and involved a self-reported questionnaire and lab samples. Studies sampled women from health clinics where they were (N = 13) or were not (N = 14) presenting for vaginal health complaints. Women's primary motivation for douching was for "general cleanliness" (N = 13), and most douche solutions contained water (N = 12). There was little empirical agreement between vaginal douche use and most vaginal health outcomes. Future studies of PrEP vaginal douches should be well controlled and prioritize safety to ensure positive vaginal health outcomes.

Design aspects of vaginal applicators that influence acceptance among target users

Although sensory-guided product design is most traditionally used by food and beverage companies, the approach has widespread application for many other products, including pharmaceuticals and medical devices. Previously, our team used sensory methods to explore preclinical optimization of soft-gel vaginal microbicides. Past clinical trials suggest vaginal microbicides may be an effective means for women to protect themselves from HIV and other sexually transmitted infections, but these microbicides will not work if they are not used due to poor acceptability. Our prior work suggests properties like firmness, size, and shape all influence women’s willingness to try soft-gel vaginal suppositories. As product insertion is part of the overall experience of using vaginal microbicides, understanding the features of vaginal applicators that appeal to women, and incorporating these insights into vaginal drug delivery systems, may also improve user adherence. Despite widespread use of vaginal applicators, there is minimal public data on women’s perceptions of and preferences for physical applicator features. Other work suggests women want vaginal applicators that are single use, pre-filled, made of plastic, and easy to use, store, and discard. Applicator attributes that may be important to women, such as length, color, or visual appeal, have not been investigated previously. The objective of this research was to understand what physical applicator attributes are appealing to women. Here, 18 commercially available applicators were evaluated by a convenience sample of women (n = 102) for overall liking and perceptions of various attributes (perceived length and width, ease-of-grip, expected ease-of-use, expected comfort inside the body, visual appeal, color liking, and environmental friendliness). Preference mapping using both liking data and attribute data showed attributes such as color, visual appeal, ease of grip, expected ease of use, and expected comfort inside the body drove higher liking ratings for applicators, while perceived length negatively affected liking. In general, plastic tampon applicators contained more positive features and were better liked relative to a cardboard tampon applicator or applicators for insertion of medicated gels or suppositories. Incorporating more desirable features into applicators meant for insertion of vaginal microbicides or other vaginal medications may improve the user experience, and possibly user adherence.

Smart vaginal bilayer films of Tenofovir based on Eudragit® L100/natural polymer for the prevention of the sexual transmission of HIV

In the absence of an effective vaccine, vaginal microbicides are essential for preventing the sexual transmission of HIV to women. Antiretroviral vaginal films have emerged as promising choices, especially those offering mucoadhesivity and controlled drug release. Tenofovir-loaded bilayer films based on Eudragit® L100 (EL100) and a biopolymer – gum arabic, karaya gum, pectin or tragacanth gum – were developed in a single-stage process. Cytotoxicity studies in three human cell lines indicated no toxicity of the excipients at the concentrations tested. Raman spectroscopy and SEM confirmed the formation of the two layers and their anchoring. Texture analysis showed no major differences between the batches. The swelling of the film is conditioned by its biopolymer nature and by the amount of EL100, which acts as structuring agent thus enhancing swelling. Tragacanth gum-based batches showed high mucoadhesion regardless the amount of EL100. The controlled release of Tenofovir in simulated vaginal fluid was faster in the presence of simulated seminal fluid due to the dissolution of EL100. Films containing 400 mg of EL100 and tragacanth gum are promising candidates for future studies, as they could sexually safeguard women from HIV for at least one week and ensure greater protection during intercourse.

BMS Derivatives C7-Linked to β-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides.

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4th generation, are reported here for the first time.

Mucoadhesive Microspheres of Maraviroc and Tenofovir Designed for Pre-Exposure Prophylaxis of HIV-1: An in vitro Assessment of the Effect on Vaginal Lactic Acid Bacteria Microflora.

PurposeTo formulate and evaluate microspheres of the antiretroviral drugs maraviroc and tenofovir intended for a candidate vaginal microbicide and assess its effect on the vaginal lactic acid bacteria microflora.MethodsIonic gelation technique was used to formulate maraviroc and tenofovir microspheres with subsequent characterization. The effect of varying concentrations of the polymer, crosslinking agent and the curing time on the outcome variables viz: particle size, mucoadhesion and encapsulation efficiency were investigated. Lactic acid bacteria were isolated from the vagina of healthy women using standard microbiologic methods. The analysis of their 16S rRNA sequence data identified Lactobacillus fermentum and Enterococcus faecalis strains which were assigned GenBank accession numbers. The efficacy of the microspheres on HIV-1BaL strain was evaluated using TZM-bl indicator cells.ResultsThe optimal maraviroc and tenofovir microspheres had particle sizes of (434.82 µm and 456.18 µm), mucoadhesion of (93.3% and 90%) and encapsulation efficiency (92.80% and 78.9%) respectively. Maraviroc release kinetics followed a zero-order model and tenofovir was released via Higuchi model. The assay of a 1 mg/mL suspension of the microspheres on the strains of Lactobacillus fermentum and Enterococcus faecalis showed a viability of 93.9% and 89.7%, respectively. There was a statistically significant difference between the mean absorbance readings of the test agent and that of the positive control (P = 0.001). The microspheres elicited a progressive decline in HIV infectivity until at a concentration of 1 μg/mL.ConclusionThe antiretroviral drugs loaded in the microspheres, had good mucoadhesion which is a potential for prolonged residence time in the vagina. The antiretroviral drugs were adequately released from the microspheres and showed efficacy against the HIV-1 BaL virus strain. There was no significant disruption in the growth of the lactic acid bacteria which constitute valuable bacteria microflora of the vagina.

Acceptability and feasibility of the CHARISMA counseling intervention to support women\u2019s use of pre-exposure prophylaxis: results of a pilot study

BackgroundWomen may need or seek male partner approval to safely and consistently use oral antiretroviral pre-exposure prophylaxis (PrEP) or vaginal microbicides. We developed CHARISMA, a counseling intervention to support women’s relationships and their ability to consistently use HIV prevention products.MethodsIn a pilot study with 95 female participants in Johannesburg, South Africa, lay counselors implemented CHARISMA, assessing participants’ relationship(s) with their male partner(s) and barriers or facilitators to HIV prevention method use, and then providing tailored, interactive counseling. We conducted study participant surveys and clinic staff interviews to evaluate CHARISMA’s feasibility and acceptability.ResultsThe CHARISMA pilot study indicates that a two-session relationship counseling intervention with 6-month follow-up to support women’s ability to safely and effectively use vaginal microbicides was generally acceptable and feasible. Most participants thought CHARISMA was relevant, helpful, and about the right length, and that it had a positive impact on their relationships with their partners and their product use. Staff estimated that the intervention took 1.5–2 h to implement at enrollment and 45 min to an hour for the month 1 visit. They thought that overall CHARISMA was generally feasible to implement.ConclusionsFindings from this study suggest several lessons learned that may be relevant to others developing interventions supporting women’s use of oral PrEP or vaginal microbicides. The use of lay counselors instead of nurses to deliver counseling appeared to be successful, but the counselors experienced significant stress from hearing about participants’ traumatic experiences and required emotional support to avoid burnout. Although staff and participants felt that having multiple intervention sessions over time was valuable, a similar level of intensity may not be feasible in other settings. Further research is needed to determine an intervention delivery mode and follow-up period that optimally balances participant needs and clinic resources. Male engagement was a challenge, as it has been in previous studies of vaginal microbicides. Alternative strategies to reach men that do not require them to come to the clinic or rely on their female partners may be more effective.

Topical microbicides for preventing sexually transmitted infections.

This is a updated version of our Cochrane Review published in Issue 6, 2012. Sexually-transmitted infections (STIs) continue to rise worldwide, imposing an enormous morbidity and mortality burden. Effective prevention strategies, including microbicides, are needed to achieve the goals of the World Heath Organization (WHO) global strategy for the prevention and control of these infections. To determine the effectiveness and safety of topical microbicides for preventing acquisition of STIs, including HIV. We undertook a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CLIB, Web of Science, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and reference lists of relevant articles up to August 2020. In addition, we contacted relevant organisations and experts. We included randomised controlled trials of vaginal microbicides compared to placebo (except for nonoxynol-9 because it is covered in related Cochrane Reviews). Eligible participants were sexually-active non-pregnant, WSM and MSM, who had no laboratory confirmed STIs. Two review authors independently screened and selected studies, extracted data, and assessed risks of bias in duplicate, resolving differences by consensus. We conducted a fixed-effect meta-analysis, stratified by type of microbicide, and assessed the certainty of the evidence using the GRADE approach. We included eight trials from the earlier version of the review and four new trials, i.e. a total of 12 trials with 32,464 participants (all WSM). We did not find any eligible study that enrolled MSM or reported fungal STI as an outcome. We have no study awaiting assessment. All 12 trials were conducted in sub-Saharan Africa, with one having a study site in the USA, and another having a site in India. Vaginal microbicides tested were BufferGel and PRO 2000 (1 trial, 3101 women), Carraguard (1 trial, 6202 women), cellulose sulphate (2 trials, 3069 women), dapivirine (2 trials, 4588 women), PRO 2000 (1 trial, 9385 women), C31G (SAVVY) (2 trials, 4295 women), and tenofovir (3 trials, 4958 women). All microbicides were compared to placebo and all trials had low risk of bias. Dapivirine probably reduces the risk of acquiring HIV infection: risk ratio (RR) 0.71, (95% confidence interval (CI) 0.57 to 0.89, I2 = 0%, 2 trials, 4588 women; moderate-certainty evidence). The other microbicides may result in little to no difference in the risk of acquiring HIV (low-certainty evidence); including tenofovir (RR 0.83, 95% CI 0.68 to 1.02,cellulose sulphate (RR 1.20, 95% CI 0.74 to 1.95, BufferGel (RR 1.05, 95% CI 0.73 to 1.52), Carraguard (RR 0.89, 95% CI 0.71 to 1.11), PRO 2000 (RR 0.93, 95% CI 0.77 to 1.14), and SAVVY (RR 1.38, 95% CI 0.79 to 2.41). Existing evidence suggests that cellulose sulphate (RR 0.99, 95% CI 0.37 to 2.62, 1 trial, 1425 women), and PRO 2000 (RR 0.95, 95% CI 0.73 to 1.23) may result in little to no difference in the risk of getting herpes simplex virus type 2 infection (low-certainty evidence). Two studies reported data on tenofovir's effect on this virus. One suggested that tenofovir may reduce the risk (RR 0.55, 95% CI 0.36 to 0.82; 224 participants) while the other did not find evidence of an effect (RR 0.94, 95% CI 0.85 to 1.03; 1003 participants). We have not reported the pooled result because of substantial heterogeneity of effect between the two studies (l2 = 85%). The evidence also suggests that dapivirine (RR 1.70, 95% CI 0.63 to 4.59), tenofovir (RR 1.27, 95% CI 0.58 to 2.78), cellulose sulphate (RR 0.69, 95% CI 0.26 to 1.81), and (Carraguard (RR 1.07, 95% CI 0.75 to 1.52) may have little or no effect on the risk of acquiring syphilis (low-certainty evidence). In addition, dapivirine (RR 0.97, 95% CI 0.89 to 1.07), tenofovir (RR 0.90, 95% CI 0.71 to 1.13), cellulose sulphate (RR 0.70, 95% CI 0.49 to 0.99), BufferGel (RR 0.97, 95% CI 0.65 to 1.45), Carraguard (RR 0.96, 95% CI 0.83 to 1.12), and PRO 2000 (RR 1.01, 95% CI 0.84 to 1.22) may result in little to no difference in the risk of acquiring chlamydia infection (low-certainty evidence). The evidence also suggests that current topical microbicides may not have an effect on the risk of acquiring gonorrhoea, condyloma acuminatum, trichomoniasis, or human papillomavirus infection (low-certainty evidence). Microbicide use in the 12 trials, compared to placebo, did not lead to any difference in adverse event rates. No study reported on acceptability of the intervention. AUTHORS' CONCLUSIONS: Current evidence shows that vaginal dapivirine microbicide probably reduces HIV acquisition in women who have sex with men. Other types of vaginal microbicides have not shown evidence of an effect on acquisition of STIs, including HIV. Further research should continue on the development and testing of new microbicides.