Effectiveness of vaginal microbicides in preventing HIV transmission.

OBJECTIVE: To evaluate the evidence on the effectiveness of vaginal microbicides in preventing HIV transmission in women. METHODS: Systematic review through a comprehensive search of relevant electronic databases for eligible randomised controlled trials (RCTs) published through June 2019. Two authors independently screened titles and abstracts according to eligibility criteria, then extracted data and assessed risk of bias of included studies. We conducted a random-effects meta-analysis of risk ratios (RR) of HIV infection and assessed heterogeneity using chi-squared and I2 tests. Sources of heterogeneity were investigated through subgroup analysis, publication bias was assessed using funnel plots, and certainty of evidence was graded using GRADEPro software. RESULTS: We included 18 RCTs which enrolled 40,048 sexually active, HIV-negative, non-pregnant women, aged 16 years and older, mainly from sub-Saharan Africa. The intravaginal ring containing dapivirine significantly reduced HIV risk by 29% (RR 0.71, 95% CI: 0.57-0.89; 2 RCTs, 4,564 women, moderate certainty of evidence). Estimates of effect of tenofovir 1% (RR 0.83, 95% CI: 0.65-1.06), nonoxynol-9 (RR 1.15, 95% CI: 0.93-1.42), cellulose sulphate (RR 1.16, 95% CI: 0.61-2.21), SAVVY (RR 1.34, 95% CI: 0.69-2.59), Carraguard (RR 0.89, 95% CI: 0.71-1.10), BufferGel (RR 1.02, 95% CI: 0.71-1.46), 0.5% PRO2000 (RR 0.88, 95% CI: 0.60-1.28) and 2% PRO2000 (RR 0.81, 95% CI: 0.58-1.12) failed to reach statistical significance; each had low certainty of evidence. CONCLUSION: The long-acting intravaginal ring containing dapivirine significantly reduced risk of HIV transmission in women by 29%. The remaining microbicides had no evident effect.

OBJECTIF: Evaluer les données probantes sur l'efficacité des microbicides vaginaux dans la prévention de la transmission du VIH chez les femmes. MÉTHODES: Analyse systématique à travers une recherche exhaustive des bases de données électroniques pertinentes pour les essais contrôlés randomisés (ECR) éligibles publiés jusqu'en juin 2019. Deux auteurs ont indépendamment passé en revue les titres et résumés selon des critères d'éligibilité, les données ont alors été extraites et le risque de biais évalué pour des études incluses. Nous avons effectué une méta-analyse des effets aléatoires des rapports de risque (RR) de l'infection par le VIH et évalué l'hétérogénéité à l'aide des tests Chi2 et I2 . Les sources d'hétérogénéité ont été étudiées par analyse de sous-groupes, le biais de publication a été évalué à l'aide de graphiques en entonnoir et la certitude des données a été évaluée à l'aide du logiciel GRADEPro. RÉSULTATS: Nous avons inclus 18 ECR qui ont recruté 40.048 femmes sexuellement actives, négatives pour le VIH, non enceintes, âgées de 16 ans et plus, principalement d'Afrique subsaharienne. L'anneau intravaginal contenant de la dapivirine a significativement réduit le risque de VIH de 29% (RR: 0,71 ; IC95%: 0,57-0,89; 2 ECR, 4564 femmes, certitude modérée des preuves). Les estimations de l'effet du ténofovir 1% (RR: 0,83 ; IC95%: 0,65-1,06), du nonoxynol-9 (RR: 1,15 ; IC95%: 0,93-1,42), du sulfate de cellulose (RR: 1,16 ; IC 95%: 0,61-2,21 ), du SAVVY (RR: 1,34 ; IC95%: 0,69-2,59), du Carraguard (RR: 0,89, IC95%: 0,71-1,10), du BufferGel (RR: 1,02 ; IC95%: 0,71-1,46), du PRO2000 à 0,5% (RR: 0,88 ; IC95%: 0,60-1,28) et du PRO2000 à 2% (RR: 0,81 ; IC95%: 0,58-1,12) n'ont pas atteint la signification statistique; tous avaient une faible certitude d'évidence. CONCLUSION: L'anneau intravaginal à longue durée d'action contenant de la dapivirine a réduit de manière significative le risque de transmission du VIH chez les femmes de 29%. Les autres microbicides n'ont eu aucun effet évident.

In vitro evaluation of microbial adhesion to a contraceptive vaginal ring with a new polymer composition.

Objective: The aim of the study was to evaluate in vitro the amount of Candida albicans and Lactobacillus acidophilus adhering to the surface of Ornibel, a contraceptive vaginal ring with a new polymer composition, in comparison with NuvaRing. Methods: Ornibel and NuvaRing were tested for adhesion of microorganisms in vitro. The vaginal rings were aseptically sectioned into 1 cm segments. Suspensions of C. albicans (1-2 × 107 colony-forming units [CFU]/ml) and L. acidophilus (1-2 × 108 CFU/ml) were prepared and incubated either in monoculture or as co-culture with the ring segments. After incubation, adherent C. albicans and L. acidophilus were quantified by plate counting. Results: In monoculture, the measured amount of adhesion of C. albicans on the ring surface was significantly lower with Ornibel compared with NuvaRing (p = 6.77 × 10-5), while the adherence of L. acidophilus did not differ between the two rings. Similarly, when co-incubated with C. albicans, the number of adhering L. acidophilus microorganisms was significantly lower with Ornibel compared with NuvaRing (p = .018) . This reduction also resulted in significantly lower levels of adhering L. acidophilus in co-culture compared with L. acidophilus when incubated alone (p = .003). Conclusion: The study demonstrates that the adherence of C. albicans, as well as that of L. acidophilus when co-cultured with C. albicans, is lower with the Ornibel vaginal ring compared with NuvaRing. These in vitro findings warrant future human trials using molecular techniques to assess the vaginal microbiota composition and to establish whether Ornibel can support vaginal health.

Contraceptive rings promote vaginal lactobacilli in a high bacterial vaginosis prevalence population: A randomised, open-label longitudinal study in Rwandan women.

BACKGROUND: Hormonal contraception has been associated with a reduced risk of vaginal dysbiosis, which in turn has been associated with reduced prevalence of sexually transmitted infections (STIs), including HIV. Vaginal rings are used or developed as delivery systems for contraceptive hormones and antimicrobial drugs for STI and HIV prevention or treatment. We hypothesized that a contraceptive vaginal ring (CVR) containing oestrogen enhances a lactobacilli-dominated vaginal microbial community despite biomass accumulation on the CVR's surface. METHODS: We enrolled 120 women for 12 weeks in an open-label NuvaRing® study at Rinda Ubuzima, Kigali, Rwanda. Vaginal and ring microbiota were assessed at baseline and each ring removal visit by Gram stain Nugent scoring (vaginal only), quantitative PCR for Lactobacillus species, Gardnerella vaginalis and Atopobium vaginae, and fluorescent in situ hybridization to visualize cell-adherent bacteria. Ring biomass was measured by crystal violet staining. RESULTS: Bacterial vaginosis (BV) prevalence was 48% at baseline. The mean Nugent score decreased significantly with ring use. The presence and mean log10 concentrations of Lactobacillus species in vaginal secretions increased significantly whereas those of G. vaginalis and presence of A. vaginae decreased significantly. Biomass accumulated on the CVRs with a species composition mirroring the vaginal microbiota. This ring biomass composition and optical density after crystal violet staining did not change significantly over time. CONCLUSIONS: NuvaRing® promoted lactobacilli-dominated vaginal microbial communities in a population with high baseline BV prevalence despite the fact that biomass accumulated on the rings.

Comparison of the vaginal microbial communities in women with recurrent genital HSV receiving acyclovir intravaginal rings.

Vaginally administered antiviral agents may reduce the risk of HIV and HSV acquisition. Delivery of these drugs using intravaginal rings (IVRs) holds the potential benefits of improving adherence and decreasing systemic exposure, while maintaining steady-state drug levels in the vaginal tract. Elucidating how IVRs interact with the vaginal microbiome constitutes a critical step in evaluating the safety of these devices, as shifts the vaginal microbiome have been linked with several disease states. To date, clinical IVR trials have relied on culture-dependent methods that omit the high diversity of unculturable microbial population. Longitudinal, culture-independent characterization of the microbiota in vaginal samples from 6 women with recurrent genital HSV who used an acyclovir IVR was carried out and compared to the communities developing in biofilms on the IVR surface. The analysis utilized Illumina MiSeq sequence datasets generated from bar-coded amplicons of 16S rRNA gene fragments. Specific taxa in the vaginal communities of the study participants were found to be associated with the duration of recurrent genital HSV status and the number of HSV outbreaks. Taxonomic comparison of the vaginal and IVR biofilm communities did not reveal any significant differences, suggesting that the IVRs were not systematically enriched with members of the vaginal microbiome. Device usage did not alter the participants' vaginal microbial communities, within the confines of the current study design. Rigorous, molecular analysis of the effects of intravaginal devices on the corresponding microbial communities shows promise for integration with traditional approaches in the clinical evaluation of candidate products.

Vaginal health in contraceptive vaginal ring users - A review.

BACKGROUND: To provide an overview of the available data from clinical studies of vaginal conditions in women who use a vaginal ring as a contraceptive. METHODS: A systematic review of the literature. RESULTS: Millions of women have already used the ethylene vinyl acetate vaginal ring that releases ethinylestradiol and etonogestrel for contraception. Because of its small size, more than four out of five women using the ring report that they do not feel it, even during sexual intercourse. No colposcopic or cytological changes have been observed in users, although approximately 10% have increased vaginal discharge. While in vitro studies have shown adhesion of Candida yeasts to the vaginal ring surface, clinical studies have not demonstrated a greater incidence of Candida infections compared to users of equivalent oral contraceptives. Some clinical studies suggest a lower incidence of bacterial vaginosis. No interaction exists between concomitant use of the vaginal ring and other drugs or products for vaginal use. CONCLUSION: The use of a contraceptive vaginal ring does not alter the vaginal ecosystem and therefore does not substantially affect vaginal health.

Microbial biofilms on the surface of intravaginal rings worn in non-human primates.

Millions of intravaginal rings (IVRs) are used by women worldwide for contraception and for the treatment of vaginal atrophy. These devices also are suitable for local and systemic sustained release drug delivery, notably for antiviral agents in human immunodeficiency virus pre-exposure prophylaxis. Despite the widespread use of IVRs, no studies have examined whether surface-attached bacterial biofilms develop in vivo, an important consideration when determining the safety of these devices. The present study used scanning electron microscopy, fluorescence in situ hybridization and confocal laser scanning microscopy to study biofilms that formed on the surface of IVRs worn for 28 days by six female pig-tailed macaques, an excellent model organism for the human vaginal microbiome. Four of the IVRs released the nucleotide analogue reverse transcriptase inhibitor tenofovir at a controlled rate and the remaining two were unmedicated. Large areas of the ring surfaces were covered with monolayers of epithelial cells. Two bacterial biofilm phenotypes were found to develop on these monolayers and both had a broad diversity of bacterial cells closely associated with the extracellular material. Phenotype I, the more common of the two, consisted of tightly packed bacterial mats approximately 5 µm in thickness. Phenotype II was much thicker, typically 40 µm, and had an open architecture containing interwoven networks of uniform fibres. There was no significant difference in biofilm thickness and appearance between medicated and unmedicated IVRs. These preliminary results suggest that bacterial biofilms could be common on intravaginal devices worn for extended periods of time.

Can Lactobacillus acidophilus influence the adhesion capacity of Candida albicans on the combined contraceptive vaginal ring?

BACKGROUND: This study was conducted to evaluate the influence of Lactobacillus acidophilus on the adhesion capacity of Candida albicans on the combined contraceptive vaginal ring (CCVR). STUDY DESIGN: Two vaginal isolates of C. albicans and an ATCC strain of lactobacilli were used. Isolated and associated yeasts and bacteria (co-aggregated) were employed on the CCVR adherence assays and scanning electron microscopy (SEM). RESULTS: Isolated yeasts and lactobacilli adhered strongly to the CCVR. After the co-aggregation, there were an increase in adhesion capacity of the yeasts (p<.001) and a diminished adhesion of the lactobacilli (p<.001). SEM showed the isolated and co-aggregated microorganisms intimately attached to the irregularities of the CCVR. CONCLUSIONS: If these findings correlated with the conditions in vivo, the use of probiotics based on L. acidophilus or its presence in the vaginal microbiota would not protect against the adhesion of C. albicans to the ring.

Promoting continuous use as a strategy for achieving adherence in a trial of the diaphragm with candidate microbicide.

Women need more choices for protection from HIV and other sexually transmitted infections (STIs). We conducted a randomized 4-week study in Madagascar in preparation for a Phase III randomized controlled trial (RCT) of the diaphragm with a candidate microbicide for STI prevention. All participants completed quantitative surveys; half participated in a qualitative interview. We advised women to wear the diaphragm at all times except for daily cleaning (rather than inserting it before intercourse). The objective of this analysis was to determine whether women who followed this "continuous use" approach more often used the diaphragm for 100% of sex acts as compared with other women. If so, this would support advising continuous diaphragm use in the upcoming RCT. To meet our objective, we analyzed qualitative data thematically, developed a measure of continuous diaphragm use based on qualitative data, and used multiple regression to evaluate the measure's association with adherence to diaphragm use during 100% of sex acts. Women who wore the diaphragm continuously had 4 times higher odds of reporting diaphragm use during 100% of sex acts (OR: 4.6, 95% CI: 1.2, 24.0). If the diaphragm proves effective against STI, continuous use may help women achieve high levels of protection.

Vaginal yeast adherence to the combined contraceptive vaginal ring (CCVR).

BACKGROUND: The purpose of this study was to evaluate the in vitro adherence of different yeasts, isolated from vaginal exudates of patients with vulvovaginal candidiasis (VVC), to the combined contraceptive vaginal ring--NuvaRing. STUDY DESIGN: Four isolates of Candida sp. and one isolate of Saccharomyces cerevisiae were used. Adherence assays were carried out through colony-forming units per milliliter (CFU/mL), radiolabeled quantification and scanning electron microscopy (SEM) of the ring, and the cell surface hydrophobicity (CSH) of the yeasts was determined. RESULTS: All the yeasts were capable of adhering to the vaginal ring, as determined by CFU/mL and in the radiolabeled assay. CSH was compatible with the adherence by CFU/mL. CONCLUSION: SEM proved the adhesion, which was different between Candida albicans and C. tropicalis. The adherence of the tested yeasts to the ring could potentially facilitate the development of VVC and recurrent VVC in susceptible patients using this contraceptive method.

Vaginal Staphylococcus aureus superantigen profile shift from 1980 and 1981 to 2003, 2004, and 2005.

We determined vaginal Staphylococcus aureus superantigens. Staphylococci were quantified from tampons/diaphragms in 2003 to 2005, with counts compared to those determined in 1980 and 1981. In 2003 to 2005, more women were colonized than in 1980 and 1981 (23 versus 12%). Enterotoxins G and I and enterotoxin-like superantigens M and N declined, but enterotoxin-like superantigens K, L, and Q increased.

Lea's Shield: colposcopic and microbiological testing during 8 weeks of use.

OBJECTIVES: The aims of this study were to assess the effects of Lea's Shield(R) plus nonoxynol-9 spermicide on signs and symptoms of female genital irritation and cervical and vaginal microflora during 8 weeks of use with intercourse and to analyze problems associated with the use of the device. METHODS: In this open-label, single-arm study, participants were evaluated by pelvic examination, colposcopy and vaginal and cervical cultures. RESULTS: About 13% of women (4/30) reported symptoms of irritation, and minor product-related colposcopic findings were seen in about one third (11/30). Although average colony counts for enterococcus, Escherichia coli and anaerobic gram-negative rods increased during product use, no clinical diagnoses of infection were made. Most users reported at least one problem using Lea's Shield. CONCLUSION: Lea's Shield, when used for 8 weeks during intercourse, is associated with evidence of genital irritation in a minority of users and with changes in vaginal microflora that do not appear to correlate with clinical infections.

A scanning electron microscopic study of the contraceptive vaginal ring.

OBJECTIVE: To compare by electron microscopy the surface of vaginal contraceptive rings before and after use. METHODS: A single ring was worn for 28 days by a volunteer with normal vaginal flora. This worn ring was then cut in half, with one half placed directly into fixative and the other half rinsed to remove visible mucus prior to being placed into the fixative. Another ring was taken directly from the package and placed in fixative. The surfaces of the three ring samples were studied by scanning electron microscopy at varying magnifications to ascertain if there was penetration of bacteria into the vinyl polymer or if the ring surface was altered with 1 month of use. RESULTS: The ring half placed directly into fixative with visible mucus had cellular debris on its surface but no evidence of material penetration. The other half of the ring worn for 28 days and rinsed before fixation had a similar surface appearance to the unused ring. CONCLUSIONS: The surface of the ethylene vinyl acetate contraceptive vaginal ring is remarkably uniform and after 1 month of use was without visible evidence of erosion, embedded bacteria or structural changes compared to an unused ring.