Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: A Pilot Study Incorporating Microscopy and Sequencing.

Bacterial vaginosis (BV) is associated with HIV acquisition and adverse pregnancy outcomes. Recurrence after metronidazole treatment is high. HIV-negative, non-pregnant Rwandan BV patients were randomized to four groups (n = 17/group) after seven-day oral metronidazole treatment: behavioral counseling only (control), or counseling plus intermittent use of oral metronidazole, Ecologic Femi+ vaginal capsule (containing multiple Lactobacillus and one Bifidobacterium species), or Gynophilus LP vaginal tablet (L. rhamnosus 35) for two months. Vaginal microbiota assessments at all visits included Gram stain Nugent scoring and 16S rRNA gene qPCR and HiSeq sequencing. All interventions were safe. BV (Nugent 7-10) incidence was 10.18 per person-year at risk in the control group, and lower in the metronidazole (1.41/person-year; p = 0.004), Ecologic Femi+ (3.58/person-year; p = 0.043), and Gynophilus LP groups (5.36/person-year; p = 0.220). In mixed effects models adjusted for hormonal contraception/pregnancy, sexual risk-taking, and age, metronidazole and Ecologic Femi+ users, each compared to controls, had higher Lactobacillus and lower BV-anaerobes estimated concentrations and/or relative abundances, and were less likely to have a dysbiotic vaginal microbiota type by sequencing. Inter-individual variability was high and effects disappeared soon after intervention cessation. Lactobacilli-based vaginal probiotics warrant further evaluation because, in contrast to antibiotics, they are not expected to negatively affect gut microbiota or cause antimicrobial resistance.

Impact of oral metronidazole treatment on the vaginal microbiota and correlates of treatment failure.

BACKGROUND: Metronidazole is the first-line treatment for bacterial vaginosis, but cure rates are suboptimal and recurrence rates high. OBJECTIVES: To evaluate the impact of a standard course of oral metronidazole treatment (500 mg twice per day for 7 days) on the vaginal microbiota of Rwandan bacterial vaginosis patients using microscopy and 16S rRNA gene sequencing, and to evaluate correlates of treatment failure. STUDY DESIGN: HIV-negative, nonpregnant women aged 18-45 years with bacterial vaginosis and/or Trichomonas vaginalis (N=68) were interviewed and sampled before and after metronidazole treatment. They were also screened, and treated if applicable, for other urogenital infections. The vaginal microbiota was assessed by Gram stain Nugent scoring, Illumina 16S rRNA HiSeq sequencing (relative abundances), and BactQuant 16S gene quantitative polymerase chain reaction (estimated concentrations). Only women with a pretreatment Nugent score of 7-10 and a valid posttreatment Nugent score (N=55) were included in metronidazole treatment failure analyses, with treatment failure defined as a posttreatment Nugent score of 4-10. RESULTS: The bacterial vaginosis cure rate by Nugent scoring was 54.5%. The mean total vaginal bacterial concentration declined from 6.59 to 5.85 log10/µL (P<.001), which was mostly due to a reduction in mean bacterial vaginosis-associated anaerobes concentration (all bacterial vaginosis-associated anaerobe taxa combined) from 6.23 to 4.55 log10/µL (P<.001). However, only 16.4% of women had a bacterial vaginosis anaerobes concentration reduction of more than 50%, and only 3 women had complete eradication. The mean concentration of lactobacilli (all species combined) increased from 4.98 to 5.56 log10/µL (P=.017), with L. iners being the most common species pre- and posttreatment. The mean concentration of pathobionts (defined as Proteobacteria, streptococci, staphylococci, enterococci, and a few others) did not change significantly: from 1.92 log10/µL pretreatment to 2.01 log10/µL posttreatment (P=.939). Pretreatment pathobionts concentration, and having a pretreatment vaginal microbiota type containing more than 50% Gardnerella vaginalis (compared with less than 50%), were associated with increased likelihood of treatment failure, but the latter did not reach statistical significance (P=.044 and P=.084, respectively). CONCLUSIONS: Metronidazole alone may not cure women with high G. vaginalis relative abundance, potentially due to biofilm presence, and women with high pathobionts concentration. These women may benefit from additional biofilm-disrupting and/or pathobiont-targeting treatments.

Targeted point-of-care testing compared with syndromic management of urogenital infections in women (WISH): a cross-sectional screening and diagnostic accuracy study.

BACKGROUND: Sexually transmitted and urogenital infections are typically managed by WHO-recommended syndromic algorithms in resource-poor countries, and presumptively in Europe. However, algorithms for vaginal discharge and lower abdominal pain perform poorly in women. The women's improvement of sexual and reproductive health (WISH) study in Kigali, Rwanda, sought to improve case-finding and infection management in women by introducing point-of-care tests. The main aim was to compare the performance of the WISH algorithms and the WHO vaginal discharge and lower abdominal pain algorithms with gold standard testing. METHODS: This cross-sectional screening and diagnostic accuracy study recruited women aged 18 years or older with or without urogenital symptoms at risk of acquiring sexually transmitted infections in Kigali, Rwanda. Recruitment activities were implemented by study staff with the help of community mobilisers at health centres, pharmacies, markets, women's organisations, and at "umuganda" community meetings. At the study visit, participants had a face-to-face interview that included questions about current urogenital symptoms. Participants were first asked without prompting (spontaneous reporting), followed by questions about 14 specific symptoms (structural reporting). Next, the WISH algorithms were implemented. All participants had point-of-care tests for bacterial vaginosis (vaginal pH of 5·0 or above) and Trichomonas vaginalis (immunoassay) regardless of symptom reporting. Women with a positive risk score had point-of-care tests for Chlamydia trachomatis and Neisseria gonorrhoea (nucleic acid amplification tests). Vulvovaginal candidiasis was treated presumptively. Nucleic acid amplification tests for C trachomatis, N gonorrhoeae, T vaginalis, bacterial vaginosis, and vulvovaginal candidiasis were the gold standard, and all patients provided swabs for these. FINDINGS: Participants were recruited between July 5, 2016, and March 14, 2017. 705 participants were enrolled in the study and completed a study visit, and 51 attended 53 additional visits. Prevalence by gold standard testing was 8·5% for C trachomatis, 7·1% for N gonorrhoeae, 16·1% for T vaginalis, 18·1% for bacterial vaginosis, and 8·6% for vulvovaginal candidiasis. The WISH algorithms identified similar numbers of C trachomatis, N gonorrhoeae, and T vaginalis infections, but much higher numbers of bacterial vaginosis and vulvovaginal candidiasis infections. Compared with gold standard testing, the WISH algorithms had a good sensitivity and high specificity for C trachomatis (sensitivity 71·7%, specificity 100%), N gonorrhoeae (sensitivity 76·0%, specificity 100%), and T vaginalis (sensitivity 68·5%, specificity 97·4%), high sensitivity but low specificity for bacterial vaginosis (sensitivity 95·2%, specificity 41·2%), and moderate sensitivity and specificity for vulvovaginal candidiasis (sensitivity 64·4%, specificity 69·4%). The performance of vaginal pH testing for bacterial vaginosis improved by increasing the cutoff to 5·5, followed by confirmatory testing (sensitivity 73·6%, specificity 100%). The WHO algorithms had moderate sensitivity and poor specificity for all infections compared with gold standard testing: C trachomatis sensitivity 58·3%, specificity 44·7%; N gonorrhoeae sensitivity 66·0%, specificity 45·2%; T vaginalis sensitivity 60·4%, specificity 45·6%; bacterial vaginosis sensitivity 61·6%, specificity 46·0%; and vulvovaginal candidiasis sensitivity 74·6%, specificity 50·6%. Two participants attended additional visits because they had a mild allergic reaction to metronidazole. Staff and participants considered point-of-care testing feasible and acceptable. INTERPRETATION: Point-of-care testing for urogenital infections might improve case-finding and infection management and is feasible in resource-poor settings. Point-of-care tests should be further developed, including those targeting multiple conditions. Additional studies in other populations, including populations with low prevalence of sexually transmitted and urogenital infections, are warranted. FUNDING: European and Developing Countries Clinical Trials Partnership.

The ring plus project: safety and acceptability of vaginal rings that protect women from unintended pregnancy.

BACKGROUND: Research is ongoing to develop multipurpose vaginal rings to be used continuously for contraception and to prevent Human Immunodeficiency Virus (HIV) infection. Contraceptive vaginal rings (CVRs) are available in a number of countries and are most of the time used intermittently i.e. three weeks out of a 4-week cycle. Efficacy trials with a dapivirine-containing vaginal ring for HIV prevention are ongoing and plans to develop multi-purpose vaginal rings for prevention of both HIV and pregnancy have been elaborated. In contrast with the CVRs, multi-purpose vaginal rings will have to be used continuously. Women who continuously use a CVR will no longer have menses. Furthermore, some safety aspects of CVR use have never been studied in-depth in the past, such as the impact of the vaginal ring on the vaginal microbiota, biofilm formation and induction of inflammation. We studied acceptability and these novel aspects of safety in Rwandan women. Although significant progress has been made over the past decade, Rwanda still has a high unmet need for contraception (with 47% unplanned births) and a generalized HIV epidemic, and CVRs are not yet available. METHODS: We will conduct an open label, single centre, randomized controlled trial. A total of 120 HIV-negative women will be randomized to intermittent CVR use (to allow menstruation) or continuous CVR use. Women will be followed for a maximum of 14 weeks. In parallel, we will conduct a qualitative study using in-depth interview and focus group discussion methodology. DISCUSSION: In addition to evaluating the safety and acceptability of intermittent and continuous CVR use in Rwandan women, we hope that our findings will inform the development of future multipurpose vaginal rings, will prepare Rwandan study populations for future clinical trials of multipurpose vaginal rings, and will pave the way for introduction of CVRs on African markets. TRIAL REGISTRATION: Clinicaltrials.gov NCT01796613 . Registered 14 February 2013.