Impact of Dapivirine and Placebo Vaginal Rings on the Microbiota of Adolescent, Lactating, and Postmenopausal Females

Abstract Background A 25 mg dapivirine vaginal ring has been demonstrated to reduce risk of HIV acquisition in nonpregnant adult women. In this secondary analysis of studies conducted in US adolescent, lactating, and postmenopausal females, vaginal microbiota was assessed prior to and after ring use, and between dapivirine and placebo ring users. Methods Vaginal fluid swabs were collected before and after product use for the evaluation of microbiota using Nugent’s criteria, quantitative culture, and qPCR. Results Vaginal ring use did not impact bacterial vaginosis prevalence among the three populations and was associated with minimal shifts in microbiota. Adolescents in both arms demonstrated an increased prevalence of Lactobacillus crispatus and a decrease in quantity of Megasphaera lornae. Postmenopausal active and placebo ring users demonstrated an increased prevalence of lactobacilli and non-albicans yeast while dapivirine ring users demonstrated an increased prevalence of Candida albicans, and increased quantity of Group B Streptococcus (GBS) and non-albicans yeasts. Prevotella species were increased in lactating women while P. timonensis increased in prevalence and concentration among adolescent and postmenopausal women and P. bivia increased in prevalence among adolescent dapivirine ring users. Conclusions Dapivirine vaginal ring use was associated with minimal changes in the vaginal microbiota that are likely not clinically significant.

Download Full-text

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

10.31234/osf.io/su2kw ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Ex Vivo ◽

Oral Treatment ◽

Plasma Concentrations ◽

Vaginal Ring ◽

Vaginal Fluid ◽

Cervical Tissue ◽

Double Blind ◽

Group A ◽

Group B ◽

Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

Download Full-text

Group B Streptococcus and the Vaginal Microbiota

The Journal of Infectious Diseases ◽

10.1093/infdis/jix395 ◽

2017 ◽

Vol 216 (6) ◽

pp. 744-751 ◽

Cited By ~ 18

Author(s):

Geoffrey H Rosen ◽

Tara M Randis ◽

Purnahamsi V Desai ◽

Katherine J Sapra ◽

Bing Ma ◽

...

Keyword(s):

Group B Streptococcus ◽

Vaginal Microbiota ◽

Group B

Download Full-text

Is the Risk of HIV Acquisition Increased during and Immediately after Pregnancy? A Secondary Analysis of Pooled HIV Community-Based Studies from the ALPHA Network

PLoS ONE ◽

10.1371/journal.pone.0082219 ◽

2013 ◽

Vol 8 (12) ◽

pp. e82219 ◽

Cited By ~ 12

Author(s):

Milly Marston ◽

Marie Louise Newell ◽

Amelia Crampin ◽

Tom Lutalo ◽

Richard Musoke ◽

...

Keyword(s):

Secondary Analysis ◽

Community Based ◽

Hiv Acquisition ◽

Risk Of Hiv Acquisition

Download Full-text

Is Group B Streptococcus Colonization Associated with Maternal Peripartum Infection in an Era of Routine Prophylaxis?

American Journal of Perinatology ◽

10.1055/s-0040-1709666 ◽

2020 ◽

Author(s):

Kartik K. Venkatesh ◽

Catherine J. Vladutiu ◽

Angelica V. Glover ◽

Robert A. Strauss ◽

Jeffrey S.A. Stringer ◽

...

Keyword(s):

Group B Streptococcus ◽

Secondary Analysis ◽

Lower Odds ◽

Trial Of Labor ◽

Prepregnancy Body Mass Index ◽

Key Points ◽

Routine Prophylaxis ◽

Secondary Analyses ◽

Multivariable Analyses ◽

Group B

Objective This study aimed to assess whether colonization with group B streptococcus (GBS) is associated with maternal peripartum infection in an era of routine prophylaxis. Study Design This study presented a secondary analysis of women delivering ≥37 weeks who underwent a trial of labor from the U.S. Consortium on Safe Labor (CSL) study. The exposure was maternal GBS colonization and the outcome was a diagnosis of chorioamnionitis, and secondarily, analyses were restricted to deliveries not admitted in labor and measures of postpartum infection (postpartum fever, endometritis, and surgical site infection). Logistic regression with generalized estimating equations was used accounting for within-woman correlations. Models adjusted for maternal age, parity, race, prepregnancy body mass index, pregestational diabetes, insurance status, study site/region, year of delivery, number of vaginal exams from admission to delivery, and time (in hours) from admission to delivery. Results Among 170,804 assessed women, 33,877 (19.8%) were colonized with GBS and 5,172 (3.0%) were diagnosed with chorioamnionitis. While the frequency of GBS colonization did not vary by chorioamnionitis status (3.0% in both groups), in multivariable analyses, GBS colonization was associated with slightly lower odds of chorioamnionitis (adjusted odds ratio [AOR]: 0.89; 95% confidence interval [CI]: 0.83–0.96). In secondary analyses, this association held regardless of spontaneous labor on admission; and the odds of postpartum infectious outcomes were not higher with GBS colonization. Conclusion In contrast to historical data, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis. Key Points

Download Full-text

Cytokine Profiles Before and After Exchange Transfusions in Severe Late-Onset Neonatal Group B Streptococcus Meningitis: A Case Report

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.253.269 ◽

2021 ◽

Vol 253 (4) ◽

pp. 269-273

Author(s):

Mina Chishiki ◽

Hayato Go ◽

Kisei Endo ◽

Nahoko Katayama Ueda ◽

Hiroki Takehara ◽

...

Keyword(s):

Case Report ◽

Late Onset ◽

Group B Streptococcus ◽

Cytokine Profiles ◽

Before And After ◽

Neonatal Group ◽

Group B

Download Full-text

Beyond bacterial vaginosis: vaginal lactobacilli and HIV risk

Microbiome ◽

10.1186/s40168-021-01183-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Eric Armstrong ◽

Rupert Kaul

Keyword(s):

Bacterial Vaginosis ◽

Hiv Risk ◽

Anaerobic Bacteria ◽

Vaginal Microbiota ◽

Bacterial Survival ◽

Associated Bacteria ◽

Eastern And Southern Africa ◽

Hiv Acquisition ◽

Risk Of Hiv Acquisition ◽

Species Specific

AbstractHIV incidence continues to be unacceptably high in Eastern and Southern Africa, with women disproportionately affected. An increased per-contact risk of HIV acquisition among African, Caribbean, and other Black (ACB) women has been associated with the higher prevalence of bacterial vaginosis (BV) in these communities, wherein the vaginal microbiota is predominated by diverse pro-inflammatory anaerobic bacteria. However, while the vaginal microbiota in BV-free women is typically predominated by one of several different Lactobacillus spp., the degree of HIV protection afforded by a Lactobacillus-predominant vaginal microbiota also varies considerably. Specifically, L. crispatus is associated with an immunoregulatory genital immune environment, exclusion of BV-associated bacteria, and reduced HIV risk. In contrast, less HIV protection or exclusion of BV-associated bacteria and fewer immune benefits have been associated with L. iners—which is unfortunately the most common Lactobacillus species among ACB women. These species-specific clinical differences are underpinned by substantial genomic differences between Lactobacillus species: for instance, the much smaller genome of L. iners lacks the coding sequence for D-lactic acid dehydrogenase and cannot produce the D-lactate isomer that enhances HIV trapping in mucus but encodes for epithelial cell toxins and stress resistance proteins that may enhance bacterial survival in the context of microbiota and environmental fluctuations. While more studies are needed to elucidate whether differences in HIV protection between Lactobacillus species are due to direct genital immune effects or the exclusion of proinflammatory BV-associated bacteria, the current body of work suggests that for BV treatment to succeed as an HIV prevention strategy, it may be necessary to induce a vaginal microbiota that is predominated by specific (non-iners) Lactobacillus species.

Download Full-text

Diversity and composition of vaginal microbiota of pregnant women at risk for transmitting Group B Streptococcus treated with intrapartum penicillin

PLoS ONE ◽

10.1371/journal.pone.0169916 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0169916 ◽

Cited By ~ 8

Author(s):

Luiz Fernando Wurdig Roesch ◽

Rita C. Silveira ◽

Andréa L. Corso ◽

Priscila Thiago Dobbler ◽

Volker Mai ◽

...

Keyword(s):

At Risk ◽

Pregnant Women ◽

Group B Streptococcus ◽

Vaginal Microbiota ◽

Group B

Download Full-text

Pediatric meningitis due to Neisseria meningitidis, Streptococcus pneumoniae and Group B Streptococcus in Tijuana, Mexico: active/prospective surveillance, 2005–2018

Therapeutic Advances in Infectious Disease ◽

10.1177/2049936119832274 ◽

2019 ◽

Vol 6 ◽

pp. 204993611983227

Author(s):

Enrique Chacon-Cruz ◽

Christopher Roberts ◽

Rosa Maria Rivas-Landeros ◽

Erika Zoe Lopatynsky-Reyes ◽

Lucila Alejandra Almada-Salazar ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Neisseria Meningitidis ◽

Active Surveillance ◽

Descriptive Analysis ◽

Group B Streptococcus ◽

Prospective Surveillance ◽

Conventional Culture ◽

Young Infants ◽

Before And After ◽

Group B

Introduction: In Mexico, Neisseria meningitidis is considered to be a rare cause of bacterial meningitis (BM), however, one national publication using active surveillance has suggested the opposite. Group B Streptococcus (GBS) is also considered to be infrequent in young infants as a cause of BM in central Mexico. Streptococcus pneumoniae vaccination using the 13-valent conjugate vaccine (PCV13) started in our region in May 2012. We focused our research on whether N. meningitidis and GBS are important causes of BM, and to examine the effectiveness of PCV13 on pneumococcal BM. Methods: From October 2005 to September 2018, active/prospective surveillance looking for all patients admitted with suspected BM <16 years of age was performed at the Tijuana, Mexico, General Hospital. Tijuana, Mexico to San Diego, Unites States of America (USA), is the most transited border in the world. Isolation of pathogens was by either conventional culture or Real Time-polymerase chain reaction (RT-PCR), all patients were followed during and 3 months after discharge, and a descriptive analysis was performed. The effectiveness of PCV13 was determined by comparing the proportion of cases per month on pneumococcal BM before and after its implementation. Results: There were 86 confirmed BM cases. N. meningitidis was the leading cause (60.5%, and 61.5% caused by serogroup C), followed by S. pneumoniae (18.6%). PCV13 effectiveness on pneumococcal BM was of 64.3% and was associated with the disappearance of serotype 19A. A total of 22 infants <3 months old had BM; GBS was the leading cause at this age group (27.3%), followed by N. meningitidis (22.7%). The overall mortality was 24%. Conclusions: BM by N. meningitidis is endemic in Tijuana, Mexico, and meningococcal vaccination should be seriously considered in the region. PCV13 is currently showing high effectiveness on pneumococcal BM, and we need to continue active surveillance to see whether maternal screening/prophylaxis for GBS should also be introduced in the region.

Download Full-text

Digital Image Analysis for the Detection of Group B Streptococcus from ChromID Strepto B Medium Using PhenoMatrix Algorithms

Journal of Clinical Microbiology ◽

10.1128/jcm.01902-19 ◽

2020 ◽

Vol 59 (1) ◽

pp. e01902-19

Author(s):

Justin Baker ◽

Karen Timm ◽

Matthew Faron ◽

Nathan Ledeboer ◽

Karissa Culbreath

Keyword(s):

Digital Image ◽

Molecular Detection ◽

Clinical Performance ◽

Group B Streptococcus ◽

Neonatal Morbidity ◽

The United States ◽

Nucleic Acid Amplification ◽

Adult Women ◽

True Positive ◽

Group B

ABSTRACTGroup B Streptococcus (GBS) can be found to colonize about 25% of all healthy, adult women and is the leading infectious cause of early neonatal morbidity and mortality in the United States. This study evaluated the clinical performance of PhenoMatrix (PM) chromogenic detection module (CDM) digital imaging software in detection of GBS from LIM broth plated on ChromID Strepto B chromogenic medium (ChromID) using the WASP automated processor. The performance of the PM CDM was compared to manual culture review of the digital images and molecular detection of GBS. ChromID alone had a sensitivity and specificity of 84.5% and 94.7%, respectively, after 48 h compared to nucleic acid amplification testing (NAAT). Compared to the composite reference for positivity, when PM CDM was used to detect GBS from ChromID, the sensitivity was 100%, with no true-positive GBS isolates missed by 48 h of incubation. Overall, evaluating all three methods for the detection of GBS, the sensitivities of NAAT, ChromID plus PM CDM at 48 h, and ChromID alone at 48 h were 96.8%, 95.5%, and 90.3%, respectively. The specificities of NAAT, ChromID plus PM CDM, and ChromID alone were 97.7%, 63.0%, and 95.4%, respectively. The sensitivity of ChromID in combination with the PM CDM was similar to the sensitivity of molecular detection. Further, the algorithm never called a culture negative that was determined to be positive by manual reading, and it identified an additional eight true positive specimens that were missed by manual digital image culture reading.

Download Full-text

Diversity of Vaginal Microbiota Affects Epithelial Barrier Permeability Among African Pregnant Women

10.21203/rs.3.rs-218032/v1 ◽

2021 ◽

Author(s):

Lois Bayigga BBLT ◽

Rose Nabatanzi ◽

Emilie Mausser ◽

David P. Kateete ◽

Musa Sekikubo ◽

...

Keyword(s):

Epithelial Cells ◽

Pregnant Women ◽

Inflammatory Cytokines ◽

Bacterial Cell ◽

Vaginal Microbiota ◽

Epithelial Barrier ◽

Vaginal Epithelial Cells ◽

Hiv Acquisition ◽

Risk Of Hiv Acquisition ◽

Pro Inflammatory Cytokines

Abstract BackgroundWomen with diverse genital anaerobic bacterial communities, are at over 4-fold higher risk of HIV acquisition than women with a Lactobacillus-rich vaginal microbiome. The mechanisms underlying this are poorly understood. We set out to examine how vaginal microbiota diversity affects epithelial integrity in HIV sero-negative pregnant women. We also investigated how HIV infection alters mucosal integrity within the prevalent genital microbiome diversity.MethodsWe assessed epithelial permeability by measuring the concentrations of tight junction proteins, claudin-1 and zonula occludens- (ZO)-1, in cervico-vaginal lavages (CVL) by enzyme-linked immunosorbent assay (ELISA). Cytokines in the vaginal fluids were measured by multiplex magnetic bead assay to establish the inflammatory state. Bacterial cell-free supernatants were used to treat vaginal epithelial cells and tissues, mimicking the in-vivo vaginal milieu. Gene and protein expression levels of tight junctions of vaginal epithelial cells and tissues in response to treatment were quantified by QuantiGene™ Plex Gene Expression Assay and by western blot respectively. The cytokine response of vaginal epithelial cells, VK2 (E6/E7, ATCC® CRL-2616™), to bacterial cell-free supernatants was measured by ELISA method.Results Among women with CT3 cervicotype, HIV sero-negative pregnant women had significantly higher claudin-1 in their CVL than the HIV-infected pregnant women (p=0.0011). IL-8 (p=0.0028), IL-1beta (p<0.0001) and TNF-alpha (p=0.0283) were significantly higher among HIV-negative pregnant women with a non-Lactobacillus dominant vaginal microbiota than those with a Lactobacillus-dominant vaginal microbiota. Bacterial cell-free supernatants from Lactobacillus elicited low levels of pro-inflammatory cytokines IL-1alpha, IL8, IL-6 and IL-1 beta in comparison to media and G. vaginalis. Treatment with G. vaginalis supernatant lowers claudin-1 and claudin-4 expression yet presence of either L. crispatus or L. iners mitigates this effect of G. vaginalis as observed by immuno-staining of treated vaginal cells.Conclusions Pregnant women with a non-Lactobacillus dominant microbiome had a disrupted epithelial barrier and elevated pro-inflammatory cytokines, making them at a higher risk of HIV acquisition than women with a Lactobacillus-dominant microbiome. Targeting vaginal microbiota and/or its effects on the vaginal epithelium and cervico-vaginal milieu can potentially lower rates of HIV acquisition and transmission.

Download Full-text