A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.

Assessing Per-Sex-Act HIV-1 Risk Reduction Among Women Using the Dapivirine Vaginal Ring.

BACKGROUND: Confounding introduced by individuals' sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use. METHODS: We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18-45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use. RESULTS: Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8-3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9-4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction. CONCLUSIONS: These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use. CLINICAL TRIALS REGISTRATION: NCT01617096.

Amygdalobacter indicium gen. nov., sp. nov., and Amygdalobacter nucleatus sp. nov., gen. nov.: novel bacteria from the family Oscillospiraceae isolated from the female genital tract.

Four obligately anaerobic Gram-positive bacteria representing one novel genus and two novel species were isolated from the female genital tract. Both novel species, designated UPII 610-JT and KA00274T, and an additional isolate of each species were characterized utilizing biochemical, genotypic and phylogenetic analyses. All strains were non-motile and non-spore forming, asaccharolytic, non-cellulolytic and indole-negative coccobacilli. Fatty acid methyl ester analysis for UPII 610-JT and KA00274T and additional isolates revealed C16 : 0, C18 : 0, C18:1ω9c and C18:2ω6,9c to be the major fatty acids for both species. UPII 610-JT had a 16S rRNA gene sequence similarity of 99.4 % to an uncultured clone sequence (AY724740) designated as Bacterial Vaginosis Associated Bacterium 2 (BVAB2). KA00274T had a 16S rRNA gene sequence similarity of 96.5 % to UPII 610-JT. Whole genomic DNA mol% G+C content was 42.2 and 39.3 % for UPII 610-JT and KA00274T, respectively. Phylogenetic analyses indicate these isolates represent a novel genus and two novel species within the Oscillospiraceae family. We propose the names Amygdalobacter indicium gen. nov., sp. nov., for UPII 610-JT representing the type strain of this species (=DSM 112989T, =ATCC TSD-274T) and Amygdalobacter nucleatus gen. nov., sp. nov., for KA00274T representing the type strain of this species (=DSM 112988T, =ATCC TSD-275T).

Population-Level Correlation Between Incidence of Curable Sexually Transmitted Infections and Human Immunodeficiency Virus (HIV)-1 Among African Women Participating in HIV-1 Pre-Exposure Prophylaxis Trials.

BACKGROUND: Highly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for human immunodeficiency virus (HIV)-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STIs) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP. METHODS: We analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modeling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1. RESULTS: Across 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe), STI and HIV-1 incidences were high: HIV-1 4.9, N gonorrhoeae 5.3, C trachomatis 14.5, and T vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N gonorrhoeae (r = 0.02, P = .871), C trachomatis (r = 0.49, P = <.001), and T vaginalis (r = 0.10, P = .481). The modest association with C trachomatis was driven by country-level differences in both C trachomatis and HIV-1, with no statistically significant association within countries. CONCLUSIONS: Sexually transmitted infection incidence did not reliably predict HIV-1 incidence at the population level among at-risk African women participating in 2 large PrEP trials.

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

BACKGROUND: A 25-mg dapivirine vaginal ring has been demonstrated to reduce risk of human immunodeficiency virus (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 criteria, quantitative culture, and quantitative polymerase chain reaction. RESULTS: Vaginal ring use did not impact bacterial vaginosis prevalence among the 3 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 and non-albicans yeasts. Prevotella species were increased in lactating women, whereas Prevotella timonensis increased in prevalence and concentration among adolescent and postmenopausal females and Prevotella 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.

Reduced Endometrial Ascension and Enhanced Reinfection Associated With Immunoglobulin G Antibodies to Specific Chlamydia trachomatis Proteins in Women at Risk for Chlamydia.

BACKGROUND: Previous research revealed antibodies targeting Chlamydia trachomatis elementary bodies was not associated with reduced endometrial or incident infection in C. trachomatis-exposed women. However, data on the role of C. trachomatis protein-specific antibodies in protection are limited. METHODS: A whole-proteome C. trachomatis array screening serum pools from C. trachomatis-exposed women identified 121 immunoprevalent proteins. Individual serum samples were probed using a focused array. Immunoglobulin (Ig) G antibody frequencies and endometrial or incident infection relationships were examined using Wilcoxon rank sum test. The impact of the breadth and magnitude of protein-specific IgGs on ascension and incident infection were examined using multivariable stepwise logistic regression. Complementary RNA sequencing quantified C. trachomatis gene transcripts in cervical swab samples from infected women. RESULTS: IgG to pGP3 and CT_005 were associated with reduced endometrial infection; anti-CT_443, anti-CT_486, and anti-CT_123 were associated with increased incident infection. Increased breadth of protein recognition did not however predict protection from endometrial or incident infection. Messenger RNAs for immunoprevalent C. trachomatis proteins were highly abundant in the cervix. CONCLUSIONS: Protein-specific C. trachomatis antibodies are not sufficient to protect against ascending or incident infection. However, cervical C. trachomatis gene transcript abundance positively correlates with C. trachomatis protein immunogenicity. These abundant and broadly recognized antigens are viable vaccine candidates.

MTN-033: a Phase 1 Study Comparing Applicator versus "as Lubricant" Delivery of Rectal Dapivirine Gel.

Data to inform behaviorally congruent delivery of rectal microbicides as lubricants are scant. Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor which has been demonstrated to be well-tolerated and efficacious in multiple clinical trials when used in a vaginal ring formulation. DPV gel administered rectally with an applicator was found to be well-tolerated in a phase 1 clinical trial. MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV-negative men to receive 0.05% DPV gel intrarectally using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). The study evaluated the pharmacokinetics (in plasma, rectal fluid, and mucosal rectal tissue), safety, acceptability, and pharmacodynamics of DPV gel when applied rectally. Statistical comparisons between methods of application were performed using mixed effects models or Wilcoxon's signed rank tests. Sixteen participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean, 1.8 g; SD, 0.8). DPV plasma AUC0-24h after use as lubricant was estimated to be 0.41 times the AUC0-24h (95% CI 0.24, 0.88) after use with applicator. While DPV was quantifiable in plasma and luminal fluid, it was not quantifiable in tissue for both applicator and as lubricant administration. No related adverse events (AE) were reported, and 15/15 participants felt the gel was easy to use. Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant supports the feasibility and potential for development of lubricant-delivered rectal microbicides. There were no safety concerns associated with use of DPV gel and participants reported finding it easy to use. However, lower DPV exposure in plasma and lack of quantifiable DPV in rectal tissue indicate that higher potency, concentration, and longer half-life antiretrovirals with optimized formulations will be needed to achieve protective tissue concentrations.

Topical Microbicides in HIV Prevention: State of the Promise.

HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field.

A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease.

Pelvic inflammatory disease (PID) is a syndrome that causes substantial morbidity, including chronic pelvic pain, to women globally. While limited data are available from low- and middle-income countries, national databases from the United States and Europe suggest that PID incidence may be decreasing but the rate of decrease may differ by the etiologic cause. Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a substantial fraction of PID cases. The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID. Advances in serologic testing for Chlamydia trachomatis and Neisseria gonorrhoeae could advance epidemiologic studies, while the development of vaccines against these sexually transmitted pathogens could affect incident PID and associated morbidity.

Etiology and Diagnosis of Pelvic Inflammatory Disease: Looking Beyond Gonorrhea and Chlamydia.

Pelvic inflammatory disease (PID) is a clinical syndrome that has been associated with a wide range of potential causal pathogens. Three broad groups of organisms have been isolated from the genital tract of people with PID: sexually transmitted organisms such as Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis; bacterial vaginosis (BV)-associated species and genera such as Atopobium vaginae, Sneathia, and Megasphaera; and genera and species usually associated with the gastrointestinal or respiratory tracts such as Bacteroides, Escherichia coli, Streptococcus, or Haemophilus influenza. Although PID is often considered to be synonymous with gonorrhea or chlamydia, these pathogens are found in only one quarter to one third of people with PID, suggesting that broader screening and diagnostic and treatment strategies need to be considered to reduce the burden of PID and its associated sequelae.

Host Genetic Risk Factors for Chlamydia trachomatis-Related Infertility in Women.

BACKGROUND: Chlamydia trachomatis (Ct) infection ascending to the upper genital tract can cause infertility. Direct association of genetic variants as contributors is challenging because infertility may not be diagnosed until years after infection. Investigating the intermediate trait of ascension bridges this gap. METHODS: We identified infertility genome-wide association study (GWAS) loci using deoxyribonucleic acid from Ct-seropositive cisgender women in a tubal factor infertility study and Ct-infected cisgender women from a longitudinal pelvic inflammatory disease cohort with known fertility status. Deoxyribonucleic acid and blood messenger ribonucleic acid from 2 additional female cohorts with active Ct infection and known endometrial infection status were used to investigate the impact of infertility single-nucleotide polymorphisms (SNPs) on Ct ascension. A statistical mediation test examined whether multiple infertility SNPs jointly influenced ascension risk by modulating expression of mediator genes. RESULTS: We identified 112 candidate infertility GWAS loci, and 31 associated with Ct ascension. The SNPs altered chlamydial ascension by modulating expression of 40 mediator genes. Mediator genes identified are involved in innate immune responses including type I interferon production, T-cell function, fibrosis, female reproductive tract health, and protein synthesis and degradation. CONCLUSIONS: We identified Ct-related infertility loci and their potential functional effects on Ct ascension.

Diagnosis and Treatment of Vaginal Discharge Syndromes in Community Practice Settings.

BACKGROUND: Although vaginal symptoms are common, diagnosis of bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and Trichomonas vaginalis (TV) is not standardized. Diagnostic approaches and appropriateness of treatment were evaluated for women with symptoms of vaginitis who were seeking care at community practice sites. METHODS: Three hundred three symptomatic women, across 8 University of Pittsburgh Medical Center-affiliated clinics, were evaluated per standard office-based practice. Four of 5 vaginal swabs (1 cryopreserved) were collected for a US Food and Drug Administration-authorized nucleic acid amplification test (NAAT) for vaginitis/vaginosis diagnosis; Nugent scoring (BV); yeast culture (VVC); and a second NAAT (for TV). Two hundred ninety women had evaluable samples. Medical record extraction facilitated verification of treatments prescribed within 7 days of the index visit and return visit frequency within 90 days. RESULTS: Women had a mean age of 29.4 ± 6.5 years, 90% were not pregnant, 79% were of white race, and 38% reported vaginitis treatment within the past month. Point-of-care tests, including vaginal pH (15%), potassium hydroxide/whiff (21%), and wet mount microscopy (17%), were rarely performed. Of the 170 women having a laboratory-diagnosed cause of vaginitis, 81 (47%) received 1 or more inappropriate prescriptions. Of the 120 women without BV, TV, or VVC, 41 (34%) were prescribed antibiotics and/or antifungals. Among women without infectious vaginitis, return visits for vaginitis symptoms were more common among women treated empirically compared to those not receiving treatment (9/41 vs 5/79, P = .02). CONCLUSIONS: Within a community practice setting, 42% of women having vaginitis symptoms received inappropriate treatment. Women without infections who received empiric treatment were more likely have recurrent visits within 90 days. CLINICAL TRIALS REGISTRATION: NCT03151928.

A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease.

BACKGROUND: Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID). The currently recommended PID regimen of a single dose of ceftriaxone and doxycycline for 14 days has limited anaerobic activity. The need for broader anaerobic coverage is unknown and concerns have been raised about metronidazole tolerability. METHODS: We conducted a randomized, double-blind, placebo-controlled trial comparing ceftriaxone 250 mg intramuscular single dose and doxycycline for 14 days, with or without 14 days of metronidazole in women with acute PID. The primary outcome was clinical improvement at 3 days following enrollment. Additional outcomes at 30 days following treatment were the presence of anaerobic organisms in the endometrium, clinical cure (absence of fever and reduction in tenderness), adherence, and tolerability. RESULTS: We enrolled 233 women (116 to metronidazole and 117 to placebo). Clinical improvement at 3 days was similar between the 2 groups. At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, P < .05) and cervical Mycoplasma genitalium was reduced (4% vs 14%, P < .05). Pelvic tenderness was also less common among women receiving metronidazole (9% vs 20%, P < .05). Adverse events and adherence were similar in each treatment group. CONCLUSIONS: In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium, and reduced pelvic tenderness compared to ceftriaxone and doxycycline. Metronidazole should be routinely added to ceftriaxone and doxycycline for the treatment of women with acute PID. CLINICAL TRIALS REGISTRATION: NCT01160640.

Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study.

BACKGROUND: Limited evidence suggests that the nonhormonal contraceptive copper intrauterine device (Cu-IUD) may increase bacterial vaginosis (BV) risk, possibly due to increased volume and duration of menses, a common side effect of Cu-IUD use. Although increases in bleeding typically resolve within 6-12 months following initiation, evaluations of the association between Cu-IUD and BV have not included more than 6 months of follow-up. METHODS: This secondary analysis of a human immunodeficiency virus type 1 prevention trial included 2585 African women ages 18-45 followed for up to 33 months. Women reported contraceptive use each month. BV was evaluated by Nugent score in 6-monthly intervals and, if clinically indicated, by Amsel criteria. Andersen-Gill proportional hazards models were used to (1) evaluate BV risk among Cu-IUD users relative to women using no/another nonhormonal contraceptive and (2) test changes in BV frequency before, while using, and following Cu-IUD discontinuation. RESULTS: BV frequency was highest among Cu-IUD users at 153.6 episodes per 100 person-years (95% confidence interval [CI]: 145.2, 162.4). In adjusted models, Cu-IUD users experienced 1.28-fold (95% CI: 1.12, 1.46) higher BV risk relative to women using no/another nonhormonal contraception. Compared to the 6 months prior to initiation, BV risk was 1.52-fold (95% CI: 1.16, 2.00) higher in the first 6 months of Cu-IUD use and remained elevated over 18 months of use (P < .05). Among women who discontinued Cu-IUD, BV frequency was similar to pre-initiation rates within 1 year. CONCLUSIONS: Cu-IUD users experienced elevated BV risk that persisted throughout use. Women and their providers may wish to consider BV risk when discussing contraceptive options.

Nucleic Acid Amplification Testing Compared With Cultures, Gram Stain, and Microscopy in the Diagnosis of Vaginitis.

OBJECTIVE: The aim of the study was to evaluate the performance of nucleic acid amplification testing (NAAT) for the diagnosis of vulvovaginal candidiasis (VVC), bacterial vaginosis, and Trichomonas vaginalis. METHODS: A cross-sectional analysis of women with (n = 200) and without (n = 100) vulvovaginal symptoms was enrolled from outpatient gynecology offices and a vulvovaginal referral clinic. Vaginal swabs were analyzed by wet mount microscopy, yeast culture, Gram stain, T. vaginalis culture, and NAAT. Sensitivity and specificity analyses were performed. RESULTS: Among symptomatic women, the sensitivity of microscopy was 48.5% for VVC and 75% for T. vaginalis. Sensitivities of NAAT and culture for diagnosing VVC were 92.4% and 83.3%, respectively, whereas these methods were 100% and 93.8% for T. vaginalis. The sensitivity for bacterial vaginosis diagnosis by clinical criteria ("Amsel criteria"), Gram stain, and NAAT were 98.7%, 82.7%, and 78.7%, respectively. Test concordance rates were high between culture and NAAT for Candida species (91%) and between Gram stain and NAAT for the detection of bacterial vaginosis (88%). Among asymptomatic women, 20%-21% tested positive for bacterial vaginosis by Gram stain or NAAT, and 8%-13% were colonized with Candida species based on culture or NAAT. CONCLUSIONS: Given the limitations of wet mount sensitivity for VVC and T. vaginalis, culture or NAAT testing should be considered when evaluating women with symptoms of vaginitis who test negative by microscopy. Although Amsel criteria accurately diagnosed bacterial vaginosis, NAAT is preferred for detection of T. vaginalis and performed similarly to culture for the diagnosis of VVC.

Characteristics of the vaginal microbiome in women with and without clinically confirmed vulvodynia.

BACKGROUND: Vulvodynia (idiopathic vulvar pain) affects up to 8% of women by age 40 years, has a poorly understood etiology, and has variable treatment efficacy. Several risk factors are associated with vulvodynia from a history of yeast infections to depression and allergies. Recent work suggests an altered immune inflammatory mechanism plays a role in vulvodynia pathophysiology. Because the vaginal microbiome plays an important role in local immune-inflammatory responses, we evaluated the vaginal microbiome among women with vulvodynia compared with controls as 1 component of the immune system. OBJECTIVE: The objective of the study was to characterize the vaginal microbiome in women with clinically confirmed vulvodynia and age-matched controls and assess its overall association with vulvodynia and how it may serve to modify other factors that are associated with vulvodynia as well. STUDY DESIGN: We conducted a case-control study of 234 Minneapolis/Saint Paul-area women with clinically confirmed vulvodynia and 234 age-matched controls clinically confirmed with no history of vulvar pain. All participants provided vulvovaginal swab samples for culture-based and non-culture (sequencing)-based microbiological assessments, background and medical history questionnaires on demographic characteristics, sexual and reproductive history, and history of psychosocial factors. Vaginal microbiome diversity was assessed using the Shannon alpha diversity Index. Data were analyzed using logistic regression. RESULTS: Culture and molecular-based analyses of the vaginal microbiome showed few differences between cases and controls. However, among women with alpha diversity below the median (low), there was a strong association between increasing numbers of yeast infections and vulvodynia onset, relative to comparable time periods among controls (age-adjusted odds ratio, 8.1, 95% confidence interval, 2.9-22.7 in those with 5 or more yeast infections). Also among women with low-diversity microbiomes, we observed a strong association between moderate to severe childhood abuse, antecedent anxiety, depression, and high levels of rumination and vulvodynia with odds ratios from 1.83 to 2.81. These associations were not observed in women with high-diversity microbiomes. CONCLUSION: Although there were no overall differences in microbiome profiles between cases and controls, vaginal microbiome diversity influenced associations between environmental and psychosocial risk factors and vulvodynia. However, it is unclear whether vaginal diversity modifies the association between the risk factors and vulvodynia or is altered as a consequence of the associations.

Tenofovir Gel for Prevention of Herpes Simplex Virus Type 2 Acquisition: Findings From the VOICE Trial.

BACKGROUND: Genital infection with herpes simplex virus type 2 (HSV-2) is common and increases risk of human immunodeficiency virus (HIV) transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 study. METHODS: We measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blinded, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 preexposure prophylaxis. The TFV level in plasma at the first quarterly visit was used as a measure of gel use. RESULTS: Of 566 participants at risk for HSV-2 acquisition, 532 (94%) had first-quarter plasma TFV and end-of-study HSV-2 serologic data available. Over a follow-up period of 501 person-years, 92 incident cases of HSV-2 acquisition occurred: 77 were in women with no TFV detected in plasma, and 15 occurred in women with TFV detected in plasma (incidence, 20.6 cases/100 person-years [95% confidence interval [CI], 16.2-25.7] vs 11.9 cases/100 person-years [95% CI, 6.6-19.6], respectively). TFV detection in plasma was associated with a trend toward a reduced risk of HSV-2 seroconversion, with an unadjusted hazard ratio (HR) of 0.59 (95% CI, .34-1.02; P = .060) and a HR adjusted for site, age, having ≥2 male sex partners in the past 3 months, use of hormonal contraception, having anal sex in the past 3 months, and HIV status of 0.60 (95% CI, .33-1.08; P = .086). CONCLUSIONS: Detection of TFV in plasma among TFV gel users was associated with a trend toward a reduced risk of HSV-2 acquisition, after controlling for sexual behavior and HIV-1 acquisition.

Cervical Cytokines Associated With Chlamydia trachomatis Susceptibility and Protection.

BACKGROUND: Chlamydia trachomatis can cause reproductive morbidities after ascending to the upper genital tract of women, and repeated infection can lead to worse disease. Data related to protective immune responses at the cervical mucosa that could limit chlamydial infection to the cervix and/or prevent reinfection inform vaccine approaches and biomarkers of risk. METHODS: We measured 48 cytokines in cervical secretions from women having chlamydial cervical infection alone (n = 92) or both cervical and endometrial infection (n = 68). Univariable regression identified cytokines associated with differential odds of endometrial infection and reinfection risk, and multivariable stepwise regression identified cytokine ratios associated with differential risk. RESULTS: Elevated interleukin (IL) 15/CXCL10 (odds ratio [OR], 0.55 [95% confidence interval {CI}, .37-.78]), IL-16/tumor necrosis factor-α (OR, 0.66 [95% CI, .45-.93]), and CXCL14/IL-17A (OR, 0.73 [95% CI, .54-.97]) cytokine ratios were significantly (P ≤ .05) associated with decreased odds of endometrial infection. A higher Flt-3L/IL-14 ratio was significantly (P = .001) associated with a decreased risk of reinfection (hazard ratio, 0.71 [95% CI, .58-.88]). CONCLUSIONS: Cytokines involved in humoral, type I interferon, and T-helper (Th) 17 responses were associated with susceptibility to C. trachomatis, whereas cytokines involved in Th1 polarization, recruitment, and activation were associated with protection against ascension and reinfection.

A Phase 2, Randomized, Control Trial of Group B Streptococcus (GBS) Type III Capsular Polysaccharide-tetanus Toxoid (GBS III-TT) Vaccine to Prevent Vaginal Colonization With GBS III.

BACKGROUND: Group B Streptococcus (GBS) frequently colonizes pregnant women and can cause sepsis and meningitis in young infants. If colonization was prevented through maternal immunization, a reduction in perinatal GBS disease might be possible. A GBS type III capsular polysaccharide (CPS)-tetanus toxoid conjugate (III-TT) vaccine was evaluated for safety and efficacy in preventing acquisition of GBS colonization. METHODS: Healthy, nonpregnant women aged 18-40 years and screened to be GBS III vaginal and rectal culture negative were randomized to receive III-TT conjugate or tetanus diphtheria toxoid vaccine in a multicenter, observer-blinded trial. GBS vaginal and rectal cultures and blood were obtained bimonthly over 18 months. Serum concentrations of GBS III CPS-specific antibodies were determined using enzyme-linked immunosorbent assay. RESULTS: Among 1525 women screened, 650 were eligible for the intent-to-treat analysis. For time to first acquisition of vaginal GBS III, vaccine efficacy was 36% (95% confidence interval [CI], 1%-58%; P = .044), and for first rectal acquisition efficacy was 43% (95% CI, 11% to 63%; P = .014). Two months post-immunization, geometric mean concentrations of serum GBS type III CPS-specific immunoglobulin G were 12.6 µg/mL (95% CI, 9.95 to 15.81) in GBS III-TT recipients, representing a 4-fold increase from baseline in 95% of women, which persisted. Both vaccines were well tolerated. CONCLUSIONS: GBS CPS III-TT conjugate vaccine significantly delayed acquisition of vaginal and rectal GBS III colonization. In addition to its use for maternal immunization to passively protect infants with maternally derived antibodies, a multivalent vaccine might also serve to reduce fetal and neonatal exposure to GBS. CLINICAL TRIALS REGISTRATION: NCT00128219.

Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring.

Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirine vaginal ring (VR) reduced women's risk of sexually transmitted HIV infection in two phase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, and Birmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposed to the drug, but infant dosage was estimated according to FDA guidance. Adverse events (AEs) were collected at all contacts. The study was completed with 100% participant retention. Median dapivirine concentrations were 676 pg/ml in breast milk, 327 pg/ml in plasma (milk/plasma ratio ∼2.0), and 36.25 ng/mg in CVF. Six participants experienced 10 total AEs, none of which required VR discontinuation. The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first study of dapivirine exposure during lactation, dapivirine VR use was associated with lower concentrations of detectable dapivirine in milk and plasma than in CVF samples and a favorable safety profile. Estimated daily levels of infant dapivirine exposure were also low. Additional studies are needed to evaluate longer periods of dapivirine VR use among BF mother-infant pairs living in regions with higher incidence of sexually transmitted HIV infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02808949.).