Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

Phase 4

Completed

Conditions: Menopause Related Conditions
Menopause
Atrophic Vaginitis
Aging
HIV Infection
Vaginal Atrophy
Dysbiosis
Vaginitis
Premature Aging

Interventions: Drug: Estradiol Vaginal Insert

Registration Number: NCT04079218

Lead Sponsor: Kerry Murphy

Brief Summary: During menopause, there is a decrease in a hormone estrogen, which leads to aging of the vagina. Vaginal aging includes changes in the type and amount of healthy bacteria in the vagina, inflammation and a breakdown of natural barriers that keep the vagina healthy and protected from infections. Some menopausal women develop a condition called vaginal atrophy, which causes vaginal dryness, irritation, pain with sex, and itching. We are testing whether an estradiol tablet placed inside the vagina will lead to fewer changes in the types of bacteria present in the vagina, improve vaginal atrophy symptoms and ultimately keep the vagina healthier for a longer. This is important for women with HIV as they are living longer, healthier, sexually active lives due to successful treatment with antiretrovirals.

Detailed Description: HIV may be associated with premature aging in the female genital tract including alterations in the vaginal microbiome and mucosal inflammation, which may increase risk for vaginal atrophy, urinary tract infections (UTI) and other genital tract infections. This study will determine whether use of vaginal estradiol for 12 weeks in menopausal women living with HIV with symptomatic vaginal atrophy will improve atrophy symptoms and the vaginal microbiome and reduce mucosal inflammation thereby improving vaginal health. This study will include 50 participants randomized to treatment with a vaginal estradiol insert or no therapy for 12 weeks and will have 4 study visits.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 60

Inclusion Criteria

HIV infection
Females aged 45-70
Menopause defined by having no menstrual periods for 12 consecutive months, confirmed with serum follicle-stimulating hormone (FSH) level >40 IU/ml and serum estradiol level <20 pg/ml
Symptomatic vaginal atrophy defined as reporting at least once per week in the past 30 days, 1 or more of the following symptoms of moderate or severe intensity: Dryness, Itching, Irritation, Soreness or pain OR Pain associated with sexual activity at least once
Evidence of atrophy on exam, including thin, pale and dry vaginal and vulvar surfaces
Agrees not to use vaginal products other than vaginal estradiol tablet during the clinical trial

Exclusion Criteria

Current or previous history of breast cancer or estrogen dependent neoplasia
Current or past thromboembolic disease (deep vein thrombosis or pulmonary embolism, not including thrombophlebitis)
Current or previous history of myocardial infarction or stroke
Known blood clotting disorders including Protein C, Protein S and antithrombin deficiency, Factor V Leiden or prothrombin mutations
Known severe liver disease including cirrhosis or active Hepatitis B
History of adverse reaction to vaginal estradiol
Current unexplained or unevaluated abnormal genital bleeding
Current or suspected pregnancy
If < age 55, had a hysterectomy and has at least one ovary
Pelvic or vaginal surgery in the prior 60 days
Use of systemic reproductive hormones in the past 2 months
Antibiotic use in the past 30 days
Use of immunosuppressive medications in the prior 60 days including biologics, chemotherapeutics or post-transplant immunosuppressive medications
Use of any vaginal or vulvar preparations 1 month prior to enrollment
Current active vaginal infection (diagnosed by wet mount at Visit 1 or 2)
Any serious disease or chronic condition that might interfere with study compliance
Unwilling to agree to the provisions of the protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Estradiol Vaginal Insert	Estradiol Vaginal Insert	Using a pre-loaded single-use plastic applicator, participants will insert one 10 microgram estradiol tablet intravaginally daily for 2 weeks and then one tablet twice weekly for the remainder of the study for a total of 12 weeks.

Primary Outcome Measures

Name	Time	Method
Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Between baseline (Visit 2) and 12 weeks (Visit 5)	Change in the severity of MBS of vaginal atrophy as reported during the baseline visit was assessed at 12 weeks (Visit 5). During the baseline visit, participants were asked to identify their MBS and assess the severity of the MBS on an ordinal scale of "None," "Mild," "Moderate," or "Severe." During the follow-up visit at 12 weeks participants were again asked to identify and assess the severity of their MBS. The degree of severity of the MBS reported at baseline was then compared to the severity of the MBS reported at 12 weeks and categorically summarized and reported as either "Severity Increased" "Severity Decreased" or "No change in Severity" for the given MBS. Participants whose MBS reported at baseline changed during the follow-up visit at 12 weeks were excluded from the analysis. Participants who did not report an MBS during the baseline visit were also excluded. Data for each possible type of MBS is summarized by study arm.
Vaginal Microbiome - Relative Abundance of Lactobacillus Crispatus (L. Crispatus)	Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)	The relative abundance of the protective Lactobacillus species, L. crispatus, as quantified by lllumina MiSeq sequencing will be calculated by dividing the total number of L crispatus sequences detected in a sample by the total number of sequences from all bacterial species detected in the same sample. This proportion will be expressed as a percentage. The change in relative abundance between baseline (visit 2) and 12 weeks (visit 5) will be summarized by study arm.
Vaginal Microbiome - Quantitative Determination of Protective Lactobacilli Species	Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)	Changes in the vaginal microbiome, specifically the quantities of protective Lactobacilli species (L. crispatus, L. jensenii and L. gasseri) as measured by quantitative PCR (qPCR) will be determined. The three Lactobacilli species will be identified and quantified in colony forming units per milliliter of sample (CFU/mL). Changes in abundance from baseline will be summarized by study arm using basic descriptive statistics.

Secondary Outcome Measures

Name	Time	Method
Vaginal Microbiome - Relative Abundance of Bacterial Vaginosis Associated Species	Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)	The relative abundance of bacterial vaginosis (BV) associated bacterial species as quantified by lllumina MiSeq sequencing, will be calculated by dividing the total number of the individual BV-associated species sequences in a sample by the total number of sequences from all bacterial species detected in the same sample. This proportion will be expressed as a percentage. The change in relative abundance between baseline (visit 2) and 12 weeks (visit 5) will be summarized by study arm for the 3 most common BV-associated species; Gardnerella vaginalis (G. vaginalis); Fannyhessea vaginae (F. vaginae); and Prevotella bivia (P. bivia)
Vaginal Microbiome - Quantitative Determination of Bacterial Vaginosis Associated Species	Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)	Changes in quantities of BV-associated species as measured by quantitative PCR (qPCR) will be determined. BV-associated species will be detected and quantified in colony forming units per milliliter of sample (CFU/mL). Changes in abundance from baseline for each detected species will be summarized by study arm using basic descriptive statistics.
Change in Vaginal Cytokine and Chemokine Concentrations	Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)	Change in concentrations from baseline of vaginal cytokines and chemokines in cervicovaginal lavage (CVL) was determined. Following assay, concentrations for the following cytokines and chemokines, as individually expressed, were reported in picograms per milliliter (pg/mL): IL-1A, Interleukin-8 (IL8); Interferon-gamma inducible protein 10 (IP-10); Monocyte Chemoattractant Protein-1 (MCP-1); and Secretory Leukocyte Protease Inhibitor (SLPI). Change in concentrations for the respective cytokines and chemokines from baseline are summarized by study arm using basic descriptive statistics.