Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

The Impact of HIV on Accelerated Aging in the Female Genital Tract: a Pilot Trial of Topical Estradiol to Improve the Vaginal Microbiome and Symptoms of Vaginal Atrophy in Menopausal Women With HIV

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04079218

Enrollment

Registered

2019-09-06

Start date

2020-09-01

Completion date

2023-08-09

Last updated

2025-03-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

HIV Infection, Vaginal Atrophy, Menopause, Vaginal Microbiome, Microbiome, Dysbiosis, Aging, Premature Aging, Atrophic Vaginitis

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.

Interventions

DRUGEstradiol 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Participants will be randomly assigned to receive treatment with estradiol vaginal tablets or no treatment.

Eligibility

Sex/Gender

FEMALE

Age

45 Years to 70 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.

Secondary

Measure	Time frame	Description
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.
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.

Other

Measure	Time frame	Description
HIV-1 RNA Levels in the Genital Tract	Baseline and 6 and 12 weeks	HIV-1 RNA testing from cervicovaginal lavage fluid will be used to assess HIV-1 concentrations in the genital tract. Concentrations will be summarized by study arm and subsequently analyzed by multivariate linear regression. Cervicovaginal lavage (CVL) fluid was collected for other measures however due to insufficient funding, CVL HIV-1 viral loads were not run at any time point therefore the data is not available, nor will it be available in the future.
Immunoglobulin (Ig)A and IgG Coated Bacteria	Baseline and 6 and 12 weeks	Relative differences in levels of live IgA+IgG+ coated, live IgA+IgG- coated, live IgA-IgG-coated and dead bacteria will be summarized using basic descriptive statistics and subsequently analyzed by multivariate linear regression. Vaginal swabs were collected for quantification of subsets of IgA and IgG coated bacteria however due to insufficient funding, sequencing of these samples has not been performed and therefore data is not available. If we are able to secure additional funding, the sequencing may be performed in the future.

Countries

United States

Participant flow

Pre-assignment details

60 participants were consented and randomized into the study. Of these, 51 completed the trial. One participant in the non treatment arm and 8 participants in the estradiol arm did not complete the study. An additional 19 participants were screened but deemed ineligible for the study and not randomized. There were no HIV negative participants in the trial. Study documents refer to two related but separate studies: a trial for HIV+ participants and another study which includes HIV- participants.

Participants by arm

Arm	Count
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. 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.	25
No Treatment No intervention	26
Total	51

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	1	0
Overall Study	Lost to Follow-up	0	1
Overall Study	Physician Decision	4	0
Overall Study	Withdrawal by Subject	3	0

Baseline characteristics

Characteristic	No Treatment	Estradiol Vaginal Insert	Total
Age, Continuous	59.5 years STANDARD_DEVIATION 4.92	59.3 years STANDARD_DEVIATION 4.66	59.4 years STANDARD_DEVIATION 4.75
Age, Customized 45-55 years old	6 Participants	4 Participants	10 Participants
Age, Customized 56-70 years old	20 Participants	21 Participants	41 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants	5 Participants	14 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	17 Participants	19 Participants	36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Plasma HIV-1 Viral Load Detectable	5 Participants	5 Participants	10 Participants
Plasma HIV-1 Viral Load Undetectable	21 Participants	20 Participants	41 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	20 Participants	20 Participants	40 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	3 Participants	6 Participants
Race (NIH/OMB) White	2 Participants	2 Participants	4 Participants
Region of Enrollment United States	26 participants	25 participants	51 participants
Sex: Female, Male Female	26 Participants	25 Participants	51 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants
Vaginal Cytokine and Chemokine Concentrations IL-1A	1.93 pg/mL STANDARD_DEVIATION 0.669	1.88 pg/mL STANDARD_DEVIATION 0.701	1.91 pg/mL STANDARD_DEVIATION 0.68
Vaginal Cytokine and Chemokine Concentrations IL-8	2.33 pg/mL STANDARD_DEVIATION 1.06	2.58 pg/mL STANDARD_DEVIATION 0.675	2.45 pg/mL STANDARD_DEVIATION 0.89
Vaginal Cytokine and Chemokine Concentrations IP-10	1.96 pg/mL STANDARD_DEVIATION 0.848	2.24 pg/mL STANDARD_DEVIATION 0.74	2.10 pg/mL STANDARD_DEVIATION 0.8
Vaginal Cytokine and Chemokine Concentrations MCP-1	1.12 pg/mL STANDARD_DEVIATION 0.972	1.28 pg/mL STANDARD_DEVIATION 0.753	1.20 pg/mL STANDARD_DEVIATION 0.87
Vaginal Cytokine and Chemokine Concentrations SLPI	4.47 pg/mL STANDARD_DEVIATION 0.722	4.42 pg/mL STANDARD_DEVIATION 0.584	4.45 pg/mL STANDARD_DEVIATION 0.65
Vaginal Microbiome - Detectable Bacterial Vaginosis-Associated Species F. vaginae	12 Participants	11 Participants	23 Participants
Vaginal Microbiome - Detectable Bacterial Vaginosis-Associated Species G. vaginalis	14 Participants	14 Participants	28 Participants
Vaginal Microbiome - Detectable Bacterial Vaginosis-Associated Species P. bivia	15 Participants	11 Participants	26 Participants
Vaginal Microbiome - Detectable Lactobacillus Crispatus (L. Crispatus)	7 Participants	5 Participants	12 Participants
Vaginal Symptom Index (VSI)	1.04 score on a scale STANDARD_DEVIATION 0.61	1.13 score on a scale STANDARD_DEVIATION 0.64	1.08 score on a scale STANDARD_DEVIATION 0.62

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 33	0 / 27
other Total, other adverse events	20 / 33	10 / 27
serious Total, serious adverse events	4 / 33	2 / 27

Outcome results

Primary

Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy

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.

Time frame: Between baseline (Visit 2) and 12 weeks (Visit 5)

Population: Participants whose MBS reported at baseline changed during the follow-up visit at 12 weeks and participants who did not report a MBS during the baseline visit were excluded. The overall number of participants analyzed has been updated to reflect this.

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	Severity Increased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	No change in Severity	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	Severity Increased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	Severity Increased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	Severity Decreased	9 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	Severity Decreased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	No change in Severity	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	No change in Severity	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	No change in Severity	1 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	Severity Increased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	Severity Decreased	8 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	Severity Decreased	2 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	Severity Increased	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	No change in Severity	0 Participants
Estradiol Vaginal Insert	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	Severity Decreased	1 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	No change in Severity	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	Severity Increased	1 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	Severity Decreased	4 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Itching	No change in Severity	1 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	Severity Increased	1 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	Severity Decreased	3 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dryness	No change in Severity	6 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	Severity Decreased	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	No change in Severity	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	Severity Increased	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	Severity Decreased	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Irritation	No change in Severity	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	Severity Increased	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Dyspareunia	Severity Decreased	0 Participants
No Treatment	Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy	Soreness	Severity Increased	0 Participants

Primary

Vaginal Microbiome - Quantitative Determination of Protective Lactobacilli Species

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.