Genital Tract Mucosal Immunity, Genital Tract Microflora
Conditions
Keywords
intrauterine device, IUD, levonorgestrel, copper, CD4, CCR5, microflora
Brief summary
This pilot study is being performed to investigate the influence that starting contraception with an IUD has on the local immune cell populations and features, with a particular focus on the cells and cell-surface features that are important in HIV transmission (CD4 cells and CCR5 cell receptors). Based on results from large epidemiologic studies there seems to be a consistent finding of slightly increased HIV acquisition in women who use hormonal contraception. It is not clear if this is due to a biological phenomenon or if it relates to a difference in sexual behaviors/risks of women on hormonal contraceptives. The study hypothesis is that CD4 cells and CCR5 HIV-tropic receptor density increases within the upper and lower genital tract of women 2 months after placement of progestin-containing intrauterine devices for contraception as compared with women not using hormonal contraception.
Interventions
DRUGIUD placement
Volunteer subjects who are not at risk of pregnancy because they are either surgically sterilized or heterosexually abstinent will be enrolled into the control group (no intervention). All other volunteers will be seeking an IUD for contraception and will be randomized to LNG-IUD (Mirena) or Copper IUD (ParaGard).
DRUGCopper T380A IUD
Sponsors
Sharon Achilles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. Non-pregnant, healthy females who are seeking an IUD for contraception 2. Age 18-40 years, inclusive at the time of enrollment 3. History of regular menstrual cycles defined as occurring every 21-35 days when not using hormones and with a variation of typical cycle length of no more than 5 days 4. Willing and able to sign the informed consent and to comply with the study protocol Inclusion criteria for healthy control subjects: 1. Non-pregnant, healthy females 2. Age 18-40 years, inclusive at the time of enrollment 3. History of regular menstrual cycles defined as occurring every 21-35 days when not using hormones and with a variation of typical cycle length of no more than 5 days 4. Willing and able to sign the informed consent and to comply with the study protocol 5. Prior surgical sterilization or heterosexually abstinent
Exclusion criteria
1. Use of any hormonal or intrauterine contraceptive method within the past two months 2. Use of DMPA within the past 10 months 3. Any of the following within the past two months: * Pregnancy or breastfeeding * Surgery/biopsy of the vulva, vagina, or cervix * History of STI * New sexual partner 4. Evidence of vaginal/pelvic infection on screening * Abnormal wet mount (see description above) * Pelvic exam findings clinically consistent with infection * Positive screen for Gc, Ct, or HIV (will be excluded post randomization) 5. Active HSV/ulcerative disease in the genital tract or perineum 6. History of immunosuppression (diabetes, HIV, chronic steroid use) 7. Use of vaginal product (N9, microbicide, douche, antifungal, steroid, or hormone) within the past 30 days 8. Use of any systemic or vaginal steroid or antibiotic within the past 30 days 9. Vaginal or anal intercourse within 1 week of sample collection 10. Heterosexual vaginal intercourse since last menses without condom use 11. History of hysterectomy 12. History of malignancy in the uterus or cervix 13. Uterine anomaly (bicornuate uterus, uterine septum, or uterine didelphys) 14. Allergy to copper and/or intolerance to levonorgestrel
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| %CD4 Expressing CCR5 HIV Co-receptor in the Cervix and Endometrium | 2 months | Change in CCR5 expression on T-lymphocytes 2 months after insertion of IUD (either hormonal LNG-IUD or non-hormonal Cu-IUD) in cervix and endometrium as measured by flow cytomety |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Vaginal Flora | 2 Months | Changes in vaginal flora as assessed by Nugent score The Nugent score is calculated by microscopically assessing for the presence of large Gram-positive rods (Lactobacillus morphotypes; decrease in Lactobacillus scored as 0 to 4), small Gram-variable rods (Gardnerella vaginalis morphotypes; scored as 0 to 4), and curved Gram-variable rods (Mobiluncus spp. morphotypes; scored as 0 to 2) and can range from 0 to 10. A score of 7 to 10 is consistent with bacterial vaginosis, 4-6 is consistent with intermediate vaginal flora, and 0-3 is normal vaginal flora. |
| Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | 2 Months | Changes in vaginal flora as assessed by qPCR quantitation of H2O2 producing Lactobacilli species and Gardnerella vaginalis. Quantitative PCR (qPCR) results are reported as log concentration of gene copies/swab specimen. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the medical clinic and our database of prior research participants. Public advertisements included listing on our website, letters to the database mailing list, flyers placed on local college campuses, mailings to faculty, internet postings on Craig's list, and informational booths at on or off campus fairs.
Participants by arm
| Arm | Count |
|---|---|
| Control-No IUD Healthy volunteers not at risk of pregnancy and not using any hormonal contraception. | 8 |
| Levonorgestrel IUS Healthy volunteers seeking contraception with IUD. Randomized to LNG IUS. | 17 |
| Copper T380A IUD Healthy volunteers seeking contraception with IUD. Randomized to Copper T380A IUD. | 17 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Levonorgestrel IUS | Copper T380A IUD | Control-No IUD | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 17 Participants | 8 Participants | 42 Participants |
| Age, Continuous | 26 years STANDARD_DEVIATION 6 | 27 years STANDARD_DEVIATION 4 | 28 years STANDARD_DEVIATION 6 | 26 years STANDARD_DEVIATION 5 |
| Region of Enrollment United States | 17 participants | 17 participants | 8 participants | 42 participants |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 8 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 17 | 0 / 17 |
| serious Total, serious adverse events | 0 / 8 | 0 / 17 | 0 / 17 |
Outcome results
Primary
%CD4 Expressing CCR5 HIV Co-receptor in the Cervix and Endometrium
Change in CCR5 expression on T-lymphocytes 2 months after insertion of IUD (either hormonal LNG-IUD or non-hormonal Cu-IUD) in cervix and endometrium as measured by flow cytomety
Time frame: 2 months
Population: All 40 participants who completed the study were included in the analysis. There were no lost-to-follow up participants. One participant withdrew and one participant was excluded post-enrollment. Both of these participants were replaced to fill our goal enrollment of 40 participants in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control-No IUD | %CD4 Expressing CCR5 HIV Co-receptor in the Cervix and Endometrium | 4.9 % of T-cells expressing CCR5 | Standard Deviation 17.2 |
| Levonorgestrel IUS | %CD4 Expressing CCR5 HIV Co-receptor in the Cervix and Endometrium | 11.7 % of T-cells expressing CCR5 | Standard Deviation 29.8 |
| Copper T380A IUD | %CD4 Expressing CCR5 HIV Co-receptor in the Cervix and Endometrium | 7.2 % of T-cells expressing CCR5 | Standard Deviation 32.8 |
p-value: 0.8ANOVA
p-value: 0.97ANOVA
Secondary
Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis
Changes in vaginal flora as assessed by qPCR quantitation of H2O2 producing Lactobacilli species and Gardnerella vaginalis. Quantitative PCR (qPCR) results are reported as log concentration of gene copies/swab specimen.
Time frame: 2 Months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Control-No IUD | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Lactobacilli quantity | -0.6 log gene copies/swab |
| Control-No IUD | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Garnerella vaginalis quantity | 0 log gene copies/swab |
| Levonorgestrel IUS | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Lactobacilli quantity | -0.1 log gene copies/swab |
| Levonorgestrel IUS | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Garnerella vaginalis quantity | 0 log gene copies/swab |
| Copper T380A IUD | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Lactobacilli quantity | 0.1 log gene copies/swab |
| Copper T380A IUD | Change in Quantities of Vaginal H2O2-producing Lactobacillus Species and Gardnerella Vaginalis | Change in log Garnerella vaginalis quantity | 0 log gene copies/swab |
Comparison: Change in quantity of H2O2 producing Lactobacilli species by qPCRp-value: 0.46Kruskal-Wallis
Comparison: Change in quantity of Garnerella vaginalis species by qPCRp-value: 0.62Kruskal-Wallis
Secondary
Change in Vaginal Flora
Changes in vaginal flora as assessed by Nugent score The Nugent score is calculated by microscopically assessing for the presence of large Gram-positive rods (Lactobacillus morphotypes; decrease in Lactobacillus scored as 0 to 4), small Gram-variable rods (Gardnerella vaginalis morphotypes; scored as 0 to 4), and curved Gram-variable rods (Mobiluncus spp. morphotypes; scored as 0 to 2) and can range from 0 to 10. A score of 7 to 10 is consistent with bacterial vaginosis, 4-6 is consistent with intermediate vaginal flora, and 0-3 is normal vaginal flora.
Time frame: 2 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control-No IUD | Change in Vaginal Flora | 0 units on a scale |
| Levonorgestrel IUS | Change in Vaginal Flora | 1 units on a scale |
| Copper T380A IUD | Change in Vaginal Flora | 0 units on a scale |
Comparison: Difference in paired change in Nugent score from baseline to 2 monthsp-value: 0.08Kruskal-Wallis