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Is the IUD an Appropriate Contraceptive Choice for HIV-infected Women?

Is the IUD an Appropriate Contraceptive Choice for HIV-infected Women?. Susan Cu-Uvin, M.D. Intrauterine devices. Inert plastic Progesterone Copper-bearing Levonorgestrel. Contraception Failure Rates (1st Year) Reversible Methods. Typical N/A.

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Is the IUD an Appropriate Contraceptive Choice for HIV-infected Women?

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  1. Is the IUD an Appropriate Contraceptive Choice for HIV-infected Women? Susan Cu-Uvin, M.D.

  2. Intrauterine devices • Inert plastic • Progesterone • Copper-bearing • Levonorgestrel

  3. Contraception Failure Rates (1st Year)Reversible Methods Typical N/A Hatcher: Contraceptive Technology 16th Edition 1994.

  4. Intrauterine devices • Concern about upper genital tract infection related to IUD limit their wider use (Review: Grimes DA. Lancet 2000;356:1013-19) • Observational research has commonly found an increased risk of salpingitis or tubal infertility among IUD users: this was because of consistent presence of 3 types of bias: use of inappropriate comparison group, overdiagnosis of PID, inability to control for confounding factors • Example:Oxford Family Planning Association study showed ten fold increase in salpingitis among IUD users. Updated analysis with attention to the 3 biases and exclusion of Dalkon Shield use: RR of salpingitis with medicated IUD was 1.8 (95%CI 0.8-4.0) • In settings where STDs are uncommon, PID associated with IUD is rare

  5. Intrauterine Device (IUD) • IUDs are highly effective, long lasting, and inexpensive • Major complication is PID during the first 20 days after insertion • Few studies on IUD and HIV-infected women • IUD results in inflammatory response in the endometrium and can alter the microenvironment of the uterus, cervix, and tubes • Recruitment of inflammatory cells and increased blood lymphocytes and macrophages may provide targets for HIV replication

  6. Effect of IUD on cervical shedding of HIV-1 DNARichardson BA, Morrison CS, Sekadde-Kigondu C, et al. AIDS 1999, 13:2091-2097 • A prospective study of 98 HIV(+) women undergoing IUD insertion, Nairobi, Kenya • Cervical swabs were collected before IUD (Copper T 380A) insertion and 4 months thereafter for detection on HIV-1 DNA • HIV-1 DNA shedding was 50% at baseline and 43% at follow-up (OR 0.8, 95%CI 0.5-1.2) • No difference, in multivariate model controlling for previous hormonal contraceptive use, condom use, ectopy, friable cervix, cervical infections, CD4

  7. Effect of IUD on cervical shedding of HIV-1 DNA Patterns of cervical shedding of HIV-1 DNA Follow-up n (%)____ Baseline n (%)_____PCR (-)_______PCR(+)____ PCR (-) 33 (34%) 16 (16%) PCR(+) 23 (24%) 26 (26%) Of the 49 women with who had no detectable HIV-1 DNA at baseline, 33 (67%) remained undetectable. Of the 49 who had detectable HIV-1 DNA at baseline, 26 (53%) had persistent shedding.

  8. Complications of use of IUD among HIV-1 infected womenSinie SK, Morrison CS, Sekadde-Kigondu et al. The Lancet 1998 351:1238-1241 • 649 ( 156 HIV-infected and 493 HIV uninfected) women in Nairobi, Kenya who met local eligibility criteria for IUD insertion were enrolled in 1994-1995 • No evidence of: history of ectopic pregnancy, pregnancy within previous 42 days, fibroids, active PID, malignancy in reproductive tract, abnormality of the vagina, cervix, or endometrial cavity, known copper allergy, mucopurulent cervicitis, unexplained abnormal vaginal bleeding, or high risk for STD

  9. Complications of use of IUD among HIV-1 infected women • Baseline gonorrhoea and chlamydia tests were done, including CD4 for HIV(+) women • At 4 month follow-up or unscheduled visits, gonorrhoea and chlamydia testing were done only on women with symptoms • Enrolled mainly parous, married women, aged 20-30 years, with at least a secondary school education, few reported more than one sexual partner or condom use in the last 3 months, or STD within the year, 31%HIV(+) and 38% HIV(-) had previous IUDs

  10. Complications of use of IUD among HIV-1 infected women • HIV infected women were more likely to be single or in a polygamous marriage • Of Luo origin • To be a domestic worker or laborer • Have a partner with possible STD • Have more than one partner • Have less sex in the last 3 months • Have more cervical abnormalities

  11. Complications of use of IUD among HIV-1 infected women Outcome type HIV(+) HIV(-) CRR AOR Complications_______________________________________________ Overall 11 (7.6%) 37 (7.9%) 0.97 0.80 PID 2 (1.4%) 1 (0.25) IUD removals 6 (2.1%) 18 (3.8%) IUD expulsions 3 (2.1%) 17 (3.6% Pregnancies 0 1 (0.2%)______________________ Infection 10 (6.9%) 27 (5.7%) 1.21 1.02 related comp._______________________________________________ IUD complaints 37 (25.7%) 90 (19.1%) 1.34 1.41

  12. Intrauterine System Steroid reservoir 32 mm levonorgestrel 20 mcg/day Levonorgestrel Intrauterine System (LNG IUS) • 1-r failure rate 0.1 5-year failure rate 0.7 Cost - $350 + insertion

  13. Failure Rates: IUD vs Sterilization Andersson K et al. Contraception 1994;49:56-72. Peterson HB et al. Am J Obstet Gynecol 1996;174:1161-1168.

  14. IUD Mechanism of Action • Most evidence now suggests that all IUDs induce a foreign body reaction that is spermicidal, preventing fertilization • Today’s intrauterine contraceptives have other mechanisms of action that prevent fertilization Alvarez F et al. Fertil Steril 1988;49:768-773.Segal SJ et al. Fertil Steril 1985;44:214-218.

  15. Mirena: Theoretical Mechanism of Action • Cervical mucus thickened • Sperm motility and function inhibited • Endometrial effects • Ovulation inhibited (in some cycles) Jonsson B et al. Contraception 1991;43:447-458. Nilsson CG et al. Fertil Steril 1984;41:52-55. Videla-Rivero L et al. Contraception 1987;36:217-226.

  16. 5-Year Cumulative Rates of Discontinuation for PID A. Randomized trial comparing Mirena to CuT 380A B. Randomized trial comparing Mirena to Nova T P < .05 *Nova T is not available in the US. Sivin I et al. Contraception 1990;42:361-378. Andersson K et al. Contraception 1994;49:56-72.

  17. Changes in the Endometrium Normal Menstrual Cycle Ovulation Height ofendometrium Days of cycle “Resting State” with Mirena Height ofendometrium Days of cycle

  18. Mirena: Return to Fertility 100 80 60 Cumulative pregnancyrate after removal (%) Mirena 40 Copper T 380A 20 0 0 3 6 9 12 Months Andersson K et al. Contraception 1992;46:575-584. Belhadj H et al. Contraception 1986;34:261-267.

  19. A5205A PILOT STUDY EVALUATING THE EFFECT OF THE LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE ON GENITAL HIV SHEDDING IN HIV-INFECTED WOMENA Multicenter Trial of the Adult AIDS Clinical Trials Group (AACTG)

  20. Background & Rationale • There is a critical need for safe and effective contraception for HIV-infected women. • The WHO has recently approved IUDs for use in HIV infected women who have not progressed to AIDS • Theoretically, the levonorgestrel IUD causes a sterile inflammatory response which may increase HIV vaginal shedding but the progesterone may decrease the shedding. This has not been studied in HIV infected women.

  21. Background & Rationale • Compared to the copper IUD, the levonorgestrel IUD has a decreased potential for pelvic infection and a lower rate of breakthrough bleeding and anemia. The safety and tolerability of the levonorgestrel IUD in HIV infected women has not been assessed • Systemic levonorgestrel concentrations are negligible so there is no concern with drug interaction with antiretrovirals (20mcg in 24 hours, about 10 mcg absorbed into serum, 1/10 the progestin dose found in 20mcg levonorgetrel birth control pill)

  22. Hypotheses PRIMARY • There is no increase in genital tract HIV-1 RNA and DNA after placement of the levonorgestrel IUD SECONDARY • The levonorgestrel IUD is well tolerated, with a low discontinuation rate, and is safe for use in HIV infected women

  23. Primary and Secondary Objectives Primary Objectives: 1. To evaluate the effect of the levonorgestrel IUD on HIV-1 RNA and HIV-1 DNA levels found in the endocervix 4 weeks after placement 2. To evaluate the safety and tolerability of the levonorgestrel IUD IN HIV-infected women Secondary Objective: 1. To evaluate the effect of levonorgestrel IUD on HIV-1 RNA and HIV-DNA levels found in the vaginal and endocervical canal

  24. Study Design & Regimens • Pilot, one-arm, prospective study • Subject as her own control • Intervention: Subjects will receive the levonorgestrel IUD for 1 year • assessment at 4 weeks to determine whether or not there is an increase in endocervical HIV-1 RNA and DNA shedding after placement of the IUD • Study visits: screening, entry, weeks 4, 16, 48 • followed for 12 months to determine safety and tolerability of the IUD after its placement.

  25. Study Design & Regimens • Complete physical exam • Pelvic exam: vaginal discharge, cervicalbleeding, friability, ectopy, cervical motion tenderness, uterine tenderness, adnexal tenderness, abdominal tenderness • Pap smear within one year • Labs: CBC, TB, AST, ALT, Creat, glucose, pregnancy test, CD4, PVL, gonorhhea, chlamydia, BV, candidiasis, trich, culture for actinolycosis if with genital symptoms, RPR • Menstrual diary

  26. Population & Eligibility Criteria • HIV-1 infected women  18 years • CD-4 cell count >200 cells/mm3 within 60 days prior to study entry • At least one prior pregnancy, 20 gestational weeks or greater • Off antiretroviral therapy during the 90 days prior to entry • Intention to stay off antiretroviral therapy for the first 4 weeks after study entry • Intention to continue any concomitant hormonal therapies for the first 4 weeks after study entry • Negative pregnancy test within 14 days prior to study entry • HIV-1 RNA >10,000 copies/mL obtained within 90 days prior to study entry to assist the sites in screening • HIV-1RNA >2,500 copies/mL in endocervical canal swab 60 days prior to study entry

  27. Safety Issues & Management • Abnormal vaginal discharge • the device should be removed if discharge due to PID • Abnormal vaginal bleeding • Removal of the device is not indicated unless severe anemia, PID and/or pregnancy is confirmed • Amenorrhea • 20% of levonorgestrel IUD users by one year • Removal only if pregnancy is confirmed • Abdominal and pelvic pain • Cramping due to uterine muscle spasm • Device removal if pregnancy, uterine perforation, or PID • Device replacement if partial expulsion • IUD string not visible • location of the IUD should be verified   • Ovarian cysts • Enlarged follicles have been diagnosed in about 12% of subjects • Surgical intervention is not usually required

  28. Safety Issues & Management • Pregnancy • the device should be removed if ectopic pregnancy • intrauterine pregnancy: IUD should be removed as early in pregnancy as possible if the string is visible. • If the pregnancy is beyond ten weeks and the string is still visible, the patient should be referred for an emergent pelvic ultrasound to rule out a placenta previa or the possibility that the IUD is implanted in the placenta. If the IUD cannot be removed, the woman should be warned that failure to remove the IUD increases the risk of miscarriage, sepsis, and premature labor and delivery. If the IUD string is not visible when pregnancy is detected, emergent ultrasound examination and gynecology consult should be recommended, as IUD removal can be complicated.

  29. Monitoring • Interim review (by an SMC) will be automatically triggered if any of the following criteria are met: • More than 5 women have IUD removed ( by request or necessity) within 12 weeks of insertion • More than 2 women experience clinical PID requiring removal of IUD • More than 4 women experience grade 3 or higher anemia • The core study team, based on routine safety monitoring of the study, deems that an external interim safety review needs to take place

  30. Statistical Aspects: Sample Size • Under the hypothesis of no change in viral shedding, n=41 subjects will provide 80% power to declare non-inferiority at the 0.25 non-inferiority bound, at a 0.05 significance level • This includes inflation of the sample size to account for losses to follow-up (5%) and refusal of IUD insertion post registration (5%))  • Assumes normality of changes in RNA, no left-censoring of baseline measurements and similar level of left-censoring of follow-up measurements as seen in Coombs, et.al. (2000) Projected Accrual & Study Duration • Accrual is anticipated to be completed in 12 months, and so the accrual rate is estimated at 3 women per month • Study duration: 12 months

  31. Analysis Issue – Left-censoring of RNA measurements * 2,500 c/mL is projected lower limit of detection of Dacron swab

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