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Hormonal Contraception: Special Considerations for HIV-infected Women

Hormonal Contraception: Special Considerations for HIV-infected Women. Lori E. Kamemoto, MD, MPH Hawaii AIDS Clinical Research Program University of Hawaii School of Medicine. Almost half of all pregnancies in the United States are unintended. Intended pregnancies. Unintended pregnancies.

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Hormonal Contraception: Special Considerations for HIV-infected Women

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  1. Hormonal Contraception: Special Considerations for HIV-infected Women Lori E. Kamemoto, MD, MPH Hawaii AIDS Clinical Research Program University of Hawaii School of Medicine

  2. Almost half of all pregnancies in the United States are unintended Intended pregnancies Unintended pregnancies Rates higher in: Ages 15-24 y.o. Unmarried women < 200% poverty level Black and Hispanic women Pregnancies, 1994 (6.3 million) Alan Guttmacher Institute

  3. Ethinyl estradiol EE dosage decreasing over time 80+ g  50 g  20-30 g Estradiol cypionate Lunelle Progestins Norethindrone Norgestimate Ethynodiol diacetate Levonorgestrol Desogestrel Gestodene Drospirenone Medroxyprogesterone acetate Norelgestromin Etonorgestrol Contraceptive hormones

  4. How does hormonal contraception work? • Progestins • prevent ovulation • affect the time needed for ova to travel through the fallopian tubes, interfering with precise timing needed for fertilization • increase the amount and thickness of mucus at the cervix, decreasing sperm entry • decrease the ability of sperm to fertilize an egg • interfere with the implantation of a fertilized egg on the wall of the uterus • Estrogens • used mostly to prevent progestin only effect on menses/tissues, however is associated with increase in contraceptive efficacy (i.e.-”mini-pill” vs. combination pill) • may also prevent ovulation and affect the time needed for ova to travel through the fallopian tubes, interfering with precise timing needed for fertilization

  5. Hormonal contraceptives • Oral contraceptives • Combination pills (E + P) • Progestin-only pills (“mini-pill”) • Emergency contraception (E + P or P) • Contraceptive patch (E + P) • Vaginal ring (E + P) • Injectable contraceptives • DepoProvera (P) • Lunelle (E + P)-no longer available in U.S. • Progestin IUD

  6. New hormonal contraception methods FDA approved since 1995 • Emergency contraception: Preven® (1998), Plan B® (1999) • Monthly injectable: Lunelle® (2000) • Vaginal ring: NuvaRing® (2001) • Patch: Ortho Evra® (2001) • Oral contraceptive with extended period-free regimen: Seasonale® (2003) • Awaiting approval • Single-rod implant: Implanon®

  7. Male hormonal contraception • WHO studies on testosterone (1996) • testosterone IM q week • azoospermia 65% (1 pregnancy) • oligospermia 98% (4 pregnancies) • male method should produce azoospermia, easily reversible • Progestins plus testosterone • progestins + testosterone more likely to produce azoospermia • norethistrone, DMPA, levonorgestrol, desogestrol, etonorgestrol • investigating injectables, patch, implant

  8. Contraceptive method use by Age Gallup survey, 1998-9

  9. HIV and contraceptive method • Approximately 70% of all HIV infected women are sexually active • Irish cohort of HIV+ women • Only 57% of sexually active used contraception • French SEROCO study HIV+ women • 20% of sexually active using no contraception • 24% became pregnant and 63% of conceptions ended in abortion • African DITRAME project HIV+ women • 39% used contraception • 50% of pregnancies were unplanned, and one third were terminated • Postpartum HIV+ vs. HIV – • Tubal ligation: OR 2.9 (1.4-5.9) • BCP: OR 0.2 (0.1-0.5) • Condom use: OR 0.7 (0.4-1.3) • HIV+ vs. HIV- • Consistent condom use: OR 2.31 (1.35-3.94) • BCP: OR 0.54 (0.3-0.98)

  10. Hormonal contraceptionBenefits • prevent pregnancy • including ectopic pregnancy, miscarriage, abortion •  anemia • promote cycle regularity •  ovarian cysts and ovarian cancer •  endometrial cancer •  endometriosis •  PID •  dysmenorrhea •  acne • probable  colorectal cancer,  osteopenia

  11. Hormonal contraception Risks •  thromboembolic phenomena • including DVT, pulmonary embolism, stroke •  breast cancer •  heart disease (after 35 y.o. with smoking) •  gall bladder disease, hepatoma •  bone density with DepoProvera • may be associated with hypertension • irregular bleeding • nausea, headaches, weight gain • Current lower dose pills associated with decreased risk

  12. Hormonal contraception and HIV Concerns for Women • Does hormonal contraception influence… • HIV acquisition? • HIV disease progression? • ARV pharmacokinetics? • HIV transmission to partner? • Do ARVs influence contraceptive hormone pharmacokinetics? • Which contraceptive method is best for HIV infected women? • efficacy • least risk vs. benefit

  13. Acquisition of HIV infection in hormonal contraception users • Mombasa cohort of female sex workers attending STD clinic • Depo Provera associated with increased incidence of HIV-1 infection • Adjusted Hazard Ratio 2.0 (1.3-3.1) • Oral contraceptives associated with a trend towards increased HIV-1 infection • Adjusted HR 2.6 (0.8-8.5) Martin 1998

  14. Acquisition of HIV infection in oral contraceptive users • Meta-analysis of 28 studies • Association between HIV-1 seroprevalence and use of oral contraception • All 28 studies: OR 1.19 (0.99-1.42) • 21 cross-sectional studies: OR 1.21 (1.01-1.44) • “8 best studies”: OR 1.60 (1.05-2.44) Wang 1999

  15. Acquisition of HIV infectionwith hormonal contraception Possible mechanisms that may increase susceptibility to HIV acquisition with hormone use • Thinning of vaginal wall with progestins • Increased SIV acquisition with progesterone associated with vaginal wall thinning • No evidence that vaginal wall thinning occurs in humans • Increased cervical ectropion with combination OCPs

  16. Transmission of HIV infection with hormonal contraceptives • Increased FGT HIV-1 RNA levels may lead to increased rates of transmission to partners • Cervical ectopy associated with increased HIV genital tract shedding • Oral contraceptives may be associated with increased HIV genital tract shedding • Contraceptive methods associated with irregular or heavier bleeding (progestin-only methods, IUD) may be associated with increased risk of HIV transmission to partner

  17. HIV disease progression and contraceptive hormones • Mombasa cohort; Lavreys, etal (2004) • > 1500 high risk women enrolled over 10 years • Able to estimate time of HIV-1 acquisition in 161 women • Depo Provera use at the time of acquisition of HIV associated with  HIV-1 RNA at 4 months • HIV-1 RNA higher setpoint (+0.33 log copies/cc) • No association found with OCP use • Multiple viral variants associated with Depo Provera and OCP use (OR 2.7, P=0.003) compared with no contraceptive use • Women with multiple variants, were more likely to have higher viral load and lower CD4

  18. HIV disease progression and contraceptive hormones • Women’s Interagency Study examined plasma HIV-1 RNA and CD4 count on entry and longitudinally in women on hormonal contraceptives • No apparent association with HIV-1 RNA levels • Small increase in CD4 count among hormone users of doubtful clinical significance • Mean increase 27.6 cells/l Cejtin 2003

  19. HIV-associated lipodystrophy and estrogen receptors • Increased risk of HIV-associated lipodystrophy in women • Estrogen receptor  (ER) is decreased in subcutaneous adipose tissue with HIV+ lipodystrophy • PIs appear to down-regulate ER receptors and PI withdrawal led to increase in ER mRNA • ?role of selective estrogen modulators? Barzon 2005

  20. How contraceptive hormones may affect HIV-1 disease • Physiologic effects on the vaginal epithelium • Progesterone implants increased risk of SIV acquisition due to thinning of vaginal epithelium • Subsequent human studies have not confirmed thinning of the vaginal epithelium with Depo Provera • Hormonal effects on cell-surface CCR5 levels • CCR5 is the main coreceptor in FGT • CCR5 increased in biopsies from “progesterone dominant” women • In vitro studies with progesterone showed increased CCR5 and CXCR4 expression • Direct hormonal effect on virus expression • Female hormones may govern uterine immune cell synthesis of cytokines, thus imfluencing the density and action of macrophages • More studies needed to investigate the role of hormonal contraception on HIV-1 acquisition, viral setpoint, and viral diversity in chronic HIV-1 infection Marx 1996, Patterson 1998, Hunt 1998

  21. Drug interactionsARVs and contraceptive hormones • Ethinyl estradiol (EE) and progestins (P) are substrates of cytochrome P450 CYP 3A4 system of enzymes • Liver, small intestine • ARVS may: • induce cytochromes, which increase the hepatic metabolism of contraceptive hormones • inhibit cytochromes, causing decreased clearance and increased levels of contraceptive hormones • when both interacting drugs are substrates, the interaction is less predictable • some ARVs exhibit several of these properties

  22. Drug interactionsARVs and contraceptive hormones • Most of data from pharmaceutical contraceptive industry research involving contraceptive hormone levels after single dose ARV • “use with caution” with certain ARVs • No information on longer term contraceptive hormone and ARV use • recent completion of ACTG 5093 • No data on hormonal contraceptive efficacy with ARVs

  23. Oral contraceptive failure in HIV infected women • 2035 HIV+ women in New Orleans • Retrosepctive review of 86 of these women who were on OCPs • 11 women appeared to have become pregnant while on Depo Provera or OCPs • “OCP failure” • PIs: 25% • NNRTIs: 10% • No PI or NNRTI: 0% Clarke 2004

  24. Drug interactionsARVs and contraceptive hormones • Associated with increase in oral contraceptive EE levels • EFV (EE AUC  37%) • ATZ (EE AUC  48%, NET AUC  110%) • IDV (EE AUC  24%, NET AUC  26%) • Associated with decrease in oral contraceptive EE levels • NVP (EE AUC  29%, NET  18%) • APV (NET  18%) • RTV (EE AUC  41%) • NFV (EE AUC  47%, NET AUC  18%) • LPV/r (EE AUC  42%, NET AUC  16%)

  25. Drug interactionsARVs and contraceptive hormones • NRTIs and oral contraceptives • Majority of NRTIs undergo renal excretion of 50-85% • ABC metabolized via unique pathway and excreted renally • ZDV undergoes glucoronidation to metabolite that is excreted renally • ACTG 317 demonstrated no significant difference in glucoronidation of ZDV with OCPs • Oral contraceptive effect on ARVs • Minimal data exists • Amprenavir AUC  22% (do not use with OCPs) • Likely minimal effect on ARVs, but little data exists

  26. ACTG 5093, An Open-label, Non-randomized Study of the Effect of Depo-Medroxyprogesterone Acetate (DMPA) on the PK of Selected PI and NNRTI Therapies Among HIV-infected Women Primary Objective: • Determine the effect of DMPA on the PK of selected ARV therapies among HIV-infected women comparing the AUC’s for these drugs prior to DMPA and 4 weeks later Secondary Objectives: • Determine whether PK interactions between selected ARV’s and DMPA affect the suppression of ovulation. • Evaluate other PK parameters including Cmax and Tmax of selected ARVs before and after DMPA. • Evaluate the toxicity and safety of any PK interactions between ARVs and DMPA.

  27. Enrollment and Subjects Eligible for Analysis NRTIs only NFV EFV IDV NVP or No Meds plus NRTIs plus NRTIs plus NRTIs plus NRTIs (control arm) 16 22 18 1* 16 16 20 15 14 ACTG 5093, An Open-label, Non-randomized Study of the Effect of Depo-Medroxyprogesterone Acetate (DMPA) on the PK of Selected PI and NNRTI Therapies Among HIV-infected Women ARV PK done before and 4 weeks after DMPA

  28. ACTG 5093, An Open-label, Non-randomized Study of the Effect of Depo-Medroxyprogesterone Acetate (DMPA) on the PK of Selected PI and NNRTI Therapies Among HIV-infected Women • Efficacy of DMPA does not appear to be altered in the presence of NFV, EFV, and NVP-based regimens. • DMPA was well-tolerated and side effects were similar to those reported in HIV-negative women on DMPA Progesterone levels remained low (<1.5ng/mL) following DMPA administration, with no presumptive evidence of ovulation through week 12 • Although NVP AUC levels were higher with DMPA, the increased levels do not appear to be clinically relevant • DMPA appears to be safe and effective for HIV-infected women taking NFV, EFV, and NVP-based regimens • Studies with other HIV protease inhibitors, NNRTIs and NRTIs (tenofovir) deserve consideration

  29. ACTG 5188, A Phase II Pharmacokinetic Study of the Transdermal Contraceptive System and Oral Contraceptive in HIV-1 Infected Women on Lopinavir/Ritonavir • Protease inhibitors associated with a significant decrease in oral contraceptive (OC) estradiol • LPV associated with 42%  OC estradiol levels • Primary Objective: To evaluate the effect of LPV/r on the PK of EE by comparing the EE AUC during ORTHO EVRA® transdermal contraceptive patch week 3 in women on LPV/r with the EE AUC measured in women who are not receiving PIs, NNRTIs, or any ARVtherapy. • Hypothesis: Transdermal contraceptive patch system (TCS) estradiol levels will not be significantly affected by PIs • HIV-1 infected women of reproductive age • Arm A: LPV/r containing regimen • Arm B: NRTI-only regimen or No ARVs • 6 week PK study (OC & TCS) • EE • Norelgestromin • LPV • 54 subjects • Open to enrollment

  30. Hormonal contraception and HIV Concerns for Women • Does hormonal contraception influence… • HIV acquisition? MAYBE • HIV disease progression? MAYBE • ARV pharmacokinetics? PROBABLY NOT for most ARVs, altho’ minimal data available • HIV transmission to partner? MAYBE • Do ARVs influence contraceptive hormone pharmacokinetics? YES • Which contraceptive method is best for HIV infected women? • efficacy • least risk vs. benefit

  31. *Association of Reproductive Health Professionals

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