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 Pregnancies, 1994 (6.3 million) Unintended pregnancies Intended pregnancies Alan Guttmacher Institute Rates higher in: Ages 15-24 y.o. Unmarried women < 200% poverty level Black and Hispanic women

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

4. How does hormonal contraception work? Progestins Progestins prevent ovulation prevent ovulation affect the time needed for ova to travel through the fallopian tubes, interfering with precise timing needed for fertilization 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 increase the amount and thickness of mucus at the cervix, decreasing sperm entry decrease the ability of sperm to fertilize an egg decrease the ability of sperm to fertilize an egg interfere with the implantation of a fertilized egg on the wall of the uterus interfere with the implantation of a fertilized egg on the wall of the uterus Estrogens 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) 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 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 Oral contraceptives Combination pills (E + P) Combination pills (E + P) Progestin-only pills (“mini-pill”) Progestin-only pills (“mini-pill”) Emergency contraception (E + P or P) Emergency contraception (E + P or P) Contraceptive patch (E + P) Contraceptive patch (E + P) Vaginal ring (E + P) Vaginal ring (E + P) Injectable contraceptives Injectable contraceptives DepoProvera (P) DepoProvera (P) Lunelle (E + P)-no longer available in U.S. Lunelle (E + P)-no longer available in U.S. Progestin IUD Progestin IUD

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

7. Male hormonal contraception WHO studies on testosterone (1996) WHO studies on testosterone (1996) testosterone IM q week testosterone IM q week azoospermia 65% (1 pregnancy) azoospermia 65% (1 pregnancy) oligospermia 98% (4 pregnancies) oligospermia 98% (4 pregnancies) male method should produce azoospermia, easily reversible male method should produce azoospermia, easily reversible Progestins plus testosterone Progestins plus testosterone progestins + testosterone more likely to produce azoospermia progestins + testosterone more likely to produce azoospermia norethistrone, DMPA, levonorgestrol, desogestrol, etonorgestrol norethistrone, DMPA, levonorgestrol, desogestrol, etonorgestrol investigating injectables, patch, implant 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 Approximately 70% of all HIV infected women are sexually active Irish cohort of HIV+ women Irish cohort of HIV+ women Only 57% of sexually active used contraception Only 57% of sexually active used contraception French SEROCO study HIV+ women French SEROCO study HIV+ women 20% of sexually active using no contraception 20% of sexually active using no contraception 24% became pregnant and 63% of conceptions ended in abortion 24% became pregnant and 63% of conceptions ended in abortion African DITRAME project HIV+ women African DITRAME project HIV+ women 39% used contraception 39% used contraception 50% of pregnancies were unplanned, and one third were terminated 50% of pregnancies were unplanned, and one third were terminated Postpartum HIV+ vs. HIV – Postpartum HIV+ vs. HIV – Tubal ligation: OR 2.9 (1.4-5.9) Tubal ligation: OR 2.9 (1.4-5.9) BCP: OR 0.2 (0.1-0.5) BCP: OR 0.2 (0.1-0.5) Condom use: OR 0.7 (0.4-1.3) Condom use: OR 0.7 (0.4-1.3) HIV+ vs. HIV- HIV+ vs. HIV- Consistent condom use: OR 2.31 (1.35-3.94) Consistent condom use: OR 2.31 (1.35-3.94) BCP: OR 0.54 (0.3-0.98) BCP: OR 0.54 (0.3-0.98)

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

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

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

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

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

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

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

18. HIV disease progression and contraceptive hormones Mombasa cohort; Lavreys, etal (2004) Mombasa cohort; Lavreys, etal (2004) > 1500 high risk women enrolled over 10 years > 1500 high risk women enrolled over 10 years Able to estimate time of HIV-1 acquisition in 161 women 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 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) HIV-1 RNA higher setpoint (+0.33 log copies/cc) No association found with OCP use 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 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 Women with multiple variants, were more likely to have higher viral load and lower CD4

19. 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 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 No apparent association with HIV-1 RNA levels Small increase in CD4 count among hormone users of doubtful clinical significance Small increase in CD4 count among hormone users of doubtful clinical significance Mean increase 27.6 cells/  lMean increase 27.6 cells/  l Cejtin 2003

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

21. How contraceptive hormones may affect HIV-1 disease Physiologic effects on the vaginal epithelium Physiologic effects on the vaginal epithelium Progesterone implants increased risk of SIV acquisition due to thinning of 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 Subsequent human studies have not confirmed thinning of the vaginal epithelium with Depo Provera Hormonal effects on cell-surface CCR5 levels Hormonal effects on cell-surface CCR5 levels CCR5 is the main coreceptor in FGT CCR5 is the main coreceptor in FGT CCR5 increased in biopsies from “progesterone dominant” women CCR5 increased in biopsies from “progesterone dominant” women In vitro studies with progesterone showed increased CCR5 and CXCR4 expression In vitro studies with progesterone showed increased CCR5 and CXCR4 expression Direct hormonal effect on virus 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 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 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

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

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

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

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

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

27. 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 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. Determine whether PK interactions between selected ARV’s and DMPA affect the suppression of ovulation. Evaluate other PK parameters including C max and T max of selected ARVs before and after DMPA. Evaluate other PK parameters including C max and T max of selected ARVs before and after DMPA. Evaluate the toxicity and safety of any PK interactions between ARVs and DMPA. Evaluate the toxicity and safety of any PK interactions between ARVs and 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 ARV PK done before and 4 weeks after DMPA

29. 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. 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 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 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 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 Studies with other HIV protease inhibitors, NNRTIs and NRTIs (tenofovir) deserve consideration

30. 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 ARV therapy.  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

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

32. *Association of Reproductive Health Professionals