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How does HIV therapy affect hormonal contraception?

Limited evidence suggests that certain antiretroviral (ARV) drugs can either raise or lower concentrations of contraceptive hormones in the blood of HIV-infected women using combined oral contraceptives (COCs). Theoretically, lower contraceptive hormone levels could reduce contraceptive efficacy and increase pregnancy risk, while higher levels could increase hormone-related side effects. (1)

Unanswered questions about the effects of ARV-COC interactions have led the World Health Organization (WHO) to caution that, although women on ARV therapy generally may use oral contraceptives, medical follow-up may be appropriate. (2) Questions about interactions between ARV drugs and COCs center on particular ARV drugs that affect liver enzymes, causing them to speed metabolism of hormonal contraceptives and thus reduce their levels in the blood. These enzyme-inducing ARV drugs include non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine and protease inhibitors such as ritonavir.

Reductions in blood levels of contraceptive hormones due to interactions with nevirapine or ritonavir can be substantial. One study showed a 29 percent decrease in levels of ethinyl estradiol and an 18 percent decrease in levels of norethindrone in women taking nevirapine while using a COC containing these hormones. (3) Estrogen levels were reduced by 43 percent when ethinyl estradiol was taken with ritonavir. (4)

Whether such reduced hormone levels affect contraceptive effectiveness is unclear because no studies have looked at actual clinical outcomes. But, anticipating that reduced hormone levels might affect contraceptive effectiveness, some providers recommend prescribing COCs containing 50 micrograms of estrogen rather than the usual 30- or 35-microgram dose for women on enzymeinducing ARV drugs. The disadvantage of such an approach is that higher doses of estrogen have been associated with an increased risk of side effects such as heart attacks, strokes, serious blood clots, or non-cancerous liver tumors. (5) Moreover, given the proven effectiveness of the ultra-low-dose COC containing 20 micrograms of estrogen, (6) COCs containing 30 or 35 micrograms of estrogen may still be effective even when estrogen levels are somewhat reduced. For now, WHO recommends that COC users on ARV therapy consistently use condoms for HIV prevention, noting that using a condom during each act of sexual intercourse may also compensate for any possible reduction in the effectiveness of the hormonal contraceptive. (7)

"Given the possibility of reduced effectiveness, oral contraceptives may not be the best option for women on ARV treatment who have difficulty remembering to take their pills on time," says Dr. Irina Yacobson, medical advisor to FHI's field programs and main author of a recently published provider training module on contraception for women and couples with HIV (available at http://www.fhi.org/en/RH/Training/trainmat/ARVmodule.htm).

On the other hand, some ARV drugs--including the protease inhibitors atazanavir and indinavir--may increase contraceptive hormone levels in the blood. (8) And the major NNRTI alternative to nevirapine--efavirenz--was found to increase levels of ethinyl estradiol in unpublished studies conducted by the drug manufacturer. (9) ARV drugs that do not appear to affect liver enzymes and are therefore not expected to change levels of contraceptive hormones include nucleoside reverse transcriptase inhibitors (NsRTIs), such as zidovudine, stavudine, and lamivudine; nucleotide reverse transcriptase inhibitors (NtRTIs), such as tenofovir; and fusion inhibitors, such as enfurvitide. 10 One study found no pharmacokinetic interaction between tenofovir and either deacetyl norgestimate or ethinyl estradiol. (11)

Interactions with other hormonals

Concerns about the impact of ARV drug use on the effectiveness of hormonal contraception focus primarily on COCs. This is because they provide lower doses of hormones than do the other methods and their effectiveness depends on women's ability to take them correctly. No data are available on interactions between ARV drugs and emergency contraception, but ARV drugs are not expected to substantially influence the efficacy of the higher-dose emergency contraceptive regimens. (12)

Likewise, little is known about interactions between ARV drugs and other methods of hormonal contraception. Since nevirapine reduced levels of progestin in the blood by about 18 percent in a study of COC users, (13) it could similarly reduce progestin levels in women using implants or injectables. Such a reduction would probably be too small to influence the efficacy of injectable contraceptives such as depot-medroxy-progesterone acetate (DMPA) because a dose of DMPA is considered high enough to provide a wide margin of effectiveness. (14) One study by the U.S. Adult AIDS Cooperative Trials Group (ACTG) found no significant changes in DMPA levels among 54 women using ARV regimens that included nevirapine, efavirenz, or the protease inhibitor nelfinavir compared with those in women using other ARV regimens or no ARVs.15 FHI and the Center for the Research and Control of Maternal-Infant Diseases of Campinas (CEMICAMP) in Campinas, Brazil, are evaluating the effects of a common ARV regimen (zidovudine, lamivudine, and efavirenz) on the pharmacokinetics of DMPA, with results expected in 2007.

The ACTG study did not assess the effects of ARV use on contraceptive hormone levels beyond the 12-week DMPA dosing period. The lack of data on DMPA levels among ARV users after 12 weeks underscores the need for women on ARV therapy to receive their DMPA injections on time.

Clinical outcomes still unknown

No studies of ARV-COC interactions have examined clinical outcomes, such as pregnancy rates or effects on ovulation. In the ACTG research, the researchers observed that suppression of ovulation was maintained in all 54 DMPA users receiving the study ARV regimens. The study was too small to detect statistically significant differences in ovulation between the study and comparison groups, but such differences are unlikely in the absence of any effect of ARV use on DMPA levels.

Finally, drug treatments for some HIVrelated opportunistic infections may also interact with hormonal contraceptives. Use of oral contraceptives, contraceptive rings or patches, or implants is not recommended for women taking the antituberculosis drug rifampicin because it is likely to reduce contraceptive effectiveness. WHO advises providers to exercise careful clinical judgment, providing COCs to women on rifampicin only when no other options are available. (16)

References

(1) World Health Organization (WHO). Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach. Geneva, Switzerland: WHO, 2004; Piscitelli SC, Flexner C, Minor JR, et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23(4):685-93.

(2) World Health Organization (WHO). Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use. Third Edition. Geneva, Switzerland: WHO, 2004. Available: http://www.who.int/reproductive-health/publications/mec/.

(3) Mildvan D, Yarrish R, Marshak A, et al. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr 2002;29(5):471-77.

(4) Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol 1998;46(2):111-16.

(5) Zheng JH. Data from the United States Food and Drug Administration. J Acquir Immune Defic Syndr 2005;38(Suppl 1):24-26.

(6) Coney P, Del Conte A. The effects on ovarian activity of a monophasic oral contraceptive with 100 microg levonorgestrel and 20 microg ethinyl estradiol. Am J Obstet Gynecol 1999;181(5 Pt 2):53-58; Archer DF, Maheus R, Del Conte A, et al. Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol (Alesse). North American Levonorgestrel Study Group (NALSG). Am J Obstet Gynecol 1999;181(5 Pt 2):39-44; Boerrigter PJ, Ellman H, Dolker M. International clinical experience with a new low-dose, monophasic oral contraceptive containing levonorgestrel 100 microg and ethinyl estradiol 20 microg. Clin Ther 1999;21(1):118-27; Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol 1999; 181(5 Pt 1):1263-69.

(7) Family Health International (FHI), EngenderHealth. Contraception for Women and Couples with HIV. Research Triangle Park, NC, USA: FHI and EngenderHealth, 2005. Available: http://www.fhi.org/en/RH/Training/trainmat/ARVmodule.htm.

(8) Piscitelli.

(9) Sustiva [U.S. prescribing information]. Princeton, NJ, USA: Bristol-Myers Squibb Company, 2004. Available: http://www.sustiva.com; Mitchell HS, Stephens E. Contraception choice for HIV positive women. Sex Transm Infect 2004;80(3):167-73.

(10) Nanda K. Hormonal contraceptive use in women treated with antiretroviral drugs. Expert working group meeting to update the WHO medical eligibility criteria for contraceptive use, Geneva, Switzerland, October 21-24, 2003.

(11) Kearney BP, Isaacson E, Sayre J, et al. Tenofovir DF and oral contraceptives: lack of a pharmacokinetic drug interaction. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, USA, September 14-17, 2003.

(12) FHI.

(13) Mildvan.

(14) Said S, Omar K, Koetsawang S, et al. A multicentred phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100 mg or 150 mg: 1. Contraceptive efficacy and side effects. World Health Organization Task Force on Long-Acting Systemic Agents for Fertility Regulation. Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 1986;34(3):223-35.

(15) Cohn SE, Park J-G, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral theray: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther December 27, 2006 [electronic publication ahead of print].

(16) WHO. Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use.
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Author:Shears, Kathleen Henry
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Date:Jun 22, 2007
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