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Appendix M

Summary of Evidence Regarding Potential Drug Interactions between Hormonal Contraception and Antiretroviral Therapies

Limited data from small, mostly unpublished studies suggest that some antiretroviral (ARV) therapies might alter the pharmacokinetics of combined oral contraceptives (COCs). Few studies have measured clinical outcomes. However, contraceptive steroid levels in the blood decrease substantially with ritonavir-boosted protease inhibitors. Such decreases have the potential to compromise contraceptive effectiveness. Some of the interactions between contraceptives and ARVs also have led to increased ARV toxicity. For smaller effects that occur with non-nucleoside reverse transcriptase inhibitors, clinical significance is unknown, especially because studies have not examined steady-state levels of contraceptive hormones. No clinically significant interactions have been reported between contraceptive hormones and nucleoside reverse transcriptase inhibitors.

Tables 1 and 2 summarize the evidence available about drug interactions between ARV therapies and hormonal contraceptives. For up-to-date, detailed information about human immunodeficiency virus (HIV) drug interactions, the following resources might be helpful:

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
HIV Drug Interactions website, University of Liverpool, UK. Available at www.hiv-druginteractions.org.

References

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Aweeka FT, Rosenkranz SL, Segal Y, et al. The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine. AIDS 2006;20:1833--41.
Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinyl estradiol in healthy female volunteers [Abstract 348]. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, February 1--5, 1998.
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Scholler-Gyure M, Debroye C, Aharchi F, et al. No clinically relevant effect of TMC125 on the pharmacokinetics of oral contraceptives. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, November 12--16, 2006..
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TABLE 1. Drug interactions between COCs and ARV drugs*
ARV	Contraceptive effects†	ARV effects†
Nucleoside reverse transcriptase inhibitors (NRTIs)
Tenofovir disaproxil fumarate	EE ↔, NGM ↔ (1)	Tenofovir ↔ (1)
Zidovudine	No data	Zidovudine ↔ (2)No change in viral load or CD4+ (2)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz	EE ↑ (3), EE ↔ (4), NGM ↓ (4), LNG ↓ (4) Pregnancy rate 2.6/100 woman-years in 1 study in which up to 80% used hormonal contraceptives (35% used COC) (5)	Efavirenz ↔ (3,4)
Etravirine	EE ↔, NET ↔ (6)	Etravirine ↑ (6) Concurrent administration, generally safe and well tolerated (6)
Nevirapine	EE ↔, NET ↔ (7)	Nevirapine ↔ (7)
Protease inhibitors and ritonavir-boosted protease inhibitors
Atazanavir/ritonavir	EE ↑, NET ↑ (8)	No data
Darunavir/ritonavir	EE ↓, NET ↔ (9)	Darunavir ↔ (9)
Fos-amprenavir/ritonavir	EE ↓ (10,11), NET ↓ (11)	Amprenavir ↔, ritonavir ↑, Elevated liver transaminases (10)
Indinavir§	EE ↔, NET ↔ (12)	No data
Lopinavir/ritonavir	EE ↓, NET ↔ (13)	No data
Nelfinavir	EE ↓, NET ↔ (14)	No data
Saquinavir§	No data	Saquinavir ↔ (15,16)
Tipranavir/ritonavir	EE↓ (17)	↑ Skin and musculoskeletal adverse events; possible drug hypersensitivity reaction (17)
* Abbreviations: COC = combined oral contraceptive; ARV = antiretroviral; EE = ethinyl estradiol; NGM = norgestimate; NNRTI = non-nucleoside reverse transcriptase inhibitor; LNG = levonorgestrel; NET = norethindrone. † ↔, no change or change ≤30%; ↑, increase >30%; ↓, decrease >30%. § Saquinavir and indinavir are commonly given boosted by ritonavir, but there are no data on contraceptive interactions with the boosted regimens.

TABLE 2. Drug interactions between DMPA and ARV drugs*
ARV	Contraceptive effects†	ARV effects†
Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine	No data	Zidovudine ↔ (2)No change in viral load
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz	MPA ↔ (18,19) No ovulations during 3 cycles(18,19)Pregnancy rate 2.6/100 woman-years in 1 study where up to 80% used hormonal contraceptives (65% used POIs) (5)	Efavirenz ↔ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)
Nevirapine	MPA ↔ (18)No ovulations during 3 cycles(18)	Nevirapine ↑ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)
Protease inhibitors and ritonavir-boosted protease inhibitors
Nelfinavir	MPA ↔ (18)	Nelfinavir ↔ (18)No change in viral load or CD4+, no grade 3- or 4-related adverse events§ (20)
* Abbreviations: DMPA = depot medroxyprogesterone acetate; ARV = antiretroviral; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase; MPA = medroxyprogesterone acetate; POI = progestin-only injectables. † ↔, no change or change ≤30%; ↑, increase > 30%. § The trial applied the standardized National Institutes of Health Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, 2004 (http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GradingTable_Clarification_August2009_Final.pdf). Grade 3 events are classified as severe. Severe events are defined as symptoms that limit activity or might require some assistance; require medical intervention or therapy; and might require hospitalization. Grade 4 events are classified as life threatening. Life-threatening events include symptoms that result in extreme limitation of activity and require substantial assistance; require substantial medical intervention and therapy; and probably require hospitalization or hospice.

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