- Section 2: Testing and Assessment
- Initial History
- Initial Physical Examination
- Initial and Interim Laboratory and Other Tests
- Interim History and Physical Examination
- HIV Classification: CDC and WHO Staging Systems
- CD4 and Viral Load Monitoring
- Risk of HIV Progression/Indications for ART
- Early HIV Infection
- Expedited HIV Testing
- Resistance Testing
- Karnofsky Performance Scale
- Occupational Postexposure Prophylaxis
- Nonoccupational Postexposure Prophylaxis
- Preventing HIV Transmission/Prevention with Positives
- Immunizations for HIV-Infected Adults and Adolescents
- Preventing Exposure to Opportunistic and Other Infections
- Opportunistic Infection Prophylaxis
- Latent Tuberculosis Infection
- Smoking Cessation
- Abnormalities of Body-Fat Distribution
- Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy
- Coronary Heart Disease Risk
- Renal Disease
- Immune Reconstitution Inflammatory Syndrome
- Anal Dysplasia
- Candidiasis, Oral and Esophageal
- Candidiasis, Vulvovaginal
- Cervical Dysplasia
- Cryptococcal Disease
- Cytomegalovirus Disease
- Gonorrhea and Chlamydia
- Hepatitis B Infection
- Hepatitis C Infection
- Herpes Simplex, Mucocutaneous
- Herpes Zoster/Shingles
- Kaposi Sarcoma
- Molluscum Contagiosum
- Mycobacterium avium Complex Disease
- Mycobacterium tuberculosis
- Pelvic Inflammatory Disease
- Pneumocystis Pneumonia
- Progressive Multifocal Leukoencephalopathy
- Seborrheic Dermatitis
Antiretroviral Medications and Hormonal Contraceptive Agents
Publish date: April 2014
Few pharmacokinetic or clinical studies have examined interactions between antiretroviral (ARV) medications and hormonal contraceptives, but it is known that certain protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well as the boosted integrase inhibitor combination elvitegravir/cobicistat, do interact with hormonal contraceptives. These interactions may increase the risk of medication failure or medication adverse effects of either the ARV or the contraceptive. There are no known interactions between hormonal contraceptives and nucleoside analogues or the CCR5 antagonist.
All oral contraceptives currently marketed in the United States, with the exception of progestin-only pills (which contain norethindrone), contain both ethinyl estradiol and a progestin (desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, or norgestrel). The oral contraceptives ethinyl estradiol and norethindrone may interact in complex ways with PIs and NNRTIs. The mechanism of these interactions may be multifactorial and includes the activity of these agents on cytochrome P450 enzymes. Pharmacokinetic studies have shown changes (either increases or decreases) in levels of ethinyl estradiol and norethindrone in women who are taking certain PIs, NNRTIs, or elvitegravir/cobicistat. Other studies have shown decreases in levels of amprenavir (the active agent of fosamprenavir) in women taking oral contraceptives.
The clinical significance of these drug interactions has not been evaluated thoroughly, but may cause oral contraceptive failure, ARV failure, or medication toxicity, depending on whether drug levels are lowered or raised by the interacting drug. The consequences of decreased hormone levels may include an increased risk of pregnancy, so an alternative or additional method of contraception is commonly recommended. The consequences of decreased ARV levels may include virologic failure and development of resistance mutations. The consequences of a higher level of hormones may include risk of thromboembolism, breast tenderness, headache, nausea, and acne.
The available pharmacokinetic data are summarized in Table 1. For further discussion of oral and non-oral contraceptives for HIV-infected women, see chapter Health Care of HIV-Infected Women Through the Life Cycle.
|Antiretroviral Agent||Pharmacokinetic Changes with Oral Contraceptives||Comments|
Key to symbols:
Abbreviations: AUC = area under the time-concentration curve (drug exposure); C max = maximum concentration; C min = minimum concentration; EE = ethinyl estradiol; LN = levonorgestrel; NE = norethindrone; NG = norgestimate; OC = oral contraceptive; RTV = ritonavir; /r = low-dose ritonavir
Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services.
|Atazanavir (ATV, Reyataz) (unboosted)||!|
|Darunavir (DRV, Prezista) DRV/r||✖|
|Fosamprenavir (FPV, Lexiva)||✖|
|Indinavir (IDV, Crixivan)||✓|
|Lopinavir/r (LPV/r, Kaletra)||✖|
|Nelfinavir (NFV, Viracept)||✖|
|Ritonavir (RTV, Norvir)||✖|
|Saquinavir (SQV, Invirase)/r||✖|
|Tipranavir (TPV, Aptivus)/r||✖|
|Nonnucleoside Reverse Transcriptase Inhibitors|
|Efavirenz (EFV, Sustiva)||✖|
|Etravirine (ETR, Intelence)||✓|
|Nevirapine (NVP, Viramune)||✖|
|Rilpivirine (RPV, Edurant)||✓|
|Maraviroc (MVC, Selzentry)||✓|
|Dolutegravir (DTG, Tivicay)||✓|
|Raltegravir (RAL, Isentress)||✓|
Non-Oral Hormonal Contraceptives
Hormonal contraceptives using delivery methods other than oral include the following:
- Products containing both progestin and estrogen components: transdermal patch, vaginal ring
- Products containing a progestin alone (medroxyprogesterone acetate, levonorgestrel, norelgestromin, or etonogestrel): subcutaneous or IM injection, intrauterine system, implantable device
There has been little research on the interactions between ARVs and most of these agents. Theoretically, interactions with ARVs would be less likely with contraceptive methods that have primarily local action and minimal systemic absorption, and for injection or transdermal delivery systems, since first-pass metabolism is avoided. However, caution is still warranted, as this assumption has not been proven.
Because the transdermal patch and vaginal ring contain ethinyl estradiol, women who take ARVs that increase or decrease serum estradiol levels (see Table 1) are advised to use an alternative (or additional) contraceptive method. Small studies of depo-medroxyprogesterone acetate (DMPA, or Depo-Provera) have shown no significant interactions between DMPA and nelfinavir, efavirenz, or nevirapine. Interactions between DMPA and other ARVs have not been studied, but DMPA's interactions with PIs and NNRTIs would be expected to be similar to those of norethindrone (see Table 1). For other non-oral hormones, pending further study, an alternative (or additional) method of contraception should be considered.
- Anderson MS, Wenning L, Moreau A, et al. Effect of raltegravir on the pharmacokinetics of oral contraceptives. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago. Abstract A-1425.
- Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs. J Fam Plann Reprod Health Care. 2002 Apr;28(2):78-80.
- Carten M, Kiser J, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel, and efavirenz. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010; San Francisco. Abstract 934.
- Chu JH, Gange SJ, Anastos K et al. Hormonal contraceptive use and the effectiveness of highly active antiretroviral therapy. Am J Epidemiol. 2005 May 1;161(9):881-90.
- Cohn SE, Park JG, Watts DH, et al.; ACTG A5093 Protocol Team. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. 2007 Feb;81(2):222-7.
- Gupta S. Non-oral hormonal contraception. Curr Ob Gyn. 2006 Feb;16(1):30-8.
- Heikinheimo O, Lehtovirta P, Suni J, et al. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women - effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod. 2006 Nov;21(11):2857-61.
- Implanon [package insert]. Kenilworth, NJ: Schering-Plough; 2009.
- Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacokinetic interaction between efavirenz (DMP 266) and ethinylestradiol in healthy female volunteers. In: Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; February 1-5, 1998; Chicago. Abstract 348.
- Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy. 2009 Aug;29(8):924-9.
- Mayer K, Poblete R, Hathaway B, et al. Efficacy, effect of oral contraceptive, and adherence in HIV infected women receiving Fortovase (saquinavir) soft gel capsule thrice and twice daily regimens. In: Program and abstracts of the XIII International AIDS Conference; July 9-14, 2000; Durban, South Africa. Abstract TuPeB3226.
- McNicholl I. Database of Antiretroviral Drug Interactions. HIV InSite. San Francisco: UCSF Center for HIV Information. Accessed December 1, 2013.
- Mitchell HS, Stephens E. Contraception choice for HIV positive women. Sex Transm Infect. 2004 Jun;80(3):167-73.
- Nanda K, Amaral E, Hays M, et al. Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril. 2008 Oct;90(4):965-71.
- 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 Aug;46(2):111-6.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
- Scholler-Gyure M, Debroye C, Aharchi F, et al. No effect of TMC125 on the pharmacokinetics of oral contraceptives. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow. Abstract P277.
- Sekar VJ, Lefebvre E, Guzman SS, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther. 2008;13(4):563-9.
- Sevinsky H, Eley T, He B, et al. Effect of efavirenz on the pharmacokinetics of ethinylestradiol and norgestimate in healthy female subjects. In: Program and abstracts of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington. Abstract A-958.
- Tackett D, Child M, Agarwala S, et al. Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-13, 2003; Boston. Abstract 543.
- Watts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008 Feb;77(2):84-90.
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Abbreviations for Dosing Terminology
- twice daily
- twice weekly
- intramuscular (injection), intramuscularly
- intravenous (injection), intravenously
- oral, orally
- Q2H, Q4H, etc.
- every 2 hours, every 4 hours, etc.
- every morning
- once daily
- every hour
- every night at bedtime
- four times daily
- every other day
- every evening
- three times daily
- three times weekly