2 Infectious Diseases in Obstetrics and Gynecology As access to both modern methods of contraception andantiretroviral drugs (ARVs) expands, women with HIV enterthe largely uncharted territory of potential drug interactions.In this paper we will summarize the available literatureregarding coadministration of ARVs and hormonal contra-ception, with a focus on whether ARVs lead to alterations inhormonal contraceptive e
cacy.Modern hormonal birth control methods available inthe United States include daily pills (combined oral con-traceptives (COCs) that contain estrogen and a progestin,as well as progestin-only pills (POPs)), a weekly com-bined hormonal patch, a monthly combined hormonalvaginal ring, injectable depot medroxyprogesterone acetate(DMPA) given every three months, a three-year etonogestrel(progestin) implantable rod, and a ﬁve-year levonorgestrelintrauterine system (LNG-IUS). The latter two are oftendescribed as long-acting reversible contraceptives (LARCs).All of these methods are highly e
ective at preventingpregnancy, with the typical-use failure rate ranging from0.1% (LNG-IUS) to 8% (POPs, COCs, ring) . Hormonalemergency contraceptives (ECs) are also available, whichreduce the risk of pregnancy by 89% when taken within 72hours of unprotected sex . Contraceptive hormones aremetabolizedbythehepaticcytochrome(CYP)P450pathway,which is also responsible for the metabolism of many ARVs. Orally administered contraceptive hormones are subjectto extensive ﬁrst-pass gut and hepatic metabolism, whichnecessitates higher estrogen and progestin doses than thoserequired when these hormones are given via routes thatlead to minimal ﬁrst-pass metabolism . Whether noveldelivery systems (i.e., transdermal or transvaginal) a
ectthe pharmacokinetics of contraceptive hormones, and how these drugs will interact with ARVs, remains unclear. It isalso uncertain how LARC methods interact with HAARTregimens.Contraceptive steroids mainly work by negative feedback inhibition of the hypothalamic-pituitary-ovarian (HPO)axis, with additional e
ects on cervical mucus and theendometrium. Exogenous estrogen and progestin both pro-foundly suppress pulsatile secretion of follicle-stimulatinghormone (FSH) and luteinizing hormone (LH) [6,7].
However, most of the contraceptive e
ects (i.e., ovulationsuppression, thinning of the endometrium, and cervicalmucus thickening) are due primarily to progestin and aredose-dependent [6,8]. Ethinyl estradiol (EE), the estrogenic
component of most currently marketed COCs, is primarily metabolized through the hepatic CYP pathway. Speciﬁcally,hydroxylation of EE is catalyzed by the hepatic enzymesCYP3A4 and CYP2C9. Wide variation in the levels of these enzymes among individuals is thought to contributesigniﬁcantly to large intersubject variability of EE pharma-cokinetics . The contraceptive progestins available today also vary widely in their metabolism and pharmacokinetics,with large intersubject and intrasubject variability .Modern management of HIV typically involves a com-bination of ARVs, commonly described as highly activeantiretroviral therapy (HAART), since monotherapy canlead to the development of viral resistance to drug therapy.In treatment-na¨ıve patients, a starting regimen typically includes two nucleoside reverse transcriptase inhibitors(NRTIs) and a protease inhibitor (PI), two NRTIs and anonnucleoside reverse transcriptase inhibitor (NNRTI), orthree NRTIs . Table1lists the ﬁve preferred regimens
described by the Department of Health and Human Services(DHHS). Ritonavir, a protease inhibitor, is rarely used for itsown antiretroviral activity, but is used for its inhibitory e
ecton CYP3A4, the liver enzyme that normally metabolizes pro-tease inhibitors. A low dose of ritonavir is used to enhance,or“boost,”otherproteaseinhibitors,therebyimprovingARVe
cacy.This paper will examine the available evidence regardingdrug interactions between ARVs and all types of hormonalcontraception (HC), including transdermal and transvaginalroutes as well as LARC options. Pertinent pharmacokinetic(PK)parameters,suchasthemaximumserumconcentration(
), minimum serum concentration (
), and the area under the concentration-time curve(AUC), will be discussed for each drug interaction, whenavailable. We will also include recommendations made in theCenters for Disease Control and Prevention Medical Eligibil-ity Criteria (CDC MEC). This tool provides evidence-basedrecommendations about appropriate use of contraceptives inwomen with various medical comorbidities, including HIV.The document cross-references contraceptive methods andmedical conditions, assigning a recommendation category toeach combination of these. These categories are as follows:Category 1—a condition for which there is no restriction foruse of the contraceptive method; Category 2—a conditionfor which the advantages of using the method generally outweigh the theoretical or proven risks; Category 3—acondition for which the theoretical or proven risks usually outweigh the advantages of using the method; Category 4—a condition that represents an unacceptable health risk if thecontraceptive method is used .
We performed a literature search using PubMed andOvid databases to identify English-language articles pub-lished from January 1980 to February 2012. Search termsincluded contraception, hormonal contraception, contra-ceptives, hormonal contraceptives, birth control, HIV, fam-ily planning, and the generic names of individual ARVsand HC components: abacavir, amprenavir, atazanavir,darunavir, delavirdine, didanosine, efavirenz, emtricitabine,enfuvirtide, etravirine, fosamprenavir, indinavir, lamivu-dine, lopinavir, maraviroc, nelﬁnavir, nevirapine, ralte-gravir, rilpivirine, ritonavir, saquinavir, stavudine, teno-fovir, tipranavir, zalcitabine, zidovudine, ethinyl estradiol,ethynodiol diacetate, etonogestrel, levonorgestrel, depotmedroxyprogesterone acetate, norethindrone, desogestrel,drospirenone, norgestrel, norgestimate, mifepristone, andulipristal. We included randomized and nonrandomizedtrials, observational studies, and case reports that providedpharmacokinetic data for any of the hormonal contra-ceptives. Hand searches of relevant journals, references