Case 4: Discussion
Contraception is an important aspect of the management of HIV-infected individuals. Unfortunately, the concurrent use of oral contraceptives and antiretrovirals can generate significant drug-drug interactions. Oral contraceptives most often consist of a fixed combination of estrogen and progestin; the estrogen is ethinyl estradiol (EE) whereas numerous different types of progestin components are used, including norethindrone, norethindrone acetate, ethynodiol, norgestrel, levonorgestrel, norgestimate, desogestrel, and drosperinone. The main pathway of metabolism for oral contraceptives occurs via the cytochrome P450 enzyme system, predominantly in the gastrointestinal tract and liver. The cytochrome P450 3A4 isoenzyme (CYP3A4) is the dominant enzyme involved in the metabolism of oral contraceptives. Although most of the metabolism of the oral contraceptives occurs via the cytochrome p450 system, glucuronidation also plays a role. Potentially significant drug-drug interactions with use of oral contraceptives and antiretroviral medications occurs primarily with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors, since they medications also undergo metabolism via the CYP3A4 enzyme pathway. Significant drug-drug interactions do not occur with oral contraceptives and medications in other antiretroviral drug classes, including the nucleoside analogue reverse trancriptase inhibitors (NRTIs)[3,4], integrase inhibitors, and CCR5 antagonists. In addition, the oral contraceptives are not known to have a significant impact on antiretroviral medication drug levels[6,7].
Oral Contraceptives and NNRTIs
Among the NNRTIs, nevirapine (Viramune) and efavirenz (Sustiva) both act as inducers of the CYP3A4 enzyme and thus typically diminish plasma levels of similarly metabolized drugs. One study found the concurrent use of nevirapine and oral contraceptives resulted in a 29% decrease in the area under the curve (AUC) of EE, a significant reduction in the half-life of EE, and an 18% reduction in the AUC of norethindrone. The clinical impact of these interactions was not determined. Nevertheless, for patients taking nevirapine, oral contraceptives are not recommended as the primary method of birth control. Although efavirenz generally acts as a CYP3A4 inducer, in a study involving 28 healthy HIV-negative women, it did not cause a signifant alteration in EE levels, but it did lower the norelgestromin AUC by 64% and levonorgestrel levels 80 to 86%. Earlier studies suggested efavirenz increased EE levels, but this may have resulted from efavirenz interference with the estradiol ELISA assay and artificially elevate serum levels of estradiol. Because the efavirenz and oral contraceptive drug-drug interaction remains poorly characterized, it is recommended that women taking efavirenz not use oral contraceptives as the primary method of birth control. Etravirine (Intelence) does not have significant interactions with oral contraceptives. Similarly, in a study involving 18 HIV-negative women, rilpivirine (Edurant) was shown to have insignificantly impact on EE levels. Delavirdine (Rescriptor), a rarely used NNRTI, is an inhibitor of CYP3A4 enzymes and would presumably elevate EE levels, but there are no formal studies investigating interactions between oral contraceptives and delavirdine. For patients using the long-acting birth control shot depomedroxyprogesterone (Depo-Provera), the levels of depomedroxyprogesterone are not significantly changed by efavirenz or nevirapine[18,19]. In contrast, levels of levonorgestrel (the active agent in treatment used for emergency contraception) are significantly lowered with efavirenz.
Oral Contraceptives and Protease Inhibitors
The HIV protease inhibitors generally function as inhibitors of the CYP3A4 enzyme and thus one would anticipate protease inhibitors would increase EE levels. The available data, however, surprisingly shows that most protease inhibitors lower EE levels, but the impact on levels of norethindrone or norgestimate are less predictable. For example, ritonavir (Norvir) is a very potent inhibitor of the CYP3A enzyme, but when given with oral contraceptives it resulted in a 41% decrease in the EE AUC. In a study involving 19 HIV-negative women taking an oral contraceptive pill containing EE plus norethindrone, the addition of darunavir (Prezista) and low dose ritonavir resulted in a 44% decrease in the EE AUC and a 14% decrease in the norethindrone AUC. In a similar study involving 20 healthy women, atazanavir (Reyataz) and low-dose ritonavir reduced the EE AUC by 19%, but increase the norgestimate AUC by 85%. Lopinavir-ritonavir (Kaletra) decreases the EE AUC by approximately 40% and decreased norethindrone levels by 17%. Similarly, nelfinavir (Viracept) decreased the EE AUC by 47% and decreased the norethindrone AUC by 18%. The explanation for the findings that protease inhibitors typicaly lower EE levels remains poorly understood, but presumably this results from enhanced glucuronidation of EE, an alternative pathway used to metabolize drugs. For patients on ritonavir or nelfinavir, oral contraceptives are not recommended as the primary means of birth control. Indinavir (Crixivan), a moderate CYP3A4 inhibitor, increased the EE AUC by 24% and the norethindrone AUC by 26%.
Oral Contraceptives and Antiretrovirals: Summary and Recommendations
The major potential antiretroviral therapy interactions with oral contraceptives involve the NNRTI and protease inhibitor classes of drugs. The DHHS antiretroviral therapy guidelines provide a summary these key interactions and recommendations for patients concomitantly taking oral contraceptives and antiretroviral therapy. In general, use of the NNRTIs efavirez and nevirapine is problematic with oral contraceptives and is not recommended, but use of etravirine and rilpivirine with oral contraceptives dose not appear to result in any major drug-drug interactions (Figure 1). The use of protease inhibitors is not recommended in conjunction with oral contraceptives, although it may be possible with atazanavir (if the oral contraceptive contains at least 35 mcg of ethinyl estradiol if using ritonavir-boosted atazanavir or no more than 30 mcg of ethinyl estradiol if using unboosted atazanavir)(Figure 2).Interactions involving Ritonavir-Boosted Protease InhibitorsInteractions involving Protease Inhibitors (without Ritonavir)
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