Using Hormonal Contraceptives and Antiretroviral Medications
Contraception is an important aspect of the management of HIV-infected women. Unfortunately, the concurrent use of hormonal contraceptives and antiretrovirals have potential for significant drug-drug interactions. Although multiple studies have examined drug interaction pharmacokinetics with contraceptives and antiretroviral medications, little data exist regarding the clinical implications of these interactions. Oral contraceptives most often consist of a fixed combination of estrogen and progestin. Ethinyl estradiol (EE) is the estrogen combined with different types of progestins, including norethindrone, norethindrone acetate, ethynodiol, norgestrel, levonorgestrel, norgestimate, desogestrel, and drosperinone. The main pathway of metabolism for oral contraceptives occurs via the cytochrome P450 (CYP450) enzyme system, predominantly in the gastrointestinal tract and liver. Cytochrome P450 3A4 (CYP3A4) is the primary enzyme pathway involved in the metabolism of oral contraceptives. Primary metabolism of the oral contraceptives occurs via the cytochrome p450 system, although glucuronidation may also play a role. Significant drug-drug interactions can occur with concomitant use of oral contraceptives and antiretroviral medications. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) also undergo metabolism via the CYP3A4 enzyme pathway. Significant drug-drug interactions do not occur with oral contraceptives and the nucleoside analogue reverse transcriptase inhibitors (NRTIs) or the C-C chemokine receptor type 5 (CCR5) antagonists.[,,] Hormonal contraceptives are not known to have a significant impact on antiretroviral medication drug plasma levels.[,]
Hormonal Contraceptives and NNRTIs
Significant drug-drug interactions may occur with concomitant use of NNRTIs and hormonal contraceptives (Figure 1). Both nevirapine (Viramune) and efavirenz (Sustiva) are known to induce CYP3A4 enzymes, which may lead to decreased plasma levels of similarly metabolized drugs. One study demonstrated 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 significant alteration in EE levels, but it lowered 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 efavirenz and oral contraceptive drug-drug interactions remain poorly characterized, it is recommended that women taking efavirenz should 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 not shown to have a significant impact on EE levels. Plasma levels of the long-acting birth control shot depomedroxyprogesterone (Depo-Provera) are not significantly changed by efavirenz or nevirapine.[,] In contrast, plasma levels of levonorgestrel (the active agent in treatment used for emergency contraception) are significantly lowered with efavirenz.
Hormonal Contraceptives and Protease Inhibitors
The PIs generally cause inhibition of the CYP3A4 enzymes which could increase EE plasma levels. The available data, however, surprisingly shows that most PIs decrease EE plasma levels, but the impact on levels of norethindrone or norgestimate are less predictable (Figure 2). Ritonavir (Norvir) is a very potent inhibitor of the CYP3A enzyme, but when administered with oral contraceptives it decreases the AUC of EE by 41%. In a study involving 19 HIV-negative women taking an oral contraceptive 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 both the EE AUC by 47% and the norethindrone AUC by 18%. The explanation for the findings that PIs typically lower EE levels remains poorly understood, but may result from enhanced glucuronidation of EE, an alternative pathway of metabolism. Oral contraceptives are not recommended as the primary means of birth control for patients taking nelfinavir or any PI boosted with ritonavir.
Hormonal Contraceptives and Integrase Strand Transfer Inhibitors
The potential for drug-drug interactions with hormonal contraceptives and ISTIs parimarily occurs when using the fixed-drug combination elvitegravir-cobicistat-tenofovir-emtricitabine (Stribild); in the fixed-dose combination, cobicistat is use to inhibit CYP450 enzymes to elvitegravir plasma levels, but this also has the unwanted effect of altering hormonal contraceptive levels (Figure 3). The INSTIs raltegravir (Isentress) and dolutegravir (Tivicay) do not significant alter hormonal contraceptive plasms levels and can be used without dose adjustments. If the INSTI elvitegravir (Vitekta) is boosted with ritonavir (Norvir), the recommendation is to use an alternative or additional contraceptive methods.