The majority of women with human immunodeficiency virus −1 (HIV) are of reproductive age and may use an efavirenz- (EFV-) containing antiretroviral (ARV) regimen [¹, ²]. EFV is a nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV [³]. EFV is an FDA pregnancy category D drug based on animal studies and human case reports of fetal neural tube defects [³–⁶]. Thus, preventing pregnancy is critical in HIV-infected women receiving EFV.

Pregnancy rates for HIV-infected women range from 6.0 to 8.2 pregnancies per 100 person-years, and in 2001, 49% of all pregnancies in the United States were unintended [⁷–⁹]. Women with HIV not desiring pregnancy are advised to use dual methods of contraception to prevent pregnancy and HIV transmission to their partners. Some women use emergency hormonal contraception to prevent pregnancy after unprotected sex or contraceptive failure (condom breakage).

Plan B is a levonorgestrel- (LNG-) containing emergency contraceptive pill indicated for pregnancy prevention following unprotected intercourse or a known or suspected contraceptive failure [¹⁰]. It is taken as soon as possible within 72 hours after unprotected intercourse either as a single dose (LNG 1.5 mg) or as two doses (0.75 mg) taken twelve hours apart. LNG use for emergency hormonal contraception has been shown to reduce pregnancy rates by 85% [¹¹]. The mechanism of action of Plan B is not fully elucidated. It may inhibit ovulation, fertilization, or implantation [¹⁰, ¹¹]. The minimum effective LNG plasma concentration is unknown.

Few data are available on the pharmacokinetics (PK) of progesterone-based contraceptives with NNRTIs. A study of depomedroxyprogesterone acetate (DMPA) depot injections in HIV-infected women on antiretroviral therapy revealed no significant change in plasma levels of MPA or EFV, nevirapine, or nelfinavir [¹²]. However, in a study of EFV and the combination oral contraceptive pill OrthoTriCyclen-Lo and OrthoCyclen (25 mcg ethinyl estradiol plus 0.18–0.25 mg norgestimate), LNG area under the concentration time curve from 0 to 12 hours (AUC₁₂), maximum concentration (C_max⁡), and minimum concentration (C_min⁡) were decreased by 80%, 83%, and 86%, respectively [¹³]. A case of contraceptive failure with ectopic pregnancy in an HIV-infected woman occurred with the etonogestrel contraceptive implant and EFV [¹⁴]. No PK interaction studies of Plan B and concomitant efavirenz have been performed [¹⁴].

Data are limited regarding the use of hormonal contraception in HIV-infected women on antiretroviral therapy. Interactions have been described between steroid hormones and both protease inhibitors and NNRTI which could lead to decreased protection from pregnancy or increased contraceptive side effects [¹⁷]. Previous studies have focused predominantly on combined oral contraceptive pills, injectable DMPA, and one small study evaluated PK with the transdermal contraceptive patch [¹², ¹³, ¹⁸]. Women taking EFV are specifically advised to avoid pregnancy due to this agents' potential role in fetal neural tube defects [³, ¹⁹]. Thus, emergency hormonal contraception, like Plan B, may be even more important for these women.

We sought to evaluate the effect of EFV on plasma concentration of LNG in Plan B in healthy HIV-negative women. We found that pretreatment with EFV for 14 days was associated with a 56%, 41%, and 67% decrease in LNG AUC₁₂, C_max⁡, and C_min⁡, respectively.

The mechanism for this interaction is likely EFV induction of LNG metabolism. EFV is an inducer of CYP3A and uridine-diphosphate glucuronosyl transferases (UGTs) in vivo [³]. LNG exposures are reduced approximately 40% with the anticonvulsants phenytoin and carbamazepine (inducers of CYP3A) and 19% with lamotrigine (an inducer of glucuronidation enzymes) [²⁰, ²¹]. A study of rifampin and oral contraception demonstrated considerable reduction in contraceptive hormone levels; however, ovulation suppression persisted [²²].

These findings may have important ramifications with regard to the efficacy of Plan B when taken with this ARV. However, the clinical relevance of this finding is unclear as the minimal effective LNG plasma concentration is unknown. We did not monitor for ovulation which may signal failed contraception. It is possible the alternate Plan B single dosing of LNG 1.5 mg would mitigate this effect; however, this is unlikely given the magnitude of our observed difference. Further clinical studies of Plan B and EFV are thus needed to inform providers of potential need for Plan B dosing adjustments for these women. HIV providers' role in providing family planning services including contraception and preconception counseling is significant given the inherent complexities with HIV and antiretroviral therapy.

Drs. M. L. Carten, J. J. Kiser, A. Kwara, and S. Cu-Uvin have no conflict of interests to report.

This study was supported by an investigator-initiated study grant from Bristol-Meyers Squibb Co, the Colorado Translational Research Center (1UL1 RR025780), the Colorado Center for AIDS Research P30AI054907 (J. Kiser), and Lifespan/Tufts/Brown University Center for AIDS Research P30AI4285 (S. Cu-Uvin), K24A1066884 (S. Cu-Uvin). The study team would like to thank Michelle Ray with the Colorado Antiretroviral Pharmacology Laboratory for quantifying the EFV levels, the Miriam Hospital HIV Research Unit, and all of the study subjects. This data was presented as abstract at the 17th Conference on Retroviruses and Opportunistic Infections in San Francisco, CA, February 27-March 2, 2010 (ref).