Efavirenz-Based ART Associated with Reduced Efficacy of Birth Control with Levonorgestrel

Nevirapine-based ART did not have a negative impact on levonorgestrel exposure or efficacy.

Antiretroviral therapy with efavirenz appeared to reduce the efficacy of the levonorgestrel-releasing subdermal implant in HIV-positive women in Uganda when compared with women who were not on antiretroviral therapy.

However, levonorgestrel levels were higher in patients taking nevirapine compared with women who were naive to antiretroviral therapy.

Kimberly K. Scarsi, PharmD, associate professor in the College of Pharmacy, University of Nebraska Medical Center, was part of the research team conducting the nonrandomized, open-label, parallel group, pharmacokinetic study. She said researchers noticed significantly lower levonorgestrel concentrations in women taking efavirenz-based antiretroviral therapy as early as 1 week.

“Efavirenz is the WHO’s preferred antiretroviral therapy and long-acting contraception, either in an implant or the IUD are the preferred forms of contraception by both the American College of Obstetrics and Gynecologists and international bodies,” Dr Scarsi told Infectious Disease Advisor. “We need to find to away to make this combination work.”

World Health Organization (WHO) guidelines for prevention and first-line treatment of HIV recommend efavirenz-based antiretroviral therapy. The WHO also recommends long-acting, reversible contraceptives such as progestin-releasing subdermal implants. Dr Scarsi and her colleagues set out to explore potential drug-drug interactions between the recommended medications.

From June 2013 to December 2013, researchers enrolled 60 HIV-positive women in the study. All participants asked about family planning at the Infectious Diseases Institute at Makerere University College of Health Sciences, Uganda.

Participants received either efavirenz 600 mg daily plus 2 reverse transcriptase inhibitors, nevirapine 200 mg twice daily plus 2 reverse transcriptase inhibitors, or did not receive antiretroviral therapy. There were 20 women in each group.

Researchers observed no change in CD4+ cell count between baseline and 48 weeks for any of the 3 groups.

At 24 weeks, levonorgestrel concentrations were significantly lower for patients in the efavirenz group compared with the treatment-naive group 24-week (geometric mean ratio: 0.53; 90% CI, 0.50 to 0.55). Researchers noted higher levonorgestrel concentrations in the nevirapine group compared with the treatment-naive group throughout the study period (geometric mean ratio: 1.35; 90% CI, 1.29 to 1.43).

The 24-week area under the concentration curve (AUC) was 8053 pg wk/mL in the efavirenz group and 19 643 pg wk/mL in the nevirapine group relative to the treatment-naive group (15 168 pg wk/mL).

Nineteen women in each group participated in the planned 48-week of follow-up. There were no pregnancies in the antiretroviral treatment-naive or nevirapine groups.

“We expected that concentrations of levonorgestrel might be lower, but we didn’t expect that to affect efficacy over the first year,” Dr Scarsi said. “Unfortunately, we had a significant clinical outcome associated with low concentrations of the hormone.”

There were a total of 3 pregnancies (15%) in the efavirenz group. Researchers first identified 2 pregnancies, approximately 2 weeks and 10 weeks post-conception, then halted the efavirenz group follow-up. The entire group then returned for a study discontinuation visit and researchers identified a third pregnancy, approximately 2 weeks post-conception.

Each of the 3 women who became pregnant made their last study visit prior to pregnancy at 36 weeks. At that point, levonorgestrel concentrations were 122 pg/mL, 299 pg/mL, and 303 pg/mL.

Eleven participants in the efavirenz group participated through 48 weeks. Their final levonorgestrel geometric mean ratio was 0.43 (90% CI, 0.42 to 0.44) compared with the treatment-naive group.

Dr Scarsi’s group is now researching levonorgestrel dose adjustments that will allow the contraceptive implant to maintain efficacy when used in combination with efavirenz. She said contraceptive implants were introduced without much research into potential interactions with antiretroviral therapy, and these results show the risks of making assumptions about combination therapy in the absence of data.

She added that the combination is still of vital importance to HIV-infected women, but those patients should be fully informed about their contraceptive options.

“I don’t want to take the implant off the table for these patients,” she said. “We have to find better ways to combine the 2 drugs.”


  1. Scarsi KK, Darin KM, Nakalema S, Back DJ, et al. Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks. Clin Infect Dis. 2016; doi:10.1093/cid/civ1001.