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  22nd Conference on Retroviruses and
Opportunistic Infections
Seattle Washington Feb 23 - 26, 2015
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Levonorgestrel contraception fails in 15% of women taking efavirenz
  CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
Levonorgestrel (LNG), a popular long-acting contraceptive implant, failed to prevent pregnancy in 3 of 20 women (15%) taking an efavirenz regimen in a pharmacokinetic study [1]. The surprising finding suggests that the proposed threshold for LNG efficacy, 180 pg/mL, may be too low. These results have immediate implications for efavirenz-treated women relying on LNG for contraception.
LNG is a popular contraceptive because it has a failure rate below 1% and because it works for 4 to 5 years after insertion. LNG may be a particularly attractive option for HIV-positive women because monthly injections of depot medroxyprogesterone acetate (DMPA) have been linked to HIV transmission [2]. Because LNG is metabolized via CYP 3A4 enzymes and efavirenz potently induces CYP 3A4, the nonnucleoside may reduce systemic exposure of LNG. To address that issue, Kimberly Scarsi of the University of Nebraska and colleagues at other centers conducted this nonrandomized, open-label, parallel-group pharmacokinetic analysis in Ugandan women.
The study included HIV-positive women at least 18 years old who wanted the LNG implant. The efavirenz group had taken an efavirenz regimen for at least 30 days and had a viral load below 400 copies. A control group included women not yet eligible for ART in Uganda because they had a CD4 count above 350. The researchers excluded women taking drugs that may interact with LNG or efavirenz.
Health workers drew blood samples at day 0 and weeks 1, 4, 12, 36, and 48. At each study visit women received family planning counseling and a urine pregnancy test. The LNG assay used can detect levels between 50 and 1500 pg/mL.
The analysis focused on 20 women taking efavirenz and 17 not on antiretroviral therapy. Age averaged 31 in the efavirenz group and 29 in the control group, with respective CD4 counts averaging 568 and 758. Women taking efavirenz weighed significantly less than women in the control group (average 59 versus 73 kg, P < 0.01). LNG exposure and body weight are inversely correlated--the lower the weight the higher the LNG level.
At week 24 LNG concentrations were almost 50% lower in the efavirenz group than in the control group (efavirenz/control geometric mean ratio 0.53, 90% confidence interval [CI] 0.50 to 0.55). At week 48 LNG levels were even lower relative to the control group (geometric mean ratio 0.43, 90% CI 0.42 to 0.44). Overall, Scarsi and colleagues calculated that LNG concentrations were 45% to 57% lower over 48 weeks in efavirenz users. LNG area under the concentration-time curve was 48% lower in efavirenz users.
Three women in the efavirenz group (15%) and none in the control group became pregnant. One pregnancy was detected at an early discontinuation visit and 2 were detected at week 48. At that point researchers halted the efavirenz arm. The highest LNG concentration at which pregnancy was observed was 303 pg/mL, well above the proposed efficacy threshold of 180 pg/mL. Fifteen women in the efavirenz group (75%) had LNG concentrations below 303 pg/mL, compared with none in the control arm.
The researchers concluded that the proposed LNG efficacy threshold of 180 pg/mL is inadequate. Their findings, they proposed, validate "concerns for reduced subdermal implant efficacy in women on efavirenz." A 570-woman retrospective study of unintended pregnancy in LNG users taking efavirenz supports the pharmacokinetic study finding [3].
Scarsi and colleagues advised health workers to counsel women taking LNG and efavirenz about the risk of unintended pregnancy and to discuss other forms of contraception. They noted that only limited data support use of subdermal implants with nevirapine or lopinavir regimens. The researchers see an urgent need for further study of novel subdermal implant dosing strategies and alternative antiretroviral options for implant users.
1. Scarsi KK, Darin KM, Nakalema S, et al. Levonorgestrel implant + EFV-based ART: unintended pregnancies and associated PK data. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 85.
2. Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12:19-26. Erratum in Lancet Infect Dis. 2012 Feb;12(2):98.
3. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies. AIDS. 2014;28:791-793.