We previously described 57% lower levonorgestrel (LNG) exposure in women receiving the LNG subdermal implant (standard dose, 150mg) with efavirenz (EFV)-based antiretroviral therapy (ART) compared to ART-naïve women. Three of 20 women (15%) had an unintended pregnancy within 48 weeks of LNG-EFV combined use, with observed LNG concentrations ≤303 pg/mL at the visit prior to pregnancy. Among women receiving LNG-EFV, 18 (90%) had any LNG concentration ≤303 pg/mL during the study. We hypothesized this interaction could be overcome by doubling the LNG implant dose; specifically, LNG 300mg exposure over 48 weeks in women receiving EFV-based ART would be similar to ART-naïve women receiving LNG 150mg.
This was a pharmacokinetic evaluation of double-dose (300mg) LNG implants in Ugandan women receiving EFV-based ART with an undetectable HIV-RNA (DoubLNG group; n=28). LNG implants, one in each arm, and a copper intrauterine device were placed at entry. Historical controls were ART-naïve Ugandan women (n=17) who received a standard-dose (150mg) LNG implant at entry. Plasma was collected at 1, 4, 12, 24, 36, and 48 weeks. LNG concentrations were analyzed by a validated LC-MS/MS method (range 50-1500 pg/mL), summarized as median (IQR), and compared between groups by geometric mean ratio (GMR) with 90% CI. The proportion with LNG ≤303 pg/mL were compared by Fisher’s Exact test.
All women were Black African. The DoubLNG group had a median age of 33 years and median weight of 58 kg; the control group was 29 years and 69 kg, respectively. The Table summarizes LNG results by visit. After 48 weeks, LNG concentrations were 373 (319, 540) pg/mL in the DoubLNG group versus 651 (469, 879) pg/mL in the control group [GMR (90% CI) 0.66 (0.61, 0.72)]. During the study, 18% (n=3) in the control group and 46% (n=13) in the DoubLNG group had any LNG value ≤303 pg/mL (p=0.06).
We observed 33-44% lower LNG concentrations over 48 weeks in women receiving EFV-based ART plus LNG 300mg implants compared to ART-naïve women on LNG 150mg implants. Relative to our prior study, the magnitude of the interaction with EFV at week 48 was smaller with double-dose LNG (34% lower) vs standard-dose LNG (57% lower). Also, fewer women receiving EFV-based ART had an LNG ≤303 pg/mL in the double- vs standard-dose group (46% vs 90%, respectively; p=0.002). Doubling the dose of LNG implants does not fully overcome the interaction with EFV, and the contraceptive effectiveness of this approach remains uncertain.