You are here
DOUBLE-DOSE LEVONORGESTREL IMPLANT DOES NOT FULLY OVERCOME INTERACTION WITH EFAVIRENZ
Kimberly K. Scarsi1, Lauren Cirrincione1, Shadia Nakalema2, Kristin Darin3, Ian Musinguzi2, Isabella Kyohairwe2, Pauline Byakika-Kibwika2, Andrew Owen4, Lee Winchester1, Anthony Podany1, Susan E. Cohn3, David Back4, Courtney V. Fletcher1, Marco Siccardi4, Mohammed Lamorde2
1University of Nebraska Medical Center, Omaha, NE, USA,2Infectious Disease Institute, Kampala, Uganda,3Northwestern University, Chicago, IL, USA,4University of Liverpool, Liverpool, UK
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.