Concomitant use of efavirenz-containing antiretroviral therapy (ART) is known to reduce etonogestrel (ENG) concentrations, leading to reduced contraceptive effectiveness of subdermal implants. Dolutegravir (DTG)-containing ART is now the preferred first-line regimen for women of reproductive potential. However, DTG’s drug-drug interactions with hormonal contraceptives have been narrowly evaluated thus far, and understanding any potential for interactions between subdermal implants and DTG is important as countries pursue national rollout of DTG-containing ART.
We conducted a prospective, open-label pharmacokinetic study among women of reproductive potential in Kisumu, Kenya. Women were either HIV-positive, virologically suppressed, and receiving DTG-containing ART for at least 30 days prior to enrollment, or HIV-negative and not receiving any antiretrovirals (control group). An ENG 68mg subdermal implant was placed as part of routine clinical care and women were enrolled in this study within 2 weeks of implant placement. Blood samples were drawn at 2, 4, 8, 12, 16, 20, and 24 weeks after study entry. We analyzed plasma ENG concentrations using a validated LC-MS/MS assay (range 25-30,000 pg/mL). We describe per visit ENG concentrations using median (range) and compare the concentrations per visit between DTG-containing ART and the control groups using geometric mean ratio (GMR; 90% confidence interval) and the Wilcoxon rank sum test.
All women were black African. The median age was 35 and 25 years, and weight was 62.5 and 59.0 kg in the DTG-containing ART and control groups, respectively. Women in the DTG-containing ART group were on this ART for a median of 6.7 (range 4.3-8.3) months prior to study enrollment. ENG plasma concentrations for the DTG and control groups were 692 (470-989) and 588 (277-1050) pg/mL at week 2, respectively, and decreased to 456 (250-720) and 268 (136-496) pg/mL by week 24, respectively (Table). ENG exposure in the DTG-containing ART group was 19-54% higher compared to controls (all p<=0.05).
In the first of its kind study, we observed modestly higher ENG concentrations among women using DTG-containing ART vs. HIV-negative women. Our findings suggest that no detrimental drug-drug interactions exist with concomitant use of ENG implants and DTG. DTG-containing ART represents a preferable alternative to efavirenz-containing ART for women already using or desiring an ENG implant.