Comparative Effectiveness of the Levonorgestrel (LNG) Implant and Depot Medroxyprogesterone Acetate (DMPA) Injectable for Prevention of Pregnancy among Women Living with HIV on Efavirenz

Background: Effective contraception and antiretroviral treatment (ART) for HIV are crucial for the health of many women in sub-Saharan Africa (SSA). However, a drug-drug interaction (DDI) between the levonorgestrel (LNG) implant and efavirenz (EFV) based ART may cause contraceptive failure. Generally, the typical use 1-year contraceptive failure rate is <1% for LNG implant and 1.7-6% for Depot Medroxyprogesterone Acetate (DMPA) injection, but these rates appear higher among women living with HIV in SSA. Findings remain mixed on whether LNG implant or DMPA injection is more effective for women living with HIV on EFV.

Objectives: Compare the effect of typical use LNG implant vs. DMPA injection on pregnancy incidence rates among women on EFV-based ART.

Methods: We conducted a prospective cohort study of HIV-infected Malawian women on EFV-based ART with visits and urine pregnancy testing at entry, 1 month, and every 6 months after contraception start. At entry, participants were 18-40 years of age and sought reversible contraception to prevent pregnancy for 4 years. Pregnancy incidence per 100 woman years (WY) of life was analyzed according to contraception at entry and regardless of subsequent contraception changes. Follow-up was censored at the earlier of last study visit, tubal ligation, or 28 days after stopping EFV. We used a marginal structural Poisson model with inverse probability weights for contraception choice at entry to estimate an incidence rate difference and rate ratio, each with a corresponding, percentile-based bootstrap 95% CI. We adjusted for 9 baseline variables in a complete-case analysis according to our causal directed acyclic graph: age, gravidity, coital frequency, post-partum lactation, plans for future children, education, site, years with HIV, and tuberculosis medication.

Results: From August 2017 to March 2020, we enrolled 1,192 eligible women on EFV: 598 initiated LNG implant and 594 initiated DMPA. Median age was 30 years (IQR: 26, 34) and median gravidity was 3 (Range: 0-9 prior pregnancies); 63% of women were lactating at entry. Median follow-up on EFV of 1.1 years (IQR: 0.5, 1.7) was similar for the LNG and DMPA groups. Adjusted pregnancy rates were 6.8 (95% CI: 5.0, 8.7) per 100 WY in the LNG implant group (48 pregnancies) and 7.6 (95% CI: 5.4, 9.9) per 100 WY in the DMPA group (53 pregnancies), with an estimated rate difference of -0.7 per 100 WY (95% CI: -3.6, 2.2) and a rate ratio of 0.90 (95% CI: 0.61, 1.37).

Conclusions: In many settings, LNG implant has better contraceptive effectiveness than DMPA injection. However, for women on EFV, the LNG implant performed below expected with effectiveness similar to DMPA injection. These results support the presence of a clinically relevant DDI between the LNG implant and EFV-based ART.