Genital Inflammatory Responses in Women Living with HIV Randomized to Copper or Levonorgestrel Intrauterine Contraceptives: A secondary analysis of a randomized trial

Background: Intrauterine contraceptives (IUCs) are effective, but effects on genital inflammation among women living with HIV (WLHIV) by antiretroviral therapy (ART) use are unclear. We evaluated the longitudinal effects of copper IUC (C IUC) and the levonorgestrel intrauterine system (LNG IUS) on cervicovaginal cytokine profiles in a secondary analysis of a randomized trial (NCT01721798, 2013 to 2016). Methods: Cervicovaginal secretions were collected from 100 WLHIV (non ART users; ART users) randomized 1:1 to C IUC or LNG IUS. Twenty eight cytokines were measured prior to insertion and 3 and 6 months post insertion. Cytokine concentrations at each follow up visit were compared with baseline, using participant fixed effects models stratified by ART status. Results: At enrolment, non ART users had higher average concentrations of most cytokines (21/28) than women using ART. Among non-ART users, IUC use was not associated with cytokine increases; only MCP1 increased significantly at 3 months among C IUC users (log10 geometric mean ratio 0.77, 95%CI 0.38 to 1.17), while none increased with LNG IUS use. Among ART users, C IUC insertion resulted in broad and sustained cytokine increases at both 3 (16/28) and 6 months (15/28). At month 3, the largest increases in log10 geometric mean were observed for IL6 (1.04, 0.72 to 1.36), RANTES (0.97, 0.54 to 1.40), MCP1 (0.71, 0.46 to 0.96), MIP1; (0.66, 0.37 to 0.94), and GCSF (0.63, 0.36 to 0.89), which was maintained until month 6. Cytokine changes following LNG IUS insertion were minimal (IL5, month 3). Conclusions: Among ART users, C IUC is associated with increases in cervicovaginal cytokines, across functional classes. This supports LNG IUS as a less inflammatory option for WLHIV to minimize genital immune activation.