Injectable Contraceptives Differentially Affect Select CD4+ HIV-1 Target Cells in the Genital Tract but Not Systemically: Implications for HIV-1 Acquisition

PROBLEM: Observational data suggest lower HIV susceptibility in women using the injectable contraceptive norethisterone enanthate (NET-EN) versus intramuscular depo medroxyprogesterone acetate (DMPA-IM). Clinical data investigating the effects of injectables on HIV target cells are inconsistent or limited. No data on HIV target cells are available from head-to-head randomized trials comparing DMPA-IM and NET-EN, nor at peak progestin concentrations. METHOD OF STUDY: The women's health, injectable contraception, and HIV (WHICH) trial randomized women to DMPA-IM or NET-EN at two South African sites (2018-2019). Cells from blood and cytobrushes from women at one site, taken at baseline and 1 week post the 24-week injection (at peak progestin levels), were analyzed by flow cytometry for select HIV-1 target cells (CD4(+) cells expressing HIV-1 co-receptors, an integrin and/or activation markers). RESULTS: Systemically, DMPA-IM and NET-EN similarly reduced the frequency and number of some CD4(+) cells and expression of some CD4(+) cell surface markers. In contrast, female genital tract (FGT) results showed significantly different cell numbers between contraceptives for most cell populations; DMPA-IM tended to increase, but NET-EN tended to decrease cell numbers. Excluding for non-study progestin use revealed significant increases in frequency and/or number of several FGT cell populations from baseline to 25 weeks, within the DMPA-IM arm. CONCLUSIONS: Both contraceptives exert minimal effects on systemic CD4(+) cells but have differential effects in the FGT. The changes in frequency and numbers of HIV-1 target cells investigated, particularly after exclusion for non-study progestin use, suggest that DMPA-IM use may increase HIV-1 acquisition in the FGT compared to NET-EN use.