Biological effects, hormone levels and mechanisms relevant to HIV-1 infection for women randomized to the injectable contraceptives depo-medroxyprogesterone acetate or norethisterone enanthate.

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The proposed research seeks to understand plausible biological mechanisms whereby different injectable contraceptives may or may not affect susceptibility to infections such as HIV-1. High usage of injectable contraceptives correlates with high prevalence of HIV-1 infection in sub-Saharan Africa and South Africa. A strong gender bias for HIV-1 infection occurs towards young women in sub-Saharan Africa. Depo- medroxyprogesterone acetate (DMPA-IM), a three-monthly, intramuscular (IM) injection of 150 mg MPA is the most commonly used, while Norethisterone enanthate (NET-EN), a two-monthly, IM injection of 200 mg NET- EN is widely used in South Africa, especially among young women. Higher quality observational clinical data show a significant 40-50% increased risk of HIV-1 acquisition compared to no hormonal contraception for DMPA-IM. Limited observational studies found no significant increased risk for HIV-1 acquisition compared to no hormonal contraception for NET-EN, while two head-to-head comparisons found a potential 32-40% increase in HIV-1 risk for DMPA-IM versus NET-EN users. Recent results from the randomized ECHO trial do not inform on the risk of HIV-1 infection of DMPA-IM compared to NET-EN, or for DMPA-IM compared to no hormonal contraception. However, they do suggest progestin-specific effects with a best estimate of 23-29% increased risk for DMPA-IM compared to a levonorgestrel-containing implant over only 18 months. It is possible that a 32-40% difference in HIV-1 risk between DMPA-IM and NET-EN, taking into account both vertical and horizontal transmission, may have an important impact on the epidemic over a longer time period in high risk populations and may be highly relevant for individual women who desire informed choice. Given the potential for confounding factors in observational studies, a definitive answer as to the relative HIV-1 risks of DMPA-IM and NET-EN remains elusive. Another approach to gaining insights into the relative risks of DMPA- IM versus NET-EN is to obtain and evaluate high quality clinical biological data on responses strongly implicated in HIV-1 acquisition from women randomized to DMPA-IM and NET-EN. We will obtain archived samples from such a randomized trial (The WHICH (part 1) trial), and measure biomarkers of immune function and other potential markers of HIV-1 susceptibility. We will also perform a series of in vivo and ex vivo mechanistic studies to investigate plausible biological mechanisms for MPA and NET for HIV-1 acquisition and determine how those results correlate with the clinical data. The results will provide insight into whether and how DMPA-IM and NET-EN exert different biological effects, with implications for HIV-1 acquisition in women. The results will contribute significantly to scientific knowledge in the contraception and HIV-1 fields. They are likely to impact on clinical practice, health policy and international guidelines, to either reassure the interchangeable use or suggest preferential use of one of these injectable contraceptives over the other in populations at high risk of HIV-1 infection.