Incidence of Herpes Simplex Virus Type 2 Infection Among African Women Using Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: A Nested Randomized Trial

Abstract

Background: Globally, women have higher herpes simplex type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of certain contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM). \n \nMethods: Within a randomized trial of the effect of three contraceptive methods – DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant – on HIV acquisition, we assessed HSV-2 acquisition. We followed women who were HSV-2 and HIV seronegative, aged 16-35 years, and seeking effective contraception for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015-2018. HSV-2 serologic testing was done at enrollment and final study visits according to a standardized algorithm. Intention–to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method. \n \nFindings: At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval [CI] 0.65-0.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI 0.71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI 0.89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55, 95% CI 2.78-4.48). \n \nInterpretation: In a randomized trial, DMPA-IM was not associated with increased risk of HSV-2 acquisition. HSV-2 incidence was >10% per year, emphasizing the need for development of novel HSV-2 prevention strategies for African women. \n \nClinical Trial Registration Details: ClinicalTrials.gov number NCT02550067. \n \nFunding Information: The ECHO Trial was made possible by the combined generous support of the Bill & Melinda Gates Foundation, the American people through the United States Agency for International Development and the President’s Emergency Plan for AIDS Relief, the Swedish International Development Cooperation Agency as part of the EDCTP2 programme supported by the European Union, the South African Medical Research Council, and the United Nations Population Fund. Contraceptive supplies were donated by the Government of South Africa and United States Agency for International Development. Additional funding for testing for herpes simplex type 2 infection was provided in part by the US Centers for Disease Control and Prevention (U48 DP 005013 SIP 14-023) and the University of Washington/Fred Hutch Center for AIDS Research (US National Institutes of Health P30 AI057757). \n \nDeclaration of Interests: None. \n \nEthics Approval Statement: Ethics review committees at each study site approved the study protocol. All participants provided written informed consent, which included counseling about randomization, each study contraceptive method, and their rights as research participants.