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Nov 17, 2014 - one acetate, or no hormonal contraception. Women were ..... medroxyprogesterone acetate; HSV-2, herpes simplex virus type 2; M. genitalium ...
MAJOR ARTICLE

Mycoplasma genitalium Is Associated With Increased Genital HIV Type 1 RNA in Zimbabwean Women Sue Napierala Mavedzenge,1 Etienne E. Müller,2 David A. Lewis,2,3,4 Tsungai Chipato,5 Charles S. Morrison,6 and Helen A. Weiss7 1

Women’s Global Health Imperative, RTI International, San Francisco, California; 2Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases, 3Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and 4Division of Medical Microbiology, University of Cape Town, South Africa; 5University of Zimbabwe College of Health Science, Harare; 6Clinical Sciences, FHI 360, Durham, North Carolina; and 7MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, United Kingdom

Background. Mycoplasma genitalium is a common sexually transmitted infection associated with human immunodeficiency virus (HIV) infection. Some studies suggest that M. genitalium may increase the risk of HIV acquisition. However, results have been inconsistent, and this association has never been examined longitudinally. Methods. Stored endocervical samples from a longitudinal cohort study of 131 Zimbabwean women in whom HIV-1 seroconversion recently occurred were tested for detection and quantity of M. genitalium using polymerase chain reaction analysis. The associations between M. genitalium and the detection and quantity of genital HIV type 1 (HIV-1) RNA, the detection and quantity of plasma HIV-1 RNA, and the CD4+ T-cell count was analyzed using mixed-effects regression analysis. Results. M. genitalium was detected in 10.5% of stored specimens (44 of 420), and infection persisted for up to 300 days. M. genitalium was independently associated with detection of genital HIV-1 RNA (adjusted odds ratio, 2.67; 95% confidence interval, .99–7.20), after adjustment for plasma viral load, viral set point, CD4+ T-cell count, herpes simplex virus type 2 detection, and gonorrhea. There was no evidence of an association between M. genitalium detection or quantity and either plasma HIV-1 RNA load or CD4+ T-cell count. Conclusions. The growing evidence for an association between M. genitalium and HIV genital shedding and the high prevalence and persistence of M. genitalium in this population suggest that further research into this association is important. Consideration of the cost-effectiveness of M. genitalium screening interventions may be warranted. Keywords. Mycoplasma genitalium; HIV; genital HIV-1 RNA; epidemiology; Zimbabwe.

Mycoplasma genitalium is a common sexually transmitted infection (STI). It is one of the leading causes of nonchlamydial, nongonococcal urethritis in men [1] and has been associated with upper and lower genital tract infections in women [2–7]. The prevalence of M. genitalium varies widely by population but is generally

Received 10 July 2014; accepted 7 November 2014; electronically published 17 November 2014. Presented in part: 19th Meeting of the International Society for Sexually Transmitted Diseases Research, Quebec City, Canada, July 2011. Abstract P1-S1.57. Correspondence: Sue Napierala Mavedzenge, PhD, RTI International, 351 California St, San Francisco, CA 94104 ([email protected]). The Journal of Infectious Diseases® 2015;211:1388–98 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jiu644

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higher than that of Neisseria gonorrhoeae and typically similar to that of Chlamydia trachomatis [8–12]. A systematic review and meta-analysis of primarily cross-sectional studies suggested a strong association between M. genitalium and human immunodeficiency virus (HIV) infection (summary odds ratio [OR], 2.01; 95% confidence interval [CI], 1.44–2.79) [13]. Among studies in sub-Saharan Africa, where the burden of HIV infection is greatest, this association was stronger still (summary OR, 2.60; 95% CI, 2.17–3.11). A >2fold increased risk of HIV acquisition was found in longitudinal research among African women infected with M. genitalium, at both the visit before (adjusted OR, 2.42; 95% CI, 1.01–5.80) and the time of (adjusted OR, 2.18; 95% CI, .98–4.85) HIV type-1 (HIV-1) acquisition [14]. Among sex workers in Uganda,

M. genitalium infection at enrollment was associated with incident HIV infection (adjusted hazard ratio [HR], 2.28; 95% CI, 1.15–4.52) [15]. A number of studies have measured the concentration of HIV in genital secretions as a proxy for the sexual transmissibility of HIV, and higher genital concentrations are considered indicative of increased HIV infectivity [16–19]. Three previous studies, all cross-sectional, have examined the role of M. genitalium on HIV transmissibility [20–22]. The first study was conducted among couples in the United States [21] and found that M. genitalium was independently associated with a 2–3-fold risk of HIV seroconcordance, compared with serodiscordance, suggesting a role for M. genitalium in HIV transmission. A second study among HIV-1 seropositive Kenyan women found that high M. genitalium organism burden was independently associated with a 3-fold increased risk of detectable genital HIV-1 DNA [20]. Finally, among HIV positive women in the United States, there was no evidence of an association between M. genitalium and vaginal HIV-1 RNA (adjusted OR, 0.93; 95% CI, .31–2.79) [22]. Implications of the measurement of genital HIV-1 RNA versus DNA are unclear. Cell-associated genital HIV-1 DNA [23] may include a high quantity of latent and/or defective genome material and therefore may not be representative of cell-free RNA, which is primarily derived from recent HIV-1 replication [24–26] and is better correlated in plasma and genital samples [27]. Regardless, these studies suggest that M. genitalium may increase HIV transmissibility, but the association between prevalent M. genitalium and HIV transmissibility has never been examined longitudinally. The present study uses longitudinal data from individuals who HIV seroconverted in Zimbabwe to assess whether prevalent M. genitalium in endocervical samples is associated with an increased quantity of genital HIV-1 RNA and whether M. genitalium enhances HIV-1 disease progression, as defined by increased plasma HIV-1 RNA load or decreased CD4+ T-cell count. METHODS This study was nested among a cohort of HIV-infected Zimbabwean women recruited between 2001 and 2007 into the Effect of Hormonal Contraception on HIV Genital Shedding and Disease Progression among Women with Primary HIV Infection (GS) study (n = 188). GS study participants were recruited from among those who recently (≤6 months) underwent HIV seroconversion during the course of the Hormonal Contraception and the Risk of HIV Acquisition (HC-HIV) study. Details of these studies are described elsewhere [28, 29]. Briefly, eligibility criteria included being sexually active, not pregnant, and using either combined oral contraception, depot medroxyprogesterone acetate, or no hormonal contraception. Women were ineligible if they had a blood transfusion or injected drugs in the previous 3 months. Genital and plasma HIV-1 loads, CD4+

T-cell counts, and presence of other sexually transmitted or reproductive tract infections (gonorrhea, chlamydial infection, bacterial vaginosis [BV], and candidiasis) were ascertained at quarterly visits, together with clinical and behavioral data. Endocervical samples were collected and stored at all regularly scheduled visits. All samples used in this research were collected before initiation of antiretroviral therapy (ART). Samples were tested for detection and quantity of M. genitalium DNA at up to 4 visits at which genital HIV-1 RNA data was available following HIV-1 detection (1–4 visits per woman). Laboratory Procedures

Detection of M. genitalium was diagnosed using the commercially available M. genitalium Real-TM assay (Sacace Biotechnologies, Como, Italy) [30]. All samples testing positive at screening and 10% of negative samples underwent repeat testing for quality control, using an in-house real-time polymerase chain reaction (PCR) targeting the pdhD gene of M. genitalium [31]. Positive samples were quantified for bacterial load, using an in-house quantitative PCR developed specifically for this research [31]. HIV infections were diagnosed in the HC-HIV parent study [29], using an enzyme-linked immunosorbent assay (ELISA), with positive results confirmed using rapid testing followed by Western blot or PCR. For confirmed incident HIV infections, HIV PCR was performed on previous visit blood specimens, and HIV-1 acquisition was defined as the first positive result following a negative PCR result. Plasma viral load was measured using the Roche Amplicor HIV-1 Monitor Test (Amplicor HIV Monitor Kit v1.5, Roche Diagnostics Systems, Indianapolis, Indiana) as per the manufacturer’s instructions. If the initial plasma viral load was >750 000 copies/mL, plasma was diluted 100-fold, and the assay was repeated to accurately quantify plasma viral load. For samples with a plasma viral load of