A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

UNAIDS Population Reference Bureau, 2008, 2008 Polis, 2014, Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence, Contraception, 90, 360, 10.1016/j.contraception.2014.07.009 Polis, 2013, Hormonal contraceptive use and female-to-male HIV transmission: a systematic review of the epidemiologic evidence, AIDS, 27, 493, 10.1097/QAD.0b013e32835ad539 Heffron, 2012, Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study, Lancet Infect. Dis., 12, 19, 10.1016/S1473-3099(11)70247-X Wand, 2012, The effects of injectable hormonal contraceptives on HIV seroconversion and on sexually transmitted infections, AIDS, 26, 375, 10.1097/QAD.0b013e32834f990f Baeten, 2007, Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women, AIDS, 21, 1771, 10.1097/QAD.0b013e328270388a Morrison, 2010, Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling, AIDS, 24, 1778, 10.1097/QAD.0b013e32833a2537 Mostad, 1997, Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina, Lancet, 350, 922, 10.1016/S0140-6736(97)04240-2 Graham, 2010, Antiretroviral adherence and development of drug resistance are the strongest predictors of genital HIV-1 shedding among women initiating treatment, J. Infect. Dis., 202, 1538, 10.1086/656790 Blish, 2011, Hormonal contraception and HIV-1 transmission, Am. J. Reprod. Immunol., 65, 302, 10.1111/j.1600-0897.2010.00930.x World Health Organization, 2014 Rasheed, 1998, Infectivity and dynamics of HIV type 1 replication in the blood and reproductive tract of HIV type 1-infected women, AIDS Res. Hum. Retrovir., 14, S105 Sonnex, 1998, Influence of ovarian hormones on urogenital infection, Sex. Transm. Infect., 74, 11, 10.1136/sti.74.1.11 Trunova, 2006, Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques, Virology, 352, 169, 10.1016/j.virol.2006.04.004 Hel, 2010, Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection, Endocr. Rev., 31, 79, 10.1210/er.2009-0018 Patton, 2000, Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle, Am. J. Obstet. Gynecol., 183, 967, 10.1067/mob.2000.108857 Kutteh, 1996, Variations in immunoglobulins and IgA subclasses of human uterine cervical secretions around the time of ovulation, Clin. Exp. Immunol., 104, 538, 10.1046/j.1365-2249.1996.36742.x Lu, 2002, The strength of B cell immunity in female rhesus macaques is controlled by CD8+ T cells under the influence of ovarian steroid hormones, Clin. Exp. Immunol., 128, 10, 10.1046/j.1365-2249.2002.01780.x Lu, 2003, Effects of ovarian steroids on immunoglobulin-secreting cell function in healthy women, Clin. Diagn. Lab. Immunol., 10, 944, 10.1128/CDLI.10.5.944-949.2003 Lu, 1999, Immunoglobulin concentrations and antigen-specific antibody levels in cervicovaginal lavages of rhesus macaques are influenced by the stage of the menstrual cycle, Infect. Immun., 67, 6321, 10.1128/IAI.67.12.6321-6328.1999 Paavonen, 1981, Sex hormone regulation of in vitro immune response. Estradiol enhances human B cell maturation via inhibition of suppressor T cells in pokeweed mitogen-stimulated cultures, J. Exp. Med., 154, 1935, 10.1084/jem.154.6.1935 Shrier, 2003, Mucosal immunity of the adolescent female genital tract, J. Adolesc. Health, 32, 183, 10.1016/S1054-139X(02)00536-0 Sthoeger, 1988, Regulation of the immune response by sex hormones. I. In vitro effects of estradiol and testosterone on pokeweed mitogen-induced human B cell differentiation, J. Immunol., 141, 91, 10.4049/jimmunol.141.1.91 Franklin, 1999, Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones, J. Reprod. Immunol., 42, 93, 10.1016/S0165-0378(98)00086-2 Nardelli-Haefliger, 2003, Specific antibody levels at the cervix during the menstrual cycle of women vaccinated with human papillomavirus 16 virus-like particles, J. Natl. Cancer Inst., 95, 1128, 10.1093/jnci/djg018 Fish, 2008, The X-files in immunity: sex-based differences predispose immune responses, Nat. Rev. Immunol., 8, 737, 10.1038/nri2394 White, 1997, CD3+ CD8+ CTL activity within the human female reproductive tract: Influence of stage of the menstrual cycle and menopause, J. Immunol., 158, 3017, 10.4049/jimmunol.158.6.3017 Hao, 2007, Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors, Int. Immunopharmacol., 7, 1765, 10.1016/j.intimp.2007.09.017 Gillgrass, 2003, Prolonged exposure to progesterone prevents induction of protective mucosal responses following intravaginal immunization with attenuated herpes simplex virus type 2, J. Virol., 77, 9845, 10.1128/JVI.77.18.9845-9851.2003 Kaushic, 2003, Progesterone increases susceptibility and decreases immune responses to genital herpes infection, J. Virol., 77, 4558, 10.1128/JVI.77.8.4558-4565.2003 Kaushic, 1998, Chlamydia trachomatis infection in the female reproductive tract of the rat: influence of progesterone on infectivity and immune response, Infect. Immun., 66, 893, 10.1128/IAI.66.3.893-898.1998 Quispe Calla, 2016, Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection, Mucosal Immunol., 10.1038/mi.2016.22 Roxby, 2016, Changes in vaginal microbiota and immune mediators in HIV-1-seronegative Kenyan women initiating Depot Medroxyprogesterone Acetate, J. Acquir. Immune Defic. Syndr., 71, 359, 10.1097/QAI.0000000000000866 Morrison, 2004, Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections, Sex. Transm. Dis., 31, 561, 10.1097/01.olq.0000137904.56037.70 Critchlow, 1995, Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking, and douching, Am. J. Obstet. Gynecol., 173, 534, 10.1016/0002-9378(95)90279-1 Pedraza, 1999, Heterosexual transmission of HIV-1 is associated with high plasma viral load levels and a positive viral isolation in the infected partner, J. Acquir. Immune Defic. Syndr., 21, 120 Baeten, 2004, Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial, J. Infect. Dis., 189, 1466, 10.1086/383049 McClelland, 2001, Treatment of cervicitis is associated with decreased cervical shedding of HIV-1, AIDS, 15, 105, 10.1097/00002030-200101050-00015 Avonts, 1990, Incidence of uncomplicated genital infections in women using oral contraception or an intrauterine device: a prospective study, Sex. Transm. Dis., 17, 23, 10.1097/00007435-199017010-00006 Louv, 1989, Oral contraceptive use and the risk of chlamydial and gonococcal infections, Am. J. Obstet. Gynecol., 160, 396, 10.1016/0002-9378(89)90456-0 Wira, 2005, Innate and adaptive immunity in female genital tract: cellular responses and interactions, Immunol. Rev., 206, 306, 10.1111/j.0105-2896.2005.00287.x Hunt, 1998, Hormonal regulation of uterine macrophages, Dev. Immunol., 6, 105, 10.1155/1998/87527 Zang, 2002, Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-kappa B, J. Neuroimmunol., 124, 106, 10.1016/S0165-5728(02)00016-4 Miller, 2000, Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium, Obstet. Gynecol., 96, 431 Prakash, 2002, Oral contraceptive use induces upregulation of the CCR5 chemokine receptor on CD4(+) T cells in the cervical epithelium of healthy women, J. Reprod. Immunol., 54, 117, 10.1016/S0165-0378(01)00125-5 Arici, 1999, Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by estrogen and progesterone, Biol. Reprod., 61, 85, 10.1095/biolreprod61.1.85 Sonoda, 1998, Physiologic regulation of postovulatory neutrophil migration into vagina in mice by a C-X-C chemokine(s), J. Immunol., 160, 6159, 10.4049/jimmunol.160.12.6159 Laskarin, 2002, Progesterone induced blocking factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity, Am. J. Reprod. Immunol., 48, 201, 10.1034/j.1600-0897.2002.01133.x Whitelaw, 1996, Granulated lymphocytes of pregnancy, Placenta, 17, 533, 10.1016/S0143-4004(96)80070-1 Wieser, 2001, Progesterone increases the number of Langerhans cells in human vaginal epithelium, Fertil. Steril., 75, 1234, 10.1016/S0015-0282(01)01796-4 Kutteh, 2005, Mucosal immunity in the human female reproductive tract, 1631 De, 1990, Influence of oestrogen and progesterone on macrophage distribution in the mouse uterus, J. Endocrinol., 126, 417, 10.1677/joe.0.1260417 Byrne, 2016, Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study, Lancet Infect. Dis., 16, 441, 10.1016/S1473-3099(15)00429-6 Straub, 2007, The complex role of estrogens in inflammation, Endocr. Rev., 28, 521, 10.1210/er.2007-0001 Baeten, 2001, Hormonal contraception and risk of sexually transmitted disease acquisition: results from a prospective study, Am. J. Obstet. Gynecol., 185, 380, 10.1067/mob.2001.115862 Lavreys, 2004, Hormonal contraception and risk of cervical infections among HIV-1-seropositive Kenyan women, AIDS, 18, 2179, 10.1097/00002030-200411050-00010 Rotchford, 2000, Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions: systematic review and data synthesis, Sex. Transm. Dis., 27, 243, 10.1097/00007435-200005000-00001 Wasserheit, 1992, Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases, Sex. Transm. Dis., 19, 61, 10.1097/00007435-199219020-00001 Cohen, 2012, Classical sexually transmitted diseases drive the spread of HIV-1: back to the future, J. Infect. Dis., 206, 1, 10.1093/infdis/jis303 Bradshaw, 2013, Recurrence of bacterial vaginosis is significantly associated with posttreatment sexual activities and hormonal contraceptive use, Clin. Infect. Dis., 56, 777, 10.1093/cid/cis1030 Calzolari, 2000, Bacterial vaginosis and contraceptive methods, Int. J. Gynaecol. Obstet., 70, 341, 10.1016/S0020-7292(00)00217-4 Holzman, 2001, Factors linked to bacterial vaginosis in nonpregnant women, Am. J. Public Health, 91, 1664, 10.2105/AJPH.91.10.1664 Mitchell, 2014, Long-term effect of depot medroxyprogesterone acetate on vaginal microbiota, epithelial thickness and HIV target cells, J. Infect. Dis., 210, 651, 10.1093/infdis/jiu176 Rifkin, 2009, Hormonal contraception and risk of bacterial vaginosis diagnosis in an observational study of women attending STD clinics in Baltimore, MD, Contraception, 80, 63, 10.1016/j.contraception.2009.01.008 Riggs, 2007, Longitudinal association between hormonal contraceptives and bacterial vaginosis in women of reproductive age, Sex. Transm. Dis., 34, 954, 10.1097/OLQ.0b013e31811ed0e4 Sivin, 2001, Levonorgestrel concentrations during 7years of continuous use of Jadelle contraceptive implants, Contraception, 64, 43, 10.1016/S0010-7824(01)00226-8 Hubacher, 2007, Contraceptive implants in Kenya: current status and future prospects, Contraception, 75, 468, 10.1016/j.contraception.2007.02.008 Africander, 2011, Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception, Steroids, 76, 636, 10.1016/j.steroids.2011.03.001 Ildgruben, 2005, Steroid receptor expression in vaginal epithelium of healthy fertile women and influences of hormonal contraceptive usage, Contraception, 72, 383, 10.1016/j.contraception.2005.05.018 Mishell, 1996, Pharmacokinetics of depot medroxyprogesterone acetate contraception, J. Reprod. Med., 41, 381 WHO. World Health Statistics Chasela, 2010, Maternal or infant antiretroviral drugs to reduce HIV-1 transmission, N. Engl. J. Med., 362, 2271, 10.1056/NEJMoa0911486 Sha, 1997, Evaluation of immunologic markers in cervicovaginal fluid of HIV-infected and uninfected women: implications for the immunologic response to HIV in the female genital tract, J. Acquir. Immune Defic. Syndr. Hum. Retrovirol., 16, 161, 10.1097/00042560-199711010-00004 Ahmed, 2001, Immunity in the female lower genital tract and the impact of HIV infection, Scand. J. Immunol., 54, 225, 10.1046/j.1365-3083.2001.00927.x Heffron, 2011, Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study, Lancet Infect. Dis. Mostad, 1998, Cervical and vaginal shedding of human immunodeficiency virus type 1-infected cells throughout the menstrual cycle, J. Infect. Dis., 178, 983, 10.1086/515665 Wang, 2004, The effect of hormonal contraception on genital tract shedding of HIV-1, AIDS, 18, 205, 10.1097/00002030-200401230-00009 Cu-Uvin, 2000, Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA, AIDS, 14, 415, 10.1097/00002030-200003100-00015 Kovacs, 2001, Determinants of HIV-1 shedding in the genital tract of women, Lancet, 358, 1593, 10.1016/S0140-6736(01)06653-3 Fiscus, 2013, Changes in HIV-1 subtypes B and C genital tract RNA in women and men after initiation of antiretroviral therapy, Clin. Infect. Dis., 57, 290, 10.1093/cid/cit195 World Health Organization (WHO), 2008 Adams, 2013, Tenofovir diphosphate and emtricitabine triphosphate concentrations in blood cells compared with isolated peripheral blood mononuclear cells: a new measure of antiretroviral adherence?, J. Acquir. Immune Defic. Syndr., 62, 260, 10.1097/QAI.0b013e3182794723 Andreoletti, 2003, Independent levels of cell-free and cell-associated human immunodeficiency virus-1 in genital-tract secretions of clinically asymptomatic, treatment-naive African women, J. Infect. Dis., 188, 549, 10.1086/377104 Robinson, 2012, Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy, Infect. Dis. Obstet. Gynecol., 2012, 890160, 10.1155/2012/890160 Perry, 2014, Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies, AIDS, 28, 791, 10.1097/QAD.0000000000000177 Scarsi, 2014, Efavirenz—but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant, J. Int. AIDS Soc., 17, 19484, 10.7448/IAS.17.4.19484 Scarsi, 2016, Unintended pregnancies observed with combined use of the Levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: A three-arm pharmacokinetic evaluation over 48weeks, Clin. Infect. Dis., 62, 675, 10.1093/cid/civ1001 Technical Issue Brief, 2014 Cohen, 2011, Prevention of HIV-1 infection with early antiretroviral therapy, N. Engl. J. Med., 365, 493, 10.1056/NEJMoa1105243 Clark, 2007, Lack of association between genital tract HIV-1 RNA shedding and hormonal contraceptive use in a cohort of Louisiana women, Sex. Transm. Dis., 34, 870, 10.1097/OLQ.0b013e3180ca9633 Debiaggi, 2001, Viral excretion in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy, Eur. J. Clin. Microbiol. Infect. Dis., 20, 91, 10.1007/s100960000442 Roccio, 2011, Low-dose combined oral contraceptive and cervicovaginal shedding of human immunodeficiency virus, Contraception, 83, 564, 10.1016/j.contraception.2010.10.008 Del Romero, 2010, Combined antiretroviral treatment and heterosexual transmission of HIV-1: cross sectional and prospective cohort study, BMJ, 340, c2205, 10.1136/bmj.c2205 Donnell, 2010, Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis, Lancet, 375, 2092, 10.1016/S0140-6736(10)60705-2 Fiore, 2003, Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies, AIDS, 17, 2169, 10.1097/00002030-200310170-00004 Neely, 2007, Cervical shedding of HIV-1 RNA among women with low levels of viremia while receiving highly active antiretroviral therapy, J. Acquir. Immune Defic. Syndr., 44, 38, 10.1097/01.qai.0000248352.18007.1f Ofotokun, 2012, A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study, AIDS Res. Hum. Retrovir., 28, 1196, 10.1089/aid.2011.0336 Anton, 2011, HIV transmission: time for translational studies to bridge the gap, Sci. Transl. Med., 3, 10.1126/scitranslmed.3002329 Burns, 2010, Rethinking prevention of HIV type 1 infection, Clin. Infect. Dis., 51, 725, 10.1086/655889 Baeten, 2011, Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission, Sci. Transl. Med., 3, 10.1126/scitranslmed.3001888 Cu-Uvin, 2006, Association between paired plasma and cervicovaginal lavage fluid HIV-1 RNA levels during 36months, J. Acquir. Immune Defic. Syndr., 42, 584, 10.1097/01.qai.0000229997.52246.95 Goulston, 1996, Human immunodeficiency virus in plasma and genital secretions during the menstrual cycle, J. Infect. Dis., 174, 858, 10.1093/infdis/174.4.858 Blish, 2012, Genital inflammation predicts HIV-1 shedding independent of plasma viral load and systemic inflammation, J. Acquir. Immune Defic. Syndr., 61, 436, 10.1097/QAI.0b013e31826c2edd Cohen, 2012, Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples, PLoS Med., 9, 10.1371/journal.pmed.1001251 Hughes, 2012, Determinants of per-coital-act HIV-1 infectivity among African HIV-1-serodiscordant couples, J. Infect. Dis., 205, 358, 10.1093/infdis/jir747