Download The Etiology of Genital Ulcer Disease in Zimbabwe: Implications for

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The Etiology of Genital Ulcer Disease in Zimbabwe: Implications for Syndromic
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Management
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More Mungati, MBChB, MPH1
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Anna Machiha, DNS1
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Owen Mugurungi, MD1
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Mufuta Tshimanga, MD, MPH2
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Peter H. Kilmarx, MD3,4
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Justice Nyakura, MPH1
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Gerald Shambira, MD, MPH2
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Vitalis Kupara, DNS5
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David A. Lewis FRCP (UK), PhD 6.7
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Elizabeth Gonese, MPH3
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Beth Barr, DrPH3
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Cornelis Rietmeijer, MD, PhD, MSPH8,9
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for the
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The Zimbabwe STI Etiology Study Group
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Affiliations:
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Zimbabwe Ministry of Health and Child Care
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Department of Community Medicine, University of Zimbabwe, College of Health Sciences
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CDC, Atlanta. USA
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Zimbabwe Community Health Intervention Research (ZiCHIRe) Project
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Western Sydney Sexual Health Centre, Parramatta, New South Wales, Australia
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Marie Bashir Institute for Infectious Diseases and Biosecurity & Sydney Medical School-
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Westmead, University of Sydney, Sydney, New South Wales, Australia
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Colorado School of Public Health, University of Colorado Denver, USA
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Rietmeijer Consulting LLC, Denver, Colorado, Denver, USA
U.S. Centers for Disease Control and Prevention, Zimbabwe and Division of Global HIV/AIDS,
Fogarty International Center, National Institutes of Health, Bethesda, MD, USA.
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Words in Summary: 41
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Words in Abstract: 325
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Words in manuscript: 3475
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Tables: 5
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Keywords: STI, Etiology, Syndromic Management, Genital Ulcer Disease
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The Zimbabwe STI Etiology Study was supported by funds from the President’s Emergency
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Plan for AIDS Relief (PEPFAR) through a cooperative agreement between the U.S. Centers for
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Disease Control and Prevention and the University of Zimbabwe Department of Community
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Medicine SEAM Project under the terms of Cooperative Agreement Number: 1U2GGH000315-
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01.
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Brief Summary: Among 200 women and men presenting with genital ulcer disease at a diverse
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group of Zimbabwe STI clinics, 35% of patients tested positive for herpes simplex virus and
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11.5% for Treponema pallidum, while none tested positive for Haemophilus ducreyi.
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Abstract
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Background: In many countries, sexually transmitted infections (STI) are treated
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syndromically. Thus, patients diagnosed with genital ulcer disease (GUD) in Zimbabwe receive a
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combination of antimicrobials to treat syphilis, chancroid, lymphogranuloma venereum (LGV)
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and genital herpes. Periodic studies are necessary to assess the current etiology of GUD and
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assure the appropriateness of current treatment guidelines.
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Materials and Methods: We selected six geographically diverse clinics in Zimbabwe serving
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high numbers of STI cases to enroll men and women with STI syndromes, including GUD. STI
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history and risky behavioral data were collected by questionnaire and uploaded to a web-based
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database. Ulcer specimens were obtained for testing using a validated multiplex polymerase
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chain reaction (M-PCR) assay for Treponema pallidum (TP; primary syphilis), Haemophilus
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ducreyi (HD; chancroid), LGV-associated strains of Chlamydia trachomatis (CT-LVG) and
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herpes simplex virus types 1 and 2.). Blood samples were collected for testing with HIV,
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treponemal and non-treponemal serological assays.
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Results: Among 200 patients, 77 (38.5%) were positive for HSV, 32 (16%) were positive for
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TP, and 2 (1%) positive for CT-LGV. No HD infections were detected. No organism was found
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in 98 (49%) of participants. The overall HIV positivity rate was 52.2% for all GUD patients with
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higher rates among women (56% v. 44%, p<0.05) and among patients with HSV (68.6% vs.
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41.8%, p<0.0001). Among patients with GUD, 54 (28%) had gonorrhea and/or chlamydia
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infection. However, in this latter group, 66.7% of women and 70% of men did not have abnormal
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vaginal or urethral discharge on examination.
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Conclusions: HSV is the most common cause of GUD in our survey, followed by TP. No cases
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of chancroid were detected. The association of HIV infections with HSV may suggest high risk
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for co-transmission, however some HSV ulcerations may be due to HSV reactivation among
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immunocompromised patients. The overall prevalence of gonorrhea and chlamydia was high
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among patients with GUD and the majority of them did not meet criteria for concomitant
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syndromic management covering these infections.
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Introduction
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Sexually transmitted infections (STIs) associated with genital ulcer disease (GUD) continue to be
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an important cause of morbidity and mortality worldwide. While the etiology of GUD varies in
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different parts of the world, herpes simplex virus is considered the leading cause of this
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syndrome globally. In a recently published study1, the World Health Organization estimates that
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in 2012 19.2 million people aged 15-49 were newly infected with herpes simplex virus type 2
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(HSV-2) resulting in 417 million people aged 15-49 years living with HSV-2 infection, for a
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global prevalence of 11.3%. Adding an increasing number of genital herpes caused by herpes
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simplex type 1 virus (HSV-1), it is estimates that well over 40-80 million people suffer from
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recurrent genital herpes in any given year. In addition to this morbidity, HSV-2 infection is an
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important risk factor for HIV acquisition2,3 and can cause debilitating disease in the maternally
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exposed fetus and neonate.4,5 The global HSV burden disproportionally affects Africa with over
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30% of people aged 15-49 years chronically infected.1
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Likewise, Africa, and specifically sub-Saharan Africa is also disproportionally affected by
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syphilis. While the incidence of syphilis is substantially lower and has been declining over recent
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years, it is estimated that in 2012, 5.6 million incident syphilis cases occurred worldwide of
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which 32% in Sub-Saharan Africa.6 Syphilis continues to be a major global public health
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problem. In 2012, an estimated 930,000 maternal syphilis infections caused 350,000 adverse
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pregnancy outcomes, including 143,000 early fetal deaths and stillbirths, 62,000 neonatal deaths,
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44,000 preterm or low weight births, and 102,000 infected infants worldwide.7
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The relative proportion of GUD caused by chancroid and lymphogranuloma venereum (LGV)
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appears to be decreasing. For example, in a study from Botswana in 2002, 2% of patients with
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GUD were infected with Treponema pallidum and 1% with Haemophilus ducreyi, compared to
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58% with HSV-2.8 In a study from Malawi conducted between 2004 and 2006, the proportion of
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GUD caused by H. ducreyi was higher (15%) compared to T. pallidum and LGV strains of
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Chlamydia trachomatis (both at 6%) while 67% tested positive for HSV-2.9 In a more recent
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study from Zambia, none of the patients with GUD had H. ducreyi detected and 3% were
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positive for LGV strains of C. trachomatis.10 Changes in the underlying epidemiology of GUD
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have been linked to the change in management when the WHO introduced syndromic
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management for the treatment of GUD after 2000.11
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In the absence of etiologic testing, STI reporting and management in many countries, including
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Zimbabwe, is based on presenting symptoms. Thus, in 2015 a total of 252,406 adult STI cases
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were reported syndromically to the Zimbabwe Ministry of Health and Child Care, comprising
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20,063 men and 18,996 women with genital ulcer disease, in addition to 56,540 men with
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urethral discharge, 79,371 women with vaginal discharge, 27,782 women with PID, and 21,489
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men and 26,165 women with other STI syndromes, including genital warts.12
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Syndromic treatment of genital GUD, as recommended by the Zimbabwe Ministry of Health
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and Child Care (MOHCC), includes the combined use of benzathine penicillin, erythromycin,
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and acyclovir to treat potential infections with T. pallidum, H. ducreyi, LGV-associated C.
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trachomatis strains, and HSV respectively.13 However, no recent studies have been undertaken in
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Zimbabwe in recent years to determine the underlying etiology of GUD and thus assess the
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adequacy of current treatment guidelines.
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As part of a recently completed STI etiology study in Zimbabwe, the primary aim of this analysis
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was to determine the prevalence of syphilis, chancroid, lymphogranuloma venereum, and genital
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herpes infections among women and men presenting with GUD. Secondary aims were to
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determine the prevalence of vaginal or urethral Neisseria gonorrhoeae and C. trachomatis as
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well as the prevalence and association of human immunodeficiency virus infections (HIV) with
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GUD in this population.
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Materials and Methods
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The Zimbabwe STI Etiology Study was conducted in 2014-2015 to determine the causation of
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the most important STI-associated syndromes in Zimbabwe: male urethral discharge syndrome,
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vaginal discharge syndrome, and genital ulcer disease. A full description of study methods is
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reported elsewhere14 and a copy of the full study protocol is available online.15 The most relevant
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details are summarized below. Results of the female and male genital discharge syndromes will
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be reported elsewhere.
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Clinic Selection
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Using 2012 surveillance statistics, we identified a regionally diverse sample of six clinics with
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high numbers of reported STI syndromes. Specifically, we selected two clinics from Harare
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(Mbare and Budiriru), the country’s capital and largest city in the north-eastern part of the
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country; two clinics in Bulawayo (Nkulumane and Khami Road) the second largest city located
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southwest and ethnically distinct from Harare, one clinic from Beitbridge (Dulibadzimu) on the
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southern border with South Africa, and finally one clinic from rural Gutu (Gutu Road Hospital),
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located near the country center. These clinics were deemed to be sufficiently representative of
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risky populations regionally to yield meaningful and generalizable results. More details on clinic
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selection can be found elsewehere.14,15
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For purposes of the analysis in this manuscript, clinics were combined into 3 regions: Harare,
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Bulawayo, and Beitbridge/Gutu.
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Sample Size
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We aimed to enroll 200 subjects in each of the STI syndromes categories, including 100 men and
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100 women presenting with GUD. This sample size was deemed to yield sufficiently robust
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prevalence estimates of the major GUD causes and at the same time be practical from the
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perspective of the project’s limited budget and enrollment window. Since the study population
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was, in essence, a convenience sample, we did not intend to apply sample weights.15
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Patient Selection
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During the enrolment period at each clinic, all sexually active women and men aged 18-55 years
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presenting with genital ulcer disease were eligible for the study. Excluded from the study were
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those who did not speak English, Shona or Ndebele (the 3 major languages in Zimbabwe), those
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unable to provide consent, those who had received antibiotics for STI treatment in the previous 4
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weeks, or those previously enrolled in the study.
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Study Procedures
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A team of 3 nurses was trained in study procedures and deployed sequentially for a period of 10-
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17 weeks to each of the 6 study sites, starting in the Harare clinics, then moving to Bulawayo and
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finally to Beitbridge and Gutu. The start of enrollment at each site was preceded by at least two
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site visits involving the study leadership of the team lead (VK), the lead consultant (CAR) and
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senior researchers representing the MOHCC (AM and MM).
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Patients with GUD were enrolled after obtaining informed consent and a paper-copy
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questionnaire was completed by the study nurse that included demographic information, sexual
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history, description of symptoms, history of STI/HIV, and current use of medications. GUD
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patients had swabs taken from the ulcer bases. Vaginal swabs for women and urine samples for
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men were obtained for chlamydia and gonorrhea testing. Blood specimens were collected from
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patients for syphilis serology and HIV testing. A separate consent for HIV testing was obtained.
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Refusing a blood draw was not a reason from exclusion from the study.
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All patients were treated for their presenting STI syndrome according to the 2013 Zimbabwe STI
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treatment guidelines.16 After completion of the visit, paper data were reviewed by the lead study
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nurse and then transcribed into a computer-based data system on handheld devices. Data were
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uploaded daily from study sites to an online secure central database.
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Laboratory procedures
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All specimens were kept refrigerated after collection and shipped in a cooler box with cooling
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packs by courier overnight to the receiving laboratory at Wilkins Hospital in Harare, where all
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samples were kept refrigerated until further processing.
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A number of tests were conducted at the receiving laboratory, including rapid HIV serologic
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testing using the standard testing algorithm in ZimbabweI, treponemal testing by SD Bioline
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HIV testing in Zimbabwe follows a standard algorithm of the following HIV rapid tests: 1)
initial test by First Response HIV1-2-O; 2) confirmatory test by Alere Determine HIV1/2 if
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DUO rapid test (Standard Diagnostics Inc, Gyeonggi-do, Republic of Korea) and TPHA, and
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non-treponemal testing by RPR. These tests were all conducted according to test package inserts.
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All ulcer samples were stored in a -70 oF freezer and batched for shipment to the STI reference
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laboratory at the National Institute of Communicable Diseases (NICD) in Johannesburg, South
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Africa. Using an in-house developed multiplex polymerase chain reaction (M-PCR), ulcer
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specimens were tested for T. pallidum, H. ducreyi, LGV-associated strains of C. trachomatis,
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and HSV-1/HSV-2. Test details are described by Lewis et al. elsewhere.17
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Vaginal and urine samples were shipped to two local laboratories and tested for N. gonorrhoeae
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and C. trachomatis by nucleic acid amplification testing (NAAT) using Becton Dickenson
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ProbeTec (BD Molecular Diagnostics, Franklin Lakes, NJ, USA) at the University of
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Zimbabwe/University of California San Francisco (UZ-UCSF) laboratory in the Obstetrics and
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Gynaecology Department of the University of Zimbabwe School of Medicine and using
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GeneXpert (Cepheid, Sunnyvale, CA, USA) at the Flowcytometry laboratory in Harare. All
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testing was done according to test package inserts under standard operating procedures. More
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detail on laboratory procedures can be found in the online supplement.15
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the initial test is positive, and 3) CHEMBIO HIV1/HIV2 as a tie breaker if the initial and
confirmatory tests are discrepant.
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Statistical Methods
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Data on participant demographics, sexual health and STI history were analyzed using SAS
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software (Cary, NC, USA). Tests for statistical significance included the Chi-Square test for
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categorical variables and Student’s T-test for continuous variables.
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Institutional Review
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The protocol, including consent forms and questionnaires, was reviewed and approved by the
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Joint Research and Ethics Committee of Parirenyatwa Central Hospital, the Zimbabwe Medical
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Research Council and the U.S. Centers for Disease Control and Prevention.
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Results
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Participant Recruitment
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Of the 100 women and 100 men with GUD, m-PCR results were available for all ulcer
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specimens; however, urine samples taken from two men were inadequate for
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gonorrhea/chlamydia NAAT. Enrollment data by study site are summarized in Table 1. Only 4
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women and 1 man were recruited at Gutu Road Hospital. The low enrollment at the Gutu site
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was the result of low STI patient volume and a pragmatic decision to focus our limited resources
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on sites where patient volume was higher and recruitment more productive. Nonetheless, we did
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not see any reason to exclude these persons from our analyses. For statistical purposes we
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included them with the Beitbridge sample.
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Demographic characteristics
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As expected, a higher proportion of men and women enrolled at the Bulawayo clinics reported
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Ndebele ethnicity, as this is the capital of Matabeleland with a prominent Ndebele population. In
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addition, there was a statistically significant difference across regions in the number of
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participants who reported more than one sex partner in the previous 3 months, with participants
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from Beitbridge/Gutu reporting the highest number of partners (p<0.05). There were no
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significant differences between regions with regards to age, condom use with main or non-main
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partners, self-reported HIV status, and a history of STD (Table 1).
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Men in the study were significantly older (mean 29.6; median 28.5) than women (mean 27.9;
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median 26, p<0.05) and men were also significantly more likely to be unmarried (68% vs. 51%,
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p<0.05) and less likely to be unemployed (59% vs. %, p<0001) when compared to women.
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However, there were no differences between men and women with respect to number of sex
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partners in the past 3 months, condom use with main or non-main partners, self-perceived HIV
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status, or history of STI (data not shown).
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Etiology of GUD
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Overall 77/200 (38.5%, 95% C.I.: 32.0% - 45.5%) of patients with GUD were infected with HSV
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(all but one typed as HSV-2), and 32/200 (16%, 95% C.I.: 11.6% - 21.7%) had T. pallidum
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infection detected by m-PCR. Nine patients (4.5%) were dually infected with HSV and T.
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pallidum. Only 2 patients (1%, 95% C.I.: 0.2% - 3.5%) had C. trachomatis-LGV serovars
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detected, and none (95% C.I.: 0% - 1.9%) had H. ducreyi infection identified. No organism was
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found in 49.5% (95% C.I. 42.6% - 56.4%) of participants (Table 2). Of those with any pathogen
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detected (N=101), 76.2% had HSV, 31.7% had T. pallidum infection and 1.9% had chlamydia13
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LGV serovars. HSV infection was the most common cause of GUD in both women (39%) and
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men (38%) followed by T. pallidum infection (13% of women and 19% of men). There was no
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statistically significant difference between men and women with respect to causative organisms
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(P=0.88).
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Multiplex PCR results varied by study site with Harare sites having significantly higher
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proportions of patients with no pathogen identified (65.3% for Harare sites vs. 37.8% for
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Bulawayo sites vs 44.4% for Beitbridge, p<0.05). However, the proportion of patients diagnosed
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with HSV and treponemal infections were not different across sites when excluding patients who
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had no pathogens identified (data not shown).
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In a further analysis of patients either infected with HSV or T. pallidum (thus excluding those
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with mixed infections), we found that shorter duration of symptoms (1-7 vs. >7 days) was
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significantly associated with detection of HSV, but not T. pallidum. Significantly lower rates of
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HSV were found in patients concomitantly infected with C. trachomatis. Rates were also lower
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among patients infected with N. gonorrhoeae, but this difference was not statistically significant.
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Finally, higher HSV rates were also observed among patients who self-reported as HIV infected
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(Table 3).
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Treponemal and Non-Treponemal Test Results
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Blood specimens from 181 patients were available (19 patients declined to submit a blood
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sample). Valid RPR results were available for all 181 patients, of which 37 (20.4% were
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positive) and valid TPHA results for 165 patients, of which 42 (25.4%) were positive. Both RPR
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and TPHA were positive for 26/165 (15.8%) patients; 15/27 (55.5%) of those testing positive for
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T. pallidum and 11/138 (7.9%) testing negative (Table 4).
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HIV Co-infection
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HIV test results were available for all 181 patients who submitted a blood sample. Overall 59.8%
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of women and 45.2% of men with GUD tested positive for HIV (p<0.05). There was no
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variation by region. Testing results for the causative agent by m-PCR varied significantly by
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HIV status. When excluding mixed infections (N=170), HIV-positive participants had a higher
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prevalence of HSV infection compared to HIV-negative participants (53.9% vs. 28.4%,
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p<0.0001), but similar prevalence of T. pallidum (20.5% vs. 17.2%, Table 3), with no gender
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differences observed (data not shown).
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Chlamydia and Gonorrhea Infection
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Results of genital C. trachomatis and N. gonorrhoeae testing are summarized in Table 5.
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Overall, 31/100 (31%) of women and 23/98 men (23.5%) of men were NAAT positive for either
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infection. After excluding those with missing observations, 20 of 30 (67%) women and 14 of 20
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(70%) men with either infection had no discharge observed. Thus of 50 men and women with
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GUD and concurrent chlamydia and/or gonorrhea infection, 34 (68%) were not eligible for
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concomitant genital discharge syndrome management, representing 17% of all patients with
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GUD in our study.
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Discussion
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Our study results confirm the continued high prevalence of HSV infections as the probable cause
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of genital ulcer disease. They also confirm the decline of chancroid as a cause of GUD as shown
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previously in other African and non-African countries8,9. In 1979, chancroid accounted for 38%
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of STI cases in Salisbury (now Harare) but declined to just 3% among men with GUD in 199518,
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and, in the current study, no cases were found. This decrease may be due to either syndromic
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management used in treating STIs or widespread use of antibiotics treating other infections. The
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apparently sustained decline in chancroid in Zimbabwe and the southern African region, has
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called into question whether syndromic treatment guidelines should continue to make specific
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provisions for treating this disease.10
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HSV prevalence in our study (38.5%) was lower than found in recent surveys in the southern
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African region; 60.5% in Botswana (2002)8, 62% in Mozambique (2005)19, 67% in Malawi
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(2004-2006)9, and 73.6% in South Africa (2005-2006)17, but higher than a more contemporary
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study in Zambia, Zimbabwe’s neighbor to the north: 28% (2010)10. A common finding among
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these and our studies is the significant association between HSV and HIV infection; close to 54%
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of persons with HSV in our study were HIV-infected, compared to 28% without HIV. In our
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study, we could not distinguish primary HSV infections from recurrences, but in the Malawi
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study, 75% of HSV infections were recurrences.9 Thus, the prevalence of HSV infection among
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persons presenting with genital ulcer disease appears to be influenced by recurrent HSV
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infection among HIV-infected patients, especially those experiencing immunosuppression. As
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access to HIV antiretroviral therapy is rapidly increasing in many sub-Saharan countries,
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including Zimbabwe, the epidemiology and relative prevalence of etiologic determinants of
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GUD may change.
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While HSV infections may be declining, the relative prevalence of syphilis as a cause of GUD
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may be increasing. In our study, 16% of patients with GUD tested positive for T. pallidum and
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an additional 8% of patients submitting blood specimens had negative T. pallidum results but
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positive RPR and TPHA tests suggesting recent syphilis. Thus, overall, up to 24% of patients
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with GUD in our study had evidence of active syphilis.
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T. pallidum rates in our study were considerably higher than rates found in the Botswana
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(5.1%)8, Mozambique (0%)19, Malawi (6%)9 and South African (4.9%)17 studies. However, these
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studies were conducted 10 to 14 years ago, a timeframe that saw rapid increases in early syphilis
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cases in the U.S. and Europe. While the recent epidemiology of syphilis in the U.S. and Europe
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is largely driven by syphilis increases among men who have sex with men, there are now
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indications that syphilis is also increasing among heterosexuals with subsequent rises in
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congenital syphilis rates20, and there is no reason the assume that the epidemiology in other
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world regions, including Africa might be different. Indeed, the more recent study from Zambia
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also saw higher T. pallidum rates (10%).10 Of course, a study of a highly selective group of
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patients presenting with STI, cannot be generalized and, as discussed above, the relative
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proportion of syphilis cases may also be a function of a decline in genital herpes cases in our
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study. Nonetheless, our study raises the possibility of re-emerging syphilis in Zimbabwe and the
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southern African region that should be further studied and, in the meantime, should reinforce
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efforts to screen pregnant women to prevent congenital syphilis.
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Compared to previous studies in the region, we found a higher proportion of GUD cases with
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unknown etiology, i.e., 49.5% compared to 39.4% in Botswana8, 30% in Mozambique19, 20% in
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Malawi9, and 20.6% in South Africa.17 By contrast, the more recent study in Zambia found a
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higher proportion: 55%10. Reasons for failure to find etiologic pathogens include patient
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selection, staff training and quality of samples, and test performance. We found significantly
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lower rates of any pathogens detected in the Harare clinics, and since these were the first clinics
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to enroll patients, we cannot rule out that staff training, differences in patient selection and
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quality of ulcer sampling could have played a role. As has been shown in other studies, retrieving
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etiologic agents, especially HSV, is dependent on how long lesions have been present.10 In our
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study, we confirmed that significantly fewer cases of HSV infection were found in persons with
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lesions 7 days or older. No such association was found for T. pallidum.
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Finally, we documented a high prevalence of chlamydia and gonorrhea co-morbidity among our
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patients with GUD, with 31% of women and 23% of men co-infected. Further analysis indicated
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that 68% of men and women with co-infections did not have vaginal or urethral discharge and
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would thus not receive optimal treatment for these infections. These represent 17% of all patients
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with GUD in this study. This finding suggests that current syndromic management guidelines
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may be inadequate for women and men with GUD with concurrent gonorrhea and should be
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considered in the development of syndromic management guidelines.17
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The findings of our study are subject to a number of limitations. First, we included clinics that
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also provide care to HIV-infected people. Thus, we may have oversampled HIV-infected people
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for this study and, because HIV infection was closely related to HSV infections, may have
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caused a bias in study results. Second, the variation in etiologic patterns by clinic location
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suggests potential limitations in generalizability. Third, as has already been mentioned, the
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relatively large proportion of GUD patients with no pathogens identified may indicate biases in
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patient selection and consistency of study and testing procedures. Finally, by its nature, only
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symptomatic patients were enrolled in the study, and generalizations outside this group to the
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general population cannot be made.
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In conclusion, HSV-2 infection was the most common cause of genital ulcer disease in our study,
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followed by syphilis. No cases of chancroid were found. The strong association of concurrent
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HIV and HSV infections may in part be explained by recurrent genital herpes in the
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immunocompromised patient. Nonetheless, the high co-occurrence of HIV infection in this
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group of patients suggests very high risks of HIV transmission. Patients with genital ulcer
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disease should therefore receive the highest priority for HIV prevention.
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19
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References
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Looker KJ, Magaret AS, May MT, et al. Global and Regional Estimates of Prevalent and Incident
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Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2
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infection increases HIV acquisition in men and women: systematic review and meta-analysis of
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Chen CY, Ballard RC, Beck-Sague CM, et al. Human immunodeficiency virus infection and genital
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