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Aetiological Surveillance of Genital Ulcer
Disease (GUD) in Johannesburg,
South Africa 2007-2015
Ranmini Kularatne
MBChB, FCPath (SA)
Centre for HIV & STIs
National Institute for Communicable Diseases
National Health Laboratory Service
South Africa
10 May 2016
Introduction
• Major STI syndromes
– Male urethritis syndrome
(MUS)
– Vaginal discharge
syndrome (VDS)
– Genital ulcer syndrome/
disease (GUS/ GUD)
• Others
– Lower abdominal pain (LAP)
– Scrotal swelling (SSW)
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Aetiological Surveillance of STI Syndromes
• 9 sentinel sites (1 per province)
– Annually in Gauteng Province (Johannesburg) since 2007
• Determine microbial aetiologies of the 3 major STI
Syndromes: MUS, VDS, GUD
• Determine sero-prevalence of STI co-infections: HIV,
HSV-2, Syphilis
• Monitor gonococcal antimicrobial resistance
Validate existing syndromic treatment guidelines
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OBJECTIVES
• Describe sentinel aetiological surveillance of GUD
in Johannesburg 2007-2015
– Report on microbial aetiology of GUD and relative
prevalence of GUD pathogens
– Seroprevalence of STI co-infections: HIV, HSV-2,
Syphilis (RPR)
– Aetiological trends of GUD over a 9-year period
METHODS
Patient inclusion criteria:
• 18 years and above
• Presenting with new episode of GUD confirmed on
genital examination by nurses (clinical evidence)
• Able to read and understand the consent forms as
judged by the attending nurse
• Recruitment:
• Primary healthcare facility in Johannesburg
• Consecutive consenting adult patients
• January– April each year
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Specimen Collection
•
Ulcer swab (Dacron)
– Smear on slide: Giemsa stain for
Klebsiella granulomatis
– Swab-extracted DNA:
in-house multiplex real-time PCR
• Herpes simplex virus
• Treponema pallidum
• Haemophilus ducreyi
• Chlamydia trachomatis
– Type-specific PCR:
• HSV (Sacace Biotechnologies);
• CT LGV-specific (L1-L3) in-house
PCR
•
•
10ml venous blood
Serology:
– HIV (Unigold Trinity Biotech &
Alere Determine)
– HSV-2 (Focus HerpeSelect-2)
– RPR (Immutrep Omega
Diagnostics)
Results: GUD aetiology
• 2007-2015: 775 genital specimens
– 505 (65%) ulcer-derived pathogens
– 270 (35%) no PCR-detectable pathogens
Pathogen (n= 505)
Prevalence (95% CI)
N
Herpes simplex virus
(HSV)
60%
(57 – 64)
470
Treponema pallidum (TP)
3.5%
(2.7 - 5.4)
30
Chlamydia trachomatis
1.0%
(CT) L1-L3
Haemophilus ducreyi (HD) 0.5%
(0.5 - 2.0)
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(0.2 - 1.3)
4
Klebsiella granulomatis
0%
0
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Prevalence of PCR-derived pathogens
1%
0.5%
3.5%
HSV
No pathogen
35%
TP
60%
CT L1-L3
HD
6 /775 (< 1%) had mixed aetiology: all co-infected with
HSV and a bacterial pathogen
TP (3); LGV (2); HD (1)
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Results: demographic/ clinical data
Variable
Age (years)
(median, IQR)
Males
n (%)
Previous STI
n (%)
Previous GUD
n (%)
Concomitant STI
Syndrome
n (%)
N
672
29 (25 - 35)*
681
404 (60.8)
681
352 (51.7)
681
258 (37.9)
681
218 (32.0)
153 VDS (70.0)
65 MUS (30.0)
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Prevalence of Treponema pallidum
% TP positivity by PCR
160
4.9%
3.5%
140
7
5
120
5.0%
100
5
60
40
0%
137
TP PCR neg
2.3%
5
6.6%
80
TP PCR pos
137
2
3.4%
0
95
4.2%
85
71
2
68
46
20
2
56
4.2%
2
46
0
2007
2008
2009
2010
2011
2012
2013
2014
2015
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Genital herpes
• Type
– All caused by HSV-2
– Seroprevalence of HSV-2: 80.2%
• First episode vs reactivation disease
– 83.5% genital herpes cases (391/468) were both HSV-2 PCR
and HSV-2 serology positive: reactivation disease
– Prevalence of first-episode HSV-2: 16.5% (77/468)
• Association with HIV infection
– 68% co-infected with HIV (p< 0.001)
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Prevalence of first-episode HSV-2
100
11%
PCR Pos/ Serology Neg
90
10
80
70
11%
8
17%
PCR Pos/ Serology Pos
13
13%
60
50
40
12%
5
25%
79
66
30
20
63
7
33%
27%
10
48
36
30
10
9
12
12%
3
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24
21
2013
2014
2015
0
2007
2008
2009
2010
2011
2012
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Genital herpes
• Aetiological trends over time
– Significant decline in prevalence of ulcer-derived
HSV, predominantly between 2013-2015 (p=0.012)
– Trend towards a decline in HIV seropositivity rate
(p=0.166)
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Trends in HSV / HIV prevalence
80.0
70.0
% HSV PCR Pos
60.0
50.0
%
% HIV Serology Pos
40.0
30.0
20.0
10.0
0.0
2007 2008 2009 2010 2011 2012 2013 2014 2015
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Prevalence of HIV in GUD of unknown aetiology
HIV positive
48%
52%
HIV negative
HIV uninfected patients more likely to have GUD of unknown
aetiology compared to HIV-infected patients
(OR 1.87, 95% CI: 1.38 – 2.52)
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Conclusions
• HSV-2 has remained the leading cause of pathogendetectable GUD in Gauteng
• Lewis D et al. Sex Transm Dis 2012; 39: 880-885
– Validates use of anti-viral therapy in NDoH GUD
treatment algorithm since 2008.
– Change in epidemiology to HSV-1 over time not
observed.
• Genital HSV-1 leading cause of incident GUD in highincome countries, especially in younger heterosexual
women and MSM.
– Ryder N et al. Sex Transm Infect 2009; 85: 416-419
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Conclusions
• Syphilis and LGV are relatively uncommon
causes of GUD in Gauteng heterosexual
populations.
– Surveillance important in key populations e.g. MSM
• Hope-Rapp E et al. Sex Transm Dis 2010; 37: 153-158
• Childs T. Euro Surveill 2015; 20(48): 3007
• Last case of chancroid detected in 2009.
– From 2000 onwards, proportion of GUD caused by
Haemophilus ducreyi has declined worldwide.
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Beiras Gonzales C et al. 20
Emerg Infect Dis 2016; 22
Conclusions
• High prevalence of HIV among GUD patients
(>60%)
– Linkage to universal HIV testing and treatment
mandatory for high-risk population groups
• Decline in HSV-associated GUD and HIV coinfection rates over-time.
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Conclusions
• Scale-up of ARV coverage and increasing access to
care for HIV-infected individuals in SA public sector
since 2004.
– ARV therapy not associated with reduced HSV shedding
• Tan D et al. BMJ Open 2014; 4: e004210
– ? Associated reduction in clinically apparent reactivation
disease
• Posavad C et al. J infect Dis 2004; 190: 693-696
– ? Reduction in incident HSV disease associated with male
medical circumcision
• Tobian A et al. NEJM 2009; 360: 1298-1309
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Conclusions
• Unknown aetiology for approximately 35% of ulcers
– Similar findings from other sub-Saharan African countries
• Mehta S et al. PLoS ONE 2012: 7: e38991
• Further investigation required: histopathology, nextgeneration sequencing
– ? Acute HIV infection
• Paz Bailey G et al. J Infect Dis 2010; 201: 1811-1815
– ? Non-infectious/ non-benign aetiology
• Keogan M. Clin Experimental Immunol 2009; 156: 1-11
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Acknowledgements
• Staff at CHIVSTI, NICD, South Africa
– Dr Tendesayi Kufa-Chakezha
– Mr Frans Radebe
– Ms Venessa Maseko
– Dr Etienne Muller
– Ms Lindy Gumede
– Ms Gloria de Gita
– Ms Valentia Kekana
– Mr Alex Vezi
• Prof D Lewis
– Sydney Medical School-Westmead and Marie Bashir Institute for
Infectious Diseases and Biosecurity, University of Sydney and Western
Sydney Sexual Health Centre, Australia.
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