Trends in the relative prevalence of genital ulcer disease pathogens and association with HIV infection in Johannesburg, South Africa, 2007–2015

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Abstract

Fig 1

Relative prevalence of GUD aetiologies by year of enrolment, 2007–2015 (n = 771).

 

 

Fig 2

Number of T. pallidum PCR positive and negative genital ulcers, with the prevalence trend for PCR-confirmed syphilitic ulcers (red line), 2007–2015 (n = 771).

Table 3

Microbial aetiology of GUD at a community healthcare centre in Johannesburg, 2007–2015.

Pathogen	Prevalence (95% CI)	N = 771
Herpes simplex virus	60.7% (57.2–64.1)	468
Treponema pallidum	3.9% (2.7–5.5)	30
Chlamydia trachomatis L1-L3 (Lymphogranuloma venereum)	0.9% (0.4–1.9)	7
Haemophilus ducreyi	0.5% (0.2–1.4)	4
Klebsiella granulomatis	0%	0
Mixed aetiology (HSV-2 + bacterial pathogen)	0.8% (0.4–1.7)	6
No STI pathogen	34.8% (31.5–38.2)	268

Seroprevalence of co-infections

Seroprevalence rates were as follows: HIV 61.7%; HSV-2 80.2% and RPR 5.8%. Among patients with genital herpes, 83.5% (391/468) were both HSV-2 PCR and HSV-2 serology positive, representing reactivation disease. The average prevalence of first-episode HSV-2, where patients with ulcer-detected HSV-2 tested negative on HSV-2 serology, was 16.5% (77/468); and ranged from 11% in 2008–2009 to 33% in 2014 (Fig 3). Among 30 patients with primary syphilis confirmed by ulcer PCR, the sensitivity of RPR serology was 60% (18/30). Forty-percent (12/30) of patients with laboratory-confirmed primary syphilis were RPR negative; of these the majority, 75% (9/12), were HIV-infected. Most patients with RPR-positive primary syphilis were HIV-uninfected (12/18; 66.7%). HIV co-infection rates among GUD patients ranged from 72.6% (55/76) in 2007 to 44.8% in 2014 (26/58).

 

 

Fig 3

Number of reactivation and first-episode HSV-2 among patients with ulcer-detected HSV (n = 468), with prevalence trend for first-episode HSV-2 (red line), 2007–2015.

Trends and associations of GUD aetiologies

There was a strong association between GUD pathogen detection and HIV seropositivity (p < 0.001); 68% of cases caused by HSV-2 were co-infected with HIV. Overall, HIV-uninfected patients, as determined by serological testing, were more likely than those who were HIV-infected to have GUD of unknown aetiology by PCR (OR 1.87, 95% CI = 1.38–2.52, p < 0.001), and less likely to present with HSV-associated ulceration (OR = 0.50; 95% CI = 0.37–0.67; p < 0.001).

Logistic regression analysis for association of no ulcer aetiology and HSV by gender (in a population excluding those with other microbial causes of GUD), showed that males were less likely than females to have no ulcer aetiology (0R = 0.72; 95% CI = 0.52–0.99; p < 0.001). There was no significant difference in the likelihood of males presenting with HSV-associated GUD than females (OR = 1.19; 95% CI = 0.87–1.63; p = 0.268).

There was a significant decline in the relative prevalence of PCR-detectable ulcer-derived HSV over time, predominantly from 2013–2015 (p-value for trend 2007–2015 = 0.023); and a statistically insignificant trend towards a decrease in the HIV seropositivity rate (p-value for trend 2007–2015 = 0.209) (Fig 4). However, in an analysis which only included patients with a laboratory-proven ulcer aetiology, the decrease in the relative prevalence of ulcer-derived HSV over time was not statistically significant (p = 0.449; p-value for trend 2007–2015 = 0.297). When stratified by HIV serostatus, there was no significant change in prevalence trend of HSV over time in the HIV-infected group (p-value for trend = 0.293); however, there was an insignificant downward trend in the relative prevalence of HSV ulceration (predominantly between 2013–2015) in the HIV-uninfected population (p-value for trend = 0.063).

 

 

Fig 4

Trends in HSV and HIV prevalence in GUD, Johannesburg 2007–2015 (n = 771).

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Discussion

We present trends in the relative prevalence of GUD aetiologies over a nine-year period. Our data reveal that, in keeping with findings from other surveillance studies, HSV-2 has remained the leading cause of pathogen-detectable GUD at Alexandra Health Centre [11], and this supports the use of anti-viral therapy in the syndromic management guidelines since 2008. The WHO recommends inclusion of anti-herpes therapy in GUD treatment algorithms if HSV is responsible for 30% or more of GUD.[7] A change in epidemiology to HSV-1 has not been observed, as is the case in high-income countries where genital HSV-1 has been identified as the leading cause of incident GUD, especially in young heterosexual women and MSM.[13] This change in Western Europe and USA has been attributed to a rise in socio-economic conditions with a corresponding reduction in childhood acquisition of HSV-1, as well as a transformation in sexual practices with a preference for oro-genital sexual intercourse. Our data support anecdotal findings that oro-genital sex is not a popular practice among the predominantly heterosexual populations accessing STI services at the primary healthcare centre.

Approximately 80% of HSV ulceration in our study represented reactivated disease and there appeared to be a decline in the relative prevalence of HSV-related GUD at Alexandra Heath Centre over the time period studied. There are several factors that may have contributed to this trend. Since 2004, there has been increased access to anti-retroviral therapy (ART) for HIV-infected individuals and a scale-up of ART coverage in the South African public healthcare sector. Anti-retroviral therapy is not associated with reduced HSV shedding [14]; however, it may lead to a decrease in clinically apparent HSV reactivation.[15] Recent efforts to increase HIV testing may have led to earlier HIV diagnoses and initiation of therapy at higher CD4+ T-lymphocyte counts, resulting in less immunosuppression and reduced HSV-2 shedding in newly diagnosed HIV-infected patients. Additionally, male medical circumcision, which is a component of the national HIV/AIDS prevention package, is associated with a reduction in incident HSV ulceration.[16] However, the trend in decline of HSV over time was not statistically significant in the subgroup of patients with a confirmed ulcer-derived STI pathogen. It is possible that the sample-collecting technique of the nurses, clinical decision-making on ulcer sampling, and consequently specimen adequacy may have altered over time and maybe a contributory factor in the relative increase in ulcers without a detectable pathogen.

The sensitivity of RPR in suspected primary syphilis is expected to be 70–80%.[17] We hypothesize that it was lower in our patients with ulcer-proven Treponema pallidum aetiology because a small proportion may have presented with very early primary infection prior to seroconversion. HIV infection may also lead to an aberrant serological response, such as a delay in the development of antibody to syphilis infection. It has been noted that initial non-treponemal serology may be negative more often in primary syphilis than in other disease stages, particularly in populations with relatively high rates of HIV co-infection.[18] Increased false-negative non-treponemal serology due to prozone phenomenon has also been described.[19] Primary syphilis and LGV appear to be relatively uncommon causes of GUD among our patients. However, these pathogens are increasingly being recognised among MSM in Western Europe, where there has been a resurgence of syphilis as the predominant cause of GUD, and a rising incidence of LGV proctitis. [20, 21] An important component of future STI surveillance strategies will be the incorporation of aetiological monitoring in key populations.

From 2000 onwards, following the successful implementation of syndromic management as recommended by the WHO, the proportion of GUD caused by Haemophilus ducreyi has declined substantially worldwide.[8] Accordingly, chancroid, a predominant cause of GUD in South Africa in the 1980s and early 1990s (and, previously, responsible for up to 70% of genital ulceration), is now detected on a sporadic basis only. Donovanosis has a limited geographical distribution and is very rarely a cause of GUD aetiology in South Africa. Previous cases have been mostly located in rural Kwa Zulu Natal, and may have facilitated the acquisition and spread of the HIV epidemic in these areas.[22] The condition may be missed as diagnosis is made using relatively insensitive phenotypic methods. Commercial PCR assays have not yet been developed and validated for clinical use.

Approximately 35% of patients presented with ulcers that could not be attributed to a definitive STI pathogen. This is in keeping worldwide epidemiological trends and data from other sub-Saharan African countries.[23] In Kenya, among men enrolled in a male circumcision trial, GUD of unknown aetiology was associated with a higher bacterial diversity as determined by ribosomal RNA sequencing.[24] These included mostly anaerobic species, some of which have histolytic properties and are associated with enhancing epithelial disruptions. In our survey, GUD of unknown aetiology was relatively more common in HIV-seronegative patients. Acute HIV-associated ulceration may also be a cause. Among South African men enrolled in a clinical trial of acyclovir treatment for genital ulcer disease, acute HIV infection was associated with an almost eight times greater likelihood of having genital ulcers of unknown aetiology compared with herpetic ulcers.[2] In the same trial, over 45% of HIV-infected men were found to have detectable HIV-1 RNA in ulcers, and those with ulcers of unknown aetiology were more likely to have HIV-1 lesional shedding than those with HSV-2 ulceration.[3] Other possible causes include non-infectious conditions such as genital trauma and Behçet’s syndrome [25] or, rarely, malignancies such as squamous cell carcinoma.[26–29] Further investigation and research are needed to properly elucidate the aetiology, and should include biopsy and histopathology, as well as next-generation sequencing of ulcer material, particularly for persistent or recurrent ulceration unresponsive to standard syndromic management.

The high HIV seroprevalence rate among GUD patients reflects the epidemiological synergy between STIs and HIV, and biological plausibility for co-infection due to common sexual behaviour and transmissibility. Factors that contribute to this synergy include disruption of genital mucosal epithelium and recruitment of inflammatory HIV target cells.[30] It has been demonstrated that genital ulcer disease and HSV-2 seropositivity are associated with HIV acquisition and seroconversion, and an increased HIV viral load.[31] The risk of HIV transmission is estimated to be highest during the initial stage of early HIV infection.[32] This underscores the importance of linkage to universal HIV testing and treatment for GUD patients at primary healthcare level. These data support the 2016 universal test and treat strategy formally adopted by the South African National Department of Health, in accordance with WHO evidence-based guidelines, whereby all HIV-infected individuals are offered anti-retroviral therapy (ART) regardless of CD4+ T-lymphocyte count.

Strengths of the study include the large number of participants enrolled over a nine-year surveillance period. Seasonal variability may occur as there is a migrant male labour population that travel home to rural areas in other provinces over the December holidays, therefore sexually transmitted infections are typically seen more frequently in January and February of each year. We controlled for this by undertaking surveillance and collecting samples during the same months every year during the study period. This should have eliminated any bias due to seasonal variation in prevalence. Limitations include missing demographic and clinical data for a proportion of the participants. The lack of additional clinical or diagnostic information for patients with GUD of unknown aetiology is an important limitation that requires further investigation. Future GUD aetiological prevalence surveys should collect information on the proportion of HIV-infected individuals who are adherent on ART, as well as the proportion of male participants who have been medically circumcised. The relatively small numbers of participants enrolled in the latter years of surveillance may make prevalence estimates unstable from one year to the next. Additionally, the findings from this single-site surveillance study may not necessarily be generalizable to GUD patients presenting to primary healthcare facilities in other regions of the country.

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Conclusion

Herpes simplex virus remains the leading cause of pathogen-detectable GUD in South Africa, justifying the continued use of acyclovir in syndromic management. Aetiological trends reveal a decline in the relative prevalence of HSV-2 associated ulceration, possibly resulting from increased uptake of HIV anti-retroviral therapy and HIV preventive strategies in the public health sector. The aetiology of ulcers without detectable STI pathogens in a significant proportion of patients requires further research. The prevalence of HIV co-infection among GUD patients is high, underlining the importance of linkage to universal HIV testing and treatment for these patients in primary healthcare settings.

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Supporting information

S1 Dataset

(XLSX)

Click here for additional data file.^{(72K, xlsx)}

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Acknowledgments

The authors wish to acknowledge Valencia Kekana and Alex Vezi for patient enrolment and specimen collection for the surveillance study; and the staff of Alexandra Health Centre for the use of their clinic facilities.

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Funding Statement

The authors received no specific funding for this work.

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Data Availability

All relevant data are within the paper and its Supporting Information file.

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