Sexually transmitted infections such as herpes simplex virus type 2 (HSV-2), syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and Mycoplasma genitalium are of major public health concern and are key epidemiological markers of unprotected sex (World Health Organization. 2016). Whilst STIs affect individuals of all ages, adolescents and young people are disproportionately affected (Dehne and Riedner 2005), STIs contribute adversely to sexual, reproductive and maternal-child health; lead to pelvic inflammatory disease, genital malignancies and infertility (World Health Organization. 2016) and increase the risk of HIV acquisition and transmission (Wasserheit 1992, Rottingen et al. 2001, Freeman et al. 2006, Looker et al. 2017, Unemo et al. 2017, Cohen et al. 2019).

South Africa monitors the HIV epidemic through nationally representative population-based household surveys (Human Sciences Research Council. 2018). With a national HIV prevalence of 20.6% for among 15–49-year-old, the epidemic in the region is characterized as generalized and hyperendemic. At the provincial level, HIV prevalence in KwaZulu-Natal was the highest at 27.0% while prevalence in the Western Cape was 12.6%. However, there are no similar surveys to monitor the STI burden and surveillance for STIs is limited to the use of convenience or clinic based sampling, limiting generalizability to groups of interest (Johnson et al. 2005, Kularatne et al. 2017, Francis et al. 2018). Notwithstanding such limitations, the studies have provided useful point estimates in select sub-populations and highlight the need for population-representative surveys to determine the burden and patterns of STIs and to reliably monitor and assess the effectiveness of STI prevention programs.

With the onset of the HIV epidemic interest in STIs has grown substantially as both share a complex, synergistic bidirectional relationship (Wasserheit 1992, Barnabas et al. 2011, Looker et al. 2017). Evidence suggests that for HIV positive individuals, persistent high risk behaviours increase susceptibility to STIs (Erbelding et al. 2003, Chen et al. 2007, Lurie et al. 2014, Khaw et al. 2018). and advancing HIV infection may increase the frequency of STI treatment failures (Wolday et al. 2004, Unemo et al. 2017, Khaw et al. 2018). Conversely, asymptomatic or symptomatic STIs strongly predict susceptibility to HIV, enhance HIV shedding at genital mucosal sites and increase infectiousness from HIV positive individuals (Mwatelah et al. 2019). Potential biologic mechanisms that facilitate and activate HIV replication include alterations in the genital tract microbiome, localized inflammation, recruitment of CD4+ T-cells, monocytes, Langerhans’ cells, and increased levels of interleukin-10 (Abdool Karim et al. 2019, Cohen et al. 2019, Mwatelah et al. 2019). Whilst these findings provide strong biological plausibility for STI control as an effective HIV prevention strategy, clinical trial evidence has produced conflicting results (Grosskurth et al. 1995, Wawer et al. 1999, Kamali et al. 2003, Hayes et al. 2010, Torrone et al. 2018). The differences in trial design, robustness of the interventions, population characteristics, stage of the HIV epidemic at the time of the study and baseline prevalence of STIs may have contributed to these mixed results Stillwaggon and Sawers 2015), but nonetheless, treatment of STIs remains a public health priority (Hayes et al. 2010, Cohen 2012, Stillwaggon and Sawers 2015).

These findings suggest that monitoring, early diagnosis and treatment of STIs may reduce STI related HIV acquisition and transmission and achieve the goal of HIV epidemic control in the region (Joint United Nations Programme on HIV/AIDS (UNAIDS). 2017, Galvani et al. 2018).

The objectives of this study were to measure the population prevalence of STIs and to assess the association between STIs and HIV, CD4 cell counts and HIV viral load in a high HIV burden setting.

This population-based survey undertaken in rural and peri-urban KwaZulu-Natal, the province with the highest HIV prevalence in South Africa (Human Sciences Research Council. 2018) showed that over half of the participants in the study area had HSV-2 infection and just under one-quarter had at least one curable STI [syphilis (1.6%), N. gonorrhoeae (2.8%), C. trachomatis (7.1%), T. vaginalis (9.0%), and / or M. genitalium (5.5%)]. Similar to the low levels of reporting of genital symptoms among 15-to 24 year old’s in rural KwaZulu-Natal (Francis et al. 2018), only 3% of our participants reported having any genital symptoms, suggesting that majority of participants with STIs were either asymptomatic or that individuals were unable to recognize signs and symptoms of STIs precluding them from seeking care and treatment. In addition to contributing to adverse health outcomes, STIs interact with the immune system in genital mucosa sites facilitating HIV acquisition and transmission (Wasserheit 1992, Mayer and Venkatesh 2011, Abdool Karim et al. 2019, Mwatelah et al. 2019). Estimates of curable STIs were higher in the younger age groups, particularly in younger females, which is the same group among whom a peak in HIV incidence occurs (Kharsany et al. 2019), thus the importance of enhanced STI surveillance (Taylor and Wi 2019) and investment in targeted STI control programs for younger populations (Francis et al. 2018, Kharsany et al. 2019).

Globally and in the sub-Saharan African region, HSV-2 is the leading cause of genital ulceration and there is substantial overlap between the HSV-2 and HIV syndemics (Freeman et al. 2006). Prevalent HSV-2 leads to subclinical HSV-2 viral shedding (Wald et al. 2002) which may be exacerbated by incident HIV infections whilst incident HSV-2 infections has been associated with an elevated risk of HIV acquisition (Reynolds et al. 2003, Brown et al. 2007). The high prevalence of HSV-2 infection reflects either markers of risky sexual behaviours with HSV-2 and HIV acquired simultaneously (Corey 2007) or the biological basis of the plausibility of the increased shedding of HIV during acute, early or subclinical reactivation of HSV-2 infection thus enhancing transmission of both infections (Celum et al. 2005, Cohen et al. 2019). In this study by age 24 years, 60% of females were already HSV-2-positive, which underscores the rapid speed at which HSV-2 transmission is occurring and its potential for escalating HIV risk (Looker et al. 2017). The high HSV-2 prevalence may also help to explain the magnitude of the HIV epidemic in the region (Freeman et al. 2006, Kharsany et al. 2019).

The prevalence of T. vaginalis was higher among females and more importantly among males and females in the older age groups, suggesting that biological factors contribute to prevalence in older individuals (Lazenby et al. 2020) and that individuals’ perceptions and behaviours on sexual and reproductive health may result in sub-optimal health seeking behaviours (Rietmeijer 2019). Furthermore, as T. vaginalis is strongly associated with HIV acquisition and transmission (Kissinger and Adamski 2013), the high prevalence contributes to the spread of both infections. Similarly, the high prevalence of N. gonorrhoeae and C. trachomatis also suggests that many of these STIs remain untreated and could increase ascending genital tract infections (World Health Organization. 2016). M. genitalium has emerged as an important sexually transmitted pathogen with evidence of a temporal association between M. genitalium infection and HIV acquisition (Vandepitte et al. 2014). The prevalence of active syphilis at the population-level was 3.0% in females which is higher than the 2.3% among pregnant women in KwaZulu-Natal (South African National Department of Health. 2017). Despite the successful implementation of public health programs for the management of syphilis among pregnant women during prenatal care; programmatic interventions should be aimed at the population-level to diagnose, treat and to prevent long-term negative sequelae of untreated syphilis and of potential congenital syphilis.

The findings on the association of HIV positive status and curable STIs has important implications for the region. Recent studies have delineated the role and biologic mechanisms of STIs with disturbances in the vaginal microbiome, inducing mucosal inflammation, yielding unique cytokine profiles that evoke an influx of HIV receptor cells in genital mucosal epithelium (Abdool Karim et al. 2019, Mwatelah et al. 2019). The regression analyses revealed that HIV positive status increased the prevalence of curable STIs, though risk behaviours of more than 80% of sexually active participants reported not being married or living with partner as husband and wife, low levels of condom use, concurrent heterosexual partnerships, high number of lifetime sex partners and high levels of alcohol and substance use at a population-level could worsen and contribute to sustaining both STI and HIV epidemics in region. Even though our analysis adjusted for sexual risk behaviors, these behaviours might have been underestimated as survey procedures may not have adequately assessed the characteristics of the individual’s sexual networks or that participants may underreport on sexual risk-taking behaviours.

Among HIV positive individuals the association of CD4 cell counts of <350 cells per mL with N. gonorrhoeae and M. genitalium suggests that even with advancing HIV disease, susceptibility to STIs remains elevated. HIV-positive individuals tend to increase condom use at ART initiation (Risher et al. 2016), so it was not surprising that in this study HIV-positive individuals who were virally suppressed had a lower prevalence of curable STIs, suggestive of practicing safer sex behaviours.

In the absence of ART, STIs augment HIV viral shedding (Johnson and Lewis 2008). A meta-analysis of 39 studies showed that STIs that elicit a leukocyte response in the genital tract was associated with almost a three-fold increase in HIV viral shedding promoting potential sexual transmission of HIV (Johnson and Lewis 2008). However, HIV positive individuals using ART correctly and consistently benefit by achieving HIV viral suppression to prevent onward transmission (Abdool Karim 2019). However, whilst ART itself has no impact on STIs (Champredon et al. 2015), and as STIs remain untreated, HIV viral shedding persists in genital secretions including semen (Cohen et al. 2019) though shedding may be transient or intermittent (Chun et al. 2013). Our findings on the association of HIV viral load ≥ 400 copies per mL and STIs, highlights the sustained potential elevated risk of onward HIV transmission. It is critical that combination HIV prevention programs include the early diagnosis and treatment of STIs to reduce HIV viral shedding towards the goal of achieving HIV epidemic control (Joint United Nations Programme on HIV/AIDS (UNAIDS). 2017, Galvani et al. 2018).

The strength of this study was the use of biological measurements of STIs on self-collected genital samples rather than relying on signs and symptoms of STIs. Despite the robust sampling strategy, given the cross-sectional design of the study, temporality of any associations cannot be inferred, and generalizability of our findings are limited to the study area or to similar high HIV burden settings. As the sociodemographic, behavioural and clinical data were self-report, these could potentially be prone to social desirability bias. The data on sexual partnerships were reported over the previous 12 months or further and may be subject to recall bias. Even though participants were guided on the self-collection method of obtaining genital samples, some samples may have been of inadequate quality resulting in an underestimation of the prevalence of STIs.

The high prevalence of STIs and the association with HIV and HIV viral load ≥400 copies per mL underscores the public health implications of sustained onward transmission risk of STIs and HIV. STIs remain a threat towards realizing the goal of achieving HIV epidemic control in this high HIV burden region.