2.1. Epidemiology and global burden of sexually transmitted infections

Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting the quality of life and causing serious illness and death. The illness caused by STIs profoundly affects the physical, mental and social well-being of children, adolescents and adults worldwide. Some STIs directly affect reproductive and child health by causing infertility, anogenital cancer, adverse outcomes of pregnancy, fetal deaths and abnormalities and general ill health. In addition, they have indirect effects through their role in facilitating the sexual transmission and acquisition of HIV, resulting in more suffering among people living with HIV; mental health comorbidities, including depression, anxiety, dementia and other cognitive disorders; and other comorbidities experienced by people living with HIV.

Worldwide, people acquire more than 1 million curable STIs every day. Based on prevalence data from 2009 to 2016, in 2019, WHO published estimates of new cases of chlamydia, gonorrhoea, syphilis and trichomoniasis, showing total estimated incident cases of 376.4 million among people 15–49 years old in 2016, with 127.2 million new cases of chlamydia, 86.9 million new cases of gonorrhoea, 156 million new cases of trichomoniasis and 6.3 million new cases of syphilis (1).

The burden of STIs varies by region and sex, and the burden is greatest in resource-limited countries. The global incidence rates in 2016 were estimated to be 34 new cases of chlamydia per 1000 women and 33 per 1000 men; 20 new cases of gonorrhoea per 1000 women and 26 per 1000 men; 40 new cases of trichomoniasis per 1000 women and 42 per 1000 men; and 1.7 new cases of syphilis per 1000 women and 1.6 per 1000 men. The WHO African Region had the highest numbers of new cases of gonorrhoea and trichomoniasis among women and men, and the WHO Region of the Americas had the highest numbers of new cases of chlamydia and syphilis among both men and women (1).

Although progress has been made in preventing the mother-to-child transmission of syphilis since 2012, the decline has not been substantial, since an estimated 661 000 cases of congenital syphilis occurred in 2016. The number of cases of congenital syphilis per 100 000 live births fell from 539 in 2012 to 473 in 2016, indicating that more efforts are needed to accelerate the interventions for sustainable and greater impact. Of the 661 000 cases of congenital syphilis in 2016, more than 350 000 occurred as adverse birth outcomes, including stillbirths and neonatal deaths (2,3).

The prevalence of some viral STIs is similarly high, with an estimated 417 million people infected with herpes simplex virus type 2 (HSV-2), and about 291 million women harbour human papillomavirus (HPV) at any time (4).

When left undiagnosed and untreated, STIs can result in serious complications and sequelae, such as pelvic inflammatory disease, infertility, ectopic pregnancy, miscarriage, fetal loss and congenital infections and cancer. Curable STIs accounted for the loss of nearly 11 million disability-adjusted life years (DALYs) in 2010 (5). The mental effects of STIs include stigma, shame and loss of self-worth. STIs have also been associated with fears of relationship disruption and gender-based violence, thus undermining effective partner notification (6).

Both ulcerative and non-ulcerative STIs are associated with a several-fold increased risk of transmitting or acquiring HIV (7,8). Infections causing genital ulcers are associated with the highest risk of HIV transmission. In addition to curable ulcer-causing STIs (such as syphilis and chancroid), highly prevalent HSV-2 infections substantially increase vulnerability to transmitting and acquiring HIV (9). Non-ulcerative STIs, such as gonorrhoea, chlamydia and trichomoniasis, have been shown to increase HIV transmission through genital shedding of HIV (10,11).

Preventing and controlling STIs are integral components of comprehensive sexual and reproductive health services that are needed to attain the related targets under Sustainable Development Goal 3 (Ensure healthy lives and promote well-being for all at all ages), including: target 3.2 – to end preventable deaths of neonates and children under 5 years of age; target 3.3 – to end the epidemics of AIDS and other communicable diseases; target 3.4 – to reduce premature mortality from noncommunicable diseases and promote mental health and well-being; target 3.7 – to ensure universal access to sexual and reproductive health-care services; and target 3.8 – to achieve universal health coverage.

2.2. STIs and HIV

Although HIV, which causes AIDS, is most commonly spread through sexual intercourse, the HIV epidemic has usually been addressed differently and separately from the other STIs. Initially, this was because AIDS emerged as a fatal, untreatable and rapidly spreading disease. Because of that, the focus was centred more around HIV and AIDS research and, in addition, palliative patient care programmes and community activism evolved to deal with the mounting HIV-related morbidity and mortality and acceleration of the development of antiretroviral therapy. In contrast, the care and research related to the other STIs were already embedded in other programmes. Consequently, since the 1980s, HIV and the other bacterial and viral STIs have often been addressed through separate programmes and through separate funding mechanisms, with many HIV programmes not funding STI-related interventions or costs.

2.3. Objectives and rationale for developing the guidelines

The WHO global health sector strategy on sexually transmitted infections, 2016–2021, endorsed by the World Health Assembly in 2016, aims to eliminate STIs as a public health threat by 2030 (15). The key pillars to eliminate STIs are to prevent people from becoming infected and to provide treatment and care for infected people to avoid further transmission of STIs to other people. The strategy makes a strong case for expanding the provision of high-quality STI prevention and care more widely into primary health care, sexual and reproductive health and HIV prevention and care services. Efforts should therefore be made to strengthen STI case management, which ensures the widest possible access to high-quality services at the population level, based on simplified and standardized interventions and services that can readily be taken to scale, especially in resource-limited settings.

Since WHO published the guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and progress in prevention, diagnosis and treatment of STIs and HIV have necessitated changes in approaches to managing STI prevention (16).

There has also been an upsurge of antimicrobial resistance, and there is an urgent need to update global treatment recommendations to effectively respond to the changing antimicrobial resistance patterns of STIs, especially in Neisseria gonorrhoeae. Effective treatment protocols that consider global and local antimicrobial resistance patterns are essential to curb the further spread and escalation of antimicrobial resistance globally. High-level gonococcal resistance to quinolones, a previously recommended first-line treatment, is widespread, and decreased susceptibility to the extended-spectrum (third-generation) cephalosporins, current first-line treatment for gonorrhoea, is rising (17–20). Resistance to azithromycin and treatment failures have been reported in strains of Treponema pallidum, N. gonorrhoeae and Mycoplasma genitalium. In addition, instances of Chlamydia trachomatis treatment failure have been reported for tetracyclines and macrolides (21,22).

Etiological diagnosis of STIs, although ideal, remains unfeasible for health-care providers in resource-limited settings. It constrains their time and resources, increases costs and reduces access to treatment. Near point-of-care tests based on molecular technology can be performed during the clinic visit for the same-visit test results for gonorrhoea and chlamydial infections. These tests can be strategically used when available to reduce the above challenges and ensure treatment at the first point of contact with people with STIs.

To overcome issues related to etiological diagnosis and treatment, WHO introduced syndromic case management in 1984. Syndromic management for urethral discharge among men and genital ulcers among men and women has proved to be both valid and feasible. It has resulted in adequate treatment of large numbers of infected people and is relatively inexpensive, simple and very cost-effective (16). However, given the recent data on the changing causes of genital ulcer disease, HSV-2 infections being the commonest and predominant cause of genital ulcer disease, evidence-informed flow charts need to be updated.

WHO’s simplified generic tool for syndromic management of STIs includes flow charts for women with symptoms of vaginal discharge and/or lower abdominal pain. The flow charts for abdominal pain are quite satisfactory, but those for vaginal discharge have limitations, especially in managing cervical (gonococcal and chlamydial) infections. In general, but especially in settings with low STI prevalence and among adolescent females, vaginitis rather than an STI is the main cause of vaginal discharge. Moreover, overtreatment is becoming increasingly undesirable because of the worsening antimicrobial resistance and limited treatment options. Updating these guidelines has considered mechanisms to mitigate the escalation and further development of antimicrobial resistance, especially when near-patient point-of-care tests are rapidly becoming more available.

Syndromic management is widely used. In most resource-limited settings, these flow charts are still the standard of care when laboratory diagnosis is not available or when results take several days. The STI Guideline Development Group members have reiterated that the STI syndromic approach is still an essential component of STI prevention and control but that WHO should improve the various STI syndromic case management flow charts and that these guidelines should raise the quality of STI case management for people with STI symptoms and not promote suboptimal care. Member States, nongovernmental organizations (NGOs) and partners have requested WHO to give priority to updating these guidelines.

2.4. Objectives of the guidelines

The objectives of these guidelines are as follows:

• to provide updated, evidence-informed clinical and practical recommendations on case management of people with symptoms of STIs; and
• to support countries in updating their national guidelines for the case management of people with symptoms of STIs.

These guidelines include the management of people with symptoms related to:

• urethral discharge syndrome, including persistent urethral discharge syndrome;
• vaginal discharge syndrome, including persistent vaginal discharge;
• anorectal infection;
• genital ulcer disease syndrome; and
• lower abdominal pain syndrome.

2.5. Target audience

These guidelines will be part of a consolidated set of guidelines for the prevention of STIs and management of people with STIs that are intended for programme managers for STI prevention and control at the national level and the health-care providers at the frontline in primary, secondary and tertiary health-care facilities. For the programme managers, the guidelines will assist in deciding how to organize the services for providing STI care and to determine the distribution of equipment and commodities that ensure access to high-quality STI care for people.

The guidelines can also be used as an advocacy tool for the financial and human resources required to deliver adequate, acceptable and equitable STI care for everyone who needs STI services.

Similarly, these guidelines can offer guidance to policy-makers and other stakeholders, including finance ministries at the country level, partners in providing services for STI prevention and care, such as local and international donor agencies and nongovernmental organizations, including community-based organizations, patient representatives and other stakeholders.

2.6. Guiding principles

The following principles have informed the development of these guidelines and should guide the implementation of the recommendations.

• The guidelines contribute to and expedite the achievement of key global and national goals to contribute to achieving the Sustainable Development Goals.
• The guidelines are based on a public health approach to scaling up the provision of care for people with STIs to reach everyone who needs such services, including vulnerable populations and key populations, with interventions, such as targeted screening (in accordance with WHO guidance) for N. gonorrhoeae and C. trachomatis and antimicrobial resistance monitoring in men who have sex with men who are receiving PrEP, especially in settings in which STI molecular testing is limited or not available as well as more targeted testing (in accordance with WHO guidance) around hepatitis C testing.
• Adaptation and implementation of the guidelines need to be accompanied by efforts to promote and protect the human rights of people who need services for STI care, including ensuring preventing stigma and discrimination in providing such services and promoting gender equity.
• Implementation of the recommendations in these guidelines should be informed by the local context, including the epidemiology of STIs, the availability of resources and commodities for diagnosing STIs and providing STI treatment and care in the context of the capacity of the health system and anticipated cost–effectiveness.
• The guidelines allow adaptability that aims at promoting accessibility, acceptability and effectiveness in the case management of people with STIs through public and private health-care systems, including at the primary health-care level and other first-level health-care facilities providing services for STIs, such as maternal and child health, antenatal, family planning and other sexual and reproductive health-care facilities.
• The guidelines provide guidance for acceptable and effective STI care services to populations identified as being especially vulnerable to or at higher risk of STIs, including HIV infection.
• The guidelines are constructed based on evidence of effectiveness and feasibility, providing a comprehensive approach that is easy to follow, addressing issues of diagnosis, treatment protocols, partner notification, health education and disease prevention, including condoms and vaccines.

2.7. Methods for developing the guidelines

In 2014, WHO formulated a roadmap for updating guidelines in the WHO handbook for guideline development (23). These guidelines were developed in accordance with the handbook, especially in the processes summarized below.

The WHO STI Secretariat proposed four phases of STI guideline development, and the STI Guideline Development Group members agreed, with the goal of producing a comprehensive and consolidated set of guidelines for preventing STIs and managing the people who have STIs. The phased approach for developing the guidelines was established as follows (Table 1).

• Phase 1 was to include guidelines for managing people with specific STIs and for other important and urgent STI issues and the guidelines for the syndromic management of people with STIs (managing people with STIs using a syndromic approach). The recommendations for managing people infected with specific pathogens were published as independent modules and disseminated in 2016, comprising treatment recommendation for C. trachomatis (chlamydia), N. gonorrhoeae (gonorrhoea), HSV-2 (genital herpes), T. pallidum (syphilis) and syphilis screening and treatment of pregnant women (24–28). These guidelines update the guidelines for the syndromic management of STIs to managing people with symptoms of STIs.
• Phase 2 will focus on guidelines for STI prevention.
• Phase 3 will address the treatment of additional infections, including Trichomonas vaginalis (trichomoniasis), bacterial vaginosis, Candida albicans (candidiasis), Haemophilus ducreyi (chancroid), HPV (genital warts and cervical cancer) and M. genitalium.
• Phase 4 will provide guidance on laboratory diagnosis and screening of STIs.

Table 1

Sensitivity and Specificity for different steps in the flowcharts.

These STI guidelines focus on the management of people with symptomatic STIs, which includes the etiological approach (laboratory diagnosis) and the syndromic approach (based on symptoms and signs) to diagnose symptomatic STIs. To embark on the recommendations for managing people with symptoms of STIs, systematic reviews on various syndromes and modelling work on vaginal discharge were carried out by experts from McMaster University, the Michael G. DeGroote Cochrane Canada Centre, Monash University and the University of Bristol.

2.8. Reviews of the evidence

Multiple systematic reviews were conducted by a team at McMaster University, Michael G. DeGroote Cochrane Canada Centre and a team led by Monash University, Australia. For each syndrome, systematic reviews of studies were conducted to find studies comparing approaches to each other that reported the effects on important outcomes (Annexes 3–7). When these studies were not available, additional reviews were conducted that reported the prevalence of the suspected STI and the accuracy of various syndromic approaches (including risk assessment, history taking, presence of signs and tests) (supplemental material for unpublished systematic reviews, Annex 8). Comprehensive searches for previously conducted systematic reviews, randomized controlled trials and non-randomized studies were performed up to September 2019. Additional searches were conducted to identify studies for patient values and preferences (such as qualitative research designs), acceptability, feasibility, equity and resources (such as cost–effectiveness studies). The steps of the systematic reviews were conducted in duplicate, and statistical pooling of the results from studies was performed when possible. Systematic reviews of the treatment of people with the suspected STIs (such as chlamydia, gonorrhoea, syphilis and herpes) were previously conducted for the WHO treatment guidelines (24–28) and were used to provide data for treatment outcomes.

2.9. Modelling outcomes

Because the effects on important outcomes for the people with STIs were not available from the studies, the effects were calculated using the diagnostic test accuracy from the studies. The numbers of true positives and negatives and false positives and negatives were calculated using the sensitivity and specificity of the approach and the prevalence of the STI in a population presenting with symptoms and then discussed with the Guideline Development Group the consequences of and weight of the consequences of, for example, a false negative (missing the diagnosis of a STI) on a patient or health system.

For the syndromic management of vaginal discharge, a static model using Excel was developed. The model simulates a range of management strategies to identify and treat vaginal and cervical infections. The model builds on previous work of WHO to provide a comprehensive, flexible model that can simulate a range of patient management flow charts based on syndromic management plus existing diagnostic procedures and tests (such as speculum examination and Gram stain) in different various prevalence, country or clinic settings. The strategies in the model include different combinations of risk assessment, speculum examination, microscopy and/or available and prospective rapid point-of-care diagnostic tests and the previously recommended WHO syndromic management approaches. The cost and effects were calculated based on the prevalence of the STIs.

In the cost analysis, the direct costs of managing women with vaginal discharge were incorporated: test cost, treatment cost, according to infection (chlamydia, gonorrhoea and combined bacterial vaginitis or T. vaginalis treatment) plus optionally the costs of long-term consequences (pelvic inflammatory disease, ectopic pregnancy and infertility) and/or partner management.

Because of the scarcity of evidence on the direct cost of overtreatment on antimicrobial resistance, the cost of antimicrobial resistance was incorporated in the form of an antimicrobial resistance externality tax, which can be applied to either all antibiotic treatments or to only those that are unnecessary. The antimicrobial resistance externality tax represents the current and future burden of antimicrobial resistance, including costs associated with treating resistant infections, increased morbidity and mortality and the cost of developing new drug therapies. We calculate this hypothetical antimicrobial resistance tax to be a tax associated with each single treatment of ceftriaxone and azithromycin, whether appropriate (the person has N. gonorrhoeae or C. trachomatis) or inappropriate (overtreatment – treated in the absence of infection).

The supplementary material (Annex 8) includes the Excel tool and describes the modelling of cost and effectiveness of different approaches to vaginal discharge.

2.10. Presentation of the evidence

Tables to facilitate decision-making for recommendations (evidence-to-decision frameworks) were produced for each recommendation and presented to the STI Guideline Development Group using the GRADEpro online software. These tables include a summary of the problem – test (diagnostic) accuracy, summary of the evidence for benefits and harm; certainty of the evidence; relevant patient values and preferences; and other issues, such as cost, resources, feasibility, equity and acceptability. The certainty of the body of evidence was assessed using the GRADE system, based on risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, dose-response and opposing confounding. Based on the above criteria, the overall certainty of evidence was defined as follows.

• very low: very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect;
• low: limited confidence in the effect estimate: the true effect may be substantially different from the estimate of the effect;
• moderate: moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; and
• high: very confident that the true effect lies close to that of the estimate of the effect.

2.11. Making recommendations

The STI Guideline Development Group reviewed the evidence-to decision tables and the summaries of the evidence and made judgements about the effects of the syndromic management approaches during virtual meetings (28 September to 2 October 2020). Based on the discussions, the Guideline Development Group made decisions on whether to make strong or conditional recommendations for or against an approach. The Guideline Development Group agreed by consensus. There were no disagreements in which voting was necessary. The recommendations and evidence-to decision tables were finalized electronically via email.

According to the GRADE approach, the strength of each recommendation was rated as either strong or conditional. Strong recommendations are presented as recommendations and conditional recommendations are presented as suggestions. Table 2 explains the implications of the differing strengths of recommendations for patients, clinicians and policy-makers in detail. Good practice statements were made when the Guideline Development Group agreed that the guidance was necessary to provide but a review of the literature was not warranted because the balance of desirable and undesirable consequences of an intervention was unequivocal and no other criteria would need to be considered. The External Review Group approved the methods and agreed with the recommendations made by the Guideline Development Group.

Table 2

Implications of differing strengths of GRADE recommendations.

2.12. Managing conflicts of interest

Managing conflicts of interest was a key priority throughout the process of guideline development. WHO guidelines for declaration of interests for WHO experts were implemented. Declaration of interests statements were obtained from all members of the Guideline Development Group and the External Review Group before they assumed their role. At the beginning of the STI Guideline Development Group meetings, including subgroup meetings, the members disclosed their declared interests. The declaration of interests statements were summarized in a table as suggested by the WHO Guidelines Review Committee (Annex 2).

Five STI Guideline Development Group members declared interests. After analysing each declaration of interests, the WHO STI Secretariat found that one member (JK) had a huge noncommercial research grant from the United States National Institutes of Health that is not related to the current guidelines and a minor commercial interest related to STI diagnostics and thus concluded that this STI Guideline Development Group member would be allowed partial participation. Two members declared interests as consultants with global antimicrobial resistance and research development partnership (WHO–Drugs for Neglected Diseases Initiative partnership) not related to the current guidelines and no commercial interest and thus were allowed full participation. Two members declared support from a pharmaceutical company; one was provided minimal support for attending a meeting and the other received previous consultation fees and travel expenses but currently does not have any support from any pharmaceutical companies. Both were allowed full participation.