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Periodic presumptive treatment of curable sexually transmitted infections among sex workers: a systematic review

Steen, Richarda,b; Chersich, Matthewb,c; Gerbase, Antoniod; Neilsen, Grahame; Wendland, Annikad; Ndowa, Francisd; Akl, Elie A.f,g; Lo, Ying-Rud; de Vlas, Sake J.a

doi: 10.1097/QAD.0b013e32834ed991

Background: Unprotected sex work remains a major driver of HIV/sexually transmitted infection (STI) epidemics in many countries. STI treatment can lower disease burden, complications and prevalence of HIV cofactors. Periodic presumptive treatment (PPT) has been used with sex workers to reduce their high burden of largely asymptomatic STIs. The objective of this review is to assess benefits and harms of PPT among female sex workers.

Methods: We searched MEDLINE for studies related to sex work and STIs during 1990–2010, extracted data from eligible studies in duplicate and conducted meta-analysis by study design using random effects models.

Results: Two thousand, three hundred and fifteen articles were screened, 18 studies met inclusion criteria and 14 were included in meta-analyses. One published randomized controlled trial (RCT) reported significant reductions of gonorrhoea (Neisseria gonorrhoeae) [rate ratio (RR) 0.46, 95% confidence interval (CI) 0.31–0.68] and chlamydia (Chlamydia trachomatis) (RR 0.38, 95%CI 0.26–0.57), but no effect on serologic syphilis (RR 1.02, 95%CI 0.54–1.95). Similar results were seen for N. gonorrhoeae and C. trachomatis in pooled analyses, including data from one unpublished RCT and across study designs, and correlated with initial prevalence (R2 = 0.155). One observational study reported genital ulcer disease (GUD) declines in sex workers, and two reported impact among male client populations for N. gonorrhoeae [odds ratio (OR) 0.60, 95% CI 0.38–0.94], C. trachomatis (OR 0.47, 95% CI 0.31–0.71) and GUD (OR 0.21, 95% CI 0.11–0.42). No studies reported evidence of risk compensation or antibiotic resistance.

Conclusion: PPT can reduce prevalence of gonorrhoea, chlamydia and ulcerative STIs among sex workers in whom prevalence is high. Sustained STI reductions can be achieved when PPT is implemented together with peer interventions and condom promotion. Additional benefits may include impact on STI and HIV transmission at population level.

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aDepartment of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherland

bCentre for Health Policy, Faculty of Health Sciences, School of Public Health, University of Witwatersrand, South Africa

cInternational Centre for Reproductive Health, Department of Obstetrics and Gynaecology, Ghent University, Belgium

dWorld Health Organization, Geneva, Switzerland

eFamily Health International, Bangkok, Thailand

fDepartment of Medicine, State University of New York at Buffalo, Buffalo, New York, USA

gDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.

Correspondence to Richard Steen, 11B Lanercost Road, Tulse Hill, London SW2 3DB, UK. Tel: +44 792 911 1023; e-mail:

Received 18 September, 2011

Revised 31 October, 2011

Accepted 3 November, 2011

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

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Unprotected sex work remains a major driver of HIV and sexually transmitted infection (STI) epidemics, particularly in low-income and middle-income countries. Yet several countries have succeeded in raising condom use in commercial sex, reducing STIs and stabilizing or reversing their HIV epidemics [1–3]. Common programme elements of successful interventions with sex workers include peer outreach, sex worker mobilization, condom promotion and improved STI services [4,5]. Interventions that reduce STI prevalence complement condom programmes which aim to reduce rates of reinfection. When implemented in a supportive environment, such ‘combination’ interventions have reported high uptake and utilization of services by sex workers, increased condom use, reduced STI prevalence and other positive health and social outcomes [6,7].

Most STIs in women are asymptomatic, however, and sensitive screening tests are expensive and rarely available in low-income and middle-income settings. For these reasons, periodic presumptive treatment (PPT) has been used with sex workers to reduce their high burden of largely hidden infections. PPT is defined as treatment of curable STIs based on sex workers’ high risk and prevalence of infection, rather than on symptoms, signs or results of laboratory tests. PPT is, thus, similar to other forms of epidemiologic treatment, including treatment of identified sex partners of STI index cases.

An expected direct benefit to sex workers is reduced STI-related morbidity, including pelvic inflammatory disease, infertility, ectopic pregnancy, sepsis and adverse pregnancy outcomes. At population level, reduced prevalence among sex workers may also slow transmission to clients and their regular partners [8]. To the extent that STIs amplify HIV transmission – estimated cofactor effects range from two to four for discharges to 25 or more for ulcerative STIs, lower STI prevalence may also reduce efficiency of HIV transmission [9]. A 2005 WHO consultation reviewed experience from nine countries and recommended that PPT be considered as part of a package of services to rapidly reduce STI prevalence in sex work settings, particularly where STI control is poor [10].

The main objective of this systematic review of PPT among sex workers is to assess evidence of benefits and harms in controlled trials and under field conditions. Primary outcomes of interest include reduced STI prevalence among sex workers themselves and improved STI control among male client or general population groups. Changes in reported condom use by sex workers and adverse effects associated with PPT were also reviewed.

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The systematic review of PPT forms part of a WHO initiative to develop evidence-based guidelines for HIV/STI interventions with sex workers. A guidelines development working group and a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodologist (E.A.A.) guide the process. Population, Intervention, Comparison, Outcomes (PICO) questions were drafted for PPT and other interventions involving sex workers [11]. This review follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12].

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Eligibility criteria

We included studies of female sex workers or their clients that took place in low-income or middle-income countries. Randomized controlled trials (RCTs), cross-sectional surveys with adjusted analyses, cohort and time series were eligible if they reported STI or HIV outcomes of a PPT intervention in female sex workers using a drug regimen with high cure rates for Neisseria gonorrhoeae (gonorrhoea), Chlamydia trachomatis (chlamydia), Treponema pallidum (syphilis), Haemophilus ducreyi (chancroid) or genital ulcer disease (GUD). Trials in which the control arm was another PPT regimen or STI screening were excluded.

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Search strategy

MEDLINE was searched in September 2010 for relevant articles published between 1990 and 2010 using the following search terms: prostitution or prostitut* or ‘sex work*’ and HIV or STI or STD or ‘sexually transmitted disease’ or ‘sexually transmitted infection’ or syphilis or ‘chlamydia’ or gonor*. References of review articles were reviewed; conference abstracts and unpublished reports were searched through Gateway, National Library of Medicine, researchforsexwork.or and First authors and experts in the field were contacted to obtain information on unpublished work, forthcoming manuscripts and research in progress.

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Titles and abstracts were first screened to determine whether the study involved female sex workers, took place in a low-income or middle-income country and referred to STIs or HIV. Subsequent steps involved full-text review of the remaining articles to determine whether the study included a PPT intervention and to assess its design and methods. In all stages, two researchers (R.S. and M.C.) evaluated the studies independently and differences were reconciled. Quality of evidence was assessed using GRADE methods (Supplementary Table S1, For randomized trials, information is presented on allocation concealment and blinding procedures, whereas for observational studies we report, where available, cohort retention and whether the primary objective of these studies was the same as the review's objectives.

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Data extraction and analysis

Data from studies that met inclusion criteria were extracted in duplicate using a standardized data collection form. Extractions were compared and differences reconciled. Interventions and outcomes were evaluated using ent populations – was also sought.

STIs assessed consisted of N. gonorrhoeae (gonorrhoea), C. trachomatis (chlamydia), T. pallidum (syphilis), H. ducreyi (chancroid) and GUD. Other STI/reproductive tract infections reported in a few studies – Trichomonas vaginalis and bacterial vaginosis – were excluded from analysis, as they are not sensitive to the antibiotic regimens used in most studies. As HIV does not respond to antibiotic treatment, any reported results were treated as secondary outcomes. Other secondary outcomes included reported condom use and evidence of antimicrobial resistance.

A series of meta-analyses, stratified by study design, summarize outcome effects of PPT on each STI. We examined heterogeneity using the I2-statistic which describes the percentage of total variation across studies that is due to heterogeneity other than chance [13]. An I2-value of 50–75% was interpreted as indicating moderate heterogeneity and a value of more than 75% as showing pronounced study heterogeneity. The inverse variance method of Review Manager 5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) was used to combine different effect measures and construct forest plots [14]. Evidence was graded using GRADEpro software (Computer program version 3.2 for Windows), as described by the Cochrane Collaboration [15].

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The initial search identified 2315 articles and two reports with detailed data on several PPT interventions. Figure 1 illustrates the results of screening at each stage of the review.

Fig. 1

Fig. 1

Eighteen studies, spanning 10 countries, met inclusion criteria for the qualitative analysis. Five RCTs were identified, two from peer-reviewed publications [16,17] and three from two reports and a modelling article [10,18,19]. Observational studies included four peer-reviewed cross-sectional studies assessing PPT exposure and STI outcomes, adjusted for confounding [7,20–22], and eight peer-reviewed cohort or time series studies of sex workers receiving PPT [23–30]. Four studies were excluded from meta-analysis: one published RCT lacking a non-PPT comparison group [17], one unpublished RCT with incomplete outcome data [10], one time series with a small convenience sample [26] and one cross-sectional study without disaggregated N. gonorrhoeae and C. trachomatis outcomes [22]. One RCT without a non-PPT comparison group was included as a cohort study [19]. One modelling study provided data for an unpublished RCT [31].

Study characteristics and main outcomes of studies included in the meta-analysis are summarized in Supplementary Tables S1 and S2 ( Most studies provided azithromycin 1G or azithromycin 1G with cefixime 400 mg or azithromycin 1G with ciprofloxacin 500 mg, all single-dose treatments that can be administered under direct observation. Two included studies used combined regimens with ampicillin or amoxicillin in combination with probenicid and/or clavulanic acid.

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Changes in sexually transmitted infection prevalence and/or incidence

All studies reported some change in STI prevalence and/or incidence over the course of the study (Supplementary Table S2, In all but one, overall declines were reported in the primary curable STIs that were measured, most commonly N. gonorrhoeae and C. trachomatis. The few studies that included results for GUD also reported declines [18,24]. Results for Trep. pallidum and Trich. vaginalis were variable and their interpretation complicated by additional treatment (for syphilis or trichomoniasis based on symptoms or screening). One study from Indonesia reported overall rising syphilis trends among sex workers of whom a small proportion had received PPT [21].

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Efficacy of periodic presumptive treatment in experimental studies

One randomized trial from Kenya reported significantly lower rate ratios for N. gonorrhoeae [rate ratio (RR) 0.46, 95% confidence interval (CI) 0.31–0.68] and C. trachomatis (RR 0.38, 95% CI 0.26–0.57) in the PPT group compared with control (Figs 2 and 3) [7,16,19,20,23–25,27–30]. No significant differences were seen for Trep. pallidum (Fig. 4) [7,16,20,21,24], or for GUD or HIV. The quality of this study was rated as high with no serious inconsistency, indirectness, imprecision or other limitation for the main STI outcomes (N. gonorrhoeae and C. trachomatis). Quality of evidence was rated down for Trep. pallidum, GUD and HIV due to imprecision (wide CIs), and additionally for HIV due to indirectness.

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

Preliminary results from a second, unpublished RCT were available from authors [10,18]. Pooled effects from both RCTs were calculated for N. gonorrhoeae (RR 0.50, 95% CI 0.24–1.03) and for C. trachomatis (RR 0.38, 95% CI 0.19–0.77) with low heterogeneity across studies.

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Effectiveness of periodic presumptive treatment in observational studies

Three observational studies provide adjusted effect measures for PPT in sex worker populations that were exposed to interventions with a PPT component [7,20,21]. Quality of this evidence is rated as moderate (observational design without inconsistency, imprecision, indirectness or other limitations). Figures 2–4 depict pooled adjusted odds ratios (OR) for N. gonorrhoeae (OR 0.54, 95% CI 0.27–1.06), C. trachomatis (OR 0.53, 95% CI 0.32–0.88) and Trep. pallidum (OR 0.86, 95% CI 0.58–1.26).

A fourth study reported that sex workers who received PPT three or more times in the past 6 months had lower combined prevalence of N. gonorrhoeae and/or C. trachomatis (OR 0.54, 95% CI 0.42–0.7, P < 0.001). These results were not disaggregated by pathogen and are, thus, not reflected in the forest plots for N. gonorrhoeae or C. trachomatis[22].

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Effectiveness of combined interventions including periodic presumptive treatment

Other studies (cross-sectional time series and cohorts) report on combined interventions that included a PPT component [23–30]. Common to these studies conducted under nonexperimental, real-world conditions is relatively high initial STI prevalence. The cohort studies also report high population turnover and loss to follow-up, introducing potential bias in long-term outcomes. Reports of short-term (1–3 months) and longer term (up to 9 months) outcomes with reasonable follow-up rates, however, show large declines (Figs 2 and 3). Quality of this evidence was upgraded from low (observational design) to moderate based on large effect size.

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Evidence of broader public health impact

Finally, several studies report STI results from men, who are likely or actual clients of sex workers, providing evidence of public health impact beyond the group of sex workers exposed to the intervention (Figs 2–4) [24,27]. In South Africa, a significant decline in curable STIs was measured over 9 months, larger for ulcerative STIs than for N. gonorrhoeae and C. trachomatis[24]. Both cross-sectional surveys and ongoing STI surveillance among migrant mine workers showed an effect gradient with lower STI rates measured closer to the intervention site. In the Philippines, cross-sectional prevalence of gonorrhoea and chlamydia among clients of brothel-based sex workers were less than half as high as they were before the intervention [27].

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Stratified meta-analysis by initial prevalence (Neisseria gonorrhoeae and Chlamydia trachomatis)

Given the wide range of baseline STI prevalence in the different studies, N. gonorrhoeae and C. trachomatis results from the meta-analyses are stratified by initial prevalence in Fig. 5[7,16,19,20,23–25,27–30].

Fig. 5

Fig. 5

In two thirds of studies, including all RCT data points, in which initial prevalence of gonorrhoea or chlamydia was between 5 and 20%, reported OR/RR clustered around 0.5 (range 0.32–0.78). Where N. gonorrhoeae or C. trachomatis was greater than 20%, larger effects of PPT were measured.

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A considerable body of evidence permits assessment of PPT, as an intervention component for STI control. Results from 15 studies using a range of study designs show consistent reductions on the order of 50% where gonorrhoea and chlamydia are prevalent. More limited data suggest an even larger effect on ulcerative STIs in chancroid-endemic settings, as well as potential impact on STI transmission beyond sex workers themselves. Results for syphilis are mixed, however, with no effect measured in one RCT. We were unable to identify sufficient evidence to assess effects of PPT on HIV infection, quality of life or adverse effects, including antibiotic resistance.

Some limitations were identified in nearly all studies. The few RCTs were conducted under conditions of relatively good STI control, limiting the amount of change that could be demonstrated as well as the types of STIs that could be studied. Studies with less rigorous designs were more often carried out in areas with poorer STI control, yet potential confounding limits differentiation of PPT effects from those of other intervention components, particularly condom use. Despite these limitations, this review found a high degree of consistency in the direction of effect for gonorrhoea and chlamydia across geographic regions and study designs.

The evidence shows that PPT works, first and foremost, to reduce existing high burden of two STIs that cause significant morbidity among many sex workers. Efficacy in reducing prevalence of gonorrhoea and chlamydia – common infections with severe reproductive tract sequelae – was demonstrated in controlled trials, with effectiveness under field conditions supported across study designs. Without intervention, such infections would go largely untreated, leading to many preventable cases of pelvic inflammatory disease, infertility and ectopic pregnancy.

Apart from averting morbidity among sex workers themselves, PPT addresses several important obstacles to STI control in low-income and middle-income countries. First, it offers an effective approach to the problem of asymptomatic STIs in women, at least those at very high risk. In the absence of sensitive and affordable screening tests, PPT, thus, complements standard symptom-dependent case management approaches. Second, PPT addresses the core epidemiology underlying STI transmission and control. Reducing STIs among sex workers has long been known to interrupt transmission to and beyond clients, contributing to broader STI control [32,33]. Data supporting such public health impact were reported in two studies in this review [24,27].

Although fewer studies have reported on PPT for ulcerative STIs (which were not prevalent in many sites), the magnitude of effect may be even greater than for N. gonorrhoeae and C. trachomatis. Rapid control of chancroid in one study suggests that elimination of select STIs may be a feasible objective, as has been achieved in Thailand and elsewhere following effective interventions with sex workers [34]. Given the importance of ulcerative STIs – and chancroid specifically – as HIV cofactors, and their close association with sex work and male noncircumcision, the contribution of PPT to GUD control could also contribute significantly to HIV prevention [31].

Given the lack of clear evidence for an effect on syphilis – despite reported effectiveness of azithromycin in at least incubating and early stages – other control strategies are advisable. Syphilis serology is a feasible and affordable screening test and many programmes that provide PPT also offer periodic (usually 6-monthly) screening with rapid plasma reagin or other nontreponemal test. Syphilis screening also provides a useful surveillance indicator to monitor STI transmission trends among sex workers [5].

Furthermore, given the strong association between curable STIs, particularly genital ulcers and HIV acquisition and transmission, improved STI control due to PPT may also slow HIV transmission. Although hard evidence is lacking – the one published study that tried to measure it had insufficient power to do so – such an indirect effect of PPT on HIV is supported by empirical evidence and modelling [9,31]. In a recent study in Indonesia, higher HIV incidence was measured among sex workers who had not received PPT during the previous 6 months, as well as among those who had active syphilis or genital ulcers in the past year [35]. To the extent that specific ulcerative and other STIs are cofactors that facilitate HIV acquisition and transmission, removing those cofactors – through a combination of condoms, PPT and other STI interventions – would reduce HIV transmission efficiency. Modelling supports such a potential impact on HIV transmission, depending largely but not solely on prevalence of ulcerative chancroid [31].

Although this review did not identify any harm related to PPT, several cautions are warranted. Nearly all programmes made efforts to reinforce condom use as PPT was introduced and only one study reported a decrease in reported condom use (vaginal prostate-specific antigen also decreased, however) [19]. Nevertheless, programme implementers should recognize the potential for risk compensation, promote the primary importance of consistent condom use and monitor behavioural trends.

No study reported increases in antibiotic resistance associated with use of PPT, although few attempted to monitor it and existing surveillance is inadequate. The risk of developing resistance may be low, however, given current PPT regimens – azithromycin and cefixime are both highly active against N. gonorrhoeae and, as single dose treatments, can be given under observation, eliminating the risk of ineffective treatment. Nonetheless, antimicrobial sensitivity should be regularly monitored by STI programmes, regardless of specific interventions, to ensure continuing high levels of cure.

These findings have implications for programming of targeted interventions with sex workers and for related operations research. Feasibility of implementing at scale is one important consideration. Although most early reports of PPT come from interventions that were implemented in one or several communities, reports describing experience with PPT as part of large-scale implementation efforts have appeared since 2008 [7,20–22,29]. The Avahan India AIDS Initiative rapidly scaled-up targeted interventions including PPT, reaching more than 300 000 sex workers in six states over 5 years [7,20,36]. In Indonesia, PPT was rolled out in government clinics with non-governmental origanization-supported peer outreach in 10 districts with large sex work networks [21,22,29].

Other operational considerations relate to decisions about where and how to introduce PPT. Where STI prevalence among sex workers is high and alternative methods for detecting and treating asymptomatic STIs are not feasible or affordable, adding PPT can strengthen efforts to reduce morbidity and control transmission. However, less benefit has been reported in a few sites where effective STI interventions were in place and prevalence was already low [10]. This argues for implementing PPT as a short-term control measure, to be phased out once conditions have improved and prevalence has declined, assuming other measures are in place to maintain control. The heterogeneous and dynamic conditions of sex work itself that determine exposure and rates of reinfection – including numbers of clients, condom use and STI prevalence – are, thus, factors that would influence the optimal frequency and duration of PPT for STI control. These and other operational issues have been investigated through operations research and mathematical modelling and are the subject of a separate review [18,31,37].

In conclusion, PPT can rapidly reduce prevalence of gonorrhoea, chlamydia and ulcerative STIs among sex workers. When implemented together with peer interventions, condom promotion and other clinical services, additional potential benefits include reinforced condom use, reduced HIV cofactors and impact on transmission at population level. Greater short-term impact can be expected where rates of condom use are low and prevalence of curable STIs is high. As these conditions improve, reduced STI prevalence may be sustainable with less intensive interventions.

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All authors participated in the WHO GRADE process for guidelines development which was led by A.G., Y.-R.L. and F.N. M.C. drafted the study protocol in consultation with E.A.A., a GRADE methodologist who monitored all steps of the work for GRADE compliance. A.W. and G.N. contributed to the literature search and identification of studies. R.S. and M.C. conducted the literature review, data analysis and interpretation. R.S. wrote the first draft. S.J.V. provided scientific oversight for all steps from data analysis and interpretation to manuscript review. All authors provided critical review of the manuscript at several stages.

Funding was provided by WHO, Department of HIV/AIDS and the German BACK UP Initiative, Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) with funds from the German Federal Ministry for Economic Cooperation and Development (BMZ). WHO and Department of HIV/AIDS commissioned this systematic review to inform guidelines development work following GRADE methodology, but was not directly involved in the manuscript preparation or decision to submit for publication.

No funding support was received from a pharmaceutical company or other agency.

The corresponding author (R.S.) had full access to all data in the study and final responsibility for deciding to submit for publication.

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Conflicts of interest

There are no conflicts of interest.

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female sex workers; periodic presumptive treatment; sex work; sexually transmitted infections

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