IT HAS LONG BEEN acknowledged that a high proportion of gonococcal and chlamydial infections in women are asymptomatic. However, little is known about the correlates of asymptomatic gonorrhea infection, particularly in men. Asymptomatic carriers of Neisseria gonorrhoeae, particularly if infected with other sexually transmitted infections (STIs), may contribute disproportionately to STI transmission and maintenance of the core group. Asymptomatic infections are one of the key driving factors of STI transmission, along with sexual behaviors, health-seeking behaviors, and inadequate partner notification measures and lower accessibility of health care services.1,2 Because of lack of symptoms, these patients are less likely to seek medical care and may develop complications of untreated infections. Previous reports have found associations between asymptomatic gonococcal infections and certain gonococcal strains such as auxotypes AHU (requires arginine, hypoxanthine, and uracil for growth) and PCU(H) (requires proline, citrulline, uracil, and hypoxanthine for growth), as well as certain host immunologic characteristics.3–6
In 2003, 23,432 cases of uncomplicated gonorrhea were diagnosed in genitourinary medicine (GUM) clinics in England, an increase of 51% compared to 1999.7,8 Data from GUM clinics suggest that the highest rates of infection in 2003 occurred in women aged 16 to 19 (233/100,000) and men aged 20 to 24 (306/100,000). Uncomplicated genital chlamydial infection was the most commonly diagnosed bacterial STI in GUM clinics in England in 2003, with the highest rates in 16- to 19-year-old women (1410/100,000) and 20- to 24-year-old men (999/100,000). The number of uncomplicated chlamydial infection rose since 1999 by 74% in men and 62% in women. Increased public awareness of chlamydial infection, better diagnostic tests, and targeted screening programs might have contributed to the increase in the number of recorded infections.9–11
In this paper, we describe demographic, behavioral and clinical correlates of asymptomatic gonococcal infection using data collected in Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP), which monitors antimicrobial resistance to N gonorrhoeae in England and Wales.
Materials and Methods
Established in 2000, GRASP is a sentinel surveillance program covering 2 regions: London, with 7 laboratories and 9 GUM clinics; and outside London, with 17 GUM clinics and laboratories selected to provide regional representation. Information collected in the GRASP data collection form include the following demographic and behavioral characteristics: gender, age, sexual orientation, number of partners and sex abroad within the past 3 months (country of sexual contact, if available), ethnicity, site of infection, presence of symptoms, previous diagnosis with gonorrhea, concurrent STIs diagnosed this episode, antibiotic treatment given for current episode of gonorrhea, and test of cure. All gonococcal isolates (1 from each patient episode) identified in participating laboratories during June, July, and August are sent to the GRASP reference laboratories. When more than 1 isolate is collected from a patient, a hierarchy of desired isolates for collection is as follows: male rectal, male urethral, female cervical, and any other site. Primary isolates of N gonorrhoeae are subcultured at each local laboratory to obtain pure growth. On arrival at the central testing laboratory, isolates are retrieved on nonselective or selective medium, as necessary, with a minimum of subcultures. Identification of N gonorrhoeae is checked using the oxidase test, Gram-stained film, and finally confirmed using coagglutination reagents (Phadebact or specific monoclonal antibodies).12,13 Isolates of N gonorrhoeae are classified by auxotyping according to their nutritional requirements, and the method involves the inoculation of a suspension of the isolate into media that lack certain amino acids.14,15 Auxotyping was not undertaken outside London in 2002 and 2003. Gonorrhea was recorded as asymptomatic at the participating clinics if there was no discharge and no dysuria and symptomatic if discharge or dysuria was present. The GUM clinics that participate in the GRASP data collection follow the Clinical Effectiveness Guidelines of the British Association for Sexual Health and HIV (BASHH) that recommend that patients attending GUM clinics be screened for other STIs.16,17 Men are routinely screened from the urethra, and rectal or oropharyngeal tests are taken when symptomatic at these sites or where that is indicated by sexual activity. Specimens in women are taken from endocervix or from urethra, and rectal and oropharyngeal samples are taken in the same circumstances as in men. The recommended tests to diagnose chlamydial infection are those that have sensitivity >90% and specificity >99%, primarily nucleic acid amplification tests (NAAT), though most of the clinics use enzyme immunoassays (EIA) and direct fluorescent antibody (DFA) tests.
Data on reasons for attendance are not collected. GRASP data collection form categorizes sexual orientation into “heterosexual,” “homosexual,” “bisexual,” and “unknown.” In this study, men who reported homosexual and bisexual orientation are grouped together as men who have sex with men (MSM). We took as the units of analysis women, heterosexual men, and MSM, rather than the site of infection (genital, rectal, throat) as over 95% of heterosexual men and women had genital site of gonococcal infection (shown in Table 1). The sites of other coinfections are not known. Genital site (the urethra) was the site of gonococcal infection in the majority of symptomatic MSM, and the rectum was a predominant site among asymptomatic MSM, so the site of infection could influence the symptom presence more among this group of patients, as STIs are more likely to be asymptomatic in rectal infections compared to urethral. Urethral swabs are also included in the analyses of specimens taken from women.
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TABLE 1: Proportion of Site of Infections in Symptomatic and Asymptomatic Patients by Gender and Sexual Orientation, Gonococcal Resistance to Antimicrobials Surveillance Programme 2001–2003
Univariate analyses were done using χ2 tests and logistic regression. Multivariate logistic regression was undertaken to compare the likelihood of asymptomatic gonorrhea across demographic, behavioral and clinical categories, including coinfections with syphilis, chlamydia, first attack of genital herpes, first attack of genital warts, and “all other STIs” in women and heterosexual and homosexual men. “All other STIs” included bacterial vaginosis, trichomoniasis, chancroid, genital candidiasis, molluscum contagiosum, lymphogranuloma venereum, scabies, and pediculosis, but the contribution of specific infections is not known. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CI). Data were analyzed using STATA 8.0. Data on symptom presence were missing for 466 (7.4%) patients, and these were excluded from the analysis, as well as 139 patients who reattended (2.2%). Missing data for other variables examined were also excluded from the analysis.
Results
A total of 5799 GRASP isolates and patients were available from 2001 to 2003; 1649 (28.4%) were women, 2668 (46.0%) heterosexual men, and 1482 (25.6%) MSM. Asymptomatic gonococcal infection was diagnosed in 661 (40.1%) women, 228 (8.6%) heterosexual men, and 388 (26.2%) MSM (P <0.01). Table 1 shows the distribution of sites of infection in symptomatic and asymptomatic patients. Genital infection accounted for over 95% of all symptomatic and asymptomatic gonococcal infections in heterosexual men and women. In MSM, the commonest site of symptomatic infection was the urethra (diagnosed in 86.5% of cases), and common sites for asymptomatic infection were the rectum (68.7%) and throat (29.3%). Among those with only genital site of infection, symptoms were not present in 8.3% of heterosexual men, 5.4% of MSM, and 39.2% of women. Only throat infections were asymptomatic in over 70% of patients. Rectal infection was asymptomatic in 63.6% of MSM. Gonorrhea was diagnosed at more than 1 site in 0.9% of heterosexual men and 13.2% of MSM, and 7.2% of women with asymptomatic infection, and in 1.4%, 13.7%, and 5.2% of those with symptomatic infection, respectively.
Thirty-nine percent of asymptomatic women were 13 to 19 years old, whereas the highest number of asymptomatic heterosexual men was found in the age group 20 to 24 (34.8%) and MSM among those 25 to 34 years old (45.4%). No significant differences were observed in distribution of age groups in patients with and without symptoms. There were statistically significant differences (P <0.01) in distribution of ethnic groups between women with and without symptoms. A higher proportion of white women were asymptomatic (50.3% asymptomatic, 41.0% symptomatic), whereas a higher proportion of black Caribbean women were symptomatic (29.2% and 35.9%, respectively). Similarly, white individuals were more represented among asymptomatic (40.3%) than symptomatic (33.8%) heterosexual men and black Caribbean individuals less so (39.4% and 43.6%, respectively), but the differences were not statistically significant. Very similar distribution of ethnic groups was observed in MSM with and without symptoms, with white individuals being the most commonly observed group (89.1% in both). Having more than 1 partner in the past 3 months before diagnosis was reported by 29.6% of women, 64.2% of heterosexual men, and 73.4% of MSM without symptoms, and there were no significant differences in number of partners reported between asymptomatic and symptomatic patients.
In the subgroup of patients who had asymptomatic gonorrhea and were coinfected with another STI, 87 (29.3%) women, 81 (71.7%) heterosexual men, and 53 (65.4%) MSM had more than 2 partners in the past 3 months, suggesting substantial risk of further transmission of STI pathogens, particularly in men.
Five percent of women, 9% of heterosexual men, and 10% of MSM without symptoms had a partner from abroad in the past 3 months, without significant differences in terms of presence of symptoms. Significantly smaller proportions of those with previous gonorrhea were observed among asymptomatic compared to symptomatic women (17.4% and 24.4%, respectively; P <0.01) and MSM (30.8% and 40.4%, respectively; P <0.01), but not heterosexual men (28.4% and 30.0%, P = 0.61).
Table 2 illustrates the distribution of coinfections in asymptomatic and symptomatic patients. Among women, 52% of those who presented with symptoms had a coinfection with another STI, significantly more than those without symptoms (45.7%, P <0.01). In contrast, a significantly higher proportion of heterosexual men with an asymptomatic infection was diagnosed with another STI (50.9%) compared to those (27.2%) with symptoms (P <0.01). Although MSM with asymptomatic gonorrhea were more likely to be diagnosed with another STI (21.5%) compared to those with symptoms (18.0%), this difference was not statistically significant (P = 0.13). Genital Chlamydia trachomatis was the most common coinfection, diagnosed in 37.0% of both asymptomatic and symptomatic women, 4.4% of MSM without symptoms, and 7.6% of MSM with symptoms. However, much higher proportion of asymptomatic (42.0%) compared to symptomatic (22.5%) heterosexual men had chlamydial coinfection (P < 0.01). Coinfection with syphilis was more common in MSM than in other groups.
TABLE 2: Prevalence of Coinfections With Other Sexually Transmitted Infections in Symptomatic and Asymptomatic Patients by Gender and Sexual Orientation, Gonococcal Resistance to Antimicrobials Surveillance Programme 2001–2003
Table 3 shows the prevalence of asymptomatic gonorrhea by demographic, behavioral, and clinical characteristics and results of univariate and multivariate logistic regression analysis.
TABLE 3: Prevalence of Asymptomatic Gonococcal Infection Across Demographic, Behavioral and Clinical Characteristics, and Results of Logistic Regression Analysis; Dependent Variable: Diagnosed With Asymptomatic Gonorrhea, Gonococcal Resistance to Antimicrobials Surveillance Programme 2001–2003
TABLE 3: (Continued)
The characteristics significantly associated with asymptomatic gonorrhea in univariate analysis in women were ethnicity, having gonorrhea previously, and being coinfected with any other STIs except chlamydia, syphilis, warts, and herpes. In multivariate analysis, decreased likelihood of asymptomatic gonorrhea was found in women who had gonorrhea previously and were coinfected with any other STIs except chlamydia, syphilis, warts, and herpes. Lower odds of asymptomatic infection were also found in black Caribbean women compared to white.
In heterosexual men, the univariate analysis showed that the likelihood of being diagnosed with asymptomatic gonorrhea was significantly increased in heterosexual men coinfected with C trachomatis and warts. After adjusting for other variables, having coinfection with C trachomatis remained the only characteristic significantly associated with increased likelihood of asymptomatic gonorrhea. As with women, black Caribbean heterosexual men had slightly lower odds of asymptomatic infection compared to white men.
Results of univariate analysis showed that, among MSM, the increased likelihood of being diagnosed with asymptomatic gonorrhea was found in those who did not have gonorrhea previously, were not coinfected with C trachomatis, had coinfections with warts, and other STIs. In multivariate analysis, not having gonorrhea previously and having coinfection with syphilis and warts were found to increase likelihood of asymptomatic gonorrhea.
Analysis of the distribution of most prevalent auxotypes by symptom presence was done for the London sample only (n = 2025). Data from 36 individuals with less frequent auxotypes were excluded from the analysis. The auxotypes were grouped into 7 most common categories (Table 4). Statistically significant differences in distribution of auxotypes between asymptomatic and symptomatic patients were observed only in heterosexual men (P <0.01). Among asymptomatic heterosexual men, (P)AOU auxotype (requires proline, arginine, ornithine, and uracil for growth) accounted for the highest proportion of infections (36.8%) and was less common in symptomatic heterosexual men (13.0%). Nonrequiring (NR) was the commonest auxotype found in MSM. Further analysis showed that 53.3% of heterosexual men from the London clinics who were asymptomatic and diagnosed with chlamydia had (P)AOU gonococcal auxotype in comparison to 24.0% (P = 0.03) of those with symptoms and chlamydial coinfection. This could imply that there is an interaction going on between C trachomatis and that particular gonococcal auxotype, which could potentially influence symptom presentation. Similarly, a higher proportion of asymptomatic women with chlamydial coinfection had this auxotype (31.9%) compared to 24.1% with symptoms, but the differences were not significant (P = 0.50).
TABLE 4: Distribution of Main Gonococcal Auxotypes in Symptomatic and Asymptomatic Patients by Gender and Sexual Orientation, Gonococcal Resistance to Antimicrobials Surveillance Programme 2001–2003
Discussion
This study provided estimates of prevalence and patterns of distribution of asymptomatic gonorrhea in a sample of GUM clinic patients in England. We also examined relationship with other factors, in particular concurrent infection status, with expression of disease caused by N gonorrhoeae. The prevalence of asymptomatic infection in a clinic-based population depends on the patient selection and the effectiveness of contact tracing and partner notification practices, the stage of infection at which patients attend a clinic, the validity of diagnostic tests used, and the extent of testing from all the sites that have been exposed during sexual intercourse.18 It has previously been demonstrated that a high proportion of women infected with gonorrhea have chlamydial infection, and MSM are less likely to be coinfected compared to heterosexual men.19,20
This research has shown the role that auxotype (P)AOU might have in asymptomatic gonorrhea in heterosexual men and particularly in those coinfected with C trachomatis. Other studies found the association of the auxotype AHU and PCU(H) with asymptomatic infections in men.4,6 The predilection of AHU auxotype for heterosexual men was attributed to their sensitivity to fecal lipids, which limits their transmission between MSM.21 The association of the CU (requires citrulline and uracil for growth) auxotype with less symptomatic urethritis in heterosexual men and concurrent chlamydial infection was found by Whittington and Holmes,22 and it was hypothesized that the CU auxotype and C trachomatis may share the same ecological niche. Monitoring prevalence of gonococcal auxotypes that are associated with asymptomatic infection is important as such strains are less likely to be eliminated from the population and might present a reservoir of infection.
Substantial heterogeneity was found in the correlates of asymptomatic gonococcal infection from GRASP. Our findings confirm the overlapping gonococcal and chlamydial transmission networks among patients attending GUM clinics and highlight the importance that infection with C trachomatis might have in asymptomatic gonococcal infection in heterosexual men. We have demonstrated that certain characteristics related to simultaneous infections with other sexually transmitted pathogens are independently associated with asymptomatic gonorrhea, in particular in men of both sexual orientations. However, the observed differences could be partly due to different testing approaches and difficulties in testing on STIs from rectal samples, which could have biased the findings in homosexual men.
The site of infection has importance in symptom presentation. The finding that 8.6% of heterosexual men were diagnosed with asymptomatic infection is broadly in line with the results from the study conducted by Sherrard and Barlow,23 which found that that in 10.2% of episodes of urethral infection, male patients had no symptoms referable to gonorrhea. They also noticed that patients with chlamydial coinfection were more likely to be asymptomatic. It has been found that half of men with rectal gonorrhea might be asymptomatic.24 Urethral chlamydial infection can be symptomless in more than half of cases, rectal infection in about 40%, and endocervical in more than two-thirds of women.25 However, these estimates differ across the studies, with some reporting that 85% of rectal chlamydial and gonococcal infections among MSM in clinical settings might be asymptomatic, as well as 10% of urethral gonococcal infections.26 Lister et al.27 reported that 23.2% of homosexual men diagnosed with gonorrhea or chlamydia reported site-specific symptoms. This points out to the need to apply the appropriate screening tests to diagnose infections that are more likely to be symptomless, particularly NAAT that have been shown to have high validity when testing at nongenital sites.28,29
The findings from our study would need to be explored in other types of community-based research studies. Although GRASP is the enhanced clinic-based surveillance that links laboratory and clinical data, it suffers from biases inherent to surveillance. Potential differences in testing approaches across GUM clinics and missing data on the extent of testing rectal samples on specific STIs in MSM are some of the main limitations for the broader generalizability of the findings. However, the BASHH guidelines recommend STI screening tests for all patients seen in GUM clinics. The review of policies on management of early syphilis in GUM clinics in the UK found that 92% of clinics surveyed have clinic policy on performing syphilis serology on all new patients.30 The clinical audit of the management of C trachomatis in the UK GUM clinics found that 96% of patients with chlamydia were screened for the presence of other STIs.31 This audit found that the most commonly used detection methods to test for chlamydia were EIA and NAAT.
Importantly, a high proportion of men with asymptomatic infection, as well as those with multiple STIs, was found to be sexually active with more than 1 partner in the 3 months preceding the asymptomatic gonorrhea diagnosis, which creates chances for the further propagation of STIs, though asymptomatic infections can be less infectious.32 STI control strategies focused on the decrease in the level of asymptomatic infection would enable the interruption of transmission and reduction in the exposure to the STI pathogen in the population. This finding has thus implications for planning STI prevention services, particularly in subgroups with high prevalence of coinfections and in settings where testing for both infections is not done routinely. The findings also highlight the importance of strengthening contact tracing and raising awareness of STI screening in the GUM setting among men at high risk, particularly at younger ages as this group bears the highest burden of chlamydial infection and is less likely to attend as contacts.33
Acknowledgment
We would like to thank Dr. Philippe Mayaud and Dr. George Rutherford for the comments on the earlier drafts of the paper.
References
1. Fenton KA, Hughes G. Sexual behaviour in Britain: why sexually transmitted infections are common. Clin Med 2003; 3:199–202.
2. Hook EW 3rd, Richey CM, Leone P, et al. Delayed presentation to clinics for sexually transmitted diseases by symptomatic patients: a potential contributor to continuing STD morbidity. Sex Transm Dis 1997; 24:443–448.
3. Grosskurth H, Mayaud P, Mosha F, et al. Asymptomatic gonorrhoea and chlamydial infection in rural Tanzanian men. BMJ 1996; 312:277–280.
4. Crawford G, Knapp JS, Hale J, et al. Asymptomatic gonorrhoea in men: caused by gonococci with unique nutritional requirements. Science 1977; 196:1352–1353.
5. Ross JD, Moyes A, McMillan A, et al. Temporal changes in the sensitivity to
Neisseria gonorrhoeae to penicillin in Edinburgh, Scotland. Int J STD AIDS 1995; 6:110–113.
6. Brunham RC, Plummer F, Slaney L, et al. Correlation of auxotype and protein I type with expression of disease due to
Neisseria gonorrhoeae. J Infect Dis 1985; 152:339–343.
7. The UK Collaborative Group for HIV and STI Surveillance. Focus on prevention. HIV and other sexually transmitted infections in the United Kingdom in 2003. London: Health Protection Agency Centre for Infections, 2004.
8. Health Protection Agency Centre for Infections. Diagnoses and rates of selected STIs seen at GUM clinics: 1999–2003: national and regional level summary tables. London: Health Protection Agency Centre for Infections, 2004.
9. LaMontagne DS, Fenton KA, Randall S, et al. Establishing the National Chlamydia Screening Programme in England: results from the first full year of screening. Sex Transm Infect 2004; 80:335–341.
10. Fenton KA, LaMontagne DS, Randall S. National screening programme for chlamydia exists in England. BMJ 2004; 329:172.
11. Low N, McCarthy A, Macleod J, et al. The chlamydia screening studies: rationale and design. Sex Transm Infect 2004; 80:342–348.
12. Paine TC, Fenton KA, Herring A, et al. GRASP: a new national sentinel surveillance initiative for monitoring gonococcal antimicrobial resistance in England and Wales. Sex Transm Infect 2001; 77:398–401.
13. Fenton KA, Hughes G, Herring A, et al. The Gonococcal Resistance to Antimicrobials Surveillance Programme: Protocol 2004 Collection. London: Health Protection Agency Centre for Infections, 2004.
14. Copley CG, Egglestone SI. Auxotyping of
Neisseria gonorrhoeae isolated in the United Kingdom. J Med Microbiol 1983; 16:295–302.
15. Catlin BW. Nutritional profiles of
Neisseria gonorrhoeae,
Neisseria meningitidis, and
Neisseria lactamica in chemically defined media and the use of growth requirements for gonococcal typing. J Infect Dis 1973; 128:178–194.
16. British Association for Sexual Health and HIV. National guideline on the diagnosis and treatment of gonorrhoea in adults: clinical effectiveness group: British Association for Sexual Health and HIV. Available at:
http://www.bashh.org/guidelines/2005/gc_final_0805.pdf. Accessed September 25, 2005.
17. British Association for Sexual Health and HIV. Guideline for the management of
Chlamydia trachomatis genital tract infection: clinical effectiveness group: British Association for Sexual Health and HIV. Available at:
http://www.bashh.org/guidelines/2002/c4a_0901c.pdf.htm. Accessed September 25, 2005.
18. Handsfield HH, Lipman TO, Harnisch JP, et al. Asymptomatic gonorrhoea in men: diagnosis, natural course, prevalence and significance. N Engl J Med 1974; 290:117–123.
19. Hijazi L, Thow C, Winter AJ. Factors affecting co-infection with genital chlamydia and genital gonorrhoea in an urban genitourinary medicine clinic. Sex Transm Infect 2002; 78:387.
20. Creghton S, Tenant-Flowers M, Taylor CB, et al. Co-infection with gonorrhoea and chlamydia: how much is there and what does it mean? Int J STD AIDS 2003; 14:109–113.
21. Morse SA, Lysko PG, McFarland L, et al. Gonococcal strains from homosexual men have outer membranes with reduced permeability to hydrophobic molecules. Infect Immunol 1992; 37:432–438.
22. Whittington WLH, Holmes KK. Unique gonococcal phenotype associated with asymptomatic infection in men and with erroneous diagnosis of nongonococcal urethritis. J Infect Dis 2000; 181:1044–1048.
23. Sherrard J, Barlow D. Gonorrhoea in men: clinical and diagnostic aspects. Genitourin Med 1996; 72:422–426.
24. Young H, McMillan A. Gonorrhoea. In: McMillan A, Young H, Ogilvie MM, Scott GR, eds. Clinical Practice in Sexually Transmissible Infections. London: Saunders, 2002:313–356.
25. McMillan A, Ballard RC. Non-specific genital tract infection, including lymphogranuloma venereum. In: McMillan A, Young H, Ogilvie MM, Scott GR, eds. Clinical Practice in Sexually Transmissible Infections. London: Saunders, 2002:281–312.
26. Kent CK, Chaw JK, Wong W, et al. Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis 2005; 41:67–74.
27. Lister NA, Smith A, Tabrizi S, et al. Screening for gonorrhoea and
Chlamydia trachomatis in men who have sex with men at male-only saunas. Sex Transm Dis 2003; 30:886–889.
28. Lister NA, Tabrizi SN, Fairley CK, et al. Validation of Roche COBAS Amplicor assay for detection of
Chlamydia trachomatis in rectal and pharyngeal specimens by an omp1 PCR assay. J Clin Microbiol 2004; 42:239–241.
29. Young H, Manavi K, McMillan A. Evaluation of ligase chain reaction for the non-cultural detection of rectal and pharyngeal gonorrhoea in men who have sex with men. Sex Transm Infect 2003; 79:484–486.
30. Rogstad KE, Simms I, Fenton KA, et al. Screening, diagnosis and management of early syphilis in genitourinary medicine clinics in the UK. Int J STD AIDS 2005; 16:348–352.
31. Challenor R, Pinsent S, Chandramani S, et al. The management of
Chlamydia trachomatis on genitourinary medicine clinics: a national audit in 2004. Int J STD AIDS 2005; 16:494–499.
32. Brunham RC, Plummer FA. A general model of sexually transmitted diseases and its implication for control. Med Clin North Am 1990; 74:1339–1352.
33. Jungmann E, Ison C, Martin IMC, et al. Gonorrhoea in young heterosexuals attending urban STD clinics in Britain: a cross-sectional survey. Int J STD AIDS 2004; 15:243–248.
