Lewis, David A. FRCP(UK), PhD*,†; Chirwa, Tobias F. PhD‡; Msimang, Veerle M. Y. MSc*; Radebe, Frans M. MSc*; Kamb, Mary L. MD, MPH§; Firnhaber, Cynthia S. MD, MS†,¶
Sexually transmitted infections (STI) are important cofactors in HIV transmission.1 HIV viral loads (VLs) are increased in cervicovaginal, seminal, and ulcer-derived secretions in the presence of other STIs, such as gonorrhoea or herpes.2–4 For a given plasma VL, HIV-infected individuals with STI are at greater risk of transmitting HIV than those individuals without STIs.5 The immunosuppressed status of HIV-infected individuals may also increase their vulnerability to STIs.1
Many people living with HIV/AIDS (PLWHA) remain sexually active, and some retain high-risk behavioral traits for STI acquisition.6 The observed health and life expectancy gains due to antiretroviral therapy (ART) may also influence levels of sexual activity among PLWHA.7 Although there are both personal and public health gains received from enhancing the quality of sexual and reproductive health care of PLWHA, it has been recognized that the provision of sexual health care for this group of individuals has been suboptimal.6 Importantly, from the public health standpoint, new STIs in PLWHA typically represent episodes of unprotected sexual intercourse during which HIV may also have been transmitted to the sexual partner.
Within South Africa, there are an estimated 5.3 million PLWHA aged 15 years and older, of whom 340,000 were thought to be newly infected with HIV in 2009.8 Within South Africa, patients attending public facilities are treated for STIs using the syndromic approach, either as a symptomatic individual or as a sexual contact. Screening for STIs will identify many of the asymptomatic infections, which would otherwise remain untreated. Detection of asymptomatic STIs in PLWHA through screening provides opportunities to counsel PLWHA about safe sex strategies to reduce both HIV transmission and future STI acquisition and, additionally, to test discordant partners for HIV when they attend for STI contact treatment.
At present, there are very limited data on the prevalence of asymptomatic STIs in PLWHA attending African HIV treatment centers. The aims of the current study were, first, to determine the burden of asymptomatic STIs among PLWHA attending a major HIV treatment center in Johannesburg and, second, to determine demographic, clinical, and behavioral factors associated with the presence of urethritis/cervicitis pathogens.
MATERIALS AND METHODS
Patient Recruitment and Follow-Up
A pilot STI screening service for PLWHA aged 18 years or older was initiated in January 2007 at a busy urban HIV outpatient clinic in Johannesburg, South Africa. Sexually active PLWHA were referred to study staff for STI screening. For this study, men were only screened in the absence of a history and examination findings consistent with male urethritis syndrome and/or scrotal swelling syndrome; likewise, women were only screened in the absence of symptoms and signs of vaginal discharge syndrome and/or lower abdominal pain syndrome. However, individuals were offered screening if they had symptoms and/or signs of other nondischarge-related STIs, for example, genital ulceration. Each PLWHA was offered STI screening only once in a year. Those screened were asked to return for their results after 2 weeks; any STIs detected were treated on an etiological basis. A letter outlining the STI pathogen(s) detected, with recommended treatment, was given to the index patient to assist with partner management. All work was conducted in accordance with the Declaration of Helsinki, and screening was conducted with the understanding and the written consent of each patient. The study was approved by the University of the Witwatersrand's Human Research Ethics Committee (approved protocol M061021).
Collection of Demographic and Clinical Data
Demographic, behavioral, and clinical data were collected by a nurse-administered questionnaire. Data collected included gender, age, details of sexual partnerships, knowledge of partners' HIV status, frequency of condom use, and symptoms/signs of common STI syndromes in the previous year.
Specimen Collection and Laboratory Testing
Urine (men) and endocervical swabs (women) were collected to screen for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV), and Mycoplasma genitalium (MG) pathogens using an in-house real-time multiplex polymerase chain reaction assay on a Rotor-Gene 3000 platform (Corbett Robotics Pty Ltd, Sydney, Australia), as described previously.9 Gram staining of vaginal discharge material was performed to detect the presence of Candida species, through visualization of spores and/or pseudohyphae, and bacterial vaginosis by Nugent scoring. The rapid plasma reagin (Becton Dickinson and Co., Sparks, MD) and Treponema pallidum particle agglutination (Fujirebio, Diagnostics, Inc., Tokyo, Japan) assays were used to screen sera for syphilis. Antibodies to herpes simplex virus type 2 (HSV-2) were detected by ELISA (Focus Diagnostics, Inc., Cypress, CA).
VL and CD4 Data
Where possible, within a window of ±3 months from the STI screening date, the most recent routine clinical HIV VL and CD4 data for each PLWHA were provided by HIV center staff. The level of detection of the VL assay was 50 copies/mL. These data were delinked from patient identifiers before entry into the study database.
Data Analysis and Statistical Calculations
Clinical and laboratory data for all PLWHA screened during 2007 were entered onto an Access database and analyzed using STATA version 10 (StataCorp LP, College Station, TX). A descriptive analysis, in which missing data were excluded, was conducted to obtain STI prevalence data and frequency distributions of demographic, behavioral, and clinical data by gender. The χ2 test was used to investigate statistical associations at a 5% level of significance. The analysis of CD4/VL by gender was adjusted by status of ART use. To investigate factors associated with individual urethritis/cervicitis pathogens, a univariate logistic regression model was applied. Any factors, which were univariately associated with each pathogen at the 20% significance level were considered further in urethritis/cervicitis pathogen-specific multiple logistic regression models. However, factors that were significant at univariate level but were specific to one gender were excluded from these analyses. Factors were reported as significant in the final logistic regression models at the 5% significance level.
Patient Recruitment and Demographics
A total of 1109 PLWHA (551 men and 558 women) were screened between January and December 2007. Enrolled women had a mean age of 35.0 years (95% confidence interval [CI]: 34.3–35.6; standard deviation [SD], 7.29), with an age range of 19 to 67 years. The mean age of the enrolled men was 37.9 years (95% CI: 37.2–38.5; SD, 7.88), with an age range of 20 to 67 years. Although the peak age-group was 30 to 39 years for both sexes, women had a younger age distribution compared with men (P < 0.001).
Sexual Behavior and Condom Use
Most PLWHA reported sexual intercourse with a regular sexual partner in the past 3 months (Table 1). Sexual intercourse in the past 3 months with one or more nonregular partners was reported by significantly more men than women (94/541, 17.4% vs. 14/538, 2.6%; P < 0.001) (Table 1). Although approximately two-thirds of patients reported that they always used condoms with regular partners, more men than women reported no condom use with regular partners (52/427, 12.2% vs. 25/406, 6.2%; P = 0.002). Condoms were not used by 18.6% (19/102) of PLWHA with their recent nonregular partners. There was no significant gender difference in condom use with nonregular partners (P = 0.819).
Knowledge of Regular Partner's HIV Status
Overall, 58% of patients knew the HIV status of their regular sexual partner, although women were significantly less likely to know this fact compared with men (53.1% vs. 62.3%, P = 0.007) (Table 1). Among those with regular sexual partners, condoms were always used significantly more often in serodiscordant compared with seroconcordant partnerships (105/139, 75.0% vs. 216/341, 63.3%; P = 0.023). Adjusting for gender, this association remained statistically significant for male patients (P = 0.031) but not for female patients (P = 0.341).
History of STIs
The proportion of patients with a self-reported history of STI symptoms in the preceding 12 months is shown in Table 1. Significantly more women than men reported STI symptoms/syndromes in the previous 12 months (65.5% vs. 56.5%, P = 0.002). The most common genital STI syndromes reported in this 1-year period were discharges, ulceration, and warts (Table 1).
ART Use, CD4 Count, HIV Plasma VL Distributions, and the Effect of ART
Significantly more women (387/550, 70.4%) than men (319/534, 59.7%) were on ART (P < 0.001) (Table 1). The mean CD4 count of women was significantly higher than that of men (346 cells/mm3, SD 203 vs. 232 cells/mm3, SD 173; P < 0.001) (Table 1). Significantly more men than women had CD4 counts below 200 cells/mm3 (236/468, 50.4% vs. 128/458, 27.9%; P < 0.001), irrespective of being on or off ART. Overall, and for those off ART, the VL was significantly higher among men than women (P < 0.001 and P = 0.02, respectively); there was no gender association for VL for those on ART (P = 0.184). There was no association between the detection of urethritis/cervicitis pathogens, individually or as a whole, with declining CD4 counts.
Prevalence of Urethritis and Cervicitis Pathogens, Bacterial Vaginosis, and Vaginal Candidal Infections
Urethritis pathogens were detected in 16.4% (90/550) of men, and cervicitis pathogens in 21.3% (119/558) of women (Table 2). Although most were single infections, 10 men and 14 women had multiple pathogens. For men, the most frequent pathogen detected was MG (7.1%), followed by TV (4.9%), NG (4.4%), and CT (2.0%). For women, TV (10.2%) was the most frequent pathogen detected, followed by NG (6.4%), MG (5.2%), and CT (2.2%).
Bacterial vaginosis and evidence of infection with Candida species were detected in 155 (28.0%) and 101 (18.35) women, respectively (Table 2). The detection of Candida species was twice as frequent among those women with a history of vaginal discharge in the past 3 months compared with those without (30/107, 28.0% vs. 68/439, 15.5%; P = 0.01). There was no association between a history of recent vaginal discharge and detection of bacterial vaginosis (P = 0.927).
Seroprevalence of Syphilis and HSV-2 Infection
The overall prevalence of rapid plasma reagin seroreactivity was 2.4% (26/1080) with no difference by gender (Table 2). Significantly more men than women had evidence of previous syphilis infection, as defined by detection of a positive Treponema pallidum particle agglutination assay result (133/550, 24.2% vs. 104/556, 18.7%; P = 0.026). Approximately 85% of individuals were HSV-2 seropositive (Table 2).
Associations Determined by Multiple Logistic Regression Models
The results of multiple logistic regression models for key factors relating to infection with urethritis/cervicitis pathogens are presented in Table 3. Detection of NG was significantly associated with sexual intercourse with a regular partner in the past 3 months (aOR, 2.26; 95% CI: 1.01–5.08) and a history of genital warts in the past year (odds ratio [OR], 2.25; 95% CI: 1.26–4.03). Detection of TV was associated with female gender (OR, 2.53; 95% CI: 1.47–4.37) and suboptimal use of condoms with the regular sexual partner in the past 3 months (OR, 2.07; 95% CI: 1.25–3.42). There were no significant associations in the multiple logistic regression models for either CT or MG infections.
Our study has demonstrated a substantial “silent” burden of urethritis/cervicitis pathogens among PLWHA who are asymptomatic for genital discharges and/or their complications at a large HIV treatment center in Johannesburg. Overall, we report a prevalence of 7.6% for trichomoniasis, 6.1% for MG infection, 5.4% for gonorrhoea, and 2.1% for chlamydial infection. The screened population was characterized by suboptimal condom use, low levels of knowledge regarding partners' HIV serostatus, and, particularly among males, recent sexual intercourse with more than one partner.
As recognized early in the HIV epidemic, STIs enhance HIV transmission in resource-limited settings, and there is evidence that improved STI control reduces HIV transmission.1 Syndromic STI management remains a cost-effective approach in populations experiencing generalized HIV epidemics, particularly where there are high-risk behaviors and/or low male circumcision rates.10 However, this approach aims to diagnose and treat symptomatic STIs and is not a tool for the diagnosis of asymptomatic infections. With the introduction of large-scale HIV counseling and testing programs, many sub-Saharan HIV treatment centers are now in a position to integrate a variety of HIV prevention approaches, including STI screening, into the routine management of PLWHA.11 Depending on available resources, STI screening could take the form of any combination of the following 3 activities: (i) asking key clinical and behavioral questions to ascertain STI risk factors, (ii) undertaking a genital examination, and (iii) laboratory testing for specific STI pathogens. Currently, the use of periodic STI screening with directed treatment for PLWHA requires substantial funding and laboratory infrastructure.11 Costs may be reduced in the future through the introduction of cheaper point-of-care rapid tests for STIs.12
As STI coinfections may undermine future efforts to use ART for HIV prevention by increasing genital secretion infectiousness, there are potential benefits to be gained from strengthening STI screening activities within existing HIV treatment programs.2,13 Despite the opportunities that exist, STI screening is still not being implemented in many countries with high HIV/STI prevalence as evidenced by a recent survey of 22 urban ART programs in resource-limited settings, including 16 within sub-Saharan Africa.14 Spaar et al reported that HIV prevention activities still focus on health education, the provision of male condoms, and social support; only one-third of the programs reported regular screening for STIs, and the extent of laboratory-based testing of genital specimens was unclear. The authors concluded that prompt diagnosis and treatment of STI in addition to enhanced partner notification may be equally or more important HIV prevention strategies in such settings.14
There are few previously published molecular-based screening studies reporting the prevalence of genital discharge pathogens in asymptomatic PLWHA attending HIV clinics, and none of these are from sub-Saharan Africa. A urine-based screening program for patients attending an HIV clinic in New Orleans detected NG and CT infections in 1.7% and 2.1% of PLWHA, respectively.15 Although the prevalence of both pathogens was higher among symptomatic individuals, more infections overall were diagnosed in asymptomatic subjects.15 In comparison, we observed a higher prevalence of asymptomatic gonococcal and chlamydial infections in our study (5.4% vs. 0.4% for gonorrhoea; 2.1% vs. 1.3% for chlamydial infection), which likely reflects the higher bacterial STI burden in the sub-Saharan Africa region. The relatively low prevalence of chlamydial infection in comparison with gonorrhoea observed in our study may be, in part, attributable to the widespread use of trimethoprim/sulfamethoxazole as routine prophylaxis in PLWHA with low CD4 counts. By use of an existing mathematical model, Farley et al were able to show that a screening-based approach to the detection and treatment of STIs was cost-saving in terms of preventing new HIV infections.15,16 The impact of detecting and treating STIs in PLWHA has been estimated to be approximately 27% reduction in HIV transmission in the absence of other behavioral interventions.17
Our study had a number of limitations. First, recruitment relied on clinicians referring asymptomatic PLWHA to the study nurse for enrollment; accordingly, those screened represent an undetermined but, given the large number recruited, fairly random proportion of the eligible PLWHA attending the center during 2007. Second, patient data were not collected in relation to either ethnicity or sexual orientation. However, it is known from routine clinic datasets that >95% of PLWHA attending this HIV center are African and the majority of these Africans self-report heterosexual relationships (C.F., personal communication, 2011). Third, our study was neither designed to determine the rates of patient returning for results and, if required, treatment nor the proportion of sexual partners who attended health care services for contact treatment. However, a retrospective analysis of 137 (65%) available hospital notes and treatment charts, for those 209 patients in whom urethritis/cervicitis pathogens were detected, demonstrated that 86% of men and 85% of women returned for their results and were treated appropriately.
In conclusion, our study has demonstrated that urethritis/cervicitis pathogens are highly prevalent among asymptomatic HIV-infected patients attending a large HIV treatment center in Johannesburg, South Africa. We identified only a few significant urethritis/cervicitis pathogen-associated patient characteristics, emphasizing the need for affordable STI diagnostics to screen HIV-infected patients. Given that an effective HIV vaccine remains elusive, that effective microbicides are not yet widely available, and that the roll out of male circumcision is still in its infancy as a public health tool in sub-Saharan Africa, reduction of asymptomatic STIs among HIV-infected patients by screening and subsequent treatment offers a readily available complementary strategy for the enhancement of HIV prevention efforts in countries with high HIV and STI prevalence. Further health economic analyses are warranted to determine the potential impact of STI screening, using clinical and/or laboratory-based algorithms, on both the long-term reproductive health of PLWHA and the risk of HIV transmission to sexual partners.
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