Incidence and Risk Factors for Genital Chlamydia trachomatis Infection: A 4-Year Prospective Cohort Study : Sexually Transmitted Diseases

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Incidence and Risk Factors for Genital Chlamydia trachomatis Infection: A 4-Year Prospective Cohort Study

Skjeldestad, Finn Egil MD, PHD*†; Marsico, Mark A. MPH; Sings, Heather L. PHD§; Nordbø, Svein Arne MD; Størvold, Gunnar MD

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Sexually Transmitted Diseases: May 2009 - Volume 36 - Issue 5 - p 273-279
doi: 10.1097/OLQ.0b013e3181924386
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CHLAMYDIA TRACHOMATIS (CT) IS THE MOST common bacterial sexually transmitted infection in the United States and Europe.1–3 Untreated infection can lead to pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and tubal infertility.4,5 In the Unites States, the annual medical cost of CT infection exceeds $2 billion.2,3 Large-scale CT screening programs are established in the US and the United Kingdom.6–8 In Norway, health authorities recommend that men and women younger than 25 years with a new sexual partner over the last 12 months be tested for CT.9

Recommendations for CT screening or opportunistic testing are based on cost-effectiveness analysis.9 These simulations are sensitive to the annual incidence, probability of persistent infection, probability of long-term complications and costs related to testing, and treatment of long-term complications.10,11 These models apply the best available data for any dimension and rely upon the notion that uninfected women have an age-specific probability (incidence) of developing an acute CT infection that may be symptomatic or asymptomatic. In these simulations, age-specific probability for infection is a proxy variable for partner change. Annual incidences of CT infection in the range from 3 to 5 per 100 woman-years are found cost effective for liberal testing of sexually active women.10,11

Few long-term studies reporting incidence and behavioral data for (CT) infection in the general population have been published. Such studies are important to develop screening recommendations. The aim of the current study was to investigate incidences of first and repeat infection and risk factors of genital CT infection by number of new sexual partners in a 4-year prospective cohort study of Norwegian women aged 16 to 23.

MATERIALS AND METHODS

Study Design and Population

Between September 1998 and December 2000, healthy Norwegian women aged 16 to 23 years with intact uteri were recruited to participate in a longitudinal prospective study of 4-years duration on the natural history of genital human papillomavirus infections. Women were eligible for participation if they had a self-reported lifetime history of at least 1 male sexual partner, if they agreed to refrain from using vaginal medications or sexual intercourse for 24 hours before any scheduled visit, and if they were not pregnant or if at least 3 months had passed since the last completed pregnancy. Individuals concurrently enrolled in clinical studies of investigational agents or studies involving collection of cervical specimens were not eligible for enrollment.

Twenty-nine physicians at 16 medical centers in 3 major cities in Norway enrolled a total of 898 women. Each physician recruited from 10 to 62 participants (mean = 31 participants). The study was conducted in conformance with applicable Norwegian requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research.

At baseline (day 0), a standardized interview was administered. The information collected included: 1general demographic and behavioral characteristics such as age, education, occupation, marital status, smoking, and alcohol consumption; 2medical and gynaecological history including concomitant diseases, previous STDs, menstrual history, and status, Papanicolaou smear history, and pregnancy history; and 3sexual history, including lifetime number of male sexual partners, number of new male sexual partners in the past 6 months, frequency of intercourse, and use of contraception.

The study was planned for 4 years with subsequent visits at months 6, 12, 18, 24, 30, 36, 42, and 48 months. At each visit, a structured interview and a gynaecological examination were conducted. Specimen collection for CT was done at baseline and on annual basis at month 12, 24, 36, or 48 unrelated to genitourinary symptoms. If the final study visit took place before the month 48 visit, a genital specimen collection was undertaken at that particular visit.

Specimen Collection and Laboratory Analyses

Specimen collection for CT was done with a Dacron-tipped swab. The swab was placed immediately in a tube-containing transport medium according to the instructions of the manufacturers and transported on the same day to the Department of Medical Microbiology, Trondheim University Hospital, Norway or the Department of Microbiology, Ullevål University Hospital, Oslo, Norway.

During the first study year (September 1998-April 1999), a nucleic acid hybridization test for detection of CT-specific ribosomal RNA (PACE 2; Gen-Probe, San Diego, CA) was applied. For the remaining study period (through January 2005), polymerase chain reaction (PCR; Amplicor: Roche Molecular Systems) was the routine detection method for CT at the Trondheim laboratory. The Oslo laboratory used Ligase Chain Reaction (LCx CT Assay, Abbott Laboratories) until the beginning of 2002,12 and Strand Displacement Amplification (BD ProbeTec ET CT Amplified DNA Assay, Becton Dickinson),13,14 thereafter.

If a CT test was negative, it was not retested. If a CT test was positive, it was retested. If the positive result was reproduced, the test result was reported as positive. Discrepant results upon retest initiated an additional test using the same method. Two out of 3 outcomes determined the final result (i.e., 2 out of 3 negative results yielded a negative test result and vice versa for positive outcomes). Patients with consecutive inconclusive test results were considered negative and were not invited for an extra specimen collection/visit and no treatment was initiated. Recent use of antibiotics was no exclusion criteria at study start or withdrawal criteria during study.

Statistical Analysis

All analyses were performed using SPSS for windows, version 14.0. Sociodemographic, sexual history, and lifestyle covariates were described for the population. χ2 test Fisher exact tests were used to assess the univariate associations between covariates and incident CT infection. Variables that were moderately associated with the outcome (P <0.10) were considered for inclusion into the multivariate models. The multivariate regression models were used to test for an association between covariates and CT positivity. Person-time was calculated from the date of enrolment until the date for visit of first chlamydial infection in study (incidence), or date of last visit with a negative test result (for most subjects at study end). Individual person-time was estimated in survival analyses by month as observational unit. Incidence is reported as events per 100 women-years and was calculated by dividing the number of CT events by the cumulative person-time of follow-up. For all analyses, a significance level of P <0.05 was chosen.

Eligible for analyses of incident infection were women who, at baseline, had a negative test result regardless of CT history before study start. Eligible for analyses on incidence of repeat CT infection were women who at baseline, or at subsequent visits, were diagnosed with a CT infection and had a negative test-of-cure 6 to 8 weeks after treatment. Time of repeat infection was estimated from date of first infection in study (baseline or later) until an outcome of repeat infection or date of last visit in study with a negative test result.

Role of the Funding Source

The study was designed by the principle investigator (F.E.S.) in collaboration with the Sponsor (Merck & Co., Inc.). SINTEF Health Research was responsible for recruitment of study centres, all handling of logistics related to specimen collection and shipment, field monitoring, data entry, and data review (including integrity and consistency checks). The authors were actively involved in the collection, analysis, or interpretation of the data, the revising of the manuscript for important intellectual content, and approved the final manuscript. The sponsor compensated study participants for their time and inconvenience with a per visit rate of 35 US dollars for the first 4 visits, and 50 US dollars for the remaining 5 visits (months 24–48).

RESULTS

Of the 898 women enrolled, 817 (91%) were eligible for analyses of incident CT infection. Excluded from the incidence analysis were 62 (6.9%) women who left the study before their initial 12-month visit and 19 (2.2%) women who were positive (prevalent) for genital CT infection at start of study. Of the 817 women, 597 (73%) women completed the final 42- or 48-month visit with a valid CT test. Over the course of the study, 90% of the valid tests were collected within ±6 months of the scheduled 12-, 24-, 36-, and 48-month intervals. Study participants were followed for 35,070 women-months with a median follow-up time of 48.0 months (range = 10–74 months).

Table 1 displays the number tested at each interval, the test outcome, and the number of women who withdrew from the study. At beginning and end of study all eligible participants were tested for genital CT, whereas 93.5%, 89.4%, and 87.4% of study subjects were tested at the scheduled 12-, 24-, and 36-months intervals, respectively. Among 3935 tests collected, only 12 (0.3%) tests had an inconclusive outcome. Over the study course, some participants withdrew actively (n = 111) whereas others were lost-to-follow-up (n = 119). Most women that withdrew from study terminated because they moved out of the catchment areas for the study due to educational or work-related issues.

T1-2
TABLE 1:
Specimen Collection, CT Test Outcome, and Cumulative Withdrawals for the 817 Women Who Were Eligible for Analysis of Incident CT Infection

Over the study course (through month 50), 57 women were diagnosed with an incident chlamydial infection. The 4-year cumulative incidence of CT infection was 7.7 (95% CI: 6.7–8.7) with annual incidences ranging from 1.2 to 2.9 per 100 woman-years. A total of 76 women were eligible for repeat infection analyses, including 19 prevalent CT cases detected at baseline and 57 incident CT cases detected during follow-up (1 case diagnosed at month 51). Of the 76 eligible women, 62 women who had more than 6 months of follow-up after first infection were included in the analyses on incidence of repeat infection. The cumulative rate of repeat infection through 26 months of follow-up was 11.2 (95% CI: 9.3–13.1) per 100 woman-years. There was insufficient follow-up data to assess repeat infection past 26 months of observation and there were too few incident cases (n = 10) of repeat infection to display risk factor distributions.

The mean age of the study population for incident infection at study start was 20.7 years (standard deviation = 1.7). More than 97% (795/817) of the women reported being sexually active during the previous 6 months with 42% (333/795) reporting having a new sexual partner during that time period. The average number of lifetime partners reported was 4.5 (standard deviation = 4.5). Most women (87%, 711/817) reported using some method of contraception with oral contraceptives being the most common (72%, 586/817) at study start.

Table 2 displays unadjusted univariate analysis assessing the relationship between baseline covariates and incident CT infection. The significant predictors for increased risk of incident CT Infection were younger age at sexual debut, having 10 or more lifetime sexual partners and having moderate vaginal discharge. The 3 aforementioned variables were added to the multivariate model (P <0.10).

T2-2
TABLE 2:
Covariates at Study Start Predicting Incident CT Infection: Univariate Analysis

Table 3 displays covariates at study end significantly associated (P <0.05) with incident CT infection. The strongest predictor of incident CT infection was the number of new male partners over the last 12-months prior testing. Also significantly associated with incident CT infection at study end were younger age and the number new sexual male partners since study start.

T3-2
TABLE 3:
Covariates at Study End Predicting Incident CT Infection: Univariate Analyses

In the multivariate analysis (Table 4), we found an interaction between the variables “age at study end” and the “number of new partners of the last 12 study months” on prediction of incident CT infection. Women 25 years or older, who had no new partner over the last 12-months before study closure were chosen as reference when we combined the variables age at study end and number of new partners last 12 study months. Women ≤24 years with no new partner and women ≥25 years with 1 to 2 new partners over the last 12-months before study closure showed a nonsignificant increased relative risk for incident CT-infection. Women ≤24 years with 3 to 9 partners over the last 12-months before study closure had the highest relative risk for incident CT infection (adjusted OR: 32.0; 95% CI: 11.9–86.2), whereas smaller and similar risks were found for women ≥25 years with 3 to 9 partners (adjusted OR: 11.4; 95%CI: 3.2–39.8) compared to women ≤24 years with 1 to 2 new partners over the last 12-months period of the study (adjusted OR: 12.2; 95% CI: 4.6–32.5).

T4-2
TABLE 4:
Significant Risk Factors of CT Infection (Multivariate Analyses)

Cumulative incidences of CT infection stratified by age and sexual behavior are displayed in Figure 1. At study end, women 25 years or older, for each category of number of new partners showed a smaller cumulative incidence of CT infection at the 48-month intervals than did women ≤24 years. At 48 months, the cumulative incidence for women 25 years or older, with no new partner, was 1.4 per 100 women-years, 1.3 for women with 1 to 2 new partners, and 4.7 per 100 women-years for women with 3 to 9 new partners. For women 24 years or younger, the respective cumulative incidence rates at 48 months were 4.8 per 100 women-years for women with no new partner, 21.4 per 100 women-years for women with 1 to 2 new partners, and 45, 8 per 100 women-years for women with new 3 to 9 partners. The 48-month cumulative incidence for incident CT-infection among women of any age (n = 300) who stated no new partner at each visit during follow-up was 2.7 per 100 women-years.

F1-2
Figure 1.:
Cumulative incidence (per 100 woman-years) of genital CT infection by age and number of new sexual partners during the last 12 months before a positive test (cases) or number of new partners the last 12 months prior last visit in study with a negative CT test (noncases) by age.

DISCUSSION

In the current study, we found a 4-year cumulative incidence of 7.7 and an overall 4-year incidence of 1.9 per 100 woman-years (95% CI: 0.94–2.9). The 2-year cumulative incidence of repeat CT infection was 11.2; the 2-year incidence of repeat infection was 5.6 per 100 woman-years (95% CI: 4.2–7.0). The annual incidences were remarkably stable for the entire study population by age and partner change. The annual incidences observed among women 24 years or younger, with 1 or more new partners over the last 12 months, support recommendations for liberal testing for CT in this age group in Norway.

The strengths of this study are the prospective study design, high continuation rates, personal interview on behavioral data at 6-month interval, the uniform test-window of 12 months for repeat testing (good compliance), and the fact that all positive specimen are retested within same allocate and confirmed with at least 2 positive tests (high reproducibility). Furthermore, the study is undertaken in medical settings; 3 outpatient gynecologic clinics, 2 university health clinics, and 11 general practices; where women are routinely tested for asymptomatic genital CT infections in Norway. At study start (1998), the participants displayed similar age-specific contraceptive pattern as found in a 1998 representative sample of Norwegian women15 and they revealed a distribution of number of lifetime partners at study start as reported from female respondents 18 to 25 years of age participating in the third Norwegian survey on sexual practices undertaken in 1997.16 The study is accompanied by some limitations. The lack of blinding when reading chlamydia test results could cause a more optimistic reading of low level/gray zone readings in the test-retest reliability assessment if the laboratory personnel knew that the test was positive in first run. However, we considered this issue to be of minor importance. Furthermore, we tested for CT infection at 12-month intervals, therefore the possibility exists that we missed “short lived” CT infections. A literature review of studies related to the natural course of CT infection did not find data published before 1999 reliable enough to estimate duration of untreated female genital CT infection.17 However, 2 prospective studies of sample sizes 82 and 30, published in 200318 and 2005,19 reported that among untreated asymptomatic CT positive women, repeatedly tested at 3- to 8-month intervals, 46% and 54% still had persistent CT infection after 1 year. Both studies indicated that an average female genital CT infection is of greater duration than 12 months. It is therefore less likely that we have missed many short lived CT infections in our study by testing at 12-month interval. In addition, we have not done test performance of our diagnostic methods in our laboratories. However, high sensitivity and specificity are reported from direct comparison of PACE 220,21 Amplicor,22,23 LCx,12 and Strand Displacement Amplification13,14 in comparison with other test systems. If there was a difference in sensitivity between the different tests applied throughout the 7-year study-period, we find it unlikely that this issue have had any major impact in underestimating CT infections in such a way that the overall incidence rates are inflated.

Incidence and occurrence of repeat CT infections have been reported in follow-up studies from male and female patients recruited in STD clinics,24–26 adolescent, family planning and STD clinics,27 and from a laboratory register-based study.28 A study of predominantly inner-city adolescent females attending family planning, STD, and school-based clinics in Baltimore, MD, reported an overall incidence rate of 33.6 infections per 100 woman-years.27 Another US study among STD clinic attendees reported an incidence rate of 11.4 per 100 women-years with a rate of repeat infection roughly 2.5-fold higher (28.9/100 women-years).24 As expected, these rates are significantly higher than those reported in this study, likely due to the underlying behavioral risk factors associated with young inner-city adolescences and STD clinic attendees. Cumulative population-based laboratory incidences from Norway at ages 20 and 25 for the birth-cohorts 1976 to 1979 were 6.0 and 14.7%, respectively.28 At age 25, 44% of men and 84% of women in the general Norwegian population had been tested at least once for genital CT infection.28 It has been shown that repeat infection rates for CT among patients with a baseline infection are higher than incident infection among patients without a baseline infection of CT.24,26,27 However, it should be noted that there are difficulties associated with comparing repeat infection rates and incidences across studies, primarily due to differences in selective attendance, study duration, lack of uniform testing interval(s), and demographic/behavioral characteristics of study participants.

It is difficult to explain why CT incidence differed by age and number of new sexual partners. Whereas women 25 years or older had a relative low incidence regardless of partner change, the incidence among younger women was highly associated with number of new partners. The relative small group of young women (n = 50; 14% among ≤24 years of age at study end) who have had 3 or more partners had a 37% probability of acquiring a genital CT infection within 42 study-months, whereas the same probability was 6.9% for the few women 25 years or older (n = 30; 6% among >24 years of age at study end) who had 3 or more partners over the 4-year study-period. These results indicate that universal recommendations for genital CT screening without taking age and partner change into consideration are invalid. Our study has shown that incidence of genital CT infection is age and partner change dependent, which makes results from prevalence studies unreliable for assumptions of modelling cost-effectiveness of CT screening.10,11 Only young women, 24 years of age or younger, with 1 or more partners reached annual incidence that reaches threshold “incidence” in cost-effectiveness modelling on benefits from CT “screening.”

In this study, we gathered data on sexual exposure at 6-month intervals, whereas we collected specimens unrelated to genitourinary symptoms for analyses of CT infection at 12-month intervals. Recognizing that an average CT infection lasts for 12 or more months,18,19 analyses of partner change since last test precisely estimates the risk of CT infection. We can state that women 24 years or younger, with 3 or more partners, select their partners from high-risk core group of CT-infected men. Our study has shown that women 25 years or older select their partners from groups of men with little exposure to CT because CT infection rates are that low in all subanalyses of number of new partners in this age segment.

In summary, our cohort of women 24 years or younger, with 1 or more partners, the annual incidences are reassuring for continuing recommendations for liberal annual testing for CT among asymptomatic women 24 years or younger in Norway.9

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