Sexually Transmitted Diseases:
The Clinical and Economic Consequences of Screening Young Men for Genital Chlamydial Infection
GINOCCHIO, RACHEL H. S. MPH*; VEENSTRA, DAVID L. PharmD, PhD†; CONNELL, FREDERICK A. MD, MPH*; MARRAZZO, JEANNE M. MD, MPH‡
From the *Department of Health Services, Maternal and Child Health; †Pharmaceutical Outcomes Research and Policy Program; and ‡Department of Medicine, University of Washington, Seattle, Washington
The authors thank Patty Belestra for providing the Medicaid fee schedules for Washington State.
Supported by a grant from the Department of Health and Human Services, Health Resources and Services Administration (HRSA), Maternal and Child Health Bureau (research and training grant no. T 76 MC 00011 to Rachel Ginocchio).
Correspondence: Jeanne M. Marrazzo, MD, MPH, Division of Allergy and Infectious Diseases, University of Washington, Harborview Medical Center, Mailstop #359931, 325 Ninth Avenue, Seattle, WA 98104. E-mail: email@example.com
Received April 2, 2002,
revised July 3, 2002, and accepted July 8, 2002.
Background: Wide-scale application of urine-based screening of asymptomatic men for chlamydial infection has not been thoroughly assessed.
Goal: The goal was to compare clinical and economic consequences of three strategies: (1) no screening, (2) screening with ligase chain reaction (LCR) assay of urine, and (3) prescreening urine with a leukocyte esterase test (LE) and confirming positives with LCR.
Study Design: We used a decision analytic model.
Results: At a chlamydia prevalence of 5%, the no screening cost was $7.44 per man screened, resulting in 522 cases of pelvic inflammatory disease (PID) per 100,000 men. LE-LCR was most cost-effective, preventing 242 cases of PID over no screening at an additional cost of $29.14 per male screened. The LCR strategy prevented 104 more cases of PID than LE-LCR but cost $22.62 more per male screened. For this to be more efficient than LE-LCR, the LCR assay cost needed to decline to ≤$18.
Conclusion: At a chlamydia prevalence of 5%, LE-LCR is the most efficient use of resources. If LCR cost decreases or chlamydia prevalence increases, the LCR strategy is favored.
AN ESTIMATED 4 MILLION genital chlamydial infections occur each year in the United States, and 74% of all reported cases occur among 15- to 24-year-olds. 1 Up to 90% of chlamydial infections in women and 60% in men are asymptomatic and can result in serious upper-genital-tract and neonatal sequelae. 2,3 The annual direct and indirect costs of treating chlamydial infections and their sequelae are estimated at $2.0 billion. 4
In 2000, reported rates of chlamydial infection among women (404.1 per 100,000) were four times greater than among men (102.8 per 100,000). 1 Low reported rates among men may reflect that asymptomatic men are unlikely to seek routine screening and that many sex partners of infected women are not tested. 1 While large-scale screening programs for women have affected major declines in Chlamydia trachomatis prevalence in some areas, 5 these trends have stabilized. Therefore, asymptomatic men infected with C trachomatis are likely an unaddressed source of infection for women. Inclusion of men in strategies to prevent chlamydial infection is a logical next step in preventing disease transmission to women. Use of nucleic acid amplification technology (NAAT) to detect C trachomatis in urine obviates the need for urethral swabs, formerly a considerable barrier to testing asymptomatic men. While NAAT is more sensitive and as specific as the most commonly used diagnostic tests, it is more expensive.
Few cost-effectiveness studies of C trachomatis screening have focused on men. Of these, many were done before NAAT became available, relied on cost and outcome estimates from outside the United States, accounted for only the direct cost of the diagnostic test, and did not include the cost of treatment and sequelae or did not include the outcome of subclinical pelvic inflammatory disease (PID). 6–10 None formally considered the utility of prescreening urine for nonspecific inflammation in order to direct NAAT testing for C trachomatis. We assessed the cost, effectiveness, and cost-effectiveness of three strategies for detection of C trachomatis in a population of asymptomatic young men, using current United States costs. The three strategies were: (1) NS: no screening; (2) LCR: testing all young men with ligase chain reaction [LCR] assay of urine; and (3) LE-LCR: testing all young men with a leukocyte esterase [LE] strip test of urine, followed by confirmatory LCR. While inexpensive, the LE strip has low specificity and variable sensitivity for chlamydial infection.
A decision tree was developed to model events, costs, and clinical outcomes of chlamydial infection in a hypothetical cohort of 100,000 asymptomatic young men. The cohort was based on two groups of asymptomatic men universally tested for C trachomatis with LCR of urine samples. The first group comprised 3982 asymptomatic men tested in a community-based screening effort. 11 The second comprised 1625 asymptomatic men seen in a sexually transmitted disease (STD) clinic. 12 Data from these groups were used to examine potential selective screening criteria for chlamydial infection and to estimate the associated predictive value of urine LE testing. As previously reported, only age <25 years and a positive urine LE test were associated with asymptomatic chlamydial infection in these men. 11,12 Outcomes assessed included untreated chlamydial infection of males and subsequent complications, transmission to female partners, development of PID, infertility, ectopic pregnancy, chronic pelvic pain, and neonatal transmission. The decision model was developed with use of DATA 3.5.6 software (TreeAge Software, Williamstown, MA). Key structural components of the tree are shown in Figure 1 (full model available upon request).
The analysis took the perspective of the healthcare payor and estimated direct medical costs. Current clinical guidelines were used to determine medical management (inpatient and outpatient visits, procedures, and medication). 13,14 The time horizon for events before the development of PID complications was 1 year. Infertility was assumed to be evaluated 10 years after contraction of C trachomatis infection, and ectopic pregnancy and chronic pelvic pain 5 years after. 2 All future costs and outcomes were discounted at a rate of 3% per year. 15
Probability estimates associated with chlamydial infection and sequelae were obtained from a review of current literature (Table 1). 2,3,5,6,8,9,11,12,16–26,28–43,46,53–64 The most plausible estimate was assigned a range of values to account for uncertainty. The C trachomatis prevalence of 5% used for young men in the base-case scenario was derived from recent studies using urine-based testing of asymptomatic men. 16–20 LE and LCR test performance measures were obtained from recent research on asymptomatic men in STD and non-STD clinic settings. 6,9,11,12,16,18,21–23 For transmission of C trachomatis, we accounted for data on the prevalence of coinfection in couples, 24–26 that transmission does not occur with every episode of intercourse, and that 35% of sexually active young men report two or more sex partners in the previous 3 months. 27 We conservatively estimated that each infected male transmitted C trachomatis to one female partner per year.
Although few firm data on clinical outcomes of partner management are available, we estimated that 75% of men returned to their provider for treatment after the detection of C trachomatis infection through screening 28 and that 50% of infected female partners were successfully contacted and treated. 29,30 Of those female partners who did not return for treatment, we assumed that 5% would have the infection detected through routine screening. 5 Of those not screened or whose screen was falsely negative, we estimated that 50% of men and 20% of women with C trachomatis were symptomatic. 2 We estimated that 20% of men with discharge or dysuria and 10% of women with nonspecific genitourinary complaints would seek care. These estimates were based on evidence that many young adults with health problems forego care 31 and that the nonspecific symptoms of chlamydial infection in women may not prompt evaluation.
Studies that demonstrate the role of C trachomatis in laparoscopically confirmed salpingitis or biopsy-confirmed endometritis were used to estimate that 25% of women with untreated cervical chlamydial infection develop PID. 32–34 Approximately 60% of all women with upper-genital-tract inflammation are thought to have subclinical PID. 33,35–37 Longitudinal and population-based studies estimate that tubal infertility occurs in 15% of women with laparoscopically confirmed salpingitis. 38,39 Of women with an ectopic pregnancy, 75% were estimated to seek outpatient laparoscopic treatment, 40 20% to use methotrexate, 41 and 5% to require inpatient surgery. 40 We estimated that 18% of women who have one episode of PID develop chronic pelvic pain. 42,43
We used Medicaid maximum allowable fee schedules for Washington state (WA) to derive cost estimates (Table 2). Fee schedules included the resource-based relative value reimbursement schedule (RBRVS) for physician and surgeon reimbursement, the prospective payment system (PPS) for hospital fees, the prospective payment system for ambulatory surgical center (ASC) reimbursement, the clinical diagnostic laboratory fee schedule, and the maximum allowable cost (MAC) prescription fee schedule. The 1999 Drug Topics Red Book44 was used for prescriptions not covered under WA Medicaid. To account for uncertainty in cost estimates, a plausible range was estimated by assessing costs used by other economic evaluations of C trachomatis screening. 8,9,45–47 To account for variation in published costs relative to WA Medicaid estimates, we used a range of −10% to +60% of the base-case estimates.
For each strategy, cost, effectiveness, and incremental cost-effectiveness were assessed. Total cost accounted for screening, treatment, and sequelae. Number of cases of PID prevented was the primary measure of effectiveness, but prevented cases of urethritis, epididymitis, infertility, ectopic pregnancy, chronic pelvic pain, neonatal conjunctivitis, and pneumonia were also evaluated. Incremental cost-effectiveness was defined as the incremental cost of preventing an additional case of PID with one strategy, compared to the next-most-effective strategy.
Sensitivity analyses were performed to evaluate uncertainty in the model. After one-way sensitivity analyses were conducted on all parameters, detailed one- and two-way sensitivity analyses were conducted on the prevalence of infection and the cost of the LCR assay—variables that showed the greatest impact on overall strategy cost and effectiveness.
As shown in Table 3, the LCR strategy was the most effective approach, preventing on average 66% more PID cases than no screening. In comparison, the LE-LCR strategy prevented 46% more PID cases than no screening. Costs associated with the three strategies are presented in Table 4. The cost to screen one man was $55.67 with the LCR strategy, compared to $31.91 with LE-LCR, due to the high cost of the LCR assay. Treatment costs of $1.14 per male screened were also highest for the LCR strategy, because use of LCR led to detection and treatment of more infected men. The $0.30 treatment cost associated with no screening represents young men who developed symptoms and sought care. Costs of sequelae due to untreated chlamydial infection were markedly different across strategies; those for no screening were three times that of the LCR strategy. The LE-LCR strategy showed a $3.34 cost savings in sequelae costs per male screened over no screening, and the LCR strategy showed an additional $1.41 savings over LE-LCR per male screened. In incremental analysis, the LE-LCR strategy cost $29.14 more per male screened than no screening and prevented 242 additional cases of PID. The LCR strategy cost $22.62 more than the LE-LCR strategy and prevented 104 additional cases of PID.
One-Way and Two-Way Sensitivity Analyses
One- and two-way sensitivity analyses examined how the prevalence of male infection and the cost of the LCR assay affected overall strategy cost. As prevalence increased, total program costs for each strategy differed. At a prevalence of 3%, no screening cost $4.47, LE-LCR cost $34.38, and LCR cost $57.80 per screened male. At a prevalence of 5%, no screening cost $7.44, LE-LCR cost $36.58, and LCR cost $59.20 per screened male. At a prevalence of 10%, no screening cost $14.89, LE-LCR cost $42.08, and LCR cost $62.72 per screened male. The LCR strategy became less expensive than LE-LCR above a prevalence of 60% and became less expensive than no screening above a prevalence of 70%.
Figure 2 shows the effect of varying the cost of the LCR assay on total strategy cost. At the base-case scenario prevalence (5%), the LCR strategy became less expensive than the LE-LCR strategy when the cost of the LCR assay fell below $4.20. At prevalences of 3% and 10%, the cost of the LCR must fall below $3.60 and $5.90, respectively, for the LCR strategy to be less expensive than LE-LCR.
Figure 3 shows the results of a two-way sensitivity analysis that examined the impact of varying both the prevalence of chlamydial infection among males and the cost of the LCR assay on total strategy cost. The dotted line indicates the point at which the LCR and LE-LCR strategies cost an equal amount. The area to the right of the line represents the prevalence and LCR assay cost at which the LCR strategy is less expensive than the LE-LCR strategy, and the area to the left of the line represents when the LE-LCR strategy is less expensive than LCR. Overall, as the prevalence of infection among males increases or as the cost of the LCR assay decreases, the LCR strategy becomes less expensive.
One-way sensitivity analyses examined how the prevalence of male infection and the cost of the LCR assay affected overall strategy effectiveness. As shown in Figure 4, at any prevalence of male infection, the LCR strategy was more effective in preventing cases of PID than was the LE-LCR strategy, which in turn was more effective than the no screening strategy. Varying the cost of the LCR assay had no effect on program effectiveness.
Incremental cost-effectiveness analysis.
At 5% prevalence, LE-LCR cost $12,041 to prevent an additional case of PID over no screening, and LCR cost $21,750 to prevent an additional case over LE-LCR. However, if the if the cost of the LCR assay fell to $18 or less, or if the prevalence of infection increased to 49%, the LCR strategy cost less to prevent an additional case of PID than the LE-LCR strategy.
We assessed the incremental cost-effectiveness of a variety of scenarios that account for some important analytic limitations. Inclusion of indirect costs or costs to private payors increased the cost of all strategies but did not significantly change the incremental cost-effectiveness of the strategies. When additional C trachomatis–associated sequelae (endometritis, perihepatitis, and proctitis) were included, the cost of the no screening strategy increased by 55% to $11.55 per male screened, LE-LCR increased by 6% to $38.78, and LCR increased by 2% to $60.59. In incremental analysis, LE-LCR became cost-saving over no screening at or above a prevalence of 41%, and the LCR strategy became cost-saving over LE-LCR at or above a prevalence of 44%. When costs of a clinic visit associated with screening in traditional healthcare settings were removed, LE-LCR became cost-saving over no screening at a prevalence of 23%, but the LCR strategy did not become cost-saving over the LE-LCR strategy until a prevalence of 62%. When costs from a recent economic evaluation of screening asymptomatic women were used, 48 both the LE-LCR and the LCR strategy became cost-saving at a prevalence of infection among men of 4% or higher.
We found that at a prevalence of chlamydial infection of 5% among asymptomatic men, prescreening urine for LE, followed by confirmatory testing with urine-based LCR, was the most cost-effective strategy. Relative to no screening, LE-LCR resulted in 242 fewer cases of PID per 100,000 males screened and cost $29.14 per male tested. While testing all men with LCR prevented more chlamydia-associated sequelae than LE-LCR, the additional cost was substantial ($22.62 per man screened). In sensitivity analysis, the cost of the LCR assay and the prevalence of C trachomatis infection in males critically impacted outcomes. In order for a strategy using only urine LCR screening to be more efficient than LE-LCR at the chlamydia prevalence in our base-case analysis (5%), the cost of the LCR assay needed to decline to $18 or less.
In general, our results concur with those of other investigators. Genc and colleagues 9 estimated that screening asymptomatic men with urine LE testing confirmed by a specific enzyme immunoassay (EIA) test was more cost-effective than screening with only EIA. Two other large studies also concluded that applying an initial nonspecific screening test (such as an LE test) followed by specific testing was the most cost-effective approach to screening asymptomatic men. 6,7 Our analysis extends this work in several ways. We evaluated the use of a nucleic acid amplification assay and, of critical importance, included costs of managing female partners of infected men. We accounted for outcomes of symptomatic and subclinical PID and incorporated new treatment protocols, including the use of methotrexate for ectopic pregnancy. All direct costs associated with chlamydial infection, not just the cost of diagnostic tests, were included (such as office visits, hospital fees, surgical procedures, laboratory work, medication). Finally, we performed extensive sensitivity analyses on cost variables to ensure applicability of the analysis to a wide array of settings and payor types.
Howell and colleagues 48 evaluated the use of urine LCR to screen a hypothetical asymptomatic cohort of 18,000 women and reported a cost-saving of $3,689 for use of an LCR strategy over no screening. When compared directly to our results, this suggests that the benefits of using LCR versus no screening are greater when women are screened than when men are screened. However, the two studies used significantly different probability and cost estimates. For example, Howell used a lower LCR assay cost ($5.32) than we did ($33.42), and higher costs for evaluating PID and associated sequelae. Our sensitivity analyses showed that such a cost structure favored the efficiency of the LCR strategy over no screening. When we recalculated our costs using estimates from the Howell study, we found that both the LE-LCR and LCR strategies became cost-saving over no screening at or above a C trachomatis prevalence of 4%. A comprehensive approach to assess the cost-effectiveness of screening young men versus women would be to use our probability and cost estimates to calculate total costs and outcomes for screening a comparable cohort of asymptomatic women.
Our study has several limitations. First, the validity of our model depends on the accuracy of the incorporated probabilities. Extensive sensitivity analyses mitigated some of this uncertainty. Second, our analysis was done from the perspective of the healthcare payor. An analysis from the societal perspective would include nonmedical direct costs, indirect costs, and intangible costs. Inclusion of indirect costs increased the overall cost of each strategy but did not significantly change the incremental cost of preventing an additional case of PID for either strategy. Third, we chose Medicaid reimbursements to Washington state providers and facilities. These cost values are likely to be lower than the cost to private health plans. Raising these estimates to more substantially represent private fee schedules did not change our general conclusions. Fourth, we did not include all C trachomatis–associated outcomes, such as urethritis, bartholinitis, endometritis, and perihepatitis in women and proctitis, prostatitis, and Reiter syndrome in men. Studies have also demonstrated an association between chlamydial infection and low birth weight, postpartum endometritis, premature rupture of membranes, and chorioamnionitis;3 enhanced risk of HIV transmission;49 and cervical cancer. 50 Inclusion of such events would favor the LCR strategy, since more of these expensive outcomes would be avoided.
Fifth, our base-case scenario modeled the cost of C trachomatis screening as a separate office visit. If screening were integrated with other health visits such as sports physicals, the cost of testing could be significantly less. Finally, partner management strategies have the potential to greatly impact reinfection rates in women. For our analysis, we used existing data available for traditional approaches to partner management. However, innovative methods for partner management are under study and may prove more effective and less costly.
Ten US regions that target women with large-scale C trachomatis screening programs have shown a 60% decline in reported cases of C trachomatis since 1988. 51 However, from 1997 to 1998, C trachomatis prevalence increased in nine of these regions. This increase is likely to be due solely to the use of more sensitive diagnostic methods or to expansion of screening programs to populations with higher prevalence. However, the implementation and evaluation of screening strategies aimed at males may be important to further control chlamydial infections in women, particularly when coupled with strategies to enhance partner management. 52 Our analyses indicate that for healthcare organizations that serve populations with a prevalence of male infection of approximately 5%, the LE-LCR strategy is a more efficient use of healthcare dollars than the LCR strategy. However, if the cost of the LCR assay decreases—or in populations with high chlamydia prevalence—the LCR option may be preferred.
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