Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the United States and a major cause of reproductive morbidity in women.1–4 Because most chlamydial infections are asymptomatic but easily treated if detected early,5 routine screening in women has emerged as a key public health intervention.6–8 Current screening recommendations are based on the high prevalence of C trachomatis reported in young women and elevated risk for reinfection among those with recently diagnosed infection.9–14 These recommendations have been evaluated using economic analyses, which found screening to be cost-effective and, in some studies, cost-saving.15,16 In a previous study, we examined the cost-effectiveness of recently proposed strategies for C trachomatis screening in U.S. women and found routine annual screening for women aged 15 to 29 years, followed by selective targeting of those with documented infection for semiannual screening, to be a cost-effective intervention compared with other well-accepted clinical practices.17 Although our results were robust over a plausible range of parameter estimates in sensitivity analyses, we identified a number of assumptions requiring further exploration. These included the clinical significance of asymptomatic compared to symptomatic infection and the relative contribution of persistent versus repeated infection to repeat test positivity.
One attribute of a decision analytic approach is the ability to test the relative import of uncertain assumptions using a series of modeling exercises.18 We have revised our previously published model to permit an exploration of alternative hypotheses regarding the clinical significance of asymptomatic chlamydial infection and to include updated data on the prevalence of chlamydial infection in the United States. Our objective is to provide a better understanding of the impact of natural history assumptions on the composition (i.e., target age range, screening frequency of average risk women, follow-up screening schedule for high-risk women) of optimal screening strategies and their estimated cost-effectiveness, and to highlight priority areas for future clinical research.
We used a previously published state-transition Markov model to simulate the natural history of disease following C trachomatis infection in women.17 Superimposed on the natural history model was a screening module capable of simulating screening, diagnosis, and treatment of chlamydial infection. Transition probabilities, cost estimates, and health-related quality weights were derived from the published literature and are described in detail elsewhere (Table 1).1,5,7,9,15,19–57 Plausible ranges for each parameter were based on all available data. This study differs from our previous work in that the model was modified to (1) incorporate more recent prevalence data on U.S. adolescents and young adults (estimated at 4% in the age range 15–25 years) from the National Longitudinal Study of Adolescent Health (Add Health Study)19; (2) separately simulate asymptomatic and symptomatic chlamydial infections of the upper and lower genital tract; and (3) adjust the risk for long-term complications (i.e., chronic pelvic pain, ectopic pregnancy, and tubal infertility) according to the number of episodes of pelvic inflammatory disease (PID).37,38
In this analysis, a cohort of nonpregnant, disease-free, sexually active 15-year-old females entered the model and was followed until death. Every 6 months, women faced a risk of acquiring uncomplicated C trachomatis infection that was dependent on age and history of prior chlamydial infections. Within an average of 6 months of acquiring C trachomatis, lower genital tract infections could remain persistent, progress to PID, or resolve (either spontaneously or through treatment). Persistent infection refers to a lower genital tract chlamydial infection that lasts for more than 6 months from the time of initial acquisition of C trachomatis. These assumptions translated to an average duration of infection of 0.93, which closely approximates the value of 0.96 years cited by Groseclose et al.58 and others.22 Those who developed PID could remain chronically but subclinically infected, suffer long-term complications (i.e., chronic pelvic pain, ectopic pregnancy, or tubal infertility), or experience a spontaneous or treatment cure. Every 6 months, women also faced a risk of dying from PID, ectopic pregnancy, and age- and sex-specific all-cause mortality.
In the screening module, acute infection detected through screening was distinguished from undetected infection and subsequently was treated with antibiotics if the patient was compliant with follow-up. Women with false-positive test results were also offered treatment and incurred costs associated with treatment and potential antibiotic-associated side effects. We assumed that testing was performed using urine-based nucleic acid amplification tests (NAATs), which were chosen for (1) their enhanced sensitivity and specificity,41,42 and (2) their high acceptability among adolescents and other high-risk populations compared to other commonly available screening tests.59,60
In the base case, we made several assumptions about the natural history of C trachomatis, which were specifically tested in sensitivity analyses. We assumed the development of PID from unrecognized or unsuccessfully treated acute lower genital tract chlamydial infection was not differentially affected by symptomatology or persistence. We assumed persistence indicated a state of infection in which the host response does not eliminate the microbe because either treatment is lacking or therapy is inadequate, resulting in continuing risk for damage over time.61 For the base case analysis, we applied an average risk for the development of PID to symptomatic, asymptomatic, and persistent chlamydial infections.17 Some researchers argue this estimated average risk is too high because it is based on studies of patients at higher risk for complications compared to the general population.62,63 There is also some evidence asymptomatic and persistent chlamydial infection may be associated with a decreased risk for complications compared to symptomatic infection.64 To explore the impact of our base case assumptions, we (1) used a wider range of plausible values for the average risk of PID than what has traditionally been used in earlier studies (base case, 30%; and range, 0.43–40%), (2) explored an alternative assumption of a lower relative risk for acute PID among women with asymptomatic and persistent chlamydial infection (relative risk of 0.05×, 0.25×, 0.50×, 0.75×, and 1×) compared to those with symptomatic infection, and (3) assessed the effect of assuming the risk of development of long-term complications (i.e., chronic pelvic pain, ectopic pregnancy, and tubal infertility) might not be the same for women with symptomatic and asymptomatic PID (relative risk of 0.05×, 0.25×, 0.50×, 0.75×, and 1× in asymptomatic compared to symptomatic PID).
In our previous study, we assumed the high prevalence of repeat test positivity reported during follow-up of women with recently diagnosed C trachomatis is due to both reinfection and persistent infection.17 Specifically, we assumed the relative risk of reinfection was twice the risk for first-time infection and the risk of persistent infection was 30% among women with untreated or unsuccessfully treated acute infection.17
In several studies, 28% to 78% of women with previously diagnosed C trachomatis have positive test results upon follow-up (range, 28 days to 16 months).25–28 However, the degree to which repeat test positivity represents persistent infection versus reinfection (a new infection after eradication of the initial infection)65 is unclear. In 2-way sensitivity analyses, we examined the impact of alternative assumptions by simultaneously varying the risk for persistence (0%, 15%, 30%, 45% and 60%) and the relative risk of reinfection (0.50×, 1×, 2×, 3×, and 4×) compared to first-time infection. Finally, because the duration of elevated risk of reinfection is unknown, we examined the impact of different assumptions about this parameter (i.e., 6 months, 1 year, 2.5 years, and 5 years compared to the base case assumption of a woman’s lifetime) in sensitivity analysis.
We used our model to compare 7 screening strategies targeted to specific age groups (15–19 years, 15–24 years, and 15–29 years): (1) no screening, (2) biennial (i.e., every other year) screening for all women, (3) biennial screening followed by a single repeat test within 3 to 6 months after a positive test result, (4) biennial screening followed by a shift to semiannual screening (i.e., every-6 months) for those with a positive test result, (5) annual screening for all women, (6) annual screening followed by a single repeat test within 3 to 6 months after a positive test result, and (7) annual screening followed by a shift to semiannual screening (i.e., every 6 months) for those with a positive test result.
We adopted a modified societal perspective, which included direct medical costs, as well as the costs of time lost from work for women in the cohort (Table 1).15,31,32,34,39,48–57 Costs were expressed in 2000 US dollars and clinical benefits were expressed in years of life saved and quality-adjusted life years (QALY) gained. Future costs and life years were adjusted to current values by applying a discount rate of 3% annually.
Base Case Analysis
The discounted lifetime costs and quality-adjusted life expectancies associated with each screening strategy under base case assumptions are shown in Figure 1. The cost-effectiveness of moving from one strategy to a more costly alternative is represented by the difference in cost divided by the difference in life expectancy associated with the 2 strategies.66 Strategies lying on the efficiency curve dominate those lying to the right of the curve because they are more effective and either cost less or have a greater cost-effectiveness ratio than the next best strategy. A cost-effectiveness ratio is shown for each nondominated strategy and is the reciprocal of the slope of the line connecting the 2 screening strategies under comparison; this slope will be steeper when the net gain in life expectancy per U.S. dollar is greater.
In the absence of screening, the average per-person discounted lifetime costs were $268, and quality-adjusted life expectancy (QALE) was 27.3020 years. Screening increased lifetime costs and QALE by $24 to $134 and 0.0035 to 0.0209 year, respectively. Under base case assumptions, there are 5 nondominated strategies: no screening, biennial screening (15–24 years age), biennial screening followed by a shift to semiannual screening for those who test positive (age groups, 15–24 and 15–29 years of age), and annual screening followed by a shift to semiannual screening for those who test positive (15–29 years age). The most efficient and cost-effective strategy is to screen all sexually active women aged 15 to 29 years annually and to rescreen women who test positive every 6 months. This strategy has an incremental cost-effectiveness ratio (ICER) of $7180 per QALY gained compared to the next best strategy. The remaining 3 nondominated screening strategies incorporate biennial screening and have ICERs ranging from $5660 to $6770 per QALY. Results unadjusted for quality of life decrements show much higher cost-effectiveness ratios, ranging from $236,700 to $303,000 per life year gained (data not shown). This large difference between results, which are adjusted and unadjusted for quality of life, reflects the low mortality but high morbidity associated with chlamydial disease.
We performed 1-way sensitivity analyses on all key parameters, including those shown in Table 1. Results were insensitive to the probability of symptoms with either acute infection or PID; sensitivity or specificity of the screening test; compliance with follow-up after a positive test result or with treatment for an acute infection; risk of persistent infection; relative risk of reinfection in women with a previous chlamydial infection; proportion of PID treated in the inpatient setting (as compared to outpatient setting); effectiveness of treatment for acute PID; proportion of women with tubal infertility seeking workup; direct medical costs associated with the treatment of acute infection, acute PID, or any of the individual sequelae; time costs; and the quality of life decrement associated with symptomatic acute infection, acute PID, or any of the 3 long-term complications.
Cost-effectiveness results were most sensitive to the screening test cost and certain natural history parameters, such as the yearly probability of acquiring an acute chlamydial infection; the risk of developing acute PID; the risk of developing long-term complications; and the yearly decline in the risk of acute chlamydial infection after 25 years of age. Screening became cost-saving (relative to no screening) when the screening test cost is less than $4.50 (base case, $13) or when the annual risk of acquiring C trachomatis exceeds 14% (base case, 4%). Screening strategies were associated with an ICER that exceeded $50,000 per QALY gained (compared to the next-best strategy), a commonly cited upper limit threshold for well-accepted preventive health care interventions,67 when the risk of developing PID was less than 6% (base case, 30%) or the risk of developing long-term complications was less than 15% of the base case values.
Clinical Impact of Asymptomatic Infections
In addition to exploring the impact of alternative assumptions about the average risk for PID and its sequelae, we also evaluated the implications of assuming asymptomatic chlamydial infection (acute infection and PID) is associated with a lower relative risk of future complications (0.05×, 0.25×, 0.50×, 0.75×, and 1×) compared to symptomatic infections. Figure 2 shows the results of a 2-way sensitivity analysis for the relative risk of acute PID (asymptomatic relative to symptomatic acute lower genital tract infection) and the risk of acute PID, given symptomatic acute infection (5%, 10%, 20%, and 30%), for the most cost-effective screening strategy in this analysis: annual screening in all women aged 15 to 29 years, followed by a shift to semiannual screening if test-positive. Under the base case assumption of a 30% risk for acute PID among women with symptomatic acute infection (green curve), this strategy had an ICER greater than $50,000 per QALY when the relative risk for acute PID among women with asymptomatic compared to symptomatic acute infection was less than 25%. As expected, when we assumed the risk of acute PID among those with symptomatic acute infection was less than 30%, a higher relative risk for acute PID for asymptomatic versus symptomatic acute infection was required for screening strategies associated with an ICER greater than $50,000 per QALY. When the relative risk for PID was less than 20% in those asymptomatically infected compared to symptomatically infected women, none of the screening strategies was associated with an ICER that was less than $50,000 per QALY.
In contrast, results were less sensitive to assumptions about the relative risk for long-term complications among women with asymptomatic PID compared to symptomatic acute PID. Among the range of relative risks (0.05×–1×) considered, the ICER for the nondominated screening strategies increased base case ICERs by as much as 4 times but never exceeded the $50,000 per QALY threshold.
Clinical Impact of Reinfection and Persistent Infection
Since the relative proportion of repeat test positivity for C trachomatis attributable to persistence versus reinfection is unknown, we explored the impact of this uncertainty by simultaneously varying the probability of persistent infection (0%, 15%, 30%, 45% and 60%) and the relative risk for reinfection (0.50×, 1.0×, 2.0×, 3.0×, and 4.0×) compared with the probability of a first-time chlamydial infection in 2-way sensitivity analysis. Figure 3A–C shows results for 2-way sensitivity analyses using selected values of the risk of persistence (0%, 30%, 60%) and the relative risk of repeat infection (0.5×, 2.0×, and 4.0×). Over the plausible range of values for persistence and relative risk of reinfection, the strategy of annual screening in women aged 15 to 29 with semiannual screening for those who test positive remained the most effective and cost-effective strategy with an ICER that was less than $500,000 per QALY compared to the next best strategy. While different assumptions about the probability of persistence and reinfection did not greatly alter the magnitude of ICERs, they did affect the number and choice of optimal strategies. For example, when we assumed the relative risk for reinfection was high (3× or 4× the risk of first-time infection), screening strategies that targeted the age group 15 to 29 years and allowed for women with a history of a positive test to be screened on a semiannual basis dominated over most other strategies. When we assumed the probability of persistent infection was high (45% or greater), screening strategies involving a single repeat test after a positive test result became cost-effective. This was particularly notable when the relative risk of reinfection was low (1× or 0.5× the risk of first-time infection) (Fig. 3C).
We also conducted a 2-way sensitivity analysis of the duration of elevated risk for reinfection (i.e., 6 months, 1 year, 2.5 years, 5 years, and a lifetime) and the relative risk for reinfection (0.5×, 1×, 2×, and 3×) and found our results were stable over the range of plausible values for these 2 parameters.
Our analyses suggest that certain assumptions about the natural history of C trachomatis have a critical and distinct impact on the cost-effectiveness of screening. While these assumptions did not challenge the overall cost-effectiveness of screening as a clinical intervention (as compared to other well-accepted preventive health measures), they influenced the relative cost-effectiveness of different screening strategies. Assumptions about the risk for PID had the greatest influence on the magnitude of ICERs, whereas assumptions about persistent and repeated infections more strongly affected the number and choice of optimal (nondominated) screening strategies.
The most influential natural history parameter on the overall cost-effectiveness of chlamydial screening was the risk of developing PID for women with acute chlamydial infection. Within the range of values (10–40%) used in previous cost-effectiveness analyses, our results remained stable. However, some researchers have recently questioned whether the literature-based risk estimates used in these analyses overestimate the true average risk of acute PID in the general population because these estimates are drawn from studies of populations at particularly high risk because of either symptomatology or sociodemographics.7,24 For instance, using population registry data from Amsterdam, van Valkengoed et al.63 have estimated the risk of PID to be 0.43%, a value far lower than what has been used in published cost-effectiveness analyses. On the basis of this study, we expanded the range of values (0.43%–40%) and in sensitivity analysis found that when the risk of acute PID per episode of acute infection was less than 6%, screening had an ICER exceeding $50,000 per QALY when compared to no screening. Another study by Morre et al.64 suggests asymptomatic and persistent acute lower genital tract C trachomatis infection may have a differentially smaller impact on the development of acute PID than symptomatic infection. These findings are in contrast with the results of a randomized, controlled trial where C trachomatis screening in high-risk women was found to be associated with a reduced incidence of PID (relative risk of 0.44) compared to the control group.7 In a sensitivity analysis, we explored the assumption that asymptomatic and persistent acute infection have a lower relative risk for PID than symptomatic acute infection and found that at a relative risk of 20% or less, none of the screening strategies used in this study had ICERs less than $50,000 per QALY. Since the rationale behind C trachomatis screening programs is that early detection and treatment of asymptomatic infections will prevent PID and its complications, our results indicate assumptions about (1) what proportion of acute lower genital tract chlamydial infections eventually lead to PID and (2) whether asymptomatic infections have a different clinical course than symptomatic infections can have a critical impact on the relative cost-effectiveness of different screening strategies.
Assumptions about the risk of persistent infection and reinfection also had a significant impact on cost-effectiveness results. In 2-way sensitivity analysis, we found the number and composition (i.e., target age, screening frequency for average risk women, and management of screening in high-risk women) of optimal screening strategies varied widely, depending on the specific values assigned to the risk of persistence and relative risk of reinfection. Although the strategy of annual screening in women ages 15 to 29 years, followed by a shift to semiannual screening for those who test positive, remained the most effective and cost-effective strategy under the range of plausible values for persistence and reinfection, ascertainment of alternative strategies that are cost-effective but less costly is important because even though a strategy may be cost-effective (i.e., have value for the money), it may not necessarily be affordable. For example, many publicly funded health clinics have limited resources and are unable to offer screening for all patients or at the frequency recommended by national practice guidelines. In such cases, it is important to identify a cost-effective screening strategy that fits a particular budget. Our results suggest further clinical research aimed at clarifying the relative proportion of persistence and reinfection will help determine the most appropriate target age range and frequency for C trachomatis screening programs within the context of budgetary constraints.
Assumptions about the age-specific annual risk of acquiring C trachomatis infection affected both the magnitude of ICERs and the choice of optimal screening strategies. When we assumed the yearly risk for chlamydial infection was greater than 14%, consistent with reports from STD clinics and inner cities,13,14 screening became cost-saving. The base case scenario incorporated recent data on the national chlamydial prevalence in U.S. adolescents and young adults from the Add Health study, which reported a prevalence of 4% for adolescent and young adult males and females ages 18 to 26 years.19 This prevalence was significantly lower than estimates reported by the CDC Chlamydial Prevalence Monitoring Project2 and used in our previous cost-effectiveness analysis, where we applied a C trachomatis prevalence of 6% to a narrower age range of 15 to 19 years of age.17,68 When these 2 alternative sets of prevalence data were used to inform assumptions about the age-specific annual risk of acquiring C trachomatis infection, the results differed mainly with regard to the number and choice of optimal target age ranges for C trachomatis screening (data not shown). The prevalence of C trachomatis in women older than age 25 years is not well studied, and our results indicate further assessment of the risk of chlamydial infection in older women will help determine the optimal target age range for routine chlamydial screening in the general population.
Our study has several limitations. First, the inclusion of refined estimates on the time course between acquisition of C trachomatis infection and development of PID, as well as the impact of delayed treatment of acute infection on the development of complications, were beyond the scope of this analysis. A more thorough understanding of these factors will likely contribute to improved screening program design and a more accurate assessment of the effects of screening. Second, health-related quality of life measures, especially with regard to PID sequelae, were based on limited data. Since PID and its sequelae are associated with negligible mortality, accurate quantification of the attributable morbidity and quality of life effects is crucial to understanding the overall impact on women’s long-term outcomes and the cost-effectiveness of screening programs. Finally, we chose to focus on the uncertainty regarding the relationship between characteristics of chlamydial infection, once acquired (i.e., asymptomatic versus symptomatic, persistent versus repeat infection) and downstream long-term clinical sequelae using a simple state-transition model. Therefore, this model does not incorporate the transmission of chlamydial infection to newborns or sexual partners or the impact of partner notification, treatment, and averted male sequelae. As we and others have found previously, their inclusion would likely make screening appear even more cost-effective.15,17
There is a role for both static and dynamic models in the evaluation of C trachomatis screening programs. Our focus on this analysis was on the uncertainty of disease outcomes in individuals following acquisition of infection rather than the uncertainty surrounding acquisition of infection and its impact on outcomes at the population level. In this instance, static models can serve as a useful tool when one wants to focus on the disease trajectory following infection within individual women. In particular, these models are quite easy to manipulate to explore a wide range of alternative disease risk assumptions following infection. Dynamic models take into account the infectious and transmissible nature of chlamydial infections and require detailed data on sexual behavior (e.g., number of sexual partners, duration of sexual partnerships, information about core spreaders, frequency of sexual activity, probability of transmission, the likelihood of partner referral for treatment) to estimate the effect of screening on the force of infection, as well as on health and costs.69 These models are necessary in order to explore the effect of strategies that incorporate the screening or treatment referral of sexual partners, the potential impact of screening programs on the force of infection, and the relative role of targeting average risk individuals compared to core spreaders.
In conclusion, the cost-effectiveness of routine C trachomatis screening in women is dependent on assumptions about the natural history of disease following infection. Different assumptions have a wide range of effects on cost-effectiveness results, ranging from the magnitude of ICERs to choice of optimal target age ranges and screening strategies. Priorities for future clinical research should include determination of the risk for PID associated with asymptomatic and symptomatic acute infection, the relative contribution of persistence versus reinfection to repeat test positivity rates, and risk of chlamydial infection in women over the age of 25 years. The availability of this important information will be critical for the optimal design of future screening strategies and a more accurate assessment of the health and economic consequences of C trachomatis prevention and control programs.
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