Owing to accelerated prevention and control measures, syphilis cases in the United States were relatively low in the early and mid 1990s.1 However, by the 21st century, reports of the burden of syphilis indicated resurgence, in part, because of an increase in rates for men who have sex with men.2,3 Curbing this trend requires training health-care officials, renewed vigilance, and detection methods, as well as innovative evidence-based prevention interventions.4
The control and prevention of syphilis is important because untreated syphilis can progress into serious and financially burdensome conditions such as gummatous, cardiovascular and neurologic complications that can lead to significant disability and premature death.5 Syphilis may cause congenital infections resulting in fetal or perinatal death in 40% of affected pregnancies,5,6 as well as disease complications in surviving newborns, such as central nervous system abnormalities; deafness; multiple skin, bone, and joint deformities; and hematological disorders.7,8 Recent estimates suggest that congenital syphilis results in serious adverse outcomes in approximately 80% of cases and affects more than 1 million pregnancies annually worldwide.9–11 In addition, syphilis increases the likelihood of transmission and acquisition of human immunodeficiency virus.12–15
A major component of effective interventions or programs to control and prevent syphilis is detection and treatment,4,16 which require financial investment. Therefore, cost estimates are needed for planning (such as for program cost projections) and implementation of such programs. Cost estimates for primary and secondary (P&S) syphilis are important components when estimating the lifetime cost per case (or episode) of syphilis. Finally, cost estimates are vital in studies of the burden of disease as well as in program evaluation studies such as cost-effectiveness and cost-benefit analyses.
Previous estimates of the cost of P&S syphilis in the United States ranged from $71 to $512 per case (adjusted for inflation to 2007 dollars).17 Because of rapidly changing technology and treatment recommendations, periodic updates of cost are considered necessary. Therefore, our objective in this article was to present updated estimates of the direct outpatient medical cost of care per P&S syphilis infection using claims data from the employer-sponsored commercially insured population in the United States.
MATERIALS AND METHODS
We focused on the most recent outpatient claims data (years 2003–2007) from the MarketScan database (MarketScan Database, Thomson HealthCare, Inc, Ann Arbor, MI). The MarketScan contains data on persons who have employment-based health insurance and lists claims annually on more than 7 million insured persons from more than 100 payers, including large employers, health plans, and government and public organizations in 2003. The majority (approximately 60%18) of the insured population in the United States is enrolled in employer-sponsored commercial health plans, and the database includes weights that allow analyses of the data to be representative of all commercially-insured persons in the United States. The database includes tables with records on outpatient and drug claims. Linkage between the tables is achievable by the use of unique enrollee identifiers that are associated with each record.19
International classification of diseases, ninth revision codes were used to identify patients diagnosed with P&S syphilis (091.0–4, 091.50–2, 091.61–2, 091.69, 091.70, 091.81–2, and 091.89–90). We extracted claims for all outpatient visits in which P&S syphilis were identified as the primary or secondary diagnosis, or both.
We used Healthcare Common Procedure Coding System (HCPCS) codes (which are based on current procedural terminology [CPT] codes) for parenteral treatment as recommended by the Centers for Disease Control and Prevention (CDC) for P&S syphilis16 (J0120, J0456, J0530, J0540, J0550, J0560, J0570, J0580, J0696, and J2510) to identify those treated. Although penicillin (administered parenterally) has been used effectively for over 50 years, there are certain cases where it is not suitable (such as for penicillin-allergic patients).16 Other prescription drug therapies have been shown to be effective for P&S syphilis and have been suggested as alternatives (ceftriaxone,20–23 tetracycline or doxycycline,16,24 and azithromycin25–28). Thus, we used the national drug codes to identify prescription drug (ceftriaxone, tetracycline, doxycycline, and azithromycin) claims and linked them to those diagnosed with P&S syphilis. Following previous studies,29–31 we assumed that drug claims received 7 days before through 30 days after initial outpatient visit were associated with a given episode. Given that P&S syphilis has a substantially longer duration, we also examined drug claims 7 days before through 180 days after initial outpatient visit. We also determined prescription drug coverage for all enrollees.
There are no indicators in claims data to differentiate claims for visits associated with particular infections for an enrollee. This makes determining episodes for multiple infections a challenge. Previous studies have based this determination on the known post-treatment characteristics in relation to the natural history of the disease.29–31 Consequently, claims for visits after an initial visit within a certain number of days (such as 30 days) may be counted as 1 episode and the cost for each episode is the sum of the payments over the specified period.29–31 This implies that the follow-up period used might substantially impact the cost estimates.
Reports on syphilis treatment response indicate that lesions may disappear within days of successful antibiotic treatment of P&S syphilis.32 In addition, the CDC recommends reexamination (clinically and serologically) of patients in 6 and 12 months after treatment.16 In view of this, we estimated the number of episodes and the associated average costs per episode using 1 month, 3 months, 6 months, and 12 months as follow-up periods to examine the sensitivity of the estimated average cost per episode to the follow-up period used. We estimated average cost per patient as well using the end of the period of the analysis (December, 2007) as the end of follow-up period for each patient.
To ensure that costs for other diseases were not included in our final estimate, we analyzed claims in which diagnosis were exclusively for P&S syphilis (i.e., we excluded claims for visits if the primary or secondary diagnosis code was for another disease). We then estimated the average total cost exclusively for those with treatment claims. We also estimated overall average cost for claims that included non-P&S syphilis codes (i.e., either the primary or secondary diagnosis code was a non-P&S syphilis diagnosis code) for comparison. Finally, we identified and analyzed CPT codes for syphilis screening (80055, 86592, 86593, 86781, and 87285).33
Costs provided in the database included costs paid by both the enrollee and insurance plan, and the cost per episode was the sum of all claims paid during the follow-up period. A 2-sided t test was used to test for differences in average costs and a 2-sided z test was used to test for differences in proportions. All cost estimates were weighted using the national weights available in the MarketScan database. We adjusted all costs to 2007 US dollars using the medical care component of the Consumer Price Index for All Urban Consumers.34
A summary of the results is presented in Table 1. Based on a 12-month follow-up period, there were a total of 2123 males with P&S syphilis who had 3341 outpatient visits, and 1667 females with 2274 visits between 2003 and 2007. Overall, the outpatient parenteral treatment rate was very low (7%), but was significantly higher (P < 0.05) for males than females (11% vs. 2%). The oral drug treatment rate was also very low even when we used the 180-day window (2%). When we used the 30-day window, the treatment rate was approximately 1%.32
Our results indicated that the average cost per episode of P&S syphilis on an outpatient basis was $194 (males, $198; females, $192). There was no significant difference between males and females. Estimated average cost per parenteral treatment was $52. However, the average parenteral treatment cost was significantly higher (P < 0.05) for males ($54) than for females ($39). When we estimated the cost exclusively for those who were treated parenterally on an outpatient basis, average cost per episode was $229 (Table 1). However, there was no significant difference in the estimated average total cost per episode between males ($233) and females ($227). Finally, we found that the overall average total cost per episode for visits with diagnoses that included non-P&S syphilis diagnosis codes was $228. However, the average cost for visits with diagnoses that included non-P&S syphilis diagnosis was significantly higher (P < 0.05) for males ($247) than for females ($218).
Results of the sensitivity of the estimated average cost per episode and total number of episodes with the associated follow-up period are summarized in Figure 1. As expected, the estimated total number of episodes decreased as we increased the follow-up period from 1 month to 12 months and beyond. However, the greatest difference in total estimated number of episodes was between the 1- and 3-month follow-up period. The total number of episodes decreased from 4913 to 4441—a 10% decrease. Decreases in the estimated total number of episodes were as follows: 6%—from 3 months (4441) to 6 months (4172), 5%—from 6 months to 12 months (3977), and 5%—from 12 months to per patient/end of analysis period (3790).
The 1-month follow-up yielded average cost estimate ($160) that was significantly lower (P < 0.05) than the estimates for all the follow-up periods used. However, there was no significant difference between the estimated average cost per episode for the 6-month follow-up ($186), 12-month follow up ($194) and per patient ($194) estimates. Therefore, the cost estimate was stable at follow-up periods 6 months and beyond (Fig. 1). Given the known postdiagnoses/treatment characteristics of P&S syphilis and the recommendation by CDC to follow-up for 12 months after treatment, we analyzed the associated claims information based on the 12-month follow-up estimates. As a result, all the information reported earlier and shown in Table 1 was based on a 12-month follow-up period.
We found more than 70% (n = 48) of the oral prescription drug claims were for azithromycin whereas 28% were for tetracycline. We found only 1 claim for ceftriaxone associated with a patient diagnosed with P&S syphilis. However, almost one-third of the claims (n = 20) were for supplies greater than 14 days. The average cost of oral therapy was $122. However, the estimated average cost for azithromycin ($170) was significantly higher (P < 0.05) than tetracycline ($6).
Over 87% (n = 238) of the outpatient parenteral treatment CPT codes were penicillin parenteral treatment codes (J0530, J0540, J0560, J0550, J0570, and J0580). Approximately 10% (n = 27) was for parenteral ceftriaxone (J0696).
Among the CPT codes for testing of persons with P&S syphilis, more than 82% (n = 678) were for nontreponemal tests (86592 [qualitative] and 86593 [quantitative], e.g., venereal disease research laboratory or rapid plasma regain). The remaining 18% (n = 116) were for confirmatory tests (86781, treponemal test e.g., Treponema pallidum particle agglutination (TP-PA), enzyme immunoassay, or fluorescent treponemal antibody absorbed). As expected, estimated average cost for the treponemal test (86781, $19) was significantly higher (P < 0.05) than the nontreponemal tests (86592, $11; 86593, $8).
We estimated the direct outpatient cost of P&S syphilis using the most recent data from the employer-sponsored commercially insured population in the United States. Our results indicated that the overall average cost per episode of P&S syphilis for those who were diagnosed and treated parenterally on an outpatient basis was $229. This estimate is substantially lower (over 50%) than the upper bound estimate reported in an earlier study, but over 3 times higher than the lower bound.17 We did not find any significant difference between the total costs for males and females although the cost per parenteral treatment was significantly higher for males.
The estimated screening cost for initial nontreponemal test was significantly lower than the cost for confirmatory treponemal tests. Our estimates for these serologic tests for syphilis are consistent with reported cost estimates in other settings.35 We found that a large proportion of the screening was done using the cheaper nontreponemal test, which may suggest that the nontreponemal tests were used as initial tests which were then followed, if positive by the more expensive and time-consuming confirmatory treponemal tests as recommended by the CDC and the United States Preventive Services Task Force.5,16 However, recent reports indicate a reversal of the order of testing due to the development of cheaper automated treponemal tests (enzyme immunoassays/chemiluminescence assays) in many settings.36 Unfortunately, the CPT codes we identified do not distinguish a confirmatory test from initial screening tests so we could not examine the order, nor type of treponemal test, and the potential associated impact on the cost estimates in this study.
This study has limitations that are characteristically associated with the use of medical claims data to estimate diagnoses and treatment rates. The major limitation was the substantially small number of treatments found for the cases identified although we tried to identify both parenteral and oral drug regimen. However, the relatively low treatment rate we found in this study is consistent with treatment rates reported for other sexually transmitted diseases (STDs) by previously published studies that used this database.29,31,37 The low treatment rate we found may be due to one or a combination of several reasons including low use of the HCPCS code in the database, referral to public clinics for treatment, treatment with a regimen not recommended by CDC, incorrect or inconsistent CPT coding, use of free samples, or with a regimen not covered by the insurance plan or not paid via insurance claim.
The claims rate (based on the number of claims and the overall number of enrollees) found was substantially lower compared to the national rates reported for the same year.3 This may be because some patients sought care in public STD clinics that were not acquired in the database. Previous studies have reported that STD rates are relatively higher for persons with low socioeconomic status.38–41 Thus, another reason for the relatively low rates found in this study is that the insured population have higher socioeconomic status.42
Second, diagnosis codes in claims data can be inaccurate for one or a combination of several reasons, including clinician diagnostic and data entry errors.43,44 Chart review might make the identification of P&S syphilis cases as well as the estimation of associated costs substantially more accurate. In addition, as mentioned earlier, it is difficult to differentiate between visits that represent follow-ups for a particular episode and those that represent repeat infection episodes. These have implication for the estimates of cost and the number of episodes of repeat infections. To address this concern, we demonstrated the sensitivity of our estimates to the follow-up period used. Given that our results for the number of episodes of infection stabilized at 12 months and beyond, coupled with the known post-treatment history of syphilis, we believe that the 12-month follow-up was the most accurate.
Our final estimate of the overall average of treatment cost was based on parenteral treatments only because this is the recommended treatment and the most common.16 Second, it is possible that the drugs found within the time window we used could be for a coinfection that may not have been caused by P&S syphilis. For instance, the majority of oral therapies were azithromycin that is also one of the major drugs prescribed for other STDs (such as chlamydia, chancroid, and nongonococcal urethritis).16 Additionally, azithromycin is no longer recommended as therapy for syphilis as a result of reported resistance in several geographic areas.45 Although we found relatively small number of patients with treatment, we believe that because this is an insured population, the majority of the confirmed cases were treated.
Therefore, we believe that our estimate of the average cost for those who were treated is the more accurate estimate of the outpatient medical cost of care per case of P&S syphilis for those who were diagnosed and treated on an outpatient basis. To the extent that we were interested in the average cost, the relatively small number of parenteral treatments found should not affect our final estimate substantially.
Another limitation of our study is that the estimates we determined are only representative of the employer-sponsored commercially insured population and are not representative of the entire US population.
Our estimate represents a lower-bound estimate of the economic burden per case of P&S syphilis because we did not include other associated costs such as intangible costs (e.g., pain and suffering) and lost productivity costs. We did not include the cost of testing for later stages of syphilis (such as lumbar puncture procedures for cerebrospinal fluid tests32) and caring for syphilis-related sequelae such as gummatous, cardiovascular, neurologic complications, premature death, perinatal death5,6; central nervous system abnormalities such as deafness; multiple skin, bone, and joint deformities; and hematological disorders in newborns7,8 for those not adequately treated. Finally, we did not include the cost attributable to the elevated likelihood of acquiring human immunodeficiency virus as a result of syphilis.12–15
Despite the limitations listed previously, this study provides the first and most recent direct estimate of the outpatient medical cost of care for P&S syphilis in the US employer-sponsored commercially insured population.
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