Epidemiological study Cost-effectiveness oj screening for C. trachomatis in Slovenia K E Y WORDS Chlamydia trachomatis, screening, cost-effec- tiveness, adolescent females Cost-effectiveness oj screeni-ngfor Chlamydia traclwmat-is in adokscent femaks in SWVenia A. Skaza and I. Eržen SUMMARY The aim of the study was to evaluate the cost-effectiveness of screening at an estimated asymptomatic Chlamydia trachomatis prevalence of 6% in a cohort of 67,870 adolescent females by using the cost- effectiveness analysis (CEA). There were two screening strategies evaluated; screening by means of a direct immunofluorescence (DIF) assay and screening by means of a polymerase chain reaction (PCR). Both screening strategies have proved cost-effective when considering the current prices of DIF and PCR assays in Slovenia (population 2 million). Screening by means of DIF would generate a saving of 3.7 million US dollars, whereas with the PCR such saving would amount to 660,000 US dollars. Introduction Chlamydia trachomatis exists as an intracellular parasite of cuboidal epithelium cells in human body only. It is known to cause trachoma, inclusion conjunc- tivitis, urinary and genital inflammatory diseases, lym- phogranuloma venereum, neonatal pneumonia, arthri- tis , there is also a possible association with the devel- opment of cervical cancer (1,2). In mastering and controlling sexually transmitted C. trachomatis infections, asymptomatic infections repre- sent the greatest problem. In women, up to 70% of cer- vical infections and about 30% of pelvic inflammatory diseases develop asymptomatically (3). The most se- vere complications of chlamydial tuba! inflammation are those of ectopic pregnancy and infertility ( 4). As severa! sexually transmitted C. trachomatis in- fections develop with no evident signs of infection, it is essential that such infections are detected and treated in tirne, if we are to master them, and above all, their consequences. And this is precisely what screening far C. trachomatis infection is aimed at: to reduce the oc- currence of the infection, as well as treat the infected persons and their sexual partners in tirne and thus pre- vent the sequelae of such infection (55. Screening of both adult and adolescent females can be considered cost-effective not only at high but also at low prevalence of 3% to 6% (5 , 6, 7, 8). The economic analyses of screening programmes are based on the evaluation of costs and results of procedures imple- Acta Dermatoven APA Vol 11, 2002, No 4 - ------------ - - - -----119 Cost-ejfectiveness of screening for C. trachomatis in Slovenia mented to achieve the set health objectives. As the case with all preventive programmes, the invested funds should be justified on the grounds of improved health status in the target population (9). Materials and methods In the cost-effectiveness analysis (CEA), direct costs were taken into consideration, which include the cost of laboratory testing, the cost of other diagnostic pro- cedures as well as the cost of medica! treatment, as rec- ognized by the Institute of Health Insurance of Slovenia in accounting the costs of health services. In Slovenia, the Institute of Health Insurance is the only payer of health services. Furthermore, indirect costs were also considered , incurred by the absence from work due to illness (sick leave). The strategy of screening adoles- cent females anticipated two methods of detecting the persons infected: the direct immunofluorescence (DIF) assay and the polymerase chain reaction (PCR) method. According to the estimate of the Institute of Health Insurance of Slovenia, the financial burden brought upon the state due to !ost working days in Slovenia in 2001 was 264 million US dollars. The average gross in- come was 840 US dollars. There was an average of 25 US dollars paid per employed insured person per day of sick leave (10). In treatment of infected persons and their partners only the cost of such medication was considered, which is available on prescription only and in Slovenia paid for to the pharmacies by the Institute of Health Insur- ance of Slovenia and thus considered no direct cost for the patient (11,12). Such costs were compared to the costs of female adolescent screening. The costs of con- sumer material, specimen transportation as well as trav- eling expenses due to treatment outside the place of permanent residence were not evaluated. The average direct costs in adolescent females, in- curred as a result of C. trachomatis infection , originate from the treatment of cervicitis , acute pelvic inflamma- t01y diseases, ectopic pregnancy, infertility and chronic pain in women (3,5). The costs of treating neonates, bom to mothers with chlamydial cervicitis, were not considered, as the costs associated with such infections had been evaluated in adolescent females aged from 15 to 19 years (13). In Slovenia, only 0.7% of those give birth to a child (14). With regard to chlamydial cervicitis, from 30% to 50% of infected adolescent females were anticipated to visita gynecologist and undergo treatment on an out- patient basis (3). In the remaining females not undergoing treatment, 20% of infem;d females develop an acute pelvic inflam- matory disease (5,15). For a half of those, outpatient 120 Epidemiological stud y treatment was anticipated, whereas for the rest treat- ment on an inpatient basis. In that case, no costs due to absence from work were taken into consideration, as the acute inflammatory disease was assumed to develop in adolescent females not yet employed. The consequences of pelvic inflammatory disease as a result of C. trachomatis infection can at a later stage show as infertility, ectopic pregnancy; women are suf- fering from chronic pelvic pain. There were 20% of women estimated to experience chronic pain, ectopic pregnancy was estimated to occur, on average , in 15% of women, whereas 20% of women were estimated to suffer from infertility (5). The costs of diagnostic procedure and treatment of an adolescent female for chlamydial cervicitis as well as treatment of her partner with azithromycin were es- timated at 50 US dollars. In 10% of adolescent females, such costs would increase by 14 US dollars due to de- veloping moniliasis asa result of azithromycin therapy. The cost of treating acute pelvic inflammatory dis- ease on an outpatient basis was estimated at 44 US dol- lars, whereas the cost of hospitalization at 970 US dol- lars. In Slovenia, in accounting the costs of services the Institute ofHealth Insurance ofSlovenia pays the "cases" to service providers for ali hospitalized patients. A "case" includes ali activities provided for the insured person in the period of his/ her stationary inpatient treatment (16). With all later complications (chronic pain, infertil- ity, ectopic pregnancy), we, in addition to direct costs, also considered the absence from work due to health problems as recognized by the Institute of Health In- surance of Slovenia in the sick-leave accounting. In women with chronic pain, the costs including at least 14 days of sick leave were estimated at 310 US dollars. With regard to ectopic pregnancy and diagnosing of infertility, where in both cases at least 1 month of sick leave was anticipated, the estimated costs amounted to 1,520 US dollars. With reference to infertility treat- ment, there were 4 attempts of in vitro fertilization an- ticipated at the costs of the Institute of Health Insur- ance of Slovenia , these connected with a month's ab- sence from work (17). In Slovenia, there are three cen- ters to provide such services of infertility manageme~t. The average cost at the tirne of the concluded labora- tory portion of the attempt amounts to 1,400 US dollars (Elena Nikolavčič , personal information). In Slovenia, women are within the scope of compulsory health in- surance entitled to four attempts of in vitro fertilization per pregnancy in their fenile period (18). With the screening costs, we took into account the cost of laborato1y testing with the PCR and the DIF methods as well as the cost of treating the infected per- sons and their partners with 1 g of azithromycin. Acta Dermatoven APA Vol 11, 2002, No 4 Epidemiological study The cost of PCR method to test urine specimens far C trachomatis in Slovenia is 80 US dollars. The aver- age cost of DIF assay to identify C. trachomatis in cer- vical smear is 32 US dollars. The cost of treating an in- fected adolescent female and her partner with azithromycin is 28 US dollars. The calculations to evaluate the cost-effectiveness of screening by comparing the screening costs to the costs associated w ith the infection sequelae were made by using computer programme Office Pro 97 Microsoft Excel (Win 32, Authorization No. 97922239AAB0001 , License No. 97923634, SL3). Results On the basis of the 2.6% prevalence found by using the PCR method on urine specimens of 1272 adoles- cent males (confidence interval from 1.7 to 3.5, p<0.05) and the results of the cross-sectional epidemiological study in adolescent females (19, 20), it was estimated that in Slovenian adolescent females aged from 15 to 19 years there w ere at least 6% infected with C. trachomatis. Such estimation also originates from the information that in the age group from 15 to 19 years the number of females infected with C. trachomatiswas 3- to 9-fold w hen compared to males from the same age group (21). With regard to the estimated prevalence, the cohort of 67,870 adolescent females in Slovenia in- cludes at least 4,072 with C. trachomatis infection. Of the infected population, only 35% (1,425) are being treated for cervicitis . The acute pelvic inflamma- tory disease was anticipated in 530 adolescent females, 529 women will have chronic pain at a later stage, 397 women will experience an episode of ectopic preg- nancy, whereas due to chronic pelvic inflammatory dis- ease 529 women will suffer from infertility and will un- dergo 4 attempts of in vitro fertilization at the cost of the Institute of Health Insurance of Slovenia (Table 1). The costs of screening and infection treatment in a cohort of adolescent females , when using the DIF as- say on cervical smear specimens , would at the current price of DIF assay in such population amount to 2.3 million US dollars. Thus, such screening would already at present generate a saving of 3.7 million US dollars. A presently implemented DIF screening strategy in ado- lescent females would prave cost-effective at the preva- lence as low as 2.4% (Figure 1). With screening in a cohort of adolescent females by implementing the PCR method on urine specimens, the required funds would amount to 5.3 million US dollars . When compared to costs associated with complications (6 million US dollars) , there would be a saving of 660,000 US dollars. At a prevalence of 5.3%, the screening costs would equal the saving generated, if any (Figure 2). Cost-effectiveness oj screening for C. trachomatis in Slovenia Discussion In economic evaluation of adolescent female popu- lation based screening we have, on the assumption of a 6% prevalence of asymptomatic infection in such popu- lation, evaluated the cost-effectiveness of screening by means of DIF assay on cervical smear specimens and PCR assay on urine specimens. We anticipated to have tested ali adolescent females in the cohort, which is, however, difficult to achieve in practice. According to the first screening strategy, the detec- tion of persons infected with C. trachomatiswas based on DIF assay on cervical smear specimens, which is at our estimated prevalence rate considered a suitable method with regard to sensitivity and specificity (22). There are ten laboratories in Slovenia to implement such tests within the scope of public health service network. The costs without screening in a cohort of 67,870 adolescent females at a 6% prevalence of C. trachomatis were estimated at 6 million US dollars, whereas the es- timated costs of DIF assay screening including treat- ment of an infected adolescent female and her partner with azithromycin were 2.3 million US dollars. The DIF screening strategy proved highly cost-effective, as it would generate a saving of 3.7 million US dollars . The problem with this strategy, however, lies in the afore- mentioned inability of encompassing the population as a whole, whereas the advantage is that of a developed laboratory network. The major problem with screening strategies planned is in the response rate of the population to be screened. The majority of opportunistic screening programmes have to encounter too low number of par- ticipants in such programmes, as the recruitment solely depends on coincidental visits of individuals. Accord- ing to J. Paavonen, gynecological checks would cover less than a half of females aged from 15 to 25 years (5). In Finland, the evaluation of universal screening strategy, which anticipated 75% of women participat- ing on the assumption of a 5% prevalence of C. trachomatis, led to the conclusion that the PCR screen- ing strategy on urine specimens might prave cost-ef- fective already at the prevalence as low as 3.9% (5). Furthermore, one attempt of in vitro fertilization was anticipated for every woman suffering from infertility, and not four attempts as the case in our country. The cost of such attempt was estimated at 2,444 US dollars. In extensive cross-sectional epidemiological study, ].M. Marazzo with associates observed a 6.6% preva- lence of women infected with C. trachomatis. The in- fection was diagnosed by using the DIF assay. In their estimation, the universal screening "of women has praven most cost-effective, regardless of the age of the participants (8). According to Dutch studies, preventing one of the anticipated late complications as a result of C. tracho- matis infection would require examination of 479 Acta Dermatoven APA Vol 11, 2002, No 4 -------------- - - --------,21 Cost-effectiveness oj screening for C. trachomatis in Slovenia 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Prevalence (~ -....costs without screening -Screening costs Figure 1 . Prevalence effect on total costs of screening by means of DIF assay to detect C. trachomatis in a cohort of 67,870 adolescent females and on costs without screening. DIF=direct immunofluorescence women aged from 15 to 40 years. The costs associated with such examination were estimated at 15 ,800 US dollars. An average of 2 attempts of in vitro fertilization was foreseen, with 70% of infertile women to decide on undergoing such treatment (we anticipated all in- fertile women would decide on undergoing such treat- ment as infertility was to have been identified in women, younger than 30 years). On the assumption of urine specimens tested by using the lygase chain reaction (LCR) method in a co- hort of 161,065 women, they concluded that at the esti- mated 2.2% prevalence of C. trachomatisthe universal screening programme for detection of C. trachomatis in the cohort woulcl not be cost-effective (23). In our evaluation, it was anticipatecl that all women would clecide on undergoing in vitro fertilization , and Epidemiological study C, = -2 -~ ~ -4 CI) -6 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 . Prevalence (%) ----e-costs without screening--Screening costs Figure 2. Effect of C. trachomatis prevalence on cost-effectiveness of the PCR screening strategy in a cohort of 67,870 adolescent females in Slovenia. PCR=polymerase chain reaction that at least four times, which they are entitled to in accorclance with the Slovenian legislation and the rights arising from the compulsory health insurance (18). Costs were also estimated for the case of the second attempt of in vitro fertilization having proved successful and the woman giving birth to a child. In such case, however, the costs do not cliffer consiclerably from the costs as- sociated with four attempts of in vitro fertilization. After successfully performed in vitro fertilization, the major- ity of pregnant women in Slovenia are namely on sick leave from 28 to 42 days respectively prior to the date of delivery, and receive a sick pay. The consequences in babies, live bom to an infected adolescent female with cervicitis, were not considered in our calculations. According to statistical data, 507 adolescent females aged from 15 to 19 years gave birth Table 1. Estimated costs of infection sequelae at the estimated 6% prevalence of C. trachomatis in a cohort of 67,870 adolescent females in Slovenia. Wection sequelae No. of persons Costs per person· Costs total* Cervicitis 1425 50 71 ,250 Moniliasis treatment 143 14 2,002 Acute pelvic inflammatory disease outpatient treatment 265 44 11,660 Acute pelvic inflammatory clisease hospitalization 265 970 257,050 Chronic pelvic pain 529 310 164,000 Ectopic pregnancy 397 1520 603,440 Infertility - identification 529 1520 804,080 Infertility - 4 attempts 529 1400 740,600 Costs tata! (in million)* 6.000.000 *US dollars 122 --------------------------- -------- Acta Dermatoven APA Vol 11, 2002, No 4 Epidemiological study Cost-eff'ectiveness r!f' screening .for C. trachomatis in Sloveiiia to a live bom baby in Slovenia in 2000, which in this cohort represents 0.7% of adolescent females (14). (5.3%). Although no saving would be generated in such case, both screening ancl timely treatment woulcl never- theless prevent severa! health problems. In Slovenia, the calculated average incidence rate of ectopic pregnancies in the 1990s was 10.5/10,000 women in their fertile period, which represents an aver- age of 458 women with ectopic pregnancy per year. The cost associated with one ectopic pregnancy was esti- mated at 1,520 US dollars, such pregnancy being a pos- sible sequelae of C. trachomatisinfection in 180 women. Conclusions Screening programmes are an opportunity far health care education, a benefit which can hardly be measured in money and on a short term-basis. Economic evalua- tions of screening strategies and analyses are based on estimation, a more or less successful approximation of the actual situation. Due to great importance of sexu- ally transmitted C. trachomatis infections in puhlic health care system in Slovenia, the economic burden of such infections needs to be evaluated. Our evaluation of screening strategies may prave helpful in elaborat- ing a national doctrine of mastering sexually transmit- ted C. trachomatis infections. Here again, the old and already familiar problem of financing arises. And this is, also in Slovenia, one of the key reasons why the screening programmes are not implemented in prac- tice although they have praven cost-effective. The implementation of urine-based PCR screening strategy in adolescent females would improve the sen- sitivity as well as increase costs, which were with such strategy estimated at 5.3 million US dollars. In Slovenia, only the Medica! Faculty in Ljubljana presently imple- ments the PCR assay in diagnosing chlamydial infec- tions. Besides the problem of capturing the population as a whole in this strategy, there is also the disadvan- tage of an underdeveloped laborato1y network far such diagnostics and, of course, the high cost of PCR assay. 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