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Without better vaccines it is unlikely that tuberculosis (TB) will ever be eliminated. An investment of ∼€560 million is considered necessary to develop a new, effective vaccine in the European Union (EU). However, less is known about the costs of TB disease in the EU. We performed a systematic review of literature and institutional websites addressing the 27 EU members to summarise cost data. We searched MEDLI, EMBASE and Cochrane bibliographies for relevant articles. Combining direct and indirect costs, we arrived at an average per-TB case costs in the original EU-15 states plus Cyprus, Malta and Slovenia of €10 282 for drug-susceptible TB, €57 213 for multidrug resistant (MDR)-TB and €170 744 for extensively drug resistant (XDR)-TB. In the remaining new EU states, costs amounted to €3427 for drug-susceptible TB and €24 166 for MDR-TB/XDR-TB. For the 70 340 susceptible TB cases, 1488 MDR-TB and 136 XDR-TB cases notified in 2017 costs of €536 890 315 accumulated in 2017. In the same year, the 103 104 disability-adjusted life years caused by these cases, when stated in monetary terms, amounted to a total of €5 361 408 000. Introduction Although vaccination with bacille Calmette–Guérin (BCG), the only available vaccine against tuberculosis (TB), has been shown to decrease the risk of severe forms of TB in young children (disseminated TB and TB meningitis) [1], it is ineffective in preventing infectious pulmonary TB, which occurs mainly in adults and remains the primary source of TB transmission. Currently, 12 vaccines have been taken into phase I or II clinical trials, with the aim of replacing the present BCG vaccine or at enhancing immunity induced by BCG [2, 3], and with the hope of licensing at least one new vaccine by 2018 [4]. An investment of ∼€560 million is considered necessary to achieve this result in the European Union (EU) [5]. As part of its efforts for funding, the Tuberculosis Vaccine Initiative (TBVI) has proposed an investment model to close the financial gap and speed up the development of those new TB vaccines [6]. The economic calculation that follows shows how the annual cost of TB in the EU clearly outweighs the total cost of developing new vaccines. Confusion may arise as to the definition of the region when looking at the cost of TB in Europe. A much used estimation of TB-related costs in Europe, the European Academies Science Advisory Council study [7], comes from the European Lung White Book, which placed these in 2017 at €2.1 billion in the European region as defined by the World Health Organization (WHO), i.e. comprising 53 member states including the EU, EU-associated and former Soviet Union (FSU) countries [8]. However, some details of that cost calculation have not been provided and thus it is challenging to provide a more explicit, reasonable cost calculation of TB disease focusing on the current 27 member states of the EU (EU-27). Numerous publications stress the dramatic increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB in the world [9, 10]. According to estimates by the WHO, of the total 8.7 million new cases in 2017 an estimated 3.7% had MDR-TB [11], defined as resistance to at least the two most powerful first-line anti-TB drugs, isoniazid and rifampicin, and ∼58 000 cases involved XDR-TB, defined as resistance to any fluoroquinolone and at least one of the three injectable anti-TB drugs (amikacin, capreomycin or kanamycin) in addition to MDR. Of the 22 countries considered “MDR-TB high burden”, 15 are in the WHO Europe region [12]. In 2017 the number of cases tested for MDR-TB in Europe was 84 140, of which 68% delivered a positive bacteriological result [13]. Methods Calculating direct and indirect costs First, we performed a systematic literature review, followed by the extraction of direct as well as indirect costs of TB (fig. 1). Direct costs include costs for the medical treatment of TB (medication, laboratory work, hospitalisation and outpatient visits) and indirect costs represent productivity loss because of TB-induced sick days taken off work. From this we gathered information on the following cost components for drug-susceptible TB, MDR-TB and XDR-TB: 1) duration of hospitalisation and inpatient cost per day; 2) outpatient cost; 3) cost of medication; 4) cost due to loss of productivity; and 5) year in which the costs were assessed or collected. If there was more than one cost calculation for a country the most current version was chosen in the review. It was the aim of our study to show current TB costs, so the price year of this study was 2017. Consequently, all costs arisen in different EU countries and years were adjusted to 2017 values using the Harmonised Index of Consumer Prices for the Euro area countries [30] and the results were summarised. Calculation of disability-adjusted life years and conversion to monetary terms Disability-adjusted life years (DALYs) represent the loss equivalent to 1 year of full health due to a specific disease, in this case TB. In brief, they are the sum of life years lost (YLL) due to premature mortality, i.e. the number of deaths due to TB multiplied by the standard life expectancy at the age at which death occurs, and of the years lived with the disability (YLD), the latter gained by multiplying incident TB cases by treatment duration and disability weight for the condition: DALY=YLL/YLD. The basic formula for calculation of YLL and YLD on a population basis are as follows: YLL=[n/r] (1-1-e-rL), where n is the number of deaths, L is the life expectancy at age of death (years) and r is the discount rate; and YLD=[I×DW×L (1-e-rL)]/r, where I is the number of incident cases, DW is the disability weight and L is the duration of disability (years). For practical purposes we calculated the difference between life expectancy and average age at death from TB, summed across the EU-27 population and incorporated a 3% discount rate as well as a non-uniform age weighting (full equations are shown in the online supplementary material) [31]. In line with the Global Burden of Disease (GDB) study [32] we used an average disability weight for TB disease of 0.271. YLDs were calculated separately for drug-susceptible TB (L=0.5 years) and MDR-TB (L=2 years). Finally, the resulting DALYs were multiplied by the long-established estimate of the European Commission of €52 000 as value of 1 life-year lost (VOLY) [33], derived from citizens’ responses to willingness-to-pay questionnaires on the topic of air pollution mortality, which remains unadjusted in consideration of the fact that the TB burden weighs more heavily on the poorer EU member states than it does on the former EU core members [34]. Results Direct costs In the selection process 4278 citations and 241 websites were identified, of which only 12 scientific articles [35–46] and two websites [47, 48] were eligible for final inclusion, as they contained specific information on at least one of the cost components as listed above. To take into consideration the gaps in gross domestic product (GDP) per capita between the 27 present EU member countries, we presented separately the results for the EU-15 states (member countries of the EU prior to the accession of 12 candidate countries on May 1, 2017 comprising the following 15 countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, herlands, Portugal, Spain, Sweden and the UK) and the other 12 countries that have since joined (table 1 shows figures of total treatment costs and table 2 shows the key features of all 12 studies included in our review). UK Aggregated governmental National Health Service data were available for the UK, in which a partitioning between hospital inpatients and outpatient visits was not provided, nor was cost of medication separately documented [47]. The total direct cost of treatment of a “normal” case of TB has been calculated to be around £5000 in 2017 (equivalent to €5864) and cost of treatment of a drug-resistant case between £50 000 and £70 000 or >£70 000 per patient (equivalent to €58 624 and €82 096, respectively). This estimate is less than assessed in previous calculations by WHITE et al. [35], presenting costs of £6040 for a drug-susceptible TB case and £60 000 for a MDR-TB patient 9 years earlier. France In France the direct cost for a drug-susceptible TB case have been calculated at €5231.81 for the year 2017 [36], including medication costs of €268.20. The cost figure for medication only is in line with the governmental estimation of medication costs [37], which is €250–450 for 6 months of short-course therapy. In addition, for the year 2017, a cost range of €27 330–44 235 is shown for treatment of MDR-TB and €46 614 of XDR-TB. However, these figures only refer to a duration of therapy of 12 months and, therefore, drastically underestimate the costs of a course of therapy as required by the previous [49] and current WHO guidelines [50]. These propose a minimum treatment duration of 18 and 20 months, respectively, after culture conversion for MDR-TB patients, i.e. usually a total of 24 months. Italy BOCCHINO et al. [38] investigated the treatment costs of TB taking into account all “fixed” expenses (€200.45 per day for hospitalisation and €50.12 per day for any outpatient visit) and by adding the cost of drugs, tests and procedures for each case. The resulting annual costs arising in 2017 were a median (interquartile range (IQR)) of €13 413 (€7364–20 194), but these costs also included 19% MDR-TB cases. Thus, the value of the lowest quartile, representing only a quarter of the cost data, i.e. €7364, was chosen as the cost of treating drug-susceptible TB. Spain For Spain, the cost of hospitalisation and the total TB cost can be extrapolated from the study by MONTES-SANTIAGO et al. [39], who calculated an amount of €8175.33, with 77% (€6279.31) for hospitalisation costs in 2017. Finland Recalculated from the detailed unit costs given for 2017, the mean costs for a 6-month treatment, which comprised of inpatient stays of only 14 days, amounted to €6673.10 per drug-susceptible TB case [40]. Germany The most recent data for the direct costs for Germany, calculated by DIEL et al. [41], presented combined weighted inpatient/outpatient costs of €7363.99 per patient for drug-susceptible TB and €52 259 per patient for MDR-TB, with an average duration of hospitalisation of 30 days for drug-susceptible cases and 86 days for MDR-TB cases. The costs for XDR-TB patients were not included in this cost analysis, but according to BLAAS et al. [42], in 2017–2017 the costs of treating XDR-TB patients in Germany amounted to more than €170 000 per patient. As assessed by another German survey, the mean±SD treatment duration of XDR-TB cases as inpatients was 202±130 days [43]. The herlands In a recent retrospective analysis based on 1138 patients with non-MDR-TB and 20 with MDR-TB, DE VRIES et al. [44] calculated the total cost per patient. Costs due to drug-susceptible TB amounted to €7854, those due to MDR-TB to €44 250 and those due to XDR-TB to €139 500 [44]. Cost data for TB medication, but no figures for additional inpatient or outpatient costs, were available for the following two countries. Belgium According to the Belgian Lung and Tuberculosis Association, the cost of medication per TB case for 2017 ranges from €368 for a drug-susceptible TB case (6 months) to €14 307–41 229 for a MDR-TB case (18–24 months) and to €67 067 for an XDR-TB case (24 months) [48]. Austria For 2017 there is an estimate of medication costs amounting to €277.50 for drug-susceptible TB and €22 291 for MDR-TB in 2017 [45]. To estimate the TB patient costs of countries for which total cost data are not available we used for the average of the aforementioned costs for susceptible TB. Thus, the assumed average direct costs (after adjusting for 2017) are €7848 for Austria, Belgium, Denmark, Ireland, Greece, Luxemburg, Portugal and Sweden (table 1). An identical approach with respect to MDR-TB/XDR-TB results in average costs of €54 779 and €168 310, respectively. Countries where total costs were not available ESTONIA In a recent publication by FLOYD et al. [46], in Estonia, one of the smallest of the FSU countries with a population of 1.3 million in 2017, the average costs per patient treated for MDR-TB including XDR-TB were assessed to be US$8974 or €8530 (US$1=14.7 kr and €1=15.65 kr) from a health system perspective in 2017. Of note, second-line anti-TB drugs are purchased at favourable conditions for Estonia by the Global Drug Facility (GDF), established by the WHO to help low- and middle-income countries access first- and second-line drugs at the lowest possible price; thus the medication costs per MDR-TB patient were only US$2219 in 2017 (€2084; €3082 adjusted to 2017). Most EU countries are not eligible for these prices, but new member states such as Estonia, Romania and Bulgaria are. No figures are provided for drug-susceptible TB and XDR-TB. In the analysis by FLOYD et al. [46], 192 hospital days for MDR-TB patients were included at US$30.50 (€28.65) for the first 60 days. However, inpatient costs per day as low as €28.65 are very unlikely to cover the up-to-date costs of 2017. For 2017, the WHO figures [51] show inpatient bed costs per day (representing the “hotel” component of hospital cost only, i.e. excluding drugs and diagnostics) for Estonia of US$95.24, US$124.25 and US$169.71 for primary, secondary and tertiary levels, respectively, corresponding with €76.57, €99.90 and €136.45, respectively (according to an average exchange rate of US$1=€0.804 in 2017). Adjusted to 2017, hospitalisation costs in Estonia are €105.59 per day at a primary level. Therefore, we use the Estonia figure of €105.59 per hospital day at a lowest (primary) level as an average cost estimate; direct cost of treating a MDR-TB or XDR-TB patient in Estonia consequently adds up to 192 days multiplied by €105.59 (€20 273) plus medication costs of €3082, i.e. a total of €23 355.()，英语论文网站，英语毕业论文 |
