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Article DOi: 10.5504/bbeq.2011.0141

biOecONOMicS

Biotechnol. & Biotechnol. eq. 26/2012/1

Biotechnol. & Biotechnol. eq. 2012, 26(1), 2811-2816

Keywords: hepatitis B, vaccination, health economics, cost of pharmacotherapy

Introductionimmunisations are widely accepted as cost-saving and cost-effective strategies worldwide (1). it is considered that only clean water performs better than vaccines in terms of reducing the negative consequences of infectious disease (20). the universal immunisations against wide spread infections was proven to be not only effective, but also cost-effective due to the coverage of a lot of potential beneficiaries (5, 6, 13). For diseases with low or intermediate endemicity preliminary economic evaluations have yielded contradictory results which imply the necessity for posterior evaluation (2). introduction of the vaccine against hepatitis B virus (hBV) in the universal immunisation programmes is carefully evaluated from the point of view of cost-effectiveness before the start of the programmes (3, 4, 10, 15). A limited number of studies focus on the evaluation of the long term economic results (11, 14).

the aim of this study was to evaluate the main economic results 20 years after the introduction of obligatory immunisation against hBV in Bulgaria.

Materials and MethodsA prospective epidemiology and retrospective cost analysis was done. At the National Center of Infectious and Parasitic Diseases (NCIPD) information was collected about the number of vaccinated individuals in the new born cohorts and about the reported acute HPV infection cases per year in Bulgaria for the period 1992-2010. the number of averted cases was calculated: Number of averted cases in Yearn = (average number of acute

infections till 1992 – number of acute infections after immunisation in Yearn)After interviews with national clinical experts and literature

review it was assumed that chronification appears in 15% of the infected patients and that the hospitalization rate of the chronic cases is 30% per year (7, 12, 23). Out of all chronic cases 12% will develop cirrhosis and 0.5% will develop hepatocellural carcinoma. Based on these assumptions the numbers of chronic cases, hospitalisation, cirrhosis, and carcinoma cases per year and for the whole period was derived.

only direct medical costs were included in the analysis. Retrospectively, information was collected on the cost of ambulatory pharmacotherapy after hospital discharge of acute cases, hospital charges for acute cases, yearly pharmacotherapy of chronic hepatitis B, cost of hospitalisation due to chronic

ECONOMIC ANALYSIS 20 YEARS AFTER THE INTRODUCTION OF UNIVERSAL HBV IMMUNISATION IN BULGARIA

Alexandra Savova1, Guenka Petrova1, Aneliya Gotseva2, Anna Kurcatova3, Mira Koguharova3

1Medical University – Sofia, Faculty of Pharmacy, Sofia, Bulgaria2University Specialized Hospital for Intensive Care in Infectious and Parasite Diseases “Prof. Ivan Kirov”, Sofia, Bulgaria3National Center of Infectious and Parasitic Diseases, Sofia, BulgariaCorrespondence to: Alexandra SavovaE-mail: alex_savova@mail.bg

ABSTRACTThe aim of this study was to evaluate the main economic results 20 years after the introduction of obligatory immunisation against hepatitis B virus (HBV) in Bulgaria. Prospective epidemiology and retrospective cost analysis was done. During the period 1992-2010 information was collected about the number of vaccinated individuals in the new born cohorts, and about the reported acute HBV infection cases per year in Bulgaria. The number of averted cases was calculated. Only direct medical costs were included in the analysis: the cost of ambulatory pharmacotherapy after hospital discharge of acute cases, hospital charges for acute cases, yearly pharmacotherapy of chronic hepatitis B, cost of hospitalisation due to chronic hepatitis B, and cost of cirrhosis and hepatocellular carcinoma as the most common complication of HBV infection. The net health benefits were analyzed in two scenarios – for the whole period, and for the last 10 years after considering only the acute or both the acute and chronic cases therapy. For the whole period, the investments still prevail over the benefits because of the relative parity between the total number of infections and averted cases. The latter is true for both scenarios – considering only the acute cases cost, and considering both the acute and chronic cases, as well as the complications cost. If the calculations are repeated only for the last 10 years of the observed period (2001 - 2010), the investments nearly equalize the benefits, most evidently in the second scenario, probably due to the highest number of averted chronic cases and hospitalizations.Universal vaccination against HBV is socially beneficial for the Bulgarian population. Its positive economic effects became visible during the last 10 years since its introduction in the immunisation calendar.

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TABLE 1Sources of cost information

Health care resources Description Source

Vaccines 3 doses per individual per year Officially registered prices of vaccines (www.mh.government.bg)

cost of pharmacotherapy of acute cases 6 months after discharge from hospital

Patient registriesPublished studies (17)

hospital charges of acute and chronic casesPublished studies -cost per daynhiF tariff www.nhif.bg

(17)(18)

Ambulatory pharmaco-therapy of chronic hepatitis B Published studiesnhiF tariff www.nhif.bg

(24)(18)

cost of cirrhosis and hepatocellular carcinoma nhiF tariff www.nhif.bg (18)

tABLE 2number of cases included in both scenarios

Type of cases Mean value (SD) for all yearsnumber of infected patients 1228.79 (563.15)Chronic cases (15% of infected patients) 184.32 (84.47)Hospitalized chronic cases (30% of chronic cases) 55.29 (25.34)Cirrhosis in infected group (12% of chronic cases) 22.12 (10.14)Carcinoma cases in infected group (0.5% of chronic cases) 0.92 (0.42)cases averted 1464.53 (564.98)Averted chronic cases 219.68 (84.75)Averted hospitalizations from chronic cases 65.90 (25.42)Averted cirrhosis 175.74 (67.79)Averted carcinoma 7.32 (2.82)

TABLE 3Pharmacotherapy of acute and chronic cases during 1992-2010

Period Acute HBV infections pharmacotherapy Chronic HBV infection pharmacotherapy1992

Serum glucose solutions, hepatoprotectors, vitamins, antibiotic if necessary, spasmolytic if necessary, methylprednisolone if necessary, antiemetic if necessary.

Recombinant IFN-α2a for 6 months 1996 Recombinant IFN-α2a for 12 months 2000 lamivudine 2004 PEG-IFN α2a + Ribavirine2009 telbivudine 2009 entecavir 2009 tenofovir

TABLE 4Mean costs in both scenarios

Costs per acute case Costs per chronic case Type of cost Mean value BGN (SD) Type of cost Mean value BGN (SD)

hospital cost of acute case 702.53 (95.41) hospital cost of chronic case 712.42 (20.27)Ambulatory pharmaco-therapy of acute case 186.84 (42.07) Ambulatory pharmaco-therapy cost of

chronic case 13789.89 (5761.56)

cirrhosis cost per case 712.42 (20.27)carcinoma cost per case 1094.74 (115.34)

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hepatitis B, and cost of cirrhosis and hepatocellular carcinoma as the most common complication of hBV infection.

the sources of cost data were the reviewed patients’ records at three national centres for acute infections treatment, official health insurance fund tariffs and published studies (Table 1). Vaccine prices were taken from the prices in the national positive drug lists since 2003, and officially registered wholesale prices before that (16).

the cost per patient was calculated by multiplying the cost of particular health care resource by its price in the year under consideration. Finally the total cost for a particular type of health care service was calculated and the total therapy cost was obtained.

All costs are presented in national currency BGN (Exchange rate 1 Euro = 1.954 BGN). No discounting was performed due to the fact that real prices were used in the years of consideration.

For assessing the economic impact of the vaccination, the net health benefits were calculated following the formula proposed by Rascati (net benefit = total benefits – total costs) (21). As benefits were considered the averted cases and as costs were considered the immunisation cost and therapy of acute cases appearing instead of the immunisation. the formula was modified in two scenarios – for the whole period, and for the last 10 years (second half of the observed period):

Net health benefit1 = (cost of immunisation + cost of acute cases therapy) –

cost of averted acute cases therapyNet health benefit2 = (cost of immunisation + cost of

acute cases therapy + cost of possible chronic cases and complications therapy) – (averted costs of acute cases

therapy + averted cost of chronic cases and complications therapy)

Results and DiscussionEpidemiology analysisthe vaccine against hBV infection was introduced in the immunisation calendar in 1990 but during the first two years immunisation was not obligatory and reached from 5% to 20% of the new born cohort. After the introduction of the obligatory immunisation the number of vaccinated increased from 68 393 to 76 105 during 1992-2010, thus reaching 100% coverage of all new born individuals in 2010.

A tremendous decline of acute HBV cases was registered from 2268 to 387 during 1992-2010. The average number of acute HBV infections before 1992 was 2717 cases per year. considering the decrease in the acute cases, the number of averted acute hBV cases was calculated, which increased from 449 in 1992 to 2330 in 2010 (Fig. 1).

Based on the assumptions made for chronic cases, cirrhosis, and hepatocellular carcinoma frequency, their expected number was calculated per year and for the whole period in both groups – infected patients and averted cases. the total number

of expected chronic cases during 1992-2010 was 3502, and 4174 chronic cases were expected to be averted. One thousand and fifty-one hospitalizations due to chronification will appear in the infected group and 1252 hospitalizations will be averted. The cirrhosis and carcinoma cases will decrease to 420 and 18 respectively, in the infected group, while the averted cases of cirrhosis and carcinoma are expected to become 3339 and 139, respectively for the whole period (Table 2).

Figure 1. Acute cases of HBV infection and avoided cases per year during 1992-2010

0

500

1000

1500

2000

2500

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

number of acute hBV infections number of avoided acute infections

Fig. 1. Acute cases of HBV infection and avoided cases per year during 1992-2010.

Economic analysisit is a common practice in Bulgaria to hospitalize patients with acute hBV infections with the aim to control the disease progression. the pharmacotherapy of acute and chronic cases differs among the years and follows international standards (Table 3). During the acute phase the pharmacotherapy cost includes mainly hepatoprotectors, infusion solutions, and vitamins. long term low salt diet is recommended. on the contrary, the pharmacotherapy of chronic hepatitis had changed several times. Until 2000 recombinant interferons were used, then lamivudine was accepted as standard therapy, then for 5 years pegilated interferons in combination with ribavirine became a standard, and finally since 2008 the peroral antivirus medicines telbivudine, adefovire and entecavire began to be used (Table 3). the changes in the chromic hepatitis B pharmacotherapy significantly influenced the cost (Fig. 2). the highest was the cost when interferons were used in combination with ribavirine. introduction of per oral antivirus medicines significantly reduced the cost.

Figure 2. total cost of infected and avoided cases

0

1000000

2000000

3000000

4000000

5000000

6000000

7000000

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2 009 2 010

total cost of acute infections total cost of chronic cases total cost of avoided acute infections total cost of avoided chronic infections

Fig. 2. total cost of infected patients and averted cases.

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TABLE 5Results for both scenarios for the whole 20-year period

Scenario 1 - Acute casesInvested costs Averted costs Net health benefit

Type of cost Value BGN Type of cost Value BGN Invested – Averted

total cost of immunisation 34 045 191 total cost of averted acute cases therapy (hospitalization + ambulatory therapy)

25 683 625

total cost of acute cases therapy (hospitalization + ambulatory pharmacotherapy)

19 863 291

SUM 53 908 482 25 683 625 28 224 857Scenario 2 – Acute and chronic cases

Invested costs Averted costs Net health benefitType of cost Value BGN Type of cost Value BGN Invested – Averted

total cost of immunisation 34 045 191total cost of averted acute cases therapy (hospitalization + ambulatory therapy)

25 683 625

total cost of acute cases therapy (hospitalization + ambulatory pharmacotherapy)

19 863 291 total cost of averted chronic cases (hospitalization, pharmacotherapy, cirrhosis and carcinoma)

56 259 627

total cost of chronic cases (hospitalization, pharmacotherapy, cirrhosis and carcinoma)

55 961 805

SUM 109 870 287 81 943 252 27 927 035TABLE 6

Results for both scenarios for the last 10-year period

Scenario 1 - Acute casesInvested costs Averted costs Net health benefit

Type of cost Value BGN Type of cost Value BGN Invested – Averted

total cost of immunisation 26 121 523 total cost of averted acute cases therapy (hospitalization + ambulatory therapy)

18 563 856

total cost of acute cases therapy (hospitalization + ambulatory pharmacotherapy)

7 516 627

SUM 33 638 150 18 563 856 15 074 294Scenario 2 – Acute and chronic cases

Invested costs Averted costs Net health benefitType of cost Value BGN Type of cost Value BGN Invested – Averted

total cost of immunisation 26 121 523 total cost of averted acute cases therapy (hospitalization + ambulatory therapy)

18 563 856

total cost of acute cases therapy (hospitalization + ambulatory pharmacotherapy)

7 516 627 total cost of averted chronic cases (hospitalization, pharmacotherapy, cirrhosis and carcinoma)

28 496 031

total cost of chronic cases (hospitalization, pharmacotherapy, cirrhosis and carcinoma)

13 558 591

SUM 47 196 741 47 059 887 136 854

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immunisation cost permanently increases during the years due to the coverage of more newborn individuals, thus reaching 34 045 191 BGN for the whole period. The first two years 1992-1993 the vaccines were donated and no cost was added.

Due to the decreasing number of infected individuals the total cost of care for acute infections decreased every year, while the cost of averted cases increased (Fig. 2). in 1996-2002 the main driver of the cost of chronic cases was the pharmacotherapy, mainly performed with interferons. After 2002 the new generations of per oral medicines were introduced in the practice which led to a decrease in the cost of chronic cases therapy (Table 4).

For the whole period, still the investments prevail above the benefits because of the relative parity between the total number of infections and averted cases. the latter is true for both scenarios – considering only acute cases cost, and considering acute and chronic cases, as well as complications cost (Table 5). When we repeated the calculations only for the last 10 years of the observed period (2001 - 2010), the investments nearly equalized the benefits, mostly evident in the second scenario, probably due to the higher number of averted chronic cases and hospitalizations (Table 6).

Prevention of chronic HBV infection in Bulgaria is in line with the global World health organization (Who) initiatives to reduce the burden of hBV infection. in 1992, the World Health Assembly appealed to integrate cost-effective new vaccines, including hBV, into national immunization programs and recommended that vaccine against hBV be included in the routine immunisation schedules for all children in all countries (25). The epidemiology results from our study confirmed similar ones for other countries, namely that universal immunisation benefits society by reducing the risk of transmission of infection in particular groups or in general (8, 11, 22).

the universal immunisation against the diseases with intermediate endemicity, as is the case of hBV infection in Bulgaria, could be considered as beneficial for society (5). The social benefits observed were the higher decrease in the number of chronic cases and their consequences. the economic benefits became visible in the last 10 years of the universal immunisation. Additional social and economic benefits might appear after considering factors such as increased travelling and immigration (26).

our analysis differed from similar ones focusing on the immunisation against influenza where the net costs (savings) were calculated after substracting the costs averted due to immunisation from the costs of immunisation (19). this is probably due to the acute character of influenza. We also added the cost of therapy of chronic and complicated cases, having in mind the possibility for chronification of the HBV infection. This might explain the delay in the visibility of the positive economic results because at the beginning of the analysis all

chronic and complicated cases appeared as a result of lack of immunisation.

A limitation of the study is the lack of information about physicians’ visits, which were excluded from the analysis. Another limitation is that it was focused on the direct health care cost. no mortality losses or absence of work were included in the analysis. If indirect costs are included, the benefits will prevail above the investments due to the fact that all patients with decompensated cirrhosis and hepatocellular carcinoma are reassigned, and due to the sharp decrease in the mortality rate, especially in young groups of people (9). We also chose the lowest possible frequencies for chronification and complications which might have underestimated the benefits.

ConclusionsUniversal vaccination against HBV is socially beneficial for the Bulgarian population. its positive economic results became visible during the last 10 years after its introduction in the immunisation calendar.

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