Abstract

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Cost Effectiveness of Replacing Recombinated

Interferon

αα

−2b with its Pegylated Form

in Combination with Ribavirin for the Therapy

of Chronic HCV Infection in Poland

Korzyści ekonomiczne zamiany rekombinowanego interferonu

αα

−2b

na jego postać pegylowaną w skojarzeniu z rybawiryną

w terapii przewlekłego wirusowego zapalenia wątroby

związanego z zakażeniem HCV w Polsce

1_{Department of Infectious Diseases, Hepatology, and Acquired Immune Deficiencies, Silesian Piasts University}

of Medicine in Wrocław, Poland

2_{HTA−consulting}

Adv Clin Exp Med 2006, 15, 3, 453–462 ISSN 1230−025X

ORIGINAL PAPERS

Abstract

Objectives.This analysis was carried out in order to define the therapeutic effectiveness, costs, and profitability of treatment with peginterferon alpha−2b plus ribavirin in patients with chronic hepatitis C infection compared with treatment with interferon alpha−2b plus ribavirin or lack of treatment.

Material and Methods. A cohort of 743 HCV−infected patients treated in authors’ Department were analyzed. Cal− culations of the effects and costs of applying a combined treatment with IFN−alpha−2b plus ribavirin in patients with chronic hepatitis C were based on the assumptions of an economic analysis presented in the computer pro− gram “Spears Hepatitis C” using a Markov decision model. The cost analysis was carried out from the extended point of view of the payer (National Health Service, National Health Fund, and the patient) for a time−span equal to the average period of the clinical trials included in this analysis (48 weeks) and based on data concerning the ef− fectiveness of the frequency of salubrious events obtained from clinical trials.

Results. It was demonstrated that treating patients with chronic hepatitis C with peginterferon + ribavirin in a weight−based dose is more efficient and cost effective than interferon + ribavirin therapy. The cost of PEG + RBV treatment (regardless of the ribavirin dose) for a 70−kg patient amounts to 40,534.27 PLN in the category of FULL costs, 32,236.71 PLN ACTUAL costs, 28,094.76 PLN STOP costs, and 23,700.12 PLN STOP 2/3 costs. The ef− fectiveness analysis on the basis of a single clinical trial showed that undergoing therapy with peginterferon alpha− 2b plus ribavirin causes a prolongation of the patient’s life by at least 0.12 years (maximum: 0.70 years) compa− red with treatment with interferon alpha−2b plus ribavirin. Compared with lack of treatment, PEG + RBV therapy resulted in a prolongation of life from 1.84 to 4.03 years.

Conclusions. Treatment with pegylated interferon alpha−2b plus ribavirin is more effective and profitable than treatment with interferon alpha−2b plus ribavirin, regardless of the ribavirin dose, irrespective of the HCV geno− type with which the patient is infected (Adv Clin Exp Med 2006, 15, 3, 453–462).

Key words:HCV infection, pegylated interferon alpha−2b, ribavirin, economic analysis.

Streszczenie

Cel pracy.Określenie skuteczności terapeutycznej, kosztów i opłacalności leczenia peginterferonem α−2b z ryba− wiryną u pacjentów chorych na przewlekłe wirusowe zapalenie wątroby typu C w porównaniu z leczeniem inter− feronem α−2b z rybawiryną lub brakiem leczenia.

Materiał i metody. Ocenie poddano 743 pacjentów zakażonych HCV i leczonych w Katedrze i Klinice Chorób Za− kaźnych, Chorób Wątroby i Nabytych Niedoborów Odporności. Obliczenia rezultatów i kosztów leczenia kombino−

The number of HCV−infected persons in Po− land is believed to be about 540–730 thousand, and a slow, systematic increase in HCV infection incidence is being observed, with 5.4/100,000 in 2000 and 5.59/100,000 in 2003 [1–5]. These data are undoubtedly underestimated and actually show only a part of newly acquired HCV infections, be− cause the majority of cases are infections acquired many years before. Considering the chronic cha− racter of the infection, the extent of the problem is better reflected by disease incidence connected with HCV. The lack of specific prophylaxis to date may cause a two− or threefold increase in mortali− ty due to HCV in the next 10–20 years, as pointed out by world experts. Estimated cumulative stati− stical assessments from the USA indicate that the growing number of patients infected with HCV may, in 20 years time, be the cause of more than 260,700 premature deaths, 960,000 advanced he− patopathy cases, and the loss of 3.1 million years of life. Moreover, the costs of healthcare for HCV− infected persons are already alarming and steadily rising, now amounting to billions of dollars yearly. This concerns both the direct costs of healthcare for HCV−infected persons and indirect costs con− nected with handicap and premature death [4]. These cases mostly concern persons who are the most active and at a productive age.

The Aim of HCV Therapy

The above epidemiological data as well as the developing modern therapeutic possibilities deter− mine the therapeutic aims giving specified ther− apeutic benefits in infected persons [6]. The most important are:

– inhibition, retardation, or regression of hepa− titis and liver fibrosis (histological response, HR),

– biochemical normalization of the inflamma− tion process (biochemical response, BR),

– elimination of HCV RNA from blood serum and tissues (viral response, VR),

– decrease of HCC development risk, – increase of survival rate,

– improvement of the quality of life (QL), – limitation of the infectiousness and spread of HCV infection.

Therapeutic Possibilities,

Current Treatment Schemes,

and Therapy Monitoring

In spite of significant progress in recent years, the efficacy and, in Polish conditions, the availabi− lity of HCV−associated chronic hepatitis treatment are still unsatisfactory. Currently, the “gold stan− dard” in treatment is interferon alpha (IFN−alpha, in different forms) in combination with ribavirin (RBV) [6, 7]. Administration of both of these drugs is restricted by numerous contraindications and numerous adverse effects appearing during treatment. These particularly concern interferon, as can be found in literature concerning this sub− ject [7–9, 10]. Accumulating experience has called attention to predisposing factors enabling progno− stication of a favorable therapeutic response to treat− ment with IFN−alpha and RBV [11–13]. On the basis of data from literature, the recommendations of the European Medicine Evaluation Agency and of Polish experts, and authors’ own experience, treatment with pegylated interferon alpha plus ri− bavirin is currently accepted as the most efficient therapeutic standard. Only two preparations of pegylated interferon alpha are available on the market: PEG−IFN−alpha2b (PEG−INTRON from

wanego IFN−α−2b z ribawiryną u pacjentów z p.w.z.w. t.C oparto na założeniach analizy ekonomicznej przedstawio− nej w programie komputerowym Spears Hepatitis C wykorzystującym model decyzyjny Markowa. Analizę kosztów przeprowadzono z poszerzonej perspektywy płatnika (Kasa Chorych, NFZ + pacjent) dla horyzontu czasowego rów− nego średniemu okresowi badań klinicznych włączonych do tej analizy (48 tyg.) oraz opierając się na danych doty− czących efektywności zdrowotnych częstości zdarzeń zdrowotnych, które uzyskano z badań klinicznych.

Wyniki.Wykazano, że leczenie pacjentów chorych na przewlekłe wirusowe zapalenie wątroby typu C za pomocą peginterferonu z rybawiryną w dawce zależnej od masy ciała jest leczeniem skuteczniejszym, także ze względów ekonomicznych, w porównaniu z terapią interferonem i rybawiryną. Koszt takiego leczenia (bez względu na daw− kę rybawiryny) dla pacjenta, którego masa ciała wynosi 70 kg to: w kategorii kosztowej FULL 40 534,27 PLN, ACTUAL 32 236,71 PLN, STOP 28 094,76 PLN, STOP 2/3 23 700,12 PLN. Analiza skuteczności na podstawie pojedynczego badania klinicznego wykazała, że poddanie się terapii peginterferonem α−2b z rybawiryną powodu− je u jednego pacjenta wydłużenie życia co najmniej o 0,12 roku, maksymalnie o 0,70 lat w porównaniu z lecze− niem interferonem α−2b z rybawiryną. W porównaniu z brakiem leczenia terapia PEG + RYB powoduje wydłuże− nie życia od 1,84 do 4,03 roku.

Wnioski.Leczenie pegylowanym interferonem α−2b z rybawiryną jest leczeniem bardziej skutecznym i opłacal− nym w porównaniu z leczeniem interferonem α−2b z rybawiryną (bez względu na dawkę rybawiryny), niezależnie od rodzaju genotypu HCV, jakim zakażeni są pacjenci (Adv Clin Exp Med 2006, 15, 3, 453–462).

Schering−Plough) and PEG−IFN−alpha2a (Pegasys from Roche). PEG−IFN−alpha2b is administered 1×a week at a dose of 1.5 µg/kg−bw intramuscu− larly, PEG−IFN−alpha2a is also administered 1 × a week but at a fixed dose of 180 µg intramuscu− larly, and ribavirin must be taken orally every day at a dose >10.6 mg/kg−bw. Treatment duration de− pends on the HCV genotype: 48 weeks for genoty− pes 1, 4, 5, and 6 and 24 weeks for genotypes 2, and 3. In specific cases, i.e. with coexisting renal failure or hemoglobinopathy, treatment with IFN− alpha alone is allowed [14–20]

The efficacy of this therapy in an optimally evaluated patient amounts to about 72% when con− sidering all genotypes together; the efficacy is lo− west with genotype 1 infection and does not exceed 61%, while that of genotypes 2 or 3 is as much as 80% [6, 14, 21]. In cases qualified for re−therapy, another form of IFN−alpha, also in combination with ribavirin, is recommended [22]. However, the final duration of therapy is determined by the re− sults of periodic control tests, particularly the eva− luation of the degree of HCV replication inhibition after 12 weeks of treatment in patients infected with genotypes 1, 4, 5, or 6 (HCV RNA quantita− tive test). To monitor the safety and efficacy of the therapy, it is recommended to carry out a medical consultation, morphological evaluation with blood cell count, and standard biochemical tests at weeks 2, 4, 8, 12, 24, 36, and 48 of treatment. Moreover, in infections with genotype 1, HCV RNA determi− nation in serum should be done, preferably with a quantitative method, after 12 weeks (3 months) and 48 weeks. According to the operative standard, the therapy should be discontinued when there is presence of HCV RNA after 12 weeks of treatment or the decrease in HCV RNA is found to be < 2 log. With confirmed presence and a simultaneously ob− served decrease in HCV RNA >2 log, the examina− tion should be repeated after 24 weeks, and if HCV RNA is still present, the treatment should also be discontinued. In an infection with genotypes 2 or 3, HVC RNA determination is done after 24 weeks, i.e. after treatment termination. Determination of TSH concentration and evaluation of autoantibody presence at weeks 24 and 48 are also recommended because of the possibility of the appearance of ad− verse effects and the manifestation of auto−aggres− sive syndromes.

After treatment termination, the patient under− goes periodic hepatological check−ups for a mini− mum of 12 months, consisting of medical consul− tation, evaluation of blood morphology, and stan− dard biochemical tests every 12 weeks. At week 72 (in genotypes 1, 4, 5, 6) and week 48 (in geno− types 2 and 3) from the moment of treatment ini− tiation, qualitative determination of HCV RNA is

done; if this is negative (SVR), the chances for a stable therapeutic response are estimated at about 97%. It is also recommended, though cur− rently it is only a verifying diagnostic option, to carry out a control liver biopsy 12 months after treatment termination [6, 8–10, 14, 18, 23].

Although the efficacy of treating patients with chronic hepatitis C in accordance with the schema presented above has been confirmed in a number of clinical trials and found optimal in clinical and financial evaluation, the high direct cost of this therapy (particularly at the moment of its initia− tion: initial diagnosis, drug purchase) inclines some managers of the Polish health service as well as clinicians to try to maintain the older, seemingly cheaper therapeutic−monitoring schemes. This is motivated by the rising costs of healthcare and li− mitations in accessing financial sources, e.g. for molecular studies, particularly at a time of incon− sistent transformations in the Polish health service. Directed above all by the patients’ interest (i.e. to find the most beneficial therapeutic option) and in view of the economic affairs of the State, the au− thors have undertaken the trial to evaluate objecti− vely: 1) the costs borne by the payer (National Health Service, currently the National Health Fund) for treating HCV infection in the region of Lower Silesia; 2) a cost comparison of the three therapeutic schemes applied in authors’ clinic for the treatment of chronic hepatitis C, i.e.: a) PEG− INTRON at a dose of 1.5 µg/kg−bw/week combi− ned with ribavirin at a fixed dose of 800 mg/daily, b) PEG−INTRON−A at a dose of 1.5 µg/kg−bw/week combined with ribavirin at a dose > 10.6 mg/kg− bw/day, and c) Intron A at a dose 3 × 3 million units/week combined with ribavirin at a dose of 800 mg/day; 3) the costs of treatment with compa− rable therapeutic options (for a period of one year) for specified HCV complications; 4) the course of the disease after treatment.

Material and Methods

model was described and discussed in detail in lite− rature [14, 15, 24, 25]. it is not elaborated here. The “Spears Hepatitis C” program includes: the results of clinical trials on the natural course of HCV infec− tion [26–28], the results of primary clinical trials evaluating the efficacy of the combined therapy with IFN−alpha2b plus ribavirin and Peg−IFN−al− pha2b plus ribavirin for the treatment of chronic he− patitis C [14–22, 29–33], and the assumptions of the methodology of treatment cost assessment worked out by Wong and Sibert [29, 34, 35]. Exploitation of international clinical data was possible because of the fact that clinical trial results for the majority of diseases are not specific to a given country, but only to particular populations [36, 37].

The cost analysis was carried out from the extended perspective of the payer (National Health Service, National Health Fund, and patient) for a time−span equal to the average period of the clin− ical trials included in this analysis (48 weeks) and based on the data concerning the effectiveness of salubrious event frequency, which were obtained from clinical trials [14, 15, 38–42].

For the analysis, cost data were collected on a cohort of 743 patients infected with HCV, having an average age of 44 years, and hospitalized, con− sulted, and treated at the Department of Infectious Diseases, Hepatology, and Acquired Immune De− ficiencies of the Medical University in Wrocław between 1999–2002 Women constituted 24% of this population, patients with genotypes 2 or 3 amounted to 32% of all patients, and the patients had the following disease characteristics: 15% with mild chronic hepatitis, 78% with moderately advanced hepatitis and bridging fibrosis, and 7% with cirrhosis. Then the cost data concerning one year of treatment of the patients with the patholo− gical states appearing in the natural course of he− patitis C virus infection were evaluated [2, 14, 26, 28, 29, 34, 37].

The scheme of the yearly treatment procedure in the patients with these clinical states was worked out on the basis of clinical trials and expert opi− nions concerning the populations evaluated in the primary trials included in the “Spears Hepatitis C” program. Using the “Spears Hepatitis C” program it was also possible to calculate:

1) the sustained viral response (SVR) index for patients in comparable therapeutic groups,

2) disease duration in years of specific clinical states of chronic hepatitis C progression for pa− tients treated with comparable options of anti−viral therapy and for untreated patients,

3) incremental analysis of the profitability ratio. The incremental ratio of cost effectiveness is defined as the quotient of the difference in costs between two comparable programs, P1 and P2, and the difference

in salubrious effects between these programs. The incremental ratio was calculated in a program for comparable options of anti−virus treatment and for its lack. The results of treatment effectiveness were related to Life Years Gained (LYG),

4) costs borne in accordance to the acceptance of a perspective for the patient’s gains in life expectancy, which were calculated on the basis of costs borne during subsequent stages of the disea− se’s progression and complications. They appear with the probability and frequency calculated in the Markov model,

5) the costs of therapies with Peg−IFN−al− pha2b 1.5 µg/kgbm/week + ribavirin > 10.6 mg/kg−bw/day and Peg−IFN−alpha2b 1.5 µg/kg− bw/week + 800 mg of ribavirin daily, with the spe− cified assumptions of the therapeutic procedure depending on patient response to therapy (SVR) and the genotype of the virus.

Four cost categories were distinguished. The FULL category defines the average cost of treat− ment of one patient with full drug doses for a period of 48 weeks. The ACTUAL category is the average cost of treatment of one patient for the duration of the trial, taking into consideration discontinuation of the trial, withdrawal from the trial, and a decrease in drug dosage on the basis of the actual data obtai− ned in the Manns trial [13]. The STOP category is the average cost of treatment of one patient with the assumption that the treatment was discontinued in patients in whom presence of the virus was ascerta− ined in the 24th _{week of the trial (on the basis of}

PCR test results). STOP 2/3 is the average cost of treatment of one patient with the assumption that the treatment was discontinued in patients in whom presence of the virus was ascertained in the 24th

week of the trial (on the basis of PCR test results) and, additionally, that patients with genotypes 2 and 3 of the virus were treated for only 24 weeks.

Sources of Data

cost categories: costs of treatment with compara− ble drugs according to established treatment sche− mes; costs of additional drugs; costs of diagnostics (according to the above schema, e.g. standard exa− minations evaluating and monitoring the treat− ment, serologic tests, molecular tests (PCR), ima− ging diagnostics, liver biopsy, histopathological evaluation of the bioptate); costs of hospitaliza− tion; costs of consulting visits at the outpatient cli− nic; and costs of treating specific complications connected with the particular disease entity (costs of diagnostics, sanitary transport, check−up visits, drugs administered in the treatment, highly specia− lized procedures, and other procedures or opera− tions). Costs of drugs were calculated on the basis of the average wholesale prices of Peg−IFN−al− pha2b, interferon alpha−2b, and ribavirin, quoted for the particular package sizes available on the Polish market.

Results and Discussion

The obtained results are presented here and in Tables 1–5 and Figures 1 and 2. On the basis of the data obtained from the Polish health service provi−

ders (Silesian Piasts University of Medicine in Wro− cław, Chair and Department of Infectious Diseases, Hepatology, and Acquired Immune Deficiencies, J. Gromkowski Provincial Specialist Hospital, Na− tional Health Fund, Lower Silesia, Department) concerning the costs of treatment of different clin− ical manifestations of HCV infection, the yearly costs of treating these patients are shown below and a part of them is represented in Fig. 1. The yearly cost of treating advanced forms of hepatitis C infec− tion and its complications were for one patient:

– with mild chronic hepatitis C: 651.98 PLN, – with moderate chronic hepatitis C: 896.76 PLN,

– with hepatocellular carcinoma: 15,556.34 PLN,

– with compensated cirrhosis: 12,197.80 PLN, – after liver transplantation (first year): 176,973.80 PLN,

– in the second year after liver transplanta− tion: 30,000.00 PLN,

– with ascites responding to treatment with diuretics: 8,620.18 PLN,

– with ascites resistant to treatment with diu− retics: 17,615.27 PLN,

– with symptoms of encephalopathy (first year): 22,195.48 PLN,

– in the second year from the appearance of encephalopathy symptoms: 25,341.44 PLN,

– with bleeding from esophageal varices (first year): 60,032.56 PLN,

– in the second year from the appearance of bleeding from esophageal varices: 17,693.10 PLN. In accordance with expectations as well as with data from literature [6, 30, 36, 38], the high− est was the yearly cost of liver transplantation in HCV−infected patients (including the costs of eva− luation, transplantation, and post−transplantation care). In own material these costs exceeded by over five times the costs of one−year treatment with pegylated interferon plus ribavirin in a weight− −based dose, which is a therapy which prevents cli− nical situations in which it would be necessary to

Table 1. Cost of anti−HCV drugs, 48−week treatment

Tabela 1.Koszt leczenia przeciwwirusowego – 48−tygo− dniowy cykl leczenia

Dosage PEGINT PEGINT INT A+RBV

method 1.5 µg/kg + 1.5 µg/kg + PLN (Dawko− 800 mg RBV WBRBV

wanie) PLN PLN

82 kg 70 kg

FULL 47 483,00 40 534,27 34 702,56 ACTUAL 37 763,00 32 236,71 30 364,74 STOP 32 911,00 28 094,76 24 052,72 STOP 2/3 27 763,00 23 700,12 20 290,36 PEGINT – PEG−Intron, INT A – Intron A, RBV– ribavi− rin, FULL, ACTUAL, STOP, STOP 2/3 – cost categories discussed in text.

2 7763 zł

Cost of drugs for one year of treatment: genotype 1 – 48 weeks, genotype 2/3 – 24 weeks

176 973 zł

27 115 zł

12 197 zł

15 556 zł

Transplantation Przeszczepienie wątroby

Decompensation Niewyrównana marskość wątroby

Compensated cirrhosis Wyrównana marskość wątroby

HCC Pierwotny rak wątroby

48 weeks PEG−RBV 48 tyg. PEG + RBV

0.00 40000.00 80000.00 120000.00 160000.00 200000.00

Koszt leków zużytych w ciągu roku leczenia: genotyp 1 – 48 tygodni, genotyp 2/3 – 24 tygodnie

Fig. 1. Yearly cost of treat− ment of choosen liver diseases in the Department of Infectious Diseases, Hepatology and Acquired Immune Deficiencies, Medical University of Wro− cław (state for 2003 year)

Ryc. 1. Roczny koszt leczenia wybranych chorób wątroby w Klinice Chorób Zakaźnych, Chorób Wątroby i Nabytych Niedoborów

carry out liver transplantation (Table 1). Although the calculated yearly costs of treating patients with hepatic carcinoma or cirrhosis associated with HCV infection are lower than the yearly costs of treating chronic hepatitis patients with PEG−IFN− alpha plus RBV, it is apparent that these costs in− volve patients with small gains in life expectancy. These data also do not reflect indirect costs, inclu− ding social costs connected with the handicap as well as with the premature death of these patients. Treatment with PEG−IFN−alpha plus RBV influen− ced in a significant way (consistent with the results of other clinicians’ observations) the prolongation

of the asymptomatic period of life of HCV−infec− ted persons, the inhibition of disease progression, the delay of the appearance of handicap connected with disease progression, and the prolongation of life (Fig. 2). It was demonstrated that therapy with peginterferon alpha−2b plus ribavirin caused a per− patient prolongation of life by at least 0.12 years, with a maximum by 0.70 years, compared with treatment with interferon alpha−2b plus ribavirin. In comparison with lack of treatment, PEG + RBV therapy resulted in a prolongation of life from 1.84 to 4.03 years.

Using the obtained cost data and the “SPE− ARS Hepatitis C” program (developed by Wong and described by Siebert et al. [34]), the costs of anti−viral drugs were calculated for a comparable therapeutic schema, also depending on the method of dose−cost categories (Table 1). The profitability of the anti−viral treatment was also compared with the administration of peginterferon alpha−2b plus ribavirin in comparison with interferon alpha−2b plus ribavirin or lack of treatment (Tables 2 and 3). The salubrious benefit gained by the patient as a result of anti−viral treatment was expressed with the help of the Life Year Gained (LYG) in view of the expected length of remaining life (20 years). It was demonstrated that treatment with peginterfe− ron alpha−2b plus ribavirin (taking into account the

Table 2. Cost effectiveness results – PLN /1 LYG (treatment duration in accordance with the current data from the Manns trial 2001 – 48 weeks)

Tabela 2.Wyniki kosztów leczenia – PLN /1 zyskany rok życia (czas leczenia zgodny z aktualnymi danymi badań Mannsa z 2001 r. – 48 tygodni)

Treatment schedule All genotypes Genotype 1 Genotype 2/3

(Schemat leczenia) (Wszystkie genotypy) (Genotyp 1) (Genotyp 2/3)

INT A lack of INT A lack of INT A lack of

+ RBV treatment + RBV treatment + RBV treatment

(brak (brak (brak

leczenia) leczenia) leczenia)

PEGINT + 800 mg RBV 23 844 11 159 18 588 15 526 83 875 6 447

PEGINT + WBRBV 9 124 9 165 7 151 12 184 19 549 5 530

PEGINT – PEG−Intron, INT A – Intron A, RBV – ribavirin, WBRBV – weight−based ribavirin dose, PLN – Polish złoty, LYG – Life Year Gained.

0 2 4 6 8 10 12 14 16 Lack of treatment

Brak leczenia

PEGINT + 800 mg RBV INT A + RBV

PEGINT + WBRBV

lack of virus in blood brak HCV we krwi liver cirrhosis marskość wątroby

mild CHC łagodne przewlekłe zapalenie wątroby hepatic failure niewydolność wątroby

moderate CHC umiarkowane przewlekłe zapalenie wątroby

16.6

15.48 13.79

16.48

Fig. 2. Life years in specified stages of HCV infection progression – all genotypes

Ryc. 2.Lata życia na danych etapach rozwoju zakażenia HCV – wszystkie genotypy

Table 3. Results of cost effectiveness PLN/ 1 LYG (patients with genotype 2/3 treated for 24 weeks)

Tabela 3.Wyniki kosztów leczenia – PLN /1 zyskany rok życia (pacjenci z genotypem 2/3 leczeni przez 24 tygodnie)

Genotype All Genotype 2/3

(Genotyp) (Wszystkie) (Genotyp 2/3)

Treatment schedule INT A + RBV lack of treatment INT A + RBV lack of treatment

(Schemat leczenia) (brak leczenia) (brak leczenia)

PEGINT + 800 mg RBV 19 434 8 505 32 223 307

PEGINT + WBRBV 6 517 6 739 4 606 –254

dosage scheme) is a profitable therapy compared with therapy with interferon alpha−2b plus ribavi− rin or with lack of treatment in patients infected with all HCV RNA genotypes. Treatment with peg− interferon alpha−2b plus ribavirin of patients with genotype 1 for 48 weeks in a weight−based dose turned out to be particularly profitable, also in pa− tients in circumstances described here. Similar re− sults were obtained in the group of patients with genotypes 2 or 3 in whom treatment with peginter− feron alpha−2b + ribavirin in a weight−based dose administered for 24 weeks also turned out to be more profitable than therapy with interferon alpha− 2b + ribavirin. This is consistent with the observa− tions of other authors who have been carrying out such analyses on their own clinical material. The profitability of therapy using PEG−Intron has been demonstrated in all countries whose reports are cited here [30–36].

The therapeutic cost category STOP 2/3 inclu− ded in the evaluation demonstrates an average cost of treating one patient calculated on the basis of the average obtained in the patients with no res− ponse to treatment whose treatment was disconti− nued in the 24th_{week, patients with HCV RNA ge−}

notype 2 or 3 treated for 24 weeks, and the rest of the patients treated for 48 weeks, and so it most ac− curately reflects the magnitude of the real costs of anti−viral therapy in the Polish system of healthcare. It turned out that shortening the time of treatment of patients with genotype 2 or 3 to 24 weeks and discontinuing treatment in those patients in whom the presence of HCV RNA in blood was still con− firmed after 12 weeks of treatment leads to a de− crease in anti−viral therapy costs by about 40% compared with treatment maintained for 48 weeks. This confirms the advisability of bearing the addi− tional expenditures of molecular diagnostics (HCV RNA in the 12th _{week) which, in consequence,}

leads to a significant reduction in costs connected

with the standard therapy of chronic hepatitis C in− fection.

These results are also consistent with the re− sults of observations carried out in Germany, Italy, Spain, and the USA and also with the results of the only study in Poland which compared the costs and effects of combined therapy with IFN−al− pha2a plus ribavirin with the standard therapy with IFN−alpha2b plus ribavirin [30–36]. It was simul− taneously demonstrated that the time of maintai− ning a stable viral response (SVR) in patients after anti−viral therapy is several times longer (several years) than in a group of untreated patients. No presence of HCV RNA in the blood of patients in whom a stable therapeutic effect has been gained over several years of observation has significant social implications which can be expressed by, for example: increased productivity; decreased finan− cial expenditures borne by the patient and the State on the treatment, these patients generate lower he− althcare costs; decreased patient demand for social services; decreased risk of infecting healthy persons. The yearly cost of dialysis therapy, amounting to about 60,000 PLN, is accepted as the limit of the profitability of therapeutic intervention in the world and in Poland. If the cost of gaining one sa− lubrious effect is lower than this sum, then the in− tervention is considered profitable, naturally irre− spective of the financially incommensurable indi− vidual benefits.

In the analyzed material it was found that for the equivalent of the yearly cost of dialysis therapy (60,000 PLN), an additional life year can be ga− ined (1 LYG) when peginterferon alpha−2b + riba− virin in a weight−based dose is administered to 8 patients with genotype 1 for 48 weeks and 13 pa− tients with genotype 2 or 3 treated for 24 weeks in− stead of therapy with interferon alpha−2b + ribavi− rin (Table 4). It was also demonstrated that for the equivalent of the yearly cost of dialysis therapy,

Table 4. Number of patients in whom one life year can be gained for the cost of yearly dialysotherapy

Tabela 4.Liczba pacjentów, których życie można przedłuzyć o rok za cenę rocznej dializoterapii

Type of treatment (Leczenie) INT A + RBV Lack of treatment (Brak leczenia) cost of 1 LYG number of cost of 1 LYG in number of in one patient (PLN) patients one patient (PLN) patients (koszt – PLN/1 LYG) (liczba pacjentów) (koszt – PLN/1 LYG) (liczba pacjentów)

Dialysotherapy (Dializoterapia) 60 000 1 60 000 1

PEGINT + 48 weeks 7 151 8 12 184 5

WBRBV – 1 genotype

HCV RNA

24 weeks 4 605 13 –254 +236

– 2/3 genotype HCV RNA

1 life year can be gained by administering pegin− terferon alpha−2b + ribavirin in a weight−based dose in 5 patients, and in 236 others saving addi− tional costs (of the duration of therapy connected with the HCV genotype), instead of lack of treat− ment. It was also shown that in spite of the higher direct costs of therapy with peginterferon alpha plus ribavirin in a weight−based dose, it is possible to obtain a stable viral response (SVR) in a larger number of patients compared with a treatment with interferon alpha−2b + ribavirin, assuming we have a fixed budget (1 million PLN) at our disposal (Table 5). If we have a budget of 1 million PLN at our disposal and make use of the cost categories, then in the case of patients treated for a duration of 48 weeks (FULL), the number of persons in whom it was po− ssible to obtain a stable viral response amounted to: 15 in the group treated with peginterferon alpha−2b + ribavirin in a weight−based dose, 14 in the group tre− ated with interferon alpha−2b + ribavirin.

Assuming that the HCV RNA genotype is de− termined in the patients before treatment initiation and that it is possible to shorten the time of treat− ment of patients with genotype 2 or 3 to 24 weeks (STOP 2/3), then the number of patients in whom a stable viral response can be gained, having a 1−mil− lion−PLN budget at our disposal, amounted to: 26 in the group treated with peginterferon alpha− 2b + ribavirin in a weight−based dose, 23 in the group treated with interferon alpha−2b + ribavirin. It was also demonstrated that the number of patients who did not gain a stable viral response as a result of treatment with interferon plus ribavirin is larger (by a factor of from 1 to 3) than in treat− ment with peginterferon plus ribavirin.

The limitation of funds assigned to the treat− ment of patients with chronic hepatitis C leads to the necessity of introducing a therapeutic program with the highest efficacy and cost profitability, which means peginterferon alpha−2b in a weight− based dose administered for 48 weeks in patients with HCV genotype 1 and for 24 weeks in patients with genotype 2 or 3. Discontinuation of the ther− apy in the 12th_{week of treatment in patients with}

HCV RNA presence in the blood in PCR examina− tion can additionally lower the costs of the anti−vi− ral therapy and enable a larger number of patients to profit by the new, most effective therapy with peginterferon alpha−2b plus ribavirin.

The authors conclude that 1) treatment with PEG−INTRON plus ribavirin is more profitable than treatment with INTRON A plus ribavirin (re− gardless of the ribavirin dose) in patients with all types of HCV genotypes, treated for 48 weeks, 2) 24−week treatment with PEG−INTRON plus riba− virin of patients infected with HCV genotypes 2 or 3 is also more profitable than treatment with IN− TRON A plus ribavirin (regardless of the ribavirin dose), 3) Treatment with PEG−INTRON plus riba− virin in a weight−based dose is an intervention which saves costs compared with lack of treatment in pa− tients with genotypes 2 or 3 treated for 24 weeks, 4) Discontinuation of therapy in patients who do not eliminate HCV or in whom there is a decrease in HCV RNA smaller than 2 log in the blood in the 12th _{week of therapy is essentially reasonable and}

simultaneously brings significant economic bene− fits, permitting lowering the yearly costs of anti− viral therapy.

Table 5. Number of patients in whom SVR can be gained with a 1 million PLN budget at disposal

Tabela 5.Liczba pacjentów, u których można uzyskac SVR, mając do dyspozycji budżet w wysokości 1 mln PLN

Average weight of the patient – 70 kg Full Stop 2/3

(Średnia masa ciała pacjenta – 70 kg) IFN + RBV PEGIFN + WBRBV IFN + RBV PEGIFN + WBRBV

Full cost of yearly therapy (PLN) 34 703 40 534 20 290 23 700

(Całkowity koszt rocznej terapii)

Number of patients treated 29 25 49 42

(Liczba leczonych pacjentów)

SVR (%) 47% 61% 47% 61%

Number of patients with SVR 14 15 23 26

(Liczba pacjentów z SVR)

Cost of treatment of one patent 73 836 66 449 43 170 38 852

with SVR (PLN)

(Koszt leczenia 1 pacjenta z SVR)

PEGINT – PEG−Intron, INT A – Intron A, RBV – ribavirin, WBRBV – weight−based ribavirin dose, PLN – Polish złoty, SVR – sustained viral response, FULL, STOP 2/3 – cost categories discussed in the text.

Acknowledgements

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Address for correspondence:

Department of Infectious Diseases, Hepatology, and Acquired Immune Deficiencies Silesian Piasts University of Medicine in Wrocław

ul. Koszarowa 5 51−149 Wrocław Poland

Tel.: +48 071 3261325

E−mail: [email protected]

Conflict of interest: None declared.

Received: 29.08.2005 Revised: 15.09.2005 Accepted: 15.09.2005

Praca wpłynęła do Redakcji: 29.08.2005 r. Po recenzji: 15.09.2005 r.