Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9

2015, p. 3 16, published online: September 2015

Chronic viral hepatitis - costs of diagnosis and treatment

Irina Dijmrescu,
MD, PhD student,
"Grigore Alexandrescu Emergency Children's Hospital, Bucharest, Romania,
irinaandronie@yahoo.com

Abstract:

Chronic hepatitis is a highly endemic disease. Management of the condition is important not
only from a medical point of view, but also from economic and social ones. Interdisciplinary
approaches are not very frequent. We performed a cost-analysis, which was based on the
protocol we use for the treatment of pediatric patients with chronic hepatitis B and C in our
department, using the rates used by the hospital. In our country, most of the expenses are
supported by The National Health Insurance House. The initial evaluation of chronic hepatitis
B pediatric patients in order to establish the indication of treatment costs 998 RON, while for
chronic hepatitis C the initial evaluation costs 882 RON. Exact costs for treatment are hard to
be established, not only because outcome is variable and it influences the decision of
maintaining or stopping the treatment, but also because indirect costs cannot be appreciated.
Regarding follow-up, annual reevaluation is needed for both patient with hepatitis B and C,
and the cost is estimated at 998 RON for chronic hepatitis B patients and 882 RON for
chronic hepatitis C. Chronic viral hepatitis is a highly expensive disease, both for the national
economy and for the family of the infected child. Complications increase the costs of care
directly and indirectly, because long-lasting treatments generate larger and larger
expenditures. We should focus on prevention, screening programs and early treatment of the
disease, because these are the most adequate tools to diminish the volume of disease
expenses.

Key words: pediatric chronic viral hepatitis, treatment, costs.

JEL Classification: I13, I18, H51.
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

1. Introduction:

Chronic hepatitis B and C are highly endemic diseases, affecting people worldwide,
generating an important burden. For instance, "the World Health Organization calls hepatitis
C a silent disease", not only because it may be symptomless even in late stages, but because it
is often "overlooked and underfunded in the political sphere". The infection becomes chronic
in about 80% of the cases, and this generates an important increase in the risk of cirrhosis and
hepatocellular carcinoma. [Mllhaupt et al., 2015]. Reducing the impact of the condition has
been a continuous concern not only in the medical field, but in the economic and social ones
as well. All aspects should be considered when elaborating a strategy against the condition in
order to maximize the desired effects on the population at the lowest expense possible. Thus,
according to the "UN Millennium Development Goals", a multidisciplinary approach is
needed, imposing coordinated efforts worldwide in order to improve the health status and
achieve reduction of child mortality.

These were the premises for the present research, which has an interdisciplinary approach,
bringing together social, economic and medical points of view, with a special concern
towards social and economic aspects. Anyhow, we do not mean to underestimate the
importance of the medical facet that has an essential role in identifying and keeping together
the other two aspects of the problem.

The importance of this specific approach resides in the fact that there is a rapid and
continuous change both in the economic field and in the society, and that there is a great
impact generated by the globalization processes. The intense exchange of goods and services
has a crucial influence on the health status of the population, and the increase in the
international financial flows and the globalization of financial markets has an essential impact
on investment processes, which can affect the health field as well. Unprecedented dynamics
regarding scientific and technological cooperation accentuates the universal nature of science
and the essential contribution of multidisciplinarity.

Determining economic and social aspects of the disease is important for the socio-economic
efficiency, cost-benefit analysis and coordination among the three pylons of sustainable
development (economic, social and environmental).
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

An important problem derived from our research, which, as mentioned above, focused on
economic and social aspects, is the lack of or scarcity of resources, financial means and
funds, needed in order to bring certain diseases (among witch hepatitis B and C) to "normal
rates". This situation may be solved by using a series of models and techniques meant to
optimize the expenditures by both minimizing the use of resources and maximizing the
beneficial effect on the health status.

The research is aimed to offer a framework for rational approach using optimizing elements,
beginning with a cost-benefit analysis. In our study there were no particular issues regarding
cost measurement, but we encountered a series of difficulties in quantifying the outcome,
especially medium and long term effects.

The cost-benefit analysis is widespread and an intensely used tool, part of the larger domain
of economic efficiency, which is, in one way or another, practically involved in all research
studies, especially in those focused on economic or social aspects. [Zaman and Geamnu,
2014]

Increasing efforts towards prevention and treatment is of major importance. Even though
universally prevention is more cost-effective than treatment, there are a series of objective
and subjective factors that turn attention from preventive measures and policies and generate
big expenses for treatment. This is where social and economic factors, like for instance
education, knowledge and income, need to intervene in turning the scales for prevention.

Costs for treatment of pediatric patients with chronic hepatitis B and C in Romania are not
known to date. An estimation is difficult to be made because treatment plans may be
different, depending on the response of each patient (for non responsive ones, medication
may be stopped).

2. Literature review:

Hepatitis B and C viruses are two of the most important causes of chronic liver disease with
associated morbidity and mortality globally. According to the World Health Organization, the
prevalence of viral hepatitis may be as high as 500 million, with an estimated mortality of 1.3
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

million people annually. Developing countries are incriminated in generating most of this
burden, because of the high rates of vertical and iatrogenic transmission of the hepatitis
viruses, but also because access to the health care system is low. It appears that 40-80% of
the infected population in unaware of the disease, due to the fact that most of the people with
viral hepatitis are asymptomatic during the early stages of the disease. [Sharma et al., 2015]

Chronic hepatitis B is usually defined by the presence of hepatitis B surface antigen in the
blood or serum for longer than 6 months. In some people, the hepatitis B virus is inactive and
does not lead to liver disease, but in other cases it may generate liver fibrosis, cirrhosis and
hepatocellular carcinoma and in the end liver failure. The goal of treatment
for chronic hepatitis B is to prevent these complications. Antiviral therapy suppresses
hepatitis B virus replication and reduces hepatic inflammation and fibrosis, thereby reducing
the likelihood of serious clinical disease. [National Clinical Guideline Centre, 2013]

The anti-hepatitis B vaccine is considered to be effective for the prophylaxis of the disease
and was introduced in 1982. Hepatitis B being one of the most frequent causes of chronic
liver disease and hepatocellular carcinoma, vaccination contributes to a decrease in the
burden of the disease, especially in the case of young adults born after 1984. Through the
World Health Organization - sponsored expanded program of immunization, vaccination of
all children against hepatitis B virus in most African countries was achieved, but with a low
coverage (79%). It is important that the first dose of anti-hepatitis B vaccine is administered
soon after birth, because children infected early in life (either through mother-to-child
transmission or by early horizontal transmission) are more likely to develop chronic infection
(over 90%), adding to the risk of cirrhosis and hepatocellular carcinoma. [Lemoine et al.,
2014]

Interferon-alpha appears to be the most effective treatment option for children with HBeAg-
positive chronic hepatitis B. Randomized trials are still needed for further comparing
interferon to newer antiviral agents in terms of efficacy, safety, emergence of mutant variants,
and cost/benefit ratio. [El Sherbini and Omar, 2014] Antiviral drugs (Lamivudine, Adefovir,
Entecavir, Telbivudine and Tenofovir), which interfere with the viral DNA synthesis, are
another treatment option that has proven to be effective for chronic hepatitis B patients.
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

Neither antiviral drugs or Interferon can eradicate viral DNA from the infected hepatocytes,
impeding eradication of hepatitis B virus infection. [De Clercq, 2015]

Costs of treatment depend on the disease stage: in the early stages costs for treatment are
lower, while in the late stages, when complications arise, higher treatment costs are imputed.
"In patients with chronic hepatitis B infection, nearly 47% of direct costs are allocated to
medical diagnostic services (such as laboratory tests, biopsy takings, ultrasonography, etc.),
followed by the cost of drugs (32%)". [Kavosi et al., 2014] The outcome from the hepatitis B
virus infection is influenced by both viral and host factors. These factors are important in the
development of chronic infection, and involved mechanisms need to be explored in order to
understand how infection persistence is obtained. All this knowledge should be used in
developing new treatment opportunities. [Thursz, 2014]

In an article published in 2014, Stahmeyer JT et al, estimated costs for chronic hepatitis B
management: "The calculation was modelled for a period of five years. Costs for virological
diagnostics and imaging account for a large proportion of diagnostic costs. The main cost
factors are expenses for pharmaceutical treatment with interferon or hepatitis B virus
polymerase inhibitors. On the assumption that only 25 % of the infected patients are
diagnosed, 5-year total costs in Germany account for more than 2.5 billion Euros."
[Stahmeyer et al., 2012]

Forty-one percent of the worlds population live in countries where no public funding is
available for viral hepatitis B/C treatment, with a particular gap in access to anti-HCV
treatments. [Lemoine et al., 2014]

Early detection programs may be useful in preventing the development of serious chronic
conditions, improve health, and consequently save resources, considering that effective (but
also expensive) medical treatments are available for hepatitis C, a disease with a high
prevalence. These new treatments may be able to considerably change the prognosis of this
condition. [Coretti et al., 2015]

Improvement in collection and process of statistic data regarding the prevalence of the
disease and epidemiologic characteristics of patients infected with hepatitis viruses (age, sex,
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
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territorial distribution - urban to rural, county distribution) is needed. Knowledge of these

aspects, as well as the effort of bringing them to controllable rates, represents an essential
condition to ensure economic and social endogenous growth. [Zaman et al., 2015]

In the last decades, new treatment options for viral hepatitis C have become available, and
treatment duration was reduced from 48 weeks to 6-12 weeks when direct acting antiviral
treatment is used. [Attar, 2015] By using the medicine actually available for treatment of
chronic hepatitis C, healing rates were improved to up to 90% (sustained virologic response
obtained). [Attar and Van Thiel, 2015; Coretti et al., 2015] Another advantage of this
treatment option is that it can be administered orally. A small number of patients may present
a relapse, of uncertain origin, months to years after. It is yet to be established whether current
of new developing treatment options may be useful in obtaining the eradication of chronic
hepatitis C. [Attar and Van Thiel, 2015]

These new compounds have proven effective in treating genotypes that were previously
difficult to treat. Currently, approved treatments for chronic hepatitis C infection include
Pegylated and standard Interferon alpha, Ribavirin and protease inhibitors (Boceprevir,
Telaprevir, Simeprevir and Sofosbuvir). The use of these new molecules is expensive,
showing us the important role of prevention and early detection, which should be
reconsidered in the management of the infection. Even if the new molecules imply higher
costs than the standard of care (Pegylated Interferon associated to Ribavirin), they may
dramatically improve the patients prognosis in terms of survival and quality of life and are
also effective in patients with severe liver disease. [Coretti et al., 2015] Direct antiviral agents
have proven to be more effective and with less adverse reactions than the previously used
treatment (standard). [Chae, 2015]

Natural history suggests that out of all hepatitis C infected patients, 70%-90% develop
chronic infection. Of those with chronic hepatitis C, 10%-20% progress to cirrhosis. Hepatitis
C associated cirrhosis leads to liver failure and death in about 20%-25% patients, and 1%-5%
of patients with chronic hepatitis C will develop hepatocellular carcinoma. Treatment for
HCV is currently evolving showing new hope for healing. Nowadays there are many highly
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
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effective, but also expensive antiviral drugs effective against different targets. [Bansal et al.,
2015]

In 2014 Stahmeyer J.T. et al conducted a retrospective multicenter observational study in

Germany on patients with chronic hepatitis C, estimating costs of guideline based therapy.
"The average total cost was 19147 including ambulatory care and diagnostics (1686),
pharmaceuticals (14875), inpatient care (1293), and sick leave (1293)." [Stahmeyer,
2014] " Costs for baseline diagnostics account for 302.75 and monitoring accounts for 596
to 1173. Dual therapy with pegylated interferon and ribavirin results in average costs of
7709 to 34692. Total costs of a guideline-based treatment range between 8,608 and
36167 depending on hepatitis C viral genotype and length of therapy. Triple-therapy with
telaprevir accounts for 43280 respectively 54844. Costs for Boceprevir treatment range
from 34143 to 6099." [Stahmeyer, 2014]. Another study, conducted by Meyers et al in
Canada in 2014 assesed the average lifetime cost for chronic hepatitis C to be $64694. They
estimated that the total cost will increase by 60%, from $161.4 million in 2013 to $258.4
million in 2032 (considered the peak). [Meyers et al., 2014]

3. Chronic viral hepatitis B and C burden in a Pediatrics department in Romania - cost

analysis

The present research was conducted in the department of Pediatrics of "Grigore

Alexandrescu" Emergency Children's Hospital in Bucharest, Romania. The objective of the
study was to analyze the costs of care for pediatric patients with chronic hepatitis B and C
admitted to our department. We considered the costs for diagnosis and treatment as well as
costs for follow-up (per year). Cost analysis was made considering the treatment protocol
used in our department, based on the rates established for certain investigations needed.
Because our hospital is outsourcing laboratory services to Romgermed Medical Group, we
listed the official rates assigned by them to each investigation we included.

Diagnostic costs refer to costs for both hospitalization and investigations. Costs for treatment
and monitoring include the actual medication (either Interferon or Pegylated-Interferon and
Ribavirin, depending on the implicated virus), admission to hospital (the standard protocol in
our hospital requires the admission of the patients for 24 hours in order to administer the first
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
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dose of Interferon/ Pegylated Inteferon under medical supervision) and monitorization of

treatment (a number of laboratory investigations need to be performed every month and a
complex evaluation is needed at the end of the treatment plan, in order to assess response to
therapy and decide future course of treatment). Follow-up needs to be done annually after the
treatment is completed and it consists of a clinical, biological and ultrasonographic
evaluation.

3.1. Diagnostic costs:

We considered the costs of paraclinical investigations needed to establish the diagnosis of

chronic viral hepatitis B and C and to evaluate the liver function before initiation of
treatment: complete blood count (19 RON); transaminases - ALT (9 RON), AST (28 RON);
bilirubin - total (9 RON), direct (9 RON); alkaline phospatase (12 RON); gamma-glutamyl
transpeptidase (10 RON); total lipid content (15 RON); lactate dehydrogenase (12 RON);
total cholesterol (9 RON); blood glucose level (9 RON); total protein (9 RON); serum protein
electrophoresis (22 RON); coagulation tests (29 RON); fibrinogen (18 RON); erythrocyte
speed sedimentation (5 RON); C-reactive protein (14 RON); diagnostic markers of viral
hepatitis: anti HBc antibodies (39 RON), anti HBe antibodies (36 RON), anti HBs antibodies
(38 RON), HBs antigen (35 RON), HCV antibodies (58 RON), HDV antigen (60 RON),
HDV antibodies (60 RON); HBV viral load - HVB-DNA (256 RON); HCV viral load -
HCV-RNA (386 RON); HDV viral load - HDV-DNA (375 RON); abdominal
ultrasonography (50 RON); hepatic biopsy (250 RON); FibroScan (150 RON).

In order to establish the diagnosis of chronic viral hepatitis B, elevated transaminases and
positive HBs antigen should be identified for a 6 months period. Consequently, these two
tests should be performed twice. So the total cost for diagnosis of chronic viral hepatitis B is
144RON. For chronic hepatitis C diagnosis, elevated transaminases and anti-HCV antibodies
for a 6 month period of time are required. As in the case of hepatitis B, these tests must be
performed twice. The final cost for the diagnosis of chronic hepatitis C is 190 RON. The
initial evaluation of chronic hepatitis B for pediatric patients in order to establish the
indication of treatment costs 998 RON, while for chronic hepatitis C the initial evaluation
costs 882 RON.
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3.2. Treatment and monitoring costs:

For pediatric patients with chronic hepatitis B the standard treatment approved in our country
is standard Interferon alpha 2B - 3 times a week, 6 months. Recently, Entecavir has been
approved for use for patients above 2 years of age. In order to establish the indication of
treatment, certain criteria should be met:

elevated transaminases (twice the normal value) should be persistent more than 6
months;
positive HBs-antigen for more than 6 months;
HVB-DNA (viral load) should be higher than 100 000 copies/ml;
HVD antibodies should be negative. (M.H., 2006)

Different forms of Interferon alpha 2B are supplied in Romania: 18 million units/vial and 30
million units/vial. Interferon alpha 2B is recommended 5-10 million units/ square meters of
corporal surface. The National Health Insurance House lists the 18 million units Interferon
alpha 2B vial at a price of 434,34 RON. A vial may be used for 12 administrations. For
patients with o body weight above 20 kg, 30 million units vials should be used - listed at a
price of 715.89 RON/ vial. In Romania, treatment of chronic viral hepatitis is entirely
supported by The National Health Insurance House. (CNAS, 2014)

During the 6 months of treatment, monthly evaluations should be performed - complete blood
count (19 RON) and transaminases (ALT 9 RON, AST 28 RON) - a total of 5 determinations.
So monitoring the interferon treatment of chronic hepatitis B costs approximately 280 RON.
At the end of the treatment plan, a complex evaluation is needed and all the investigations
performed at the initiation of treatment should be repeated - the total cost of this is estimated
at 878 RON.

Transaminases elevation during the Interferon treatment require a viral load determination,
and if the viral load rises during the treatment, the patient is considered to be resistant to
treatment. Resistance and lack of therapeutic response (persistent elevated transaminases
after 6 months of treatment) call for reevaluation and reconsideration of the treatment plan
(Interferon should be stopped). In this case, reevaluation of the viral load brings additional
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

costs (the price of one determination is 256 RON, as listed above). (CNAS, 2014; M.H,
2006). In case of associated pathologies (for example: chronic hepatitis B and D, chronic
hepatitis B and C, chronic hepatitis B and HIV, etc) costs for evaluation and treatment are
higher.

For chronic hepatitis C in children criteria that should be met in order to start the treatment
are: normal or elevated transaminases associated with positive HCV-RNA. The approved
treatment in children is Pegylated-Interferon alpha 2B - 1 administration per week - 24 weeks
(for genotypes 2 and 3) and 48 weeks (for genotypes 1 and 4). Pegylated-Interferon alpha 2B
should be administered for the first time (at the initiation of treatment) under medical
supervision (the patient should be admitted). (CNAS, 2014; M.H., 2006). Pegylated-
Interferon alpha 2B is supplied in different forms: 50ug vial (listed at a price of 358.21 RON)
and 100ug vial (listed at a price of 652.37RON). The recommended dose is 1.5ug/kg/week.
(CNAS, 2014). Aside from the Pegylated-Interferon treatment, hepatitis C patients receive
Ribavirin. Ribavirin is listed at a cost of 4.35RON/capsule (REBETOL 200mg) or at
3.96RON/film-coated tablet (COPEGUS 200mg). It is recommended at a dose of
15mg/kg/day fractioned in two doses. (CNAS, 2014)

Treatment monitoring and surveillance of possible side effects should be made monthly by
evaluating complete blood count (19 RON) and transaminases (ALT 9 RON, AST 28 RON).
Five determinations are needed for genotype 2 and 3 patients (a total cost of 280 RON) and
eleven for genotype 1 and 4 patients (a total cost of 616 RON).

Response to treatment should be appreciated by laboratory tests (normal transaminases and

negative viral load should be obtained). Viral load should be repeated in weeks 12 and,
eventually in 24 weeks, in order to establish whether the treatment should be continued (for
the patient to be considered responsive to treatment, the viral load should be lower by 2log10
out of the initial value at week 12; otherwise the treatment should be stopped) (M.H., 2006).
The cost of the viral load determination is 386 RON. At the end of the treatment a complex
evaluation of the patient should be made - all investigations performed before treatment
initiation should be repeated - the total cost for this is 882 RON.

Insert (Figure 1) here

Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

Both Pegylated-Interferon alpha 2B and Ribavirin costs are supported by The National Health
Insurance House.

3.3. Follow-up costs per year:

Patients with chronic hepatitis B and C should be reevaluated annualy by laboratory tests,
ultrasonography and FibroScan. Laboratory tests should include: complete blood count (19
RON); transaminases - ALT (9 RON), AST (28 RON); bilirubin - total (9 RON), direct (9
RON); alkaline phospatase (12 RON); gamma-glutamyl transpeptidase (10 RON); lactate
dehydrogenase (12 RON); blood glucose level (9 RON); total protein (9 RON); serum protein
electrophoresis (22 RON); coagulation tests (29 RON); C-reactive protein (14 RON);
hepatitis B viral load - HVB-DNA (256 RON); hepatitis C viral load - HCV-RNA (386
RON). Annual reevaluation cost is 998 RON for chronic hepatitis B patients and 882 RON
for chronic hepatitis C patients.

4. Conclusions

Chronic liver disease due to hepatitis B and C viruses is an important burden on the economy
of our country. Most of the expenses are supported by The National Health Insurance House.
A good prevention program may be effective in reducing the costs. Disease awareness is also
an important fact that must be improved in order to reduce costs.

Our analysis only estimates direct costs, consisting of admission, evaluation and treatment
costs. These expenses are supported by The National Health Insurance House. Indirect costs,
for example number of workdays missed by parents and schooldays missed by children or
transportation and supportive treatment costs, must be covered by the parents. The family's
education and economic level determines the moment of diagnosis. The earlier the diagnosis
is established, the lower the expenses for treatment and monitoring.

New, more effective molecules used for chronic viral hepatitis treatment in the adult
population are still not approved for pediatric use. Approval of new treatment options could
improve the outcome, reduce further complications and subsequently reduce expenses. Some
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

of these new treatments are used for children in other countries, but are still not available in
Romania.

Prophylaxis costs are considerably lower than treatment costs. Prevention measures for
hepatitis B include vaccination and active immunization immediately after birth (for selected
groups) along with basic rules that should be applied for hepatitis C as well. Screening
programs may be cost-efficient as early detection of the disease can considerably reduce
expenses.

Different responses to treatment may be obtained and the treatment plan may sometimes be
modified according to this, costs for supportive treatment may vary and patient outcome can
be different. In addition, treatment costs may vary considering the fact that treatment doses
depend on the body surface area of the child. Therefore we cannot establish the exact burden
of the disease in our country or the cost for treatment per individual.

Still, prevention is certainly less expensive than disease management. It can be obtained both
by general measures and vaccination. Early detection is as well an important tool in reducing
costs. Therefore, screening programs should be applied to at risk population (families of
patients with chronic hepatitis B and C, i.v. drug users, etc). So these are the tools we should
focus on in order to reduce the expenses generated by the disease.

In conclusion, chronic viral hepatitis is a highly expensive disease, both for the national
economy and for the family of the infected child. Complications increase the costs of care
(both investigation and treatment costs are higher) and need to be avoided, not only because
of the economic factor, but also because they affect the patient's quality of life.

Acknowledgements

This paper is made and published under the aegis of the Research Institute for Quality of Life, Romanian
Academy as a part of programme co-funded by the European Union within the Operational Sectorial
Programme for Human Resources Development through the project for Pluri and interdisciplinary in doctoral
and post-doctoral programmes Project Code: POSDRU/159/1.5/S/141086
Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

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Annals of the University of Bucharest, Economic and Administrative Series, ISSN: 1842-9327, Volume 9
2015, p. 3 16, published online: September 2015

Figure 1: Hepatitis C treatment strategy (M.H., 2006; Ferreira, 2007)