VALUE IN HEALTH 14 (2011) S24 S28

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Chronic Hepatitis B Treatment: The Cost-Effectiveness of Interferon

Compared to Lamivudin e
Alessandra Maciel Almeida, ScD1,*, Anderson Loureno da Silva, MSc2, Maringela Leal Cherchiglia, MD, PhD1,
Eli Iola Gurgel Andrade, PhD1, Gustavo Laine Arajo de Oliveira, postgraduate student1, Francisco de Assis Acurcio, MD, ScD2
1

Department of Preventive and Social Medicine, Universidade Federal de Minas Gerais, Brazil; 2Department of Social Pharmacy, Universidade Federal de Minas
Gerais, Brazil

A B S T R A C T

Objective: To perform a cost-effectiveness evaluation from the perspective of the Brazilian National Health System of alternatives strategies (i.e., conventional interferon, pegylated interferon, and lamivudine) for the treatment of patients with chronic hepatitis B who present
elevated aminotransferase levels and no evidence of cirrhosis at the
beginning of treatment. Methods: A Markov model was developed for
chronic hepatitis B (hepatitis B antigen e [HBeAg] positive and negative)
with 40 years time horizon. Costs and benefits were discounted at 5%.
Annual rates of disease progression, costs due to complications, and
the efficacy of medicines were obtained from the literature. One-way
and probabilistic sensitivity analysis evaluated uncertainties.
Results: For HBeAg positive patients, peginterferon (48 weeks) resulted
in an increase of 0.21 discounted life-years gained compared to interferon (24 weeks). The incremental cost-effectiveness ratio (ICER) converted to US dollars using the 2009 purchasing power parity conversion
factor was US$100,752.24 per life-year gained. For HBeAg negative patients, it was observed that interferon (48 weeks) compared with longterm lamivudine presented an increase of 0.45 discounted life-years
gained and ICER of US$15,766.90 per life-year gained. In the sensitivity

Introduction
Hepatitis B is one of the most common infectious diseases
worldwide. An estimated 350 million people worldwide are
chronically infected with hepatitis B virus (HBV) [1]. In Brazil, at
least 15% of the population has been in contact with HBV and 1%
present with chronic disease [2]. Persistently high HBV DNA
levels are associated with an increased risk of cirrhosis and
hepatocellular carcinoma (HCC) [3,4], which contributes to the
increase of treatment costs due to morbidity [5].
Until recently and according to the Clinical Protocols and
Therapeutic Guidelines for High Cost Medications of the Brazilian Ministry of Health [6], pharmacological options for the treatment of chronic hepatitis B were restricted to interferon and
lamivudine. Currently, three antiviral medications (tenofovir,
entecavir, and adefovir) have extended the treatment alternatives for the control of HBV action [7].

analysis, the ICER was more sensitive to variation in the probability of

transition from chronic hepatitis B to compensated cirrhosis, discount
rate, and medicine prices. Cost-effectiveness acceptability curve for
HBeAg positive (pegylated interferon vs. conventional interferon) and
negative (conventional interferon vs. lamivudine) showed that conventional interferon was cost-effective until three times the gross domestic product per capita. Conclusions: For patients with chronic hepatitis
B with elevated aminotransferase levels in the pretreatment and no
cirrhosis who were HBeAg positive, pegylated interferon (48 weeks)
provided more life-years gained when compared to conventional interferon (24 weeks), and the ICER surpasses the countrys buying power,
which makes conventional interferon the chosen alternative. For
HBeAg negative patients, conventional interferon (48 weeks) compared
to lamivudine provided more life-years gained at a favorable ICER.
Keywords: chronic hepatitis B, cost-effectiveness, interferon, lamivudine, peginterferon.
Copyright 2011, International Society for Pharmacoeconomics and
Outcomes Research (ISPOR). Published by Elsevier Inc.

In a systematic review [8], it was observed that interferon

(IFN) presented the advantages of long-term response in hepatitis B antigen e (HBeAg) positive patients, a short treatment
duration and absence of resistance. The main advantages of
pegylated interferon (PEG-IFN) were its extended biological effect and the lower number of treatments it required. Both treatment options showed the disadvantages of limited use in patients with a lower alanine aminotransferase (ALT) level at
pretreatment or with a decompensated liver, their association
with several adverse events and the inconvenience of subcutaneous injection.
The first nucleoside analogue to be approved and used for HBV
was lamivudine (LAM) [9], which is associated with minimal adverse events, low maintenance response rates, and a need for
long-term therapy [10]. Its greatest limitation is the selection of
resistant mutants, with patients becoming resistant after a year of
treatment [11].

Conflicts of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article.
* Address correspondence to: Alessandra Maciel Almeida, Prof. Antnio Aleixo Street, 760/602 Bairro de Lourdes, Belo Horizonte, MG,
Brazil. CEP 30180-150.
E-mail: alessandraalm@gmail.com.
1098-3015/$36.00 see front matter Copyright 2011, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
doi:10.1016/j.jval.2011.05.011

VALUE IN HEALTH 14 (2011) S24 S28

The objective of this study was to perform a cost-effectiveness

evaluation from the perspective of the Brazilian Public Health System (SUS) of alternative strategies (IFN, PEG-IFN, and LAM) for the
treatment of patients HBeAg positive and negative (i.e., antibodies
to HBeAg), who present high ALT levels and no evidence of cirrhosis at the beginning of treatment. This group of patients was chosen because it is considered to represent the most prevalent and
clinically relevant chronic HBV infection.

Methods
Decision analysis software (DATA, version 1.3.1, Tree Age software, Inc., Williamstown, MA) was used for the cost-effectiveness
analysis aimed at evaluating a hypothetical cohort of patients
with chronic HBV infection with a histological diagnosis of the
disease, positive for serum hepatitis B surface antigen for more
than 6 months, with detectable HBV DNA levels and high ALT
levels (more than twofold the upper normal limit [UNL]) and no
clinical or histological evidence of cirrhosis. Clinical research
shows differences in the age profile among HBeAg positive and
negative patients [12,13]. As a result, two models were built, considering the average age at the onset of treatment as 32 years for
HBeAg positive patients [12,14] and 40 years for HBeAg negative
patients [14]. A Markov model was used with 1-year cycles and
both models evaluate short-course and longer duration treatments with time-horizon of 40 years, given that most of the patients in the cohort would be dead after this period.
Ideally, economic analysis should be established prospectively,
and together with the results of clinical research. The disease progression involves decades and it is difficult to realize prospective
studies. The model parameters, including efficacy/effectiveness
measures were obtained from a specific systematic review [8] and
from review of selected studies.
The efficacy measures used were: 1) HBeAg positive patients:
HBeAg seroconversion; and 2) HBeAg negative patients: response
to treatment [low levels of HBV DNA ( 300 400 copies/mL) and
normalisation of ALT levels] [13]. The long-term results were modelled using the stages in the Markov model considering the annual
failure in the durability of HBeAg seroconversion and treatment
response.
In this study, like previous economic analyses of antiviral
treatment for chronic hepatitis B [15], HBeAg seroconversion was
used as a treatment-stopping criterion. However a patient could
experience a relapse and return to the chronic hepatitis B stage
[16]. For HBeAg negative patients, sustained remission was also
not considered common [17].
The model did not assume any explicit consideration in regard
to LAM resistance. However, some effects of resistance to the
medication were captured with the reduction in long-term seroconversion rates [15].

HBeAg positive
The model consisted of six disease stages (Fig. 1A in Supplementary Materials found at: doi:10.1016/j.jval.2011.05.011). The model
structure was adapted from the model of Crowley et al. [18].
All patients in the model started at the chronic hepatitis B disease stage with no cirrhosis and received treatment alternatives.
The model evaluated short-term treatment for HBeAg positive patients: IFN dosed at 9 to 10 MU three times a week (24 weeks),
PEG-INF alfa 2a (180 g) once a week (48 weeks) or long-term LAM
(100 mg) daily (LAM use after 4 years of treatment in patients who
did not undergo HBeAg seroconversion did not bring any added
benefit; however, in the Markov model, these patients continued
to receive LAM and the cost was calculated in subsequent years).
The model doesnt assume rescue therapy in case of treatment
failure associated with emergence of drug-resistant virus.

S25

Efficacy measures were obtained for 1 year of treatment considering results from clinical research in patients with ALT levels
greater than or equal to twice the UNL, HBeAg seroconversion
rates for IFN (24%) [18], LAM (19%) [12], and PEG-IFN (32%) [12]. The
seroconversion estimates sustained for LAM for the second, third,
and fourth year of treatment were 10%, 6%, and 5%, respectively,
based on observational studies [12,19,20]. The rate of seroconversion observed in the fourth year (5%) [20] was used from the fifth
year onward (Table 1 in Supplementary Materials found at: doi:
10.1016/j.jval.2011.05.011).
In all therapeutic alternatives, after treatment cessation, all
patients could experience a relapse. Van Nunen et al. [21] and
Wang et al. [22] demonstrated a 35% relapse for LAM in patients
with ALT levels greater than or equal to two to five times the UNL
6 months after the treatment; that rate was considered until the
fourth year of treatment. For the fifth year, a relapse of 25% was
estimated considering the potential long-term impact on the durability of seroconversion [21,22]. Spontaneous seroconversion
rates of 9% were considered for patients in the beginning of the
treatment with PEG-IFN and IFN [18] (Table 1 in Supplementary
Materials found at: doi:10.1016/j.jval.2011.05.011).
There was limited published data on the annual loss of response following treatment with PEG-INF, so cconservative relapse rates of 8% were used in the analysis for IFN and PEG-IFN
[21], despite PEG-IFN has showed fewer relapses than conventional IFN (Table 1 in Supplementary Materials found at: doi:
10.1016/j.jval.2011.05.011). All the efficacy assumptions for LAM
and PEG-INF are similar to what was used by Veenstra et al. [14];
thus, relapse rates for INF and PEG-INF were obtained in the same
study. The annual rates of disease progression or effectiveness
measures were described in Table 2 in Supplementary Materials
found at: doi:10.1016/j.jval.2011.05.011.

HBeAg negative
All HBeAg negative patients in the model started at chronic hepatitis B disease stage with no cirrhosis. The model consisted of six
disease stages (Fig. 1B in Supplementary Materials found at: doi:
10.1016/j.jval.2011.05.011). The treatment alternatives considered
were IFN at a dosage of 9 to 10 UM three times a week (48 weeks),
PEG-IFN (48 weeks) once a week, or long-term LAM daily (until the
patient responds to treatment).
To obtain efficacy measures, the estimates for sustained combined response (suppression of HBV DNA and ALT normalization)
6 months after the treatment was stopped were derived from the
randomized controlled trial by Marcellin et al. [13] that compared
PEG-IFN with LAM (48 weeks). The response rates for PEG-IFN were
36% at the end of treatment and at follow-up and 69% for LAM at
the end of treatment. There is some data in the literature on relapse rates after 6 months of treatment with LAM, but two studies
pointed out that the combined response rates were around 11% to
20% 1 to 2 years after treatment [23,24]. These authors reported
relapse rates of 83% after 6 months and after a year of follow-up
[23,24]. Based on these data, a conservative annual rate of relapse
of 80% for LAM was considered. For IFN, a complete response rate
to the treatment of considered 60% [25].
There are no long-term data on combined response for PEG-IFN
and there are few for IFN. One study suggested that 50% of patients
treated with IFN experienced relapse between 6 months and 32
months post treatment [26]. Considering that there were no relapses 6 months after treatment with PEG-IFN [13], a relapse of 25%
was assumed after 6 months of treatment [27]. Spontaneous relapses of 6% were considered [28,29]. These estimates were obtained from Veenstra et al. [27]. The annual rates of disease progression or effectiveness measures are described in Table 2 in
Supplementary Materials found at: doi:10.1016/j.jval.2011.05.011.

S26

VALUE IN HEALTH 14 (2011) S24 S28

The costs
Only direct costs were taken into account in this study. All costs
were originally calculated in the national currency (Brazilian real
[BRL]). These values were converted to US dollars using the 2009
purchasing power parity (PPP) conversion factor according to the
International Monetary Fund. It was assumed 2009 PPP conversion
factor (US$1 1.56 BRL).

Prices of the medication therapies

Prices were based on the list of medication prices from the Medication Market Regulating Chamber (Cmara de Regulao do Mercado de Medicamentos) on November 13, 2009. The average factory price was used with a state tax on goods and services of 0%
and the price adjustment coefficient of 24.92%, which is a mandatory minimum discount that affects the factory price of some
medications purchased by public entities. The average prices were
of US$51.42 (US$87.87US$110.85) for IFN, US$578.69 (US$338.69
US$730.02) for PEG-IFN and US$1.39 (US$0.43US$2.16) for LAM.
The calculation of the minimum and maximum prices used the
lowest and the highest price found in the Medication Market Regulating Chamber table and then applied the price adjustment coefficient. Because there was no price variation for the PEG-IFN, the
same variation found for the IFN was used.

Annual costs due to chronic hepatitis B complications

Annual costs per patient with compensated cirrhosis (CC), decompensated cirrhosis, and HCC were obtained from the study by Castelo et al. [30] that evaluated the chronic hepatitis B costs in 2005 in
Brazil with a Delphi panel of specialists. The direct costs included
those generated by medical fees, lab exams, diagnostic and therapeutic procedures, hospitalizations, and medications. Data on
costs were predominantly obtained from SUS billing tables and
medication prices. The annual costs of the evolving chronic hepatitis B stages were updated to 2009 and estimated as follows:
chronic hepatitis B (US$870), CC (US$1243), decompensated cirrhosis (US$7763), and HCC (US$1679).

Cost-effectiveness analysis
The Markov model was used to estimate the clinical benefits in
life-years gained (LYG) and the costs of the medication alternatives in the time horizon period. The comparison among the treatment alternatives was measured by the incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold developed
by the World Health Organization [31] is one to three gross domestic product (GDP) per capita for an additional disability adjusted
life year prevented. A discount rate of 5% per year was adopted for
the costs and results.
A unidirectional sensitivity analysis was conducted to determine the impact in the ICER estimate. This analysis was carried
out by changing individual inputs: therapy response at the first
year of treatment (interval confidence), prices of the medication
(lowest, highest), discount rates (0%, 5%, and 10%) or magnitude of
treatment effectiveness in a Tornado analysis. A probabilistic sensitivity analysis was conducted and generated a cost-effectiveness
acceptability curve using Monte Carlo simulation methods. Triangular distributions were assigned to probability based on the parameter ranges (minimum, maximum) listed in Table 2 in Supplementary Materials found at: doi:10.1016/j.jval.2011.05.011.

Results
The clinical results and economic estimates for each medication
alternative (IFN, PEG-IFN, and LAM) for chronic hepatitis B treatment are presented in Table 3 in Supplementary Materials found
at: doi:10.1016/j.jval.2011.05.011.

In HBeAg positive patients, it was observed that PEG-IFN (48

weeks) resulted in more LYG compared to IFN (24 weeks), with a
difference of 0.21. The ICER was US$100,752.24 per LYG. The LAM
strategy was dominated. In the case of HBeAg negative patients, it
was observed that IFN (24 weeks) presented an ICER of
US$15,766.90 per LYG compared to LAM (lifetime), with a difference of 0.45 LYG. The LAM strategy and PEG-INF were dominated.
For HBeAg positive patients, the treatment with LAM resulted
in an average of 13.58 LYG compared to 14.25 LYG (IFN) and 14.46
LYG (PEG-IFN). The accumulated incidence of CC across 10 years
was 18%, 15%, and 14%, respectively. For HBeAg negative patients,
the treatment with IFN results in an average of 13.12 LYG compared to 12.93 LYG (PEG-IFN) and 12.67 LYG (LAM). The incidence
accumulated of CC in 10 years was 22.7%, 23.3%, and 26%, respectively.

Sensitivity analysis
For both groups, when the discounts (0%, 5%, and 10%) were applied to the costs, the ICER estimates decreased.
For HBeAg positive patients, when the worst and the best scenarios (minimum or maximum values of the seroconversion rates)
were modelled for the first year of treatment, there was no affect
on the ICER comparing PEG-INF versus INF.
For HBeAg negative patients comparing INF versus LAM, when
the best scenario (maximum value of response) was used for the
first year of treatment, we observed a reduction in the ICER
US$4894.87. Concerning the worst scenario, the ICER was not altered. For HBeAg positive patients comparing PEG-INF versus INF,
when medicines minimum prices were applied to the medications, there was a decrease in the ICER US$57,341.40 and the ICER
increased (US$128,248.29) when maximum prices were applied.
The same phenomenon was observed for the HBeAg negative patients comparing INF versus LAM, with ICERs of US$4895.94 and
US$24,507.22, respectively.
The Tornado analysis demonstrated that the ICER estimates
were more sensitive to the variation in the probability of chronic
hepatitis B evolving to CC, seroconversion to CC and response to
CC (Figs. 2 and 3 in Supplementary Materials found at: doi:10.1016/
j.jval.2011.05.011).
For HBeAg positive patients, the cost-effectiveness acceptability curve generated from the PSA for the discounted incremental
cost-effectiveness ratio indicated that INF was cost-effective compared with PEG-INF until three GDP per capita. To willingness to
pay up than US$104,487.20, using the 2009 PPP conversion factor,
PEG-INF has up than 50% to be cost-effective compared with INF.
For HBeAg negative patients, INF was cost-effective compared
with LAM at the Brazilian threshold.

Discussion
In this study, for HBeAg positive patients, PEG-IFN when compared
to the IFN showed a little better result, but presented an ICER
above the current Brazil cost-effectiveness threshold. The ICER
was more sensitive to variation in the progression probability of
the chronic hepatitis B to CC and seroconversion for CC. Therapy
response did not impact the sensitivity analysis and can be related
to the small seroconversion interval observed in the literature.
Greater variation in the ICER was noticed when medication price
and discount rate was varied. In probabilistic sensitivity analysis,
INF was cost-effective compared with PEG-INF until three GDPs
per capita.
Using a Markov model system and data from clinical research,
Sullivan et al. [32] evaluated the ICER of treatment with PEG-IFN
compared to that of LAM in HBeAg positive patients from the perspective of Taiwan. Treatment with PEG-IFN was considered more
cost-effective considering factors such as disease progression,

VALUE IN HEALTH 14 (2011) S24 S28

LYG, therapy cost, and effectiveness. The ICER was sensitive to the
same variations observed in this study and was considered favorable because it was within the buying power parameters of that
country. Veenstra et al. [14] observed that even though PEG-IFN
was a more expensive alternative than LAM, it provided better
results in terms of health and cost-effectiveness within the buying
power constraints of the United Kingdom.
In our study, for HBeAg negative patients, INF compared to
LAM demonstrated more LYG and ICER within the buying power of
the country. The PEG-IFN alternative was dominated. In the sensitivity analysis, we observed that varying the interval of the transition probabilities caused less variation in the ICER. Greater variation in the ICER was observed when medications price and
discount rate varied. In PSA, INF was cost-effective even for values
up to three GDPs per capita.
The results of our study show that the progression to CC in
HBeAg negative patients was higher than in HBeAg positive patients and that LAM resulted in greater progression in both groups.
Lacey et al. [16] observed similar results and concluded that shortterm treatment with IFN, PEG-IFN, or LAM presented limited influence on the disease progression.
Comparing PEG-IFN with LAM in HBeAg negative patients,
Veenstra et al. [27] demonstrated that PEG-IFN had incremental
benefits on life expectancy and quality of life with an acceptable
ICER in Taiwan. Kanwal et al. [28] verified that IFN was more costeffective compared to LAM in HBeAg negative patients. The authors emphasized that IFN could reduce costs because it eliminated the need for longer therapy and that it could be effective
when it did not present viral resistance.
Some limitations to our study can be identified and they pertain to treatment compliance, patient profiles, natural history of
the disease, annual costs, time-horizon, no natural mortality
rates, and the estimates obtained in the literature. All long-term
modeling studies are inherent uncertainties in projecting longterm results.
The modelling did not consider the occurrence of problems in
compliance with LAM long-term antiviral treatment, which can
generate worse results than those observed in the clinical trials.
The same can be considered in the treatment with IFN due to
adverse events. Low adherence rates to the treatment can reduce
the therapy response, thereby risking the treatments effectiveness on the disease progression.
The profile of the patients included in our study does not allow
for the extrapolation of the results to patients with a different
profile. However, that choice was considered the most prevalent
and clinically relevant form of chronic HBV infection. High levels
of ALT in the pretreatment is a predictable factor for the response
at the end of the treatment and that IFN may be adverse to patients in advanced stages of the disease [18]..
We assumed that patients in different stages of chronic hepatitis B present the same clinical course and progression rates as
nontreated patients. This condition is consistent with several published analyses of cost-effectiveness, where the patients without
response and nontreated patients progress in a similar manner
[28,32,33].
In addition, the estimates in the literature are limited and international studies that are mainly focused on Asian populations
are the main sources of findings on the medications used in the
treatment of chronic hepatitis B.

Conclusions
This analysis suggests that for HBeAg positive patients with high
levels of ALT in the pretreatment and without cirrhosis or HCC at
the beginning of the treatment, PEG-IFN (48 weeks) provided more
LYG when compared to IFN (24 weeks), but the ICER surpasses the
countrys buying power, which makes IFN the chosen alternative

S27

for those patients. For HBeAg negative patients, INF (48 weeks)
compared to LAM (long-term) provided more LYG at an acceptable
ICER to the country. The sensitivity analyses show that the ICER
was more sensitive to variation in the probability of transition
from chronic hepatitis B to CC, discount rate, and medicine prices.
Our findings suggest that interferon could be considered the chosen alternative in health care systems with limited resources.

Acknowledgements
The authors thank the members of the Pharmacoepidemiology
Research Group, the Health Economy Research Group of the
UFMG, and infectious disease specialist Dr. Ricardo Andrade
Carmo for valuable contributions.
Sources of financial support: Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico CNPq (process No. 551412/
2007-0) Edital MCT/CNPq/MS-SCTIE-DECIT/CT-Sade No. 033/
2007, and Fundao de Amparo Pesquisa do Estado de Minas
Gerais FAPEMIG (Process No. 4611-5.01/07).

Supplemental Materials
Supplemental material accompanying this article can be found in
the online version as a hyperlink at doi:10.1016/j.jval.2011.05.011
or if hard copy of article, at www.valueinhealthjournal.com/issues
(select volume, issue, and article).
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