Volume 13 • Number 8 • 2010
VA L U E I N H E A LT H
Cost–Utility Analysis of Tenofovir Disoproxil Fumarate in the
Treatment of Chronic Hepatitis B
Helen Dakin, MSc,1,2 Anthony Bentley, BSc,1 Geoff Dusheiko, MD3
1
Abacus International, Bicester, Oxfordshire, UK; 2Health Economics Research Centre, University of Oxford, Department of Public Health,
Headington, Oxford, UK; 3Centre for Hepatology, Royal Free Hospital London, London, UK
A B S T R AC T
Objective: The aim of this study was to assess the cost-effectiveness of
tenofovir disoproxil fumarate (TDF) in the treatment of chronic hepatitis
B (CHB) versus alternative nucleos(t)ides from a UK National Health
Service (NHS) perspective.
Methods: A Markov model was used to calculate costs and benefits of
nucleos(t)ide strategies in hepatitis B e antigen (HBeAg)-positive and
HBeAg-negative patients with hepatitis B virus mono-infection and com-
pensated liver disease. The model included 18 disease states representing
CHB progression. Quality-of-life data and costs for severe disease states
were based on published studies, while monitoring costs for other disease
states were based on expert opinion. Transition probabilities for move-
ments between states were based on a meta-analysis, clinical trials, and
natural history studies.
Results: First-line TDF generated the highest net benefits of all
211 nucleos(t)ide strategies evaluated at a threshold of £20,000 per
Introduction
An estimated 326,000 people in the UK are thought to have
chronic hepatitis B (CHB) [1], which can lead to cirrhosis, hepa-
tocellular carcinoma (HCC), and death [2]. Current treatment
options in the UK and Europe include nucleosides (entecavir
[ETV], lamivudine [LAM], and telbivudine [LdT]), nucleotides
(adefovir dipivoxil [ADV] and tenofovir disoproxil fumarate
[TDF]), and interferons (peginterferon-alpha-2a and interferon-
alpha-2a/b).
Although interferons are effective for carefully selected
patients [2], many people do not tolerate treatment [3–5]. A
year’s treatment with peginterferon-alpha-2a leads to hepatitis B
e antigen (HBeAg) seroconversion in approximately 32% of
HBeAg-positive patients, and suppresses viral load to <20,000
copies/mL in around 43% of HBeAg-negative patients [6]; the
remaining patients are likely to require nucleos(t)ides to achieve
sustained viral suppression.
Although nucleos(t)ides are well tolerated, resistance to LAM
arises rapidly, with up to 70% of patients becoming resistant
after 4 years of continuous therapy [7]. Nevertheless, newer
nucleos(t)ides (particularly TDF and ETV) are associated with
substantially lower resistance rates [8–10], and are significantly
more effective than LAM or ADV [11–14].
TDF is a nucleotide reverse transcriptase inhibitor with
potency against hepatitis B virus (HBV) [14], including LAM-
resistant HBV [15–17]. In the UK, TDF was licensed for use in
CHB in 2008, although it has been used to treat HIV since 2002.
Recent registration randomized, controlled trials (RCTs) have
Address correspondence to: Helen Dakin, Abacus International, 4 Market
Square, Bicester, Oxfordshire OX26 6AA, UK. E-mail: helen.dakin@
abacusint.com
10.1111/j.1524-4733.2010.00782.x
922 © 2010, International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
vhe_782 922..933
quality-adjusted life-year (QALY) gained. First-line TDF cost £19,084/
QALY gained compared with giving lamivudine (LAM) first-line and
switching to TDF when LAM resistance occurs. First-line TDF was also
more effective and less costly than first-line entecavir (ETV), and showed
extended dominance over first-line adefovir and strategies reserving ade-
fovir, ETV, or combination therapy until after LAM resistance develops.
For patients who have developed LAM resistance, TDF was also the most
cost-effective treatment, generating greater net benefits than any other
second-line strategy.
Conclusions: First-line TDF is the most cost-effective treatment for
patients with CHB at a £20,000 to £30,000/QALY ceiling ratio, costing
£19,084/QALY gained compared with the next best alternative.
Keywords: cost–utility analysis, hepatitis B virus infection, lamivudine, net
benefit approach, nucleoside, nucleotide, tenofovir, Viread.
shown that TDF is superior to ADV in treatment-naive patients
[14], and is also effective in patients with persistent viremia
during ADV therapy [18]. TDF displays a favorable resistance
profile: no cases of virological HBV resistance have been identi-
fied to date during intensive surveillance, which includes 8 years
of clinical experience in HIV/HBV coinfected patients (who
received TDF alongside other antiretroviral drugs) [16,17,19,20]
and up to 96 weeks of continuous use in controlled clinical trials
on CHB [14,21]. Nevertheless, the cost-effectiveness of TDF in
the treatment of CHB remains to be determined in a UK setting.
We set out to identify the most cost-effective first-line nucleo-
s(t)ide treatment for CHB from the perspective of the UK
National Health Service (NHS), and assess which drug(s) should
be given to patients who develop resistance to first- or second-
line treatment. This analysis focuses on nucleos(t)ides as they
represent the most commonly used treatments for CHB in the
UK.
Methods
Outline of the Economic Model
A Markov model was constructed to model the progression of
CHB, and the costs and benefits of nucleos(t)ide treatment,
taking account of drug resistance and HBeAg-negative, as well as
HBeAg-positive, CHB. Health benefits were measured in quality-
adjusted life-years (QALYs), which take account of changes in
both length and quality of life.
In addition to calculating the cost per QALY gained, we used
the net benefit approach [22,23] to compare the total monetary
benefits of each treatment with those for all other possible treat-
ment strategies whenever this simplified the interpretation of
results. Total net benefits are calculated by multiplying the
number of QALYs accrued over a lifetime by the ceiling ratio (the
1098-3015/10/922 922–933
Cost-Effectiveness of Tenofovir DF in CHB 923

maximum amount that society is willing or able to pay to gain
one QALY) and subtracting the total NHS costs accrued over a
lifetime. The treatment with the highest total net benefit at the
ceiling ratio of interest is the optimal choice for managing that
population and will always correspond to the treatment that is
optimal based on the cost-effectiveness ratio approach.
TotalNetBenefit TreatmentX = QALYsTreatmentX ⋅ CeilingRatio
− CostTreatmentX
The National Institute for Health and Clinical Excellence
(NICE) generally considers treatments costing less than £20,000
to £30,000 per QALY gained to be cost-effective [24]. Net ben-
efits were therefore calculated at ceiling ratios of £20,000 and
£30,000 per QALY; results at a £10,000/QALY threshold are
also presented to test the impact of using a lower ceiling ratio.
The analysis was based on a heterogeneous cohort of
nucleos(t)ide-naive adults (aged ⱖ18 years) with compensated
CHB, detectable HBV DNA, and evidence of active liver disease
for whom nucleos(t)ide therapy is considered appropriate.
CHB was defined as persistence of hepatitis B surface antigen
(HBsAg) for at least 6 months. Patients coinfected with HIV or
hepatitis C were excluded. Based on an audit conducted by the
authors of this article in which anonymized hospital records
of 85 HBsAg-positive adults attending a London hepatology
outpatient clinic were reviewed [25], it was assumed that 5.3%
of the patients were cirrhotic at baseline, and that 50% of cir-
rhotic patients and 55.5% of non-cirrhotic patients had HBeAg-
negative CHB. Additional details on this audit are available on
request.
Disease progression was modeled as movements between 18
disease states (Fig. 1). Treatments that slow disease progression
were assumed to reduce disease management costs and extend
patients’ healthy life expectancy, and may therefore be cost-
effective compared with less potent drugs. Furthermore, drug
resistance may increase the risk of disease progression; subse-
quently, treatments with higher resistance rates may be less
cost-effective. Each year, patients were assumed to move
between disease states based on the transition probabilities
shown in Appendix 1 at: http://www.ispor.org/Publications/
value/ViHsupplementary/ViH13i8_Dakin.asp. A lifetime time
horizon was used in the model; because the mean age of
patients in the London clinic audit was 38, of whom 63% were
men, the model was run over a 42-year time horizon (the life
expectancy of this age group [26]).
As resistance to drugs such as LAM develops rapidly [7,27],
it is important to consider second-line (or third-line) treatment
options that are used after resistance develops. The model
allowed for switches between nucleos(t)ide therapies following
development of drug resistance. Patients were assumed to receive

Figure 1 Patient flow diagram for the Markov model.The model uses a 1-year cycle length, such that patients may move between disease states along the arrows
shown once each year. Patients enter the model in one of the four states with a bold black border; as stated in the text, 5.3% of the patients were assumed to be
cirrhotic at baseline, with 50% of cirrhotic patients and 55.5% of noncirrhotic patients having HBeAg-negative CHB. Patients in the disease states shown in white ovals
will be indicated for any treatments available in the relevant treatment strategy. Although patients in the states indicated by * would not be eligible to start therapy
with one or more of the agents considered in the analysis, it was assumed that treatment would not be discontinued if they entered these states after the start of
treatment. Viral suppression was defined as HBV DNA <300 copies/mL occurring without seroconversion, generally as a result of antiviral medication. The liver
transplant state encompassed the year of the transplant operation (from 3 months before the operation to 9 months afterward), after which time surviving patients
progress to the post–liver transplant state. CC, compensated cirrhosis; CHB, chronic hepatitis B; c/ml, copies per milliliter; HBeAg, hepatitis B e antigen; HBsAg,
hepatitis B surface antigen; HBV, hepatitis B virus.
924 Dakin et al.

Table 1 Nucleos(t)ide treatments included in the model and their respective daily dosages and costs

Drug Dose Drug cost

BSC (no antiviral therapy) — £0.00/patient-day

LAM (Zeffix, GSK) 100 mg/day £2.79/patient-day [5]
TDF* (Viread, Gilead Sciences) 300 mg/day £8.50/patient-day [5,66]
ADV (Hepsera, Gilead Sciences) 10 mg/day £10.50/patient-day [5]
TDF* plus LAM 300 mg/day TDF £11.29/patient-day [5,66]
100 mg/day LAM
ETV (Baraclude, BMS) 0.5 mg/day for treatment-naive patients and £12.60/patient-day for both doses [5]
1 mg/day for patients resistant to ⱖ1 nucleos(t)ide
ADV plus LAM 10 mg/day ADV £13.29/patient-day [5]
100 mg/day LAM
ETV plus ADV 10 mg/day ADV £23.10/patient-day [5]
0.5 mg/day ETV for treatment-naive patients and
1 mg/day for patients resistant to ⱖ1 nucleos(t)ide

*300 mg tenofovir disoproxil fumarate (TDF) is equivalent to 245 mg tenofovir disoproxil (as fumarate).
ADV, adefovir; BSC, best supportive care; ETV, entecavir; LAM, lamivudine; TDF, tenofovir disoproxil fumarate.

sequences of up to three nucleos(t)ides (or nucleos(t)ide combi-
nations) followed by best supportive care (BSC), which com-
prised monitoring with no antiviral therapy. The nucleos(t)ide
treatments included in the model are shown in Table 1. For
simplicity, only three combination therapies were included
(Table 1), which represented the most plausible combinations for
ADV, ETV, and TDF. It should be noted that the UK license
indications for nucleos(t)ides neither specifically mention combi-
nation therapy nor advise against use in combination therapy
[28–31]. Nonetheless, in practice, the drug combinations listed in
Table 1 may be considered clinically appropriate.
All sequences of the treatments shown in Table 1 other than
those in which patients will be resistant to their third-line agent
before starting that treatment were considered in the analysis,
giving a total of 211 different treatment strategies for which costs
and benefits were calculated. Nevertheless, for clarity, results are
only presented for 20 treatment pathways that represent the most
cost-effective of each of the main options; results for other strat-
egies are available on request.
Historically, LAM followed by BSC with no antiviral treat-
ment was the only treatment option available, and this strategy
has been shown to be cost-effective [32], although it is no longer
considered clinically appropriate for patients with high levels of
HBV replication because potent second-line agents are now
available [2,33–35]. BSC and LAM followed by BSC were there-
fore included in the analysis to enable assessment of whether
TDF is the most cost-effective strategy out of all plausible nucleo-
s(t)ide strategies (including those no longer used), and to ensure
that TDF is compared against low-cost strategies with proven
cost-effectiveness.
Interferon-alpha and peginterferon-alpha were not consid-
ered as comparators because these are given as short-term initial
options in selected patients rather than maintenance treatments
[2], and are used by less than 10% of patients [12]. LdT was
excluded because it is rarely used in the UK and is not recom-
mended by NICE [36].
The development of drug resistance and switches between
treatments were modeled by duplicating the 18 disease states
shown in Figure 1, such that separate replica sets of these 18
disease states were used for first, second, and third-line treat-
ments, fourth-line treatment with BSC, and for the year(s) in
which resistance developed. Separate sets of states were also used
to allow for variations in transition probabilities and resistance
rates over time.
For simplicity, the risk of resistance was assumed to be the
same for all disease states; the resistance rate data used in the
model are described in Appendix 2. Resistance was defined as
ⱖ 1 log10 copies/mL rise in HBV DNA from nadir. Virological
resistance was assumed to be identified an average of 1.5 months
after the rise in HBV DNA, because interviews with five consult-
ant gastroenterologists suggested that levels are monitored quar-
terly in UK clinical practice. During the year in which resistance
developed, patients were therefore assumed to spend 10.5
months with the same risk of progression/improvement as drug-
sensitive treated patients. When viral load rose at 10.5 months,
patients in the “HBeAg-positive/negative viral suppression”
states and the “HBeAg-positive/negative compensated cirrhosis
HBV DNA <300 copies/mL” states were assumed to switch to
the corresponding states for patients with detectable HBV DNA.
For the remaining 1.5 months of the year, patients who devel-
oped resistance were assumed to have the transition probabilities
of untreated patients, before treatment was switched to the next
treatment in the pathway at the start of the next annual cycle. As
there is some evidence that patients are at increased risk of
hepatic flares and/or decompensation after developing LAM
resistance [27], this assumption may bias the analysis slightly in
favor of the treatments with high resistance rates (e.g., LAM),
although this assumption is unlikely to have any significant effect
on the results as patients spend only 1.5 months in this state
before starting their new therapy.
The key assumptions used in the analysis are outlined below:
• The analysis was conducted from the perspective of the
NHS [37].
• Costs and benefits were discounted at a rate of 3.5% per
year [37].
• The reference year for costs was 2006/2007.
• A half-cycle correction was applied, whereby patients were
assumed to move between states halfway through each year.
• It was assumed that patients who were initially infected
with HBeAg-positive HBV could only develop HBeAg-
negative CHB from the HBeAg-seroconverted disease state
[38].
• It was assumed that once patients develop HBeAg-negative
CHB (excluding the HBeAg-seroconverted carrier state),
they could not move back to any HBeAg-positive disease
state.
• Patients were assumed to continue treatment for an average
of 5.6 (range: 0–9) months after HBsAg seroconversion,
and 10.2 (range: 6–12) months after HBeAg seroconver-
sion, based on estimates by four UK clinicians.
• Transition probabilities were assumed to be constant over
time, except for the probability of HBeAg seroconversion,
viral suppression, and reversion from decompensated to
Cost-Effectiveness of Tenofovir DF in CHB
compensated cirrhosis, which were assumed to be higher
in the first year of treatment than subsequent years (see
Appendix 1 at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH13i8_Dakin.asp).
• Resistance rates were assumed to vary over the first five
years of treatment with any given therapy, and remain
constant at the year 5 values for all subsequent years (see
Appendix 2 at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH13i8_Dakin.asp).
• HBeAg seroconversion was assumed to have the same out-
comes regardless of whether the patient had previously been
cirrhotic. Nevertheless, movement directly from the
HBeAg-seroconverted state to compensated cirrhosis was
permitted because this has been observed in natural history
studies [32,39–41].
• Because literature reviews identified no papers quantifying
the costs, utilities, and transition probabilities for patients
with both HCC and decompensated cirrhosis, it was
assumed that patients with HCC could not undergo hepatic
decompensation and that preexisting hepatic decompensa-
tion did not affect outcomes, costs, or quality of life in
HCC; this simplification is unlikely to affect the results as
only 1.2% to 1.6% of life-years experienced by the cohort
are spent in the HCC state.
• In cases where two nucleos(t)ides were used in combination,
it was assumed (given a shortage of published data) that the
probability of viral suppression or HBeAg seroconversion
with any combination therapy was equal to that of the most
effective component of that combination, because RCTs
conducted to date do not suggest that combination therapy
increases viral suppression [18,42,43].
• It was conservatively assumed that nucleos(t)ide treatment
does not affect the probability of HBsAg seroconversion
because few trials identified in a systematic review [11]
reported data on HBsAg seroconversion. Nevertheless, this
assumption may bias the analysis against TDF, which has a
higher incidence of HBsAg seroconversion than ADV in
HBeAg-positive patients [44].
• For the decompensated cirrhosis, liver transplant, and post–
liver transplant disease states, data on total mortality
(including deaths from causes other than hepatitis B) were
used in the model, and no all-cause mortality was applied;
for other disease states, the annual risk of all cause mortal-
ity [26] was added to the excess mortality associated with
the disease state in question to give the total risk of death
each year (see Appendix 1 at: http://www.ispor.org/
Publications/value/ViHsupplementary/
ViH13i8_Dakin.asp).
• Nucleos(t)ides were conservatively assumed to have no
impact on mortality in patients with HCC or compensated
cirrhosis.
• The (generally mild [28–31]) adverse events associated with
nucleos(t)ides were assumed to have no effect on costs,
mortality, or quality of life, although the cost of renal
monitoring was included in the analysis (Table 2). The cost
of osteopenia monitoring was excluded as this is not rou-
tinely conducted in UK clinical practice [28–31].
Further technical details about the model are available from
the authors on request.
Data Sources Used in the Analysis
The majority of model inputs were based on studies identified in
a systematic literature review of all nucleos(t)ide therapies [11].
925
Table 2 Frequency and cost of consultations for patients in precirrhotic
disease states
Mean (range) Cost per
no. consultations consultation*
Disease state per year (range)
Active CHB or viral 3.3 (2, 4) £114.69 (£46.23, £236.95)
suppression (treated)
Active CHB or viral 2.8 (1, 4) £121.21 (£16.12, £251.26)
suppression (untreated)
HBeAg seroconverted 2.0 (1, 4) £121.21 (£16.12, £251.26)
HBsAg seroconverted 0.03 (0, 1) £121.21 (£16.12, £251.26)
Number of additional 1.17 (0.5, 2) £114.69 (£46.23, £236.95)
consultations required in
the year when resistance
develops†
Number of additional 1 (1, 1) £240.60 (£6.25, £742.04)
consultations required in
year 1 (excluding the
consultation in which
treatment is initiated)
*The cost per consultation includes the cost of staff, clinic overheads, and laboratory tests
such as full blood count, liver function profile, and HBV DNA quantification by polymerase
chain reaction (PCR).All treated patients were assumed to receive quarterly renal monitor-
ing (urea and electrolytes) and, where appropriate, testing for the presence of HBeAg, HBe
antibody, and/or HBsAg. The total cost of tests/investigations was calculated by multiplying
the unit cost per test by the proportion of consultations in which particular tests are
conducted (which was estimated by clinicians) and summing across all tests. In line with its
product license [29], TDF-treated patients were assumed to receive renal monitoring (as-
sumed to comprise urea and electrolyte tests on blood samples taken in practice nurse
consultations) every 4 weeks in their first year of treatment, rather than the quarterly
monitoring assumed for all other treated patients. It was assumed that patients would not
receive bone scans, because no clinicians interviewed felt that these would be conducted
routinely.
†
In addition to the cost of a consultation, 33% (range: 0–100%) of patients developing drug
resistance were assumed to receive HBV sequencing in the year resistance developed.
The numbers of consultations/patient-year are based on the mean (and range) of estimates
from five gastroenterologists working in the UK. Full details of the unit costs and quantities
used in the analysis are available on request.
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen;
HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate.
Additional literature searches were conducted to identify studies
on the natural history of CHB.
All studies identified in the systematic review that reported
the incidence of drug resistance over at least 1 year’s follow-up
were pooled to generate overall estimates of the annual risk of
developing resistance to each medication (see Appendix 2
at: http://www.ispor.org/Publications/value/ViHsupplementary/
ViH13i8_Dakin.asp). Trials on LAM-resistant patients
[15,45–52] were analyzed separately from those on
nucleos(t)ide-naive patients (see Appendix 2). Nevertheless, resis-
tance rates calculated from studies on LAM-resistant patients
were also applied to patients who were resistant to nucleos(t)ides
other than LAM.
Although no cases of virological resistance to TDF have been
observed to date, experience with older nucleos(t)ides suggests
that drug resistance may eventually be observed. To enable cal-
culation of resistance rates for TDF and for other drugs where no
resistance was observed in any particular year, it was assumed
that the next patient to be treated and monitored would develop
virological resistance. For example, because 0% (0/130) of LAM-
resistant patients receiving TDF at year 1 developed resistance
(see Appendix 2), the highest that the incidence of resistance with
TDF can be is 0.76% (1/131). The resistance rates calculated in
this way therefore represent the maximum rates that we can
expect to see given available evidence and are subsequently likely
to overestimate the actual risk of resistance.
Transition probabilities for the key transitions that differ
between active treatments (the probability of achieving undetect-
able HBV DNA or HBeAg seroconversion with each nucleo-
s(t)ide therapy or nucleos(t)ide combination) were based on a
926 Dakin et al.

Table 3 Disease management costs for severe liver disease

Cost per patient or patient-year

No. pts included (inflated to 2006/2007 values using HCHS [56])
Disease state in mean cost Mean cost Lower 95% CI Upper 95% CI

Compensated cirrhosis: cost/patient-year [55] 115 £1,341 £807 £1,876

Decompensated cirrhosis: cost/patient-year [55] 40 £10,750 £7,240 £14,261
HCC: cost/patient-year [55] 20 £9,580 £5,167 £13,992
Liver transplant: cost/patient for waiting list phase lasting 3 months [55] 67 £4,393 £2,604 £6,182
Liver transplant: cost of transplant operation per patient (excluding HBIg) [55] 67 £32,215 £25,550 £38,880
Liver transplant: cost/patient for first 8 months’ posttransplant follow-up 67 £7,432 £3,508 £11,357
(excluding HBIg) [55]
Liver transplant: cost/patient for HBIg during year of transplant* — £16,250 £13,750 £18,750
Total cost/patient for liver transplant (over 12 months) — £60,291 — —
Post–liver transplant: cost per patient-year (excluding HBIg) [55] 67 £1,633 £812 £2,453
Post–liver transplant: HBIg in posttransplant: cost per patient-year* — £5,000 — —
Total cost of posttransplant state per patient-year — £6,333 — —

*Cost of HBIg was based on personal communications with a UK transplant center.

CI, confidence interval; HCHS, Hospital and Community Health Services; HCC, hepatocellular carcinoma; HBIg, hepatitis B immunoglobulin.

mixed treatment comparison meta-analysis conducted by the
authors, which is described in the accompanying paper [11].
Transition probabilities for untreated patients were based on
data from natural history studies, economic evaluations, or the
placebo arms of meta-analyses or RCTs (see Appendix 1 at:
http://www.ispor.org/Publications/value/ViHsupplementary/
ViH13i8_Dakin.asp).
For some of the transitions that may be influenced by treat-
ment (predominantly those affecting patients with severe liver
disease), data were only available for ADV or LAM. In these
cases, all treated patients were assumed to have the same chance
of improvement/progression regardless of which nucleos(t)ide
was used.
Because the cost of managing severe liver disease is likely to
differ little between hepatitis B and C, costs for the compensated
cirrhosis, decompensated cirrhosis, HCC, liver transplant, and
post–liver transplant disease states were based on large, retro-
spective UK microcosting studies on patients with hepatitis C
[53–55] (Table 3). Costs were inflated to 2006/2007 values [56],
and the cost of hepatitis B immunoglobulin was included in the
cost of liver transplantation and posttransplant follow-up. The
cost of nucleos(t)ide therapy was also added where applicable.
The cost of managing patients in other disease states was
based on clinicians’ estimates of the frequency of outpatient
consultations for each patient group and the tests that would be
performed at each consultation (Table 2), which were derived
from telephone interviews with five consultant gastroenterolo-
gists. The resources used in each consultation were valued, based
on published sources [56,57] and provider tariffs, to produce the
total consultation costs shown in Table 2. Further details on unit
costs and resource use quantities are available on request.
Health state preference values or utilities for most disease
states were based on standard gamble valuations of each health
state from a study involving 93 UK patients with CHB [58,59]
(Table 4). It was conservatively assumed that achieving undetect-
able HBV DNA (in the absence of seroconversion) would not
improve quality of life. The quality of life of HBsAg-
seroconverted patients was based on UK population norms [60];
however, the utility of patients in the HBeAg-seroconverted state
was assumed to be 1% lower than populations norms, based on
a previous economic evaluation [61].
All model parameters other than unit costs were varied inde-
pendently over the range of values that they could plausibly take
in one-way sensitivity analyses. We also conducted probabilistic

Table 4 Utilities used in the economic evaluation

Lower Upper
State Mean 95% CI 95% CI Reference

HBsAg seroconverted 0.86 0.85 0.87 Age-dependent population norm for all ages, based on a representative sample of
3395 members of the UK general population [60]
HBeAg seroconverted 0.85 — — Age-dependent population norm multiplied by 0.99 (an adjustment for presence of
HBsAg based on Wong et al. [61]). The quality of life of the general population
was varied over its 95% CI, while the disutility associated with detectable
HBsAg was varied between 0% and 15% in sensitivity analyses, but was not
varied in PSA.
Active CHB 0.77 0.71 0.81 Ossa et al. [58]*
Viral suppression 0.77 0.71 0.81 Assumed to be the same as for active CHB
Compensated cirrhosis, HBV 0.73 0.65 0.77 Ossa et al. [58]*
DNA-negative
Compensated cirrhosis, HBV 0.73 0.65 0.77 Assumed to be the same as for compensated cirrhosis with detectable HBV DNA
DNA-positive
Decompensated cirrhosis 0.34 0.25 0.39 Ossa et al. [58]*
HCC 0.36 0.28 0.41 Ossa et al. [58]*
Liver transplant 0.56 0.49 0.62 Ossa et al. [58]*
Posttransplant 0.67 0.59 0.73 Ossa et al. [58]*

*Utilities from the study by Ossa et al. comprise standard gamble valuations by a sample of 93 UK patients with CHB [58,59].
CHB, chronic hepatitis B; CI, confidence interval; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.
Cost-Effectiveness of Tenofovir DF in CHB 927

Table 5 Results of the base-case analysis for the 20 most commonly used or most cost-effective treatment strategies

Cost/QALY vs. Total net Total net Total net

Cost/QALY Cost/QALY next most benefit at a benefit at a benefit at a
Total QALYs/ Total cost/ vs. LAM vs. LAM effective strategy £10,000 £20,000 £30,000
Treatment strategy patient patient then BSC then ETV on frontier* ceiling ratio ceiling ratio ceiling ratio

Strategies that would lie on the cost-effectiveness frontier* if BSC and LAM–BSC are considered to be relevant comparators
BSC 9.18 £11,189 — — — £80,574 £172,338 £264,101
LAM then BSC 9.56 £14,877 — — £9,636 £80,714 £176,304 £271,895
LAM then TDF 10.68 £30,614 £14,064 £2,098 £14,064 £76,166 £182,946 £289,726
TDF then LAM 11.17 £39,914 £15,587 £8,480 £19,084 £71,739 £183,393 £295,046
TDF then TDF + LAM 11.19 £40,610 £15,747 £8,827 £24,992 £71,322 £183,254 £295,186
TDF then TDF + LAM then ETV 11.19 £40,612 £15,748 £8,829 £38,474 £71,320 £183,252 £295,185
Other strategies dominated by treatment pathways on the cost-effectiveness frontier*
TDF then BSC† 11.16 £39,844 £15,630 £8,484 — £71,720 £183,285 £294,850
TDF then ETV‡ 11.17 £40,268 £15,776 £8,731 — £71,418 £183,103 £294,789
LAM then ETV†§ 9.87 £28,915 £45,398 — — £69,768 £168,451 £267,133
LAM then ADV†|| 10.27 £31,129 £22,727 £5,456 — £71,612 £174,354 £277,096
ADV then LAM¶|| 10.53 £40,771 £26,614 £17,863 — £64,549 £169,869 £275,189
LAM then TDF + LAM† 10.85 £38,774 £18,546 £10,068 — £69,702 £178,177 £286,653
LAM then ADV + LAM¶|| 10.51 £43,624 £30,208 £22,897 — £61,483 £166,590 £271,696
ADV then TDF¶ 10.77 £45,327 £25,075 £18,132 — £62,407 £170,141 £277,876
ADV then TDF + LAM¶ 10.82 £47,878 £26,113 £19,866 — £60,350 £168,578 £276,807
ADV then ADV + LAM¶ 10.74 £49,071 £29,022 £23,195 — £58,302 £165,674 £273,047
ETV then LAM¶ 11.03 £52,082 £25,220 £19,869 — £58,261 £168,604 £278,946
ETV then TDF¶ 11.10 £53,429 £24,958 £19,842 — £57,608 £168,645 £279,683
ADV + LAM then TDF + LAM¶ 10.78 £54,735 £32,513 £28,166 — £53,115 £160,964 £268,814
ETV + ADV then LAM¶ 11.09 £88,206 £47,877 £48,503 — £22,701 £133,607 £244,514

*The cost-effectiveness frontier links all the treatments that are not dominated by other options (by either strong or extended dominance) and are therefore potentially cost-effective. Strong
dominance means that the treatment in question is less costly and more effective than its comparator, while extended dominance means that the treatment in question is more effective and
has lower cost-effectiveness ratios than its comparator [73].
†First-line use of TDF and LAM shows extended dominance [73] over this treatment strategy, because TDF then LAM generates more QALYs and has a lower incremental cost-effectiveness

ratio compared with LAM then BSC than this strategy.

‡TDF then LAM and TDF then TDF + LAM show extended dominance over this strategy.
§Second-line use of TDF (in LAM-resistant patients) and LAM then BSC shows extended dominance [73] over this treatment strategy, because LAM then TDF generates more QALYs and has

a lower incremental cost-effectiveness ratio compared with LAM then BSC than this strategy.
||Second-line use of TDF (in LAM-resistant patients) shows strong dominance over this treatment strategy, because it is less costly and generates more QALYs.
¶
First-line use of TDF shows strong dominance over this treatment strategy, because it is less costly and generates more QALYs.
A mixed cohort of patients with HBeAg-positive or -negative disease with/without compensated cirrhosis was considered. All results are per patient and are discounted at a rate of 3.5% per
annum. The highest net benefits at each threshold are shown in bold typeface.
ADV, adefovir; BSC, best supportive care; ETV, entecavir; LAM, lamivudine; QALY, quality-adjusted life-year; TDF, tenofovir disoproxil fumarate.

sensitivity analysis [62], in which all model parameters except
unit costs were varied over distributions defined by the mean and
95% confidence intervals shown in Tables 2–4 and Appendices
1–2. Costs and relative risks were assumed to follow gamma
distributions, while utilities and probabilities were assigned beta
distributions, in line with best practice [62,63]. Further details of
the distributions used are available on request. In each of the
6500 simulations generated, values for all model parameters
were randomly sampled from their distributions, and the costs,
QALYs, and net benefits for each treatment strategy were calcu-
lated. The proportion of simulations in which the treatment
strategy(ies) in question had the highest total net benefit is
presented.
Results
Treatment strategies involving first-line use of TDF generated
more QALYs than strategies involving first-line use of any other
nucleos(t)ide (Table 5, Fig. 2). In addition to being more effec-
tive than first-line use of ETV or any combination therapy
strategies, first-line TDF was also less costly than these treat-
ment strategies.
The net benefit approach provides a useful mechanism for
identifying which treatment strategy is most cost-effective out of
a large number of alternative treatment strategies that may be
used to treat the same population. Results were analyzed at
several different ceiling ratios because of uncertainty about soci-
ety’s willingness to pay for health gains.
Strategies involving first-line use of TDF produced the highest
net benefits at all ceiling ratios over £19,084/QALY gained,
demonstrating that first-line TDF is the most cost-effective strat-
egy for managing CHB if the NHS is willing to pay at least
£19,084/QALY gained. Except where LAM was used first line,
the choice of a second- or third-line agent had minimal impact on
costs or benefits (Table 5). Nevertheless, the model suggests that
adding in or switching to LAM may be the most cost-effective
treatment for any patients who may, in the future, develop TDF
resistance. For brevity, results are only presented for the most
cost-effective or widely used treatments (Table 5; Fig. 2).
First-line use of TDF was found to dominate ADV then LAM
and first-line use of ETV or any of the combination therapies
evaluated, being less costly and more effective. Furthermore,
first-line TDF and LAM showed extended dominance (more
effective with a lower cost-effectiveness ratio) over all strategies
in which use of ADV, ETV, or combination therapy was delayed
until after LAM resistance has developed. In other words, first-
line TDF generated greater health benefits and had lower cost-
effectiveness ratios (relative to LAM followed by BSC) than these
treatments.
First-line TDF was found to cost £19,084/QALY gained rela-
tive to LAM then TDF, which comprised the next most effective
strategy that is not dominated by any other treatment.
Based on the costs and benefits of strategies in which LAM is
used first line, TDF monotherapy was also found to be the most
cost-effective treatment for patients who have already developed
LAM resistance. In this patient group, TDF produced higher net
928 Dakin et al.

£100,000
ETV+ADV then LAM
£90,000

Discounted lifetime cost per patient

£80,000

£70,000

£60,000
1st line ETV
£50,000
LAM then ADV+LAM
£40,000
1st line TDF
LAM then ADV £19,084/QALY
£30,000 LAM then TDF
LAM then ETV

£20,000 LAM then BSC £14,064/QALY

BSC
£9,636/QALY
£10,000

£0
9.0 9.5 10.0 10.5 11.0 11.5
Discounted lifetime QALYs per patient

Figure 2 Scatter graph plotting total costs against total QALYs for 20 treatment strategies. Because the choice of second- or third-line agent had minimal impact
on costs or benefits, results are only presented for the most cost-effective or widely used treatments within each cluster, and those lying on the cost-effectiveness
frontier. The base-case results shown in this figure are based on a mixed cohort of patients with HBeAg-positive or -negative disease with/without compensated
cirrhosis.The diagonal lines represent the cost-effectiveness frontier, which joins the treatments that are not dominated by any other treatment and have highest net
benefit at some ceiling ratios.The gradient of this line at any point represents the incremental cost-effectiveness ratio for the comparison between the treatments
at either end of the line. All treatments lying above or to the left of the frontier are dominated by treatments lying on the frontier; in other words, the treatment
strategies above/to the left of the line would generate fewer QALYs and/or be more costly than the treatment(s) that lie on the cost-effectiveness frontier. ADV,
adefovir; BSC, best supportive care; ETV, entecavir; HBeAg, hepatitis B e antigen; LAM, lamivudine; QALY, quality-adjusted life-year;TDF, tenofovir disoproxil fumarate.

benefits than second-line use of ETV, ADV, ADV plus LAM, and
cost £14,064/QALY gained compared with giving no second-line
treatment and £2098/QALY compared with second-line use of
ETV (Table 5).
Rerunning the results for specific patient subgroups demon-
strated that first-line use of TDF is the most cost-effective nucleo-
s(t)ide strategy for HBeAg-positive and HBeAg-negative patients,
and for patients with and without compensated cirrhosis at
ceiling ratios of £22,200/QALY and above (Table 6).
Extensive one-way sensitivity analyses were conducted by
varying all model parameters over their 95% confidence intervals
or the range of values shown in the literature (Fig. 3); ranges are
shown in Tables 2–4 and Appendices 1–2 (available at: http://
www.ispor.org/Publications/value/ViHsupplementary/ViH13i8_
Dakin.asp). One-way sensitivity analyses focused on the compari-
son between TDF then LAM versus LAM then BSC, because this
comparison is likely to be most sensitive to changes in the assump-
tions: if TDF remains cost-effective compared with LAM then BSC
when the assumptions and data inputs are varied, the conclusion
that TDF is cost-effective relative to all other comparators is also
likely to be robust. These analyses demonstrated that only one
individual model input could cause first-line TDF (followed by
LAM) to cost more than £30,000/QALY relative to LAM followed
by BSC when varied over the range of values that it was likely to
take (Fig. 3): if the probability of HBeAg-negative patients devel-
oping cirrhosis was reduced to its minimum value (0.4%/year),
this cost-effectiveness ratio increased to £35,096/QALY.
Further sensitivity analyses investigated cost-effectiveness in
specific situations (Table 6). This demonstrated that the results
are sensitive to the time horizon used in the analysis: when all
costs and benefits occurring more than 19 years in the future
(including years of life lost because of deaths that occurred soon
after start of treatment) were excluded from the model, no treat-
ments (including either first- or second-line use of TDF) were
cost-effective relative to LAM then BSC at a £20,000/QALY
threshold. This suggests that for patients with a life expectancy of
less than 19 years, no treatment beyond LAM then BSC would be
cost-effective. Nevertheless, no other sensitivity analyses changed
the conclusions of the analysis.
Probabilistic sensitivity analysis confirmed that TDF then
LAM generates the highest net benefits at a £20,000 to £30,000/
QALY ceiling ratio. At a £20,000/QALY ceiling ratio, there was
a 0.46 probability that TDF is the most cost-effective first-line
nucleos(t)ide, and a 0.25 probability that it is most cost-effective
to give LAM followed by TDF. Nevertheless, if society is willing
to pay £30,000/QALY, the probability that first-line TDF is the
most cost-effective strategy for managing CHB increases to 0.78.
By contrast, the probability that first-line ETV is the most cost-
effective treatment at a £30,000/QALY ceiling ratio approaches
zero. First-line tenofovir showed strong dominance over first-line
ETV in 76% of probabilistic simulations, and showed strong or
extended dominance over LAM followed by tenofovir in 47%.
Discussion
This economic evaluation demonstrates that first-line use of TDF
is the most cost-effective strategy for managing CHB with
nucleos(t)ides if the NHS is willing to pay at least £19,084 per
QALY gained. Because treatments costing no more than £20,000
to £30,000 per QALY gained are generally considered to be
cost-effective [24], TDF should be considered a highly cost-
effective treatment option for CHB. Furthermore, first-line TDF
was also more effective and less costly than first-line ETV, and
showed extended dominance over ADV followed by LAM and
over strategies reserving ADV, ETV, or combination therapy until
after LAM resistance develops.
TDF also generated the greatest net benefits of all treatments
that may be considered appropriate salvage therapy for patients
who have already developed LAM resistance. TDF was cost-
effective at a £30,000/QALY threshold in all subgroups
Table 6 Results of sensitivity/scenario analyses in which the assumptions and data inputs were changed from the values used in the base-case analysis

Cost/QALY for LAM then TDF relative to: Cost/QALY for TDF then LAM relative to:
Change to model assumptions or data inputs LAM then BSC LAM then ADV LAM then BSC LAM then TDF LAM then ADV ETV then BSC
Base-case £14,064 Dominant £15,587 £19,084 £9,858 Dominant
Discounting (base-case: 3.5% for both costs and effects)
No discounting £11,512 £1,355 £11,947 £12,971 £7,440 Dominant
Costs discounted at 6%, benefits at 1.5% £6,890 Dominant £8,170 £11,163 £5,286 Dominant
Time horizon (base-case: 42 years)
5-year time horizon* £99,857 Dominant £114,670 £124,956 £91,066 Dominant
10-year time horizon* £38,470 Dominant £45,607 £56,056 £31,244 Dominant
20-year time horizon* £19,423 Dominant £22,325 £28,679 £13,827 Dominant
Cost-Effectiveness of Tenofovir DF in CHB

60-year time horizon* £13,392 Dominant £14,741 £17,755 £9,470 Dominant

Patient group (base-case: mixed cohort)
HBeAg-positive no cirrhosis £11,131 Dominant £14,110 £20,014 £10,303 Dominant
HBeAg-negative no cirrhosis £15,392 Dominant £16,514 £19,320 £9,708 Dominant
HBeAg-positive compensated cirrhosis £7,281 Dominant £7,524 £7,872 £5,270 Dominant
HBeAg-negative compensated cirrhosis £15,787 £4,008 £17,608 £22,190 £14,115 Dominant
Resource use
Assuming that treated patients have 11 secondary care consultations per year £15,913 Dominant £16,937 £19,288 £10,389 Dominant
as assumed by Shepherd et al. [57]
Increasing all disease management costs by 25% £14,293 Dominant £15,684 £18,878 £9,749 Dominant
Decreasing all disease management costs by 25% £13,835 Dominant £15,490 £19,291 £9,966 Dominant
Excluding cost of HBIg £14,008 Dominant £15,569 £19,154 £9,900 Dominant
Resistance rates
TDF resistance rates assumed to be same as those for ADV £13,900 Dominant £15,516 £19,999 £6,630 £110,928
TDF resistance rates assumed to be same as those for ETV £13,711 £71,192SW £15,544 £16,721 £9,330 Dominant
TDF resistance rate assumed to double each year: 0.23% yr 1, 0.46% yr 2, 0.93% £13,503 Dominant £15,388 £17,957 £6,952 £148,518
yr 3, 1.85% yr 4, and 3.0% in subsequent years
Transition probabilities
Probability of HBeAg-negative pts in active CHB state developing Min value (0.4%) £32,603 Dominant £35,014 £39,844 £21,732 Dominant
cirrhosis Max value (20%) £13,095 £51 £14,189 £16,583 £9,368 Dominant
Patterns of care
Assuming that no patients undergo liver transplantation £14,186 Dominant £15,674 £19,081 £9,929 Dominant
Interval between development of virological resistance and switching 0 £13,985 Dominant £15,628 £19,506 £9,953 Dominant
therapy (months) 3 £14,142 Dominant £15,546 £18,686 £9,762 Dominant
6 £14,297 Dominant £15,465 £17,957 £9,573 Dominant
12 £14,594 Dominant £15,311 £16,720 £9,212 Dominant

*The time horizon defines the period over which costs and benefits are calculated.Taking a 10-year time horizon means that all costs and benefits occurring more than 10 years in the future are excluded from the analysis: including the life-years lost from premature
deaths that arise within the time horizon. For example, if a patient died at year 5, they would be assumed to lose only 5 life-years if a 10-year time horizon was taken.
SWThe cost-effectiveness ratio in question is in the southwest quadrant, whereby the TDF strategy is less effective and less costly than its comparator. In this quadrant,TDF would be considered cost-effective if its cost-effectiveness ratio is above £20,000 to £30,000/QALY.

ADV, adefovir; BSC, best supportive care; ETV, entecavir; HBeAg, hepatitis B e antigen; HBIg, hepatitis B immunoglobulin; HBV, hepatitis B virus; LAM, lamivudine; QALY, quality-adjusted life-year; TDF, tenofovir disoproxil fumarate.
929
930 Dakin et al.

Probability of HBeAg-negative pts in active CHB state developing cirrhosis

Discount rate for outcomes

Discount rate for costs

Excess mortality for viral suppression state

RR of HBeAg seroconversion in 2nd/subsequent year of therapy vs 1st year

Drug cost for tenofovir

RR of viral suppression in 2nd/subsequent year of therapy vs 1st year

Probability of HBeAg-positive pts in active CHB state developing cirrhosis

Probability of HBeAg seroconversion (treatment-naïve pts): with TDF

Transition probability for VS to HBsAg seroconverted

Utility for HBeAg-negative patients in viral suppression state

Transition probability for active CHB to HBsAg seroconverted

Model time horizon

Probability of HBeAg seroconversion: with BSC

Annual risk of decompensation from CC with detectable HBV DNA: with BSC

Utility for HBeAg-negative patients with CC and undetectable HBV DNA

RR of death for pts with CC with undetectable vs detectable HBV DNA: BSC

Utility for HBeAg-negative patients in active CHB state

Annual risk of decompensation from CC: with any treatment

£5,000 £10,000 £15,000 £20,000 £25,000 £30,000 £35,000 £40,000

Cost/QALY for TDF then LAM vs LAM then BSC

Figure 3 Impact of different variables on the cost per quality-adjusted life-year (QALY) gained for first-line TDF relative to LAM, then best supportive care (BSC).
Each bar represents the range of values for the cost/QALY that would be generated by varying the parameter in question over its likely range or 95% confidence
interval.Variables are ranked in descending order of importance. For clarity, only the 20 variables having most impact on the results are shown in this diagram.The
vertical line shows the base-case value of £15,587/QALY gained. BSC, best supportive care; CC, compensated cirrhosis; CHB, chronic hepatitis B; HBeAg, hepatitis
B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; pts, patients; TDF, tenofovir disoproxil fumarate;VS, viral suppression.

investigated, and the conclusions remained robust in extensive
sensitivity analyses.
The base-case analysis included all plausible nucleos(t)ide
treatment strategies for managing CHB, and demonstrated that
first-line use of TDF is the most cost-effective strategy of all those
considered, generating highest net benefits at a £20,000 to
£30,000/QALY threshold. Although LAM followed by BSC may
be cost-effective at lower willingness-to-pay thresholds, it is now
not used in the UK because it is clinically inferior to other
strategies and is not recommended in clinical treatment
guidelines [2].
This analysis focused on comparing the costs and benefits of
nucleos(t)ides, and did not assess the cost-effectiveness of nucleo-
s(t)ides relative to (peg)interferon-alpha. Previous economic
evaluations comparing nucleos(t)ides with interferons have
reported conflicting results [12,57,64,65]. Although interferon
and peginterferon are effective treatments for some patients with
CHB, they are typically used only as initial treatment for a
specific subset of patients (most commonly those with HBeAg-
positive CHB) who are willing and able to tolerate the side effects
of treatment. By contrast, nucleos(t)ides provide long-term viral
suppression in those patients who are unsuitable for, do not
respond to, or do not tolerate interferon therapy. The current
analysis also excluded LdT, which is rarely used in the UK and is
not recommended by NICE [36]. Nevertheless, because TDF is
less costly [5,66], more potent [11], and has a lower risk of
resistance than LdT [19,67–71], the inclusion of LdT would not
have changed the conclusion that first-line TDF is the most
cost-effective nucleos(t)ide strategy for CHB.
Although the net benefit approach is commonly used to
produce cost-effectiveness acceptability curves and analyze
uncertainty [22], the current analysis is, to our knowledge, the
first application of the net benefit approach to aid interpretation
of deterministic base-case results from an economic evaluation
considering a large number of comparators. Although the con-
clusions are not affected by the choice of approach, the net
benefit approach simplifies interpretation of results and makes it
substantially easier to identify the optimal strategy and strongly/
extended dominance. Nevertheless, a disadvantage of the net
benefit approach is the need to specify a ceiling ratio and repeat
analyses at alternative threshold values.
Like all model-based economic evaluations, this analysis is
limited by the quality of data available and the assumptions that
were necessary to simplify the analysis. Nevertheless, where pos-
sible, assumptions were based on peer-reviewed journal articles
and were validated by clinical experts. In particular, lack of data
necessitated assumptions about the probability of response, sero-
conversion, or resistance associated with combination therapy or
second-line TDF. The efficacy of TDF in nucleos(t)ide-resistant
patients was also based on a meta-analysis that included trials on
HIV-coinfected patients, as no RCTs of TDF in this indication
have yet been published. Furthermore, as no cases of virological
HBV resistance to TDF have yet been identified, the resistance
rates used in the model were based on the highest incidence rates
possible, conservatively underestimating the potential benefits
associated with TDF. Transition probabilities were also generally
assumed to be constant over time because of a shortage of data
on how probabilities vary over time; in the absence of such data,
Cost-Effectiveness of Tenofovir DF in CHB
it is difficult to anticipate what impact this simplification may
have had on the results.
The costs used in this analysis were based on clinical practice
in the UK, which limits the extent to which the cost-effectiveness
ratios calculated can be applied to clinical practice in other
settings. Even within the UK, variations in clinical practice and
patient mix may affect the costs and benefits of treatment within
any given region. Nevertheless, first-line TDF remained cost-
effective in extensive sensitivity analyses, including when the cost
of all disease states was varied ⫾25%.
At present, there are large regional disparities in the manage-
ment of CHB across the UK, particularly with respect to the
availability of nucleos(t)ides, with many patients currently
receiving no antiviral therapy [72]. Nevertheless, recent NICE
guidance recommending use of TDF [34] may reduce post–code
prescribing and make management of CHB more cost-effective.
Sensitivity analyses suggested that the cost-effectiveness of
TDF depends on the risk of HBeAg-negative patients develop-
ing cirrhosis. The clinical indications for treating HBeAg-
negative CHB are based on a combination of HBV DNA
concentrations, aminotransferase levels, and histology [2]. In
practice, it can be difficult to reliably predict the rate of pro-
gression in patients at this stage of the disease, given the fluc-
tuations in these clinical parameters. Nevertheless, our model
has clinical utility and demonstrates to clinicians the impact of
this variable on the cost-effectiveness of first-line TDF. Thus,
clinicians can use the results of this sensitivity analysis to judge
the appropriate timing and indications for treating HBeAg-
negative disease, taking account of the uncertainty around the
rate of disease progression.
Further clinical trials on use of nucleos(t)ide combinations
and use of newer nucleos(t)ides in patients with more severe liver
disease are required to inform future economic evaluations and
to produce more accurate estimates of cost-effectiveness. Addi-
tionally, the cost-effectiveness of nucleos(t)ides in patients coin-
fected with HIV, hepatitis C virus, and/or hepatitis D virus has
not yet been assessed.
Conclusions
Given the threshold cost-effectiveness ratio used in the NHS [24],
first-line use of TDF is the preferred treatment for patients with
CHB who are indicated for nucleos(t)ide therapy. In particular,
first-line TDF was found to be both more effective and less costly
than first-line use of ETV. TDF was also the most cost-effective
treatment for patients who have already developed resistance to
LAM.
The authors would like to thank Steve Ashmore for his advice on
the paper, Christie Harper for design advice and editing assis-
tance, Carrie Fidler and Ruth McAllister for assistance with
referencing and proofreading and Nick Tatman for his help with
the clinic audit, as well as all of the clinicians providing expert
opinion on resource use and current clinical practice.
Source of financial support: This research was funded by Gilead Sciences
Ltd, Cambridge, UK.
References
1 Hepatitis B Foundation UK. Rising curve: chronic hepatitis B
infection in the UK. 2007. Available from: http://www.hepb.
org.uk/information/resources/rising_curve_chronic_hepatitis_b_
infection_in_the_uk/rising_curve.pdf [Accessed June 17, 2010].
931
2 European Association for the Study of the Liver. EASL clinical
practice guidelines: management of chronic hepatitis B. J Hepatol
2009;50:227–42.
3 Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone,
lamivudine alone, and the two in combination in patients with
HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:
1206–17.
4 Wong DK, Cheung AM, O’Rourke K, et al. Effect of alpha-
interferon treatment in patients with hepatitis B e antigen-positive
chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:
312–23.
5 British Medical Association. British National Formulary (BNF),
No. 54. London: British Medical Association and the Royal Phar-
maceutical Society of Great Britain, 2007.
6 Roche Products Limited. Summary of product characteristics for
Pegasys 180 microgram pre-filled syringe. 2009.
7 Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical corre-
lates of YMDD variants during lamivudine therapy for patients
with chronic hepatitis B. Clin Infect Dis 2003;36:687–96.
8 Colonno RJ, Rose RE, Pokornowski K, et al. Four year assess-
ment of entecavir resistance in nucleoside naïve and lamivudine
refractory patients. Podium presentation at the 42nd Annual
Meeting of the European Association for the Study of the Liver,
Barcelona, Spain. 2007.
9 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term
therapy with adefovir dipivoxil for HBeAg-negative chronic
hepatitis B for up to 5 years. Gastroenterology 2006;131:1743–
51.
10 Snow-Lampart A, Sorbel J, Chappell B, et al. Lack of tenofovir
DF (TDF) resistance mutations in treatment naïve and treatment-
experienced subjects with chronic HBV infection following 48
weeks of TDF mono-therapy. Presented at the 43rd Annual
Meeting of the European Association for the Study of the Liver,
April 23–27, 2008, Milan, Italy. 2008.
11 Dakin H, Fidler C, Niziol C. Mixed treatment comparison meta-
analysis evaluating the relative efficacy of nucleos(t)ides for treat-
ment of chronic hepatitis B. Value Health 2010;13:In press.
12 Bristol-Myers Squibb Pharmaceuticals Ltd. Entecavir (Bara-
clude®) for the treatment of chronic hepatitis B: single technology
appraisal submission to the National Institute for Health & Clini-
cal Excellence. November 2007. Available from: http://
www.nice.org.uk/nicemedia/pdf/BaracludeNICESTAEACD.pdf
[Accessed July 22, 2010].
13 Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for
patients with HBeAg-negative chronic hepatitis B. N Engl J Med
2006;354:1011–20.
14 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil
fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl
J Med 2008;359:2442–55.
15 Dore GJ, Cooper DA, Pozniak AL, et al. Efficacy of tenofovir
disoproxil fumarate in antiretroviral therapy-naive and
-experienced patients coinfected with HIV-1 and hepatitis B virus.
J Infect Dis 2004;189:1185–92.
16 van Bommel F, Mauss S, Schurmann D, et al. No evidence for
tenofovir resistance in patients with lamivudine-resistant HBV
infection during long-term treatment for up to 5 years. Hepatol-
ogy 2006;44(suppl. 1):A549.
17 van Bommel F, de Man R, Erhardt A, et al. First multicenter
evaluation of the efficacy of tenofovir in nucleos(t)ide analog
experienced patients with HBV monoinfection. Hepatology
2007;46:270A.
18 Berg T, Moeller B, Trinh H, et al. Tenofovir disoproxil fumarate
(TDF) versus emtricitabine plus TDF for treatment of chronic
hepatitis B (CHB) in subjects with persistent viral replication
receiving adefovir dipivoxil (ADV). Podium presentation #1219
at the 2008 European Association for the Study of the Liver
conference. 2008.
19 Dore G, Cooper D, Pozniak AL, et al. Anti-hepatitis B virus
(HBV) activity in HBV/HIV co-infected patients treated with
tenofovir DF (TDF) and lamivudine (LAM) versus LAM alone:
144-week follow-up. 15th International AIDS conference. 2004:
Abstract 3308.
932
20 Gilead Sciences Ltd. DATA ON FILE—TDF001: Patient Years
Exposure to Tenofovir Disoproxil Fumarate (TDF) (All Prod-
ucts). 2008.
21 Snow-Lampart A, Chappell B, Curtis M, et al. Week 96 resistance
surveillance for HBeAg positive and negative subjects with
chronic HBV infection randomised to receive tenofovir DF
300 mg QD. Poster presentation at AASLD 2008. 2008.
22 Zethraeus N, Johannesson M, Jonsson B, et al. Advantages of
using the net-benefit approach for analysing uncertainty in eco-
nomic evaluation studies. Pharmacoeconomics 2003;21:39–48.
23 Stinnett AA, Mullahy J. Net health benefits: a new framework for
the analysis of uncertainty in cost-effectiveness analysis. Med
Decis Making 1998;18:S68–80.
24 National Institute for Health and Clinical Excellence. Social value
judgements: principles for the development of NICE guidance.
Second edition. 2008. Available from: http://www.nice.org.uk/
media/C18/30/SVJ2PUBLICATION2008.pdf [Accessed June 15,
2010].
25 Gilead Sciences. Tenofovir (Viread®) for the treatment of chronic
hepatitis B. Single technology appraisal manufacturer submission
to the National Institute for Health and Clinical Excellence.
December 2008. Available from: http://www.nice.org.uk/
nicemedia/pdf/Tenofovir_disoproxil_manufacturer_submission_
december2008.pdf [Accessed June 17, 2010].
26 Government Actuary’s Department. Interim life tables: expecta-
tion of life based on data for years 2005–2007. Available from:
http://www.gad.gov.uk/Demography%20Data/Life%20Tables/
Interim_life_tables.html [Accessed June 17, 2010].
27 Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine
treatment in patients with chronic hepatitis B. Gastroenterology
2003;125:1714–22.
28 Gilead Sciences. Summary of product characteristics for Hepsera
10 mg tablets. 2007. Available from: http://www.medicines.
org.uk/emc/ [Accessed July 22, 2010].
29 Gilead Sciences. Summary of product characteristics for Viread
300 mg tablets. 2008. Available from: http://www.medicines.org.
uk/emc/ [Accessed July 22, 2010].
30 Bristol-Myers Squibb. Summary of product characteristics for
Baraclude 0.5 mg film and 1.0 mg film coated tablets. 2007.
Available from: http://www.medicines.org.uk/emc/ [Accessed July
22, 2010].
31 GlaxoSmithKline UK. Summary of product characteristics for
Zeffix 100 mg film-coated tablets. 2007. Available from: http://
www.medicines.org.uk/emc/ [Accessed July 22, 2010].
32 Crowley SJ, Tognarini D, Desmond PV, et al. Cost-effectiveness
analysis of lamivudine for the treatment of chronic hepatitis B.
Pharmacoeconomics 2000;17:409–27.
33 National Institute for Health and Clinical Excellence. NICE tech-
nology appraisal guidance 153: entecavir for the treatment of
chronic hepatitis B. August 2008. Available from: http://
www.nice.org.uk/nicemedia/pdf/TA153Guidance.pdf [Accessed
June 17, 2010].
34 National Institute for Health and Clinical Excellence. NICE tech-
nology appraisal guidance 173. Tenofovir disoproxil for the treat-
ment of chronic hepatitis B. July 2009. Available from: http://
www.nice.org.uk/nicemedia/pdf/TA173Guidance.pdf [Accessed
June 17, 2010].
35 National Institute for Health and Clinical Excellence. Adefovir
dipivoxil and peginterferon alfa-2a for the treatment of chronic
hepatitis B. Technology Appraisal Guidance No 96. London,
February 2006.
36 National Institute for Health and Clinical Excellence. NICE tech-
nology appraisal guidance 154: telbivudine for the treatment of
chronic hepatitis B. August 2008. Available from: http://
www.nice.org.uk/nicemedia/pdf/TA154Guidance.pdf [Accessed
June 17, 2010].
37 National Institute for Health and Clinical Excellence. Guide to
the methods of technology appraisal. June 2008. Available
from: http://www.nice.org.uk/media/B52/A7/TAMethodsGuide
UpdatedJune2008.pdf [Accessed June 17, 2010].
38 de Franchis R, Hadengue A, Lau G, et al. EASL International
Consensus Conference on Hepatitis B. 13–14 September, 2002
Dakin et al.
Geneva, Switzerland. Consensus statement (long version). J
Hepatol 2003;39(Suppl. 1):S3–25.
39 Crowley S, Tognarini D, Desmond P, et al. Introduction of lami-
vudine for the treatment of chronic hepatitis B: expected clinical
and economic outcomes based on 4-year clinical trial data. J
Gastroenterol Hepatol 2002;17:153–64.
40 Fattovich G, Brollo L, Giustina G, et al. Natural history and
prognostic factors for chronic hepatitis type B. Gut 1991;32:
294–8.
41 Liaw YF, Tai DI, Chu CM, et al. The development of cirrhosis in
patients with chronic type B hepatitis: a prospective study. Hepa-
tology 1988;8:493–6.
42 Sung JJY, Lai JY, Zeuzem S, et al. A randomised double-
blind phase II study on lamivudine compared to lamivudine
plus adefovir dipivoxil for treatment naive patients with
chronic hepatitis B: week 52 analysis [Abstract]. J Hepatol
2003;38:25–6.
43 Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine,
lamivudine, and the combination in patients with hepatitis B e
antigen-positive chronic hepatitis B. Gastroenterology 2005;129:
528–36.
44 Heathcote J, George J, Gordon S, et al. Tenofovir disoproxil
fumarate (TDF) for the treatment of HBeAg-positive chronic
hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil
switch data (study 103). Presented at the 43rd Annual Meeting of
the European Association for the Study of the Liver, April 23–27,
2008, Milan, Italy. 2008.
45 FDA. Baraclude prescribing information. 2007. Available from:
http://www.fda.gov/Medwatch/SAFETY/2007/Baraclude_PI_
jul2407.pdf [Accessed August 2, 2008].
46 Borroto-Esoda K, MIller MD, Reiser H. Clinical virology report
review and approval: adefovir dipivoxil integrated resistance
summary. Fourth Edition: May 18, 2006. 2006.
47 Schiff E, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil for
wait-listed and post-liver transplantation patients with
lamivudine-resistant hepatitis B: final long-term results. Liver
Transpl 2007;13:349–60.
48 Marzano A, Gaia S, Barbon V, et al. Therapy with adefovir alone
or combined with lamivudine in patients with lamivudine-
resistant chronic hepatitis B: clinical and virological aspects.
Hepatology 2006;44:231a.
49 Tziomalos K, Vassiliadis T, Giouleme O, et al. Adefovir dipivoxil
plus lamivudine combination treatment is superior to adefovir
dipivoxil monotherapy in lamivudine-resistant hepatitis B e
antigen-negative chronic hepatitis B patients. Presented at the
58th Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD), Boston, November 2–6, 2007. 2007:
Abstract No. 956.
50 Lampertico P, Viganò M, Iavarone M, et al. Low rates of geno-
typic resistance to adefovir in lamivudine resistant patients
treated with adefovir–lamivudine combination therapy for 3
years. Podium presentation at the 41st Annual Meeting of the
European Association for the Study of the Liver 2006. 2006;
Abstract No. 989.
51 Lampertico P, Viganò M, Manenti E, et al. Five years of sequential
LAM to LAM + ADV therapy suppresses HBV replication in most
HBeAg-negative cirrhotics, preventing decompensation but not
hepatocellular carcinoma. J Hepatol 2006;44(Suppl. S2):S38.
52 Pellicelli A, Barbaro G, Francavilla R, et al. Clinical covariates
associated with virological response and adefovir resistance in
chronic hepatitis B HbeAg negative lamivudine-resistant patients
treated with adefovir alone or in combination with lamivudine for
28 months. Presented at the 58th Annual Meeting of the Ameri-
can Association for the Study of Liver Diseases (AASLD), Boston,
November 2–6, 2007. 2007.
53 Longworth L, Young T, Ratcliffe J, et al. Economic evaluation of
the Transplantation Programme in England and Wales: An assess-
ment of the costs of liver transplantation. Unpublished Report to
the Department of Health. 2001.
54 Longworth L, Young T, Buxton MJ, et al. Midterm cost-
effectiveness of the liver transplantation program of England and
Wales for three disease groups. Liver Transpl 2003;9:1295–307.
Cost-Effectiveness of Tenofovir DF in CHB
55 Wright M, Grieve R, Roberts J, et al. Health benefits of antiviral
therapy for mild chronic hepatitis C: randomised controlled trial
and economic evaluation. Health Technol Assess 2006;10:1–113.
iii.
56 Curtis L, Netten A. Unit Costs of Health and Social Care 2007.
Canterbury, UK: PSSRU Personal Social Services Research Unit,
2007.
57 Shepherd J, Jones J, Takeda A, et al. Adefovir dipivoxil and
pegylated interferon alfa-2a for the treatment of chronic hepatitis
B: a systematic review and economic evaluation. Health Technol
Assess 2006;10:iii–iv, xi–xiv,1–183.
58 Ossa D, Briggs AH, Tafesse E, et al. Impact on quality of life of
health states induced by chronic hepatitis B infection: estimates
from uninfected and infected persons in the UK. Poster presenta-
tion at the International Society for Pharmacoeconomics & Out-
comes Research (ISPOR) 8th Annual European Congress,
Florence, Italy, November 6–8. 2005.
59 Levy AR, Kowdley KV, Iloeje U, et al. The impact of chronic
hepatitis B on quality of life: a multinational study of utilities
from infected and uninfected persons. Value Health 2008;11:
527–38.
60 Kind P, Hardman G, Macran S. UK Population Norms for
EQ-5D. York: Centre for Health Economics, 1999.
61 Wong JB, Koff RS, Tine F, et al. Cost-effectiveness of interferon-
alpha 2b treatment for hepatitis B e antigen-positive chronic
hepatitis B. Ann Intern Med 1995;122:664–75.
62 Briggs AH, Goeree R, Blackhouse G, et al. Probabilistic analysis
of cost-effectiveness models: choosing between treatment strate-
gies for gastroesophageal reflux disease. Med Decis Making
2002;22:290–308.
63 Briggs AH. Handling uncertainty in cost-effectiveness models.
Pharmacoeconomics 2000;17:479–500.
64 Kamal A, Gerson L, Ahmed A. Cost-effectiveness of new treat-
ment paradigms for e-Ag negative chronic hepatitis B. Presented
at the 58th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD), Boston, November 2–6, 2007.
2007: Abstract No. 987.
933
65 Kanwal F, Gralnek IM, Martin P, et al. Treatment alternatives for
chronic hepatitis B virus infection: a cost-effectiveness analysis.
Ann Intern Med 2005;142:821–31.
66 Monthly Index of Medical Specialities (MIMS). London: Hay-
market Medical Publications Ltd, June 2008.
67 Gilead Sciences. Study GS-US-174-0102: a randomized, double-
blind, controlled evaluation of tenofovir DF versus adefovir dipiv-
oxil for the treatment of presumed pre-core mutant hepatitis B.
Clinical study report, Gilead Sciences, data on file. 2007.
68 Marcellin P, Buti M, Krastev Z, et al. A randomized, double-
blind, comparison of tenofovir DF (TDF) versus adefovir dipiv-
oxil (ADV) for the treatment of HBeAg-negative chronic hepatitis
B (CHB): study GS-US-174-0102. Presented at the 58th Annual
Meeting of the American Association for the Study of Liver
Diseases (AASLD), Boston, November 2–6. 2007: Abstract No.
LB2.
69 Gilead Sciences. Study GS-US-174-0103. A randomised, double-
blind, controlled evaluation of tenofovir DF versus adefovir dipiv-
oxil for the treatment of HBeAg positive chronic hepatitis B.
Clinical study report, Gilead Sciences, data on file. 2007.
70 Heathcote E, Gane E, DeMan R, et al. A randomized, double-
blind, comparison of tenofovir DF (TDF) versus adefovir dipiv-
oxil (ADV) for the treatment of HBeAg positive chronic hepatitis
B (CHB): study GS-US-174-0103. Presented at the 58th Annual
Meeting of the American Association for the Study of Liver
Diseases (AASLD), Boston, November 2–6, 2007. 2007: Abstract
No. LB6.
71 Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in
patients with chronic hepatitis B. N Engl J Med 2007;357:2576–
88.
72 Foundation for Liver Research. Hepatitis B: Out of the shadows.
2004. Available from: http://www.britishlivertrust.org.uk/home/
the-liver/liver-diseases/hepatitis-b.aspx [Accessed July 22, 2010].
73 McGuire A. Chapter 1: theoretical concepts in the economic
evaluation of health care. In: Drummond M, McGuire A, eds.
Economic Evaluation in Health Care—Merging Theory with
Practice. Oxford, New York: Oxford University Press, 2001.