Cost–Utility Analysis of Tenofovir Disoproxil Fumarate in the Treatment of Chronic Hepatitis B

Authors


Helen Dakin, Abacus International, 4 Market Square, Bicester, Oxfordshire OX26 6AA, UK. E-mail: helen.dakin@abacusint.com

ABSTRACT

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 compensated 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 movements 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 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 adefovir, 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.

Introduction

An estimated 326,000 people in the UK are thought to have chronic hepatitis B (CHB) [1], which can lead to cirrhosis, hepatocellular 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 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 identified 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 nucleos(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 treatment 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 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.

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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 benefits 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 ≥18 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 cirrhotic 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; subsequently, 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]).

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.

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 sequences of up to three nucleos(t)ides (or nucleos(t)ide combinations) followed by best supportive care (BSC), which comprised 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 combination 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.

Table 1.  Nucleos(t)ide treatments included in the model and their respective daily dosages and costs
DrugDoseDrug cost
  • *

    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.

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 LAM300 mg/day TDF
100 mg/day LAM
£11.29/patient-day [5,66]
ETV (Baraclude, BMS)0.5 mg/day for treatment-naive patients and 1 mg/day for patients resistant to ≥1 nucleos(t)ide£12.60/patient-day for both doses [5]
ADV plus LAM10 mg/day ADV
100 mg/day LAM
£13.29/patient-day [5]
ETV plus ADV10 mg/day ADV
0.5 mg/day ETV for treatment-naive patients and 1 mg/day for patients resistant to ≥1 nucleos(t)ide
£23.10/patient-day [5]

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 strategies are available on request.

Historically, LAM followed by BSC with no antiviral treatment 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 therefore included in the analysis to enable assessment of whether TDF is the most cost-effective strategy out of all plausible nucleos(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 considered 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 recommended 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 treatments, 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 ≥ 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 consultant gastroenterologists suggested that levels are monitored quarterly 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 developed 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 seroconversion, 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 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 outcomes 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 decompensation 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 mortality [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 routinely conducted in UK clinical practice [28–31].
Table 2.  Frequency and cost of consultations for patients in precirrhotic disease states
Disease stateMean (range) no. consultations per yearCost per consultation* (range)
  • *

    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 monitoring (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 (assumed 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.

Active CHB or viral suppression (treated)3.3 (2, 4)£114.69 (£46.23, £236.95)
Active CHB or viral suppression (untreated)2.8 (1, 4)£121.21 (£16.12, £251.26)
HBeAg seroconverted2.0 (1, 4)£121.21 (£16.12, £251.26)
HBsAg seroconverted0.03 (0, 1)£121.21 (£16.12, £251.26)
Number of additional consultations required in the year when resistance develops1.17 (0.5, 2)£114.69 (£46.23, £236.95)
Number of additional consultations required in year 1 (excluding the consultation in which treatment is initiated)1 (1, 1)£240.60 (£6.25, £742.04)

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]. 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, resistance 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 calculation 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 undetectable HBV DNA or HBeAg seroconversion with each nucleos(t)ide therapy or nucleos(t)ide combination) were based on a 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 treatment (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, retrospective 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.

Table 3.  Disease management costs for severe liver disease
Disease stateNo. pts included in mean costCost per patient or patient-year (inflated to 2006/2007 values using HCHS [56])
Mean costLower 95% CIUpper 95% CI
  • *

    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.

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 (excluding HBIg) [55]67£7,432£3,508£11,357
 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

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 gastroenterologists. 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 undetectable 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].

Table 4.  Utilities used in the economic evaluation
StateMeanLower 95% CIUpper 95% CIReference
  • *

    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.

HBsAg seroconverted0.860.850.87Age-dependent population norm for all ages, based on a representative sample of 3395 members of the UK general population [60]
HBeAg seroconverted0.85Age-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 CHB0.770.710.81Ossa et al. [58]*
Viral suppression0.770.710.81Assumed to be the same as for active CHB
Compensated cirrhosis, HBV DNA-negative0.730.650.77Ossa et al. [58]*
Compensated cirrhosis, HBV DNA-positive0.730.650.77Assumed to be the same as for compensated cirrhosis with detectable HBV DNA
Decompensated cirrhosis0.340.250.39Ossa et al. [58]*
HCC0.360.280.41Ossa et al. [58]*
Liver transplant0.560.490.62Ossa et al. [58]*
Posttransplant0.670.590.73Ossa et al. [58]*

All model parameters other than unit costs were varied independently over the range of values that they could plausibly take in one-way sensitivity analyses. We also conducted probabilistic 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 calculated. 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 effective than first-line use of ETV or any combination therapy strategies, first-line TDF was also less costly than these treatment strategies.

Table 5.  Results of the base-case analysis for the 20 most commonly used or most cost-effective treatment strategies
Treatment strategyTotal QALYs/patientTotal cost/patientCost/QALY vs. LAM then BSCCost/QALY vs. LAM then ETVCost/QALY vs. next most effective strategy on frontier*Total net benefit at a £10,000 ceiling ratioTotal net benefit at a £20,000 ceiling ratioTotal net benefit at a £30,000 ceiling ratio
  • *

    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.

Strategies that would lie on the cost-effectiveness frontier* if BSC and LAM–BSC are considered to be relevant comparators
 BSC9.18£11,189£80,574£172,338£264,101
 LAM then BSC9.56£14,877£9,636£80,714£176,304£271,895
 LAM then TDF10.68£30,614£14,064£2,098£14,064£76,166£182,946£289,726
 TDF then LAM11.17£39,914£15,587£8,480£19,084£71,739£183,393£295,046
 TDF then TDF + LAM11.19£40,610£15,747£8,827£24,992£71,322£183,254£295,186
 TDF then TDF + LAM then ETV11.19£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 BSC11.16£39,844£15,630£8,484£71,720£183,285£294,850
 TDF then ETV11.17£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 + LAM10.85£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 TDF10.77£45,327£25,075£18,132£62,407£170,141£277,876
 ADV then TDF + LAM10.82£47,878£26,113£19,866£60,350£168,578£276,807
 ADV then ADV + LAM10.74£49,071£29,022£23,195£58,302£165,674£273,047
 ETV then LAM11.03£52,082£25,220£19,869£58,261£168,604£278,946
 ETV then TDF11.10£53,429£24,958£19,842£57,608£168,645£279,683
 ADV + LAM then TDF + LAM10.78£54,735£32,513£28,166£53,115£160,964£268,814
 ETV + ADV then LAM11.09£88,206£47,877£48,503£22,701£133,607£244,514
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.

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 society'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 strategy 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 relative 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 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 demonstrated that first-line use of TDF is the most cost-effective nucleos(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).

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
Change to model assumptions or data inputsCost/QALY for LAM then TDF relative to:Cost/QALY for TDF then LAM relative to:
LAM then BSCLAM then ADVLAM then BSCLAM then TDFLAM then ADVETV then BSC
Base-case£14,064Dominant£15,587£19,084£9,858Dominant
  • *

    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.

  • SW

    The 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.

Discounting (base-case: 3.5% for both costs and effects)      
 No discounting£11,512£1,355£11,947£12,971£7,440Dominant
 Costs discounted at 6%, benefits at 1.5%£6,890Dominant£8,170£11,163£5,286Dominant
Time horizon (base-case: 42 years)      
 5-year time horizon*£99,857Dominant£114,670£124,956£91,066Dominant
 10-year time horizon*£38,470Dominant£45,607£56,056£31,244Dominant
 20-year time horizon*£19,423Dominant£22,325£28,679£13,827Dominant
 60-year time horizon*£13,392Dominant£14,741£17,755£9,470Dominant
Patient group (base-case: mixed cohort)      
 HBeAg-positive no cirrhosis£11,131Dominant£14,110£20,014£10,303Dominant
 HBeAg-negative no cirrhosis£15,392Dominant£16,514£19,320£9,708Dominant
 HBeAg-positive compensated cirrhosis£7,281Dominant£7,524£7,872£5,270Dominant
 HBeAg-negative compensated cirrhosis£15,787£4,008£17,608£22,190£14,115Dominant
Resource use      
 Assuming that treated patients have 11 secondary care consultations per year as assumed by Shepherd et al. [57]£15,913Dominant£16,937£19,288£10,389Dominant
 Increasing all disease management costs by 25%£14,293Dominant£15,684£18,878£9,749Dominant
 Decreasing all disease management costs by 25%£13,835Dominant£15,490£19,291£9,966Dominant
 Excluding cost of HBIg£14,008Dominant£15,569£19,154£9,900Dominant
Resistance rates      
 TDF resistance rates assumed to be same as those for ADV£13,900Dominant£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£9,330Dominant
 TDF resistance rate assumed to double each year: 0.23% yr 1, 0.46% yr 2, 0.93% yr 3, 1.85% yr 4, and 3.0% in subsequent years£13,503Dominant£15,388£17,957£6,952£148,518
Transition probabilities      
 Probability of HBeAg-negative pts in active CHB state developing cirrhosisMin value (0.4%)£32,603Dominant£35,014£39,844£21,732Dominant
Max value (20%)£13,095£51£14,189£16,583£9,368Dominant
Patterns of care       
 Assuming that no patients undergo liver transplantation£14,186Dominant£15,674£19,081£9,929Dominant
 Interval between development of virological resistance and switching therapy (months)0£13,985Dominant£15,628£19,506£9,953Dominant
3£14,142Dominant£15,546£18,686£9,762Dominant
6£14,297Dominant£15,465£17,957£9,573Dominant
12£14,594Dominant£15,311£16,720£9,212Dominant

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 comparison between TDF then LAM versus LAM then BSC, because this comparison is likely to be most sensitive to changes in the assumptions: 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 developing cirrhosis was reduced to its minimum value (0.4%/year), this cost-effectiveness ratio increased to £35,096/QALY.

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.

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 treatments (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 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 nucleos(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 conclusions 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 possible, 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, seroconversion, 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, 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 management 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 developing 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 progression in patients at this stage of the disease, given the fluctuations 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. Additionally, the cost-effectiveness of nucleos(t)ides in patients coinfected 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 assistance, 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.

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