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Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis

Fasiha Kanwal, MD, MSHS; Ian M. Gralnek, MD, MSHS; Paul Martin, MD; Gareth S. Dulai, MD, MSHS; Mary Farid, DO; and Brennan M.R. Spiegel, MD, MSHS
[+] Article and Author Information

From Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine at University of California, Los Angeles, and Center for the Study of Digestive Healthcare Quality and Outcomes, Los Angeles, California; and Mount Sinai School of Medicine, New York, New York.


Acknowledgments: The authors thank Sun J. Kim for his assistance in conducting this study.

Grant Support: Dr. Kanwal is supported by a Veterans Administration Health Services Research & Development (VA HSR&D) Ambulatory Care Fellowship Award and an American Association for the Study of Liver Diseases Advanced Hepatology Fellowship Award. Dr. Gralnek is supported by a VA HSR&D Career Development Award and a VA HSR&D Merit Award (IIR 01-191-1). Dr. Dulai is supported by a National Institutes of Health NCRR K23 Award (RR-16188). Dr. Spiegel is supported by a VA HSR&D Career Development Award.

Potential Financial Conflicts of Interest: Consultancies: P. Martin (Gilead Sciences), B.M.R. Spiegel (Novartis); Honoraria: P. Martin (GlaxoSmithKline, Schering-Plough); Grants received: P. Martin (Schering-Plough, GlaxoSmithKline), B.M.R. Spiegel (Gilead Sciences).

Requests for Single Reprints: Brennan M.R. Spiegel, MD, MSHS, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, 11301 Wilshire Boulevard, Building 115, Room 215, Los Angeles, CA 90073; e-mail, BSpiegel@mednet.ucla.edu.

Current Author Addresses: Drs. Kanwal, Gralnek, Dulai, Farid, and Spiegel: VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, 11301 Wilshire Boulevard, Building 115, Room 215, Los Angeles, CA 90073.

Dr. Martin: Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029.

Author Contributions: Conception and design: F. Kanwal, I.M. Gralnek, P. Martin, G.S. Dulai, B.M.R. Spiegel.

Analysis and interpretation of the data: F. Kanwal, B.M.R. Spiegel.

Drafting of the article: F. Kanwal, B.M.R. Spiegel.

Critical revision of the article for important intellectual content: F. Kanwal, P. Martin, G.S. Dulai.

Final approval of the article: F. Kanwal, I.M. Gralnek, P. Martin, G.S. Dulai, M. Farid, B.M.R. Spiegel.

Provision of study materials or patients: B.M.R. Spiegel.

Statistical expertise: F. Kanwal, B.M.R. Spiegel.

Administrative, technical, or logistic support: I.M. Gralnek.

Collection and assembly of data: F. Kanwal, I.M. Gralnek, M. Farid, B.M.R. Spiegel.


Ann Intern Med. 2005;142(10):821-831. doi:10.7326/0003-4819-142-10-200505170-00007
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Interferon, lamivudine, and adefovir are the 3 agents currently approved for treating chronic HBV infection. The cost-effectiveness of these therapies has not been previously evaluated. We therefore performed a comprehensive decision analysis to identify the most cost-effective therapeutic approach under varying clinical and budgetary conditions. Our analysis has 3 key findings. First, the use of up-front adefovir in HBV is unlikely to be cost-effective under any circumstance. We found that adefovir monotherapy is less effective yet more expensive than competing strategies in HBeAg-positive patients and has an incremental cost of more than $90 000 per QALY gained in HBeAg-negative patients, a value that exceeds the cost of many commonly accepted medical interventions (126). Second, our data reveal that continuing lamivudine therapy in patients who develop viral resistance is not cost-effective, regardless of HBeAg status. Third, despite our finding that lamivudine is not cost-effective in the setting of viral resistance, our analysis reveals that up-front lamivudine may be highly cost-effective, assuming that patients developing viral resistance cross over to adefovir instead of continuing long-term lamivudine therapy. The adefovir salvage strategy seems highly cost-effective across a range of health care budgets, from the most liberal to the most conservative (Figure 2).

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Figures

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Figure 1.
Results of cost-effectiveness analysis stratified by hepatitis B e antigen (HBeAg) status.

The results presented assume that the entire cohort is HBeAg-negative (top) or HBeAg-positive (bottom). The vertical axes display the lifetime cumulative cost, and the horizontal axes display the quality-adjusted life-years (QALYs) gained. The “do nothing” strategy is the least expensive of the 5 competing strategies in both analyses. When the cohort is entirely HBeAg-negative (top), the lamivudine strategy is dominated as it falls above and to the left of the concave border that outlines the 4 competing strategies composing the cost-effectiveness frontier. When the cohort is entirely HBeAg-positive (bottom), the adefovir salvage strategy becomes the dominant strategy because it is the most effective and least expensive of the 5 competing strategies.

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Figure 2.
Cost-effectiveness acceptability curves of the adefovir salvage strategy versus interferon monotherapy arranged by hepatitis B e antigen (HBeAg) status.

The horizontal axis displays the willingness-to-pay budgetary thresholds to gain 1 additional quality-adjusted life-year (QALY) when using the adefovir salvage strategy instead of interferon, and the vertical axis displays the percentage of 1000 patients that fall within the available budget. There are 3 curves: 1) curve assuming that cohort is 55% HBeAg-negative (base-case analysis) (dashed line); 2) curve assuming that cohort is HBeAg-negative (solid line); and 3) curve assuming that cohort is HBeAg-positive (dotted line). For example, if a third-party payer had a budget of $17 500 per QALY gained to substitute adefovir salvage for interferon (vertical line), more than 99% of the HBeAg-positive cohort would fall within the budget, whereas only 2% and 60% of the HBeAg-negative and base-case cohorts, respectively, would fall within the budget. In contrast, the adefovir salvage strategy becomes cost-effective for close to 90% of all patients in health care systems willing to pay at least $35 000 per QALY, regardless of HBeAg status.

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Appendix Figure 1.
Truncated decision model.

The base-case patient has chronic hepatitis B virus (HBV) infection, elevated aminotransferase levels, no clinical or histologic evidence of cirrhosis, and no previous treatment for HBV infection. The clinician treats with 1 of 5 competing strategies. Within each strategy, patients are stratified by hepatitis B e antigen status (not depicted). In all strategies, patients are eligible to develop cirrhosis, in which case they enter a Markov model governing the downstream events of cirrhosis. See text for details about specific assumptions governing patient management and probability estimates for individual branch points.

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Appendix Figure 2.
Markov state diagram.

Patients enter the model with chronic hepatitis B virus (HBV) infection. During each 1-year cycle, individual patients either remain in their assigned health state (curved arrow) or progress to a new health state (straight arrow). Patients may develop cirrhosis, in which case they move from the precirrhosis submodel to the cirrhosis submodel. Transition rates between health states were derived from a systematic review of the literature (Table 2). Refer to the Appendix for additional information.

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Appendix Figure 3.
Results of literature search.
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References

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Moving Away from Lamivudine Treatment in Hepatitis B
Posted on May 26, 2005
Gil Weitzman, Ira Jacobson, M.D.
Weill Medical College of Cornell University
Conflict of Interest: None Declared

TO THE EDITOR:

In the cost effectiveness analysis by Kanwal and colleagues(1), concluding that a hybrid salvage strategy for chronic hepatitis B (lamivudine with crossover to adefovir upon resistance) is more cost- effective than adefovir monotherapy, the consequences of lamivudine resistance are not sufficiently taken into account. Entecavir (Baraclude, Bristol-Myers Squibb, New York, NY), is a newly approved nucleoside analog with greater antiviral potency than lamivudine in large comparative trials(2), and in 48 week trials in treatment naïve patients no resistance has been demonstrated. However, its potency is diminished in the presence of lamivudine-resistant HBV, with only 22% of lamivudine refractory patients becoming HBV DNA negative by PCR compared with 83% of treatment native patients(3). Moreover, the presence of pre-existing lamivudine- induced mutations has been associated with the emergence of several additional signature mutations in patients on entecavir, resulting in still further loss of potency. Given that >70% of patients will develop lamivudine resistance after 4 years of therapy, we contend that any strategy utilizing lamivudine as a first line drug has the potential to undermine the future efficacy of an entire class of potent nucleoside analogs which are already available (entecavir) or in the late phases of development (e.g. telbivudine). Adefovir is a nucleotide analog without cross resistance to lamivudine, but an increase in resistance to adefovir from 0-2% at one and two years, respectively, to 18% after four years was reported recently(4). This underscores the need for our therapeutic choices to preserve the maximum possible potency of alternative drugs.

Additionally, the authors contend that the use of interferon therapy may be preferred in health care systems with limited resources. However, we believe that the authors' interferon arm in their model is equivalent to an unacceptable "do nothing strategy" for >70% of patients, and that few clinicians would not try other alternatives in the event of nonresponse to interferon. This shortcoming of the study is acknowledged by the authors and should be amended in any future analyses.

Our greatest concern is that third party payers will impose constraints on the therapeutic regimens available to clinicians and patients based upon studies such as the present one.. The conclusion of Kanwal et al (1) comes precisely at a time when the poor resistance profile of lamivudine and its adverse implications for the subsequent use of other nucleoside analogs should be leading us away from the use of lamivudine as a first-line drug.

1. Kanwal, F., Gralnek, I. M., et al. Treatment alternatives for chronic hepatitis B virus infection: a cost-effectiveness analysis. Ann Intern Med, 142: 821-831, 2005. 2. J.L. Dienstag, L. J. W. et al. Entecavir (ETV) is superior to lamivudine and adefovir in trials of HBeAg-positive and negative chronic hepatitis B infection: A cross-study analysis with published reports. (Abstract 481) In: The European Association for the Study of the Liver. April 13-17, 2005. Paris, France 3. Baraclude ® (entecavir) [product information]. Princeton, New Jersey: Bristol-Myers Squibb, March 2005. 4. S. Locarnini, X. Q., S. Arterburn, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B. (Abstract 36) In: The European Association for the Study of the Liver. April 13-17, 2005. Paris, France

Conflict of Interest:

Dr. Jacobson is an Advisory Board member and speaker for Gilead Sciences and Bristol-Myers Squibb

Cost-effectiveness of the treatment of chronic hepatitis B
Posted on June 27, 2005
Harry L.A. Janssen
Erasmus MC, University Medical Center Rotterdam
Conflict of Interest: None Declared

TO THE EDITOR: With interest we read the cost-effectiveness analysis by Kanwal and colleagues on the treatment alternatives in chronic hepatitis B [1].

In this study, the authors state that interferon therapy in chronic hepatitis B may save costs by avoiding prolonged therapy like with nucleoside analogues such as lamivudine and adefovir. With nucleoside analogue treatment lifelong therapy may well be needed to achieve a maintained virologic response and the life time safety effects of nucleoside analogues are still unknown.

Kanwal et al. calculated an adefovir resistance of 1.3% annually. This percentage is not confirmed by Locarnini et al. [2], who showed a cumulative probability of 15% after 192 weeks of adefovir treatment in 67 naïve or lamivudine resistant chronic hepatitis B patients. Thus, this higher percentage of viral resistance to adefovir will most likely lead to a less favorable outcome for both adefovir monotherapy and adefovir salvage strategy in this cost-effectiveness analysis.

Furthermore, only the cost-effectiveness of standard interferon therapy for 4 months in HBeAg-positive and 12 months for HBeAg-negative chronic hepatitis B was analyzed. The authors advised that interferon therapy is especially an option in health care systems with limited budgetary resources. In our opinion, interferon could be the first line treatment in chronic hepatitis B in patients without contra-indications to interferon and independent of the budget of the health care system. Especially with the new pegylated interferons, which are even less expensive than standard interferons since they only need to be administered once weekly, a durable virologic response with a limited amount of side-effects can be achieved. This further underlines the importance of pegylated interferon in the current armamentarium to treat chronic hepatitis B.

Martijn J. ter Borg MD, Hajo J. Flink MSc, Harry L.A. Janssen MD PhD Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

References 1. Kanwal, F., et al., Treatment alternatives for chronic hepatitis B virus infection: a cost-effectiveness analysis. Ann Intern Med, 2005. 142(10): p. 821-31. 2. Locarnini, S., et al., Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil therapy for patients with chronic hepatitis B. Journal of Hepatology, 2005. 42(Suppl. 2): p. 17. 3. Janssen, H.L., et al., Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet, 2005. 365(9454): p. 123-9.

Conflict of Interest:

None declared

Avoid LAMIVUDINE Strategy for Chronic Hepatitis B
Posted on June 30, 2005
Aijaz Ahmed
Stanford University
Conflict of Interest: None Declared

TO THE EDITOR:

The cost-effectiveness analysis by Kanwal and colleagues (1) addressing treatment options for chronic hepatitis B contains several biases against the nucleos(t)ide analogues. First, the authors assume that patients who develop resistance to nucleoside analogues revert to the natural history demonstrated by untreated patients. However, Lai et al. (2) showed that histological improvement persists even in patients who develop resistance. Second, the rate of clinical progression in patients with advanced fibrosis/cirrhosis is assumed to be uniform among all strategies, despite evidence that continued treatment with nucleoside analogues reduces both the rate of hepatocellular carcinoma and hepatic decompensation (3). Third, although the authors account for costs and discontinuation rates associated with interferon side-effects, it is unclear if they consider the decrement in quality of life during treatment for those patients who stay on interferon for 6 to 12 months. A study of maintenance interferon for melanoma used a relative value of 0.8 (4), but reliable patient-derived values are lacking.

The comparison between lamivudine and adefovir may also need to be re -examined; it is unclear if the authors account for acute hepatitis flares and/or hepatic decompensation associated with the emergence of lamivudine resistance (5). We also found it surprising that among HBeAg positive patients, the effectiveness of adefovir as initial therapy was lower than that of the hybrid salvage strategy (lamivudine with crossover to adefovir upon resistance) despite the fact that durable virological response rates were assumed to be the same for both agents, and lower resistance rates would be expected in the adefovir-only arm. We suspect that the impact of lamivudine resistance has been underestimated in this analysis.

Entecavir (Baraclude, Bristol-Myers Squibb, New York, NY) is a nucleoside analogue that was recently approved by the FDA for treatment- naïve (0.5 mg/day) and lamivudine-refractory (1.0 mg/day) patients with chronic hepatitis B. Entecavir is the most potent drug available in United States for chronic hepatitis B. However, mutations associated with lamivudine use can result in up to a 70-fold reduction in entecavir phenotypic susceptibility (Package Insert, Baraclude, Bristol-Myers Squibb, New York, NY). At 48 weeks, entecavir genotypic resistance was 7.4% in lamivudine-refractory patients versus 0% in treatment-naïve patients. We recommend that Kanwal and colleagues' analysis (1) be revisited, and that lamivudine be avoided as first-line therapy for treatment-naïve chronic hepatitis B patients.

Ahmad Kamal, MD

Aijaz Ahmed, MD

Stanford University School of Medicine, Stanford, CA 94305

1. Kanwal F, Gralnek IM, Martin P, Dulai GS, Farid M, Spiegel BM. Treatment alternatives for chronic hepatitis B virus infection: a cost- effectiveness analysis. Ann Intern Med. 2005;142:821-31.

2. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one -year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339:61-8.

3. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-31.

4. Hillner BE, Kirkwood JM, Atkins MB, Johnson ER, Smith TJ. Economic analysis of adjuvant interferon alfa-2b in high-risk melanoma based on projections from Eastern Cooperative Oncology Group 1684. J Clin Oncol. 1997;15:2351-8.

5. Liaw YF. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. Antivir Chem Chemother. 2001;12 Suppl 1:67-71.

Conflict of Interest:

Aijaz Ahmed, MD is a consultant and speaker for Gilead Sciences and Bristol-Myers Squibb

Premature to Eliminate Lamivudine in the Treatment of Hepatitis B
Posted on July 14, 2005
Brennan M.R. Spiegel
VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA
Conflict of Interest: None Declared

To the Editor:

Drs Weitzman and Jacobson identify some key issues in the management of chronic HBV in an era where several agents are now licensed for this indication. In particular, both entecavir and peyglated interferon have been approved for chronic HBV since our manuscript was accepted for publication. Our model did not include these agents. Drs. Weitzman and Jacobson rightfully point out that the effectiveness of entecavir is diminished in the presence of lamivudine resistance, and argue that this finding should dissuade clinicians from using lamivudine as a first-line agent. We agree that this observation should give pause to routinely using lamivudine to treat chronic HBV. However, our model did not evaluate "entecavir salvage," but instead evaluated the "adefovir salvage" (i.e. using up-front lamivudine followed by adefovir in case of resistance). Our systematic review of the literature (published as an online appendix with the manuscript) found no published data to support a decrement in the effectiveness of adefovir in the presence versus absence of lamivudine resistance. Therefore, we believe that our results regarding "adefovir salvage" are valid. In contrast, it seems unlikely that "entecavir salvage" will be cost-effective, largely because of the data highlighted by Drs. Weitzman and Jacobson. Moreover, the higher price of entecavir (current average wholesale price roughly 20% higher than adefovir) may not offset its low rate of viral resistance, and up- front entecavir may ultimately be less cost-effective than competing, less expensive therapies.

Additionally, it is important to recognize the difference between patients without evidence of advanced fibrosis or cirrhosis (the subject of our analysis), and those with more advanced disease. In patients without advanced disease, viral progression is slow, poor outcomes are infrequent, and overall survival is not different than matched controls without chronic HBV. This is not an argument to avoid treatment, but instead underscores the importance of rational therapeutic decision-making in the face of health economic realities. In the case of cirrhosis or advanced fibrosis "“ health states plagued by the specter of impending clinical complications "“ patients may develop resource intensive, morbid, or mortal complications in short order. Although antiviral resistance is never a goal of therapy in either group of patients, the development of resistance has less severe health economic consequences in non-cirrhotics than cirrhotics, since patients with cirrhosis can ill-afford the emergence of viral resistance and subsequent viral flares.

In short, our analysis only applies to patients without advanced disease, and cannot be generalized to telbivudine, entecavir, or pegylated interferon. We agree that future analyses must account for these newer agents. As data evolve, the results of future models may indeed marginalize lamivudine in lieu of alternative agents. Until then, we are left with the constant presence of health economic restraints, and the fact that most HBV patients without cirrhosis never develop complications of chronic liver disease. These factors preclude any cut-and-dry proclamations about how best to treat non-cirrhotic HBV in a resource- limited environment. We look forward to updating our model to reflect this rapidly changing field as new data emerge.

Brennan M.R. Spiegel, MD, MSHS Paul Martin, MD Fasiha Kanwal, MD, MSHS

Conflict of Interest:

Consultant for Novartis. Reserach grants from Novartis and Gilead.

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Summary for Patients

Antiviral Regimens for Chronic Hepatitis B Virus Infection

The summary below is from the full report titled “Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis.” It is in the 17 May 2005 issue of Annals of Internal Medicine (volume 142, pages 821-831). The authors are F. Kanwal, I.M. Gralnek, P. Martin, G.S. Dulai, M. Farid, and B.M.R. Spiegel.

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