Friday, December 2, 2011

Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients

Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients

Shan Liu1*, Michaël Schwarzinger2, Fabrice Carrat3, Jeremy D. Goldhaber-Fiebert4

1 Department of Management Science and Engineering, Stanford University, Stanford, California, United States of America, 2 Equipe ATIP-AVENIR/UMR-S 738 INSERM, Paris Diderot University, Paris, France, 3 UMR-S 707 INSERM, Pierre et Marie Curie University, Paris, France, 4 Department of Medicine, Center for Health Policy and Center for Primary Care and Outcomes Research, Stanford University, Stanford, California, United States of America

Background and Aims
Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.

We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).

Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and $6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and $30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.

Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy.

Citation: Liu S, Schwarzinger M, Carrat F, Goldhaber-Fiebert JD (2011) Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients. PLoS ONE 6(12): e26783. doi:10.1371/journal.pone.0026783

Editor: Ravi Jhaveri, Duke University School of Medicine, United States of America

Received: June 27, 2011; Accepted: October 4, 2011; Published: December 2, 2011

Copyright: © 2011 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Ms. Liu was supported by a Stanford Graduate Fellowship. Dr. Goldhaber-Fiebert was supported in part by a U.S. National Institutes of Health National Institute on Aging Career Development Award (K01 AG037593-01A1: PI; Goldhaber-Fiebert). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction Only
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Viral hepatitis C (HCV) is a serious liver disease affecting 180 million people worldwide [1]. In the U.S., 1.3% to 1.9% of the population has been infected with HCV, and 2.7 to 3.9 million people live with chronic infection [2]. Chronic HCV causes liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), and is the most common cause of liver transplantation in the US [1].

Current practice guidelines in the U.S. recommend treatment for chronic HCV patients with significant fibrosis progression [1]. For pre-treatment evaluations of patients, liver biopsy is the current gold standard to ascertain liver histology and measure fibrosis progression. However, its expense, risk of side-effects, and potential inaccuracy from sampling and observation errors reduce its utility for frequent liver fibrosis screening [3], [4], [5]. Non-invasive tests of liver fibrosis – including serum markers such as FibroTest (FibroSure) and imaging methods such as FibroScan (transient elastography) – offer potentially viable alternatives [6]. These tests are clinically validated in most common liver diseases caused by hepatitis C, hepatitis B, and alcohol abuse.

Few published studies have addressed the cost-effectiveness of non-invasive tests as alternatives to liver biopsy for determining when to initiate treatment for HCV. A number of studies have investigated test characteristics; some have estimated at a threshold of 0.3, sensitivities and specificities of FibroTest of 74–82% and 57–65% [6], respectively, though this changes with the definition of underlying disease and FibroTest cutoff; others have examined the cost-effectiveness of various treatment options, though generally without considering combinations of screening and treatment. One existing cost-effectiveness analysis of non-invasive screening tests fails to adhere to recommended standards including evaluating options over a lifetime horizon and including quality-of-life considerations [7], [8]. Consequently uncertainties remain about the indications, accuracy, and cost-effectiveness of FibroTest and other non-invasive liver fibrosis screening technologies [3]. Furthermore, recent development in new protease inhibitors to treat HCV, such as telaprevir (Incivek™, Vertex), used in conjunction with pegylated interferon and ribavirin, have significantly improved treatment success rates compared to the standard treatment [9]. The cost-effectiveness of the new treatment is unknown.

We performed a model-based cost-effectiveness analysis of six FibroTest and liver biopsy screening strategies followed by treatment for eligible U.S. chronic HCV patients. We assessed FibroTest's viability as a tool to determine when to initiate treatment by addressing the questions: How should FibroTest be used in the context of chronic HCV, if at all? And how should HCV treatment be offered in combination with periodic screening?

Discussion Only
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For eligible men and women with chronic HCV of genotype 1, 2, and 3 in the United States, treatment without screening to determine liver fibrosis stage is cost-effective compared to periodic fibrosis screening strategies. Because there may be additional benefits to fibrosis staging prior to treatment (i.e., initiating hepatocellular carcinoma screening for patients with advanced fibrosis) and thus some clinicians may not consider treatment without testing viable, among screening strategies, using FibroTest alone is the next best alternative, and is more effective and less costly than fibrosis screening with liver biopsies. Compared to FibroTest alone, using FibroTest with biopsy reserved for patients with intermediate results has an ICER above $100,000/QALY for genotype 1 and below $50,000/QALY for other HCV genotypes. These finding are robust to multiple assumptions and sensitivity analyses.

This study addresses two important questions — whether to use and how to use non-invasive makers of fibrosis instead of liver biopsy to determine a patient's need for treatment, and the optimal timing to initiate treatment. Many clinicians have shown aversion to non-invasive biomarkers due to the tests' low sensitivity and specificity. Some are concerned that biomarkers fail to make accurate distinctions between mild and severe fibrosis and believe that biopsy may inform treatment decisions in these mid-zones. On the other hand, the apparent failure of serologic markers to distinguish between intermediate stages can be the consequence of classification errors from biopsy - several published studies suggest that when biopsy and marker results are discordant, diagnostic failure of biopsy is much more common than diagnostic failure of biomarkers [44]. Decisions to perform biopsy may depend more on physician preference than on the ability of liver biopsy to influence treatment decisions [45], [46], [47]. We acknowledge the on-going debate around the validity of FibroTest versus that of liver biopsy. However, we find that despite the uncertainties associated with FibroTest's test characteristics, FibroTest Only strategy is preferred over liver biopsy across a broad range of sensitivities and specificities because of its advantage in cost, side effect, and frequency of follow-up. Patients afraid of liver biopsy's side effects may be more accepting of non-invasive tests and consequently these tests may also increase adherence to periodic fibrosis assessment if treatment is withheld. Furthermore, treating all patients (F0–F4) is often cost-effective and therefore distinguishing between mild and significant fibrosis may not be not essential.

Our results contribute to the current debate regarding liver biopsy. Many clinicians recognize liver biopsy's disadvantages. In addition to its cost and risk of adverse effects, liver biopsy is subject to sampling errors (biopsy with a length of 25 mm has a misclassification rate of 25%) [48]. Repeating biopsy every 3–5 years may also be unrealistic due to provider variability and patient non-adherence. Despite this, the National Institute of Health (NIH) 2002 Consensus Statement indicates that liver biopsy still provides unique information on fibrosis and histology, and no panel of serologic markers can provide an accurate assessment of intermediate stages of fibrosis [14]. Similarly, the 2009 American Association for the Study of Liver Diseases (AASLD) guideline recommends liver biopsy in making treatment decisions [1]. However, it recognizes the usefulness of non-invasive tests in defining the presence or absence of advanced fibrosis. Both of the guidelines agree that liver biopsy is not necessary in managing genotype 2 or 3 patients, since their treatment success rate is substantially higher than genotype 1 patients. In support of future amendments to these guidelines, we find that even for genotype 1 patients, both immediate treatment and non-invasive screening appear cost-effective compared to liver biopsy. Furthermore, with the anticipated improvement in treatment success rate for genotype 1 patients, guidelines may soon be revised.

Our results suggest that re-examination of the necessity of screening prior to treatment decision may be appropriate. If treatment is generally effective, additional information obtained via screening may not provide sufficient additional value in guiding clinical decisions, since even with fibrosis stage uncertainty, treatment is likely to be sufficiently beneficial [45], [46]. Our research helps to map out this trade-off between fibrosis stage accuracy and treatment success rate. Though no randomized controlled trials proving that HCV antiviral therapy is associated with long-term clinical benefits, there is a broad literature that strongly suggests this relationship. The lack of long-term evidence may be due to the slow progression of the disease and the short history of the new combination therapy. We found immediate treatment to be cost-effective, given the current treatment effectiveness and anticipated improvements in the future [9]. Our results anticipate new anti-HCV drugs such as telaprevir and boceprevir becoming available that may significantly improve SVR for genotype 1 patients. Even with significantly increased drug costs and potentially increased risk of side-effects, our analyses support immediate treatment without fibrosis screening.

Our analyses and conclusions were robust to a variety of assumptions. Importantly, our conclusions were not sensitive to uncertainties regarding the speed of fibrosis progression and proportion of non-progressors in the cohort. As cost-effectiveness is also influenced by health utilities of HCV health states used in the model, our main conclusion remained robust despite uncertainties regarding these estimates. We also note depending on who is the payer, the cost of treatment can be much lower than our current assumptions (i.e. Federal Supply Schedule for government payers) in which case immediate treatment would appear even more favorable.

Previous research examined the economic outcomes of non-invasive testing in the diagnosis of significant liver fibrosis compared with liver biopsy and recommended against non-invasive testing [8]. The conclusion is made with the assumption that “misdiagnosis” leading to early treatment is harmful to health. The assumption is problematic by disregarding all future benefits and cost. By evaluating a one-time use of non-invasive test, the study ignored one major advantage of non-invasive test that enables more frequent monitoring of fibrosis progression than liver biopsy.

Our study has several limitations. The model does not stratify the population by race, and thus the fibrosis progression and treatment response rates are biased towards whites reflecting the participants in the clinical studies of our source data. Because needed information on genotypes other than 1, 2, and 3 was limited, the model only considers clinical scenarios for genotypes 1, 2, and 3, which is appropriate for a U.S. analysis where these types are most common. We did not consider co-infection with HIV and/or hepatitis B. We defined alternative screening strategies by possible combinations of FibroTest and liver biopsy. Our strategy set is not comprehensive, and we note other screening patterns exist. We did not consider other non-invasive markers and imaging methods such as FibroScan to evaluate liver stiffness. However, for non-invasive tests that are conducted at similar intervals, that have comparable test characteristics and that have comparable costs to FibroTest, our conclusion are also applicable. We also found that treatment without screening to determine liver fibrosis stage would be cost-effective compared to periodic screening strategies. This result was robust to a wide range of sensitivities, specificities, and test costs, and should, therefore, hold for many other non-invasive markers.

Depending on who bears the cost of new antiviral drugs, patients may prefer to wait to initiate treatment until there is evidence of significant fibrosis progression. The model did not include possible future advances in treatment in the base case analysis and allow patients to delay treatment for a later date. The analyses also did not include the benefits of fibrosis screening to patients being able to make an informed choice and, therefore, potentially having a stronger commitment to treatment adherence.

HCV is a serious liver disease affecting up to 4 million Americans. While current recommendations favor liver biopsies prior to treatment initiation, we find that, for the hundreds of thousands of Americans with chronic HCV, other strategies are likely more effective and cost-effective. Management of chronic HCV in the U.S. could be improved by a shift towards strategies that initiate immediate treatment without fibrosis screening or else periodic screening with a non-invasive method followed by treatment for those found likely to have significant fibrosis.

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