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Cost-Effectiveness of Hepatitis A Vaccination in Patients With Chronic Hepatitis C
Correspondence
Cost-Effectiveness of Hepatitis A Vaccination in Patients With Chronic Hepatitis C To the Editor:
To the Editor:
I read with great interest and more than a little dismay the article by Myers, Gregor, and Marotta1 on the cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. While I found the article to be very well written and thorough, I find the premise for the article to be totally unacceptable. Are we to withhold a simple vaccination from our patients, knowing that they run the risk of severe morbidity or death simply because it may not be “cost effective” in a population study? This article calls to mind a story that was recently played out in the courts in the United States. There was once a large automobile manufacturer that produced a vehicle it knew was unsafe. Not only did they know that it was unsafe, they also knew how to fix the problem to render the vehicle safe. However, rather than do the right thing and fix the vehicle (at a cost of $11 per vehicle), they embarked on a course similar to Myers et al. They first calculated the cost of correcting the defect and then compared it with the cost they may incur if the defect was not corrected. They used data from the federal government and that the National Highway Traffic Safety Administration made available to them. They calculated the average damage per person killed by their vehicle. They added medical costs, property damage, insurance administration, legal and court costs, employer losses, victim pain and suffering, and funeral bills as well as “other costs.” When they found that this cost would be less than the cost of correcting the defect on the vehicle, they elected to take their chances in court. Their strategy ultimately landed them in court and resulted in one of the largest settlements in the American legal system. The ethics involved in their decision-making process was headline news throughout the nation. The parallels between this story and the conclusions drawn from this article I find to be quite remarkable. I can see myself in the future consoling Mrs. X upon the death of her husband from hepatitis A superimposed on hepatitis C, a disease that could have been prevented by a simple vaccination, by handing her the article and saying, “but as you can see here, clearly it would not have been cost effective for me to have given your husband a simple vaccine.” I was surprised that this article did not provoke more editorial comments from the editors of HEPATOLOGY and I certainly hope that the ACIP does not reconsider its stance on vaccinating all patients with hepatitis C with the hepatitis A vaccine.
In their assessment of hepatitis A vaccination for chronic HCV patients,1 Myers et al. argue that reductions in morbidity and mortality should be weighed against vaccination costs. We fully agree. The authors estimate that universal vaccination of 1 million HCV patients would prevent just 4 liver transplantations and 3 deaths, benefits insufficient to justify vaccination costs. We believe the economic and clinical benefits of vaccination are far greater than presented. Their analysis vastly understates the risk of hepatitis A infection. First, disease incidence was based on reported cases, with no adjustment for under reporting. The CDC has historically estimated that just one third of symptomatic hepatitis A infections are reported,2,3 and a recent study indicates that only 9% to 12% of all HAV infections, and 20% to 50% of icteric infections, are captured through passive reporting.4 Second, the infection rate was only applied to HCV patients without natural HAV immunity. Because it was derived by comparing reported hepatitis A cases with the entire US population (both susceptible and immune),3 the infection rate should have been applied to all patients. Third, the predicted number of infections was reduced 20% to exclude asymptomatic infections. This measure is inappropriate, because passive surveillance cannot identify asymptomatic infections. These inaccuracies cause 3-fold, 2-fold, and 1.25-fold underestimates of disease incidence, respectively. Because they compound, the total underestimate appears to be 7.5-fold. Further, the study does not consider the likelihood of longterm protection afforded by vaccination. Kinetic models of antibody decline suggest that protection may persist for more than 20 years,5,6 and it may be extended further by immunologic memory.7 In fact, vaccine-induced protection may be life-long. Assuming a 20-year duration of protection, the decision to limit the economic model to 5 years served to understate the number of hepatitis A infections prevented by approximately 4-fold. Combined, these factors appear to result in a 30-fold underestimate of the number of hepatitis A infections prevented by vaccination. Thus, the reported ratio of $23 million per death averted may be only $767,000 per death averted. In the United States, the median age of HCV-positive persons is approximately 40 years,8 at which life expectancy is 38 additional years.9 Hepatitis A vaccination of HCV patients may therefore cost $20,175 per year of life saved, a ratio meeting conventional standards of cost-effectiveness.10 Of course, if chronic HCV patients have impaired life expectancies, fewer years of life would be saved by preventing fatal HAV infections. HCV patients may have increased rates of HAV seropositivity,11 meaning some reduction in predicted infection risk is appropriate. Age- and geographic-specific infection rates would provide useful information, as these factors strongly predict HAV incidence.3 Age-specific estimates of hospitalization, transplantation, and mortality would provide a more accurate assessment of disease outcomes.12 These factors should be considered in a revised cost-effectiveness analysis, which will likely conclude that hepatitis A vaccina-
RICHARD AYCOCK, M.D., F.A.C.G. Memphis Gastroenterology Group and Memphis Gastroenterology Endoscopy Center East Memphis, TN REFERENCE 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000; 31:834-839.
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.16179
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tion of HCV patients has a more attractive cost-effectiveness ratio. R. JAKE JACOBS Capitol Outcomes Research, Inc. Alexandria, VA
RAYMOND S. KOFF, M.D. University of Massachusetts Medical School Boston, MA REFERENCES 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000;31: 834-839. 2. Hadler SC. Global impact of hepatitis A virus infection: changing patterns. In: Hollinger FB, Lemon SM, Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore, MD: Williams & Wilkins 1991;14-19. 3. Hepatitis Surveillance Report Number 56. Atlanta, GA: Centers for Disease Control and Prevention, 1996. 4. Armstrong GL, Bell BP. Hepatitis A virus in the 20th century USA— estimated incidence of infection [Abstract]. Antiviral Ther 2000;5(Suppl 1):14. 5. Wiens B, Bohidar N, Pigeon J, Egan J, Hurni W, Brown L, Kuter BJ, et al. Duration of protection from clinical hepatitis A disease after vaccination with VAQTA. J Med Virol 1996;49:235-241. 6. Van Damme P, Thoelen S, Cramm M, De Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-451. 7. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, Andre FE. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis 1995;171(Suppl 1):S44-S49. 8. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-562. 9. Anderson RN, Kochanek KD, Murphy SL. Report of final mortality statistics, 1995. Monthly Vital Statistics Report; vol 45, no 11, supp 2. Hyattsville, MD: National Center for Health Statistics, 1997. 10. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? CMAJ 1992; 146:473-481. 11. Sjo¨gren MH. Preventing acute liver disease in patients with chronic liver disease. HEPATOLOGY 1998;27:887-888. 12. Berge JJ, Drennan DP, Jacobs RJ, Jakins A, Meyerhoff AS, Stubblefield W, Weinberg M. The cost of hepatitis A infections in American adolescents and adults in 1997. HEPATOLOGY 2000;31:469-473.
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.18856
Reply: We appreciate the insightful comments of Drs. Jacobs and Koff with respect to our recent cost-effectiveness analysis.1 Although we agree with several of their criticisms, appropriate changes in the model fail to alter our overall conclusion, that is, vaccination of North American patients with hepatitis C (HCV) against hepatitis A (HAV) is not cost-effective. We agree that the rate of infection used in our baseline analysis (10.3 cases per 100,000 population) should be adjusted to account for individuals with innate immunity to HAV. According to the Third National Health and Nutrition Examination Survey (NHANES-III), 33% of the US popula-
tion have serologic evidence of prior HAV infection.2 We also agree that the 20% reduction in the HAV infection rate to account for asymptomatic infections was inappropriate because these cases would not be identified by passive surveillance. Jacobs and Koff also recommend that the baseline rate be adjusted for under reporting of HAV infections. Although the CDC historically estimates that just one third of HAV cases are reported,2 this has not been a universal finding.3 Armstrong and Bell recently reported that upwards of 50% of icteric infections are captured by passive reporting.4 Because the primary focus of our study is the patient with symptomatic infection who requires hospitalization (a minimum of 5 days in our study), and consumes health care resources, we feel that a doubling of our infection rate is appropriate. The result of these changes is a 3.75-fold (1.5-fold ⫻ 1.25-fold ⫻ 2-fold) increase in the baseline rate of infection to 38.6 cases per 100,000 population. Regardless, the incidence of HAV infection was varied over a wide range (up to 1% annually) in our sensitivity analysis, without a change in our overall conclusion. Jacobs and Koff also suggest that the duration of our model is too short, underestimating the long-term benefits afforded by HAV vaccination. We chose a conservative 5-year time horizon for our model because of current uncertainties in the longevity of vaccine-induced protection in patients with chronic liver disease, including those with HCV. A recent study by Koff et al.5 investigating HAV vaccination in such patients showed similar seroconversion rates between subjects with HCV and controls. However, the geometric mean titers observed in the HCV group were on average 2.8 times lower than those of controls (467 vs. 1,315 mIU/ mL, respectively; P ⫽ .001). The kinetic models of antibody decline referred to by Jacobs and Koff6 were actually derived using normal subjects and, hence, do not apply to HCV patients (with a proven reduction in humoral response to HAV vaccination). In any event, applying the reductions in antibody titers projected by these kinetic models to the geometric mean titers reported by Koff et al., predicts the maximum mean duration of vaccine-induced immunity to be 10 to 13 years. Thus, the 20-year duration of protection suggested by Jacobs and Koff is overly optimistic. Jacobs and Koff calculated a cost-effectiveness ratio of $20,175 per year of life saved by assuming that the average American HCV patient has an additional life expectancy of 38 years, no different from the average uninfected individual. Unfortunately, they did not adjust for the impaired healthrelated quality of life (HRQOL) shown in patients with chronic HCV.7,8 This adjustment is critical. Younossi et al.8 recently reported a mean utility of 0.75 in HCV patients. Thus, 38 years of additional life expectancy in a patient with HCV is the equivalent of 28.5 years spent with perfect health (qualityadjusted life years [QALYs]). Incorporating these adjustments to the incidence of HAV infection, doubling the time horizon of our model to 10 years, and adjusting for the impaired HRQOL of patients with HCV, we calculate that the undiscounted incremental cost-effectiveness of the universal and selective strategies are $113,661/QALY and $95,480/QALY, respectively. These figures are clearly higher than those conventionally reported as cost-effective.9 In addition, discounting of future costs and discounting QALYs would have an additional negative influence on these already prohibitive cost-effectiveness ratios. We also appreciate the uncertainty that Dr. Aycock exhibits in his interpretation of the results of this cost-effectiveness analysis.
HEPATOLOGY Vol. 32, No. 4, 2000
Indeed, all such publications that have the potential to impact health care policies place physicians on seemingly uncomfortable middle ground. On one hand, we must act as patient advocates and do what we feel is in the best interest of our patients, in this instance, provide “a simple vaccine” to prevent morbidity and potential mortality. On the other hand, the medical community is aware of, and must function within, the finite financial resources that are inherent in any health care system. Dr. Aycock outlines this dilemma and the associated frustration that accompanies the interpretation of cost-effectiveness analysis. The analogy that Dr. Aycock utilizes however is dubious at best. The legal and financial obligations of a manufactured problem are clearly different. After all, physicians did not knowingly “infect” patients with HCV, nor do we market a consumer product for profit. The manufacturing company referred to by Dr. Aycock had “secretly” calculated the costs that would be incurred, with and without correcting the manufactured defect. In our analysis, we have provided this financial information “up front” and have made this information available to be utilized not only by individual physicians, but also by policymakers who will need to make conscientious decisions for the good health of society. Our report considers health care costs from a global perspective, and as such there must be strategies to appropriately ration these finite resources. The incidence of HAV infection in North America is low and spending an exorbitant sum, $23 million, from a limited health care budget to save one individual’s life could be considered inappropriate. There are many illnesses that may result in rare deaths, yet it is not acceptable to prevent these rarities if the cost associated in doing so is prohibitive. In a previous analysis, Jackson et al.10 evaluated routine vaccination of college students against meningococcal disease. This strategy would prevent rare fatalities from this disease, yet the millions of dollars that it would cost to accomplish this prohibit the implementation of such a policy. Dr. Aycock seems to imply that society as a whole has unlimited financial resources and, hence, we should provide the “simple vaccine” to all of our chronic HCV patients. If that were true, then we would suggest not only vaccination of HCV patients, but provision of HAV vaccination for every individual worldwide. This strategy would clearly impact the worldwide mortality associated with this infection. Physicians and policymakers must promote medical care that yields not only beneficial clinical outcomes but also achieve acceptable costs. By way of example is the recommendation by the ACIP for routine pneumococcal vaccination for elderly people. This practice not only leads to improved health but it will actually save money.11 Unfortunately, vaccination rates remain poor despite the noted benefits. In contrast to this example, we have shown that the strategy of providing HAV vaccination to all susceptible patients with chronic HCV does not fulfill these criteria. We do expect that the ACIP will reconsider its recommendation that all patients with chronic HCV are provided with vaccination against HAV. Before this chapter is considered closed, however, several questions need to be answered. (1) What is the true incidence of HAV infection in patients with chronic HCV? In this regard, long-term, prospective, serologic studies of unvaccinated North American pa-
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tients are sorely needed. As suggested by Jacobs and Koff, age- and geographic-specific rates of infection would strengthen any analysis of the cost-effectiveness of HAV vaccination. (2) What is the course of HAV superinfection in patients with chronic HCV? Again, studies must investigate age-specific rates of hospitalization, liver transplantation, and mortality associated with acute HAV infection in this population. However, the rarity of these events will certainly complicate this task. (3) For how long does HAV vaccination confer protection in patients with chronic HCV? Long-term serologic follow-up of patients already vaccinated will help resolve this issue. We thank Drs. Aycock, Jacobs, and Koff for their comments, which clearly reveal the pitfalls of a cost-effectiveness analysis as it pertains to individual physicians. While physicians must continue to do what is in their patients’ best interests, they must do so by objectively evaluating the best available evidence without ignoring the associated costs of their actions. ROBERT P. MYERS, M.D. JAMES C. GREGOR, M.D. PAUL J. MAROTTA, M.D. Division of Gastroenterology and Hepatology University of Western Ontario London Health Sciences Centre, University Campus London, Ontario, Canada REFERENCES 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000;31: 834-839. 2. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1-30. 3. Alter MJ, Mares A, Hadler SC, Maynard JE. The effect of underreporting on the apparent incidence and epidemiology of acute viral hepatitis. Am J Epidemiol 1987;125:133-139. 4. Armstrong GL, Bell BP. Hepatitis A virus in the 20th century USA—estimated incidence of infection [Abstract]. Antiviral Ther 2000;5(Suppl 1):14. 5. Keeffe EB, Iwarson S, McMahon BJ, Lindsay KL, Koff RS, Manns M, Baumgarten R, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. HEPATOLOGY 1998;27:881-886. 6. Van Damme P, Thoelen S, Cramm M, DeGroote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-451. 7. Ware JE, Bayliss MS, Mannocchia M, Davis GL, and the International Hepatitis Interventional Therapy Group. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. HEPATOLOGY 1999;30:550-555. 8. Younossi AM, McCormick M, Boparai N, Price L, Guyatt G. Health-related quality of life in hepatitis C measured by generic, disease-specific and utility instruments [Abstract]. HEPATOLOGY 1999;30(Part 2):686A. 9. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utiliztion? Tentative guidelines for using clinical and economic evaluations. Can Med Assoc J 1992;146:473-481. 10. Jackson LA, Schuchat A, Gorsky RD, Wenger JD. Should college students be vaccinated against meningococcal disease? A cost-benefit analysis. Am J Public Health 1995;85:843-845. 11. Sisk JE, Moskowitz AJ, Whang W, Lin JD, Fedson DS, McBean AM, Plouffe JF, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA 1997;278:1333-1339. Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.18857
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HEPATOLOGY October 2000
Comprehensive Allelotype Study of Hepatocellular Carcinoma development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. HEPATOLOGY 2000;31:1246-1250.
To the Editor: We read with interest the comprehensive work of Okabe et al.1 on hepatocellular carcinoma (HCC) allelotyping, which showed that some markers (e.g., 4q and 13q) are lost in advanced cancer, others (6q) in early phases of hepatocarcinogenesis, and some in chronic hepatitis B virus infection. However, their reference was adjacent noncancerous liver tissue, which in 27 of 39 cases was diseased. It has been shown that clonal populations exist in cirrhotic liver with allelic loss at chromosomal sites.2-4 If the HCC and adjacent cirrhotic tissue have exactly the same allelic loss, then the loss of heterozygosity (LOH) index would be unity and specific loss could be missed. Because the missed losses would be those occurring both in cirrhosis and HCC, they may represent early changes that contribute to tumor initiation rather than to progression. Indeed, Kawai et al.5 in a similar study, recently showed that the LOH rate in HCC decreases significantly when nontumorous liver tissue is referenced instead of peripheral blood leukocytes (P ⬍ .02). Moreover, the prevalence of LOH in liver tissue adjacent to cancer was higher than in liver not harboring HCC. MASSIMO RONCALLI, M.D., PH.D. University of Milan Istituto Clinico Humanitas Rozzano, Italy MAURO BORZIO, M.D. Fatebenefratelly and Oftalmico Hospital of Milano Milan, Italy PAOLO BIANCHI, PH.D. Istituto Clinico Humanitas Rozzano, Italy LUIGI LAGHI, M.D., PH.D. Istituto Clinico Humanitas Rozzano, Italy REFERENCES 1. Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T, Katsura N, et al. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors. HEPATOLOGY 2000;31:1073-1079. 2. Yamada T, De Souza AT, Finkelstein S, Jirtle RL. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor 11 receptor is an early event in liver carcinogenesis. Proc Natl Acad Sci U S A 1997;94:1035110355. 3. Ashida K, Kishimoto Y, Nakamoto K, Wada K, Shiota G, Hirooka Y, Kamisaki Y, et al. Loss of heterozygosity of the retinoblastoma gene in liver cirrhosis accompanying hepatocellular carcinoma. J Cancer Res Clin Oncol 1997;123:489-495. 4. Roncalli M, Bianchi P, Ceva Grimaldi G, Ricci D, Laghi L, Maggioni M, Opocher E, et al. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. HEPATOLOGY 2000;31:846-850. 5. Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y, Waguri N, Kuroiwa T, et al. Quantitative evaluation of genomic instability as a possible predictor for
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.17968
Reply: Dr. Roncalli et al. raise critical issues in allelotyping hepatocellular carcinoma (HCC). We believe that tumor-specific allelic changes contribute significantly to the carcinogenesis of HCC. We agree that the study of allelic changes in noncancerous tissues would provide valuable information concerning mechanisms of HCC carcinogenesis, but we have not examined this question yet. We wish to emphasize several inherent problems in allelotyping noncancerous tissue of the diseased liver: 1. Markers. To date, genome-wide allelotyping of noncancerous tissue in diseased liver has not been performed. Hence, investigators must evaluate the allelic changes in the diseased liver using an adequate number of microsatellite markers, which cover genome-wide changes. 2. Samples. Dr. Roncalli et al. refer to their own study published in HEPATOLOGY in which they extracted DNA from paraffin-embedded samples. Paraffin-embedded samples should be avoided in allelotype studies of this type, because these samples contain severely fragmented DNA, which increases the incidence of false-positive detection of loss of heterozygosity. 3. Pathologic Characterization. Noncancerous tissue of the diseased liver encompasses a range of findings from almost normal histology to precancerous, severe dysplastic nodules. Therefore, the noncancerous tissues must be stratified into categories according to precise pathologic evaluation and numbers of cases. 4. Selection of the Sampling Sites. Several studies have shown that cirrhotic nodules may harbor allelic losses. However, the pattern of allelic losses differs among nodules. In different lesions within the same liver, only one or few nodules may progress to HCC while others remain noncancerous. Therefore, to identify the critical LOH loci that contribute to hepatocarcinogenesis, one must examine highly susceptible lesions. For example, a nodule harboring an early stage tumor (so-called nodule-in-nodule type) would be optimal. Once these points are satisfied, allelotyping of the noncancerous tissue in diseased liver will greatly contribute to the study of HCC. HIROSHI OKABE, M.D. IWAO IKAI, M.D., PH.D. KOICHI MATSUO, M.D. SEIJI SATOH, M.D., PH.D. YOSHIO YAMAOKA, M.D., PH.D. Department of Gastroenterological Surgery Kyoto University Graduate School of Medicine Kyoto, Japan Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.17968
Cost-Effectiveness of Hepatitis A Vaccination in Patients With Chronic Hepatitis C To the Editor:
To the Editor:
I read with great interest and more than a little dismay the article by Myers, Gregor, and Marotta1 on the cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. While I found the article to be very well written and thorough, I find the premise for the article to be totally unacceptable. Are we to withhold a simple vaccination from our patients, knowing that they run the risk of severe morbidity or death simply because it may not be “cost effective” in a population study? This article calls to mind a story that was recently played out in the courts in the United States. There was once a large automobile manufacturer that produced a vehicle it knew was unsafe. Not only did they know that it was unsafe, they also knew how to fix the problem to render the vehicle safe. However, rather than do the right thing and fix the vehicle (at a cost of $11 per vehicle), they embarked on a course similar to Myers et al. They first calculated the cost of correcting the defect and then compared it with the cost they may incur if the defect was not corrected. They used data from the federal government and that the National Highway Traffic Safety Administration made available to them. They calculated the average damage per person killed by their vehicle. They added medical costs, property damage, insurance administration, legal and court costs, employer losses, victim pain and suffering, and funeral bills as well as “other costs.” When they found that this cost would be less than the cost of correcting the defect on the vehicle, they elected to take their chances in court. Their strategy ultimately landed them in court and resulted in one of the largest settlements in the American legal system. The ethics involved in their decision-making process was headline news throughout the nation. The parallels between this story and the conclusions drawn from this article I find to be quite remarkable. I can see myself in the future consoling Mrs. X upon the death of her husband from hepatitis A superimposed on hepatitis C, a disease that could have been prevented by a simple vaccination, by handing her the article and saying, “but as you can see here, clearly it would not have been cost effective for me to have given your husband a simple vaccine.” I was surprised that this article did not provoke more editorial comments from the editors of HEPATOLOGY and I certainly hope that the ACIP does not reconsider its stance on vaccinating all patients with hepatitis C with the hepatitis A vaccine.
In their assessment of hepatitis A vaccination for chronic HCV patients,1 Myers et al. argue that reductions in morbidity and mortality should be weighed against vaccination costs. We fully agree. The authors estimate that universal vaccination of 1 million HCV patients would prevent just 4 liver transplantations and 3 deaths, benefits insufficient to justify vaccination costs. We believe the economic and clinical benefits of vaccination are far greater than presented. Their analysis vastly understates the risk of hepatitis A infection. First, disease incidence was based on reported cases, with no adjustment for under reporting. The CDC has historically estimated that just one third of symptomatic hepatitis A infections are reported,2,3 and a recent study indicates that only 9% to 12% of all HAV infections, and 20% to 50% of icteric infections, are captured through passive reporting.4 Second, the infection rate was only applied to HCV patients without natural HAV immunity. Because it was derived by comparing reported hepatitis A cases with the entire US population (both susceptible and immune),3 the infection rate should have been applied to all patients. Third, the predicted number of infections was reduced 20% to exclude asymptomatic infections. This measure is inappropriate, because passive surveillance cannot identify asymptomatic infections. These inaccuracies cause 3-fold, 2-fold, and 1.25-fold underestimates of disease incidence, respectively. Because they compound, the total underestimate appears to be 7.5-fold. Further, the study does not consider the likelihood of longterm protection afforded by vaccination. Kinetic models of antibody decline suggest that protection may persist for more than 20 years,5,6 and it may be extended further by immunologic memory.7 In fact, vaccine-induced protection may be life-long. Assuming a 20-year duration of protection, the decision to limit the economic model to 5 years served to understate the number of hepatitis A infections prevented by approximately 4-fold. Combined, these factors appear to result in a 30-fold underestimate of the number of hepatitis A infections prevented by vaccination. Thus, the reported ratio of $23 million per death averted may be only $767,000 per death averted. In the United States, the median age of HCV-positive persons is approximately 40 years,8 at which life expectancy is 38 additional years.9 Hepatitis A vaccination of HCV patients may therefore cost $20,175 per year of life saved, a ratio meeting conventional standards of cost-effectiveness.10 Of course, if chronic HCV patients have impaired life expectancies, fewer years of life would be saved by preventing fatal HAV infections. HCV patients may have increased rates of HAV seropositivity,11 meaning some reduction in predicted infection risk is appropriate. Age- and geographic-specific infection rates would provide useful information, as these factors strongly predict HAV incidence.3 Age-specific estimates of hospitalization, transplantation, and mortality would provide a more accurate assessment of disease outcomes.12 These factors should be considered in a revised cost-effectiveness analysis, which will likely conclude that hepatitis A vaccina-
RICHARD AYCOCK, M.D., F.A.C.G. Memphis Gastroenterology Group and Memphis Gastroenterology Endoscopy Center East Memphis, TN REFERENCE 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000; 31:834-839.
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.16179
873
874 CORRESPONDENCE
HEPATOLOGY October 2000
tion of HCV patients has a more attractive cost-effectiveness ratio. R. JAKE JACOBS Capitol Outcomes Research, Inc. Alexandria, VA
RAYMOND S. KOFF, M.D. University of Massachusetts Medical School Boston, MA REFERENCES 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000;31: 834-839. 2. Hadler SC. Global impact of hepatitis A virus infection: changing patterns. In: Hollinger FB, Lemon SM, Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore, MD: Williams & Wilkins 1991;14-19. 3. Hepatitis Surveillance Report Number 56. Atlanta, GA: Centers for Disease Control and Prevention, 1996. 4. Armstrong GL, Bell BP. Hepatitis A virus in the 20th century USA— estimated incidence of infection [Abstract]. Antiviral Ther 2000;5(Suppl 1):14. 5. Wiens B, Bohidar N, Pigeon J, Egan J, Hurni W, Brown L, Kuter BJ, et al. Duration of protection from clinical hepatitis A disease after vaccination with VAQTA. J Med Virol 1996;49:235-241. 6. Van Damme P, Thoelen S, Cramm M, De Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-451. 7. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, Andre FE. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis 1995;171(Suppl 1):S44-S49. 8. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-562. 9. Anderson RN, Kochanek KD, Murphy SL. Report of final mortality statistics, 1995. Monthly Vital Statistics Report; vol 45, no 11, supp 2. Hyattsville, MD: National Center for Health Statistics, 1997. 10. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? CMAJ 1992; 146:473-481. 11. Sjo¨gren MH. Preventing acute liver disease in patients with chronic liver disease. HEPATOLOGY 1998;27:887-888. 12. Berge JJ, Drennan DP, Jacobs RJ, Jakins A, Meyerhoff AS, Stubblefield W, Weinberg M. The cost of hepatitis A infections in American adolescents and adults in 1997. HEPATOLOGY 2000;31:469-473.
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.18856
Reply: We appreciate the insightful comments of Drs. Jacobs and Koff with respect to our recent cost-effectiveness analysis.1 Although we agree with several of their criticisms, appropriate changes in the model fail to alter our overall conclusion, that is, vaccination of North American patients with hepatitis C (HCV) against hepatitis A (HAV) is not cost-effective. We agree that the rate of infection used in our baseline analysis (10.3 cases per 100,000 population) should be adjusted to account for individuals with innate immunity to HAV. According to the Third National Health and Nutrition Examination Survey (NHANES-III), 33% of the US popula-
tion have serologic evidence of prior HAV infection.2 We also agree that the 20% reduction in the HAV infection rate to account for asymptomatic infections was inappropriate because these cases would not be identified by passive surveillance. Jacobs and Koff also recommend that the baseline rate be adjusted for under reporting of HAV infections. Although the CDC historically estimates that just one third of HAV cases are reported,2 this has not been a universal finding.3 Armstrong and Bell recently reported that upwards of 50% of icteric infections are captured by passive reporting.4 Because the primary focus of our study is the patient with symptomatic infection who requires hospitalization (a minimum of 5 days in our study), and consumes health care resources, we feel that a doubling of our infection rate is appropriate. The result of these changes is a 3.75-fold (1.5-fold ⫻ 1.25-fold ⫻ 2-fold) increase in the baseline rate of infection to 38.6 cases per 100,000 population. Regardless, the incidence of HAV infection was varied over a wide range (up to 1% annually) in our sensitivity analysis, without a change in our overall conclusion. Jacobs and Koff also suggest that the duration of our model is too short, underestimating the long-term benefits afforded by HAV vaccination. We chose a conservative 5-year time horizon for our model because of current uncertainties in the longevity of vaccine-induced protection in patients with chronic liver disease, including those with HCV. A recent study by Koff et al.5 investigating HAV vaccination in such patients showed similar seroconversion rates between subjects with HCV and controls. However, the geometric mean titers observed in the HCV group were on average 2.8 times lower than those of controls (467 vs. 1,315 mIU/ mL, respectively; P ⫽ .001). The kinetic models of antibody decline referred to by Jacobs and Koff6 were actually derived using normal subjects and, hence, do not apply to HCV patients (with a proven reduction in humoral response to HAV vaccination). In any event, applying the reductions in antibody titers projected by these kinetic models to the geometric mean titers reported by Koff et al., predicts the maximum mean duration of vaccine-induced immunity to be 10 to 13 years. Thus, the 20-year duration of protection suggested by Jacobs and Koff is overly optimistic. Jacobs and Koff calculated a cost-effectiveness ratio of $20,175 per year of life saved by assuming that the average American HCV patient has an additional life expectancy of 38 years, no different from the average uninfected individual. Unfortunately, they did not adjust for the impaired healthrelated quality of life (HRQOL) shown in patients with chronic HCV.7,8 This adjustment is critical. Younossi et al.8 recently reported a mean utility of 0.75 in HCV patients. Thus, 38 years of additional life expectancy in a patient with HCV is the equivalent of 28.5 years spent with perfect health (qualityadjusted life years [QALYs]). Incorporating these adjustments to the incidence of HAV infection, doubling the time horizon of our model to 10 years, and adjusting for the impaired HRQOL of patients with HCV, we calculate that the undiscounted incremental cost-effectiveness of the universal and selective strategies are $113,661/QALY and $95,480/QALY, respectively. These figures are clearly higher than those conventionally reported as cost-effective.9 In addition, discounting of future costs and discounting QALYs would have an additional negative influence on these already prohibitive cost-effectiveness ratios. We also appreciate the uncertainty that Dr. Aycock exhibits in his interpretation of the results of this cost-effectiveness analysis.
HEPATOLOGY Vol. 32, No. 4, 2000
Indeed, all such publications that have the potential to impact health care policies place physicians on seemingly uncomfortable middle ground. On one hand, we must act as patient advocates and do what we feel is in the best interest of our patients, in this instance, provide “a simple vaccine” to prevent morbidity and potential mortality. On the other hand, the medical community is aware of, and must function within, the finite financial resources that are inherent in any health care system. Dr. Aycock outlines this dilemma and the associated frustration that accompanies the interpretation of cost-effectiveness analysis. The analogy that Dr. Aycock utilizes however is dubious at best. The legal and financial obligations of a manufactured problem are clearly different. After all, physicians did not knowingly “infect” patients with HCV, nor do we market a consumer product for profit. The manufacturing company referred to by Dr. Aycock had “secretly” calculated the costs that would be incurred, with and without correcting the manufactured defect. In our analysis, we have provided this financial information “up front” and have made this information available to be utilized not only by individual physicians, but also by policymakers who will need to make conscientious decisions for the good health of society. Our report considers health care costs from a global perspective, and as such there must be strategies to appropriately ration these finite resources. The incidence of HAV infection in North America is low and spending an exorbitant sum, $23 million, from a limited health care budget to save one individual’s life could be considered inappropriate. There are many illnesses that may result in rare deaths, yet it is not acceptable to prevent these rarities if the cost associated in doing so is prohibitive. In a previous analysis, Jackson et al.10 evaluated routine vaccination of college students against meningococcal disease. This strategy would prevent rare fatalities from this disease, yet the millions of dollars that it would cost to accomplish this prohibit the implementation of such a policy. Dr. Aycock seems to imply that society as a whole has unlimited financial resources and, hence, we should provide the “simple vaccine” to all of our chronic HCV patients. If that were true, then we would suggest not only vaccination of HCV patients, but provision of HAV vaccination for every individual worldwide. This strategy would clearly impact the worldwide mortality associated with this infection. Physicians and policymakers must promote medical care that yields not only beneficial clinical outcomes but also achieve acceptable costs. By way of example is the recommendation by the ACIP for routine pneumococcal vaccination for elderly people. This practice not only leads to improved health but it will actually save money.11 Unfortunately, vaccination rates remain poor despite the noted benefits. In contrast to this example, we have shown that the strategy of providing HAV vaccination to all susceptible patients with chronic HCV does not fulfill these criteria. We do expect that the ACIP will reconsider its recommendation that all patients with chronic HCV are provided with vaccination against HAV. Before this chapter is considered closed, however, several questions need to be answered. (1) What is the true incidence of HAV infection in patients with chronic HCV? In this regard, long-term, prospective, serologic studies of unvaccinated North American pa-
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tients are sorely needed. As suggested by Jacobs and Koff, age- and geographic-specific rates of infection would strengthen any analysis of the cost-effectiveness of HAV vaccination. (2) What is the course of HAV superinfection in patients with chronic HCV? Again, studies must investigate age-specific rates of hospitalization, liver transplantation, and mortality associated with acute HAV infection in this population. However, the rarity of these events will certainly complicate this task. (3) For how long does HAV vaccination confer protection in patients with chronic HCV? Long-term serologic follow-up of patients already vaccinated will help resolve this issue. We thank Drs. Aycock, Jacobs, and Koff for their comments, which clearly reveal the pitfalls of a cost-effectiveness analysis as it pertains to individual physicians. While physicians must continue to do what is in their patients’ best interests, they must do so by objectively evaluating the best available evidence without ignoring the associated costs of their actions. ROBERT P. MYERS, M.D. JAMES C. GREGOR, M.D. PAUL J. MAROTTA, M.D. Division of Gastroenterology and Hepatology University of Western Ontario London Health Sciences Centre, University Campus London, Ontario, Canada REFERENCES 1. Myers RP, Gregor JC, Marotta PJ. The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. HEPATOLOGY 2000;31: 834-839. 2. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1-30. 3. Alter MJ, Mares A, Hadler SC, Maynard JE. The effect of underreporting on the apparent incidence and epidemiology of acute viral hepatitis. Am J Epidemiol 1987;125:133-139. 4. Armstrong GL, Bell BP. Hepatitis A virus in the 20th century USA—estimated incidence of infection [Abstract]. Antiviral Ther 2000;5(Suppl 1):14. 5. Keeffe EB, Iwarson S, McMahon BJ, Lindsay KL, Koff RS, Manns M, Baumgarten R, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. HEPATOLOGY 1998;27:881-886. 6. Van Damme P, Thoelen S, Cramm M, DeGroote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-451. 7. Ware JE, Bayliss MS, Mannocchia M, Davis GL, and the International Hepatitis Interventional Therapy Group. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. HEPATOLOGY 1999;30:550-555. 8. Younossi AM, McCormick M, Boparai N, Price L, Guyatt G. Health-related quality of life in hepatitis C measured by generic, disease-specific and utility instruments [Abstract]. HEPATOLOGY 1999;30(Part 2):686A. 9. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utiliztion? Tentative guidelines for using clinical and economic evaluations. Can Med Assoc J 1992;146:473-481. 10. Jackson LA, Schuchat A, Gorsky RD, Wenger JD. Should college students be vaccinated against meningococcal disease? A cost-benefit analysis. Am J Public Health 1995;85:843-845. 11. Sisk JE, Moskowitz AJ, Whang W, Lin JD, Fedson DS, McBean AM, Plouffe JF, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA 1997;278:1333-1339. Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.18857
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HEPATOLOGY October 2000
Comprehensive Allelotype Study of Hepatocellular Carcinoma development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. HEPATOLOGY 2000;31:1246-1250.
To the Editor: We read with interest the comprehensive work of Okabe et al.1 on hepatocellular carcinoma (HCC) allelotyping, which showed that some markers (e.g., 4q and 13q) are lost in advanced cancer, others (6q) in early phases of hepatocarcinogenesis, and some in chronic hepatitis B virus infection. However, their reference was adjacent noncancerous liver tissue, which in 27 of 39 cases was diseased. It has been shown that clonal populations exist in cirrhotic liver with allelic loss at chromosomal sites.2-4 If the HCC and adjacent cirrhotic tissue have exactly the same allelic loss, then the loss of heterozygosity (LOH) index would be unity and specific loss could be missed. Because the missed losses would be those occurring both in cirrhosis and HCC, they may represent early changes that contribute to tumor initiation rather than to progression. Indeed, Kawai et al.5 in a similar study, recently showed that the LOH rate in HCC decreases significantly when nontumorous liver tissue is referenced instead of peripheral blood leukocytes (P ⬍ .02). Moreover, the prevalence of LOH in liver tissue adjacent to cancer was higher than in liver not harboring HCC. MASSIMO RONCALLI, M.D., PH.D. University of Milan Istituto Clinico Humanitas Rozzano, Italy MAURO BORZIO, M.D. Fatebenefratelly and Oftalmico Hospital of Milano Milan, Italy PAOLO BIANCHI, PH.D. Istituto Clinico Humanitas Rozzano, Italy LUIGI LAGHI, M.D., PH.D. Istituto Clinico Humanitas Rozzano, Italy REFERENCES 1. Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T, Katsura N, et al. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors. HEPATOLOGY 2000;31:1073-1079. 2. Yamada T, De Souza AT, Finkelstein S, Jirtle RL. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor 11 receptor is an early event in liver carcinogenesis. Proc Natl Acad Sci U S A 1997;94:1035110355. 3. Ashida K, Kishimoto Y, Nakamoto K, Wada K, Shiota G, Hirooka Y, Kamisaki Y, et al. Loss of heterozygosity of the retinoblastoma gene in liver cirrhosis accompanying hepatocellular carcinoma. J Cancer Res Clin Oncol 1997;123:489-495. 4. Roncalli M, Bianchi P, Ceva Grimaldi G, Ricci D, Laghi L, Maggioni M, Opocher E, et al. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. HEPATOLOGY 2000;31:846-850. 5. Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y, Waguri N, Kuroiwa T, et al. Quantitative evaluation of genomic instability as a possible predictor for
Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.17968
Reply: Dr. Roncalli et al. raise critical issues in allelotyping hepatocellular carcinoma (HCC). We believe that tumor-specific allelic changes contribute significantly to the carcinogenesis of HCC. We agree that the study of allelic changes in noncancerous tissues would provide valuable information concerning mechanisms of HCC carcinogenesis, but we have not examined this question yet. We wish to emphasize several inherent problems in allelotyping noncancerous tissue of the diseased liver: 1. Markers. To date, genome-wide allelotyping of noncancerous tissue in diseased liver has not been performed. Hence, investigators must evaluate the allelic changes in the diseased liver using an adequate number of microsatellite markers, which cover genome-wide changes. 2. Samples. Dr. Roncalli et al. refer to their own study published in HEPATOLOGY in which they extracted DNA from paraffin-embedded samples. Paraffin-embedded samples should be avoided in allelotype studies of this type, because these samples contain severely fragmented DNA, which increases the incidence of false-positive detection of loss of heterozygosity. 3. Pathologic Characterization. Noncancerous tissue of the diseased liver encompasses a range of findings from almost normal histology to precancerous, severe dysplastic nodules. Therefore, the noncancerous tissues must be stratified into categories according to precise pathologic evaluation and numbers of cases. 4. Selection of the Sampling Sites. Several studies have shown that cirrhotic nodules may harbor allelic losses. However, the pattern of allelic losses differs among nodules. In different lesions within the same liver, only one or few nodules may progress to HCC while others remain noncancerous. Therefore, to identify the critical LOH loci that contribute to hepatocarcinogenesis, one must examine highly susceptible lesions. For example, a nodule harboring an early stage tumor (so-called nodule-in-nodule type) would be optimal. Once these points are satisfied, allelotyping of the noncancerous tissue in diseased liver will greatly contribute to the study of HCC. HIROSHI OKABE, M.D. IWAO IKAI, M.D., PH.D. KOICHI MATSUO, M.D. SEIJI SATOH, M.D., PH.D. YOSHIO YAMAOKA, M.D., PH.D. Department of Gastroenterological Surgery Kyoto University Graduate School of Medicine Kyoto, Japan Copyright © 2000 by the American Association for the Study of Liver Diseases. doi:10.1053/jhep.2000.17968