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Projecting future complications of chronic hepatitis C in the United States
  Summary: Chronic hepatitis C virus (HCV) infection is common and often results in slowly progressive liver disease. Although acute hepatitis C is now uncommon, most patients with acute infection have developed chronic hepatitis, and, therefore, the pool of infected patients is large. We used a modification of a previously described natural history model for HCV infection to project the number of cases of HCV infection, cirrhosis, and liver failure over the next 40 years. The model estimated the prevalence of HCV infection in the United States was 3.07 x 106 (3 million) in 1993 (compared with an adjusted National Health and Nutrition Evaluation Survey (NHANES) III estimate of 2.8 to 3.5 x 106). A gradual decline in the prevalence of infection should occur by year 2040 because of aging and natural deaths among the infected pool. However, as the duration of infection increases in the surviving cohort, the proportion with cirrhosis will increase from 16% to 32% by 2020 in an untreated population. Complications of cirrhosis also will increase dramatically over the next 20 years: hepatic decompensation (up 106%), hepatocellular carcinoma (up 81%), and liver-related deaths (up 180%). Although current treatment regimens eradicate HCV in over 50% of cases, many more patients would need to be treated to significantly impact disease progression. Identification and treatment of every case of HCV infection (with or without cirrhosis) would reduce the number of cases of decompensated cirrhosis by almost half after 20 years. Despite the declining incidence of acute HCV infection, chronic hepatitis C is common. The prevalence of cirrhosis and the incidence of its complications will increase over the next 10 to 20 years, because the duration of infection increases among those with chronic hepatitis C. These data emphasize the need for greater access to transplantation by expansion of the donor pool, increasing use of split livers and living donors, and novel options such as xenotransplantation. (Liver Transplantation April 2003;9:331-338.)
editorial note: although the parargraph above refers only to the need for greater access to transplantation, without adequate access to testing, treatment, and care deaths and sickness will similarly increase. Right now there is little funding to support HCV testing, alcohol counseling, counseling, education for doctors & patients, public awareness, and expanding the care infrastructure to absorb patients.
A population survey a decade ago estimated that nearly 4 million Americans have detectable antibody to the hepatitis C virus (HCV). In fact, this number may be a significant underestimate of the true prevalence because certain high prevalence groups, such as prisoners and other institutionalized persons, were not included in the survey.2 Most of those infected with HCV acquired the disease 10 to 20 years ago, before identification of the virus and the availability of screening tests. The recognition of potential risk factors and the improved safety of the blood supply have led to a dramatic decrease in the incidence of new HCV infections in recent years. However, the overall prevalence of chronic infection has not fallen because most acutely infected patients develop chronic infection. Because liver disease caused by hepatitis C progresses slowly and does not result in major morbidity for many years, we are only now beginning to see the magnitude of the consequences of chronic infection.
Patients with chronic hepatitis use health care resources in obvious and direct ways such as clinic visits, diagnostic tests, drug therapy, hospitalization for management of complications of cirrhosis, and liver transplantation. Also, there are indirect costs related to lost work time and impaired quality of life. Although the current economic impact of chronic hepatitis C is substantial, there are few published studies. Cirrhosis caused by chronic hepatitis C currently accounts for 8,000 to 12,000 deaths per year in the United States and it is the leading indication for liver transplantation.
The current burden placed on the health care system by HCV infection is relatively small considering the prevalence of infection. However, as the large pool of currently infected patients age and their disease has time to progress, more patients may develop complications of liver disease and the burden on the health care system will increase as a result. Thus, the purpose of this study was to use a previously described and validated mathematical model of the natural history of chronic hepatitis C to project the future prevalence of chronic hepatitis C, the incidence of complications related to cirrhosis, and the potential impact of treatment on these events.
The previously described projections of HCV-related disease and its complications assume that no treatment was provided. Therefore, we examined the effect of treating some of the patients with chronic hepatitis C. It is not known what proportion of HCV-infected patients currently receive or could be identified to be considered for therapy or would be acceptable for treatment. One survey estimated that only 30% to 40% of infected patients in a Veterans Hospital population would be optimal candidates. Given these uncertainties, we modeled the effects of treating various proportions between 10% (a minimum estimate) and 70% (perhaps the maximum proportion of potentially treatable candidates) of infected patients. Model projections show that identification and treatment of patients with chronic hepatitis C reduces the number of cases of decompensated cirrhosis in nearly direct proportion to the proportion of the cohort identified and treated.
Treating 10%, 50%, or 70% of all hepatitis patients with compensated liver disease would decrease complications of cirrhosis after 20 years by 5%, 24%, and 34%, respectively.
Initial experience with interferon monotherapy showed that SVR was unusual in patients with cirrhosis, and, therefore, many physicians chose not to treat them. However, recent data with combination therapy suggests that patients with fibrosis or cirrhosis respond nearly as well as others. Therefore, we assessed the long-term effect on complications of limiting combination treatment to those with or without cirrhosis. Treatment of all patients was the optimal strategy for reducing both decompensation and hepatic deaths (Table 2).
Table 2. Proportion of treatment-related reduction in hepatic decompensation accounted for by different subgroups of patients.
  However, because hepatic decompensation occurs only in patients with cirrhosis, treatment responses in patients with cirrhosis account for the early reduction in disease complications and hepatic death (an average of 88% of the reduction observed during the first 5 years). Therefore, excluding patients with cirrhosis from treatment would reduce considerably the potential benefit on disease morbidity and mortality that could be observed during the first 10 years after treatment. The benefits of treating patients without cirrhosis do not accrue until much later and do not match those gained from treating patients with cirrhosis until 11 years after initial therapy. Treatment of patients with mild chronic hepatitis would have little impact on the incidence of hepatic decompensation over the next decade, but would have a substantial impact thereafter, accounting for only 11.0% of the reduction after 10 years, but 31.9% of the reduction after 20 years and 58.5% of the decrease after 40 years (Table 2). Treatment of patients with persistently normal ALT levels would reduce disease complications very little (2.0% during the next 10 years; 6.7% after 40 years). Treatment of patients with persistently normal ALT levels would decrease the number of patients with cirrhosis by only 2.1% after 20 years compared with no treatment.
Discussion by authors
Using data derived from annual incidence rates, our model estimated that there were approximately 3.07 million people infected with HCV in the United States in 1994, a figure similar to the estimate of the NHANES III survey. Mathematical modeling estimates that the total number of HCV infected cases will decrease gradually in coming years as the incidence of new infection falls and currently infected patients die from nonhepatic, age-related causes. However, the large pool of surviving patients remains at risk of progressive liver disease as the duration of their infection increases. Indeed, the model predicts that an expanding proportion of the patients with chronic hepatitis C will develop cirrhosis over the next 2 to 3 decades, doubling the current percentage by the year 2020. As a result, there will be a dramatic increase in the number of cases with complications of liver failure, hepatocellular carcinoma, and death caused by liver disease. In fact, these changes may already be occurring. Although our model did not show a significant increase in disease complications in the last decade of the twentieth century, others have reported an increase in hepatocellular carcinoma and liver failure in patients with chronic hepatitis C.
Interferon-based treatment regimens with the combination of pegylated interferon and ribavirin result in sustained loss of HCV in approximately half of treated cases.31,32 Viral eradication is associated with reduction in hepatic fibrosis, and, therefore, successful treatment might be expected to reduce future disease complications. However, despite the impressive results in clinical trials with pegylated interferons and ribavirin, many patients are unaware of their infection, are not candidates for treatment, are unable to complete the course of treatment, or fail to respond. Considering these factors and assuming that at most perhaps half of patients could be identified and treated, we predict that the most we could expect from aggressive treatment at the optimal doses and duration of medication would be a 24% reduction in the incidence of decompensated cirrhosis after 20 years. This goal is best accomplished by giving highest priority to treating patients with moderately severe inflammation or fibrosis. Our model did not consider that patients who do not permanently clear virus might benefit from treatment with a reduction in the rate of fibrosis as has been reported by some investigators. This theory remains unproven and is currently being evaluated in long-term clinical trials. Thus, our projections might underestimate the potential long-term benefit of treatment. Nevertheless, our data show that current therapy and practice patterns that identify and treat a relative minority of infected patients will not be sufficient to control the future complications of this infection.
Identification and treatment of a larger proportion of infected patients, education about the importance of abstinence from alcohol (the most important risk factor for disease progression), and development of better tolerated therapies may help to achieve a more meaningful impact on the morbidity and mortality of this disease. Altough this may support recent calls for look-back programs for transfusion recipients or large scale screening programs, such strategies have large up-front costs.37 However, the costs of screening and treatment may well be offset by reducing the later costs of treating the complications of cirrhosis, which have been estimated to exceed 1 billion dollars per year. Indirect costs, including productivity loss and other societal losses, could reach 7 to 8 billion dollars per year.38 Several studies have shown that treatment of chronic hepatitis C with either interferon alone or in combination with ribavirin is highly cost-effective.
Despite the effectiveness of current antiviral regimens, our model clearly shows that the majority of cases of cirrhosis are not prevented. Thus, the complications of cirrhosis will continue to increase over the next 20 to 30 years. The need for liver transplantation will continue to far exceed the capacity of transplant centers to handle the load. This clearly emphasizes the urgency in developing and enacting measures to increase the availability of transplant services through increased organ donation, use of living donors, or splitting cadaveric livers. Research in xenotransplantation and stem cell technology may provide future options for these patients.
Obviously, projections provided by mathematical models are limited by the accuracy of the model conditions and assumptions. We used conservative assumptions that were intentionally biased to underestimate disease complications whenever possible. However, our use of a general-population, age-adjusted, all-cause mortality rate may have resulted in an overestimation of disease complications by as much as 22%. Some evidence suggests that the nonhepatic mortality rate is higher in chronic hepatitis patients because of comorbid conditions and risk factors for other diseases. Furthermore, the model might have underestimated nonvirologic benefits of treatment, if they occur, because only SVR rates were used. Finally, we did not consider the likely availability of more effective therapies or increased transplant volume in the future. Nevertheless, the message is clear that an aggressive, proactive approach is needed to first identify, educate, and treat patients with HCV infection and, second, to increase transplant resources.
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