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Understanding Hepatitis C John G. McHutchison, MD
Abstract There are at least 4 million cases of hepatitis C virus (HCV) infection in the United States (overall prevalence 1.8%, with many of these patients unaware of their infection) and 170 million worldwide. The consequences of this virus account for 10 000 deaths every year in the United States. HCV is the primary reason for liver transplantation in this country. Most new cases are now acquired through the use of illegal injection drugs (68%) or potentially sexual transmission (18%). Although the incidence of HCV infection has dropped sharply since the early 1990s because of improved blood-supply screening, the infections that were acquired from the 1960s to the 1980s are likely to dramatically increase the morbidity, mortality, and costs of HCV disease over the next 2 decades. A proportion of these individuals with long-term HCV infection will develop cirrhosis, decompensated liver disease, or hepatocellular carcinoma (HCC). These increases in HCV-related end-stage liver disease and HCC will have significant implications for clinicians and pharmacists in managed care settings. This article reviews the virology, serology, epidemiology, natural history, and the current and projected future disease burden of HCV in the United States. (Am J Manag Care. 2004;10:S21-S29).
o understand the role of the hepatitis C virus (HCV) in progressive liver damage, cirrhosis, and hepatocellular carcinoma (HCC), it is helpful to review the virology and epidemiology of HCV as well as the serological response to HCV infection and the typical natural history, pathology, and time course of HCV disease progression. These varying perspectives on HCV infection provide the necessary broad base for subsequent exploration of current recommendations for managing this increasingly problematic disease. As will become clear in
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Dr Bacon’s accompanying review of HCV therapy, many critical HCV treatment decisions will hinge on a clinician’s or a patient’s estimate of the likelihood of disease progression and treatment success. This article reviews the many factors that feed into the complex calculus for predicting HCV progression and therapy success—and that therefore may assist the clinician in recommending the best course of action for individual patients. Much of the information in this article is adapted from the 2002 consensus statement from the National Institutes of Health (NIH) on Management of HCV.1 Readers are referred to that full publication for more details. A downloadable copy of the formal published NIH conference proceedings is available at: http://consensus.nih.gov/cons/ 105/105_statement.pdf. The Hepatitis C Virus
Hepatitis C is a small blood-borne ribonucleic acid (RNA) virus of the family Flaviviridae. This “non-A non-B” virus was first identified in 1989 by researchers in the San Francisco Bay area.2,3 The RNA genome is 9600 kilobases in length and encodes a single large polyprotein that is cleaved posttranslationally into at least 4 structural proteins and 6 nonstructural proteins (Figure 1).4 The HCV replicates preferentially in hepatocytes but is not directly cytopathic.5 The virus mutates frequently as it replicates and spreads from cell to cell, a shifting that may explain the lack of a vigorous T-cell response to HCV infection as well as the historic difficulty in treating this infection. The virus is transmitted primarily through large or repeated direct exposure to blood.6
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REPORTS Response rates of the other genotypes are less certain because these are much less common in the United States (20 years
2.0 1.0 0 1960 1970 1980 1990 2000 2010 2020 2030
Year Source: Reference 16. HCV indicates hepatitis C virus.
liver disease or HCC and lost life could approach $75 billion.32 Even allowing for the difficulties in capturing actual direct institutional HCV costs and for the inherent complexities of projecting future expenses based on current epidemiologic data, the trend is clear: managed care organizations will spend more money per member per year for HCV over the next 2 decades. The annual costs for HCV are already approaching those of other more widespread long-term diseases such as asthma35 and peptic ulcer disease.33 Between now and 2020, as just reviewed, the costs of managing HCV will increase significantly. With the recent introduction of a combination-therapy regimen that effectively abolishes the risk of liver disease in more than half of those harboring the virus, increasing numbers of HCV-positive health plan members will become potential Figure 8. Projections of HCV Disease Beyond 2000 4 3
Millions
steadily over the past 5 years while the number of available cadaveric livers has remained steady at about 4000 to 5000 per year. Looking ahead, the burden of HCV infection and cirrhosis as reflected in hospitalizations and need for transplantation is likely to accelerate. Although the overall prevalence of HCV infection is now thought to be declining—the near-term payoff for the rapid decline in incidence in the 1990s—the number of persons infected for more than 20 years could increase substantially before peaking in the year 2015 (Figure 7).16 This “bulge” of patients infected from the 1960s to the 1980s will have maturing HCV infection over the next 20 years and produce a parallel increase in clinical liver disease. This phenomenon of aging HCV infections, or “HCV gero-seropositivity,” explains why even as the overall prevalence of HCV infection declines over the next several decades, the rate of HCV cirrhosis is projected to rise (Figure 8).34 In other words, although the absolute number of patients with HCV infection will drop gradually, the percentage of these patients with ongoing long-term infections will increase and, hence, so will the relative rate of progressive cirrhosis in this population. Based on Medicare and other government and private data sources, one researcher estimated US HCV costs in 1997 at $5.46 million.34 One third of this national total went to direct health costs and two thirds went to indirect costs (for example, lost earnings); these estimates are considered conservative since costs related to diminished quality of life were not added. Approximately 92% of the total was spent on long-term liver disease while 8% was attributable to liver cancer. Separate calculations made for the year 1998 estimated HCV-related hospital costs at approximately $1 billion28 and antiHCV drug costs at $530 million.33 Based on the impending wave of HCV gero-seropositivity, the mortality, morbidity, and costs related to HCV are all expected to increase substantially over the next 10 to 20 years.15,31 One economic model predicts that from 2010-2019, there will be $10.7 billion in HCV-related direct medical expenditures (Figure 9). The harder-to-measure indirect societal costs for years of decompensated
2 1
HCV Infection
15.6%
Cirrhosis 0 1998
28.9%
23.7%
30.4%
29.5%
Assumes continuation of current incidence
2008
2018
2028
2038
Year Source: Reference 34. HCV indicates hepatitis C virus.
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Medical Care Costs ($ Billion/y)
Figure 9. Future Costs for Hepatitis C 16 14 12
High Base Case Low
10 8 6 4 2 0 1992 1996 2000 2004 2008 2012 2016 2020
Year Source: Reference 32.
candidates for an expensive course of drug treatment. The safety, efficacy, and potential cost effectiveness of this treatment regimen will be outlined in the accompanying article. Who to Treat?
As the inevitable wave of HCV disease burden approaches, clinicians and administrators will seek strategies to target screening, counseling, and provide therapy for those health plan members most at risk of cirrhosis and HCC. As made clear in this brief overview of the varying natural histories of HCV (Figure 6)—and notwithstanding the growing recognition of the psychological consequences of long-term hepatitis—only about 15 to 20 of every 100 individuals exposed to HCV will develop cirrhosis over 30 years of HCV infection, and the majority of those individuals with cirrhosis will remain stable over an extended period of 10 or more years, or compensated for the remainder of their Figure 10. Future Risk of Progression 100
Cirrhosis (%)
80 60 40 20 0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Years Mild
Source: Reference 36.
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Moderate
Severe
lives. How can clinicians and healthcare systems target counseling and treatment on those patients most likely to develop decompensated liver disease and HCC? Liver biopsy remains the traditional measure of predicting the risk of future progression. The degree of fibrosis as seen on biopsy is directly correlated with the subsequent rate of progression (Figure 10).36 Although all patients with long-term HCV are potential candidates for antiviral therapy, treatment is generally recommended for those with an increased risk of developing cirrhosis. The current NIH guidelines define these high-risk patients as those with detectable HCV RNA levels higher than 50 IU/mL and a liver biopsy with portal or bridging fibrosis and at least moderate inflammation and necrosis.7 Thus, almost all patients receiving HCV combination therapy today have had a liver biopsy. Liver enzymes or symptoms are not considered adequate guides to initiating therapy. Since patients with HCV genotypes 2 or 3 have much higher chances of treatment success (80%), a liver biopsy in these patients may not always be necessary to make these initial treatment decisions.7 Of course, many other factors shape the decision to treat HCV infection. These include the likelihood of side effects and patient adherence, patient age, the extent of liver damage, and the presence of comorbidities, coinfections, and contraindications. These and other treatment-related considerations will be discussed in the accompanying article. In addition, clinicians and pharmacists need to realize that the treatment decision is no longer an all-or-nothing proposition. New “stopping rules” to determine when to abort therapy early in patients not likely to benefit are increasingly providing clinicians with a compromise approach that can avoid drug side effects and save money. As clinicians weigh the potential for a permanent HCV cure against the risks of side effects and the substantial costs of therapy, clinical judgment and access to the evolving clinical evidence base will remain key. Ideally, fully informed patients make the final decision on whether or not to embark on a course of HCV therapy. In reality, the clinician and the health system remain responsible for shaping these decisions.
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Understanding Hepatitis C Over the next 2 decades, the collective clinical and economic effects of these decisions—hundreds of thousands of them made one by one, patient by patient, in clinics and hospitals throughout the United States—will resonate widely.
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