Chronic Hepatitis C: An Age Wave of Disease Burden

Published Online: October 15, 2005
Based on a presentation by John G. McHutchison, MD; and Bruce R. Bacon, MD

There are at least 2.7 million individuals in the United States, most of them in their 40s and 50s, who are chronically infected with hepatitis C virus (HCV). As these infected individuals get older, about 20% will develop cirrhosis, and a significant fraction of those with cirrhosis (about 1 in 10) will then develop serious decompensated liver disease or hepatocellular carcinoma. Currently, HCV is the primary cause of death in 8000 to 12 000 people every year; the virus is also the primary reason for liver transplantation in the United States. Although the number of new cases of HCV infection has been dropping steadily since the introduction of improved blood-supply screening, the "age wave" of existing chronic HCV in baby boomers is expected to contribute to a substantial rise in morbidity, mortality, and costs over the next 2 decades. Although it is difficult to predict which HCV-infected patients will progress to serious liver disease, the availability of a combination drug regimen (peginterferon alfa plus ribavirin) that essentially "cures" the disease in more than half of treated patients now provides clinicians and pharmacists in managed care settings with the tools needed to diminish the impact of the anticipated wave of liver disease. This article reviews the epidemiology, natural history, clinical and economic burden, and screening and treatment options for HCV.

(Am J Manag Care. 2005;11:S286-S295)

With the availability of effective interferon-based therapies, the fight against hepatitis C virus (HCV) has expanded from a public health-oriented focus on prevention and treatment of mainly the highest-risk ideal patient types to earlier diagnosis and drug therapy for a wider range of potentially difficult-to-treat patient types. This evolving treatment approach requires new strategies for patient risk assessment, cost-effectiveness analysis, and therapy initiation and monitoring. This article lays the groundwork for understanding these new strategies by reviewing the epidemiology, virology, burden, and therapy options of HCV.


HCV is the most common long-term blood-borne infection in the United States.1 Based on a widely-cited population survey of anti-HCV antibody, the Centers for Disease Control and Prevention (CDC) estimate that 3.9 million (1.8%) Americans have been exposed to HCV; tests for viral ribonucleic acid (RNA) in the serum indicate that 2.7 million Americans have long-term infection.1-3 Because many high-risk populations—such as prisoners, intravenous drug users, and homeless people—are generally excluded from national surveys, such estimates of HCV prevalence are likely conservative.4 A recent study of 597 homeless veterans, for example, found an anti-HCV prevalence of 42%.5

Whatever the actual absolute number of chronically-infected individuals with HCV, the problem for clinicians and healthcare systems is compounded because these individuals often remain undiagnosed. Infection with HCV is usually clinically silent not just during the acute phase but for decades afterwards.6,7 As many as three quarters of all currently-infected patients have not been identified. Without knowing who is chronically infected, early risk reduction (eg, through counseling on alcohol and weight loss) and targeted drug treatment to avoid liver complications are not possible.

Who are these infected individuals? Most of the millions who are chronically infected with HCV are now in their fourth or fifth decade of life. As they move into their 60s and 70s, these individuals constitute an "age wave" of asymptomatic HCV infection that is headed toward clinical disease.3 Presumably, many of these baby boomers were infected in the 1960s and 1970s after experimentation with injection drug use. Administrators and clinicians in all socioeconomic settings should note that this category includes many individuals who used drugs only briefly many years ago.8 A recent retrospective population-based study done in a national managed care organization (MCO) confirms this peak prevalence of chronic HCV infection among those members who are 45 to 54 years of age (Figure 1).9 Rates of HCV infection are also generally higher among men and African Americans.10


This phenomenon of an aging generational cohort of HCV-infected patients is also a result of the rapidly declining incidence of new HCV infections over the past 25 years. The number of new infections per year has declined from an average of 240 000 in the 1980s to about 30 000 in 2003.11 Among 25- to 39-year-olds—historically the age group with the highest rate of infection—the incidence has declined by 86% from 1992 to 2002.1 These positive trends can be attributed to improved blood donor screening (available since June 1992) and the related reduction in transfusion-associated cases, but even more so to safer needle practices among injection drug users due to concern about infection with human immunodeficiency virus (HIV).1

Currently, the main risk factor for HCV transmission is injection drug use involving shared, unsterilized, or poorly sterilized needles and syringes (Figure 2).10,12,13 Anyone who has ever injected illicit drugs should be tested.14 Sexual transmission is the next largest cause of HCV infection. Although patients and spouses should be reassured that the risk of transmission in a stable monogamous relationship is less than 5%,8 they should also recognize that people with high-risk sexual behavior, multiple partners, and sexually transmitted disease are at increased risk for HCV infection.8,10,13,14 Although the current prevalence among persons with hemophilia is extraordinarily high due to exposure to clotting factor concentrates produced before 1987 and/or blood transfusions before 1992, the number of new cases attributable to tainted blood products is vanishingly low. Other minor categories of risk include pre-1992 blood transfusions for any purpose, current exposure to blood products (eg, transplant patients, chronic renal failure), infants born to HCV-infected mothers (overall risk of maternal-infant transmission is 5%), and needle-stick accidents among health workers. Some studies have suggested risk of HCV transmission with percutaneous exposures, such as acupuncture, body piercing, and tattooing, but these risks are considered low.14


Overall, HCV prevalence ranges from very high (~90%) in groups such as injection drug users and persons with hemophilia, to moderate (~10%) in recipients of blood transfusions before 1992, and to low (2%-5%) in those exposed by needle stick and sexual partners of HCV-infected persons. The current CDC guideline on who should be routinely tested for HCV infection (Table 1)10 reflects this overall understanding of HCV transmission risk and prevalence.13,14


Natural History

HCV is a small single-stranded RNA virus (family Flaviviridae) with a preference for hepatocytes. Its propensity for frequent mutations allows the virus to evade a vigorous cell-mediated immune response to the initial infection. This weak early response of T cells appears to set the stage for long-term infection.4 There are 6 major strains or genotypes of HCV and at least 50 subtypes. These genotypes have different geographic distributions, with types 1a and 1b being the most common in the United States (accounting for about 75% of cases) and genotypes 2 and 3 present in about 10% to 20% of patients.8 These subtypes are clinically relevant—and now routinely determined in testing—because genotypes 2 and 3 are very susceptible to current combination therapy regimens whereas genotype 1 has a lower response rate to interferon-based therapies.

Most patients have no signs or symptoms of acute HCV infection. In those rare patients where acute symptoms can be tracked (eg, a hospital worker with a needle stick injury who is being closely monitored), symptoms appearing a few weeks after exposure may include jaundice, fatigue, anorexia, weakness, dark urine, or abdominal pain.1 Even if such symptoms are present, they are frequently mild, nonspecific, or intermittent. After initial exposure, blood tests typically reveal HCV RNA within 1 to 3 weeks and elevated serum alanine aminotransferase (ALT), which indicates liver injury, within 4 to 12 weeks; at least 90% of patients will have a positive antibody test 3 months after HCV exposure.4

Currently, the enzyme immunoassay for anti-HCV antibody is performed at the initial screening test and then, in most cases, the HCV RNA test is performed to confirm viremia. These RNA tests using the polymerase chain reaction technique are extremely sensitive and almost all patients with chronic HCV will test positive. Both the quantitative HCV RNA test and the ALT may be useful in monitoring disease severity or progression and, even more practical, in gauging response to antiviral therapy with serial measurements.4

Progression from acute to chronic infection occurs in 50% to 85% of cases.15,16 The 15% or more of patients who are able to "clear" the virus spontaneously are of great interest to researchers. Understanding the mechanisms of this natural immunity to HCV may eventually lead to creation of an effective preventive or therapeutic vaccine. Chronic infections are often defined not by symptomology (they are also usually clinically silent) but by the persistence of HCV RNA in the blood for 6 months or longer.4,13 This asymptomatic long-term phase lingers over a period of decades and, in many cases, over a lifetime.

In some individuals, however, chronic HCV infection sets the stage for progressive liver fibrosis and scarring. The factors that accelerate this steady attrition of functioning liver cells include alcohol use, nonalcoholic liver disease, coinfection with HIV or hepatitis B virus, and male sex. However, it is impossible to predict which patient with chronic HCV infection will progress rapidly to full-blown cirrhosis. Overall, about 20% of patients with chronic HCV infection will eventually develop cirrhosis, which may itself remain clinically silent until advanced disease or added risk factors produce overt hepatic decompensation. Alternatively, even without development of frank cirrhosis and liver complications, patients with chronic HCV infection may suffer from chronic fatigue or decreased quality of life.4,17,18

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