THE NATIONAL
HEPATITIS C INSTITUTE
The Hepatitis C Awareness & Prevention Campaign


Serving the Hepatitis C Community

 

Epidemiology

Hepatitis C virus (HCV) is a spherical, enveloped, RNA virus of the Flaviviridae family. Its genome is a positive, single-stranded RNA molecule that replicates at a rate of 10 trillion new virions per day. A highly heterogeneous virus, HCV has approximately 70% homology between all isolates. As HCV replicates, RNA-dependent polymerases often introduce random nucleotide errors, which over time, result in slow genetic evolution of the virus (Neumann, 1998). Six major genotypes and over 90 subtypes characterize this resultant HCV genetic diversity. The most treatment resistant genotype, HCV genotype 1, accounts for an estimated 75% of HCV infections in the United States (CDC, 1998). Furthermore, within individual patients, hepatitis C exists as a swarm of closely related variants known as quasispecies; preliminary data suggest that the complexity of the quasispecies may contribute to viral resistance to interferon-based therapies (Farci et al, 2001) (Figure 1).

Figure 1. Hepatitis C Virus.

Hepatitis C infects approximately 5% to 10% of the global population, or approximately 170 million persons worldwide. In the United States alone, roughly 4 million individuals are infected with HCV, with an average acquisition rate of 28,000 people per year.

Individuals who contract hepatitis C have an 85% chance of developing persistent or chronic HCV infection, which is associated with an increased risk of progressive liver disease leading to cirrhosis and, in some cases, hepatocellular carcinoma (HCC), end-stage liver disease (ESLD), or death. Currently, HCV-related liver disease is the leading indication for liver transplantation in the United States. The Centers for Disease Control and Prevention (CDC) estimates that there are 2.7 million chronically-infected HCV persons in the United States, accounting for more than 8000 to 10,000 deaths per year (CDC, 1998).

HCV Routine Screening Recommendations

Hepatitis C shares the transmission and behavioral risk factors associated with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, unlike HIV or HBV, sexual transmission of HCV is relatively inefficient, and while clearly possible, sexual transmission of HCV is uncommon. While transfusion of blood products was once an important route of transmission in the United States, the incidence of transmission has decreased dramatically with the implementation of antibody screening and, more recently, nucleic acid testing. Currently, injection drug use accounts for at least two thirds of new cases of HCV in the United States. While the incidence of HCV infection has decreased to less than 30,000 cases per year, the CDC estimates that nearly 2% of the US population is infected with HCV, with the highest prevalence rates observed among African American males (9%) and individuals between 30 and 49 years of age (Alter et al, 1999).

Based on the current understanding of HCV transmission, the CDC recommends routine HCV antibody screening among persons with acknowledged high-risk behaviors and for those who have experienced HCV exposure.

HCV Screening Recommendations

  • Persons who have ever injected recreational drugs, including those who experimented many years ago and who do not consider themselves drug users
  • Persons with certain medical conditions, including those who
    • Received clotting factor concentrates produced prior to 1987
    • Ever underwent chronic hemodialysis
    • Have persistently abnormal ALTs
  • Persons who received an organ transplant before July 1992
  • Persons who were notified that they received blood from a donor who subsequently tested positive for HCV infection
  • Persons who received a blood transfusion or blood component before July 1992
  • Healthcare, emergency medical, and public safety workers after needle stick, sharp, or mucosal blood exposure to HCV-positive blood
  • Infants over 12 months of age born to HCV-positive mothers.

Additionally, patients who test positive for HIV are included in this high-risk group. Related primarily to the mutuality of the IV drug use risk factor, the prevalence rate of HCV in the HIV-infected population is approximately 40% (MMWR, 1998).

Diagnostic Tools

Diagnostic assays for detection and assessment of infection with and exposure to HCV have become increasingly sensitive and specific with successive versions. Assays may be classified as either serologic tests, which detect antibodies formed against HCV-specific antigens, or virologic tests, which detect HCV RNA when active viral infection is present. Additional tests, such as liver biopsy, may be indicated to stage the progression of liver disease due to HCV infection.

Serologic tests, such as the second or third version anti-HCV enzyme immunoassay (EIA), are inexpensive, easy to perform, reliable, and specific when used on high-risk populations. Following acute infection with HCV, antibody response (ie, seroconversion) to HCV can be detected at approximately 10 weeks following exposure. It is important to note that a positive serologic assay indicates exposure and immune response to the HCV virus, but does not indicate whether the virus is active or resolved (MMWR, 1998). Accordingly, confirmatory testing is recommended for all persons with a reactive HCV EIA. In low-risk populations, such as blood donors, the positive predictive value of the EIA is limited and confirmation with an additional antibody test, the recombinant immunoblot assay (RIBA), may be recommended to determine a true positive test in this group. Conversely, in high-risk populations, such as injection drug users, the positive predictive value of the EIA is excellent, and confirmation with specific virus testing is recommended.

Virologic tests, such as the polymerase chain reaction (PCR) and the branched-chain DNA (bDNA) assays, can be either qualitative (detecting the presence or absence of HCV RNA) or quantitative (determining the number of HCV RNA copies per milliliter of serum). Hepatitis C RNA may be detected as early as 1 to 2 weeks following HCV exposure, and typically is detectable in those with chronic HCV infection. Since PCR assays are not well standardized in their specificity and sensitivity, it is important to use the same testing methodology when monitoring the course of HCV treatment (MMWR, 1998).

Following confirmation of active infection (ie, the detection of plasma HCV RNA), many hepatologists recommend liver biopsy to assess the degree of histologic disease progression. Histologic disease due to HCV can be classified in terms of grading (to assess the degree of necroinflammatory activity) and staging (to determine the amount and location of liver fibrosis). While there are many widely used classification systems, the Ishak-modified Knodell histological activity index (HAI) is commonly used in research and clinical practice. This system describes necroinflammatory activity using a grading scale of 0 to 18, where grade zero represents the absence of necroinflammation and grade 18 represents established portal inflammation, and using a staging scale of 0 to 6, where stage 0 represents the absence of hepatic fibrosis and stage 6 represents established cirrhosis.

References

Batts K, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Path. 1995;19:1409-1417.

Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morb Mortal Wkly Rep. 1998;47:1-39.

Farci P. Hepatitis C virus: the importance of viral heterogeneity. Clin Liver Dis. 2001;5:895-916.

Ishak K, Baptista A, Biancho L, et al. Histologic grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699.

Neumann A. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon alfa therapy. Science. 1998;282:103-107.

National Institutes of Health Consensus Development Conference Panel Statement. Management of hepatitis C. Hepatology. 1997;26(suppl 1):2S-10S.

Natural History

Figure 2. Natural History of HCV Infection.

Persistent viremia affects approximately 85% of those infected with HCV; some of these chronically infected persons will develop progressive liver disease (Figure 2). Some studies predict that progression to fibrosis and cirrhosis will occur in roughly 20% of patients, and further, progression to HCC will occur in 25% of fibrotic/cirrhotic patients. However, other individuals infected with HCV may have a cirrhotic-free course of illness without clinical consequence in their lifetime (Seeff, 2000).

In general, following acute infection, only 20% to 25% of individuals experience classic symptoms of hepatitis, and approximately 15% of infected individuals will clear hepatitis C viremia spontaneously (Alter et al, 1999; NIH Consensus Statement, 1997). Frequently among those with chronic hepatitis C, neither patients nor their healthcare providers recognize symptoms until the disease has progressed to decompensated cirrhosis. In a study of 2235 chronically-infected HCV patients with biopsy-detected hepatic fibrosis, Poynard and colleagues reported that rapid progression of hepatic fibrosis was associated independently with older age at time of infection (>40 years), male gender, longer duration of infection, and consumption of greater than 50 grams of alcohol daily (Poynard et al, 1997).

In a meta-analysis, Graham and coworkers found that HIV coinfection was associated with a 2-fold increased risk of cirrhosis and a 2-fold increased risk of ESLD compared to those without HIV infection (Graham, 2001). Conversely, virologic parameters, such as plasma HCV RNA level and HCV genotype, have not been associated with HCV disease progression. Based on these data, persons infected with HCV should be advised to abstain from alcohol. However, Wong and colleagues estimate that less than 5% of Americans with HCV infection are aware of their HCV status, and the majority have not been tested or diagnosed with chronic HCV infection (Wong et al, 2000). Accordingly, heightened HCV public health initiatives are needed to encourage the diagnosis and management of HCV.

Public Health Significance

Nearly 4 million Americans are chronically infected with HCV, representing a substantial public health burden. First, persons with chronic viremia provide a reservoir for ongoing HCV transmission, particularly among those who use injection drugs. Second, estimates suggest that the impact of HCV-related liver disease will increase dramatically over the next 10 to 15 years, with approximately 20,000 to 30,000 deaths due to HCV annually. Finally, the economic impact of HCV will increase significantly due to the cost of medical care for those with advanced liver disease and lost productivity of those with chronic illness. In fact, conservative estimates place the cost of HCV-related healthcare at nearly $600 million currently, and estimates indicate that without effective treatment, these costs will triple over the next 15 to 20 years. Wong and coworkers (2000) calculated that the indirect costs related to disability and mortality are projected at 3.09 million years of life lost. Societal costs of premature mortality of persons younger than 65 are predicted to be $54.2 billion, with disability costs from decompensated cirrhosis and HCC projected at $21.3 billion. It is likely that these figures underestimate morbidity and mortality costs, as they do not consider accelerated HCV progression in older patients, those with coinfection with HBV or HIV, or those individuals exhibiting excessive alcohol consumption. Figure 3 outlines the future long-term morbidity, mortality, and cost estimates that might be expected from cases of hepatitis C that existed before 1991 alone (Wong et al, 2000).
Figure 3. HCV-Related Projections for the Years 2010 to 2019.
 

References

Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States: 1988 through 1994. N Engl J Med. 1999;341:556-562.

Alter MJ. Epidemiology of hepatitis C in the West. Semin Liver Dis. 1995;15:5-14.

Management of Hepatitis C. NIH Consensus Statement. 1997;March 24-26:15(3).

Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus. Clin Infect Dis. 2001;33:562-569.

Hoofnagle J. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997;26:15SW-20S.

Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-832.

Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. 2000;132:105-111.

Wong J, McQuillan G, McHutchison J, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. American J Public Health. 2000;90:1562-1569.

Pharmacologic Management of Hepatitis C

When weighed against the economic and societal burden of potential future complications, treating the chronically-infected HCV patient prior to the onset of symptomatic disease favors a positive cost-benefit ratio and a notably reduced risk of cirrhosis, HCC, and ESLD.