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Scope of Worldwide Hepatitis C Problem
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Liver Transplantation, Vol 9, No 11, Suppl 3 (November), 2003: pp S10-S13
Robert S. Brown Jr and Paul J. Gaglio
From the Department of Medicine, Columbia University College ofPhysicians & Surgeons, and Center for Liver Disease and Transplantation,New York-Presbyterian Hospital, New York, NY.
Key Points:
1. Hepatitis C is a global health problem affecting over 170 million people worldwide.
2. There is wide geographic variation in both prevalence and genotype distribution of hepatitis C virus on a global level.
3. Most hepatitis C virus is spread parenterally, either through intravenous drug use or, in lesser-developed countries, through blood contamination during medical procedures.
4. Hepatitis C is a leading cause of end-stage liver disease and hepatocellular carcinoma.
5. Despite a declining incidence of new infections, the burden of disease, both in terms of mortality and in terms of cost, is expected to increase over the next decade.
Hepatitis C is a global health problem affecting a significant portion of the world’s population. The World Health Organization estimated that in1999, 170 million hepatitis C virus (HCV) carriers were present worldwide, with 3 to 4 million new cases per year. Based on data in blood donors from varying regions of the world, the infectivity rates range from 0.3% to 14.5%. The prevalence of HCV antibodies is relatively low in the United States, northern Europe, and Australia, ranging from 0.3% to 1.2% of the population. An increased prevalence of HCV ranging from 1.5% to 9% has been reported in Southeast Asia and the Indian subcontinent, with the highest rates of HCV (2% to 14%) present in northern and central Africa, the eastern Mediterranean, and the Ukraine. In many areas of the world, a lackof screening and case identification hinders adequate analysis of incidence and progression, and the true prevalence of HCV may be underestimated. The most comprehensive studies describing HCV prevalence are from the United States, Italy, France, and Japan. Hepatitis C is the second most common cause of chronic liver disease and hepatocellular carcinoma (HCC) worldwide after hepatitis B. In Western Europe and the United States, HCV is more prevalent than hepatitis B virus and rivals alcohol-related liver disease as the most common cause of end-stage liver disease. It is therefore not surprising that in these areas, end-stage liver disease caused by HCVrepresents the most common indication for liver transplantation and is a significant risk factor for HCC.
Incidence and Prevalence in the United States
Between 1982 and 1993, 16% of all cases of acute hepatitis in the United States were attributable to HCV. It is estimated that about 1.8% of the population carries the antibody to HCV, indicating previous or current infection with the virus. With a current US population of 274 million, it can be estimated that up to 4.9 million individuals have been infected. Based onestimates from the National Health and Nutrition Evaluation Survey (NHANHES) approximately 70% of HCV-antibody-positive patients will have evidence of chronic infection manifested as the presence of viralRNA in serum. Thus, HCV is presently the most common chronic blood-borne infection in the United States. Based on demographic data indicating that the majority of HCV infections occurred between the years 1960 and 1985, most antibody-positive individuals are between 30 and 50 years of age.
The incidence of new HCV infections in the United States has been declining steadily since 1985. In the mid-1980s, the incidence of HCV was greater than 100 cases per 100,000 people per year, which has decreased to the current incidence of less than 20 per 100,000, or 40,000 new infections per year in the United States. In 1995, approximately 25,000 newly acquired cases ofHCV were diagnosed. However, because of the chronicity of HCV infection in most individuals, the observed decline in new infections does not translate to an immediate decrease in the prevalence. Using mathematicalmodels, Armstrong et al estimated that the prevalence of HCV in the United States peaked in the mid-1990s at slightly above 2.0%, and they projectedthat the prevalence would slowly decline to 1.0% by 2030. Furthermore, the model predicted that the proportion of people with infection for 20 years or longer would increase with an anticipated peak in the mid-2010s. Indeed, there is a projected four-fold increase in the number of people with longstanding (more than 2 decades) infection between 1990 and 2015. It can thus be anticipated that the incidence of complications of end-stage liver disease caused by HCV, including manifestations of portal hypertension, decompensated liver disease, requirement for liver transplantation, andHCC, will similarly increase.
Transmission and Risk Factors
HCV is transmitted primarily through exposure to blood or blood products. In the United States, more than 50% of new cases are attributed to previous orcurrent use of illegal drugs, predominantly injected drugs and, to a lesser extent, intranasal cocaine. On a worldwide level, many cases are related to medical procedures, including blood transfusions, contaminatedvaccination needles, and hemodialysis. In Egypt, which has among the highest reported prevalence of HCV (15%), transmission is thought to have occurredwith needle reuse during a national program of schistosomiasis vaccination. Transmission has also been linked to folk remedies and other community-based needle practices, including acupuncture. The contributionof sexual and perinatal transmission of HCV as risk factors is controversial. Based on data in spouses, long-term partners of HCV-infected patients, and children born to HCV-infected mothers, sexual and perinatal transmission occur with low efficiency but are increased in patients co-infected with HIV. In addition, HCV may be transmitted more efficiently in the presenceof other sexually transmitted diseases and/or genital lesions. This may affect transmission in areas where the prevalence of HIV is high, e.g., Africa and China.
Virology
HCV is a small single-stranded RNA virus of the family Flaviviridae. It is about 40 to 60 nm in diameter and is enveloped in a protein complex. The HCV genome includes approximately 10,000 nucleotides, which are translated into a large polyprotein and processed into at least 10 proteins. The genome has been sequenced, and the functions for most of the proteins have been identified.
HCV is a genetically heterogeneous virus because of its ability to mutate rapidly. This may allow it to escape detection by the immune system and mayaccount for the variable clinical course of HCV infection. The heterogeneity of the virus and the absence of a protective antibody response no doubt contribute to the difficulty in developing effective vaccines and othertherapeutics.
There are at least six major genotypes of HCV, and more than 80 subtypes have been classified by genetic Methodologies. The six genotypes have different geographic distributions, with genotypes 1, 2, and 3 foundworldwide and genotypes 4, 5, and 6 found in more specific locales. Genotypes 1a and 1b are the most common in the United States, accounting for about twothirds of all cases of HCV infection. Genotypes 2 and 3can be detected in only 10% to 20% of patients in the United States but are more common in western Europe and Italy. Genotypes 1a and 3 are prevalent in both northern and southern Europe and Australia. Genotype 4 predominates in Egypt and the Middle East, and genotype 6 predominates in Southeast Asia, in particular Hong Kong. Despite differences in the geographic prevalence of HCV genotypes, data suggest that minimal differences exist related to the natural history, progression, severity, and outcome among the various genotypes of HCV. However, genotypes 2 and 3 are more responsive to interferon-based therapy.
Disease Progression
Acute HCV infection has an incubation period of 6 to 7 weeks after exposure, and only 25% to 35% of patients become symptomatic. When symptoms do develop, they are usually mild, nonspecific, and intermittent; jaundice occurs in only 20% to 30% of infected patients. Consequently, a diagnosis is rarely established at the time of acute infection, yet more than85% of patients with acute HCV infection develop chronic infection.
Left untreated, chronic HCV infection is likely to progress to cirrhosis in 14% to 45% of patients after 20 years, reducing survival and quality of life, as well as increasing the cost of care. Some studies have shown lower rates of cirrhosis, 2% to 17% after 8 to 25 years, thus the overall impact on life expectancy is not clearly known. Life expectancy in individuals 40 to 60years old with compensated cirrhosis may be reduced by 7 to 10 years, compared with healthy individuals of the same age.
Furthermore, studies in the United States, Europe, and Japan have shown an increasing incidence in HCC related to HCV. In the United States, approximately 70% of patients with HCC are found to be positive for the HCV antibody, and the risk of developing liver cancer is five- to seven-fold higher among HCV-positive patients.
The Centers for Disease Control and Prevention (CDC) estimates that the number of deaths from endstage liver disease in the United States will peak at 30,000 to 40,000 annually by the year 2010 barring changes in the natural history of the disease. If similar projections are recapitulated on a worldwide level, mortality from HCV over the next decade will be staggering given the large burden of disease.
Economic Impact
The direct economic impact of hepatitis C is largely related to complications of cirrhosis and HCC. Hospital care of patients with end-stage liver disease represents a significant proportion of expenditures, although hospitalization is uncommon. In 1995, approximately 27,000 hospitalizations in the United States were attributed to liver disease from HCV, for a crude incidenceof 1 hospitalization per 1,000 people infected.
The estimated annual total expenditure for hospital care of HCV-related liver disease was between $129 and $514 million. In addition, outpatient services, including antiviral therapy, contribute significantly to the economicburden of HCV infection. The cost of treating hepatitis C, including pharmaceutical costs, was estimated to be $693 million. Overall, the total economic impact of HCV in the United States is estimated to have been $1 to $1.3 billion per year. Whether these estimates are equivalent or greater in other nations is presently unknown and deserves further study. Thetrue worldwide economic and social burden of HCV remains to be fully defined: none of these estimates include the indirect costs of illness or premature deaths, which are likely to be significantly greater in less-developed nations, where the prevalence of HCV is considerable.These increased indirect costs will likely offset any decreased direct costs attributable to underutilization of health care resources for treatment.
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