Background
Hepatitis C is a worldwide problem. The hepatitis C virus (HCV) is a major cause of both acute and chronic hepatitis. The World Health Organization (WHO) estimates that 170 million individuals worldwide are infected with hepatitis C virus (HCV). However, the prevalence of HCV infection varies throughout the world. For example, 1 decade ago, Frank et al reported that Egypt had the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy.[1] This led to a mean prevalence of HCV antibodies in persons in Egypt of 22%.
The incidence of acute HCV infection has sharply decreased in the United States during the past decade. Its prevalence remains high (approximately 2.7 million Americans), however, because chronic hepatitis C (CHC) infection develops in approximately 75% of patients acutely infected.
According to the US Centers for Disease Control and Prevention (CDC), an estimated 1.8% of the US population is positive for HCV antibodies. Because 3 of 4 seropositive persons are also viremic, this corresponds to an estimated 2.7 million people with active HCV infection nationwide. Infection due to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000 new acute infections, and 8000-10,000 deaths each year in the United States.
Medical care costs associated with the treatment of HCV infection in the United States are estimated to be more than $600 million a year. Most patients infected with HCV have chronic liver disease, which can progress to cirrhosis and hepatocellular carcinoma (HCC). Chronic infection with HCV is one of the most important causes of chronic liver disease (see the image below) and, according to a report by Davis et al, the most common indication for orthotopic liver transplantation (OLT) in the United States.[2]
Hepatitis C. Causes of chronic liver disease. Courtesy of the US Centers for Disease Control and Prevention. Most patients with acute and chronic infection are asymptomatic. Patients and health care providers may detect no indications of the conditions for long periods; however, chronic hepatitis C infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Astute observation and integration of findings of extrahepatic symptoms, signs, and disease are often the first clues to underlying HCV infection.[3]
Although acute hepatitis C virus (HCV) infection is usually mild, chronic hepatitis results in at least 75% of patients.[4] (See Prognosis.) While liver enzyme levels may be in the reference range, the presence of persistent HCV-RNA levels discloses chronic infection. Biopsy samples of the liver also reveal chronic liver disease in patients. Cirrhosis develops in 20-50% of patients with chronic hepatitis C infection. Liver failure and hepatocellular carcinoma can eventually result. Hepatocellular carcinoma occurs in 11-19% of patients.
Combination therapy with pegylated interferon alfa (PEG-IFN alfa) and the nucleoside analogue ribavirin is the current standard of care in patients infected with HCV. The addition of protease inhibitors to the combination of PEG-IFN alfa and ribavirin is becoming the new standard of care. (See Treatment and Medication.)
Pathophysiology
The cause of hepatitis C, HCV, is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus. The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells.
In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C.
RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.
Etiology
Hepatitis C is caused by a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus. Lauer and Walker reported that HCV is closely related to hepatitis G, dengue, and yellow fever viruses. HCV can produce at least 10 trillion new viral particles each day.
The HCV genome consists of a single, open reading frame and 2 untranslated, highly conserved regions, 5'-UTR and 3'-UTR, at both ends of the genome. The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see the image below).
Hepatitis C viral genome. Courtesy of Hepatitis Resource Network. Structural components include the core and 2 envelope proteins, E1 and E2. Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, thought to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV.
The nonstructural components include NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7, whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. One region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region. These enzymes are critical in viral replication and are attractive targets for future antiviral therapy.
HCV genomic analysis by means of arduous gene sequencing of many viruses has led to the division of HCV into 6 genotypes based on homology. Numerous subtypes have also been identified. Arabic numerals denote the genotype, and lower-case letters denote the subtypes for lesser homology within each genotype.[4]
Genotypes
Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype details are as follows:
- Genotype 1a occurs in 50-60% of patients in the United States; this type is difficult to eradicate using current medications
- Genotype 1b occurs in 15-20% of patients in the United States; subtype 1b is also difficult to eradicate using current medications; this type is most prevalent in Europe, Turkey, and Japan
- Genotype 1c occurs in less than 1% of patients in the United States
- Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication
- Genotypes 3a and 3b occur in 4-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland
- Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa
- Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa
- Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao
Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse intravenous drugs.
Transmission
Transfusion of blood contaminated with HCV was once an important source of transmission. Since 1990, however, the screening of donated blood for HCV antibody has decreased the risk of transfusion-associated HCV infection to less than 1 case in 103,000 transfused units. With the use of more sensitive assays, such as polymerase chain reaction (PCR), Stramer et al reported that the risk of acquiring HCV from blood transfusions is estimated to be 1 in 230,000 donations.[5] The newer assays have decreased the window after infection to 1-2 weeks.
Persons who inject illegal drugs with nonsterile needles or who snort cocaine with shared straws are at highest risk for HCV infection. In developed countries, most new HCV infections are related to intravenous drug abuse (IVDA).
Transmission of HCV to health care workers may occur via needle-stick injuries or other occupational exposures. Needle-stick injuries in the health care setting result in a 3% risk of HCV transmission. According to Rischitelli et al, however, the prevalence of HCV infection among health care workers is similar to that of the general population.[6] Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992.
HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The use of disposable needles for acupuncture, which has become standard practice in the United States, eliminates this transmission route.
Yeung et al reported that uncommon routes of transmission of HCV, which affect less than 5% of the individuals at risk, include high-risk sexual activity and maternal-fetal transmission.[7] Coinfection with human immunodeficiency virus (HIV) type 1 appears to increase the risk of both sexual and maternal-fetal transmission of HCV. Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.
Epidemiology
United States statistics
Hepatitis C is the major cause of chronic hepatitis in the United States. HCV infections account for 20% of all cases of acute hepatitis and for more than 40% of all referrals to active liver clinics.
Alter et al reported that HCV infections account for approximately 30,000 new infections and 8000-10,000 deaths each year in the United States.[8] Of new infections, 60% occur in intravenous drug users; less than 20% of new cases are acquired through sexual exposure; and 10% are due to other causes, including occupational or perinatal exposure and hemodialysis.
The overall prevalence of anti-HCV antibodies in the United States is 1.8% of the population. Approximately 74% of these individuals are positive for HCV RNA, meaning that active viral replication continues to occur. Thus, an estimated 3.9 million persons are infected with HCV and 2.7 million persons in the United States have chronic infection.[8] Genotype 1a occurs in 57% of patients; genotype 1b occurs in 17%.
From 1989-1993, the occurrence of HCV decreased 80%, from 50 cases per 100,000 to approximately 28,000 new cases per year. Decreased transfusion-associated disease and a dramatic decrease in intravenous drug use accounted for this change.
El-Serag et al reported that HCV is largely responsible for the increase in the incidence of HCC in the United States during the final decades of the 20th century.[9] In the United States, the number of deaths due to HCV-related complications increased from fewer than 10,000 in 1992 to just fewer than 15,000 in 1999. According to Kim, this number is expected to increase in the future because of the current large pool of patients with chronic infections.[10]
International statistics
Worldwide, more than 170 million persons have hepatitis C virus (HCV) infection.[11] The prevalence rates in healthy blood donors are 0.01-0.02% in the United Kingdom and northern Europe, 1-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy.
Race-, sex-, and age-related differences in incidence
In the United States, HCV infection is more common among minority populations, such as black and Hispanic persons, than other populations, in association with lower economic status and educational levels. In addition, in the United States, genotype 1 is more prevalent in blacks than in other racial groups.
No sex preponderance occurs with HCV infection. In the third National Health and Nutrition Examination Survey, neither sex nor racial-ethnic group was independently associated with HCV infection.[8]
In the United States, 65% of persons with HCV infection are aged 30-49 years. Those who acquire the infection at a younger age have a somewhat better prognosis than those who are infected later in life. Infection is uncommon in persons aged 20 years and younger and is more prevalent in persons older than 40 years.[12, 13] Data suggest an association between age and transmission route, such as nonsterile medical procedures, including vaccination and parenteral drug treatment.[14]
Prognosis
Infection with HCV is self-limited in only a small minority of infected persons. Chronic infection develops in 70-80% of patients infected with HCV.[4] Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection.[15] The onset of chronic hepatitis C infection early in life often leads to less serious consequences.[16, 17] Hepatitis B virus (HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis.[18, 19]
Two studies of compensated cirrhosis in the United States and Europe showed that decompensation occurred in 20% of patients and that HCC occurred in approximately 10% of patients.[20, 21] The survival rate at 5 and 10 years was 89% and 79%, respectively. HCC develops in 1-4% of patients with cirrhosis each year after an average of 30 years.
The risk of cirrhosis and HCC doubles in patients who acquired HCV infection via transfusion.[22] Progression to HCC is more common in the presence of cirrhosis, alcoholism, and HBV coinfection.
Bellentani et al[23] and Hourigan et al[24] reported that the rate and likelihood of progression is influenced by alcohol use, immunosuppression, sex, iron status, concomitant hepatitis, and age of acquisition (see the image below).
Natural history of hepatitis C virus infection. With the currently recommended therapy for chronic hepatitis C, which includes pegylated interferon and ribavirin, cure rates are as high as 60%.
Patient Education
Patients with hepatitis C should be advised to abstain from alcohol use. Optimally, patients should use barrier protection during sexual intercourse.[25]
Patients with hepatitis C should not donate blood or organs. One exception is in patients with HCV who require liver transplantation. Arenas et al showed that liver transplant recipients who received liver grafts from HCV-positive donors had 5-year survival rates comparable to recipients who received grafts from HCV-negative donors.[26] Given the shortage of organs and the long waiting list, this strategy has proven safe and effective.
For patient education information, see the Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Hepatitis C and Cirrhosis.
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