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Background: The World Health Organization (WHO) estimates 170 million individuals worldwide are infected with hepatitis C virus (HCV). However, the prevalence of HCV infection varies throughout the world. For example, in 2000, Frank et al reported that Egypt has the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy. This has led to a mean prevalence of HCV antibodies in persons in Egypt of 22%. According to the US Centers for Disease Control and Prevention, 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 Image 1) and, according to a report by Davis et al from 2003, the most common indication for orthotopic liver transplantation (LT) in the United States.
HCV is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus. In 2001, 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. 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.
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 Image 2).
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.
Six major HCV genotypes and numerous subtypes have been identified. 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. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. Genotypes 2 and 3 are also found globally and account for a significant minority of infections. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC.
The other genotypes have a more specific geographical distribution. Genotype 3 is found in Australia, the Indian subcontinent, and Thailand. Genotype 4 is the most prevalent genotype in Egypt and the Middle East. Genotype 5 is found in South Africa, and genotype 6 is more common in Southeast Asia, particularly in Hong Kong, Macao, and Vietnam. Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among Scottish persons who abuse intravenous drugs.
Currently, HCV is predominantly transmitted by means of percutaneous exposure to infected blood. In developed countries, most new HCV infections are related to intravenous drug abuse. The screening of blood donors for HCV antibody since 1990 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 in 2004 that the risk of acquiring HCV from blood transfusions is estimated to be 1 in 230,000 donations. The newer assays have decreased the window after infection to 1-2 weeks.
HCV may also be transmitted by means of acupuncture, tattooing, and sharing razors. Needlestick injuries in the health care setting result in a 3% risk of HCV transmission, but, according to Rischitelli et al in 2001, HCV prevalence among health care workers is similar to that of the general population. Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992. Yeung et al reported in 2001 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. Co-infection with 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.
Pathophysiology: 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 recent studies suggest at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C
History: Most patients with chronic hepatitis C are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus.
Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distension (ascites), and hematemesis or melena (variceal bleeding).
Physical: Most patients do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis.
Causes: Hepatitis C is caused by a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus
Lab Studies:
Imaging Studies:
Procedures:
Histologic Findings: Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis. Some patients also may have findings indicative of HCC.
Most pathologists give separate measurements of disease activity (grade) and fibrosis (stage). Many trials use the Ishak (6-point scale) and Knodell histological activity index (18-point score); both are useful for assessing improvements in histology findings in studies but are impractical for clinical use because of interobserver disagreement. The METAVIR score was developed by the French METAVIR Cooperative Study Group and reported by Bedossa and Poynard in 1996; it is frequently used in European trials. It consists of a 3-point activity scale and 4-point fibrosis score, with good agreement among pathologists. In the United States, many pathologists use a scale described by Batts and Ludwig in 1995, which consists of an activity grade (0-4) and a fibrosis stage (0-4).
Noninvasive methods of assessing hepatic fibrosis are in development. Current serum assays are directed at measuring breakdown products of extracellular matrix constituents (eg, glycoproteins, propeptides) and their regulatory enzymes (eg, lysyl oxidase, lysyl hydroxylase, propyl hydroxylase
Combination therapy with PEG-IFN alfa and the nucleoside analog ribavirin is the current standard of care in patients infected with HCV. Patients with HCV genotype 1 have a much less favorable response to therapy and are treated for 12 mo, compared with patients infected with genotypes 2 and 3, in whom a 6-mo course of therapy is sufficient. If viremia is present after 6 mo, additional therapy has a negligible incremental benefit, and treatment should be stopped in all patients regardless of the viral genotype. With HIV co-infection, all patients with a response to therapy at the end of 6 mo should receive an additional 6 mo of combination therapy regardless of the genotype. Patients with acute HCV infection should be treated for 6 mo.
Drug Category: Antivirals -- Shorten clinical course, prevent complications, prevent latent and/or subsequent recurrences, decrease transmission, and eliminate established latency
Interferon alfa-2b (Intron-A) -- Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases
Interferon alfa-2a (Roferon) -- Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases
Interferon alfacon-1 (Infergens) -- Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases.
Synthesized by combining most common amino acid sequences from all 12 naturally occurring IFNs
Pegylated interferon alfa-2b (PEG-Intron) -- Consists of IFN alfa-2b attached to a single 12-kd PEG chain. Excreted by kidneys. Has sustained absorption, slower rate of clearance, and longer half-life than unmodified IFN. Permits more convenient once-weekly dosing. Significantly improves quality of life for patients
Pegylated interferon alfa-2a (Pegasys) -- Consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. Predominantly metabolized by liver.
Ribavirin (Rebetol) -- Antiviral nucleoside analog. Chemical name is D -ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on course of hepatitis C. Given with IFN, significantly augments SVR rate.
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