Hepatitis C

  1. Ala I. Sharara, MD;
  2. Christine M. Hunt, MD; and
  3. John D. Hamilton, MD
  1. From Duke University Medical Center and Durham Veterans Administration Medical Center, Durham, North Carolina. Requests for Reprints: Ala I. Sharara, MD, Box 3083, Duke University Medical Center, Durham, NC 27710. Current Author Addresses: Dr. Sharara: Box 3083, Duke University Medical Center, Durham, NC 27710.
     
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    Abstract

    Objectives: To review the virology, epidemiology, pathogenesis, natural history, clinical manifestations, and current treatment of hepatitis C virus (HCV) infection.

    Data Sources: The MEDLINE database (1966 to 1996) was searched for English-language articles and abstracts on HCV and non-A, non-B hepatitis. Papers cited in relevant primary articles were also reviewed.

    Study Selection: More than 500 original and review articles were evaluated, and the most relevant were selected.

    Data Extraction: Data were extracted and reviewed by all authors.

    Data Synthesis: In most patients, HCV infection results in chronic hepatitis. The disease is insidious and subclinical but may progress over decades into end-stage liver disease and hepatocellular carcinoma, which makes HCV cirrhosis a leading indication for orthotopic liver transplantation. Current diagnostic methods are highly sensitive and specific, and quantitative assessment of viral load may help to predict and monitor response to treatment. The only available therapeutic option is interferon, and this agent is effective in only a small subset of patients.

    Conclusions: Infection with HCV is a significant public health problem that has important clinical and financial consequences. The tailoring of specific therapy according to viral load or genotype, better patient selection, and use of combination drug regimens may improve the chance of viral clearance and sustained biochemical and histologic response. Further understanding of the basic virology of HCV and the exact mechanisms of viral persistence and tissue injury is needed to help define future therapeutic and preventive strategies.

    Ann Intem Med.1996; 125:658-668.

    Blood-borne non-A, non-B hepatitis was first recognized in the mid-1970s [1, 2], but identifying the major responsible agent by conventional methods proved to be difficult. In 1989, Choo and colleagues [3] used molecular techniques to clone a viral genome from chimpanzees that were experimentally infected with a contaminated human factor VIII concentrate. The development of an immunoassay based on the detection of circulating antibodies to a recombinant epitope proved that this virus, designated hepatitis C virus (HCV), was the etiologic agent in most cases of post-transfusion non-A, non-B hepatitis [4-6]. Since then, our knowledge of the biology, epidemiology, and pathophysiology of HCV has increased exponentially; HCV is the most common cause of post-transfusion and community-acquired non-A, non-B hepatitis and cryptogenic cirrhosis worldwide [7, 8]. The virus has a striking serologic association with hepatocellular carcinoma and is a leading cause of end-stage liver disease requiring liver transplantation [8-10]. In 1992, a survey taken in an inner-city emergency department in Baltimore [11] found that 18% of patients had antibodies to HCV; a seroprevalence of 83% was noted among patients with a history of drug abuse. Given that 1.4% of the U.S. population is infected with HCV, chronic hepatitis C is a burgeoning problem of public health and economic importance [12].

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    Virology

    The hepatitis C virus is a positive-strand RNA virus distantly related to the Flaviviridae family. The HCV genome consists of about 9400 nucleotides with one large open-reading frame encoding for a polypeptide (about 3000 amino acids long) consisting of structural and nonstructural domains (Figure 1) [13, 14]. On the basis of nucleic acid sequences, at least six major genotypes and more than 80 subtypes of HCV have been identified worldwide [15-18]. The major genotypes show approximately 65% homology overall, and related subtypes show 77% to 79% homology. The 5′-untranslated end contains a relatively well-conserved region that has a 92% homology among different HCV genotypes. Specific primers to this region have been designed to allow detection of viral nucleic acid of different genotypes with the polymerase chain reaction (PCR) after reverse transcription. Different genotypes have been reported to alter disease severity, change treatment response, and influence virus-host interactions and the potential for vaccine development. The most common genotypes in the United States and western Europe are 1a and 1b. Genotype 1b has been reported to be associated with higher HCV RNA levels in the infected host, more advanced disease, and suboptimal response to currently accepted therapy [19-22]. Genotypes 1b, 2a, and 2b are common in Japan and Taiwan; genotype 3 has been described in Thailand, Northern Europe, and Australia; genotype 4 is predominant in the Middle East; genotype 5 is prevalent in South Africa; and genotype 6 has been reported in Hong Kong [19].

    Figure 1.
    View larger version:
    Figure 1. Hepatitis C genome.
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    Epidemiology

    The development of reliable serologic assays for HCV has made the study of the epidemiology of hepatitis C possible. In the United States, antibodies to HCV are detected in 1.4% of the general population and in 0.1% to 0.7% of healthy volunteer blood donors [12, 22-24]. Prevalence is considerably higher in developing countries: It reaches 4% to 6% in selected populations in parts of Africa and the Middle East [25, 26]. Hepatitis C virus is transmitted primarily through contaminated blood and less effectively through human bodily secretions; HCV RNA has been detected in saliva, urine, semen, and ascitic fluid [27-29]. Risk factors for HCV infection include intravenous drug use, transfusion of blood products, hemodialysis, tattooing, high-risk sexual behavior, exposure to health care, and organ transplants from HCV-positive donors [30-33]. However, 40% to 50% of patients with HCV infection have no identifiable parenteral risk factors, and the mode of viral transmission in these “sporadic” cases remains unknown. Because of structural homology to viruses of the Flaviviridae family, such as the agents of dengue and yellow fever, arthropod-borne transmission has been suggested. This type of transmission is unlikely, however, given the clustering of multiple subtypes within distinct age groups in similar geographic locations [21].

    With the implementation of HCV testing in blood banks, the risk for HCV infection from blood transfusion decreased from 0.19% to 0.03% per unit transfused [34]. However, transfusion of blood products accounts for only 5% to 10% of cases of chronic hepatitis C; intravenous drug use accounts for 40% to 50% of cases. Transmission of HCV from contaminated lots of intravenous immune globulins has been documented [35], and the Food and Drug Administration (FDA) now requires that all immune globulin products manufactured through a process that does not include a viral inactivation step be tested for HCV RNA.

    An average of 20% of patients who receive renal hemodialysis are infected with HCV, but the incidence of infection in these patients varies widely according to geographic location and the diagnostic methods used [36-40]. Before 1989, the seroconversion rate was approximately 5% per year of dialysis, but this rate has declined since the inception of HCV testing for blood products [41, 42]. The prevalence of HCV antibodies among health care personnel at risk for exposure to infected blood is similar to that in the general population [43]. The incidence of HCV seroconversion or the presence of HCV RNA in health care workers after a needlestick injury involving an index case of chronic hepatitis C ranges from 0% to 10% [44, 45].

    Vertical transmission (from mother to infant) of HCV is infrequent but is not uncommon in the setting of high maternal viral titers or in the presence of concomitant human immunodeficiency virus (HIV) infection [46-48]. Sexual transmission occurs rarely but appears to be enhanced in patients with concomitant HIV infection, multiple sexual partners, and, possibly, longer duration of marriage [49-51]. In one study [52], a higher prevalence of HCV antibodies was noted among the female partners of HCV-positive men than among the male partners of HCV-positive women. The prevalence of HCV antibodies in homosexual men who do not use intravenous drugs ranges from 1% to 18%; this prevalence is proportional to the number of lifetime sexual partners [52-56]. Studies that have examined the household (nonsexual) spread of HCV have reported an incidence of 0% to 11% among contacts of patients with chronic hepatitis C [57-64]. The intrafamilial clustering of identical HCV genotypes supports household contact as a possible, albeit inefficient, mode of transmission [65].

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    Diagnostic Tests

    The original test for antibodies to HCV proved to be highly valuable in the diagnosis and study of the epidemiology of HCV, but it lacked sensitivity, especially in the early diagnosis of hepatitis after transfusion. False-positive results were noted in patients with alcoholic liver disease, autoimmune disorders, and hyperglobulinemia and in low-risk blood donors [66-68]. This led to the development of the second- and third-generation enzyme-linked immunosorbent assays (ELISAs) and recombinant immunoblot assays that detect circulating antibodies to multiple viral epitopes (Figure 1) and have a sensitivity and specificity that approaches 95% when compared with the gold standard, HCV RNA detected by PCR [69]. Although PCR is exquisitely sensitive, quantitative assays of HCV RNA lack standardization among laboratories [70]. Recently, however, a sensitive automated quantitative method that is based on PCR [71] and has a limit of detection of 700 Eq/mL has been developed [Amplicor HCV; Roche Molecular Systems, Branchburg, New Jersey]. Even in the same person, HCV RNA levels can fluctuate more than a millionfold over time and may be “falsely” negative if levels of viral replication are low or if viral persistence is limited to nonblood compartments. Measurement of HCV RNA by PCR should not be used as a primary test to confirm or exclude the diagnosis, but it is useful as 1) a confirmatory test in patients whose results on recombinant immunoblot assay are indeterminate and 2) to monitor perinatal transmission or response to antiviral therapy. The commercially available branched-chain DNA assay (bDNA Quantiplex; Chiron Corp., Emeryville, California) is a standardized quantitative test of HCV RNA that is based on signal amplification in a hybridization assay [72]. This test has a sensitivity of 72% to 95% when compared with RNA quantitation by end-point dilution or competitive PCR; the limit of detection by the second-generation branched DNA assay is 2.0 × 105 Eq/mL [73].

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    Clinical Manifestations

    In the United States, an estimated 21% of all community-acquired cases of acute viral hepatitis are secondary to HCV infection [12, 30]. Clinical symptoms in patients with acute hepatitis C tend to be milder than those seen in patients infected with the other hepatitis viruses. Most cases are asymptomatic, and only 25% of patients with post-transfusion hepatitis develop jaundice [74]. The risk for fulminant or subacute liver failure is rare [75, 76]. The incubation period of the virus ranges from 15 to 150 days (mean, 50 days). Infection may not be detectable by the first-generation ELISA for as long as 6 months but can be detected by the newer assays as early as 6 to 8 weeks after exposure and by reverse transcriptase PCR as early as 1 to 2 weeks after exposure [77, 78]. Unlike antibodies to hepatitis A and B viruses, antibodies to HCV are not protective and, in most cases, are a marker for disease. After acute exposure to HCV, 50% to 80% of patients with self-limited infection but only 10% of patients with evidence of chronic infection lose antibodies to HCV as detected by first-generation assays within a 10-year period [5, 79].

    The most remarkable and alarming aspects of HCV infection are its high rate of persistence and its ability to induce chronic liver disease. As many as 80% of patients have evidence of chronic hepatitis, and 20% to 35% develop cirrhosis [22, 80, 81]. The disease is subclinical and insidious in most patients: The average time to clinically significant hepatitis is 10 years, the average time to cirrhosis is 21.2 years, and the average time to hepatocellular carcinoma is 29 years [82]. The natural history of chronic HCV infection has been documented best in transfusion-associated cases, but the effect of disease on clinical outcomes has been controversial. In a controlled, multicenter study, Seeff and coworkers [83] compared the mortality rate of 568 patients with post-transfusion hepatitis with that of age-matched controls who received blood transfusions at the same time without evidence of HCV infection [83]. Over a mean of 18 years of follow-up, overall mortality rates did not differ, although a small but statistically significant excess of liver-related mortality was seen in the patients with hepatitis. Subsequent studies from both the United States and Japan [80, 82, 84] have suggested significant morbidity and mortality in the 10- to 30-year period after viral acquisition. In contrast to the study by Seeff and colleagues, in which patients were primarily elderly persons having open-heart surgery, a recent study by Tong and associates [85] examined clinical outcomes in a cohort of 131 patients with post-transfusion hepatitis C whose mean age at the time of blood transfusion was 35 years. The mean times from viral acquisition to the development of clinically significant chronic hepatitis, cirrhosis, and hepatocellular carcinoma were 18.4, 20.6, and 28.3 years, respectively. The average time to the development of these diseases was longer among patients who were infected at a younger age. During follow-up, 19 patients (14.5%) died of complications of cirrhosis or hepatocellular carcinoma, and 4 patients (3%) had liver transplantation. It is therefore clear that chronic post-transfusion hepatitis C is an insidious but progressive disease that leads to death from liver failure or hepatocellular carcinoma in some patients.

    The clinical presentation of chronic hepatitis C may vary depending on the host immune system and the source and duration of infection. Most commonly, patients are incidentally found to have elevated aminotransferase levels on “routine” biochemical tests or positive results on a test for antibodies to HCV at the time of blood donation. Most of these patients are asymptomatic or have mild fatigue, and liver synthetic function is usually preserved. Serum aminotransferase levels typically fluctuate widely over time and may even be normal on occasion. In fact, in the absence of alcohol use, this pattern strongly suggests chronic HCV infection. Many patients present with advanced liver disease complicated by variceal bleeding, ascites, coagulopathy, or encephalopathy.

    Hepatitis C has also been implicated by association in several hepatic and extrahepatic syndromes: porphyria cutanea tarda, focal lymphocytic sialadenitis, Mooren ulcers, type II cryoglobulinemia, and membranoproliferative glomerulonephritis [86-91]. Response to antiviral therapy for HCV may be the cause of the association in some of these diseases [92, 93]. A high prevalence of such autoantibodies as rheumatoid factor, antithyroglobulin, and antinuclear antibodies has been reported [94]. Antibodies to HCV have also been described in patients with type II autoimmune liver disease characterized by the development of antibodies to liver/kidney microsome type 1 and to GOR (an HCV-induced, host-derived epitope) [95, 96].

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    Mechanisms of Persistence and Injury

    The mechanisms of persistence and replication of and cellular injury by HCV are not well characterized. Unlike hepatitis B virus infection, persistent HCV infection is not related to integration into the host genome because there are no DNA intermediates in the viral life cycle. Evidence of HCV replication, based on the presence of negative-strand intermediates, has been documented in the liver but remains largely unsubstantiated in extrahepatic sites, such as peripheral blood mononuclear cells and serum [97-99]. Persistence appears to result from the ability of the virus to replicate with a high rate of mutation, resulting in a series of immunologically distinct variants or quasi-species that allow the virus to escape immunologic control [100]. Neutralizing antivirion antibodies develop but are isolate-specific and change over time [101]; this may explain why both chimpanzees and humans can be reinfected with the same or different strains of HCV [102]. An extremely high rate of mutation has been described in the HVR1 (E2HV) domain of HCV. Although the exact function of this domain has not been identified, mutations in this region of the envelope protein have been shown to contribute to the maintenance of HCV escape variants in persons with chronic infection [103-105].

    The histopathology of acute hepatitis C differs little from that of infections caused by the other hepatitis viruses [106], but the histopathology of chronic hepatitis C has more characteristic histologic findings, such as portal tract lymphoid aggregates or follicles, steatosis, and bile duct damage [107, 108]. The wide spectrum of lesions seen may be related to differences in genotype, viral load, and host immune response, but the exact mechanisms of injury and the role of cell-mediated response to HCV remain largely undefined. Cytotoxic T lymphocytes directed against more than one viral epitope have been shown in patients with acute and chronic HCV infection, and it has been suggested that escape mutations may have a role in the mechanism of viral evasion of the cellular immune surveillance system [109-114].

    Because of the absence of efficient and reliable cell culture systems for HCV, the evidence of a direct cytopathic effect of HCV remains unproven. The presence of lymphoid follicles on histopathologic examination and the occasional presence of cryoglobulins, circulating immune complexes, and autoantibodies argue for an immunologic component [87, 88, 94]. A role for hepatic iron excess in hepatic injury and resistance to therapy has been suggested [115, 116].

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    Diagnosis

    Chronic hepatitis C is suspected when serum aminotransferase levels are persistently elevated in the presence of HCV antibodies detected by second- and third-generation ELISA. The recombinant immunoblot assay is used much like a Western blot assay to confirm the ELISA results. More than 85% of patients with HCV infection show reactivity on two or more bands on the second-generation recombinant immunoblot assay but, depending on the HCV genotype and the host immune response, different patterns of reactivity to the individual antigens used in the blot may be seen [117]. If the results of these tests are indeterminate and the suspicion of disease is strong, detection of HCV RNA by PCR may be confirmatory.

    Serum aminotransferase levels correlate poorly with liver histopathologic findings and can be normal at times during the course of the illness and in patients with cirrhosis. Disease activity can be assessed by liver biopsy and is important in counseling patients about treatment. A positive result on a test for antibodies or HCV RNA in the setting of sustained normal or minimally elevated aminotransferase levels may identify healthy carriers and patients with low levels of viral replication [118]. Most of the latter have minimal or mild liver inflammation confined to the portal tracts, although substantial histologic disease activity and high levels of HCV RNA are occasionally seen [22, 119-122].

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    Treatment

    The ideal goal of treatment is to eradicate HCV early in the course of disease to prevent progression to end-stage liver disease. To date, however, no known drug can reproducibly eradicate HCV. Current therapy consists of antiviral agents and immunomodulatory agents aimed at altering viral replication and modifying the immune response of the host. Assessment of therapy is difficult in the absence of definite markers, as it is with chronic hepatitis B. The end points for successful therapy that are used in most clinical trials are normalization of serum aminotransferase levels and improvement in liver histologic findings. However, a discrepancy between biochemical and virologic responses to therapy has been recognized and has prompted the use of measurement of HCV RNA levels as an additional marker for virologic response. Pretreatment level of HCV RNA appear to be the best predictor of response to treatment [123] but is not a perfect predictor of sustained response, relapse, or viral clearance. In fact, biochemical and histologic response can be achieved and occasionally sustained after therapy despite the low-level persistence of HCV RNA [124-126]. Conversely, relapse may occur despite a transiently negative result on PCR after treatment [127]. It is still not certain, although it is likely, that improvement in these end points translates into long-term benefit in the areas of disease progression, tumorigenesis, and disease-specific mortality.

    Currently, interferon-α 2b is the only agent approved by the FDA for the treatment of chronic hepatitis C. Interferons are a family of intracellular proteins that have established antiviral and immunomodulatory properties. They bind to specific cell surface receptors, activating various enzymes and genes that affect viral replication, uncoating, assembly, and cell entry [128]. Interferons also increase natural killer cell activity, enhance maturation of cytotoxic T cells, and increase cell surface expression of HLA class I antigens, thereby promoting immune clearance of infected cells [129, 130]. Patients with substantial and persistent elevations in aminotransferase levels and active inflammation with piecemeal necrosis are suitable candidates for therapy. On the basis of results from randomized, controlled trials done in Europe and the United States, standard initial therapy has been determined to consist of recombinant interferon-α 2b, 3 million U subcutaneously three times a week for 6 months [131-133]. Response rates (response was defined as normalization of serum alanine aminotransferase levels at the end of treatment) approach 50%. Most responses occur within the first 12 weeks of therapy and are associated with histologic improvement. However, relapse occurs in about 70% of patients after the initial course of therapy; thus, long-term sustained response is seen in about 10% to 25% of patients. Favorable predictors of response include mild to moderate liver inflammation, lower body weight, absence of cirrhosis, shorter duration of infection, lower hepatic iron content, and lower serum and hepatic levels of HCV RNA (Table 1) [117, 134-141]. Virus-specific factors that predict an improved response to interferon include genotype other than genotype 1 and the presence of mutations on the NS5 region of the viral genome [20, 21, 142].

    View this table:
    Table 1. Predictors of Favorable Response to Interferon in Patients with Chronic Hepatitis C*

    Higher initial doses of interferon and longer duration of interferon therapy appear to reduce the risk for early relapse and may improve the chances of a sustained response [143-147]. Patients who have relapse after an initial response to treatment will respond to a second course of therapy, but most will have relapse again after the second course of treatment is stopped. Long-term maintenance or dose-escalation therapy may be necessary to sustain response. The limited overall response coupled with the cost (about $2500 for 3 million U three times weekly for 6 months) and dose-dependent side effects of interferon (Table 2) [148-155] make wide application of this treatment debatable. Other considerations that may argue against the use of long-term or maintenance therapy include the possibility of selection of resistant mutants and development of neutralizing antibodies to interferon [101, 156, 157]. Interferon therapy may severely exacerbate autoimmune hepatitis; thus, it is important to exclude this diagnosis before initiating therapy [158]. In addition, interferon may result in the development or exacerbation of autoimmune disorders, such as hypothyroidism or hyperthyroidism, psoriasis, lichen planus, idiopathic thrombocytopenic purpura, and a lupus-like syndrome [159-163]. Interferon is not recommended for patients with a history of major psychiatric problems because of the possible relapse or worsening of depression [150, 151].

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    Table 2. Side Effects of Interferons

    Substantial controversy surrounds the management of patients with persistently normal or minimally elevated serum aminotransferase levels. Treatment may be justified in patients who have substantial inflammation on biopsy and high HCV RNA levels. Most patients, however, have mild to moderate inflammation, and the preferred course of action for these patients remains unclear. Arguments against treatment include unknown long-term prognosis and a low overall response to standard doses of interferon in patients with HCV infection [164]. In these patients, persistently negative results on PCR assays for HCV RNA before treatment correlate with minimal histologic activity and may indicate viral clearance [22].

    Despite studies that have shown decreased markers for fibrogenesis (such as hepatic transforming growth factor-β messenger RNA levels and N-terminal propeptide of type III procollagen) with interferon therapy in patients with chronic viral hepatitis [165, 166], little evidence supports any long-term benefit of interferon in patients with advanced cirrhosis. These patients are not good candidates for interferon because of their poor response rates and the potential risk for decompensation with therapy. A recent randomized trial of high-dose lymphoblastoid interferon-α (6 million U three times weekly for 12 to 24 weeks) in patients with compensated HCV cirrhosis (Child-Pugh class A) showed improved liver function and a decreased incidence of hepatocellular carcinoma with antiviral therapy over a mean follow-up period of 4.4 years [167].

    Several agents and novel approaches to therapy for chronic hepatitis C have been evaluated, but the search continues for more effective treatment (Table 3). Corticosteroids, thymosin, acyclovir, and interferon-γ are ineffective [168-170], and alternate forms of interferon, including lymphoblastoid interferon, consensus interferon, and interferon-β do not appear to have an advantage over the recombinant interferon-α preparation [171-173]. Ribavirin, an oral nucleoside analogue, has been shown to be associated with an aminotransferase response and HCV RNA levels that do not decrease or that slightly decrease and return to pretreatment levels after therapy is stopped [174-176]. The combination of ribavirin and interferon appears promising [177] but awaits further evaluation. Ursodeoxycholic acid has been reported to cause a transient improvement in serum aminotransferase levels without affecting viral RNA levels [178]. In an uncontrolled trial by Beloqui and coworkers [179], the addition of N-acetylcysteine to lymphoblastoid interferon resulted in biochemical and virologic responses in previously unresponsive patients.

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    Table 3. Investigational Agents and Regimens for the Treatment of Chronic Hepatitis C

    The rate of response to interferon may be improved through better patient selection (identifying favorable predictors of response before treatment) or augmentation of the effects of interferon with dose escalation, prolonged duration of therapy, iron reduction, or concomitant use of nonsteroidal anti-inflammatory drugs. By inhibiting the cyclooxygenase pathway of prostaglandin synthesis, these drugs block the production of prostaglandin E2, which has immunosuppressant properties, and increase the concentration of the enzyme 2′,5′-oligoadenylate synthase that is associated with the antiviral effect of interferons [180]. Two small pilot trials by Andreone and colleagues [181, 182] that examined the combination of interferon with indomethacin or ketoprofen suggest that this condition produces an enhanced response in patients previously resistant to interferon.

    To eliminate viral persistence and prevent chronicity, treatment of early or acute cases of hepatitis C has been attempted. Controlled trials of interferon in this setting have generated conflicting results; two studies [183-186] showed sustained viral clearance and improved histopathologic findings as long as 5 years after cessation of therapy. Larger doses of interferon and longer treatment schedules appeared to increase the response rate, and the benefit of early therapy was maintained even in patients treated 1 year after infection. Given the high rate of chronicity and the chance of an improved sustained response with early therapy, interferon should be considered for patients who have persistent viremia after the acute phase of illness. Such a strategy would, however, be applicable to only a few patients because the number of cases of acute post-transfusion hepatitis C is rapidly diminishing and most cases of community-acquired acute HCV infection are asymptomatic.

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    Liver Transplantation

    Hepatitis C virus cirrhosis is one of the leading indications for orthotopic liver transplantation in North America and Europe, and short-term survival after transplantation is similar to that of patients with chronic cholestatic liver disease [187]. Most patients who have transplantation for HCV cirrhosis are viremic at the time of transplantation and may develop reinfection of the liver graft with the circulating virus. Retrospective and prospective studies [188, 189] have shown that about 40% of patients develop hepatitis with allograft damage as early as 1 to 3 years after transplantation. This, however, rarely leads to graft loss or death within 5 to 10 years of transplantation [190, 191]. Despite the theoretical risk for precipitating allograft rejection, interferon therapy has been used safely in this group and has resulted in a 10% to 30% initial response in aminotransferase levels but no sustained virologic response after cessation of therapy [192].

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    Hepatitis C Virus and Hepatocellular Carcinoma

    A strong serologic association between HCV and hepatocellular carcinoma has been documented worldwide despite variations in the attributable risk among and even within continents [193-195]. The mechanisms of hepatocarcinogenesis in chronic HCV infection remain unknown. Hepatitis C virus does not integrate in the host genome, and activation of specific protooncogenes or inactivation of tumor suppressor genes has not been documented. Hepatocellular carcinoma occurs largely in the setting of HCV cirrhosis and rarely in patients with chronic HCV infection who do not have cirrhosis [196]. The risk for hepatocarcinogenesis is increased in patients with HCV who are chronic carriers of hepatitis B surface antigen and who concomitantly use alcohol [197]. Because the incidence of hepatocellular carcinoma in patients with cirrhosis is 2% to 5% per year [198], periodic screening, including measurement of serum α-fetoprotein levels and ultrasonography of the liver every 6 to 12 months [199, 200], has been advocated in patients with HCV cirrhosis despite the lack of long-term studies documenting cost-effectiveness.

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    Prevention

    Universal screening of blood donors has almost eliminated parenteral transmission of HCV through the transfusion of blood and blood products. Public health policies aimed at reducing HIV transmission, such as the promotion of sexual barrier protection and needle exchange programs, are likely to decrease transmission of HCV in high-risk groups. General recommendations on hygiene and safe sexual activity are important [201], but it is unclear whether protected sexual intercourse should be recommended to couples with long-standing monogamous relationships or whether the spouses of patients should be followed for markers for HCV infection. Despite the suggestion of a mild increased risk for vertical transmission in the presence of high maternal HCV titers or concomitant HIV infection, evidence is insufficient to guide prenatal counseling of women of childbearing age [45-47]. Because of the potential risk for exacerbation of disease with the use of alcohol [202], abstinence should be strongly encouraged. Prophylaxis with immunoglobulin after needle-stick exposure has no proven benefit and is not currently recommended.

    The search for an HCV vaccine is encumbered by the presence of multiple genomic subtypes and mutants and the transient efficacy of neutralizing antibodies. Early research in animals appears promising in part [203] but is far from having direct or wide applications in humans.

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    Conclusions

    Chronic HCV infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. The many sporadic cases that occur in patients with no identifiable risk factors, the propensity of the virus to cause subclinical chronic hepatic injury, and the lack of definite therapy or prevention will probably result in many cases of advanced liver disease secondary to HCV infection well into the future. Treatment with interferon effectively inhibits viral replication and reduces liver injury in a subset of patients, but the response is usually brief and the effect on long-term disease progression and prognosis is usually unclear. Combining various drugs and tailoring treatment according to HCV genotype and viral load may improve the chance of response. Further research into the virology, immunology, molecular biology, and epidemiology of HCV will be essential in enhancing our understanding of this virus and defining rational approaches to the treatment and prevention of HCV infection.

    Dr. Hunt: Box 3064, Duke University Medical Center, Durham, NC 27710.

    Dr. Hamilton: Box 3867, Duke University Medical Center, Durham, NC 27710.

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