Despite rapid scientific progress in understanding the biology of viral illnesses, viral liver disease remains a common and challenging problem for physicians and their patients. Six viruses, designated hepatitis A, B, C, D, E, and G, primarily target the liver and produce inflammation, or hepatitis, as their primary clinical manifestation. Other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), may cause hepatitis as part of their clinical presentation, but the liver is usually not the primary infected organ. Of the typical hepatitis viruses, chronic infection with hepatitis C remains one of the most important clinical and public health problems. In the Western world, chronic damage from hepatitis C is the primary cause for the end-stage liver disease requiring liver transplantion.

The discovery of the hepatitis C virus (HCV) in 1989 was a major breakthrough. Before that point, it was clear that a major cause of acute hepatitis after a blood transfusion was neither related to hepatitis A nor to hepatitis B—hence, the early name for this disease, non-A, non-B hepatitis. After extensive testing of serum from experimentally infected animals, the virus was cloned using molecular biology techniques. It was found to be an RNA virus classified in the Flaviviridae family and genus Hepacivirus. ¹ It is a double-shelled, enveloped, single-stranded RNA virus, 50 to 60 nm in diameter. HCV replicates in the liver, and is detectable in serum during acute and chronic infection.

The HCV genome codes for the synthesis of a single large polyprotein of about 3000 amino acids that is then cut by specific enzymes into structural and nonstructural proteins. A schematic of the hepatitis C viral structure is shown in Figure 1, along with the proteins that each section encodes. Based on differences in the amino acid sequence of specific proteins, hepatitis C can be classified into a number of different subtypes, known as genotypes. Because of the high error rate in the production of daughter RNA viruses, infected patients typically harbor a heterogeneous group of viruses, with multiple mutations in specific proteins. This variability can be used to divide the HCV infection further in a given individual into subtypes and, beyond that, into specific quasispecies. ² This has considerable importance in determining the outcome of treatment, although it probably does not affect the natural history of the disease. Although the virus is found throughout the world, the various genotypes of hepatitis C are distributed differently; for example, genotype 4 infection is common in Egypt, but relatively rare in the United States (Fig. 2).

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Prevalence

Some patients exposed to hepatitis C do not develop chronic infection, perhaps as many as 20%. Similarly, although the remainder develop chronic infection, only a percentage will ultimately develop cirrhosis and its complications, usually over a 10- to 20-year time frame.

Because patients who develop a new infection with hepatitis C are usually asymptomatic for many years, the true prevalence is probably underestimated. It is estimated that approximately 170 million people are infected worldwide, equivalent to 3% of the world's population. Based on antibody testing on blood samples from the National Health and Evaluation Nutrition Surveys from 1999 through 2002 in the United States, it was estimated that as many as 4.1 million people were exposed to HCV. Because most patients are unable to clear the infection spontaneously, experts have estimated that between 2.7 and 3.9 million people—or about 1.3% of the U.S. population—have chronic hepatitis C infection.³

In the past, a major route of infection was via blood transfusion; after implementing the use of polymerase chain reaction (PCR) assays to screen blood donations, the risk of transfusion-associated HCV fell to less than 1 per 100,000 units transfused. Although the incidence of new infection dropped dramatically, the prevalence of infection and (the total population of patients still infected) continues to rise. The most common route of transmission is now believed to be related to intravenous drug use, responsible for perhaps as many as 50% of new infections.

Other potential avenues of infection include having multiple sexual partners, tattooing, body piercing, and sharing straws during intranasal cocaine use, all of which are linked to an increased risk of infection. Maternal-fetal transmission occurs in approximately 10% of cases and is more likely to occur in a mother who is coinfected with HIV. The rate of infection after an HCV contaminated needle stick injury has ranged from 0% to 10% in various studies. Although possible, viral transmission to a sexual partner in a monogamous relationship is rare, with a less than 5% risk. The Centers for Disease Control and Prevention (CDC) does not advocate any change in sexual practice for partners engaging in a long-term, monogamous, sexual relationship.

Based on epidemiologic studies of transmission and prevalence rates, the CDC recommends screening patients with specific risk factors, including the following: ⁴

• Patients who have previously used drugs
• Those with HIV or hemophilia
• Patients on dialysis in the past, or those who received transplants or transfusions before 1992
• Health care workers after a needle stick injury
• Possibly children of HCV-infected mothers or sexual partners of HCV-infected persons

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Pathophysiology

Although HCV can be found in multiple sites throughout the body, including the liver, peripheral blood mononuclear cells, dendritic cells, epithelium, and even the central nervous system, HCV replicates in the hepatocytes. However, in the person with a normal immune system, it is not directly hepatotoxic. Viral replication occurs through an RNA-dependent RNA polymerase process. Lymphocytes recognize infected cells and initiate an immune response to control the virus. Viral clearance is associated with the development and persistence of strong, virus-specific responses by cytotoxic T lymphocytes and helper T cells. Because of the rapid evolution of diverse quasispecies within an infected person, even a brisk B cell (e.g., antibody) response to hepatitis C has been inadequate to clear the infection, because the virus represents a moving target to the immune system. For the same reason, progress in the development of a vaccine to protect patients from an initial infection has been slow.

Damage to the liver parenchyma is mediated by inflammatory cytokines. Persistent inflammatory mediators activate stellate cells in the liver parenchyma, leading to varying degrees of hepatic fibrosis. Why some patients develop progressive fibrosis and eventually cirrhosis, and others do not, is unknown, but some predictors of progression have been identified, including male gender, age at onset of infection, and use of alcohol.

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Signs and symptoms

Acute HCV infection is uncommonly recognized, because it is usually accompanied by mild flulike symptoms. Although the vast majority of patients with acute HCV infection are asymptomatic, weight loss, fatigue, muscle or joint pain, irritability, nausea, malaise, anorexia, and jaundice have been reported to occur rarely in the 2- to 26-week incubation period. In chronic symptomatic HCV infection, fatigue is a frequent complaint, the degree of which is unrelated to the severity of liver disease. Other complaints may include depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration. Symptoms may first appear only with the onset of more advanced liver disease. Common extrahepatic manifestations of HCV infection include mixed cryoglobulinemia and porphyria cutanea tarda. Membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, focal lymphocytic sialadenitis, and idiopathic pulmonary fibrosis may occur in rare cases and are believed to be secondary to immune complex deposition in association with intact virus or viral proteins. Many patients have no specific symptoms and the finding of abnormal hepatic transaminase levels on routine testing often prompts specific testing for hepatitis C.

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Diagnosis

Serologic assays for HCV are based on detecting HCV antibodies or HCV RNA. The most commonly used serologic test for detecting antibodies to hepatitis C is the enzyme-linked immunosorbent assay (ELISA), with a sensitivity and specificity of 95%. Some laboratories automatically confirm a positive ELISA test by a supplemental recombinant immunoblot assay (RIBA) to increase the specificity of the test (e.g., to decrease the number of false-positives). In the 15% of infected individuals who clear the virus spontaneously, these antibody test results will remain positive and thus cannot be used to confirm active infection. This also applies to treated patients who clear the virus, who will maintain a positive HCV antibody indefinitely. A very small percentage of patients infected with HCV are unable to mount an immune response to the viral protein and do not produce antibody. These false-negatives occur in those with HIV infections, renal failure, or HCV-associated mixed cryoglobulinemia. Confirmation of ongoing infection therefore requires the detection of HCV RNA by PCR using a qualitative or quantitative assay. These assays may detect a viral count as low as 9.6 IU/L. A negative qualitative test result argues strongly against active viral infection. The quantitative HCV RNA test reflects the viral load, which is an important variable to predict the outcome of anti-HCV therapy but not the likelihood of disease progression. ⁴

Patients frequently come to medical attention based on elevated alanine aminotransferase (ALT) levels, which are indirect markers of liver cell necrosis. Although ALT measurements have been used to monitor HCV infection and the efficacy of therapy, the recognition that many infected patients may have normal ALT levels has limited their usefulness. Furthermore, the normalization of ALT levels with antiviral therapy is not proof of successful virus eradication. Viral quantification has replaced ALT levels, therefore, in monitoring treatment response.

In patients with documented HCV infection, a liver biopsy is often helpful in determining the need for therapy. Although not considered mandatory before initiating treatment, it documents the amount of ongoing destruction (grade) and degree of fibrosis (stage) of disease. Patients with more advanced fibrosis are at high risk of progressive liver disease, and therefore should be considered for therapy. Significant fibrosis may be present in patients with normal transaminase levels in up to 25% of patients. Conversely, patients with minimal fibrosis may choose to forego immediate therapy, weighing the likelihood of progressive scar tissue development against the side effect profile of current treatment, as well as the likelihood of response.

Viral load and viral genotype help predict the outcome of treatment, because response rates are most strongly linked to these two variables. In addition, they influence the length of therapy—patients with genotype 1, the most common form in North America, and a high viral load are more resistant to therapy, with response rates of approximately 40%, even after 1 year of combination treatment. By comparison, patients with genotype 2 or 3 may be expected to achieve sustained virologic response rates of almost 80% after 6 months of treatment. ⁴

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Treatment

Treatment outcomes depend on many factors, including whether a patient is being treated for acute or chronic disease. Acute HCV infection is uncommonly diagnosed, because it often manifests with nonspecific flulike symptoms. Available evidence suggests that interferon-based therapy given early in the course of infection decreases the risk of progression to chronic disease. ⁵ Health care workers, for example, who are accidentally exposed to HCV-infected blood via a needle stick injury, should be followed carefully for evidence of ongoing infection and, if unable to clear the infection spontaneously, be treated early.

The more common situation facing clinicians is that of patients with chronic hepatitis C, for whom the goal of treatment is elimination of the virus. This is associated with stabilization or even improvements in liver histology and clinical course. Secondary aims are symptom control, improvement in liver function, and prevention of complications of progressive liver disease, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma.

Complete abstinence from alcohol is an extremely important behavioral modification, and has been shown to affect the likelihood of progression as well as the efficacy of therapy. The usefulness of other therapies, including dietary supplements, herbs, and unconventional treatments, have not been rigorously studied, and the results are extremely varied. ⁶ Apart from interferon-based therapy, most interventions have only marginal benefit. Regardless of whether a patient elects to be treated or not, practice guidelines recommend that all patients with hepatitis C and no evidence for immunity be vaccinated for hepatitis A and, if risk factors exist, for hepatitis B as well.

Patients treated with interferon are classified into those who do not respond (i.e., fail to clear HCV from their blood), relapsers (i.e., those who cleared the virus on treatment, but afterward had detectable virus), and those who develop a sustained virologic response (SVR), defined as undetectable virus in the serum 6 months after treatment completion, which correlates well with long-term absence of virus. Although any patient with hepatitis C infection can be considered for therapy, the decision must be individualized, based on the overall risks and benefits of therapy. Patients with chronic HCV infection and evidence of damage, including elevated serum aminotransferase levels, chronic hepatitis on liver biopsy, absence of decompensation, and no contraindications, should be considered for treatment. Specific contraindications include severe concurrent disease, previous solid organ transplantation, autoimmune hepatitis, hyperthyroidism, pregnancy, or uncontrolled depression. Previous contraindications, such as HIV infection or AIDS, or otherwise immunocompromised status, are no longer considered obstacles to treatment. Often, HIV-positive patients are coinfected with hepatitis C, because the viruses may share a similar epidemiology. The most recent studies have demonstrated response rates to therapy of 14% to 73% in these patients, depending on genotype, which are somewhat better than those seen with previous treatments. These rates, however, are less than those expected in HIV-negative patients. ⁷

A pretreatment neuropsychiatric assessment should be performed in all patients. If depression, anxiety, or other psychiatric illness is evident by history, a psychiatric consultation should be sought for evaluation, treatment, and follow-up during the interferon treatment period. Psychosis and homicidal or suicidal ideation are strong contraindications to therapy.

Factors predicting a therapeutic response include low pretreatment HCV RNA level, genotype 2 or 3, female gender, low body mass index (BMI), and low hepatic iron load. Patients with advanced liver disease or decompensated cirrhosis are also unlikely to respond, and frequently are unable to tolerate treatment. ⁴

Treatment of hepatitis C infection has evolved over the last 15 years. It remains based on interferon alfa as an immune modulator. Response rates have been modest when it was used as monotherapy (10% in genotype 1 and 30% at best in genotypes 2 and 3). Side effects remain a significant problem and are typically described as flulike symptoms, including fever, arthralgia, headache, depression, injection site inflammation, and bone marrow suppression. The addition of ribavirin, a nucleoside analogue and an inhibitor of viral replication, has improved the SVR rate to approximately 50% (46% in genotype 1 and 76% in genotypes 2 and 3; Table 1 ). There is some evidence for a dose-response effect, with generally increased response rates in higher doses (usually 1000 to 1200 mg in divided doses). Ribavirin is cleared by the kidneys and therefore is contraindicated in patients with significant renal dysfunction (a creatinine clearance lower than 50 mL/min). It also has been shown to be teratogenic and is therefore strictly contraindicated in pregnancy. The most common side effect is fatigue in about 15% of patients, resulting partly from hemolytic anemia.

The most recently introduced treatment is pegylated interferon, a form of interferon covalently bound to a large, inert, polyethylene glycol molecule. The combination serves to prolong the serum half-life by decreasing the excretion rate, thereby increasing the duration of action. Enhanced response rates have been demonstrated for pegylated interferons in combination therapy with ribavirin. ⁸ If patients are able to complete a full course of treatment at optimal doses (e.g., without dose adjustments for side effects or toxicity), SVR rates may be as high as 88% in genotypes 2 and 3 patients and up to 50% in those with genotype 1 (see Table 1 ). Side effects, such as injection site reaction and bone marrow suppression, may be more pronounced with different formulations and doses.

Although the usual duration of treatment for patient with genotype 1 is 48 weeks, data from multiple studies have suggested that it is possible to predict the outcome of therapy by 12 weeks of therapy. If a patient fails to clear infection or has at least a 2-log decline in the viral load (measured with the same PCR assay as used at baseline), it is unlikely that the patient will develop a SVR. ⁹ Studies are ongoing to define new and earlier “stopping” rules.

Patients on therapy need to be monitored closely for complications or symptoms of the adverse reactions of combination therapy. This should include evaluation for depression, symptoms of irritability, sleep disturbance, and visual disturbances, as well as evidence of hyper- or hypothyroidism. Blood counts should be monitored frequently at the beginning of treatment and at least monthly afterward, if stable. An emerging literature suggests that support of the bone marrow with erythropoietin for anemia and granulating cell-stimulating factor (GCSF) for neutropenia may allow continuation of therapy, even in patients with significantly affected counts. The cost effectiveness of this approach, however, is uncertain.

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Complications

Chronic HCV infection is the most common indication for liver transplantation in the United States and, as complications related to the epidemic continue, a significant impact on the U.S. health care system is expected. It has been estimated that over the next 20 years, the proportion of infected patients with cirrhosis will increase from 16% to 32%, and other complications will also increase dramatically, including hepatic decompensation (up 106%), hepatocellular carcinoma (up 81%), and liver-related deaths (up 180%). ¹⁰

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Conclusions

HCV infection typically progresses to chronic infection in more than 60% of patients, and may lead to cirrhosis in as many as 20% over a 20-year time period. Serum aminotransferase levels reflecting hepatocellular injury may fluctuate, as does the viral load.

As the disease evolves, hepatocytes are progressively destroyed and replaced by fibrosis, insidiously leading to the development of bridging fibrosis and ultimately cirrhosis. The course of any individual patient is affected by various factors, such as age at onset of infection, gender, coinfection with other viruses (hepatitis A virus [HAV], HBV or HIV), or other medical conditions, as well as behaviors, such as alcohol consumption. Interferon-based treatment has a varying success rate in clearing the virus, as noted earlier. Careful selection and monitoring of patients are essential in undertaking therapy. In patients without cirrhosis, hepatitis C–related mortality is only slightly increased. Severe complications usually occur only in those with established cirrhosis. The risk of developing hepatocellular carcinoma (HCC) in chronic HCV patients with cirrhosis is as high as 4% per year. HCV-infected individuals with cirrhosis should be screened at periodic intervals with ultrasound and alpha-fetoprotein testing. Some retrospective studies have shown that treatment with interferon is associated with a lower rate of development of HCC, even without a SVR. Although HCV remains a major global health problem, significant advances in the understanding of its basic biology have allowed significant improvements in treatment over the last 10 years. Treatment, although difficult, has been shown to prolong life, and the pace of discovery in this field gives hope that patients will be able to be treated even more effectively in the future.

Summary

• It is estimated that approximately 170 million people are infected worldwide (3% of the world's population). It has been estimated that as many as 4.1 million Americans were exposed to HCV; from 2.7 to 3.9 million people in the United States have chronic hepatitis C infection.
• Chronic HCV infection is the most common indication for liver transplantation in the United States and, as its complications continue, a significant impact on the U.S. health care system is expected. It has been estimated that over the next 20 years, the proportion of infected patients with cirrhosis will increase from 16% to 32% and other complications will also increase dramatically.
• In the past, a major route of infection was via blood transfusion; after implementing the use of polymerase chain reaction (PCR) assays to screen blood donations, the risk of transfusion-associated HCV fell to less than 1/100,000 units transfused. However, the prevalence of infection continues to rise. The most common route of transmission is now believed to be related to intravenous drug use, responsible for perhaps as many as 50% of new infections. Maternal-fetal transmission occurs in approximately 10% of cases.
• Acute HCV infection is uncommonly recognized. Although most patients with acute HCV infection are asymptomatic, fatigue, depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration may occur in chronic symptomatic HCV infection. Common extrahepatic manifestations of HCV infection include mixed cryoglobulinemia and porphyria cutanea tarda. Many patients have no specific symptoms and the finding of abnormal hepatic transaminase levels on routine testing often prompts specific testing for hepatitis C.
• Serologic assays for HCV are based on detecting HCV antibodies or HCV RNA. Viral load and viral genotype help predict the outcome of treatment, because response rates are most strongly linked to these two variables.
• Treatment of hepatitis C infection is based on interferon alfa administration over many months. Combined with ribavirin, a sustained virologic response rate of approximately 50% (46% in genotype 1 and 76% in genotypes 2 and 3) can be anticipated. Higher response rates may be seen when the patient is younger, thinner, or female and has a low viral load and absence of hepatic fibrosis.

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Suggested Readings

• Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 244: 1989; 359-362.
• Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 351: 2004; 451-459.
• Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 9: 2003; 331-338.
• Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 38: 2003; 645-652.
• Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 347: 2002; 975-982.
• German Acute Hepatitis C Therapy Group: Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 345: 2001; 1452-1457.
• The burden of hepatitis C in the United States. Hepatology. 36: 2002; S30-S34.
• Medicinal herbs for hepatitis C virus infection: A Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol. 98: 2003; 538-544.
• Structural biology of hepatitis C virus. Hepatology. 39: 2004; 5-19.
• Diagnosis, management, and treatment of hepatitis C. Hepatology. 39: 2004; 1147-1171.