Hepatitis C

The Hepatitis C Virus (HCV)

HCV was discovered in 1989 by investigators at Chiron, Inc. Portions of the HCV genome were isolated by screening cDNA expression libraries made from RNA and DNA from chimpanzees infected with serum from a patient with post-transfusion non-A, non-B hepatitis. [Prior to the discovery of HCV, hepatitis following blood transfusion that was not caused by hepatitis A or hepatitis B was referred to as non-A, non-B hepatitis]. To identify portions of the genome that encoded viral proteins, the libraries were screened with antibodies from patients who had non-A, non-B hepatitis. These investigators went on to show that the virus they identified was responsible for the vast majority of cases of non-A, non-B hepatitis. They called the new virus hepatitis C virus (HCV). Subsequently, the complete genomes of various HCV isolates were cloned and sequenced by several groups.

HCV is a positive, single-stranded RNA virus in the Flaviviridae family. The genome is approximately 10,000 nucleotides and encodes a single polyprotein of about 3,000 amino acids. The polyprotein is processed by host cell and viral proteases into three major structural proteins and several non-structural protein necessary for viral replication. Several different genotypes of HCV with slightly different genomic sequences have since been identified that correlate with differences in response to treatment with interferon alpha.

Despite the discovery of HCV by molecular biological methods and the sequencing of the entire genome, a permissive cell culture system for propagating HCV has yet to be established. A non-primate animal model also does not exist. As a result, the production of specific drugs against HCV has been impeded although excellent diagnostic methods for have been developed.

Risk Factors for HCV Infection

Approximately 170,000,000 people worldwide and 4,000,000 in the United States are infected with HCV. The virus is transmitted primarily by blood and blood products. The majority of infected individuals have either received blood transfusions prior to 1990 (when screening of the blood supply for HCV was implemented) or have used intravenous drugs. Sexual transmission between monogamous couples is rare but HCV infection is more common in sexually promiscuous individuals. Perinatal transmission from mother to fetus or infant is also relatively low but possible (less than 10%). Many individuals infected with HCV have no obvious risk factors. Most of these persons have probably been inadvertently exposed to contaminated blood or blood products.

Consequences of HCV Infection

About 85% of individuals acutely infected with HCV become chronically infected. Hence, HCV is a major cause of chronic (lasting longer than six months) hepatitis. Once chronically infected, the virus is almost never cleared without treatment. In rare cases, HCV infection causes clinically acute disease and even liver failure, however, most instances of acute infection are clinically undetectable.

The natural history of chronic HCV infection can vary dramatically between individuals. Some will have clinically insignificant or minimal liver disease and never develop complications. Others will have clinically apparent chronic hepatitis. Of these, some go on to develop cirrhosis, however, the exact percentages is not known. About 20% of individuals with hepatitis C who do develop cirrhosis will develop end-stage liver disease. Cirrhosis caused by hepatitis C is presently the leading indication for orthotopic liver transplantation in the United States. Individuals with cirrhosis from hepatitis C are also at an increased risk of developing hepatocellular carcinoma (primary liver cancer)

A major problem in discussing prognosis in patients with chronic hepatitis C is that it is difficult to predict who will have a relatively benign course and who will go on to develop cirrhosis or cancer. One fairly clear factor for progression to cirrhosis is concurrent alcohol abuse. Certain findings on liver biopsy can also be helpful in predicting a relatively benign or progressive course. Viral genotype may also play a role. Additional research is urgently needed to identify host factors that are important in determining prognosis in chronic hepatitis C.

Diagnosis

The diagnosis of chronic hepatitis C is made by history, serological testing and liver biopsy. Most patients with chronic hepatitis C will be asymptomatic or have non-specific symptoms such as fatigue. In some individuals, the diagnosis will be suspected from the results of blood tests obtained for other reason (usually elevations in the serum alanine and aspartate aminotransferase activities).

Individuals suspected of having chronic hepatitis C include:

• Those with symptoms of chronic liver disease
• Those with risk factors such as past or current intravenous drug use or blood transfusions prior to 1990
• Those with abnormal laboratory tests suggesting liver disease

Such individuals should be tested for the presence of serum antibodies against HCV. The presence of anti-HCV antibodies in a person with a risk factor or evidence of liver disease strongly suggests the diagnosis of chronic hepatitis C. The absence of anti-HCV antibodies generally rules out the diagnosis. Tests for HCV RNA in blood should be done in those individuals with anti-HCV antibodies to confirm the diagnosis and in the rare patient who does not have anti-HCV antibodies but in whom the diagnosis is still strongly suspected on clinical grounds. Such testing shuld also be performed in patients who will undergo treatment. After making the diagnosis, a liver biopsy is usually indicated to assess the degree of liver inflammation and fibrosis and the presence or absence of cirrhosis.

Treatment

All patients with chronic hepatitis C should be evaluated by a specialist for possible treatment with these agents. In general, adults less than 70 years old with evidence of active inflammation on liver biopsy and without advanced cirrhosis are good treatment candidates. Indications for treatment of patients with very mild disease on liver biopsy are less clear. Such individuals should be considered for possible participation in clinical studies. Patients with advanced cirrhosis secondary to hepatitis C should be referred referred for evaluation for possible liver transplantation.