Hepatitis C - Course and Outcome

California Association
for
Medical Laboratory Technology

Distance Learning Program

HEPATITIS C
COURSE AND OUTCOME

Course #: DL-952
1.0 CE/Contact Hour
Level of Difficulty: Basic

Author:
Patricia L. Fawkes, CLS
Kaweah Delta Healthcare District Transfusion Service
Visalia, CA

© California Association for Medical Laboratory Technology.
Permission to reprint any part of these materials, other than for credit from CAMLT, must be obtained in writing from the CAMLT Executive Office.

CAMLT is approved by the California Department of Health Services
as a CA CLS Accrediting Agency (#0021)
and this course is is approved by ASCLS for the P.A.C.E.® Program (#519)

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In July 2000, the United States Surgeon General declared that hepatitis C represents a “silent epidemic.” Hepatitis C is the most common chronic blood-borne infection in the United States, affecting almost 3 million Americans. It is a viral infection of the liver that causes acute hepatitis and chronic liver disease. Hepatitis C virus (HCV) is spread primarily by direct contact with human blood.

Prior to 1989, hepatitis C cases were reported as non-A, non-B hepatitis. With the identification of the causative agent, Hepatitis C cases were first reported separately in 1989. There were 3,759 deaths attributed to HCV in that year. There was a 5-fold increase in the annual number of patients with HCV who underwent liver transplantation between 1990 and 2000. Currently, more than one third of transplant candidates have HCV. The total direct health care cost associated with HCV is estimated to have exceeded $1 billion in 1998. Future projections predict a 4-fold increase through 2015 in persons at risk of chronic liver disease, suggesting a continued rise in the burden of HCV in the United States in the foreseeable future.1

No vaccine is currently available to prevent hepatitis C and treatment is costly. The focus on control is to reduce exposure, particularly high risk behavior such as unsafe injection drug practices.

Hepatitis C infection is caused by a small RNA virus that belongs to the family Flaviviridae and is the sole member of the genus Hepacivirus.2 The hepatitis C virus (HCV) has a single-stranded RNA genome that is approximately 9,600 nucleotides in length and encodes a single, large polyprotein of about 3,000 amino acids. It appears to have a narrow host range. Only humans and chimpanzees are susceptible to infection.

There are 6 genotypes and more than 90 subtypes of Hepatitis C virus. Genotype 1a is most commonly found in the United States and Northern Europe. Genotype 1b has a worldwide distribution and is the most common genotype. Genotypes 2a and 2b have a worldwide distribution, representing 10% to 30% of HCV types, and are found particularly in Japan and Northern Italy. Genotype 3 is found most frequently in the Indian subcontinent and may have been recently introduced into the United States and Europe. There is speculation that this may have resulted from the spread of injection drug use between the 1960s and 1970s. Genotype 4 is the most common genotype found in Africa and the Middle East, while Genotype 5 is found in isolated areas of South Africa. Finally, genotype 6 is found in Hong Kong and Southeast Asia.

In the United States, genotypes 1a and 1b account for approximately 75% of cases of chronic hepatitis C, genotypes 2a and 2b for 13% to 15%, and genotype 3a for 6% to 7%.7 A proportion of patients have a mixture of genotypes, most commonly 1a and 1b. Infection with any of these genotypes can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The frequency of these complications appears to be similar with each genotype.

The incubation period of HCV infection before the onset of clinical symptoms ranges from 15 to 150 days. Acute hepatitis C is characterized by the appearance of HCV RNA in serum within two weeks of exposure, followed by an elevation of serum alanine aminotransferase (ALT). The most common symptoms are fatigue, malaise, anorexia, abdominal pain followed by jaundice. However, the majority of cases, 60% to 70%, are asymptomatic. Antibody to HCV tends to arise late. During the evolution from acute to chronic infection, the HCV RNA and ALT levels can fluctuate markedly, and at least a quarter of the patients who develop chronic infection exhibit periods during which the HCV RNA is undetectable and the ALT levels are normal.

About 80% of newly infected patients progress to develop chronic infection. Once chronic infection is established, serum HCV RNA levels tend to stabilize. Furthermore, spontaneous loss of HCV RNA or resolution of symptoms after 6 to 12 months of infection is unusual.

Most patients with chronic hepatitis C have few if any symptoms. The most common symptom is intermittent fatigue. In some patients, right upper quadrant pain in the liver, nausea and poor appetite occur. The major long-term complications of chronic hepatitis C are cirrhosis, end-stage liver disease, and hepatocellular carcinoma, which develops only in 1% to 5% of patients and only after many years or decades of infection.4 Cirrhosis develops in about 10% to 20% of patients with chronic infection. Once cirrhosis is present, the ultimate prognosis is poor.4 Other complications can occur with chronic hepatitis C such as B-Cell non-Hodgkin’s lymphoma, glomerulonephritis, seronegative arthritis, and other neuropathies and neurologic conditions including cognitive disorders.

Hepatitis C virus infection is most common among non-Caucasian men, ages 30 to 49 years. Acute hepatitis C is rarely recognized in children, and fulminant cases have not been reported.

HCV is spread by direct contact with human blood. Transmission is primarily through needle sharing among drug users, unscreened blood transfusions, and inadequately sterilized needles or other medical equipment. Sexual and perinatal transmission occur less frequently. It is not spread by water or food or through the air.

In developed countries about 90% of the cases are in current and former injecting drug users; in developing countries unscreened blood transfusions or inadequately sterilized equipment are more important in transmission. After the discovery of HCV in 1988 an immunoassay test was developed. In the U.S. testing of donated blood for antibodies to HCV began in 1990 followed by a more specific test in 1992. Now the frequency of transfusion associated hepatitis C is extremely low, 1 in 100,000.

The goal of much current basic research on hepatitis C is the development of an HCV vaccine. The high mutation rate of the HCV genome complicates vaccine development. Clinical research focuses not only on understanding the HCV but also on better characterization of immunologic responses and other host factors that determine the course and outcome of acute hepatitis C infection. Such knowledge is also important for developing approaches to management and therapy.1

In the absence of a vaccine prevention depends on the following World Health Organization recommendations:

Chronic hepatitis C infection that exhibits no symptoms is usually first suspected when a liver function test indicates an elevation in the liver enzymes, such as ALT. Although elevated ALT can indicate hepatitis C, many infections, toxins and diseases also cause liver enzyme elevation. Therefore, additional tests need to be performed to confirm the diagnosis of hepatitis C infection.

The first-line test for hepatitis C infection is a blood test for the detection of the presence of an HCV antibody. The blood test used for this is an enzyme immunosorbant assay (EIA).

The first version of EIA was not precise, but a new, refined version of the test (EIA-2) more accurately identifies hepatitis C antibodies. Even with this second generation test there remains a relatively high false-positive rate. This means that the EIA-2 may indicate a hepatitis infection when the person does not have one.

Because the EIA-2 may give false positive results, additional tests are required to confirm a chronic hepatitis C diagnosis. A recombinant immunoblot assay (RIBA) is performed to confirm hepatitis C infection. This test is also in its second generation (RIBA-2). When the RIBA-2 test indicates a positive hepatitis C infection, the results are considered together with a patient’s ALT levels. If the ALT levels are elevated, and the EIA-2 and RIBA-2 are positive, the probable diagnosis is chronic hepatitis C infection. If these tests repeat positive and the ALT levels remain elevated, treatment for hepatitis C infection may be advised.

Before treatment commences, the patient usually undergoes a liver biopsy that assesses the amount of liver damage caused by the virus. In this procedure, a sample of liver is extracted using a special biopsy needle that is inserted through the skin of the abdomen and into the liver.

In some cases the EIA-2 and RIBA-2 tests are positive and the liver enzyme tests are negative. This may indicate that the patient’s immune system has successfully defeated the HCV virus infection. In order to determine if there is hidden virus remaining, a polymerase chain reaction (PCR) test is used to provide the information.

The PCR based test detects the actual genetic material (RNA) of the hepatitis C virus living in the body. Patients with positive EIA-2 and RIBA-2, positive PCR, and normal liver readings are considered hepatitis C carriers with no major liver injury. In general, these would not be candidates for immediate treatment. Their liver enzymes would be monitored and if an elevation in ALT occurred, then treatment would be considered.

A patient with positive EIA-2 and RIBA-2, negative PCR, and normal ALT would be considered to have recovered from and cleared of the hepatitis C infection. However, a negative PCR could mean that the viral load has temporarily fallen below the lower detection limit of the test, so these patients would undergo follow-up testing and monitoring before being considered without infection.

Two methods of antiviral therapy of chronic hepatitis C have been approved, interferon monotherapy and interferon/ribavirin combination therapy. Monotherapy with alpha interferon was used first. The interferon is injected subcutaneously three times a week for six months. The usual criteria for therapy include elevated ALT, detectable HCV RNA and moderate grade chronic hepatitis.

The 1997 Consensus Conference, after reviewing interferon monotherapy treatment of patients with normal ALT levels, found that therapy for this category could not be recommended because it may actually worsen the course of the disease. Approximately 30% of patients with chronic hepatitis C have normal serum ALT levels while another 40% have ALT levels that are somewhat less than twice the upper limit of the normal range. Most patients with normal ALT levels demonstrate mild degrees of inflammation with mild or no fibrosis. Also the rate of disease progression is reduced compared to that found in patients with elevated ALT levels. However, some patients with normal ALT levels with either interferon monotherapy or interferon/ribavirin combination therapy have shown sustained virological response (SVR) rates that are equivalent to those achieved for patients with elevated ALT levels. Therefore patients with chronic hepatitis C should not be excluded from therapy based on ALT levels alone. 1

With the advent of combination therapy using interferon and ribavirin, and more recently using long acting pegylated interferon (peginterferon is interferon bound to polyethylene glycol, PEG) and ribavirin, sustained virological response (SVR) rates have improved dramatically. These improvements in SVR rates have resulted in a new risk-to-benefit ratio to be used when considering antiviral treatment for patients with mild or slowly progressing disease. The decision of which therapy to initiate should be based on a combination of factors independent of ALT levels. These factors include the amount of fibrosis on liver biopsy, hepatitis C (HCV) genotype and viral load, patient age and motivation, and co-morbid illness (i.e., HIV or renal disease) and the presence of other complicating conditions. 1

Alpha interferon therapy for chronic hepatitis C is typically accompanied by a biphasic decrease in hepatitis C virus (HCV) RNA levels. An initial rapid decline during the first 24 to 48 hours is followed by a second more gradual decline during subsequent weeks. The rate of second-phase decline correlates with ultimate response to interferon treatment. Thus, assessment of early virological response (EVR) may predict outcome. 1

To elaborate, the level of hepatitis C virus (HCV) RNA in the blood of patients with chronic hepatitis C reflects a balance between virus production and clearance.5 The balance of production and clearance is altered with initiation of antiviral therapy. Treatment with alpha interferon results in a decline of HCV RNA levels that can be resolved mathematically into 2 phases. After a latent period of 8 to 10 hours following the injection of interferon, there is an initial rapid decline in HCV RNA levels which correlates with the dose of interferon and viral genotype. The first phase decline is usually measured at 24 or 48 hours and the decline is likely to reflect direct inhibition of intracellular HCV production and release.5 The second phase decline in HCV RNA levels during interferon treatment begins after 24-48 hours, and is slower and more variable than the first phase. This decline is felt to reflect continued inhibition of replication and the gradual elimination of virus-infected cells.5 The second phase decay correlates less with interferon dose than does the first phase, and is more rapid with peginterferon preparations. Also second phase decay is considerably more rapid in patients with genotypes 2 and 3 than in those with genotype 1 infection.

Studies with standard interferon monotherapy led to recommendations for stopping therapy (stopping rule) after 12 weeks. Studies of patients receiving alpha interferon and ribavirin indicate a stopping therapy rule of 24 weeks. Preliminary data using peginterferon (the newest treatment of choice) suggested the most appropriate time for assessing response with that regimen was also 24 weeks.

Minimizing loss of patients who are potential responders is the most important clinical goal in defining an early stopping rule because it provides the most sustained virological responders with incentive to continue treatment.

Treatment guidelines that rely on virological testing raise issues that need to be considered by the physician and testing laboratory. Phlebotomy centers and laboratories must process samples for viral testing under conditions that do not allow degradation of HCV RNA.7 Serum should be separated from the clot within 2 hours. Serum samples should be refrigerated or preferably frozen for storage and during shipping. Quantitative testing should be performed by a method with a wide enough dynamic range to allow for accurate assessment of the pretreatment HCV RNA level.

Most patients who receive treatment with peginterferon and ribavirin have an early reduction in HCV RNA levels. This early virological response (EVR) is predictive of the response to continued treatment and can be used to design stopping rules. An early stopping rule is based on the assumption that treatment is of benefit only if virus is eradicated and requires that virological testing be accurate and reproducible. Early virological response is best defined as a fall in HCV RNA level by at least 2 log units (i.e., 10⁶ going to 10⁴) or to an undetectable level by a sensitive qualitative PCR after the first 12 weeks of treatment. Using a combination of peginterferon and ribavirin, approximately 80% of patients will fit this definition of EVR. Use of the stopping rules will reduce treatment costs by about 16% and avoid the inconvenience and side effects of treatment in patients who have little or no chance of virological response. Finally, the significance of EVR provides a powerful incentive for patients to reach week 12 of treatment, and a further incentive for patients who achieve EVR to continue therapy because of the high likelihood that they will have a sustained response.

The sensitivity and the precision of testing for HCV RNA continue to improve. The availability of more sensitive qualitative tests for HCV RNA, such as transcription-mediated amplification, will not affect the early stopping rules proposed here because the rules are based on quantitative changes as well. More sensitive testing does appear able to identify many patients who have non-durable responses to treatment. While earlier identification of these cases does not currently change their management, future treatment protocols may need to be designed to consolidate antiviral effects in these patients.

1. Hepatology, November 2002, part 2, Volume 36; Number 5; S21-S184.
2. Lauer GM, Walker BD. Hepatitis C Virus Infection. N Engl J Med. 2001; 345: 41-52.
3. Hoofnagle JH. Hepatitis C: clinical spectrum of disease. Hepatology. 1997; 26 (suppl 1):
155-205.
4. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history,
treatment and prevention of hepatitis C. Ann Intern Med. 2000; 132: 296-305.
5. Neumann AU, Lam NP, Dehari H, et al. Differences in viral dynamics in vivo and the antiviral efficacy of interferon alpha therapy. Science. 1998; 282: 103-107.
6. Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, Albrech J. Is an “al la carte” combination interferon alpha-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? Hepatology. 2000; 31: 211-218.
7. Alter MJ, Knison-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999; 341: 556-562.