Important note: Information in this article was accurate in September 2002. The state of the art may have changed since the publication date.
The National Institutes of Health (NIH) convened a Consensus Development Conference June 10-12, 2002. The primary sponsors of the meeting were the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Medical Applications of Research (OMAR) of the NIH. The event was co-sponsored by several different agencies within the Federal Government that have an interest in hepatitis C, particularly the National Institute of Child Health and Human Development (NICHD); the National Cancer Institute (NCI); the National Center for Complementary and Alternative Medicine (NCCAM); the National Institute on Alcohol Abuse and Alcoholism (NIAAA); the National Institute on Drug Abuse (NIDA); the National Institute of Allergy and Infectious Diseases (NIAID); the National Heart, Lung, and Blood Institute (NHLBI); the Centers for Medicare & Medicaid Services (CMS); the Centers for Disease Control and Prevention (CDC); the U.S. Food and Drug Administration (FDA); and the U.S. Department of Veterans Affairs (VA). The Agency for Healthcare Research and Quality (AHRQ) provided support to the Conference through its Evidence Based Practice Center Program. Under contract to AHRQ, the Johns Hopkins University Evidence Based Practice Center developed a systematic review of the literature and analysis that served as a reference for discussion at the conference and is available at http://www.ahrq.gov/clinic/epcsums/hepcsum.htm.
This 2-1/2 day conference examined the current state of the art regarding management for hepatitis C and identified directions for future research. During the first day and a half, experts presented the latest hepatitis C research findings to an independent non-federal panel. After weighing all of the scientific evidence, the panel drafted a statement, which addressed the following questions:
On the final day of the conference, Dr. James Boyer, the panel chair, read the draft statement and invited the audience to comment. A press conference followed to allow the panel and chair to respond to questions from the media. The draft statement was posted on the consensus website http://consensus.nih.gov on Wednesday June 12, 2002, and the final draft will be posted on or about September 9, 2002.
Natural History of Hepatitis C
Hepatitis C is an RNA virus of the flaviviridae family. There are 6 HCV genotypes and more than 50 subtypes. The genotypes can differ by as much as 30% to 50% in their nucleotide sequences. The virus also has a high propensity to mutate. The lack of a vigorous T cell response appears to promote a high rate of chronic infection. Genotype 1 accounts for 70% to 75% in the U.S. and has a poorer response to treatment. During acute infection the viral load can range from 105 to 107 [IU/mL]. Chronic HCV levels are variable and can range from 50,000-5,000,000 IU/mL; however, within the same person, they are generally stable.
According to the National Health and Nutrition Examination Study (NHANES), conducted by the Center for Health Statistics (NCHS) at the CDC, it is estimated that there are over 2.7 million people in the U.S. living with chronic HCV infection. This may be an under-estimate, however, since the NHANES household survey did not include high prevalence populations such as incarcerated, homeless, or institutionalized persons. There are an estimated 35,000 new infections per year, and the prevalence in the U.S. is 1.8%. The highest prevalence is seen among adults aged 40 to 59 years and among African Americans, who have a prevalence of 6.1%. Seroprevalence among inmates, the home-less, and hemophiliacs is 15% to 50%; among IDUs, it is 70% to 90%.
After initial exposure, HCV RNA can be detected in the blood at 1 to 3 weeks. Antibodies to HCV are detected by enzyme immunoassay (EIA) in approximately 50% to 80% of patients at the onset of symptoms, and this increases to 90% at three months. ALT levels are elevated at 2 to 8 weeks. Acute infection can be severe but is rarely fulminant.
Chronic HCV is defined by the detection of HCV RNA for at least 6 months. In general, prospective studies have suggested that approximately 80% of HCV infected patients develop chronic infection. Factors associated with spontaneous clearance of the infection include younger age, female gender, and certain histocompatibility complexes. African-Americans appear to be least likely to spontaneously clear the infection.
The major late sequelae of chronic infection is cirrhosis, which is seen in 20% to 25% after 20 years (in retrospective studies) and in 2% to 4% (in prospective studies). This risk is not influenced by viral load, viral genotype, or quasi species diversity. However, host risks for cirrhosis include longer duration of infection, older age, male gender, immunosuppression (HIV infection), HBV co-infection and alcohol use (defined as 40-60 g/day). Other factors include iron overload, nonalcoholic fatty liver disease, and hepatotoxic medications. One-third of patients with hepatocellular cancer (HCC) have HCV as a risk factor. HCC rarely occurs without cirrhosis or advanced fibrosis. The incidence of HCC is continuing to rise in the U.S. and worldwide. Extra hepatic manifestations of HCV include rheumatoid symptoms, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, and essential mixed cryoglobulinemia and are thought to be of immunologic origin. Cryoglobulins have been found in up to one-half of patients with chronic HCV infection, but symptoms occur significantly less frequently.
What is the Most Appropriate Approach to Diagnosis and Monitoring?
EIA tests are reproducible, inexpensive, and are approved by the FDA for the diagnosis of HCV. They are suitable for screening at risk populations, as they have a very high sensitivity and specificity (exceeding 99%). A negative EIA excludes the diagnosis in immunocompetent patients, but not in immunodeficient patients. False positives occur with autoimmune disorders, and these cases require HCV RNA for confirmation with RIBA.
Persistent HCV infection in a patient with a positive EIA should be confirmed with a PCR. The FDA-approved qualitative HCV PCR has a threshold detection of 50 IU/mL. Transcription-mediated amplification (TMA) has a lower threshold for detection, but is not approved by the FDA. Sensitivity of these assays is over 98%. Testing for HCV RNA can provide an accurate assessment of the HCV viral titer. Viral load (HCV RNA level) is measured by quantitative PCR (qPCR) or branched DNA (bDNA) and reported in international units (IU). Significant variability exists between available assays. While there is little correlation between disease severity or progression with the absolute titer of HCV RNA, deter-mination of the quantitative HCV titer can provide important information in assessing the response to treatment. Serum alanine aminotransferase (ALT) is the least expensive test to measure disease activity, but it does not correlate with severity of histopathology by liver biopsy. Serial measurements are recommended for monitoring, but do not assess progression to cirrhosis.
Liver biopsy provides information on fibrosis and histology assessment and information about concurrent liver disease due to other causes. It may help guide the decision regarding therapy: Absent or minimal fibrosis may encourage deferral, though the response with genotypes 2 or 3 is so good (80%) that routine pretreatment biopsy is sometimes considered unnecessary.
Hepatocellular cancer screening is not well studied in HCV patients. While the incidence of HCC is 0% to 3% per year after the onset of cirrhosis, no study has been able to identify a screening or surveillance protocol that improved long-term survival. One study evaluating alpha-fetoprotein and ultrasound every six months in patients with HCV showed earlier detection of HCC, but no survival analysis was performed. Therefore, further studies are needed to identify the most appropriate HCC screening protocols.
What is the Most Effective Therapy for Hepatitis C?
Since the 1997 NIH Consensus Development Conference on Management of Hepatitis C, many new therapies have been identified. Combination therapy results in better treatment responses than monotherapy. The highest response rates have been found with pegylated (PEG) interferon in combination with ribavirin. Genotype determinations influence treat-ment decisions as genotypes 2 and 3 have much higher response rates than genotypes 1 and 4.
The best indicator of effective therapy is “sustained virological response” (SVR), defined as the absence of qualitative HCV RNA by RT-PCR after 24 weeks of treatment. The highest response rates have been demonstrated in the trials with PEG-interferon plus ribavirin. Of note, these trials excluded patients with decompen-sated liver disease, cirrhosis, and other medical co-morbidities.
• Initial Treatment: SVR results are similar for PEG-interferon alpha 2A or alpha 2B when each is combined with ribavirin. Results of three large pivotal studies are summarized below:
In all three trials, the SVR for genotype 1 was based on higher doses of PEG-IFN and ribavirin for 48 weeks. Treatment for 24 weeks with lower dose ribavirin appears adequate for genotypes 2 and 3. Early viral response (EVR) is defined as a two-log decrease in viral load. EVR at 12 to 24 weeks of treatment predicts SVR, and those who fail to achieve EVR have little probability of achieving SVR even if therapy is continued a full year. Of note, SVR has not yet been correlated with improved survival. However, longer-term follow-up of these patients is currently in progress.
• Re-treatment: Decisions regarding re-treatment should be based on the following:
Definition of Previous Treatment Response
Side effects are severe enough to require discontinuation in 20% of patients in the PEG-interferon and ribavirin registration trials. The most common side effects are influenza-like symptoms, bone marrow suppression, and neuropsychiatric symptoms. Often these side effects can be adequately treated with growth factors and antidepressants.
All patients with chronic hepatitis C are potential candidates for antiviral therapy. The major indication for treatment is the risk for progression to cirrhosis based on measurable HCV RNA and liver biopsy showing portal or bridging fibrosis and at least moderate inflammation and necrosis. Age and prior behavior should not be factors in the decision to treat. Modifying circumstances include:
• Normal ALT: Thirty percent of patients with chronic HCV have a normal ALT, and an additional 40% have elevated levels that are less than two times the upper limit of normal (ULN). Currently, “experts differ on the indications for biopsy and treatment” and studies are underway to identify patients most likely to benefit from treatment. Notably, studies of PEG-interferon and ribavirin have not been completed in patients with normal ALT levels.
• Biopsy results: In patients with elevated ALT and no fibrosis plus minimal inflammation, the current recommend-ation is to monitor liver function tests and potentially to repeat the liver biopsy in 3 to 5 years. In patients with advanced liver disease (advanced fibrosis or compensated cirrhosis), sub-group analysis of studies to date have shown lower rates of SVR. However, this group of patients is being evaluated in the HALT-C trial, which should provide recommendations on re-treatment. In patients with decompen-sated cirrhosis, the main treatment is transplantation. Although re-treatment should be considered, this approach may be limited by potentially life-threatening side effects of antiviral therapy.
• Acute HCV: Currently the data available are inadequate for making a recommendation.
• Injection drug users: Data are available for treatment of HCV-infected IDUs who are in drug treatment programs. These studies show success even with continued drug use or with concurrent methadone treatment. Therefore, efforts should be made to promote collaboration between HCV experts and substance abuse providers. It should be noted that there are few data available on HCV treatment in active IDUs who are not in drug treat-ment programs.
• HIV coinfection: All HIV infected patients should be screened for HCV. Coinfection accelerates the course of HCV and HIV. Although there are no HCV therapies specifically approved for patients with HIV, these patients should be considered for treatment. Thus far, studies have only enrolled patients with stable HIV infection and well compensated liver diseases. However, in these patients, SVR can be achieved, and preliminary data suggest better responses to PEG-interferon with ribavirin than to standard interferon and ribavirin. Although treatment of HCV has not jeopardized control of HIV infection, additional studies are needed to further evaluate this possibility.
• Alcohol: Continued use of alcohol adversely affects outcome of treatment. Currently, treatment of HCV should be performed in conjunction with efforts to treat alcohol dependence. Heavy alcohol use (>80 g/day) seriously compromises HCV treatment; therefore, HCV treat-ment should be combined with abstinence whenever possible.
Injection drug use accounts for over two-thirds of new infections; therefore, it is assumed that drug rehabilitation and needle exchange programs should reduce transmission. Sexual transmission appears to be infrequent based on a seroprevalence of only 2% to 3% in partners of HCV-infected persons in long-term mono-gamous relationships and 4% to 6% among persons with multiple sex partners, sex workers and those at risk for sexually transmitted diseases. For heterosexual discordant couples, the estimated risk of transmission in this setting is 0% to 0.6% per year, with the risk to females being three-fold greater than to male partners. Use of condoms may decrease HCV transmission and should be encouraged, especially for those at risk for other sexually transmitted diseases. The risk of occupational exposure with a needle stick injury from an HCV-infected source is about 2% and currently postexposure antiviral therapy is not recommended. Perinatal transmission is approximately 2% for infants from an HIV infected mother and is higher with high maternal viral load, injection drug use (10%), and with HIV co-infection (20%). Ribavirin and interferon are contraindicated during pregnancy and there are no data on Caesarean section and the risk of trans-mission. Breastfeeding does not appear to transmit HCV. Low transmission rates (less than 1%) are associated with body piercing and tattooing.
The panel recommended that the NIH establish a Hepatitis Clinical Research Network. The goal of this network should be to conduct research related to the natural history, prevention, and treatment of hepatitis C. In addition, they recommended organizing randomized controlled trials to extend treatment to special populations not represented in current trials to determine the applicability of current antiviral combinations in those with acute hepatitis, hemophilia, stabilized depression, and HIV co-infection, as well as in IDUs and alcoholics. Such an effort should lead to decreased HCV related morbidity and mortality as well as a decrease in the reservoir of disease.
Comment from authors: This summary is based on the draft guidelines. There may be changes to the final version, but we expect that they will be minor, particularly with regard to treatment issues. Issues of particular interest and controversy are diagnostic testing and the proper duration of treatment for genotype 1 infections. Many of the initial trials used 48 weeks if the EVR showed good viral response at 12 to 24 weeks; however, the ideal treatment duration has not been defined.
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