NIH - Excerpts from Management of Hepatitis C
National Institutes of Health
Consensus Development Statement
Management of Hepatitis C
March 24-26, 1997
What Are the Most Important Areas for Future Research?
- Continued monitoring of the epidemiology of acute and chronic hepatitis C is necessary. Additional studies of the specific mode of transmission in minority groups, low socioeconomic groups, institutionalized individuals, and injection and intranasal drug users are needed, as well as more information on sexual, household, occupational, nosocomial, and perinatal transmission.
- Large-scale, long-term studies are needed to better define the natural history of hepatitis C and especially to identify factors associated with disease progression to cirrhosis. Studies of the natural history are needed in special groups, such as minorities, children, those over 60, HCV-infected patients with normal ALT, HCV-infected patients coinfected with HIV, and injection drug users. Information is also needed about the role of ultrasound and alpha fetoprotein monitoring for early detection of hepatocellular carcinoma in patients with chronic hepatitis C.
- Studies are needed on the recovery from and persistence of viral infection as well as the pathogenesis and mechanism of liver cell injury by HCV. Is damage due to cytopathic effects of the virus on the liver cell, or is it immunologically mediated? What is the mechanism of hepatic fibrosis? Can fibrosis be separated from inflammation/necrosis of the liver? Such studies would be greatly facilitated by development of suitable animal and cell culture models. The mechanism of development of hepatocellular carcinoma in patients with hepatitis C needs elucidation.
- Given the large number of persons who are already infected with HCV, there is an urgent need for effective antiviral therapeutics capable of inhibiting virus replication and stopping or delaying the progression of liver disease. A major bottleneck to the drug discovery process is the absence of a readily available cell culture system that is fully permissive for viral replication. Thus, development of such systems should be a high priority. An improved understanding of the molecular virology of HCV is also critically important to antiviral drug development. These studies should include the development of infectious molecular clones, which would allow analyses of structure-function relations among HCV nonstructural proteins that participate in the viral replication cycle.
- Alcohol ingestion clearly worsens the course of hepatitis C, but the reasons for this interaction are unknown. Studies of the interaction between HCV and obesity, diabetes mellitus, iron, and medications are also needed.
- Unresolved questions remain regarding the diagnostic tests for hepatitis C. What is the prevalence of significant liver disease among RIBA-positive, HCV RNA-negative individuals? What should be the gold standard for HCV RNA assays? What is the frequency of intermittent viremia in untreated patients? What are the criteria for selecting patients for, or withdrawing patients from, treatment? How can the reliability of HCV RNA tests be improved? How can the dynamic range and intra-assay variability of the HCV RNA test be improved?
- Future clinical trials should expand the range of outcomes studied to include quality of life from the patient's point of view, as well as costs and survival. In addition, those trials should include minorities, patients over age 60, patients under age 18, HIV-coinfected patients, and liver transplant patients. We need to identify effective, nontoxic therapeutic agents. Clinical trials are also needed to identify optimal treatment regimens for those who do not respond to interferon therapy, or who relapse following interferon therapy. Prospective studies are needed to identify and test prospectively the factors that predict response to therapy. In addition, studies are needed of possible drug interactions, especially between the antiretroviral drugs used to treat HIV infection and those drugs used to treat hepatitis C.
- Although continued education of risk groups and screening of blood, organs, tissue, and semen remain vitally important, the key to prevention is development of an effective and safe vaccine for hepatitis C. This will require a better understanding of the molecular determinants of both cellular and humoral immunity to HCV, the nature of antigenic variation as related to viral quasispecies diversity, and the mechanism(s) by which HCV regularly eludes the host immune system and establishes persistent infection.
- Strategies should be developed to educate at-risk groups concerning transmission of disease, as well as provide access to diagnosis and treatment. It would be helpful also to evaluate the role of intranasal cocaine use as a possible route of infection.
Conclusions and Recommendations
- Individuals who have a history of transfusions of blood or blood products prior to 1990, who are on chronic hemodialysis, who have a history of injection drug use, who have had multiple sexual partners, who are the spouses or close household contacts of hepatitis C patients, and who share instruments for intranasal cocaine use should be tested for hepatitis C.
- Hepatitis C is a common infection with variable course that can lead to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. The course of illness may be adversely affected by various factors, especially alcohol consumption. Therefore, more than one drink per day is strongly discouraged in patients with hepatitis C, and abstinence from alcohol is recommended. Those addicted to alcohol or drugs should be helped to obtain treatment for their addiction so that they might qualify for anti-HCV therapy.
- An EIA test for anti-HCV should be the initial test for diagnosis of hepatitis C. In low-risk populations, a supplemental RIBA test and/or a qualitative PCR test for HCV RNA should be performed in those whose EIA test is positive. In patients with clinical findings of liver disease, HCV RNA by PCR can be used for confirmation.
- Because of assay variability, qualitative and quantitative PCR testing for HCV RNA must be interpreted cautiously. Rigorous proficiency testing is recommended for clinical laboratories performing this assay. The branched DNA signal amplification assay for viral level has been standardized, but may fail to detect low titers of HCV RNA. Sequential measurement of HCV RNA levels (viral load) has not, to date, proven useful in managing patients with hepatitis C.
- Liver biopsy is indicated when histologic findings will assist decisionmaking regarding patient management. In patients who are not treated with antiviral therapy initially, liver biopsy can be considered to assess disease progression.
- HCV genotyping and tests for HCV RNA levels (viral load) may provide useful prognostic information, especially regarding response to therapy, but at present must be considered research tools.
- Currently available therapy for chronic hepatitis C is indicated for patients who have persistently abnormal ALT (greater than 6 months), a positive HCV RNA, and liver biopsy demonstrating either portal or bridging fibrosis and at least moderate degrees of inflammation and necrosis. Patients with milder histological disease, compensated cirrhosis, or who are under age 18 or over 60 should be managed on an individual basis or in the context of clinical trials. Patients with decompensated cirrhosis should not be treated with interferon but should be considered for liver transplantation. Patients with persistently normal ALT and minimal histologic abnormalities should not be treated outside clinical trials. Contraindications to treatment of patients with interferon that must be considered are a history of major depressive illness, cytopenia, active alcohol use or illicit drug use, hyperthyroidism, renal transplantation, or autoimmune disease. Therapy should not be limited by mode of acquisition, risk group, HIV status, HCV RNA level, or genotype.
- Because 12-month regimens with interferon are more successful in achieving sustained responses, initial therapy with interferon alfa (or its equivalent) should be 3 million units three times weekly subcutaneously for 12 months.
- Nonresponders to interferon therapy can be identified early by assessing the serum ALT level and presence of serum HCV RNA after 3 months of therapy. If the ALT level remains abnormal and the serum HCV RNA remains detectable, interferon therapy should be stopped, because further treatment is unlikely to produce a response. Nonresponders should not be retreated with the same regimen, but should be considered for combination therapy or enrollment in investigational protocols using different dosages or agents.
- Patients who have an end-of-treatment response to a 6-month course of interferon alfa, but then relapse, should receive retreatment with a 12-month course of interferon alfa or be considered for combination therapy with interferon plus ribavirin or other regimens, preferably in a clinical trial.
- Hepatitis A and B vaccination is recommended for all HCV-positive patients.
- Patient support groups should be encouraged, especially for those undergoing therapy, those who fail therapy, and also those recovering from addiction.
The following recommendations are made to avoid transmission of hepatitis C:
- In health care settings, adherence to universal (standard) precautions for the protection of medical personnel and patients is essential.
- HCV-positive individuals should refrain from donating blood, organs, tissues, or semen. In some situations, the use of organs and tissues from HCV-positive individuals may be considered. For example, in emergency situations the use of a donor organ in which the HCV status is either positive or unknown may be considered in a HCV-negative recipient after full disclosure and informed consent. Strategies should be developed to identify prospective blood donors with any prior history of injection drug use. Such individuals must be deferred from donating blood.
- Safer sexual practices should be strongly encouraged in persons with multiple sexual partners, including the use of latex condoms. In monogamous long-term relationships, transmission is rare. Although HCV-positive individuals and their partners should be informed of the potential for transmission, there are insufficient data to recommend changes in current sexual practice in persons with a steady partner. It is recommended that sexual partners of infected patients should be tested for antibody to HCV.
- In households with an HCV-positive member, sharing razors and toothbrushes should be avoided. Covering open wounds is recommended. Injection needles should be carefully disposed of using universal precaution techniques. It is not necessary to avoid close contact with family members or to avoid sharing meals or utensils. There is no evidence to justify exclusion of HCV-positive children or adults from participation in social, educational, and employment activities.
- Pregnancy is not contraindicated in HCV-infected individuals. Perinatal transmission from mother to baby occurs in less than 6 percent of instances. There is no evidence that breast-feeding transmits HCV from mother to baby; therefore, it is considered safe. Babies born to HCV-positive mothers should be tested for anti-HCV at 1 year.
- Needle exchange and other safer injection drug use programs may be of benefit in reducing parenterally transmitted diseases. Expansion of such programs should be considered in an effort to reduce the rate of transmission of hepatitis C.
- It is important that clear and evidenced-based information be provided to both patients and physicians regarding the natural history, means of prevention, management, and therapy of hepatitis C.