E-Notes for Adult Medicine Stat | Lytes | Drugs |  ID  | Heart | Lungs | Kidneys |  GI  | Rheum | Heme-Onc | Endo | Neuro | Derm | Misc. | Resource | Home Management of Hepatitis C National Institutes Of Health Consensus Development Conference Statement  March 24-26, 1997 Management of Hepatitis C. 1997 March 24-26;15(3):1-41.  Abstract  Introduction  1. What is the Natural History of Hepatitis C?  2. What is the Most Appropriate Approach To Diagnose and Monitor Patients?  3. What is the Most Effective Therapy for Hepatitis C?  4. Which Patients With Hepatitis C Should Be Treated?  5. What Recommendations Can Be Made To Patients To Prevent Transmission of Hepatitis C?  6. What Are the Most Important Areas for Future Research?  Conclusions and Recommendations   Abstract Objective. To provide health care providers, patients, and the general public with a responsible assessment of current available methods to diagnose, treat, and manage hepatitis C. Participants. A non-Federal, nonadvocate, 12-member panel representing the fields of general internal medicine, hepatology, gastroenterology, infectious diseases, medical ethics, transfusion medicine, epidemiology, biostatistics, and the public. In addition, 25 experts from these same fields presented data to the panel and a conference audience of 1,600. Evidence. The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. Consensus Process. The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after conference Conclusions. Hepatitis C is a common infection with variable course that can lead to chronic hepatitis, cirrhosis, 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. Initial therapy with interferon alfa (or equivalent) should be 3 million units three times per week for 12 months. Patients not responding to therapy after 3 months should not receive further treatment with interferon alone, but should be considered for combination therapy of interferon and ribavirin or for enrollment in investigational studies. Individuals infected with the hepatitis C virus should not donate blood, organs, tissues, or semen. Safe sexual practices, including the use of latex condoms, is strongly encouraged for individuals with multiple sexual partners. Expansion of needle exchange programs should be considered in an effort to reduce the rate of transmission of hepatitis C among injection drug users.     Introduction The hepatitis C virus (HCV) is one of six viruses (A, B, C, D, E, and G) that together account for the majority of cases of viral hepatitis.According to the National Health and Nutrition Examination Survey of 1988-94 and other population-based surveys, estimates of the incidence and prevalence of HCV infection have been made. Nearly 4 million Americans are infected with hepatitis C. The infection is more common in minority populations (3.2 percent of African-Americans and 2.1 percent of Mexican-Americans) than in non-Hispanic whites (1.5 percent). The incidence of hepatitis C infection appears to be declining since its peak in 1989. Currently, approximately 30,000 acute new infections are estimated to occur each year, about 25-30 percent of which are diagnosed. Hepatitis C accounts for 20 percent of all cases of acute hepatitis. Currently, hepatitis C is responsible for an estimated 8,000-10,000 deaths annually, and without effective intervention that number is postulated to triple in the next 10-20 years. Hepatitis C is now the leading reason for liver transplantation in the United States. The switch from commercial to volunteer blood donors and the development of a diagnostic blood test for hepatitis B in the early 1970s led to screening of blood donors and reduced from 30 to 10 percent the incidence of hepatitis following multiple transfusions. The remainder of these transfusion-associated cases were termed "non-A, non-B" hepatitis. In 1989, Michael Houghton and his colleagues ushered in a new era for the discovery of infectious agents when they used molecular biologic techniques to clone hepatitis C, the agent responsible for 80-90 percent of non-A, non-B hepatitis. This was a scientific tour de force because the technique was successful in identifying an agent that had not been visualized, grown in culture, or immunologically defined. Following the introduction of sensitive and effective blood tests for the detection of hepatitis C, the risk of transfusion-related hepatitis is now in the range of 1 in 100,000 units transfused. Hepatitis C is transmitted primarily by the parenteral route, and sources of infection include injection drug use, needle-stick accidents, and transfusions of blood or blood products. Since 1990 and the introduction of tests for anti-HCV, new cases of posttransfusion hepatitis C have virtually disappeared. Hepatitis C virus is not easily cleared by the host's immunologic defenses. Thus, a persistent infection develops in perhaps as many as 85 percent of patients with acute hepatitis C. This inability to clear the virus by the infected host sets the stage for the development of chronic liver disease. The range of disease states following hepatitis C infection is broad. Lastly, in contrast to hepatitis A and B, there is no effective vaccine to prevent acquisition of hepatitis C infection. For the reasons listed above, the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Medical Applications of Research of the National Institutes of Health, along with cosponsors the National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, and Centers for Disease Control and Prevention, sponsored a Consensus Development Conference on March 24-26, 1997. Following 1-1/2 days of testimony by experts in the relevant fields and discussion from the audience, a consensus panel representing general internal medicine, hepatology, gastroenterology, infectious diseases, medical ethics, transfusion medicine, epidemiology, biostatistics, and the public considered the evidence and formulated a consensus statement to address the following six predefined questions: What is the natural history of hepatitis C? What is the most appropriate approach to diagnose and monitor patients? What is the most effective therapy for hepatitis C? Which patients with hepatitis C should be treated? What recommendations to patients can be made to prevent transmission of hepatitis C? What are the most important areas for future research?     1. What is the Natural History of Hepatitis C? The Virus The hepatitis C virus is an RNA virus of the Flaviviridae family. Individual isolates consist of closely related yet heterogeneous populations of viral genomes (quasispecies). Probably as a consequence of this genetic diversity, HCV has the ability to escape the host's immune surveillance, leading to a high rate of chronic infection. Comparing the genomic nucleotide sequences from different HCV isolates enables classification of viruses into several genotypes and many more subtypes. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining variations in clinical course, difficulties in vaccine development, and lack of response to therapy. Clinical Course Data on the natural history of hepatitis C are limited, because the onset of infection is often unrecognized and the early course of the disease is indolent and protracted in many individuals. Prospective cohort studies are few, are typically small, include relatively few subjects whose date of infection can be well documented (e.g., blood transfusion recipients and victims of accidental needle sticks), and have relatively short followup. The natural history of this disease appears to differ according to geography, alcohol use, virus characteristics (e.g., genotype, viral load), coinfection with other viruses, and other unexplained factors. Acute Infection After initial exposure, HCV RNA can be detected in blood in 1-3 weeks.Within an average of 50 days (range: 15-150 days), virtually all patients develop liver cell injury, as shown by elevation of serum alanine aminotransferase (ALT). The majority of patients are asymptomatic and anicteric. Only 25-35 percent develop malaise, weakness, or anorexia, and some become icteric. Fulminant liver failure following HCV infection has been reported but is a rare occurrence. Antibodies to HCV (anti-HCV) almost invariably become detectable during the course of illness. Anti-HCV can be detected in 50-70 percent of patients at the onset of symptoms and in approximately 90 percent of patients 3 months after onset of infection. HCV infection is self-limited in only 15 percent of cases. Recovery is characterized by disappearance of HCV RNA from blood and return of liver enzymes to normal. Chronic Infection About 85 percent of HCV-infected individuals fail to clear the virus by 6 months and develop chronic hepatitis with persistent, although sometimes intermittent, viremia. This capacity to produce chronic hepatitis is one of the most striking features of HCV infection. The majority of patients with chronic infection have abnormalities in ALT levels that can fluctuate widely. About one-third of patients have persistently normal serum ALT levels. Antibodies to HCV or circulating viral RNA can be demonstrated in virtually all patients. Chronic hepatitis C is typically an insidious process, progressing, if at all, at a slow rate without symptoms or physical signs in the majority of patients during the first two decades after infection. A small proportion of patients with chronic hepatitis C -- perhaps less than 20 percent -- develop nonspecific symptoms, including mild intermittent fatigue and malaise. Symptoms first appear in many patients with chronic hepatitis C at the time of development of advanced liver disease. In chronic hepatitis, inflammatory cells infiltrate the portal tracts and may also collect in small clusters in the parenchyma. The latter instance is usually accompanied by focal liver cell necrosis. The margin of the parenchyma and portal tracts may become inflamed, with liver cell necrosis at this site (interface hepatitis). If and when the disease progresses, the inflammation and liver cell death may lead to fibrosis. Mild fibrosis is confined to the portal tracts and immediately adjacent parenchyma. More severe fibrosis leads to bridging between portal tracts and between portal tracts and hepatic veins. Such fibrosis can progress to cirrhosis, defined as a state of diffuse fibrosis in which fibrous septae separate clusters of liver cells into nodules. The extent of fibrosis determines the stage of disease and can be reliably assessed. Severe fibrosis and necroinflammatory changes predict progression to cirrhosis. Once cirrhosis is established, complications can ensue that are secondary to liver failure and/or to portal hypertension, such as jaundice, ascites, variceal hemorrhage, and encephalopathy. The development of any of these complications marks the transition from a compensated to a decompensated cirrhosis. The rate of progression is highly variable. Long-term studies suggest that most patients with progressive liver disease who develop cirrhosis have detectable ALT elevations; these can, however, be intermittent. The relationship is inconsistent between ALT levels and disease severity as judged histologically. Although patients with HCV infection and normal ALT levels have been referred to as "healthy" HCV carriers, liver biopsies can show histological evidence of chronic hepatitis in many of these patients. Cirrhosis of the Liver Chronic hepatitis C infection leads to cirrhosis in at least 20 percent of patients within 2 decades of the onset of infection. Cirrhosis and end-stage liver disease may occasionally develop rapidly, especially among patients with concomitant alcohol use. Hepatocellular Carcinoma (HCC) Chronic infection by HCV is associated with an increased risk of liver cancer. The prevailing concept is that hepatocellular carcinoma (HCC) occurs against a background of inflammation and regeneration associated with chronic hepatitis over the course of approximately 3 or more decades. Most cases of HCV-related HCC occur in the presence of cirrhosis. The risk that a person with chronic hepatitis C will develop HCC appears to be 1-5 percent after 20 years, with striking variations in rates in different geographic areas of the world. Once cirrhosis is established, the rate of development of HCC increases to 1-4 percent per year. Among patients with cirrhosis due to hepatitis C, HCC develops more commonly in men than in women and in older than in younger patients. Extrahepatic Manifestations of HCV Patients with chronic hepatitis C occasionally present with extrahepatic manifestations or syndromes considered to be of immunologic origin, including arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, and essential mixed cryoglobulinemia. Cryoglobulins may be detected in the serum of about one-third of patients with HCV, but the clinical features of essential mixed cryoglobulinemia develop in only about 1-2 percent of patients. Chronic hepatitis C may be a major underlying cause of porphyria cutanea tarda. Mortality After an average followup of 18 years, a prospective study of patients who received blood transfusions showed no difference in overall mortality between HCV-infected cases and noninfected controls. Liver-related mortality, although rare, was twice as high in the cases (3.2 percent vs. 1.5 percent). A recent European study showed that survival among hepatitis C patients with compensated cirrhosis was 91 percent after 5 years and 79 percent after 10 years. Among patients developing decompensated cirrhosis, however, 5-year survival was only 50 percent.     2. What is the Most Appropriate Approach To Diagnose And monitor Patients? A variety of tests are available for hepatitis C diagnosis. Tests that detect antibody against the virus include the enzyme immunoassays (EIAs), which contain HCV antigens from the core and nonstructural genes, and the recombinant immunoblot assays (RIBAs), which contain the same HCV antigens as EIA in an immunoblot format. In addition, several polymerase chain reaction (PCR)-based assays for HCV RNA have been developed to detect the RNA virus directly. Liver biopsy can determine the extent of liver injury due to HCV. Although some histologic findings are characteristic of HCV infection, such as portal lymphoid aggregates, steatosis, and bile duct injury, these alone are not sufficiently specific to establish a diagnosis of hepatitis C. There are currently no reliable, readily available tests for detection of HCV antigens in the liver. The EIA tests are reproducible and inexpensive and have been automated. They are suitable for screening low- and high-prevalence populations and as an initial test for patients with clinical liver disease. The RIBA test is most frequently used as a supplemental assay. Qualitative HCV RNA detection by reverse transcription (RT)-PCR is generally accepted as the most sensitive test, and a standardized assay has been developed. However, significant variability of results among laboratories has been reported in proficiency surveys. Clinicians should be aware of the proficiency record of laboratories performing HCV RNA testing to ensure test accuracy for their patients. Using carefully standardized research PCR tests for HCV RNA as a reference standard, the sensitivity of the second-generation enzyme immunoassay, EIA-2, is 92-95 percent. Its specificity has not been precisely established. Studies performed to date indicate that 25-60 percent of blood donors with no risk factors for hepatitis C who are positive by the EIA-2 test are also positive by the PCR test for HCV RNA. Of low-risk donors who are both EIA-2 and RIBA-positive, 70-75 percent are positive for HCV RNA. Positive predictive values are much higher in patients with hepatitis C risk factors, elevated ALT levels, or clinical liver disease. Practitioners frequently encounter patients suspected of having HCV infection.In low-risk populations, such as blood donors who report no risk factors for HCV (e.g., parenteral drug use, history of transfusion, multiple sexual partners), a negative EIA test is sufficient to rule out infection. However, low-risk individuals with positive EIA tests should undergo supplementary RIBA testing. If the RIBA is negative, the anti-HCV EIA result is likely to have been a false positive, and the patient is unlikely to have hepatitis C. If the RIBA is positive, the patient can be assumed to have or to have had hepatitis C. These patients can benefit by testing for HCV RNA by PCR, the result of which will indicate whether the patient has ongoing viremia or not. A single positive assay for HCV RNA by PCR confirms HCV infection; unfortunately, a single negative assay does not prove that the patient is not viremic or has recovered from hepatitis C. Followup testing for ALT levels and perhaps repeating the HCV RNA in the future may be needed. If the results of the RIBA are "indeterminate," followup testing is indicated to demonstrate whether HCV RNA is present. It is hoped that further advances in anti-HCV testing will eventually decrease the percentage of false-positive EIA and indeterminate RIBA results. Individuals with even mildly elevated ALT levels, with or without risk factors for hepatitis C, should be tested for anti-HCV by EIA and, if positive, the results confirmed by either supplemental RIBA or qualitative HCV RNA by PCR. Obviously anti-HCV testing is very helpful in all patients with clinical liver disease. In patients presenting with biochemical or clinical evidence of liver disease (e.g., repeatedly elevated ALT levels), a positive EIA test is sufficient to diagnose hepatitis C infection, especially if risk factors are present. A qualitative HCV RNA test can be used for confirmation. If the patient is being considered for antiviral therapy, liver biopsy is of value to assess disease severity. Testing for serum ALT levels is the most inexpensive and noninvasive means of assessing disease activity. However, a single determination of ALT levels is not always accurate in reflecting the severity of the underlying liver disease. In most studies, there is only a weak association between ALT levels and severity of the histopathological findings on liver biopsy. Serial determinations of ALT levels over time may provide a better means of assessing liver injury, but the accuracy of this approach has not really been shown. Nevertheless, the resolution of elevated ALT levels with antiviral therapy does appear to be an important indicator of disease response, and serial determinations of ALT levels can be recommended as the general means of monitoring patients with this disease. Testing for HCV RNA by PCR can be very helpful in initial diagnosis, but repeat testing over time is generally not helpful in management of untreated patients; almost all remain viremic, and a negative result may merely reflect a transient fall of viral titer below the level of detection rather than permanent clearance. On the other hand, repeat testing for HCV RNA during antiviral therapy can be helpful, because loss of HCV RNA with treatment is a strong predictor of a sustained beneficial response. Testing for HCV RNA level (or viral load) by a quantitative assay, either quantitative PCR (qPCR) or the branched DNA signal amplification assay (bDNA), can provide accurate information on viral titer. In many studies, the likelihood of a response to interferon alfa has correlated with a low level of HCV RNA present before treatment. However, there is no level of HCV RNA that absolutely precludes the possibility of a response and there is little or no correlation between disease severity or disease progression and level or titer of HCV RNA. Furthermore, current assays are not as sensitive as the standard, qualitative PCR test and suffer from lack of standardization. Thus, sequential testing for HCV RNA levels is not clinically helpful in management of patients. At least 6 genotypes and more than 30 subtypes of HCV RNA have been identified. HCV genotype may be an independent predictor of response to interferon alfa therapy. In many studies, patients with genotypes 2 and 3 are more likely to have a sustained treatment response than those with genotypes 1a or 1b. Methods of genotyping include PCR-based techniques and, more recently, less expensive serotyping (antibody) assays. However, both genotyping and serotyping should be considered research tools and not part of a diagnostic or therapeutic algorithm in clinical practice. Liver biopsy is considered the gold standard for assessment of patients with chronic hepatitis.When combined with serial determinations of ALT levels, liver biopsy is very helpful in judging the severity or activity of the liver disease and the stage or degree of fibrosis. Liver biopsy is recommended before treatment to assess the grade and stage of disease and to exclude other forms of liver disease or complications (such as concurrent alcoholic liver disease, medication-induced liver injury, and iron overload). However, liver biopsy is expensive and is associated with some morbidity. Therefore, serial ALT and qualitative HCV RNA testing are recommended for monitoring patients under treatment.     3. What is the Most Effective Therapy for Hepatitis C? Although several different forms of interferon have been evaluated in the treatment of patients with chronic hepatitis C, the bulk of available evidence pertains to the alpha interferons (interferon alfa). The efficacy of interferon alfa therapy currently is defined biochemically as normalization of serum ALT and virologically as loss of serum HCV RNA. Serum ALT and HCV RNA are measured at two time points: at the end of treatment (End-of-Treatment Response [ETR]) and 6 months posttreatment (Sustained Response [SR]). Based on these markers, randomized clinical trials have demonstrated that treatment with interferon alfa benefits some patients with chronic hepatitis C. In terms of biochemical response, treatment with interferon alfa at a dosage of 3 million units administered subcutaneously three times weekly for 6 months has produced a biochemical ETR of 40-50 percent and a biochemical SR of 15-20 percent. In terms of virological response, the 6-month course of treatment has produced an ETR of 30-40 percent and an SR of 10-20 percent. The biochemical and virological improvement has been accompanied by histological improvement. Increasing the duration of treatment to 12 months is not associated with higher biochemical or virological ETR, but the biochemical SR is increased to 20-30 percent. For patients who do not achieve a biochemical or virological ETR (nonresponders), retreatment with a standard dose of interferon alfa is rarely effective. Further therapy with newer interferons and/or higher dosages may achieve a virological SR of only 10 percent. For patients who achieve a biochemical ETR with 6 months of treatment, but who relapse during followup, retreatment for 12 months has been associated with a biochemical ETR rate of 75-85 percent and an SR rate of 30-40 percent. The benefit of treatment of longer duration is still being evaluated. It should be recognized that although interferon treatment may be associated with favorable effects on biochemical and virological markers, its effects on important clinical outcomes such as quality of life and disease progression remain undetermined. Three months after beginning an initial course of therapy, patients who are unlikely to respond to that dosage and frequency can be identified by persistent elevation of serum ALT levels and presence of HCV RNA in the serum.In this situation, therapy should be discontinued because the likelihood of future response is extremely low. If either HCV RNA is negative or ALT levels are normal (or both), therapy should be continued for 12 months. Nonresponders should be encouraged to participate in clinical trials directed toward this difficult-to-treat group. Most of the clinical trials in chronic hepatitis C have evaluated interferon alfa-2b. Other trials have used interferon alfa-2a, interferon alfa-n1, consensus interferon, interferon beta, and interferon alfa-n3. All forms of interferon appear to have similar efficacy in chronic hepatitis C. Because most patients do not experience sustained response, attempts have been made to identify individuals who are more likely to respond to therapy. The important factors associated with a favorable response to treatment include HCV genotype 2 or 3, low serum HCV RNA level (less than 1,000,000 copies/ml), and absence of cirrhosis. Flulike symptoms (fever, chills, malaise, headache, arthralgia, myalgia, tachycardia) occur early in the majority of patients who receive interferon, but generally diminish with continued therapy. Later side effects include fatigue, alopecia, bone marrow suppression, and neuropsychiatric effects such as apathy, cognitive changes, irritability, and depression. Relapse of drug and/or alcohol abuse may occur. Nocturnal administration of interferon reduces the frequency of side effects, and the flulike syndrome is ameliorated by pretreatment with acetaminophen. A reduction in interferon dosage is required in 10-40 percent of patients because of side effects, and treatment must be discontinued in 5-10 percent. Higher dosages tend to be associated with higher rates of side effects. Severe side effects are observed in less than 2 percent of patients. These include autoimmune disease (thyroid disease being most common), depression with suicidal risk, seizure disorder, acute cardiac and renal failure, retinopathy, interstitial pulmonary fibrosis, hearing impairment, and sepsis. Rare deaths have occurred due to liver failure or sepsis, principally in patients with cirrhosis. An important side effect of interferon in hepatitis C is a paradoxical worsening of liver disease with therapy. This exacerbation of hepatitis is probably an autoimmune reaction, and it can be severe. Indeed, fatal occurrences have been reported. Thus, patients with hepatitis C whose serum ALT levels increase on therapy should be followed more carefully, and if levels rise to greater than twice the baseline, interferon should be promptly discontinued. It is appropriate that a percutaneous liver biopsy be obtained before initiating therapy with interferon in order to assess the degree of necroinflammatory activity, the extent of fibrosis, and the presence of any other cause of liver injury.Laboratory tests that should be obtained before starting therapy include liver chemistries (serum ALT, bilirubin, albumin, prothrombin time), complete blood count (CBC) with differential and platelet count, antinuclear antibodies, thyroid stimulating hormone, serum HCV RNA, and glucose. Monitoring during therapy should be done at 2- to 4-week intervals with serum ALT and CBC. Both serum ALT and serum HCV RNA testing should be done after 3 months to assess whether the patient is responding to therapy. This should be repeated at the end of therapy to document end-of-treatment response. Followup testing, with serum ALT and serum HCV RNA, should be done 6 months after therapy is stopped to determine whether there has been a sustained response. Followup liver biopsy is not necessary. Disappointing results with interferon have prompted interest in new treatment approaches to chronic hepatitis C. Early work with corticosteroids, ursodiol, and thymosin has produced scant or no evidence of sustained benefit. High concentrations of iron in liver tissue may blunt the response to interferon. This has sparked interest in iron reduction therapy, through phlebotomy or chelation, in an attempt to enhance the response to interferon. Thus far, studies of iron reduction have been inconclusive. The adjunctive drug of most promise, at present, is ribavirin, an oral antiviral agent that, when used alone, reduces serum ALT levels in approximately 50 percent of patients. However, ribavirin by itself does not lower serum HCV RNA levels, and relapses occur in virtually all patients when therapy is stopped. Of greater promise are recent reports that the combination of interferon alfa and ribavirin leads to higher sustained virological response rates (40-50 percent) than interferon alfa alone in 6-month clinical trials. Ribavirin has not been licensed or approved for use in hepatitis C by the Food and Drug Administration. Large-scale trials of the combination in hepatitis C are now under way. Combination therapy with ribavirin and interferon has also shown promise in the retreatment of those who relapse. Hemolytic anemia has been the major side effect of ribavirin, necessitating a dosage reduction in more than 10 percent of patients.     4. Which Patients With Hepatitis C Should Be Treated? All patients with chronic hepatitis C are potential candidates for specific therapy. However, given the current status of therapies for hepatitis C, treatment is clearly recommended only in a selected group of patients. In others, treatment decisions are less clear and should be made on an individual basis or in the context of clinical trials. Treatment is recommended for the group of patients with chronic hepatitis C who are at the greatest risk for progression to cirrhosis. These patients are characterized by persistently elevated ALT, positive HCV RNA, and a liver biopsy with either portal or bridging fibrosis and at least moderate degrees of inflammation and necrosis. Indication for therapy is less obvious in other groups of patients. One such group consists of patients with persistent ALT elevations, but with less severe histological changes -- that is, no fibrosis and minimal necroinflammatory changes. In these patients, progression to cirrhosis is likely to be slow, if at all; therefore, observation and serial measurements of ALT and liver biopsy every 3-5 years is an acceptable alternative to treatment with interferon. Another such group consists of patients with compensated cirrhosis (without jaundice, ascites, variceal hemorrhage, or encephalopathy), in whom current data do not definitively show that interferon therapy will prolong survival or delay development of hepatocellular carcinoma. Similarly, firm recommendations on treatment with interferon cannot be made for patients below age 18 or over age 60 because of incomplete data. In all these groups of patients, treatment decisions should be made jointly between patient and physician, after full discussion of risks and benefits. However, where possible, treatment in these instances should be undertaken in the context of clinical trials, so that data become available for future decisionmaking. Patients with decompensated cirrhosis should not be treated with currently available therapy for hepatitis C and should be considered for liver transplantation. Therapeutic trials for hepatitis C in these patients should be performed only in the setting of clinical trials carried out in collaboration with liver transplant centers. Data suggest a benefit from interferon treatment with higher clearance of HCV RNA in patients with acute hepatitis C. In light of these findings, interferon treatment of patients with acute hepatitis C could be recommended. Current studies suggest that treatment of patients with persistently normal ALT is not beneficial and may actually induce liver enzyme abnormalities. Therefore, these patients should not receive therapy outside of placebo-controlled clinical trials. Nonspecific symptoms such as fatigue are difficult to interpret and should not influence treatment decisions. However, patients with clinical evidence of essential mixed cryoglobulinemia could benefit from long-term therapy with interferon. Because severity of disease or progression to cirrhosis has not been conclusively related to the mode of acquisition of hepatitis C or to particular risk groups, therapy should not be denied on the basis of these factors. However, treatment of patients who are drinking significant amounts of alcohol or who are actively using illicit drugs should be delayed until these habits are discontinued for at least 6 months. Such patients are at risk for the potential toxic effects of alcohol and other drugs and also present problems with compliance. Treatment for addiction should be provided prior to treatment for hepatitis C. Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of disease. Therefore, patients who have stable HIV infection with good clinical and functional status should be considered for treatment, according to guidelines outlined in this statement. Even though high HCV RNA levels or genotype 1 predict a less favorable response to therapy, treatment should not be withheld on the basis of these parameters. Contraindications to treatment with interferon that must be carefully considered are history of major depressive illness, cytopenias, hyperthyroidism, renal transplant, and convincing evidence of autoimmune disease.     5. What Recommendations Can Be Made To Patients To prevent Transmission of Hepatitis C? The large reservoir of individuals infected with HCV globally provides a source of transmission to others at risk. Prior to the identification of HCV, the majority of non-A, non-B hepatitis cases were associated with blood transfusion, injection drug use, health care, employment, or sexual or household exposure to a contact with hepatitis. HCV is now rarely transmitted by transfusion because of screening tests that exclude infectious donors. Direct percutaneous exposure is the most efficient method for transmitting HCV.In drug users, HCV infection is acquired rapidly after beginning injection drug use, with 50-80 percent of new users becoming positive for antibody to HCV within 6-12 months. Injection drug use accounts for half of all new infections annually and perhaps greater than 50 percent of chronic infections. In addition, it is thought that the majority of the rest of the cases can be explained by transfusion prior to 1990, occupational exposures to blood, hemodialysis, high-risk sexual activity (multiple partners, history of sexually transmitted diseases), and noninjection illegal drug use (intranasal cocaine). Percutaneous exposures such as body piercing and tattooing are potential sources of transmission if contaminated equipment or supplies are used, although their role in transmission of HCV in the United States has not been confirmed. It is now considered that the route of transmission is unknown in less than 10 percent of newly acquired cases of hepatitis C. Data regarding transmissibility by sexual contact have been conflicting. Based on studies in sexually transmitted disease clinics, sexual transmission appears to occur; however, even with multiple sexual partners the risk is low. The risk appears to be increased by coinfection with HIV or other sexually transmitted diseases. Although transmission in long-term monogamous relationships may occur, the risk is thought to be minimal. There is some evidence for occupational and nosocomial transmission of HCV infection. Health care workers have a higher prevalence than the general population, although many may have acquired it from other sources. However, inadvertent needle stick injuries and lack of application of universal precautions may be contributing factors. The risk of infection from needle sticks in hepatitis C is intermediate between that of HIV and hepatitis B. HCV transmission between patients in dialysis centers may be related to poor infection control practices. Although transmission from health care workers to patients has been documented, such transmission is thought to be rare. Perinatal transmission between mother and baby has been documented, although the risk is estimated at no more than 6 percent. The risk is increased if the mother is coinfected with HIV. Although data are limited, there is no evidence that breast-feeding transmits HCV from mother to baby.     6. 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.