SELECTED HIGHLIGHTS FROM THE DRAFT NIH HCV CONSENSUS STATEMENT
Reported by Jules Levin
Chronic HCV infection is diagnosed by the detection of HCV RNA at least intermittently in the blood by either qualitative or quantitative tests for a period of at least 6 months. In general, prospective studies have shown that the majority of HCV-infected persons develop chronic infection.
The most important potential bad outcomes of chronic HCV infection are progressive liver fibrosis leading to cirrhosis, end stage liver disease (ESLD), and HCC (liver cancer).
Estimates of the proportion of chronically infected persons who develop cirrhosis 20 years after initial infection have been substantially higher from retrospective studies (17 to 55 percent) than from prospective studies
(7-16 percent). There is little evidence that the risk of progression of
liver disease is affected significantly by virologic factors, including viral load, viral genotype, and quasispecies diversity. However, many host factors are observed to increase this risk, including older age at time of infection; male gender; and an immunosuppressed state, such as HIV infection.
Alcohol use plays an important role in increasing the risk of progressive liver disease, with strong evidence for the detrimental effects of 60 g/day in men (equivalent to six beers, four glasses of wine, or three mixed drinks) and 40 g/day in women, but there is suggestive evidence that lower amounts can also increase the risk of liver damage associated with HCV.
In the United States, deaths associated with chronic HCV are currently more likely to be due to ESLD than to HCC. Data from death certificates in 1999 found that approximately 4,000 deaths were attributed to HCV infection, but this is likely to be an underestimate.
The only treatment option for persons who have developed ESLD (decompensated cirrhosis) is transplantation. Currently, HCV is the primary reason for liver transplantation in the United States. Little is known about the clinical course and risks of HCV-related complications in persons who have been infected longer than two decades.
The incidence of HCV-related HCC is continuing to rise in United States and worldwide, in part because of the increasing numbers of persons who have been chronically infected for decades, the presence of comorbid factors, and the longer survival of persons with advanced liver disease due to improved management of complications.
Liver biopsy yields information on fibrosis and histology assessment that is not
obtainable by any other means. Various noninvasive methods based on biochemical or serologic tests have been evaluated in several studies. Liver enzymes have shown little value in predicting fibrosis. Extracellular matrix tests do predict severe stages of fibrosis but cannot consistently
classify intermediate stages of fibrosis. Moreover, only liver biopsy provides information on possible contributions of iron, steatosis, and concurrent alcoholic liver disease to the progression of chronic hepatitis C toward cirrhosis.
The highest response rates have been achieved with PEG-interferon in combination with ribavirin. Genotype determinations now influence treatment decisions.
Overall, PEG-interferon plus ribavirin is more effective than standard interferon-ribavirin combination or PEG-interferon alone. SVRs were similar with both forms of PEG-interferon (alpha 2a and alpha 2b) when used in combination with ribavirin. Factors associated with successful therapy include genotypes other than 1, lower baseline viral load, and less fibrosis or inflammation on liver biopsy. In all three trials, an SVR of 42 to 46 percent was achieved for genotype 1 using a higher dose of PEG-interferon and ribavirin for 48 weeks. An SVR of 76 to 82 percent was achieved for patients with genotypes 2 and 3. It appears that 24 weeks of treatment and a lower dose of ribavirin is adequate for genotypes 2 and 3. Early viral response (EVR), defined as a minimum 2 log decrease in viral load during the first 12 to 24 weeks of treatment, has been identified as predictive of SVR. Those who fail to achieve an EVR have only a small chance of achieving a SVR even if therapy is continued for a full year.
Although SVR has not yet been correlated with improved survival because of the necessity for long-term followup, the absence of a detectable serum HCV RNA has been correlated with resolution of liver injury, reduction in hepatic fibrosis, and a very low likelihood of recurrent HCV infection. Additionally, in two large recent studies from Japan, interferon treatment was associated with a reduction in the development of hepatocellular carcinoma, a finding that was more pronounced among patients with SVR.
Patients who may benefit from re-treatment include those whose HCV infection failed to achieve SVR. Decisions regarding re-treatment should be based upon: (1) previous type of response, (2) the previous therapy and the difference in potency of the new therapy, (3) the severity of the underlying liver disease, (4) viral genotype and other predictive factors for response, and (5) tolerance of previous therapy and adherence.
Relapsers achieve an initial end of treatment response (ETR) for their HCV disease, but it is not sustained over time (i.e., no SVR). Nonresponders never achieve an EVR, ETR, or SVR. Among the nonresponders, there is a subset of persons who have a substantial reduction of HCV RNA (1 to 2 log units or more) during therapy, and who can be categorized as partial responders.
Even in the absence of SVR, treatment may be associated with improved histology. Preliminary results suggest that overall only 15 to 20 percent of nonresponders treated with standard interferon/ribavirin combinations achieved an SVR on re-treatment using PEG- interferon with ribavirin. Patients with genotypes 2 or 3 have better response rates to re-treatment
than genotype 1.
The ability to achieve SVR following re-treatment with PEG-interferon/ribavirin in patients who relapsed following interferon monotherapy or standard interferon/ribavirin therapy is currently being evaluated. However, in cases where the same regimen has been used for re-
treatment, virtually all patients relapse again after treatment is stopped. Extending the duration of re-treatment without changing the dose or regimen may reduce the relapse rate, but this has not yet been proven prospectively.
Patients whose HCV infection does not respond to the current optimal therapy with PEG-interferon and ribavirin present a significant problem, particularly in the presence of advanced fibrosis or cirrhosis. The possible role of maintenance therapy with PEG-interferon alone in preventing further progression of cirrhosis, clinical decompensation, or development of hepatocellular carcinoma is currently the focus of a large-scale, multicenter United States trial, HALT-C. Until the results of HALT-C or similar studies are available, the role of long-term, continuous therapy with PEG-interferon (or ribavirin or both) for nonresponders must be considered experimental.
Knowledge of the severity of the underlying liver disease is important in recommending re-treatment. Patients with advanced fibrosis or cirrhosis are at increased risk for developing hepatic decompensation and should be considered for re-treatment, especially if they were originally treated with interferon monotherapy. For the re-treatment of patients with intermediate
degrees of fibrosis and disease activity, clinicians should consider the factors enumerated above.
WHO SHOULD BE TREATED
All patients with chronic hepatitis C are potential candidates for antiviral therapy. Treatment is recommended for patients who are at increased risk for progression to cirrhosis.
These patients are characterized by measurable HCV RNA, a liver biopsy with portal or bridging fibrosis, and at least moderate inflammation and necrosis; the majority have persistently elevated ALT values. In some patient populations, the risks and benefits of therapy are less clear and
should be determined on an individual basis or in the context of clinical trials. Many patients with chronic HCV have been ineligible for trials because of injection drug use (IDU), alcohol abuse, age, and a number of comorbid medical and neuropsychiatric conditions. Efforts should be made to increase availability of the best current treatment to these patients. Because a large number of HCV-infected persons in the United States are incarcerated,
strategies should be developed to better prevent, diagnose, and treat these individuals.
In patients with persistent ALT elevations, but with no fibrosis and minimal
necroinflammatory changes, progression to cirrhosis is likely to be slow; these patients should be monitored periodically.
Data on safety and efficacy of interferon (standard or pegylated) with or without ribavirin in patients with advanced fibrosis or compensated cirrhosis have been largely derived from subgroup analyses of larger trials. SVR is lower in patients with advanced liver disease than in patients without cirrhosis. An important goal of treatment in advanced liver disease is to delay histological disease progression, which is being evaluated in the NIH-sponsored HALT-C trial. Patients with decompensated cirrhosis should be referred to clinical trials until safety and efficacy data of treatment are established, or they should be considered for liver transplantation. In patients with ESLD, the main treatment option is liver transplantation. There are ongoing
studies of antiviral therapy of patients awaiting liver transplantation, but this approach may be limited by potentially life-threatening side effects of antivirals.
All HIV infected persons should be screened for HCV. Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of HCV disease. Therefore, although there are no HCV therapies specifically approved for patients coinfected with HIV, these patients should be considered for treatment. Thus far, studies have enrolled only patients
with stable HIV infection and well-compensated liver disease. In coinfected persons, an SVR can be achieved with HCV treatment. Preliminary data suggest better responses to PEG-interferon with ribavirin than to standard interferon with ribavirin. Although treatment of HCV has not jeopardized control of the HIV infection, additional data are needed.
Injection Drug Users
Recent experience has demonstrated the feasibility and effectiveness of treating HCV in 20 people who use illicit injection drugs (known as injection drug users or IDUs). This is important because IDUs comprise the largest group of hepatitis C patients in the United States, and successful treatment may reduce transmission. Management of HCV-infected IDUs is enhanced
by linking IDUs to drug-treatment programs. Efforts should be made to promote collaboration between experts in HCV and substance-abuse providers. HCV therapy has been successful even when the patients have not been abstinent from continued drug use or are on daily methadone.
Few data are available on HCV treatment in active IDUs who are not in drug treatment programs.
Alcohol and HCV
Alcohol is an important cofactor in the progression of HCV liver disease to cirrhosis and HCC. A history of alcohol abuse is not an absolute contraindication to therapy; however, continued alcohol use during therapy adversely affects the response to treatment. Treatment of HCV should be performed in conjunction with efforts to treat alcohol abuse or dependence. Heavy alcohol consumption of >80 g/day seriously compromises HCV treatment. Safe levels of alcohol consumption are still unclear.
Educate the American public on the transmission of HCV in order to better identify afflicted individuals and institute preventive measures.
Develop reliable, reproducible, and efficient culture systems for propagating HCV and expand basic research in the pathogenic mechanisms underlying hepatic fibrosis.
Promote the standardization and wide availability of diagnostic tests for HCV infection and its complications, leading to early diagnosis and the implementation of appropriate treatment practices.
Expand the delineation of disease manifestations, noninvasive tests, and the role of the liver biopsy, so that the application of current treatment practices may be refined.
Establish a Hepatitis Clinical Research Network for the purpose of conducting research related to the natural history, prevention, and treatment of hepatitis C.
Organize RCTs to extend treatment to special populations not represented in current,clinical trials and to determine the applicability of accepted antiviral drug combinations to populations such as children and adolescents, patients with acute hepatitis, hemophiliacs, IDUs in drug treatment
programs, alcohol abusers, patients with stabilized depression, those with coinfection with HIV, patients with decompensated cirrhosis and HCV infections in transplant recipients. Such an effort should lead to decreased morbidity and mortality from the disease, as well as a decrease in thereservoir of disease.
Evaluate strategies to interrupt mother-to-infant transmission of HCV.
Evaluate new therapies in nonresponders to current treatments, to include not just antiviral agents but also combinations of antifibrotic drugs, immunomodulatory agents, and alternative therapies.
Encourage a comprehensive approach to promote the collaboration between health professionals concerned with management of addiction with specialists involved in various aspects of HCV and its complications in order to deal with complex societal, medical, and personal issues occurring in
IDUs afflicted by the disease.
Seek appropriate support from governmental agencies and the private sector to address urgent research questions concerning epidemiology and treatment of this disease.