The Consensus Recommendations recognized that the risks and benefits of therapy are less clear in other patient populations. Treatment in such cases should be determined on an individual basis or in the context of clinical trials. Patients with ongoing injection drug use, alcohol abuse, older age, and comorbid medical or psychiatric illness have generally been excluded from trials. The NIH recommended that efforts should be made to increase the availability of the best current treatment to these patients. Similarly, better strategies are needed to prevent, diagnose, and treat individuals who are incarcerated.
The following sections represent NIH comments in particular settings.
Mild liver disease ? Patients who have persistent elevation in serum ALT but do not have fibrosis and have minimal necroinflammatory changes are likely to have only slow disease progression. Such patients can be monitored periodically. However, the decision to treat should be individualized.
Advanced liver disease ? The efficacy of treatment in patients with advanced fibrosis or compensated cirrhosis has been derived mostly from subgroup analysis of larger clinical trials. These have suggested that the response is lower than in patients without cirrhosis. Patients with decompensated cirrhosis should be referred for clinical trials until the safety and efficacy data of treatment are established. The main treatment option for such patients is liver transplantation.
Recurrence after transplantation ? Disease progression following transplantation is accelerated compared to immunocompetent patients with HCV infection. In addition, the risk of complications is higher in post-transplant HCV patients with cirrhosis compared to immunocompetent patients with cirrhosis. Recurrence correlates with HCV RNA levels at the time of transplantation, the age of the organ donor, and the degree of immunosuppression in the post-transplant period.
Children ? There are relatively few data on treatment of children and adolescents. Sustained virological response rates with interferon monotherapy are similar or better than those in adults. Studies of combination therapy in children are ongoing.
Acute infection ? The Consensus panel recognized that studies of interferon for acute HCV have been small, heterogeneous, and lacked randomization. The panel recommended that treatment of persons with acute hepatitis C is warranted, but the timing of therapy and the type of regimen to use remains to be determined from future trials.
Injection drug users ? Management of HCV-infected intravenous drug users can be enhanced by linkage with drug-treatment programs. HCV therapy can be successful even when patients have not been abstinent from continued drug use or are on daily methadone .
Coinfection with HIV ? All HIV infected persons should undergo screening for HCV. Coinfection is associated with an accelerated course of HCV disease. While no therapies have been specifically approved for coinfected patients, such patients should be considered for treatment. Preliminary data suggest better responses to pegylated interferon plus ribavirin compared to standard interferon plus ribavirin.
Alcohol ? Alcohol is an important cofactor in HCV disease progression. While a history of alcohol abuse is not an absolute contraindication to therapy, continued alcohol use decreases the response to therapy. Thus, treatment should be performed along with efforts to treat the alcohol abuse. The amount of alcohol that is safe during treatment is unknown.
AASLD GUIDELINES ? Guidelines issued by the American Association for the Study of Liver Diseases (AASLD) are consistent with the NIH guidelines but provide additional details. The AASLD recognizes three categories of patients: those in whom therapy is widely accepted, those in whom therapy should be individualized, those in whom therapy is contraindicated.
Persons for whom therapy is widely accepted ? The AASLD recommends that therapy is widely accepted in patients with the following characteristics;
At least 18 years of age
Abnormal serum ALT values
Liver biopsy with chronic hepatitis with significant fibrosis (more than portal fibrosis (Metavir score 2, or Ishak score 3).
Compensated liver disease (total serum bilirubin <1.5 g/dL; INR <1.5; albumin >3.4 g/dL; platelet count >75,000 k/mm(3); and no evidence of hepatic encephalopathy or ascites).
Acceptable hematological and biochemical indices (hemoglobin >13 g/dL for men and >12 g/dL for women; neutrophil count >1.5 k/mm(3); creatinine < 1.5 mg/dL)
Willing to be treated and to conform to treatment requirements.
Patients who fulfill these criteria had have been treated previously for HCV infection can also be considered. Those with a history of depression but the condition is well controlled can also be considered for treatment.
Persons for whom therapy should be individualized ? The AASLD recommends that therapy should be individualized for patients:
With persistently normal ALT values
Who failed prior treatment (nonresponders and relapser) consisting of either interferon given alone or in combination with ribavirin, or consisting of peginterferon given alone
Current users of illicit drugs or alcohol but willing to participate in a substance abuse program (such as a methadone program) or alcohol support program
Liver biopsy evidence of either no or only mild fibrosis (portal fibrosis: Metavir score <2; Ishak score <3)
Acute hepatitis C
Coinfection with HIV
Less than age 18
Chronic renal disease (on or not on hemodialysis)
Recipient of a liver transplant.
Persons in whom therapy is contraindicated ? The AASLD recommends that therapy is currently contraindicated in persons:
With major, uncontrolled depressive illness
Who received a renal, heart, or lung transplant
With autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin
Pregnant or unwilling/unable to comply with adequate contraception
Severe concurrent disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease
Younger than 3
Known hypersensitivity to drugs used to treat HCV.
CAUTIONS ? Interferon monotherapy and combination therapy with ribavirin are associated with several adverse effects, and may be contraindicated or should be used with extreme caution in patients with certain preexisting conditions. These include significant cytopenia, pregnancy, severe depression or other psychiatric conditions, cardiac diseases, poorly controlled diabetes, seizure disorders, and autoimmune or potentially immune-mediated diseases.
COST-EFFECTIVENESS ? Although interferon monotherapy is expensive, the costs appear to be justified [24,25]. At least four analyses on combination therapy with interferon and ribavirin suggested it was also cost-effective in patients who have never been treated and those who relapsed following interferon monotherapy [9,26-29].
Another cost-effectiveness analysis focusing on patients with mild histologic disease compared strategies of immediate treatment versus surveillance with a liver biopsy every three years . Immediate therapy was found to be cost-effective with a cost-effectiveness ratio of $7000. Immediate therapy was associated with an increase of at least 0.8 quality-adjusted life-years compared with biopsy management after accounting for age, sex, genotype, compliance, and variable rates of disease progression. At least two cost-effectiveness analyses concluded that combination therapy with pegylated interferon was cost-effective as initial treatment, and that the incremental cost-effectiveness ratio compared with standard interferon plus ribavirin was in an acceptable range [31,32].
A somewhat different approach was taken in another study in which the cost-effectiveness of therapy was considered in various patient groups with different potentials for disease progression . The authors estimated that the probability of developing cirrhosis over a 30-year period ranged from 13 to 46 percent for men and from 1 to 29 percent for women. The incremental cost-effectiveness of combination therapy with pegylated interferon plus ribavirin varied considerably depending upon the likelihood of disease progression. Overall, the greatest benefits were mostly related to improvement in health-related quality of life rather than in improved survival. The authors concluded that the cost-effectiveness of treatment depends upon an appraisal of the likelihood of disease progression and the degree to which chronic infection will impair quality-of-life. As a practical matter, however, neither of these parameters are easy to determine on an individual patient basis.
RECOMMENDATIONS ? General health measures (such as vaccination) for patients with chronic HCV and the selection of patients for treatment are discussed above. Once the decision has been made to treat, the recommended approach varies depending upon clinical setting. The efficacy and safety of the different interferon preparations are reviewed in detail separately.
The clinical trials supporting the use of combination therapy and the details of its administration are also presented elsewhere.
Acute HCV ? Treatment of acute HCV is discussed separately.
Initial therapy ? Combination therapy with pegylated interferon plus ribavirin is superior to interferon monotherapy and to standard interferon/ribavirin combination therapy. Combination therapy should be administered for 48 weeks using standard doses of ribavirin in patients with genotype 1 or 4 (ie, 1,000 mg for those 75 kg in weight and 1,200 mg for those more than 75 kg). Quantitative HCV RNA should be determined before the initiation of therapy and at week 12. Treatment can be discontinued in those who do not achieve an early virologic response (ie, at least a 2-log decline from baseline of the HCV RNA level) at week 12, although the decision should be individualized depending upon how well therapy has been tolerated, the severity of the underlying liver disease, and demonstration of some degree of biochemical and/or virologic response .
In contrast, 24 weeks of therapy using a lower dose of ribavirin (800 mg daily in divided doses) appears to be as effective as longer courses of therapy (using the standard higher dose of ribavirin) in patients infected with genotype 2 and 3.
These recommendations are consistent guidelines published by the AASLD
Relapsers and nonresponders ? The NIH consensus statement recommends that decisions regarding the retreatment of patients who failed to achieve a sustained virologic response to initial treatment should be based upon the following considerations: (http://consensus.nih.gov/cons/116/116cdc_intro.htm
The previous type of response
The previous therapy and the difference in the potency of the new therapy
The severity of the underlying liver disease
Viral genotype and other predictive factors of response
Tolerance and compliance with previous therapy
Similar recommendations have been issued by the AASLD .
The following represents our approach in various common settings and are consistent with the consensus statements from the NIH and the AASLD.
Relapsers after interferon monotherapy ? Patients who relapse after an initial response to interferon monotherapy should receive combination therapy with ribavirin (1000 to 1200 mg/day) plus pegylated interferon rather than a repeat course of interferon alfa.
Nonresponders to interferon monotherapy ? Patients who did not respond to interferon monotherapy have a relatively poor response to combination therapy compared to those who relapsed . However, it is reasonable to offer a trial of combination therapy (with pegylated interferon plus ribavirin) to patients who otherwise tolerated interferon monotherapy who have moderate to advanced histologic features.
Nonresponders to standard interferon ribavirin combination therapy ? Options for patients who did not respond to combination therapy with standard interferon and ribavirin include observation, enrollment into a study, or a trial of pegylated interferon plus ribavirin. Preliminary data suggest that the response in such patients to pegylated interferon plus ribavirin is in the range of 11 to 20 percent (with higher rates in patients infected with genotypes 2 or 3 and those who relapsed to therapy and lower rates in patients with cirrhosis) [35-38]. Treatment should be administered for 48 weeks.
Nonresponders to pegylated interferon ribavirin combination therapy ? Options for patients who did not respond to combination therapy with pegylated interferon and ribavirin include observation, enrollment into a clinical trial, or maintenance pegylated interferon therapy. The decision should be based upon a number of factors including patient preference, histologic severity, and access to clinical trials. A repeat biopsy may be warranted in selected patients since significant histologic improvement may occur even in the absence of a sustained virologic response, and appropriate decisions can be predicated on the results of the liver biopsy.
Extrahepatic manifestations of HCV infection ? Interferon alfa has been used with reasonable success for the treatment of extrahepatic manifestations of HCV infection such as essential mixed cryoglobulinemia and glomerulonephritis . Although the role of combination therapy with ribavirin has not been well-studied, it is reasonable to treat with pegylated interferon plus ribavirin provided that there is no renal dysfunction.
Decompensated cirrhosis ? Patients with decompensated cirrhosis should be referred for consideration of liver transplantation. Experienced hepatologists may consider treatment in those with mild degrees of decompensation . Use of growth factors (such as erythropoietin and granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor) may be helpful during treatment of such patients by limiting the need for reductions in the dose of antiviral therapy.
Immunocompromised patients ? The response to interferon monotherapy in immunocompromised patients (such as patients with human immunodeficiency virus infection) depends upon the status of the immune system. The role of combination therapy in this setting is being investigated
Active users of illicit drugs ? Whether treatment with interferon-based regimens should be offered to patients who are actively using illicit drugs is controversial [40,41]. Treatment of such patients should be individualized. A guideline issued by the AASLD recommends that treatment should not be withheld from those who currently use illicit drugs or those on a methadone maintenance program provided that they wish to be treated and are willing and able to maintain close monitoring and practice contraception . An important adjunct to treatment is continued support from drug abuse and psychiatric counseling services.
Renal disease ? Issues related to treatment of HCV in patients with underlying kidney disease are discussed separately.
Persistently normal ALT ? Patients with a persistently normal serum ALT who acquired HCV under the age of 35 years, are women, do not drink alcohol, and have no or minimal fibrosis on liver biopsy may have a slow rate of hepatic fibrosis progression. In such patients, it is reasonable to withhold treatment pending the results of ongoing clinical trials. In contrast, patients who do not fit this profile, and whose initial biopsy shows moderate activity or some degree of fibrosis may be at increased risk of disease progression. We offer therapy to such individuals after discussing that this approach is not scientifically proven. We usually treat such patients using combination therapy with pegylated interferon alfa plus ribavirin.