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AMERICAN LIVER FOUNDATION
Information 2002:
The Liver in Health and Disease
 

HEPATITIS C: THERAPY
Gary L. Davis, MD
University of Florida
Gainesville, Florida


 Key Points:

1. Chronic hepatitis C is a heterogeneous disease whose natural history and  response to treatment is probably influenced by multiple factors including but  not limited to viral genotype, level of viral replication, and histology.
    
2. Interferon is the only agent of proven efficacy in the treatment of  hepatitis C. Standard treatment is interferon alfa-2b at a dose of three million  units three times a week. The initial course of treatment is 6 months, but  nearly all patients relapse and require retreatment. The goal of interferon  treatment is suppression of active disease; this usually requires long term  therapy. Eradication of virus does not appear to be a realistic goal in most  patients
    
3. Higher doses and longer duration of initial therapy have limited benefit  over standard therapy. However, higher initial doses may increase the interval  before relapse and escalation of the dose may achieve response in some  non-responders.
    
4. Treatment trials have tended to study relatively homogenous patient groups  and the possibility of extrapolating these results to different patient  populations is extremely limited. This is especially true of studies from  geographic areas. Thus, future studies should: (1) consider genotype, viral  load, and histology in stratification; and (2) include a control group of  standard treatment for comparison.
    
5. Selection of patients for this chronic treatment remains controversial.  Treatment of patients with active disease is most cost- effective, but other  factors such as the degree of symptoms must be considered.
    
6. The definition of response to treatment is evolving as a technology of  measurement of HCV improves. It is likely that future treatment strategies will  be dependent upon virologic endpoints in addition to, or instead of, serum ALT.
    
7. Different agents and adjuncts have been incompletely studied to date.  Ribavirin reduces serum ALT levels to normal and improves fatigue in nearly half  of patients. Histology and virus levels do not appear to be significantly  altered. The mechanism of its action of this interesting agent is not clear.
    

INTRODUCTION

The first trial of interferon as therapy for chronic non-A, non-B hepatitis  was reported in 1986. This pilot study demonstrated that alpha interferon  therapy:
(1) was effective at low doses (in comparison to doses previously shown  to be required for hepatitis B and D); (2) decreased serum ALT levels promptly  upon initiation of therapy, a pattern suggestive of an antiviral effect of  interferon; and (3) was usually associated with relapse when treatment was  stopped, indicating a failure to eradicate the virus. Many subsequent controlled  studies have now confirmed all of these original observations. A dose of 3  million units of recombinant interferon alfa-2b thrice weekly for 6 months is  the currently approved standard for initial therapy in the United States. With  the discovery of the hepatitis C virus responsible for non-A, non-B hepatitis  and the availability of moderately sensitive techniques for detaching the virus,  it is now apparent that the biochemical response to interferon (normalization of  ALT) is associated with loss of detectable viremia; thus, the primary response  it interferon is indeed due to the antiviral effects of the drug. However, the  high relapse rate confirms the earlier suspicion that interferon is usually  unable to eradicate the virus, which persists at levels below the current limits  of detection in serum, liver, or peripheral blood mononuclear cells.

It is apparent that the usual effect of interferon in patients with chronic  hepatitis C who respond to this therapy is one of viral suppression, not  eradication or cure. Sustained or prolonged response to treatment (persistently  normal ALT levels) occurs in only 15-20% of patients and is often associated  with detectable viremia despite the biochemical absence of apparent hepatic  injury. The observations from these early studies are important and must be  considered in establishing appropriate justification and goals for interferon  therapy in clinical practice. Several crucial points must be made:

1. Interferon therapy appears to eradicate or cure infection in only a small  proportion of patients. Thus, cure is an unrealistic goal of current interferon  regimens.
2. Interferon is suppressive to the hepatitis C virus. The goal of therapy  should be to suppress infection to a degree that liver disease is minimized.
3. The currently approved regimen of therapy (3 million units 3x per week for 6  months) is suboptimal. It should be considered as initial therapy, not as  definitive therapy. The goal of chronic viral suppression will require prolonged  therapy, retreatment of relapse, or maintenance regimens
    

Currently, clinical and basic research in hepatitis C is just beginning to shed  light on the issues important to therapeutics in this confusing disease. It is  now apparent that the disease course is only slowly progressive in most  patients; thus, histology may be important in assessing the timing of  therapeutic investigation. It is evident that the natural history is different  between genotypes. The initial and long-term response to therapy is also  effected by both genotype and the level of viremia.

The differences in response to interferon therapy which occur as a result of  viral differences are critical to clinical research in therapeutics. Literally  dozens of studies of various interferon dose regimens have appeared to  demonstrate superiority of every conceivable permutation of dosing to the  currently accepted regimens. However, few have compared these novel and  potentially useful regimens to standard dosing. Since genotypes are  geographically diverse and have significant influence on response to interferon,  trials conducted on one continent or even in different countries of regions  within a continent are not comparable. Changes in therapeutic regimens from the  current standard must be based on careful comparisons of different regimens  among genotypically similar patients with similar viral loads. It is likely that  a single dosing strategy is not appropriate for all patients. Differences in the  hepatitis C virus from country to country may warrant local modifications in  interferon dosing. Unfortunately, this implies that the considerable effort and  expense of clinical trials may have little applicability outside of the area  where they are conducted. At a bare minimum, genotype and the degree of viremia  need to be considered as stratification levels in designing future clinical  trials.
 

Continued
 

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