AMERICAN LIVER FOUNDATION
The Liver in Health and Disease
HEPATITIS C: THERAPY
Gary L. Davis, MD
University of Florida
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
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:
- 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.
- 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.
- 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.
Hep C Pharmacy | Cancer
Pharmacy | Order Book | Awards
are not intended to promote, sell, advertise
or otherwise induce anyone to purchase any product on this
These statements have NOT been evaluated by the FDA
and are for informational purposes only.
images ©2001 Lloyd Wright
Website maintained by FluxRostrum