AMERICAN LIVER FOUNDATION
The Liver in Health and Disease 2002
HEPATITIS C: THERAPY
Gary L. Davis, MD
University of Florida
Gainesville, Florida
Key Points:
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.
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) wasusually
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.
Finally, the traditional marker for assessing treatment response
is normalization of the serum ALT level. Although this
endpoint was established before identification of the
hepatitis C virus, it appears to be as appropriate as
measuring HCV-RNA for determining the initial response to
interferon, i.e. normalization
of ALT is usually associated with loss of detectable virus
from the serum. However, after discontinuation of interferon,
HCV-RNA usually becomes detectable well before re-evaluation
of ALT (the traditional definition of relapse) occurs.
In fact, viremia may be present for months to years after
interferon is stopped despite persistently normal ALT levels
("sustained remission"). Other
markers include aGST, procollagen III, and cholate clearance
are under study and may serve as adjunctive markers of response.
Clearly, future studies should consider alternative
markers of response and relapse which might prove to
be more clinically useful than those currently employed.
TREATMENT OF CHRONIC HEPATITIS C
Standard Therapy Standard initial therapy for chronic hepatitis C infection
is recombinant interferon alfa-2b at a dose of 3 x 106
units administered subcutaneously 3 times per week for
6 months. This regimen is based on the results of 3
randomized controlled trials, which employed an identical
protocol and were conducted in France and the United
States. These trials demonstrated that 41% of patients
normalized the serum ALT level during treatment and 70% of
responders had histological improvement. Response to
treatment is greatest in those patients without advanced
inflammation or cirrhosis, high HCV-RNA levels, or genotypes
1a and 1b (Simmonds). Almost all responders (normal ALT) lose
detectable HCV-RNA by reverse transcription polymerase chain
reaction (RT-PCR) by the end of therapy. However, relapse
occurs in 50-70% of patients after the end of the initial
course and is associated with return of detectable HCV-RNA.
Relapse usually responds to retreatment with interferon.
Alternative regimens: Higher dose,
Longer duration
The best way to improve the efficacy of interferon treatment
is to improve the initial response and its durability.
Controlled trials of alternative regimens including
higher doses, daily dosing or longer durations of therapy
have not shown that these schedules improve the response rate.
However, higher doses of interferon may increase the
durability of the initial response, i.e. reduce early
relapse. The effect of tapering the
dose after the initial 6 months on subsequent relapse
is unclear, having been reported to both reduce or have no
effect on relapse. These findings need to be confirmed.
Adjuncts to Interferon Therapy &
Combination Therapy
Several compounds have been suggested to improve the response
to interferon in patients with chronic hepatitis C.
Ursodeoxycholic acid has been proposed as either a single
agent or adjunct to interferon, but its effects on viral
replication and inflammation have been incompletely examined.
NSAIDS have a potential role in augmenting the antiviral
effects of interferon through their ability to block
prostaglandin synthesis, increase the epoxygenase pathway,
and increase 2', 5' oligoadenylate synthetase, one of
the effectors of interferon activity. These effects
have not been proven in vivo. N-acetyl cysteine (NAC),
an antioxidant and glutathione source, has been shown in one
pilot study to induce response to interferon when patients
had previously failed to respond. However, most patients
with chronic hepatitis C are not glutathione deficient
and the therapy is expensive and distasteful. Controlled trials
need to determine if NAC has any effects in chronic
hepatitis C.
Ribavirin has not proven to significantly
increase response to interferon in a single published
study. However, several pilots studies published in
abstract form suggest a possible effect. This agent's
role has only begun to be explored. No scientific rationale
exists for prednisone pretreatment in chronic hepatitis
C. Corticosteroids increase HCV replication. Nonetheless,
prednisone pretreatment has been shown in one study
in the Orient to increase the durability of response.
These findings need to be reexamined in a controlled
fashion in genotyped patients.
Alternatives to Interferon
There are few alternatives to interferon on the horizon for
patients with HCV infection. Thymosin is not effective.
Ribavirin shows some promise as a single agent in the
treatment of chronic hepatitis C, but its effects are difficult
to interpret. Although ribavirin is a nucleoside analogue
and know antiviral agent, its ability to normalize serum
ALT levels and improve symptoms in patients with chronic
HCV infection does not appear to result from inhibition of
HCV (viral levels remain unchanged). It is possible
that the agent acts through inhibition of some effector
of tissue damage. Certainly, clarification of the mechanism
of action of this agent will help define the pathogenesis
of hepatic injury in HCV infection.
PROBLEMS WITH TREATMENT
OF CHRONIC HEPATITIS C: Interferon therapy of chronic HCV infection
is not straight-forward. Therapy is initially effective
in only a portion of patients and it appears that eradication
of infection is unusual in patient infected with the genotypes
most common in the United States and most areas of Europe.
Thus, several issues are important in understanding
the appropriateness and limitations of interferon treatment. Selection of Patients
Treatment of patients should be directed at those who will
benefit from the intervention. Several issues are important
to defining this benefit: cost, durability for response,
and natural history of disease. In the case of HCV infection,
interferon treatment is effective in only about 40%. Since
response is usually not permanent, retreatment and perhaps
long-term maintenance therapy is required to maintain
control of the disease. Natural history studies have
shown that HCV is a slowly progressive disease and that patients
at greatest risk of progression are those with moderate
to severe periportal inflammation, with or without fibrosis,
on their liver biopsy. Therapy is easy to justify in
ill patients and those at greatest risk of disease progression.
It is also most likely to cost-effective in such patients.
On the other hand, therapy which is likely to be long-term
is difficult to justify in patients with mild histologic
disease who would have a low risk of disease progression without
treatment. This area is controversial. The observation
of higher early response to treatment in patients with
minimal disease fuels the argument to initial treatment early,
but does not address the high cost of treatment in patients
who do not usually require any intervention.
Non-response
Approximately half of all patients will not respond to interferon
using a standard regimen. Few alternative exist for
these patients. If the patient has not responded after
the first 12 weeks of treatment, escalation of the dose to
10 million units will result in response in about 20% of patients.
However, this strategy is associated with the high cost
and side effects, and should therefore be reserved for
those who have aggressive liver disease or incapacitation
symptoms. The emerging role of treatment adjuncts is discussed
above. Relapse Most patients who respond to treatment
will relapse. Although initial reports suggest that
as many as only half of responders maintained the initial
response to interferon, it is now clear that only 20-30%
will maintain normal ALT levels for 6-12 months. Additionally,
recent data has suggested that virologic relapse occurs
even more commonly and many patient who continue to maintain
normal ALT levels may actually be viremic and have active
liver disease. These disturbing observations
reinforce the need for effective identification of relapse
with virologic tools and retreatment to maintain control
of infection and active live disease. Unfortunately,
the best way to treat relapse is not clear. Although
almost all patients will again normalize their ALT levels
when retreated, it is not clear whether repeated 6 month
courses, a titrated long-term maintenance regimen, or
some other schedule will best serve the patient. Long-term
retreatment with a fixed dose is clearly not well tolerated
and is associated with frequent breakthrough (see below).
An international multicenter study (US, Canada, France,
Spain, Australia) is currently underway to determine the best
way to retreat and maintain remission in interferon-responsive
patients.
Breakthrough In reported trials of interferon, between
0-50% of patients have demonstrated a phenomenon known
as breakthrough. Breakthrough occurs in patients who
normalized their serum ALT levels in the first weeks of treatment
but demonstrate re-evaluation of ALT despite ongoing
therapy. It is essentially a relapse during treatment.
These episodes are usually associated with reappearance
of detectable HCV RNA and appear to be emergence of resistance
to the effects of interferon. The cause of
this phenomenon is unclear. Naturalizing anti-interferon
antibodies are responsible for a few cases, particularly with
some recombinant interferon not approved for hepatitis treatment
in this country. These cases might also be due to loss
of host response to the virus. However, it is likely
that most cases result from changes in the virus itself
which render it resistant to the effects of interferon. This
remains to be confirmed.
Definition of Response
The currently accepted definition of response to interferon
is normalization of the serum ALT levels at the end
of treatment. This definition was arbitrarily defined
by investigators in the interferon studies initiated before
the identification of the HCV agent. Obviously, documentation
of viremia was lacking. The availability of serologic
markers of HCV replication (HCV RNA by RT-PCR) confirmed
that biochemical response (Normal ALT) was usually associated
with a virologic response (negative serum HCV RNA). However,
it has recently become apparent that exceptions occur
and are associated with early relapse. Additionally,
virologic relapse always precedes biochemical relapse, sometimes
by months or years. It is clear that the definition of response
and relapse needs to be revised to include HCV RNA.
Trials are currently underway which will test the appropriateness
of various combinations of serologic, biochemical and
virologic markers of response, remission, and relapse.
SPECIAL PATIENT GROUPS
Decompensated Cirrhosis Interferon treatment of decompensated cirrhosis due to
hepatitis B is a risky proposition because of the possibility
of further decompensation or infection with the flare
in ALT which occurs shortly after beginning treatment. Early
experiences with treatment of decompensated cirrhosis due
to hepatitis C indicate that interferon can be administered
to most of these patients with good results and no risk
of further decompensation (Balart, personal communication).
Synthetic function improves in responding patients. Cytopenia
and infection may limit therapy in some.
HIV infected patients
HIV coinfected patients have an increased risk of liver failure
from chronic hepatitis C. HCV RNA levels increase over
time after HIV seroconversion, particularly once immunodeficiency
ensues. HIV and HCV coinfected patients appear to respond
no differently to interferon than do patients not infected
with HIV, although no study has compared response to HCV RNA
levels yet. Thus, interferon treatment should be considered
in HIV coinfected patients before onset of manifestations
of immunodeficiency.
Hemophiliacs
Between 60-90% of factor-dependent hemophiliacs have serologic
evidence of HCV infection. This occurs because factor
concentrates are prepared from plasma pooled from hundreds
of individuals who, in many cases, are commercially paid
donors. HCV infection is most prevalent in those who have
received greater volumes of concentrate, especially
of unpasteurized products, and is virtually nonexistent
in patients who either have not required factor transfusion
of have received exclusively vapor-treated plasma concentrates
of recombinant clotting factors. About half of infected
patients have abnormal serum ALT levels. Interferon
treatment is as effective in this patient population as it
is in others and does not appear to be associated with
any unique problems. The question of whether or not
such patients should be biopsied before considering
treatment is controversial because of the cost and risks of
the procedure in these individuals.
Transplant Recipients
HCV infection is common in organ transplant recipients. The
true prevalence of infection is considerably underestimated
by the tendency for aminotransferase levels to be low
to normal and the insensitivity of antibody-based diagnostic
tests in immunosuppressed patients. The natural history of
HCV infection in transplant recipients is unknown. However,
there is a unique syndrome of fibrosing, cholestatic
hepatocellular injury similar to that observed in hepatitis
B which occurs in a subset of patients. The role of interferon
in treating HCV infection in transplant recipients is
not known. Complete response appears to be unusual and
there is a small but real risk of acute graft rejection.
Asymptomatic Carriers
Chronic portal or periportal inflammation (CPH or CAH) occurs
in 70-100% of anti-HCV and HCV-RNA positive patients
with normal ALT levels. In most, the degree of inflammation
is mild. Interferon is currently not indicated for these
patients for the following reasons: (1) the natural history
of the HCV carrier is not known, but is probably comparable
to CPH or mild CAH; (2) markers of response to treatment
are not available; and (3) most patients are not symptomatic.
The possible availability of affordable markers of HCV replication
may make treatment based on monitoring the viral response
feasible in the future.
Extrahepatic Disease
Mixed cryoglobulinemia, membranous glomerulonephritis, and
porphyria cutanea tarda may all be associated with HCV
infection. In the case of cryoglobulinemia, the cryoglobulins
and the associated disease improve or disappear in about half
of treated patients. Patients who do not respond to interferon
require treatment with immunosuppressive agents including
prednisone, cytoxan, and/or pheresis. HCV-associated
porphyria responds to phlebotomy. The effects of interferon
are not yet described.
TREATMENT OF ACUTE HEPATITIS C
There is a growing consensus that interferon treatment of
acute hepatitis C reduces the risk of chronicity. Four
randomized controlled trials have all demonstrated a
reduction in the proportion of patients with either abnormal
ALT levels or detectable HCV RNA following a 4-12 week
course of interferon. Although most "responders"
maintain their response, some early responders have
evidence of infection at a later follow-up. Unfortunately,
such patients are rarely identified since acute infection
is usually inapparent and it is impractical to serially
screen patients with identifiable risk factors.
FUTURE TREATMENT STRATEGIES
Considerable progress has been made in the therapy of chronic
hepatitis C in the few years since the identification
of this virus. While interferon treatment is quite effective
by antiviral standards, there is no doubt that the currently
approved regimen is far from optimal. A great deal of work
remains in order to better define the clinical guidelines
for the use of interferon in patients with chronic hepatitis
C. It is likely that strategies will develop that individualize
treatment regimens according to patient characteristics (body
size, histology, ect.) and the predominant viral isolate (genotype
and level). Better markers of treatment response will
allow fine tuning of the treatment duration and dose.
Ongoing trials will hopefully identify the utility of viral
markers of response and determine the optimal way to manage
the treatment of the infection over the long- term.
Finally, new classes of therapeutic agents such as proteinase
inhibitors, antisense compounds, and therapeutic vaccines
will eventually find their way to clinical trials.
TREATMENT OF
CHRONIC HEPATITIS C Standard Therapy
Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic
non-A, non-B hepatitis with recombinant human alpha
interferon: A preliminary report. New Engl J Med 1986;
315:1575-1578.
Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic
hepatitis C with recombinant interferon alpha: A multicenter
randomized, controlled trial. New Engl J Med 1989; 321:1501-1506.
Marcellin P, Boyer N, Giostra, et al. Recombinant human alpha-
interferon in patients with chronic non A non B hepatitis:
a multicenter randomized controlled trial from France.
Hepatology 1991; 13:393-397.
Causse x, Godinot H, Ouzan D, et al. Comparison of 1 or 3
MU of interferon alfa-2b and placebo in patients with
chronic non-A non-B hepatitis. Gastroenterology 1991;
101:497-502.
TinŽ F, Margin S, Craxi A, Pagliaro L. Interferon for non-A,
non- B chronic Hepatitis: a meta-analysis of randomized
clinical trials. J Hepatol 1991; 13:192-199.
Alternative regimens: Higher dose, Longer duration
Beloqui O, Prieto J, Suarez M, Gil B, Qian CH, Garcia N, Civeira
MP. N-acetyl cysteine enhances the response to interferon-alpha
in chronic hepatitis C: a pilot study. J Interferon
Res 1993; 13:279-282.
Kakumu S, Yoshioka K, Wakita T, Ishikawa T, Takayanagi M,
Higashi Y. A pilot study of ribavirin and interferon
beta for the treatment of chronic hepatitis C. Gastroenterology
1993; 105:507- 512.
Liaw YF, Sheen IS, Lin SM, Chen TJ, Chu CM. Effects of prednisolone
pretreatment in interferon alfa therapy for patients with
chronic non-A, non-B (C) hepatitis. Liver 1993; 13:46-50.
Alternatives to Interferon
Camps J, Garcia N, Riezu-Boj JI, Civiera MP, Prieto J. Ribavirin
in the treatment of chronic hepatitis C unresponsive
to alfa interferon. J Hepatol 1993; 19:408-412.
Bodenheimer HC, Lindsay K, Davis GL, et al. Ribavirin treatment
of chronic hepatitis C. Hepatology 1994; 20:(abstract
in press).
SPECIAL PATIENT GROUPS
Decompensated Cirrhosis Dimopoulou M, Fafoutis K, Basiliou K, Ketikoglou J, Karvountzis
G. Interferon alfa-2a for decompensated liver disease
caused by wither chronic hepatitis B or C: preliminary
results of a pilot study. Gut 1993; 34 (suppl 2):S104-105.
HIV infected patients
Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert
JJ. The natural history of hepatitis C virus infection
in multitransfused hemophiliacs: Effects of coinfection
with human immunodeficiency virus. Acquir Immune Defic
Syndr 1993; 6:602.
Eyster ME, Fried MW, DiBisceglie AM, Goedert JJ. Increasing
HCV RNA levels in hemophiliacs: Relationship to HIV
infection and liver disease. Blood 1994; (in press).
Boyer N, Marcellin P. Degott C, Degos F, Saimot AG, Erlinger
S, Benhamou JP. Recombinant interferon-alpha for chronic
hepatitis C in patients positive for antibody to human
immunodeficiency virus. J Infect Dis 1992; 165:723-726.
Hemophiliacs
Makis M, Preston FR, Triger DR, Underwood JC, Westlake L,
Adelman MI. A randomized controlled trial of recombinant
interferon-alpha in chronic hepatitis C in hemophiliacs.
Blood 1991; 78:1672-1677.
Transplant Recipients
Lim HL, Lau GK, Davis GL, Dolson DJ, Lau JYN. Cholestatic
hepatitis leading to hepatic failure in a patients with
organ- transmitted hepatitis C virus infection. Gastroenterology
1994; 106:248-251.
Ferrel LD, Wright TL, Roberts J, Ascher N, Lake J. Hepatitis
C viral infection in liver transplant recipients. Hepatology
1992; 16:865-876.
Wright HI, Gavaler JS, Van Thiel DH. Preliminary experience
with alpha-2b interferon therapy of viral hepatitis
in liver allograft recipients. Transplantation 1992;
53:121-124.
Asymptomatic Carriers
Naito M, Hayashi N, Hagiwara H, Hiram N, Kasahara A, Fusamato
H, Kamada T. Serum hepatitis C virus RNA quantity and
histological features of hepatitis C virus carriers
with persistently normal ALT levels. Hepatology 1994; 19:871-875.
Extrahepatic Disease
Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic
liver diseases: role of hepatitis C virus and liver
damage. Gastroenterology 1994; 106:1291-1300.
TREATMENT OF ACUTE HEPATITIS C
Viladomiu L, Genesca J, Estaban JI, et al. Interferon alpha
in acute posttransfusion hepatitis C: a randomized controlled
trial. Hepatology 1992; 15:767-769.
Omata M, Yokosuka O, Takano S et al. Resolution of acute hepatitis
C after therapy with natural beta interferon. Lancet
1991; 338:914-915.
Lampertico P, Rumi M, Romeo R, Craxi A, Soffrededini R, Biassoni
D, Colombo M. A multicenter randomized controlled trial
of recombinant interferon alpha-2b in patients with
acute transfusion- associated hepatitis C. Hepatology 1994;
19:19-22.
Tassopoulos NC, Koutelou MG, Papatheodoridis G, et al. Recombinant
human interferon alfa-2b treatment for acute non-A,
non-B hepatitis. Gut 1993; 34:S130-132.
