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.
