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.
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 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
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
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.
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.
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.
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
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.
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.
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.
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
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
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