Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Treatment of Chronic Viral Hepatitis Anno 1990 S. W. Schalm To cite this article: S. W. Schalm (1990) Treatment of Chronic Viral Hepatitis Anno 1990, Scandinavian Journal of Gastroenterology, 25:sup178, 111-118, DOI: 10.3109/00365529009093160 To link to this article: http://dx.doi.org/10.3109/00365529009093160
Published online: 08 Jul 2009.
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Treatment of Chronic Viral Hepatitis Anno 1990 S.W. SCHALM Dept. of Internal Medicine & Hepatogastroenterology, University Hospital Dijkzigt. Rotterdam. The Netherlands
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Schalm SW. Treatment of chronic viral hepatitis anno 1990. Scand J Gastroenterol 1990. SUPPI PI 178). 111-118 Alpha-interferon has emerged as the most effective agent for the treatment of chronic hepatitis when active replication of virus B, C, or D is present. Exogenous administration of human alpha-interferon, now possible through modern large-scale production methods, is associated with suppression of virus in blood. Amelioration of liver disease occurs in 35% of patients with hepatitis B virus and in 50% with hepatitis C virus with interferon doses of 30 and 10 MU per week, respectively, for 16-26 weeks; after therapy. persistent normalization of serum alanine aminotransferase is observed in 35% and 27?0. respectively. Similar results have now also been reported for chronic hepatitis D. Enhanced response rates (>SO%) may be obtained by prolonged intermittent interferon therapy. Combination of interferon with another 'antiviral' agent (vidarabine, acyclovir, prednisone) has not increased therapeutic efficacy. Alpha-interferon induces side effects such as fatigue, flu-like syndrome, myalgia, and changes in mood and granulocytes. Patients with decompensated cirrhosis are particularly prone to bacterial infection and disease exacerbation and should receive lower doses. Interferon, when applied skillfully, induces the highly beneficial transition of active viral replication into viral latency, thereby greatly reducing infectivity, symptoms, and activity of the liver disease. Prevention of death from liver failure or hepdtocehlar carcinoma is to be expected.
Key words: Chronic viral hepatitis; interferon therapy; liver cirrhosis; liver function; viral replication S. W. Schalm, M . D . , Depr. oflnrernal Medicine & Heparogasrroenrerology. University
Hospital Dijkzigt. 301s G D Rotterdam. The Netherlands
In 1980 treatment of chronic hepatitis was related to the indications and contraindication of corticosteroids. Advances in knowledge pertaining to the etiology of chronic hepatitis, in particular the introduction of tests to detect hepatitis B and, most recently, hepatitis C, allowed delineation of the subgroup of chronic viral hepatitis. Soon after introduction of the first test for hepatitis B, a retrospective study suggested that corticosteroids, so effective in inducing clinical and biochemical remission and in improving life expectancy in patients with HBsAg-negative chronic active hepatitis, were less effective in chronic active hepatitis type virus B (1). Subsequently, at least two consecutive controlled trials showed absence of a beneficial effect of corticosteroids in chronic hepatitis B (2, 3). Similarly, proof of beneficial
effects of corticosteroids in chronic hepatitis C and D is lacking. The failure of anti-inflammatory drugs to modify the course of chronic viral hepatitis led to the approach of antiviral therapy. Investigators from the USA documented the inhibition of hepatitis B virus (HBV) replication by human alpha-interferon and the persistent disappearance of all hepatitis B markers on prolonged therapy in a single patient (4). In a small controlled trial performed in The Netherlands the inhibitory effect of human alpha-interferon was confirmed, but induction of virus latency was similar in patients receiving interferon for 6 weeks (20%) and patients receiving control (albumin) injections (5). Interferon is therefore not a simple effective therapy of chronic hepatitis B. The
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liver biochemistry, histology, and prognosis are given in Table I. Long-term follow-up study of healthy carriers, CPH and CAH, however, has demonstrated that patients can move from one category to another and that the prognostic implications are invalid. According to Fattovich et al. (10) the incidence of development of cirrhosis is about equal for CPH and CAH; it amounts to 30-35% for a follow-up study of 5 years. Furthermore, improvement in disease activity was observed in 30-50% of CPH and CAH. Lastly, apparently healthy carriers may develop symptoms and signs of chronic hepatitis or even have silent cirrhosis of the liver. Therefore the classification is now considered outdated. Measurement of serum markers of hepatitis B virus replication (DNA-polymerase activity, HBe-antigen or HBV-DNA) during follow-up study has made it highly likely that the prognosis of chronic hepatitis B is primarily determined by the presence or absence of virus B replication. Progression of liver disease is mainly observed in patients with active viral replication, and the disease usually becomes inactive after transition of the phase with active viral replication into the phase with virus latency (DNA-polymerase, HBeantigen, HBV-DNA-negative) (1 1, 12). This finding provides the rationale for a therapeutic approach aimed at eradication of virus CHRONIC HEPATITIS B replication rather than non-specific suppression of Classification of chronic hepatitis B liver inflammation. For many years chronic hepatitis has been It has been unclear whether this new approach, classified as chronic persistent hepatitis (CPH) or accepted by virtually all hepatologists, also leads chronic active hepatitis (CAH) (8). In case of to a better prognosis-that is, an improvement in chronic hepatitis B the classification has been life expectancy. Fear has been expressed (13) that adapted to include also the 'healthy carrier' state inactivation of the liver disease may enable uncon(9). Characteristics of each entity with regard to trolled growth of hepatocytes with integrated
availability of large amounts of highly purified alpha-interferon in the last 5 years has enabled clinical trials with various dosages and durations of treatment. Recently, convincing evidence has been obtained that persistent disappearance of markers of hepatitis B virus replication and subsequent remission of the liver disease occur more frequently (35%) with interferon therapy for 16 weeks than spontaneously (10%). In 1990 alpha-interferon has emerged as the most effective treatment of chronic hepatitis B. The beneficial effects of alpha-interferon led to a pilot study of this agent in chronic hepatitis C (formerly called non-A non-B hepatitis) (6). In this disease alpha-interferon has a striking effect similar to corticosteroids in HBsAgnegative chronic active hepatitis, with induction of clinical and biochemical remission in most patients within 1-3 months. Also, similar to corticosteroids, withdrawal of the drug is often associated with relapse of disease, and prolonged or repeated therapy appears necessary to obtain sustained remission of the disease. In chronic hepatitis D, striking effects of interferon therapy have not been observed (7), and the beneficial effects of alpha-interferon are more difficult to document.
Table I. Classification of chronic hepatitis B*, 1975-1985 Aspartate aminotransferase
Histology
Prognosis ~
Healthy carrier Chronic persistent hepatitis Chronic active hepatitis *Cirrhosis excluded.
t Except for groundglass cells.
Normal Normal or
Normalt Portal hepatitis
t o r t t
Periportal hepatitis
~~~~
Normal Low risk of disease progression Poor
Chronic Viral Hepatitis, 1990
1 13
Table 11. Natural history of chronic hepatitis B in Japanese male railway workers Persons
Death at 7.3 year (mean)
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in study,
HBV status
n
HBsAg + ,HBeAg' HBsAg+, antiHBe' HBsAg-
30 238 25,034
HBV-DNA and increased incidence of hepatocellular carcinoma (HCC). Recent data from Japan (14). however, show no evidence of an increase in H C C and total mortality in patients with virus latency (HBeAg-negative) over those in patients with viral replication (HBeAg-positive) (Table 11). Data currently available strongly suggest that transition of viral replication into virus latency reduces infectivity and improves symptoms, liver biochemistry, histology, and prognosis. Therefore, a new classification of chronic hepatitis B is based on the presence or absence of viral replication. Active viral replication is best measured by HBV-DNA in serum (dot-spot hybridization (15) or liquid-phase hybridization (16) ), but for practical reasons the widely available HBeAg and alanine aminotransferase (ALAT) tests are used. Patients can thus be categorized into three groups (17): a) HBeAg-positive chronic hepatitis; b) HBeAg-negative. ALAT-positive hepatitis B; and c) HBeAg-negative, ALAT-negative hepatitis B.
Total (%)
Liver-related (Yo)
5 (16) 10 (4)
664 (3)
4 (13) 4 (2) 56 (0.2)
Selection of patients for antiviral therapy (Table 111) Patients with HBeAg-positive chronic hepatitis B are candidates for anti-viral therapy. The final decision to proceed with antiviral treatment depends on the need for therapy (low in patients without symptoms and normal liver tests), the chance of a therapeutic success (low in patients with immunodeficient conditions such as renal dialysis, organ transplantation, manifest H I V infection), and the risks of therapy (high in decompensated cirrhosis). Patients with HBeAg-negative, ALAT-positive chronic hepatitis B are a heterogenous group and require further diagnostic evaluation. Such a patient may still have active virus B replication with a virus strain incapable of expressing HBeAg (18). For this type of patient an excellent marker, in addition to serum HBV-DNA, is the presence of HBcAg in the liver, detectable by the widely available immunoperoxidase staining method (19). Patients with HBeAg-negative, ALAT-positive chronic hepatitis B and HBcAg in the liver are also candidates for anti-viral therapy. Chronic
Table 111. Chronic hepatitis B: inclusion and exclusion criteria for interferon therapy Inclusion critcria HBsAg-positive for at least 6 months or other evidence of chronicity I IBeAg/HBVDNA(p)-positive
ASATIALAT elevation Exclusion criteria Decompensated liver disease: hepatocellular carcinoma Non-compliance: alcohol, drug addiction Immunodeficiency: dialysis, transplants, AIDS Autoimmunity: psoriasis. myasthenia, rheumatoid arthritis Others: old age, pregnancy, other serious disease
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hepatitis B patients without serum HBeAg, HBVDNA, or liver HBcAg are unlikely to have virus B replication; they probably have concomitant disease such as hepatitis D, hepatitis c, alcohol abuse, hepatocellular carcinoma, schistosomiasis, or drug toxicity. For patients with HBeAg-negative, ALATnegative chronic hepatitis B anti-viral therapy is not indicated. Prognosis is excellent in the absence of symptoms or signs of cirrhosis. In case of inactive cirrhosis, twice yearly monitoring of the patient by means of liver tests, alphafetoprotein, and ultrasound can be justified as various treatment modalities for small hepatocellular carcinoma are increasingly being applied. Interferon therapy Pooled data from the initial studies of interferon therapy with various dosages and durations of treatment suggested a small beneficial effect of interferon therapy with about 25% responses (HBe seroconversion) in treated patients versus about 10% in controls (17); the percentage responders in treated patients and controls was highly variable owing to variation in selection of patients and small numbers of patients in each study. In a recently completed USA multicenter trial the number of patients in each treatment arm exceeded 40; the results are among the most reliable to assess the efficacy of alpha-interferon therapy, given for 16 weeks in a dose of 5 MU/day (Table IV). HBe seroconversion was observed in 37% of treated patients versus 7% in controls; patients receiving 1 MU of interferon per day exhibited 17% HBe seroconversion. The study also confirmed earlier observations (20) that, in addition to HBe seroconversion, loss of HBsAg
occurs more frequently (12%) in the 5MU interferon treatment group than spontaneously (2%). Combination of interferon with nucleoside analogues such as acyclovir (21) or adenine arabinoside (22) appears logical in an attempt to enhance the HBe seroconversion rate; pretreatment for 4 weeks with prednisone has also been suggested to improve results of interferon therapy (23). The outcome of recently completed randomized controlled studies with about 40 patients in each treatment group, however, showed no benefit either from pretreatment with prednisone or from combination with acyclovir (data on file at Schering-Plough and Wellcome, respectively). Re-analysis of the Rotterdam phase-I1 study on combination therapy of interferon with acyclovir (21) led to the hypothesis that the impressive results observed were related to repeated courses of anti-viral therapy rather than to the combination of interferon and acyclovir. Two independent pilot studies in London (G.J.M. Alexander) and Rotterdam tested a treatment schedule of 4 weeks of interferon pretreatment followed, after 4 weeks of no therapy, by the standard course of 1216 weeks of interferon therapy. Patients with a partial response (more than 50% decrease in HBeAg titer and HBV-DNA) at week 24 continued interferon therapy for another 4-8 weeks. Results in both studies comprising 10 and 20 patients, respectively showed HBe seroconversion in more than 50% of patients. It appears worthwhile to carry out a randomized trial comparing standard interferon therapy and prolonged interferon therapy with or without interferon pretreatment. CHRONIC HEPATITIS C
Table IV. USA multicenter interferon therapy trial for chronic hepatitis B*
percentage with Loss of HBVDNA/ HBeAg Loss of HBsAg Reactivation of HBV
IFN, IFN, Untreated 5 MU/day, 1 MUlday, controls, n=39 n=41 n=41
37
17
7
12 0
2
0 0
* Data on file at Schering-Plough.
0
Selection of patients for antiviral therapy (Table V ) Chronic hepatitis C can been diagnosed when persistent elevation of serum aminotransferases follows parenteral exposure to blood or blood products and anti-hepatitis C virus (HCV) antibodies are detectable in serum. In all other cases, the diagnosis of chronic hepatitis C should only be made after careful exclusion of other forms of liver disease. The diagnosis should be confirmed
Chronic Viral Hepatitis, 1990
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Table V. Chronic hepatitis C: inclusion and exclusion criteria for interferon therapy Inclusion criteria History of parenteral exposure to blood (products) or anti HCV-positive ALAT elevation for 6 or more months
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Exclusion criteria Liver disease of other etiology: alcohol. obesity, Wilson. alpha-I-antitrypsin deficiency, hemochromatosis, hepatotoxic drugs, virus B, autoimmune hepatitis Decompensated liver disease: jaundice, ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, cytopenia, hepatorenal syndrome Non-compliance, autoimmunity (see chronic hepatitis B) Others: old age, pregnancy, other serious disease
by anti-HCV testing (24), keeping in mind that current test systems have a 20% frequency of false-negative outcomes and a high rate of falsepositive results in autoidmune C A H (25). Chronic hepatitis C is often asymptomatic. However, 10% to 25% of patients progress to cirrhosis with its risks fot complications, such as liver failure or hepatocellular carcinoma. Patients with symptoms or signs of progressive liver disease (aminotransferases persistently more than tive times the upper limit of normal, increasing spleen size, or complications of cirrhosis) are particularly likely to benefit from interferon therapy. Since the dose of interferon used is rather low, the risks and side effects of interferon therapy are likely to be less than in chronic hepatitis B. Patients with immunodeficiency syndromes (renal dialysis, organ transplants, HIV infection) should not be excluded, since a host immune response appears not to be essential for a therapeutic response. Interferon therapy A USA multicenter trial (26) including 166 patients confirmed the therapeutic effect of alphainterferon observed in initial pilot studies (6, 27) and small controlled trials (28,29). Normalization of serum A L A T was observed in 46Y0 of patients treated with 3 MU three times a week versus 8% in controls; patients receiving 1 MU of interferon three times a week showed ALAT normalization in 28%. Relapse of active hepatitis (ALAT elevation) occurred frequently (>So%) in both interferon groups after therapy. Serum A L A T remained persistently normal in about 25% of
patients receiving 9 MU interferon a week for 24 weeks. Enhanced response rates can be expected when interferon therapy is started with higher doses of interferon, such as 5-10 M U three times a week (26. 28). Initially, serum aminotransferases should be monitored every 2 weeks. If there is no improvement in serum A L A T levels within 2 months, therapy should be stopped. If serum A L A T falls into the normal range, the dose of interferon can be decreased, and therapy should be continued for &12 months. An increase in the dose of alphainterferon may be appropriate in patients who show a partial response only or who have a breakthrough in serum A L A T during therapy (30). CHRONIC HEPATITIS D Selection of patients f o r antiviral therapy (Table VI) A chronic hepatitis D infection is considered to be present when anti-HDV antibodies are detected in chronic hepatitis B. The course of a chronic hepatitis D super-infection may be more progressive than the underlying chronic hepatitis B itself (31). Chronic hepatitis D , however, is a heterogeneous disease; in Western Europe it is diagnosed predominantly in patients from Mediterranean countries or in drug addicts. Co-infection with hepatitis C is common (32). Elevation of serum aminotransferases might be due to active viral replication of hepatitis B, C,or D ; in case of
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Table VI. Chronic hepatitis D ~
~
~~~~
Inclusion criteria HBsAg-positive for at least 6 months or other evidence of chronicity Anti-HDV-positivelHDAg-positive in liver ASATIALAT elevation Symptoms
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Exclusion criteria Decompensated liver disease (see chronic hepatitis C) Immunodeficiency (see chronic hepatitis B) Non-compliance, autoimmunity (see chronic hepatitis B) Others: old age, pregnancy, other serious disease
intravenous drug abuse toxic hepatitis may also be present. The most reliable method to document active viral replication of hepatitis D is the finding of HDV antigen in the liver; the presence of HDVRNA in serum together with the absence of HBVDNA and HCV-RNA provides additional proof that the liver disease is due to a hepatitis D infection. Unfortunately, reliable assays for HDV-RNA are not widely available, and the development of a sensitive serum test for HDVRNA (33) appears essential to monitor the effects of interferon therapy.
suppress hepatitis D viral replication and the activity of the liver disease, but confirmation of these data is required. SIDE EFFECTS O F INTERFERON THERAPY
The side effects of alpha-interferon may interfere with its therapeutic efficacy. Early side effects commonly occur during the first few days of treatment but do not usually present a clinical problem. Late side effects appear after 2 weeks of treatment and are less common. The medical or psychiatric complications, however, can be of major clinical significance and often require adInterferon therapy An Italian multicenter trial including 48 justment of the interferon dosage or other medical patients has recently been completed (34). Homo- interventions. Early side effects of interferon include fever, sexual men and persons with HIV antibodies or a history of drug abuse were excluded. During the chills, fatigue, myalgia, sleep disturbance, loss of first 4 months the dose of interferon was 5 MU/m* concentration and anorexia. These complications three times a week, followed by 3MU/m2 a week can be partly prevented by administration of 500 mg paracetamol every 6 h for the initial 3 days during the next 8 months. Initiation of therapy was followed within a few or 75-mg indomethacin slow-release tablets twice weeks by a decline in serum ALAT in 58O/0 of daily. Late side effects can be classified into systemic, treated patients; the serum ALAT, however, increased to pretreatment levels in most patients hematologic, psychiatric, infectious, and autoduring therapy with the lower maintenance dose. immune (37). Systemic side effects include weight In only one patient was ALAT normalization loss, hair loss, and decreased libido, in addition to those mentioned above. Hematologic side effects observed after therapy. Enhanced response rates have been reported are neutropenia, thrombocytopenia, and anemia. from another Italian controlled trial in which 10 The spectrum of psychiatric side effects is wide MU of interferon was given three times a week for and includes irritability, anxiety, depression, and 12 months; after therapy a normal serum ALAT psychosis. Return to drug addiction or alcohol persisted in about 33% of patients (35). These and abuse may occur. These side effects usually have other uncontrolled data (36) suggest that high an insidious onset in the 2nd or 3rd month of doses of interferon for prolonged periods may treatment and occur in 1&20% of patients.
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Chronic Viral Hepatitis, 1990
Perhaps secondary to the decrease in neutrophils, patients receiving alpha-interferon are more susceptible to bacterial infections, particularly in the case of pre-existing cirrhosis. Development of autoantibodies during interferon therapy is common, but overt autoimmune disease is rare. Autoimmune thyroiditis has been reported (38), as has exacerbation of autoimmune CAH in case of interferon therapy for incorrectly diagnosed chronic hepatitis C. Management of late side effects requires extra patient-physician interaction. The goal of management is to keep the patient on interferon until the maximum benefit has been derived (37). Often reassurance and encouragement will suffice; occasionally, hospital admission for several days may help to regain tolerance. In case of neutropenia (less than 500/mm3) or severe psychiatric effects, the dose of interferon should be reduced. Side effects are rarely so intolerable or medically so severe that interferon will have to be withdrawn completely.
5.
6.
7. 8. 9. 10.
11.
12.
13.
CONCLUSIONS Current results with alpha-interferon indicate a new area in the therapeutic approach to patients with chronic viral hepatitis but also underline the limited effectiveness of therapy with alpha-interferon alone. Since dosage and duration of interferon therapy are limited by side effects, a further search for complementary drugs appears essential.
14.
15.
16.
REFERENCES Schalm SW. Summerskill WHJ, Gitnick GL, Elveback LR. Contrasting features of severe chronic active liver disease with and without hepatitis B, antigen. Gut 1976, 17, 1422-1430 Lam KC. Lai CL. Ng RP, Trepo C. Wu PC. Deleterious effect of prcdnisolone in HBsAgpositive chronic active hepatitis. N Engl J Med 1981, 304, 380-386 A trial group of the European Association for the Study of the Liver. Streroids in chronic B-hepatitis. A randomized, double-blind, multinational trial on the effect of low-dose, long-term treatment on survival. Liver 1986, 6, 227-232 Greenberg HB. Pollard RB. Lutwick LI, Gregory PB, Robinson ES, Merigan TC. Effect of human leucocyte interferon on hepatitis B virus infection in
17.
18.
19 20 21
117
patients with chronic active hepatitis. N Engl J Med 1976, 295, 517-522 Weimar W. Heijtink RA, Ten Kate FJP. Schalm SW, Masurel N, Schellekens H. Double-blind study of leucocyte interferon administration in chronic HBsAg-positive hepatitis. Lancet 1980, 1. 336-338 Hoofnagle JH, Mullen KM. Jones DB, et al. Pilot study of recombinant human alpha-interferon in chronic nonAnonB hepatitis. N Engl J Med 1986. 31.5, 1575-1.578 Rosina F, Saracco G , Actic GC, et al. Treatment of chronic delta hepatitis with alpha-2 recombinant interferon (IFN). Gastroenterology 1986. 90. 1762 Review by an international group. Acute and chronic hepatitis revisited. Lancet 1977.2.914-919 Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the 'healthy' HBsAg carrier state. Hepatology 1987. 7, 75b763 Fattovich G , Brollo L, Alberti A, Pontisso P, Realdi G, Ruol A. Chronic persistent hepatitis type B: a clinical and morphological follow-up study. J Hepatology 1990 (in press) Realdi G, Alberti A, Rugge M, Bortolli F, Rigoli AM, Tremolada F. Seroconversion from hepatitis B e antigen to antiHBe in chronic hepatitis B virus infection. Gastroenterology 1980, 195. 195-199 Schalm SW, Heijtink RA. Spontaneous disappearance of viral replication and liver cell inflammation in HBsAg-positive chronic active hepatitis: Hepatology 1982. 6. 791-794 Shafritz DA. Hepatitis B virus DNA molecules in the liver of HBsAg carriers: mechanistic considerations in the pathogenesis of hepatocellular carcinoma. Hepatology 1982. 2, 35S-41S Yoshino 1, Iijima T, lmai Y. Nambu M, NamiaisaT. The natural history of the HBsAg chronic carrier state in Japanese National Railway. Hepatology 1983, 3, 1085 Scotto J. Hadchouel M. Hery C, Yvart J . Tiollais P, Brechot C. Detcction o f hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology 1983, 3. 279-284 Kuhns MC, McNamara AL. Cabal CM. et al. A new assay for the quantitative detection of hepatitis B viral DNA in human serum. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. Alan R. Liss, New York, 1988, 25b262 Schalm SW, De Man RA. Thomas HC. Jacyna M, Hadziyannis SJ. Manessis E. Chronic hepatitis B: therapeutic controversies and randomized controlled trials. Gastroenterol Int 1989. 2, 16-24 Carmen WF, Hadziyannis S. McGarvey MJ. Jacyna MR, Karayiannis P. Makris A. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989, 2, 58859 I Huang SN. Immunohistochemical demonstration of hepatitis B core and surface antigens in paraffin sections. Lab Invest 1975, 33, 88-95 Alexander GJ, Brahm J, Fagan EA, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987, 2, 66423 Schalm SW, Heijtink RA, van Buuren HR, de Man
118
22.
23.
Downloaded by [RMIT University Library] at 04:14 03 April 2016
24.
25.
26.
27.
28.
29.
S. W. Schalm
RA. Acyclovir enhances the antiviral effect of interferon in chronic hepatitis B. Lancet 1985, 1, 358-360 Garcia G . Smith CI, Weissberg JI. et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leucocyte interferon in the treatment of chronic hepatitis B. Ann Intern Med 1987, 107, 278-285 Perillo RP, Regenstein FG, Peters MG, et al. Prednisone withdrawal followed by recombinant alpha-interferon in the treatment of chronic type B hepatitis. A randomized controlled trial. Ann Intern Med 1988, 109, 95-100 Kuo G, Choo QL, Alter HJ, et al. An assay for Circulating antibodies to a major etiologic virus of human nonAnonB hepatitis. Science 1989, 244, 362-364 McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani D, Williams R. Hepatitis Cvirusantibodies in chronic active hepatitis: pathogenetic factor or false-positive result? Lancet 1990, 754-757 Davis GL, Balart LA, Schiff ER, 8 a l . Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med 1989, 321, 1501-1506 Thomson BJ, Doran M, Lever AMI, Webster ADB. Alpha-interferon therapy for nonAnonB hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987, 1. 539-541 Jacyna MR, Brooks MG, Loke RHT, Main J, Murray-Lyon IM, Thomas HC. Randomised controlled trial of interferon alpha (lymphoblastoid interferon) in chronic nonAnonB hepatitis. Br Med J 1989, 80-82 Di Bisceglie AM, Martin P. Kassianides C, et al. Recombinant interferon alfa therapy for chronic
hepatitis C. A randomized, double-blind, placebocontrolled trial. N Engl J Med 1989, 321, 15061510 30. Hoofnagle JH, Di BIsceglie AM. Treatment of chronic type C hepatitis with alpha-interferon. Semin Liver Dis 1989, 9, 259-263 31. Rizzetto M, Verme G, Gerin JL, Purcell RH. Hepatitis delta virus disease. Prog Liver Dis 1986.8, 417-431 32. Berk L, Man de RA, Housset C, Berthelot P, Schalm SW. Alpha lymphoblastoid interferon and acyclovir for chronic hepatitis delta. In: Gerin JL, ed. Hepatitis delta virus. Alan R. Liss. New York, 1990 (in press) 33. Smedile A, Rizzetto M, Denniston KJ. et al. Type D hepatitis: the clinical significance of HDV-RNA in serum as detected by a hybridization-based assay. Hepatology 1986, 6, 1297-1302 34. Rosina F, Pintus C. Long-term interferon therapy of chronic hepatitis delta virus using recombinant alpha-interferon: A controlled study [Abstract]. Hepatology 1988, 8, 1408 35. Farci P, Karayiannis P, Brook MG, et al. Treatment of chronic hepatitis delta virus (HDV) infection with human lymphoblastoid alpha-interferon. In: Gerin JL. ed. Hepatitis delta virus. Alan R Liss, New York, 1990 (in press) 36. Hoofnagle JH. Type D (delta) hepatitis. JAMA 1989, 261, 1321-1325 37. Renault PF, Hoofnagle JH. Side-effects of alphainterferon. Semin Liver Dis 19?? 273-277 38. Fentiman IS. Thomas BS, Balkwill FR, Rubens RD, Hayward JL. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1985, I , 1166
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Treatment of Chronic Viral Hepatitis Anno 1990 S. W. Schalm To cite this article: S. W. Schalm (1990) Treatment of Chronic Viral Hepatitis Anno 1990, Scandinavian Journal of Gastroenterology, 25:sup178, 111-118, DOI: 10.3109/00365529009093160 To link to this article: http://dx.doi.org/10.3109/00365529009093160
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [RMIT University Library]
Date: 03 April 2016, At: 04:14
Treatment of Chronic Viral Hepatitis Anno 1990 S.W. SCHALM Dept. of Internal Medicine & Hepatogastroenterology, University Hospital Dijkzigt. Rotterdam. The Netherlands
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Schalm SW. Treatment of chronic viral hepatitis anno 1990. Scand J Gastroenterol 1990. SUPPI PI 178). 111-118 Alpha-interferon has emerged as the most effective agent for the treatment of chronic hepatitis when active replication of virus B, C, or D is present. Exogenous administration of human alpha-interferon, now possible through modern large-scale production methods, is associated with suppression of virus in blood. Amelioration of liver disease occurs in 35% of patients with hepatitis B virus and in 50% with hepatitis C virus with interferon doses of 30 and 10 MU per week, respectively, for 16-26 weeks; after therapy. persistent normalization of serum alanine aminotransferase is observed in 35% and 27?0. respectively. Similar results have now also been reported for chronic hepatitis D. Enhanced response rates (>SO%) may be obtained by prolonged intermittent interferon therapy. Combination of interferon with another 'antiviral' agent (vidarabine, acyclovir, prednisone) has not increased therapeutic efficacy. Alpha-interferon induces side effects such as fatigue, flu-like syndrome, myalgia, and changes in mood and granulocytes. Patients with decompensated cirrhosis are particularly prone to bacterial infection and disease exacerbation and should receive lower doses. Interferon, when applied skillfully, induces the highly beneficial transition of active viral replication into viral latency, thereby greatly reducing infectivity, symptoms, and activity of the liver disease. Prevention of death from liver failure or hepdtocehlar carcinoma is to be expected.
Key words: Chronic viral hepatitis; interferon therapy; liver cirrhosis; liver function; viral replication S. W. Schalm, M . D . , Depr. oflnrernal Medicine & Heparogasrroenrerology. University
Hospital Dijkzigt. 301s G D Rotterdam. The Netherlands
In 1980 treatment of chronic hepatitis was related to the indications and contraindication of corticosteroids. Advances in knowledge pertaining to the etiology of chronic hepatitis, in particular the introduction of tests to detect hepatitis B and, most recently, hepatitis C, allowed delineation of the subgroup of chronic viral hepatitis. Soon after introduction of the first test for hepatitis B, a retrospective study suggested that corticosteroids, so effective in inducing clinical and biochemical remission and in improving life expectancy in patients with HBsAg-negative chronic active hepatitis, were less effective in chronic active hepatitis type virus B (1). Subsequently, at least two consecutive controlled trials showed absence of a beneficial effect of corticosteroids in chronic hepatitis B (2, 3). Similarly, proof of beneficial
effects of corticosteroids in chronic hepatitis C and D is lacking. The failure of anti-inflammatory drugs to modify the course of chronic viral hepatitis led to the approach of antiviral therapy. Investigators from the USA documented the inhibition of hepatitis B virus (HBV) replication by human alpha-interferon and the persistent disappearance of all hepatitis B markers on prolonged therapy in a single patient (4). In a small controlled trial performed in The Netherlands the inhibitory effect of human alpha-interferon was confirmed, but induction of virus latency was similar in patients receiving interferon for 6 weeks (20%) and patients receiving control (albumin) injections (5). Interferon is therefore not a simple effective therapy of chronic hepatitis B. The
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liver biochemistry, histology, and prognosis are given in Table I. Long-term follow-up study of healthy carriers, CPH and CAH, however, has demonstrated that patients can move from one category to another and that the prognostic implications are invalid. According to Fattovich et al. (10) the incidence of development of cirrhosis is about equal for CPH and CAH; it amounts to 30-35% for a follow-up study of 5 years. Furthermore, improvement in disease activity was observed in 30-50% of CPH and CAH. Lastly, apparently healthy carriers may develop symptoms and signs of chronic hepatitis or even have silent cirrhosis of the liver. Therefore the classification is now considered outdated. Measurement of serum markers of hepatitis B virus replication (DNA-polymerase activity, HBe-antigen or HBV-DNA) during follow-up study has made it highly likely that the prognosis of chronic hepatitis B is primarily determined by the presence or absence of virus B replication. Progression of liver disease is mainly observed in patients with active viral replication, and the disease usually becomes inactive after transition of the phase with active viral replication into the phase with virus latency (DNA-polymerase, HBeantigen, HBV-DNA-negative) (1 1, 12). This finding provides the rationale for a therapeutic approach aimed at eradication of virus CHRONIC HEPATITIS B replication rather than non-specific suppression of Classification of chronic hepatitis B liver inflammation. For many years chronic hepatitis has been It has been unclear whether this new approach, classified as chronic persistent hepatitis (CPH) or accepted by virtually all hepatologists, also leads chronic active hepatitis (CAH) (8). In case of to a better prognosis-that is, an improvement in chronic hepatitis B the classification has been life expectancy. Fear has been expressed (13) that adapted to include also the 'healthy carrier' state inactivation of the liver disease may enable uncon(9). Characteristics of each entity with regard to trolled growth of hepatocytes with integrated
availability of large amounts of highly purified alpha-interferon in the last 5 years has enabled clinical trials with various dosages and durations of treatment. Recently, convincing evidence has been obtained that persistent disappearance of markers of hepatitis B virus replication and subsequent remission of the liver disease occur more frequently (35%) with interferon therapy for 16 weeks than spontaneously (10%). In 1990 alpha-interferon has emerged as the most effective treatment of chronic hepatitis B. The beneficial effects of alpha-interferon led to a pilot study of this agent in chronic hepatitis C (formerly called non-A non-B hepatitis) (6). In this disease alpha-interferon has a striking effect similar to corticosteroids in HBsAgnegative chronic active hepatitis, with induction of clinical and biochemical remission in most patients within 1-3 months. Also, similar to corticosteroids, withdrawal of the drug is often associated with relapse of disease, and prolonged or repeated therapy appears necessary to obtain sustained remission of the disease. In chronic hepatitis D, striking effects of interferon therapy have not been observed (7), and the beneficial effects of alpha-interferon are more difficult to document.
Table I. Classification of chronic hepatitis B*, 1975-1985 Aspartate aminotransferase
Histology
Prognosis ~
Healthy carrier Chronic persistent hepatitis Chronic active hepatitis *Cirrhosis excluded.
t Except for groundglass cells.
Normal Normal or
Normalt Portal hepatitis
t o r t t
Periportal hepatitis
~~~~
Normal Low risk of disease progression Poor
Chronic Viral Hepatitis, 1990
1 13
Table 11. Natural history of chronic hepatitis B in Japanese male railway workers Persons
Death at 7.3 year (mean)
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in study,
HBV status
n
HBsAg + ,HBeAg' HBsAg+, antiHBe' HBsAg-
30 238 25,034
HBV-DNA and increased incidence of hepatocellular carcinoma (HCC). Recent data from Japan (14). however, show no evidence of an increase in H C C and total mortality in patients with virus latency (HBeAg-negative) over those in patients with viral replication (HBeAg-positive) (Table 11). Data currently available strongly suggest that transition of viral replication into virus latency reduces infectivity and improves symptoms, liver biochemistry, histology, and prognosis. Therefore, a new classification of chronic hepatitis B is based on the presence or absence of viral replication. Active viral replication is best measured by HBV-DNA in serum (dot-spot hybridization (15) or liquid-phase hybridization (16) ), but for practical reasons the widely available HBeAg and alanine aminotransferase (ALAT) tests are used. Patients can thus be categorized into three groups (17): a) HBeAg-positive chronic hepatitis; b) HBeAg-negative. ALAT-positive hepatitis B; and c) HBeAg-negative, ALAT-negative hepatitis B.
Total (%)
Liver-related (Yo)
5 (16) 10 (4)
664 (3)
4 (13) 4 (2) 56 (0.2)
Selection of patients for antiviral therapy (Table 111) Patients with HBeAg-positive chronic hepatitis B are candidates for anti-viral therapy. The final decision to proceed with antiviral treatment depends on the need for therapy (low in patients without symptoms and normal liver tests), the chance of a therapeutic success (low in patients with immunodeficient conditions such as renal dialysis, organ transplantation, manifest H I V infection), and the risks of therapy (high in decompensated cirrhosis). Patients with HBeAg-negative, ALAT-positive chronic hepatitis B are a heterogenous group and require further diagnostic evaluation. Such a patient may still have active virus B replication with a virus strain incapable of expressing HBeAg (18). For this type of patient an excellent marker, in addition to serum HBV-DNA, is the presence of HBcAg in the liver, detectable by the widely available immunoperoxidase staining method (19). Patients with HBeAg-negative, ALAT-positive chronic hepatitis B and HBcAg in the liver are also candidates for anti-viral therapy. Chronic
Table 111. Chronic hepatitis B: inclusion and exclusion criteria for interferon therapy Inclusion critcria HBsAg-positive for at least 6 months or other evidence of chronicity I IBeAg/HBVDNA(p)-positive
ASATIALAT elevation Exclusion criteria Decompensated liver disease: hepatocellular carcinoma Non-compliance: alcohol, drug addiction Immunodeficiency: dialysis, transplants, AIDS Autoimmunity: psoriasis. myasthenia, rheumatoid arthritis Others: old age, pregnancy, other serious disease
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hepatitis B patients without serum HBeAg, HBVDNA, or liver HBcAg are unlikely to have virus B replication; they probably have concomitant disease such as hepatitis D, hepatitis c, alcohol abuse, hepatocellular carcinoma, schistosomiasis, or drug toxicity. For patients with HBeAg-negative, ALATnegative chronic hepatitis B anti-viral therapy is not indicated. Prognosis is excellent in the absence of symptoms or signs of cirrhosis. In case of inactive cirrhosis, twice yearly monitoring of the patient by means of liver tests, alphafetoprotein, and ultrasound can be justified as various treatment modalities for small hepatocellular carcinoma are increasingly being applied. Interferon therapy Pooled data from the initial studies of interferon therapy with various dosages and durations of treatment suggested a small beneficial effect of interferon therapy with about 25% responses (HBe seroconversion) in treated patients versus about 10% in controls (17); the percentage responders in treated patients and controls was highly variable owing to variation in selection of patients and small numbers of patients in each study. In a recently completed USA multicenter trial the number of patients in each treatment arm exceeded 40; the results are among the most reliable to assess the efficacy of alpha-interferon therapy, given for 16 weeks in a dose of 5 MU/day (Table IV). HBe seroconversion was observed in 37% of treated patients versus 7% in controls; patients receiving 1 MU of interferon per day exhibited 17% HBe seroconversion. The study also confirmed earlier observations (20) that, in addition to HBe seroconversion, loss of HBsAg
occurs more frequently (12%) in the 5MU interferon treatment group than spontaneously (2%). Combination of interferon with nucleoside analogues such as acyclovir (21) or adenine arabinoside (22) appears logical in an attempt to enhance the HBe seroconversion rate; pretreatment for 4 weeks with prednisone has also been suggested to improve results of interferon therapy (23). The outcome of recently completed randomized controlled studies with about 40 patients in each treatment group, however, showed no benefit either from pretreatment with prednisone or from combination with acyclovir (data on file at Schering-Plough and Wellcome, respectively). Re-analysis of the Rotterdam phase-I1 study on combination therapy of interferon with acyclovir (21) led to the hypothesis that the impressive results observed were related to repeated courses of anti-viral therapy rather than to the combination of interferon and acyclovir. Two independent pilot studies in London (G.J.M. Alexander) and Rotterdam tested a treatment schedule of 4 weeks of interferon pretreatment followed, after 4 weeks of no therapy, by the standard course of 1216 weeks of interferon therapy. Patients with a partial response (more than 50% decrease in HBeAg titer and HBV-DNA) at week 24 continued interferon therapy for another 4-8 weeks. Results in both studies comprising 10 and 20 patients, respectively showed HBe seroconversion in more than 50% of patients. It appears worthwhile to carry out a randomized trial comparing standard interferon therapy and prolonged interferon therapy with or without interferon pretreatment. CHRONIC HEPATITIS C
Table IV. USA multicenter interferon therapy trial for chronic hepatitis B*
percentage with Loss of HBVDNA/ HBeAg Loss of HBsAg Reactivation of HBV
IFN, IFN, Untreated 5 MU/day, 1 MUlday, controls, n=39 n=41 n=41
37
17
7
12 0
2
0 0
* Data on file at Schering-Plough.
0
Selection of patients for antiviral therapy (Table V ) Chronic hepatitis C can been diagnosed when persistent elevation of serum aminotransferases follows parenteral exposure to blood or blood products and anti-hepatitis C virus (HCV) antibodies are detectable in serum. In all other cases, the diagnosis of chronic hepatitis C should only be made after careful exclusion of other forms of liver disease. The diagnosis should be confirmed
Chronic Viral Hepatitis, 1990
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Table V. Chronic hepatitis C: inclusion and exclusion criteria for interferon therapy Inclusion criteria History of parenteral exposure to blood (products) or anti HCV-positive ALAT elevation for 6 or more months
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Exclusion criteria Liver disease of other etiology: alcohol. obesity, Wilson. alpha-I-antitrypsin deficiency, hemochromatosis, hepatotoxic drugs, virus B, autoimmune hepatitis Decompensated liver disease: jaundice, ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, cytopenia, hepatorenal syndrome Non-compliance, autoimmunity (see chronic hepatitis B) Others: old age, pregnancy, other serious disease
by anti-HCV testing (24), keeping in mind that current test systems have a 20% frequency of false-negative outcomes and a high rate of falsepositive results in autoidmune C A H (25). Chronic hepatitis C is often asymptomatic. However, 10% to 25% of patients progress to cirrhosis with its risks fot complications, such as liver failure or hepatocellular carcinoma. Patients with symptoms or signs of progressive liver disease (aminotransferases persistently more than tive times the upper limit of normal, increasing spleen size, or complications of cirrhosis) are particularly likely to benefit from interferon therapy. Since the dose of interferon used is rather low, the risks and side effects of interferon therapy are likely to be less than in chronic hepatitis B. Patients with immunodeficiency syndromes (renal dialysis, organ transplants, HIV infection) should not be excluded, since a host immune response appears not to be essential for a therapeutic response. Interferon therapy A USA multicenter trial (26) including 166 patients confirmed the therapeutic effect of alphainterferon observed in initial pilot studies (6, 27) and small controlled trials (28,29). Normalization of serum A L A T was observed in 46Y0 of patients treated with 3 MU three times a week versus 8% in controls; patients receiving 1 MU of interferon three times a week showed ALAT normalization in 28%. Relapse of active hepatitis (ALAT elevation) occurred frequently (>So%) in both interferon groups after therapy. Serum A L A T remained persistently normal in about 25% of
patients receiving 9 MU interferon a week for 24 weeks. Enhanced response rates can be expected when interferon therapy is started with higher doses of interferon, such as 5-10 M U three times a week (26. 28). Initially, serum aminotransferases should be monitored every 2 weeks. If there is no improvement in serum A L A T levels within 2 months, therapy should be stopped. If serum A L A T falls into the normal range, the dose of interferon can be decreased, and therapy should be continued for &12 months. An increase in the dose of alphainterferon may be appropriate in patients who show a partial response only or who have a breakthrough in serum A L A T during therapy (30). CHRONIC HEPATITIS D Selection of patients f o r antiviral therapy (Table VI) A chronic hepatitis D infection is considered to be present when anti-HDV antibodies are detected in chronic hepatitis B. The course of a chronic hepatitis D super-infection may be more progressive than the underlying chronic hepatitis B itself (31). Chronic hepatitis D , however, is a heterogeneous disease; in Western Europe it is diagnosed predominantly in patients from Mediterranean countries or in drug addicts. Co-infection with hepatitis C is common (32). Elevation of serum aminotransferases might be due to active viral replication of hepatitis B, C,or D ; in case of
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Table VI. Chronic hepatitis D ~
~
~~~~
Inclusion criteria HBsAg-positive for at least 6 months or other evidence of chronicity Anti-HDV-positivelHDAg-positive in liver ASATIALAT elevation Symptoms
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Exclusion criteria Decompensated liver disease (see chronic hepatitis C) Immunodeficiency (see chronic hepatitis B) Non-compliance, autoimmunity (see chronic hepatitis B) Others: old age, pregnancy, other serious disease
intravenous drug abuse toxic hepatitis may also be present. The most reliable method to document active viral replication of hepatitis D is the finding of HDV antigen in the liver; the presence of HDVRNA in serum together with the absence of HBVDNA and HCV-RNA provides additional proof that the liver disease is due to a hepatitis D infection. Unfortunately, reliable assays for HDV-RNA are not widely available, and the development of a sensitive serum test for HDVRNA (33) appears essential to monitor the effects of interferon therapy.
suppress hepatitis D viral replication and the activity of the liver disease, but confirmation of these data is required. SIDE EFFECTS O F INTERFERON THERAPY
The side effects of alpha-interferon may interfere with its therapeutic efficacy. Early side effects commonly occur during the first few days of treatment but do not usually present a clinical problem. Late side effects appear after 2 weeks of treatment and are less common. The medical or psychiatric complications, however, can be of major clinical significance and often require adInterferon therapy An Italian multicenter trial including 48 justment of the interferon dosage or other medical patients has recently been completed (34). Homo- interventions. Early side effects of interferon include fever, sexual men and persons with HIV antibodies or a history of drug abuse were excluded. During the chills, fatigue, myalgia, sleep disturbance, loss of first 4 months the dose of interferon was 5 MU/m* concentration and anorexia. These complications three times a week, followed by 3MU/m2 a week can be partly prevented by administration of 500 mg paracetamol every 6 h for the initial 3 days during the next 8 months. Initiation of therapy was followed within a few or 75-mg indomethacin slow-release tablets twice weeks by a decline in serum ALAT in 58O/0 of daily. Late side effects can be classified into systemic, treated patients; the serum ALAT, however, increased to pretreatment levels in most patients hematologic, psychiatric, infectious, and autoduring therapy with the lower maintenance dose. immune (37). Systemic side effects include weight In only one patient was ALAT normalization loss, hair loss, and decreased libido, in addition to those mentioned above. Hematologic side effects observed after therapy. Enhanced response rates have been reported are neutropenia, thrombocytopenia, and anemia. from another Italian controlled trial in which 10 The spectrum of psychiatric side effects is wide MU of interferon was given three times a week for and includes irritability, anxiety, depression, and 12 months; after therapy a normal serum ALAT psychosis. Return to drug addiction or alcohol persisted in about 33% of patients (35). These and abuse may occur. These side effects usually have other uncontrolled data (36) suggest that high an insidious onset in the 2nd or 3rd month of doses of interferon for prolonged periods may treatment and occur in 1&20% of patients.
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Chronic Viral Hepatitis, 1990
Perhaps secondary to the decrease in neutrophils, patients receiving alpha-interferon are more susceptible to bacterial infections, particularly in the case of pre-existing cirrhosis. Development of autoantibodies during interferon therapy is common, but overt autoimmune disease is rare. Autoimmune thyroiditis has been reported (38), as has exacerbation of autoimmune CAH in case of interferon therapy for incorrectly diagnosed chronic hepatitis C. Management of late side effects requires extra patient-physician interaction. The goal of management is to keep the patient on interferon until the maximum benefit has been derived (37). Often reassurance and encouragement will suffice; occasionally, hospital admission for several days may help to regain tolerance. In case of neutropenia (less than 500/mm3) or severe psychiatric effects, the dose of interferon should be reduced. Side effects are rarely so intolerable or medically so severe that interferon will have to be withdrawn completely.
5.
6.
7. 8. 9. 10.
11.
12.
13.
CONCLUSIONS Current results with alpha-interferon indicate a new area in the therapeutic approach to patients with chronic viral hepatitis but also underline the limited effectiveness of therapy with alpha-interferon alone. Since dosage and duration of interferon therapy are limited by side effects, a further search for complementary drugs appears essential.
14.
15.
16.
REFERENCES Schalm SW. Summerskill WHJ, Gitnick GL, Elveback LR. Contrasting features of severe chronic active liver disease with and without hepatitis B, antigen. Gut 1976, 17, 1422-1430 Lam KC. Lai CL. Ng RP, Trepo C. Wu PC. Deleterious effect of prcdnisolone in HBsAgpositive chronic active hepatitis. N Engl J Med 1981, 304, 380-386 A trial group of the European Association for the Study of the Liver. Streroids in chronic B-hepatitis. A randomized, double-blind, multinational trial on the effect of low-dose, long-term treatment on survival. Liver 1986, 6, 227-232 Greenberg HB. Pollard RB. Lutwick LI, Gregory PB, Robinson ES, Merigan TC. Effect of human leucocyte interferon on hepatitis B virus infection in
17.
18.
19 20 21
117
patients with chronic active hepatitis. N Engl J Med 1976, 295, 517-522 Weimar W. Heijtink RA, Ten Kate FJP. Schalm SW, Masurel N, Schellekens H. Double-blind study of leucocyte interferon administration in chronic HBsAg-positive hepatitis. Lancet 1980, 1. 336-338 Hoofnagle JH, Mullen KM. Jones DB, et al. Pilot study of recombinant human alpha-interferon in chronic nonAnonB hepatitis. N Engl J Med 1986. 31.5, 1575-1.578 Rosina F, Saracco G , Actic GC, et al. Treatment of chronic delta hepatitis with alpha-2 recombinant interferon (IFN). Gastroenterology 1986. 90. 1762 Review by an international group. Acute and chronic hepatitis revisited. Lancet 1977.2.914-919 Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the 'healthy' HBsAg carrier state. Hepatology 1987. 7, 75b763 Fattovich G , Brollo L, Alberti A, Pontisso P, Realdi G, Ruol A. Chronic persistent hepatitis type B: a clinical and morphological follow-up study. J Hepatology 1990 (in press) Realdi G, Alberti A, Rugge M, Bortolli F, Rigoli AM, Tremolada F. Seroconversion from hepatitis B e antigen to antiHBe in chronic hepatitis B virus infection. Gastroenterology 1980, 195. 195-199 Schalm SW, Heijtink RA. Spontaneous disappearance of viral replication and liver cell inflammation in HBsAg-positive chronic active hepatitis: Hepatology 1982. 6. 791-794 Shafritz DA. Hepatitis B virus DNA molecules in the liver of HBsAg carriers: mechanistic considerations in the pathogenesis of hepatocellular carcinoma. Hepatology 1982. 2, 35S-41S Yoshino 1, Iijima T, lmai Y. Nambu M, NamiaisaT. The natural history of the HBsAg chronic carrier state in Japanese National Railway. Hepatology 1983, 3, 1085 Scotto J. Hadchouel M. Hery C, Yvart J . Tiollais P, Brechot C. Detcction o f hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology 1983, 3. 279-284 Kuhns MC, McNamara AL. Cabal CM. et al. A new assay for the quantitative detection of hepatitis B viral DNA in human serum. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. Alan R. Liss, New York, 1988, 25b262 Schalm SW, De Man RA. Thomas HC. Jacyna M, Hadziyannis SJ. Manessis E. Chronic hepatitis B: therapeutic controversies and randomized controlled trials. Gastroenterol Int 1989. 2, 16-24 Carmen WF, Hadziyannis S. McGarvey MJ. Jacyna MR, Karayiannis P. Makris A. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989, 2, 58859 I Huang SN. Immunohistochemical demonstration of hepatitis B core and surface antigens in paraffin sections. Lab Invest 1975, 33, 88-95 Alexander GJ, Brahm J, Fagan EA, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987, 2, 66423 Schalm SW, Heijtink RA, van Buuren HR, de Man
118
22.
23.
Downloaded by [RMIT University Library] at 04:14 03 April 2016
24.
25.
26.
27.
28.
29.
S. W. Schalm
RA. Acyclovir enhances the antiviral effect of interferon in chronic hepatitis B. Lancet 1985, 1, 358-360 Garcia G . Smith CI, Weissberg JI. et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leucocyte interferon in the treatment of chronic hepatitis B. Ann Intern Med 1987, 107, 278-285 Perillo RP, Regenstein FG, Peters MG, et al. Prednisone withdrawal followed by recombinant alpha-interferon in the treatment of chronic type B hepatitis. A randomized controlled trial. Ann Intern Med 1988, 109, 95-100 Kuo G, Choo QL, Alter HJ, et al. An assay for Circulating antibodies to a major etiologic virus of human nonAnonB hepatitis. Science 1989, 244, 362-364 McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani D, Williams R. Hepatitis Cvirusantibodies in chronic active hepatitis: pathogenetic factor or false-positive result? Lancet 1990, 754-757 Davis GL, Balart LA, Schiff ER, 8 a l . Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med 1989, 321, 1501-1506 Thomson BJ, Doran M, Lever AMI, Webster ADB. Alpha-interferon therapy for nonAnonB hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987, 1. 539-541 Jacyna MR, Brooks MG, Loke RHT, Main J, Murray-Lyon IM, Thomas HC. Randomised controlled trial of interferon alpha (lymphoblastoid interferon) in chronic nonAnonB hepatitis. Br Med J 1989, 80-82 Di Bisceglie AM, Martin P. Kassianides C, et al. Recombinant interferon alfa therapy for chronic
hepatitis C. A randomized, double-blind, placebocontrolled trial. N Engl J Med 1989, 321, 15061510 30. Hoofnagle JH, Di BIsceglie AM. Treatment of chronic type C hepatitis with alpha-interferon. Semin Liver Dis 1989, 9, 259-263 31. Rizzetto M, Verme G, Gerin JL, Purcell RH. Hepatitis delta virus disease. Prog Liver Dis 1986.8, 417-431 32. Berk L, Man de RA, Housset C, Berthelot P, Schalm SW. Alpha lymphoblastoid interferon and acyclovir for chronic hepatitis delta. In: Gerin JL, ed. Hepatitis delta virus. Alan R. Liss. New York, 1990 (in press) 33. Smedile A, Rizzetto M, Denniston KJ. et al. Type D hepatitis: the clinical significance of HDV-RNA in serum as detected by a hybridization-based assay. Hepatology 1986, 6, 1297-1302 34. Rosina F, Pintus C. Long-term interferon therapy of chronic hepatitis delta virus using recombinant alpha-interferon: A controlled study [Abstract]. Hepatology 1988, 8, 1408 35. Farci P, Karayiannis P, Brook MG, et al. Treatment of chronic hepatitis delta virus (HDV) infection with human lymphoblastoid alpha-interferon. In: Gerin JL. ed. Hepatitis delta virus. Alan R Liss, New York, 1990 (in press) 36. Hoofnagle JH. Type D (delta) hepatitis. JAMA 1989, 261, 1321-1325 37. Renault PF, Hoofnagle JH. Side-effects of alphainterferon. Semin Liver Dis 19?? 273-277 38. Fentiman IS. Thomas BS, Balkwill FR, Rubens RD, Hayward JL. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1985, I , 1166
