Scand J Infect Dis 21: 127-132, 1989

Interferon Alpha-2b Treatment of Chronic Posttransfusion Non-A, Non-B Hepatitis: Interim Results of a Randomized Controlled Open Study

OLA WEILAND,~ ROBERT SCHVARCZ.' R U N E WEJSTAL,! GUNNAR NORKRANS.' ULLA FOBERG7 and ARIL FRYDEN' From the Departments of Infectious Diseases, 'Kurolinsku Institute. Roslugstull Hospital, Stockholm, 'East Hospital. Goteborg and 'University Hospital, Linkoping, Sweden

32 patients with biopsy-proven chronic non- A, non-B posttransfusion hepatitis and raised aminotransferase levels since more than 1 year were randomized 2 : l to treatment with interferon alpha-2b, Intronaa, or to controls. The interferon group received 3 MU interferon 3 times weekly subcutaneously. Interim results 12 weeks after randomization showed that 14/21 (67 %) patients in the treatment group had normalized their serum alanine aminotrans- ferase levels whereas none of 11 patients in the control group had @<0.001). If interferon alpha-2b is only suppressive during ongoing therapy or curative will be shown later during continued follow-up.

0. Weiland, MD, PhD, Department of Infectious Diseases, Roslagstull Hospital, Box 5651, S-11489 Stockholm, Sweden

INTRODUCTION

Approximately 50 5% of non-A, non-B posttransfusion hepatitis (NANB PTH) cases pro- ceed to chronicity ( 1 , 2 ) and a substantial proportion of these patients will eventually develop cirrhosis (3, 4). So far no established therapy is available or generally agreed upon. Preliminary reports, however, have suggested a beneficial effect with long-term alpha interferon treatment of patients with chronic NANB hepatitis, in whom both normalization of aminotransferases and histological improvement has occurred (5-8).

The following report presents the interim results of a controlled open study using interferon alpha-2b subcutaneously in small doses to treat patients with chronic NANB PTH.

MATERIALS AND METHODS Putients. 32 patients (3 females) over 18 years of age with biopsy-proven chronic NANB PTH were entered into an open, prospective, randomized, controlled 3-center trial conducted at the Depart- ments of Infectious Diseases, Roslagstull Hospital, Stockholm. East Hospital. Goteborg and Univer- sity Hospital, Linkoping. Patients with a history of blood transfusion. persistent elevation of amino- transferases for at least 1 year prior to entry and a liver biopsy consistent with chronic hepatitis were entered. Patients with decompensated liver disease were excluded. as well as patients with other causes for chronic liver disease like hepatitis B . alcohol. hemochromatosis, Wilson's disease, alpha-I antitrypsin deficiency, drug related liver disease. obesity induced liver disease, autoimmune hepatitis and primary biliary cirrhosis.

Before entry, after the first liver biopsy had been performed, all patients were stratified according to histology to ensure an even number of patients with chronic active hepatitis (CAH) and chronic persistent hepatitis (CPH) in the treatment and control groups, respectively. Hereafter, patients in the

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128 0. Weiland et al.

CAH and CPH groups were randomized separately with closed envelopes 2 : 1 to receive alpha-2b interferon or no treatment.

Treatment. The treatment group was scheduled to receive alpha-2b interferon, Introna@, 3 million units (MU) subcutaneously 3 times a week, for 36 weeks. During the first week all patients were treated at the hospital and taught how to self-administer the interferon. Hereafter all patients took the interferon as outpatients.

Laboratory studies. Serum alanine aminotransferase (s-ALAT) levels (reference value <0.70 pkat/l) were determined 3 times during the 2 months preceding randomization and the mean value of these determinations was set as the starting level. After initiation of therapy s-ALAT levels were analyzed at weeks 1, 2 and 4 and thereafter every 4th week in all patients.

Histopathological methods. A liver biopsy was performed by a modified Menghini technique (9) within 6 months prior to randomization and a second was scheduled after 36 weeks both in controls and treated patients.

Side effects. Side effects were monitored clinically and hemoglobin, white blood cells and differen- tial count, platelet count and serum creatinine were determined at weeks I , 2 and 4 and thereafter every 4th week.

Statistical methods. Statistical analyses were performed with Fisher’s exact test on a Macintosh SE computer using the Statview 512+TM program from Abacus Concepts, Inc, version 1.0, June 19, 1986.

Scand J Infect Dis 21 (1989)

RESULTS

Out of 32 patients enrolled in the study, 21 were randomized to the treatment group and 11 to the control group. The number of patients in the control and treatment groups, sex, mean age and range, disease duration and prestudy mean s-ALAT are given in Table I. In the initial liver biopsy 23 patients had CAH and 9 CPH whereof 15 patients with CAH were randomized to the treatment group and 8 to the control group. The corresponding numbers for patients with CPH were 6 to the treatment group and 3 to the control group.

There were no significant differences between the treatment and control groups in age, sex, disease duration and mean s-ALAT level prior to enrolment.

Normalization of s-ALAT in treated and control patients The number of patients with normal s-ALAT levels in the treatment and control groups initially and at the 4 and 12 week controls are presented in Table 11. After 4 weeks 10121 (48%) and after 12 weeks 14121 (67%) of the treated patients had normalized their s-ALAT levels versus none of the 11 control patients (p<O.OOl) . One patient with CAH in the treatment group failed to take his interferon during 2 weeks prior to the 12 week control and 2 other patients, one with CAH and CPH each, had their dose reduced by 50% before

Table I. N o . of patients, sex, mean age and age range, disease duration, mean alanine aminotransferase (s-ALAT) level and liver histopathology prior to randomization into the control and interferon alpha-2b treatment groups CAH=chronic active hepatitis, CPH=chronic persistent hepatitis

Treatment group Control group

No. of patients 21 11 Males :females 19:2 10: 1 Mean age (range), years 55.1 (28-71) 55.2 (21-75) Disease duration (range), months 42.6 (12-128) 50.4 (12-195) Mean prestudy s-ALAT (pkat/l)” 2.67 2.73 Liver histopathology prior to randomization, CAH : CPH 15:6 8 : 3

3 determinations for each patient taken at least 2 weeks apart 4-8 weeks prior to entry.

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Scand J Infect Dis 21 (1989) Intrrjeron treutrnent of chronic non-A, non-B hepatitis 129

the 12 week control due to adverse reactions (see below). The overall normalization rate of s-ALAT at the 12 week evaluation was 72% (13/18) if these 3 subjects were excluded. Among treated patients with CAH, 2 patients were partial responders with more than 50% reduction but no normalization of s-ALAT levels.

The mean s-ALAT value (and range) prior to treatment was 2.67 pkat/l (1.13-5.02) and 0.99 (0.23-2.97) and 0.98 (0.17-3.60) at the 4 and 12 week controls respectively in the treatment group as compared to 2.73 (1.26-4.36), 2.50 (0.774.29) and 2.61 (0.794.36) prior to treatment, at 4 and 12 weeks respectively in the control group.

Normalization of s-ALAT in patients with CPH and CAH The number of patients with normal s-ALAT levels in the treatment and control groups initially, at the 4 and 12 week controls according to the histological findings prior to enrolment are presented in Table 111 for patients with CAH and in Table IV for patients

Table 11. Serum alanine aminotransferase (s-ALAT) levels in interferon alpha-2b treated and control patients initially and after 4 and 12 weeks of follow-up

No. of patients (%) with normalized ALAT No. of pat. Initially 4 weeks 12 weeks

Treated 21 0 Controls 11 0 10 (48%) l4 (67%)") p<O.OOl

0 0

a 1 patient with normal s-ALAT level at the 4 week control and raised levels at the 12 week control had his interferon dose reduced by 50% at the 4 week control.

Table 111. Serum alanine aminotransferase (s-ALAT) levels in interferon alpha-2b treated and control patients with chronic active hepatitis initially, after 4 and 12 weeks of follow- U P

No. of patients (%) with normalized ALAT No. of pat. Initially 4 weeks 12 weeks

Treated 15 0 Controls 8 0

6 (40%) 0 0 (60%)] p<O.OOS

Table IV. Serum ulanine aminotransferasr (s-ALAT) levels in interferon alpha-2b treated and control patients with chronic persistent hepatitis initiully, ufter 4 und I2 weeks of follow-up

No. of patients (5%) with normalized ALAT No. of pat. Initially 4 weeks 12 weeks

Treated 6 0 Controls 3 0

4 ( 6 7 4 ) (83 "'"1 p<0.025 0 0

1 patient with normal s-ALAT level at the 4 week control and raised levels at the 12 week control had his interferon dose reduced by 50% at the 4 week control.

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Scand J Infect Dis 21 (1989) 130 0. Weiland et al.

with CPH. If only patients on full dose of interferon were analyzed all patients with CPH had normalized their s-ALAT at the 12 week control. However, patients both with CPH and CAH who were treated normalized their s-ALAT significantly more often than control patients. Treated patients who did not respond with normalization of s-ALAT levels in the CAH group were heavier than patients who responded completely: 97.3 kg body weight (range 85-109) versus 77.4 kg (range 6686).

Adverse reactions Side effects among patients in the treatment group are presented in Table V. They were generally mild and tolerable. Most patients 18/21 (86%) had a flu-like illness with fever after the first interferon injection. This reaction subsided gradually over the next few injections and was reduced by paracetamol orally. Beside the initial flu-like symptoms also fatigue and myalgias were common complaints which tended to resolve with time. Granu- locytopenia was seen in 33% of the treated patients but in only 1 to the extent that the interferon dose had to be reduced (granulocyte count 0 .5-0 .75~ 109/l). One patient had a mild thrombocytopenia. At the 8 week control, 2 patients had their interferon dose reduced by 50 %, one due to granulocytopenia, the other suffered from vertigo. None of the patients withdrew due to side effects during the first 12 weeks of the study. The afore-mentioned patient with vertigo, however, later withdrew due to the severity of his vertigo which was fully reversible after cessation of treatment.

DISCUSSION

The overall interim results in this study show that two-thirds of patients with chronic NANB PTH will normalize their s-ALAT values with prolonged treatment with alpha-2b interferon given subcutaneously in small doses. This is in accordance with the results of 2 uncontrolled studies (5, 6) and our own results in 2 patients with chronic NANB hepatitis caused by intravenous gammaglobulin (7). In the first report by Hoofnagle et al. (5) patients who had their interferon treatment stopped after 4 months relapsed. When treatment was reinstituted they responded again. Due to this finding the treatment time in

Table V. Adverse reactions in the 21 interferon alpha-2b treated patients with posttransfu- sion non-A, non-B hepatitis

Reaction No. of pat. 9%

Initial flu-like disease Fatigue Myalgias Erythema at the injection site Apathy Headache Imtability Nausea Palpitations Vertigo Granuloc ytopenia

(0.75-1.5~ 109/1)

Thrornbocytopenia (o.5-o.75x109/1)

(50- OX 10~111

18 14 I 1 4 3 3 1 I I I

6 I

1

86 67 52 19 14 14 5 5 5 5

29 5

5

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Scand J Infect Dis 21 (1989)

the present study was set to 9 months and if relapse will occur within 3 months after cessation of therapy another 3 months of treatment will be offered. The optimal length and dosage of interferon treatment is for the present time not known. If the favourable response seen so far will be sustained will be shown by further follow-up.

Not all patients responded to the interferon treatment, however. Thus among patients with CAH who received the 3 MU interferon alpha-2b dose all 12 initial weeks in our series, 3/13 (23 %) were nonresponders. Whether these treatment failures are related to the type of NANB agent (there are probably more than one bloodborne agent), or to individual differences in interferon response in different patients is not yet known. It could, however, possibly be related to the fact that these 3 patients were heavier than the responders and thus received a smaller dose per weight basis than the responders. Slightly raised amino- transferases are also commonly seen in obese patients caused by the overweight per se, however. Another possibility is the emergence of interferon antibodies during treatment, interfering with the therapy as has been shown in patients with hairy cell leukemia treated with alpha interferon (10). Whether interferon antibodies have reduced the therapeutic effect has not yet been tested.

Interferon has also been shown to be effective in chronic hepatitis B infection, where it induces a hepatitis-like illness 8-12 weeks after therapy has been instituted ( 1 1 ) . This is thought to be due to immune clearance of hepatitis B infected hepatocytes (12). In contrast, the results of the present study indicate that in chronic NANB infection, interferon produces a rapid fall in s-ALAT levels already within the first few weeks of therapy. This could be due to the antiviral effect of interferon and indicates that the NANB agent is directly cytopathogenic for hepatocytes, and that immune mediated hepatocyte damage, like in hepatitis B virus infection. is not so important (13).

The interim analysis of the present study indicates that a significant therapeutic re- sponse can be anticipated with interferon alpha-2b in patients with chronic NANB PTH. If this response is sustained after therapy has been stopped or if it is only suppressive during ongoing therapy will be proven by later analysis. If the favorable response with normalized s-ALAT levels in many patients is coupled also with improvement in the histological findings as indicated in the pilot studies (8) will also be answered by further follow-up.

l i i r w f t r o r i frrnfment oJ’i,hrotiic. non-A, non-B hepatitis 131

ACKNOWLEDGEMENT The authors thank Essex Lakemedel AB for financial wpport and for providing the alpha-% interferon.

REFERENCES I . Realdi G , Alberti A . Rugge M. Long-term follow up of acute and chronic non-A. non-B hepatitis:

evidence of progression to liver cirrhosis. Gut 23: 27&275, 1982. 2. Mattsson L, Aberg B, Weiland 0. Sellman M. Davilen J . Non-A. non-B hepatitis after open-heart

surgery in Stockholm: Declining incidence after introduction of restrictions for blood donations due to the human immunodeficiency virus. Scand J Infect Dis 20: 371-376. 1988.

3. Mattsson L. Weiland 0. Glaumann H. Long-term follow up of chronic posttransfusion non-A. non-B hepatitis: Clinical and histological outcome. Liver 8: 184-188. 1988.

4. Wejst%l R. Lindberg J , Lundin P. Norkrans G. Chronic non-A, non-B hepatitis. A long-term follow-up study in 49 patients. Scand J Gastroenterol 22: 1115-1122. 1987.

S. Hoofnagle JH. Mullen KD. Jones DB, Rustgi V. Di Bisceglie A . Peters M . Waggoner JG. Yoon Park BA, Jones EA. Treatment of chronic non-A. non-B hepatitis with recombinant human alpha interferon. N Engl J Med 315: 1575-1578. 1986.

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7. Schvarcz K. Weiland 0, Glaumann H. Alpha interferon treatment of chronic non-A. non-B hepatitis caused by intravenous gammaglobulin. Scand J Infect Dis 20: 731-232. 19x8.

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