Journal of Gastroenterology and Hepatology (1991) Suppl. 1, 15--17
ADONIS 081593 1991OOO9OA
Alpha-interferon therapy for chronic hepatitis B virus infection in children and Oriental patients ANNA S . F. LOK Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong Previous papers in these Proceedings have provided a background on the response of Caucasian patients with chronic hepatitis B to interferon (IFN) therapy. Approximately 75% of the world’s hepatitis B surface antigen (HBsAg) carriers are Orientals. It is important to understand the differences in natural history of chronic hepatitis B virus (HBV) infection between Oriental and Caucasian patients to appreciate why there are differences in response to anti-viral therapy. Most Oriental patients with HBV infection acquired it perinatally or during early childhood. Infection at such an early age may induce immune tolerance to HBV. Thus, despite the fact that most children and teenagers have high levels of viraemia, they are often asymptomatic with normal serum transaminase levels. Immune tolerance to HBV accounts for a low rate of spontaneous hepatitis B e antigen (HBeAg) to antibody (anti-HBe) seroconversion in children and teenagers. Immune tolerance gradually wears off in adult life, with the appearance of symptoms and elevation in serum transaminase levels in some patients, and a higher rate of spontaneous HBeAg to anti-HBe seroconversion. 3,4 Despite an initial period of quiescent disease, Oriental patients with chronic HBV infection have a high morbidity as well as mortality from HBV-related cirrhosis and hepatocellular c a r ~ i n o m a . ~ The results of four randomized controlled trials of a-IFN in Chinese patients with chronic HBV infection conducted in Hong Kong over the past 6 years are summarized in the following sections. The designs of the trials were similar and the entry criteria identical. All patients had chronic HBV infection with evidence of HBV replication: HBeAg and serum HBVDNA positivity. They had stable serum alanine aminotransferase (ALT) and HBV-DNA levels. Patients who were positive for antibody to hepatitis D virus (anti-HDV) or human immunodeficiency virus (anti-HIV) were excluded. More than 300 patients had been screened for these four trials. No patient was excluded because of superinfection with HDV, one was excluded because of HIV infection. It is obvious that there are substantial differences between the Oriental patients seen in Hong Kong and the Caucasian patients that present to most European and American liver centres.
u2a-IFN IN CHINESE ADULTS The first study was a randomized controlled trial of recombinant 02a-IFN in Chinese adults.6 Eligible patients were randomized into one of four groups after informed consent was obtained. Three groups received IFN in doses of 2.510 x lo6 units/m2 given intramuscularly thrice weekly for 12-24 weeks. The fourth group received no treatment. In total, 72 patients were recruited into this study. Serum HBV DNA levels fell in most patients during IFN treatment but in many patients this effect was transient. Only eight treated patients ( lSo/0) had sustained clearance of HBeAg; none cleared HBsAg (Table 1). The response appeared to be better in patients who received the highest dose of IFN. In contrast, studies in Caucasian patients found that 30-40% treated patients cleared HBeAg, while 5-10% also cleared H B s A ~ Nevertheless, .~ the Oriental patients who received IFN therapy still fared better than the controls, as none of the 18 controls had sustained clearance of HBeAg. None of the eight responders cleared HBsAg, after a mean follow-up of 4.5 years. In contrast, Hoofnagle’s group recently reported that most of the Caucasian responders who cleared HBeAg subsequently cleared HBsAg.8 As in Caucasian patients, Oriental patients who had sustained anti-viral response also had biochemical and histological improvement in liver disease with decrease in serum ALT levels and histological activity index. Overall, a2a-IFN in the dose regimen used only benefited a minority of Chinese adults who had chronic HBV
Table 1 Anti-viral response to a2a-IFN in Chinese adults: results at 12 months IFN dose ( x lo6 unitdm’) 2.5 No. patients No. cleared HBeAg No. cleared HBsAg
5
18 18 1 (6%) 3 (17%) 0 (0%) 0 (0%)
10
Controls
18 5 (28%) 0 (0%)
18 0 (OYo) 0 (0%)
Correspondence: Dr Anna Lok, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.
A . S. F , Lock
16
infection. Several factors may account for the difference in response rates between Oriental and Caucasian patients. One possibility is a much longer duration of infection, as most Oriental patients were infected perinatally or during early childhood. Thus, many patients in this study had been infected for several decades before treatment was initiated. It is possible that in some of these patients, HBV-DNA had already been integrated into the host genome making eradication of the virus difficult. Nevertheless, in most patients studied, there was no definite evidence of integration in the liver biopsies.’ An alternative explanation for the poor response may be immune tolerance due to early onset of infection. Finally, although only eight patients had sustained anti-viral response, seven patients had transient response with subsequent reactivation. This high rate of reactivation had not been reported in Caucasian patients. In some patients, loss of response was related to the development of IFN neutralizing antibodies,” but in others the cause was not clear.
rxZa-IFN IN CHINESE CHILDREN To determine whether a better response can be achieved by instituting treatment at an earlier age, a randomized controlled trial of aZa-IFN was conducted in Chinese children.” Twenty-four children, aged 2-5 years, were randomized to receive u2a IFN in doses of 10 x lo6 units/m2 given intramuscularly thrice weekly for 12 weeks, or no treatment. The duration of infection in these children was comparable with that in Caucasian adult patients. Nevertheless, at 1 year, none of the children had cleared HBeAg, although one child in each group had become HBeAg negative by 18 months (Table 2). The poor response in children suggests that immune tolerance to HBV may be the most important reason for lack of response in Chinese patients. A valuable observation in this study was that children seemed to tolerate IFN therapy very well. The initial febrile illness was minimized by gradually increasing the dose from 2.5 to 10 x lo6 units over a period of 2 weeks.
’‘
in two randomized controlled trials in Chinese patients. Ninety children with chronic HBV infection and markers of HBV replication were randomized to one of three groups. Group I received a 6 week tapering course of prednisone 0.6-0.2mdkg per day followed by a 2 week rest period and then 16 weeks of a2b-IFN at 5 x lo6 units/m2 given subcutaneously thrice weekly. Group I1 received a 6 week tapering course of placebo syrup followed by a 2 week rest period and then 16 weeks of a2b-IFN as in Group I. Group 111 received no treatment. The overall response was poor, although there was a slightly higher response rate in the prednisone primed group: 13% cleared HBeAg, compared with 3% in the group that received IFN alone and 0% in the controls (Table 3 ) . One child in each treated group cleared HBsAg. When the response was analysed in relarion to pre-treatment ALT levels, it was obvious that the response in children with elevated ALT levels was higher. However, the vast majority of Oriental children with chronic HBV infection have normal serum ALT levels, so IFN therapy with or without prednisone priming will only benefit a small proportion of Oriental children.
u2b-IFN WITH OR WITHOUT PREDNISONE PRIMING IN CHINESE ADULTS
Several investigators suggested that pre-treatment with a short course of prednisone may augment the response to subsequent IFN therapy. This hypothesis was tested
Studies in Caucasian patients showed that patients with more active liver disease - elevated serum ALT levels and chronic active hepatitis - are more likely to respond to IFN Most of the patients in the previous three trials had normal serum ALT levels. To determine wheiher Chinese patients with elevated serum ALT levels respond similarly to Caucasian patients, patients with normal ALT levels were randomized separately from those with elevated ALT levels (mean of three pre-entry ALT readings, taken 1 month apart, being higher than 1.5 times the upper limit of normal). Eligible patients were randomized to one of three treatment groups. Group I received a 6 week tapering course of prednisone 45-15mg/day, followed by a 2 week resi period and then a 16 week course of a2b-IFN 10 x 10” units subcutaneously thrice weekly. Group I1 received a 6 week tapering course of placebo tablets followed by a 2 week rest period and then a 16 week course of IFN as in G r m p I. Group 111 received no treatment. Among 55 patients with normal pre-treatment serum ALT levels, only two treated patients cleared HBeAg. Both received IFN therapy without prednisone priming.
Table 2 Anti-viral response to a2a-IFN in Chinese children: results at 12 months
Table 3 Anti-viral response to a2b-IFN with or without prednisone priming in Chinese children: results at 12 months
02b-IFN IN CHINESE CHILDREN WITH OR WITHOUT PREDNISONE PRIMING
No. children No. cleared HBeAg No. cleared HBsAg
Interferon
Placebo
12 0 (0%) 0 (070)
12 0 (0%) 0 (0%)
-
PrednisondIFN
No. children No. cleared HBeAg No. cleared HBsAg
31 4 (13%) 1(3’/0)
Placebo/IFN 29 1 (39/0) 1 (3%)
Control 30 0 (0%) 0 (oo/o)
17
Alpha-interferon for chronic HBV in Orientals
The response was significantly better in those with elevated pre-treatment serum ALT levels and comparable with that reported in Caucasian patients. At 1 year, 64% of patients in the prednisone-primed group, 36% of those who had received IFN only and 19% of the controls had cleared HBeAg. These results indicate that the difference in response rates between Chinese and Caucasian patients is not related to genetic differences. Unfortunately, there was also a high spontaneous seroconversion rate in the controls with elevated ALT levels, so the difference in rate of HBeAg clearance between treatkd patients and controls failed to reach statistical significance. Prednisone priming did not provide any additional advantage over treatment with IFN alone in patients with normal serum ALT levels but may benefit some patients with elevated pre-treatment ALT levels.
SUMMARY In summary, these four studies showed that a-IFN therapy alone produced sustained inhibition of HBV replication in a minority of Chinese adults with chronic HBV infection. The response was not improved by instituting treatment at an earlier age. The major reason for the poor response in Chinese patients is probably immune tolerance as a result of early exposure to HBV. The response in Chinese patients with elevated pre-treatment serum ALT levels, who presumably had ongoing endogenous immune lysis of infected hepatocytes, was significantly better than and comparable with that reported in Caucasian patients. Prednisone priming did not provide any additional advantage over therapy with IFN alone in patients with normal pre-treatment serum ALT levels, but appeared to have additional benefit in patients with elevated ALT levels.
REFERENCES LOK A. S. F. & LAI C. L. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positiveChinese children. Hepatology 1988; 80: 1130-3. CHANCM. H . , SUNGJ. L., LEEC. Y. er al. Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children.3 . Pediatr. 1989; 115: 385-90. LOKA. S. F., LAIC. L., Wu P. C., LEUNG E. K. Y. & LAM T. S. Spontaneous hepatitis B e antigen to antibody serocon-
version and reversion in Chinese patients with chronic hepatitis
B virus infection. Gastroenterology 1987; 92: 1839-43. 4. LOKA. S. F. & LAIC. L. Acute exacerbations in Chinese
patients with chronic hepatitis B virus infection: incidence, predisposing factors and etiology.J . Hepatol. 1990; 10: 29-34. 5. BEASLEYR. P. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. 6. LOKA. S. F, LAIC. L., Wu P. C. & LEUNG E. K. Y. Longterm follow-up in a randomized controlled trial of recombinant alpha-interferon in Chinese patients with chronic hepatitis B infection. Lancet 1988; ii: 298-302. 7. PERRILLO R. P. Treatment of chronic hepatitis B with IFN: experience in western countries. Sem. Liver. Dis. 1989; 9: 240-8. 8. KORENMAN J. C., DI BISCECLlE A. M., BAKER B. L., WAGGONER J. G. & HOOFNACLE J. H. Loss of hepatitis B surface
antigen following treatment of chronic hepatitis B with alpha interferon. Abstract no. 3 19, 1990 International Symposium on Viral Hepatitis and Liver Disease, Houston. 9. LOKA. S. F., MA 0. C. K. & LAUJ. Y. N. Interferon alfa therapy in patients with chronic hepatitis B virus infection: effects on hepatitis B virus DNA in the liver. Gastroenterology 1991; 100: 756-61. 10. LOK A. S. F., LAI C. L. & LEUNGE. K. Y. Interferon
antibodies may negate the antiviral effects of recombinant alpha-interferon treatment in patients with chronic hepatitis B virus infection. Hepatology 1990; 12: 1266-70. 11. LAIC. L., LOKA. S. F., LIN H. J., WU P. C., YEOH E. K. & YEUNGC. Y. Placebo controlled trial of recombinant alphainterferon in Chinese HBsAg-carrier children. Lancet 1987; ii: 877-80. 12. OMArA M., IMAZEKIF., YOKOSUKA0 . et al. Recombinant
leukocyte A interferon treatment in patients with chronic hepatitis B virus infection: pharmacokinetics, tolerance and biologic effects. Gastroenterology 1985; 88: 870-80. 13. PERRILLO R. P., REGENSTEIN F. G., PETERSM. G. et al. Prednisone withdrawal followed by recombinant alpha interferon as the treatment of chronic type B hepatitis in a randomized, controlled trial. Ann. Intern. Med. 1988; 109: 95-100. 14. LOK A. S. F., LAIC. L., Wu P. C., LAUJ. Y. N., LEUNG E. K. Y. & WONCL. S. K. Treatment of chronic hepatitis B
with interferon: experience in Asian patients. Sem. Liver Dis. 1989; 9: 249-53. 15. BROOK M. G., KARAYIANNIS P. & THOMAS H. C. Which
patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989; 10: 761-3. 16. SCULLARD G . H., POLLARD R. B., SMITH J. L. er al. Anti-viral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside.3. Infect. Dis. 1981; 143: 772-83.
ADONIS 081593 1991OOO9OA
Alpha-interferon therapy for chronic hepatitis B virus infection in children and Oriental patients ANNA S . F. LOK Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong Previous papers in these Proceedings have provided a background on the response of Caucasian patients with chronic hepatitis B to interferon (IFN) therapy. Approximately 75% of the world’s hepatitis B surface antigen (HBsAg) carriers are Orientals. It is important to understand the differences in natural history of chronic hepatitis B virus (HBV) infection between Oriental and Caucasian patients to appreciate why there are differences in response to anti-viral therapy. Most Oriental patients with HBV infection acquired it perinatally or during early childhood. Infection at such an early age may induce immune tolerance to HBV. Thus, despite the fact that most children and teenagers have high levels of viraemia, they are often asymptomatic with normal serum transaminase levels. Immune tolerance to HBV accounts for a low rate of spontaneous hepatitis B e antigen (HBeAg) to antibody (anti-HBe) seroconversion in children and teenagers. Immune tolerance gradually wears off in adult life, with the appearance of symptoms and elevation in serum transaminase levels in some patients, and a higher rate of spontaneous HBeAg to anti-HBe seroconversion. 3,4 Despite an initial period of quiescent disease, Oriental patients with chronic HBV infection have a high morbidity as well as mortality from HBV-related cirrhosis and hepatocellular c a r ~ i n o m a . ~ The results of four randomized controlled trials of a-IFN in Chinese patients with chronic HBV infection conducted in Hong Kong over the past 6 years are summarized in the following sections. The designs of the trials were similar and the entry criteria identical. All patients had chronic HBV infection with evidence of HBV replication: HBeAg and serum HBVDNA positivity. They had stable serum alanine aminotransferase (ALT) and HBV-DNA levels. Patients who were positive for antibody to hepatitis D virus (anti-HDV) or human immunodeficiency virus (anti-HIV) were excluded. More than 300 patients had been screened for these four trials. No patient was excluded because of superinfection with HDV, one was excluded because of HIV infection. It is obvious that there are substantial differences between the Oriental patients seen in Hong Kong and the Caucasian patients that present to most European and American liver centres.
u2a-IFN IN CHINESE ADULTS The first study was a randomized controlled trial of recombinant 02a-IFN in Chinese adults.6 Eligible patients were randomized into one of four groups after informed consent was obtained. Three groups received IFN in doses of 2.510 x lo6 units/m2 given intramuscularly thrice weekly for 12-24 weeks. The fourth group received no treatment. In total, 72 patients were recruited into this study. Serum HBV DNA levels fell in most patients during IFN treatment but in many patients this effect was transient. Only eight treated patients ( lSo/0) had sustained clearance of HBeAg; none cleared HBsAg (Table 1). The response appeared to be better in patients who received the highest dose of IFN. In contrast, studies in Caucasian patients found that 30-40% treated patients cleared HBeAg, while 5-10% also cleared H B s A ~ Nevertheless, .~ the Oriental patients who received IFN therapy still fared better than the controls, as none of the 18 controls had sustained clearance of HBeAg. None of the eight responders cleared HBsAg, after a mean follow-up of 4.5 years. In contrast, Hoofnagle’s group recently reported that most of the Caucasian responders who cleared HBeAg subsequently cleared HBsAg.8 As in Caucasian patients, Oriental patients who had sustained anti-viral response also had biochemical and histological improvement in liver disease with decrease in serum ALT levels and histological activity index. Overall, a2a-IFN in the dose regimen used only benefited a minority of Chinese adults who had chronic HBV
Table 1 Anti-viral response to a2a-IFN in Chinese adults: results at 12 months IFN dose ( x lo6 unitdm’) 2.5 No. patients No. cleared HBeAg No. cleared HBsAg
5
18 18 1 (6%) 3 (17%) 0 (0%) 0 (0%)
10
Controls
18 5 (28%) 0 (0%)
18 0 (OYo) 0 (0%)
Correspondence: Dr Anna Lok, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.
A . S. F , Lock
16
infection. Several factors may account for the difference in response rates between Oriental and Caucasian patients. One possibility is a much longer duration of infection, as most Oriental patients were infected perinatally or during early childhood. Thus, many patients in this study had been infected for several decades before treatment was initiated. It is possible that in some of these patients, HBV-DNA had already been integrated into the host genome making eradication of the virus difficult. Nevertheless, in most patients studied, there was no definite evidence of integration in the liver biopsies.’ An alternative explanation for the poor response may be immune tolerance due to early onset of infection. Finally, although only eight patients had sustained anti-viral response, seven patients had transient response with subsequent reactivation. This high rate of reactivation had not been reported in Caucasian patients. In some patients, loss of response was related to the development of IFN neutralizing antibodies,” but in others the cause was not clear.
rxZa-IFN IN CHINESE CHILDREN To determine whether a better response can be achieved by instituting treatment at an earlier age, a randomized controlled trial of aZa-IFN was conducted in Chinese children.” Twenty-four children, aged 2-5 years, were randomized to receive u2a IFN in doses of 10 x lo6 units/m2 given intramuscularly thrice weekly for 12 weeks, or no treatment. The duration of infection in these children was comparable with that in Caucasian adult patients. Nevertheless, at 1 year, none of the children had cleared HBeAg, although one child in each group had become HBeAg negative by 18 months (Table 2). The poor response in children suggests that immune tolerance to HBV may be the most important reason for lack of response in Chinese patients. A valuable observation in this study was that children seemed to tolerate IFN therapy very well. The initial febrile illness was minimized by gradually increasing the dose from 2.5 to 10 x lo6 units over a period of 2 weeks.
’‘
in two randomized controlled trials in Chinese patients. Ninety children with chronic HBV infection and markers of HBV replication were randomized to one of three groups. Group I received a 6 week tapering course of prednisone 0.6-0.2mdkg per day followed by a 2 week rest period and then 16 weeks of a2b-IFN at 5 x lo6 units/m2 given subcutaneously thrice weekly. Group I1 received a 6 week tapering course of placebo syrup followed by a 2 week rest period and then 16 weeks of a2b-IFN as in Group I. Group 111 received no treatment. The overall response was poor, although there was a slightly higher response rate in the prednisone primed group: 13% cleared HBeAg, compared with 3% in the group that received IFN alone and 0% in the controls (Table 3 ) . One child in each treated group cleared HBsAg. When the response was analysed in relarion to pre-treatment ALT levels, it was obvious that the response in children with elevated ALT levels was higher. However, the vast majority of Oriental children with chronic HBV infection have normal serum ALT levels, so IFN therapy with or without prednisone priming will only benefit a small proportion of Oriental children.
u2b-IFN WITH OR WITHOUT PREDNISONE PRIMING IN CHINESE ADULTS
Several investigators suggested that pre-treatment with a short course of prednisone may augment the response to subsequent IFN therapy. This hypothesis was tested
Studies in Caucasian patients showed that patients with more active liver disease - elevated serum ALT levels and chronic active hepatitis - are more likely to respond to IFN Most of the patients in the previous three trials had normal serum ALT levels. To determine wheiher Chinese patients with elevated serum ALT levels respond similarly to Caucasian patients, patients with normal ALT levels were randomized separately from those with elevated ALT levels (mean of three pre-entry ALT readings, taken 1 month apart, being higher than 1.5 times the upper limit of normal). Eligible patients were randomized to one of three treatment groups. Group I received a 6 week tapering course of prednisone 45-15mg/day, followed by a 2 week resi period and then a 16 week course of a2b-IFN 10 x 10” units subcutaneously thrice weekly. Group I1 received a 6 week tapering course of placebo tablets followed by a 2 week rest period and then a 16 week course of IFN as in G r m p I. Group 111 received no treatment. Among 55 patients with normal pre-treatment serum ALT levels, only two treated patients cleared HBeAg. Both received IFN therapy without prednisone priming.
Table 2 Anti-viral response to a2a-IFN in Chinese children: results at 12 months
Table 3 Anti-viral response to a2b-IFN with or without prednisone priming in Chinese children: results at 12 months
02b-IFN IN CHINESE CHILDREN WITH OR WITHOUT PREDNISONE PRIMING
No. children No. cleared HBeAg No. cleared HBsAg
Interferon
Placebo
12 0 (0%) 0 (070)
12 0 (0%) 0 (0%)
-
PrednisondIFN
No. children No. cleared HBeAg No. cleared HBsAg
31 4 (13%) 1(3’/0)
Placebo/IFN 29 1 (39/0) 1 (3%)
Control 30 0 (0%) 0 (oo/o)
17
Alpha-interferon for chronic HBV in Orientals
The response was significantly better in those with elevated pre-treatment serum ALT levels and comparable with that reported in Caucasian patients. At 1 year, 64% of patients in the prednisone-primed group, 36% of those who had received IFN only and 19% of the controls had cleared HBeAg. These results indicate that the difference in response rates between Chinese and Caucasian patients is not related to genetic differences. Unfortunately, there was also a high spontaneous seroconversion rate in the controls with elevated ALT levels, so the difference in rate of HBeAg clearance between treatkd patients and controls failed to reach statistical significance. Prednisone priming did not provide any additional advantage over treatment with IFN alone in patients with normal serum ALT levels but may benefit some patients with elevated pre-treatment ALT levels.
SUMMARY In summary, these four studies showed that a-IFN therapy alone produced sustained inhibition of HBV replication in a minority of Chinese adults with chronic HBV infection. The response was not improved by instituting treatment at an earlier age. The major reason for the poor response in Chinese patients is probably immune tolerance as a result of early exposure to HBV. The response in Chinese patients with elevated pre-treatment serum ALT levels, who presumably had ongoing endogenous immune lysis of infected hepatocytes, was significantly better than and comparable with that reported in Caucasian patients. Prednisone priming did not provide any additional advantage over therapy with IFN alone in patients with normal pre-treatment serum ALT levels, but appeared to have additional benefit in patients with elevated ALT levels.
REFERENCES LOK A. S. F. & LAI C. L. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positiveChinese children. Hepatology 1988; 80: 1130-3. CHANCM. H . , SUNGJ. L., LEEC. Y. er al. Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children.3 . Pediatr. 1989; 115: 385-90. LOKA. S. F., LAIC. L., Wu P. C., LEUNG E. K. Y. & LAM T. S. Spontaneous hepatitis B e antigen to antibody serocon-
version and reversion in Chinese patients with chronic hepatitis
B virus infection. Gastroenterology 1987; 92: 1839-43. 4. LOKA. S. F. & LAIC. L. Acute exacerbations in Chinese
patients with chronic hepatitis B virus infection: incidence, predisposing factors and etiology.J . Hepatol. 1990; 10: 29-34. 5. BEASLEYR. P. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. 6. LOKA. S. F, LAIC. L., Wu P. C. & LEUNG E. K. Y. Longterm follow-up in a randomized controlled trial of recombinant alpha-interferon in Chinese patients with chronic hepatitis B infection. Lancet 1988; ii: 298-302. 7. PERRILLO R. P. Treatment of chronic hepatitis B with IFN: experience in western countries. Sem. Liver. Dis. 1989; 9: 240-8. 8. KORENMAN J. C., DI BISCECLlE A. M., BAKER B. L., WAGGONER J. G. & HOOFNACLE J. H. Loss of hepatitis B surface
antigen following treatment of chronic hepatitis B with alpha interferon. Abstract no. 3 19, 1990 International Symposium on Viral Hepatitis and Liver Disease, Houston. 9. LOKA. S. F., MA 0. C. K. & LAUJ. Y. N. Interferon alfa therapy in patients with chronic hepatitis B virus infection: effects on hepatitis B virus DNA in the liver. Gastroenterology 1991; 100: 756-61. 10. LOK A. S. F., LAI C. L. & LEUNGE. K. Y. Interferon
antibodies may negate the antiviral effects of recombinant alpha-interferon treatment in patients with chronic hepatitis B virus infection. Hepatology 1990; 12: 1266-70. 11. LAIC. L., LOKA. S. F., LIN H. J., WU P. C., YEOH E. K. & YEUNGC. Y. Placebo controlled trial of recombinant alphainterferon in Chinese HBsAg-carrier children. Lancet 1987; ii: 877-80. 12. OMArA M., IMAZEKIF., YOKOSUKA0 . et al. Recombinant
leukocyte A interferon treatment in patients with chronic hepatitis B virus infection: pharmacokinetics, tolerance and biologic effects. Gastroenterology 1985; 88: 870-80. 13. PERRILLO R. P., REGENSTEIN F. G., PETERSM. G. et al. Prednisone withdrawal followed by recombinant alpha interferon as the treatment of chronic type B hepatitis in a randomized, controlled trial. Ann. Intern. Med. 1988; 109: 95-100. 14. LOK A. S. F., LAIC. L., Wu P. C., LAUJ. Y. N., LEUNG E. K. Y. & WONCL. S. K. Treatment of chronic hepatitis B
with interferon: experience in Asian patients. Sem. Liver Dis. 1989; 9: 249-53. 15. BROOK M. G., KARAYIANNIS P. & THOMAS H. C. Which
patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989; 10: 761-3. 16. SCULLARD G . H., POLLARD R. B., SMITH J. L. er al. Anti-viral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside.3. Infect. Dis. 1981; 143: 772-83.
