Gastroenterologia Japonica Copyright 9 1991 by The Japanese Society of Gastroenterology
Vol. 26, Suppl. 3 Printed in Japan
Therapeutic efficacy of interferon of HCV-RNA in chronic hepatitis C T. KUROKI t, S. NISHIGUCHI 1, T. UEDA 1, T. YABUSAKO 1, K. FUKUDA 1, T. TAKEDA 1, K. KIM 1, S. NAKAJIMA 1, S. SHIOMI 1, S. SEKI 1, K. KOBAYASHI 1, S. OTANI 2, I. YANO 3, S. YAMAMOTO 4, N. HAYASHI, and T. SHIKATA 5
1Third Department of Internal Medicine, 2Second Department of Biochemistry, and 3Department of Bacteriology, Osaka City University Medical School, Osaka, Japan; 4Osaka Socio-Medical Center, Osaka, Japan; and SDepartment of Pathology, Nihon University School of Medicine, Tokyo, Japan
Introduction
Greenberg et al. 1 treated patients with chronic hepatitis B with interferon (IFN) and reported it to be effective. The relationship between the efficacy of IFN and anti-viral systems of IFN for hepatitis B virus in patients with chronic hepatis B was studied by the authors 2-5. On the other hand, there has been no effective treatment for chronic hepatitis C, which usually leads to hepatic cirrhosis or hepatocellular carcinoma. Hoofnagle et al. 6 attempted IFN for the treatment of non-A, non-B chronic hepatitis and they found that transaminase levels improved during the treatment in many patients. We treated these patients with IFN and evaluated the results of therapy by assaying RNA of hepatitis C virus (HCV) in the serum using the polymerase chain reaction (PCR). Our purpose was to find if IFN had direct anti-viral effects on HCV. We also studied the correlation between the results of therapy evaluated in this way and the changes in the serum level of alanine aminotransferase (ALT), which has been used to evaluate the response to therapy. Patients and Methods
The subjects were 17 patients with anti-HCV (C100) antibody 7 in 23 patients diagnosed as having non-A, non-~ chronic hepatitis or hepatic cirrhosis by excluding factors such as alcoholism,
autoimmune disease, or hepatitis B virus. Before therapy, these 17 patients gave positive results for anti-HCV, and were diagnosed as having hepatitis type C. Anti-HCV in serum was measured by the ELISA test (Ortho D.S. Co). For the detection of HCV-RNA, R N A was extracted from 100/.tl of serum by the method of Chomczynski et al. and c D N A was prepared using reverse transcriptase. Primers and a probe were constructed for the NS 5 region based on sequence data for HCV. The c D N A we prepared was amplified by 40 cycles of the PCR. The product obtained was treated by electrophoresis and then by Southern blotting with a probe labeled with 32p. IFN treatment was done on one of two schedules. On one, 3 million IUs of human lymphoblastoid IFN-a (Sumitomo Pharm. Co) or human fibroblastoid IFN-/3 (Toray Co) was given daily for four weeks conservatively. Five patients were on this four-week schedule. On the other schedule, the same daily dose of IFN-a was used, but the therapy was continued for only two weeks, followed by a two-week period without therapy. This made up one cycle, and the cycles were repeated for a total of either 4 or 6 times. Twelve patients were on this 2 weeks on, 2 weeks off schedule. The background of these 17 patients is given in Table 1, together with the details about IFN therapy. Three patients were treated with IFN-/3
Gastroenterol Jpn 1991:26(Suppl 3)239-242 Address for correspondence: Tetsuo Kuroki, M.D., The Third Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545, Japan.
T. K u r o k i et al.
240
V o l . 26, S u p p l . 3
Table 1 The background of patients with HCV-RNA positive chronic hepatitis treated with IFN Case No.
Age/Sex
ALT (IU)
Histological diagnosis
Kind of IFN
Length/Cycles
Total dose (10-61U)
1 2 3 4 5
55 40 22 29 55
F M M M M
77 175 242 487 98
CAH CAH CPH CPH CPH
a a ,6 ,6 ,6
4 4 4 4 4
weeks/1 weeks/1 weeks/1 weeks/1 weeks/1
84 84 84 102 102
6 7 8 9 10 11 12 13 14 15 16 17
59 51 46 28 58 41 31 31 58 53 57 50
F F M M M M M M M M M M
187 168 183 94 223 261 235 292 263 161 81 191
CPH LC CAH CAH LC LC CPH CAH LC CAH CAH LC
a
2 2 2 2 2 2 2 2 2 2 2 2
weeks/4 weeks/6 weeks/6 weeks/6 weeks/6 weeks/4 weeks/6 weeks/6 weeks/4 weeks/4 weeks/6 weeks/6
168 252 252 252 252 168 252 252 168 168 252 252
a a a a a a a a a a a
Table 2 The effects of IFN therapy for chronic hepatitis with serum HCV-RNA Case No.
Age/Sex
Treatment for 4 weeks 1 55 F 2 40 M 3 22 M 4 29 M 5 55 M
Therapy with IFN
Histological diagnosis
Kind of IFN
CAH CAH CPH CPH CPH
a a ,6 ,/3 ,6
1 1 1 1 1
[] [] [] [] 9
Partially Partially Partially Partially Inflect.
9 Poor 9 Poor 9 Poor /k Transient 9 Poor
a a
4 6 6 6 6 4 6 6 4 4 6 6
C) Effective C) Effective 9 Effective 9 Effective O Effective [] Partially [] Partially [] Partially 9 Ineffect. 9 Ineffect. 9 Ineffect. 9 Ineffect.
(3 Complete [] Good 9 Compelte O Complete O Complete 9 Poor /k Transient A Transient [] Good 9 Poor 9 Poor 9 Poor
Treatment by the 2 weeks on 92 weeks off 6 59 F CAH 7 51 F LC 8 46 M CAH 9 28 M CAH 10 58 M LC 11 41 M LC 12 31 M CPH 13 31 M CAH 14 5~ M LC 15 53 M CAH 16 57 M CAH 17 50 M LC
Cycles
a a a a a a a
a a a
Effect on HCV-RNA
Effect on serum ALT
CPH: chronic persistent hepatitis, CAH: chronic active hepatitis, LC: liver cirrhosis
and 14 patients were treated with IFN-a. The effects on HCV-RNA by the therapy were classified 3 groups. In the effective group, HCVRNA was negative when the therapy ended and
remained negative. In the Partially effective group, HCV-RNA had become negative when the therapy ended and but reappeared, while in the ineffective group, HCV-RNA did not disappear.
July 1991
IFN treatment for chronic hepatitis C
Table 3 Classification of therapeutic efficacy for chronic hepatitis with HCV-RNA
Response Type I Type II Type III
Effect on HCV-RNA
Effect on serum ALT
No. of cases
Persistently negative Transiently negative Persistently positive
Complete Transient or poor Almost poor
5* 7 5*
*Only one case showed good response in each group
The efficacy in terms of serum A L T levels were classified 4 groups. In the complete effect group, serum A L T level decreased to normal with the therapy and remained normal during follow-up for at least 1 year. Cases in which serum A L T level decreased to nearly normal with the therapy and remained at levels less than twice the normal range during follow-up were classified as good effect. In the transient effect group, serum A L T level decreased to less than half of the pretreatment level with the therapy but increased during follow-up, while in the poor effect group, serum A L T did not decrease with therapy. Results
The therapeutic efficacy in patients given IFN for 4 weeks The effect for H C V - R N A and the efficacy for serum A L T in patients treated with IFN for 4 weeks is given in Table 2. H C V - R N A was detected immediately before therapy in all 5 patients. With IFN therapy, 4 out of 5 patients became negative for H C V - R N A when IFN therapy ended but H C V - R N A was detected 1 to 3 months later in all cases. Serum A L T became normal treansiently in one case which was partially effective for H C V - R N A when IFN therapy ended. In the other 4 cases in which treatment yolded only a poor effect, serum A L T did not decrease to less than half of the normal range.
The therapeutic efficacy in patients given IFN by the 2 weeks on~2 weeks off schedule The effect for H C V - R N A and the efficacy for
241
serum A L T in 12 patients treated with IFN by the 2 weeks on/2 weeks off schedule is given Table 2. H C V - R N A was detected immediately before therapy in all 12 patients. With IFN therapy, 5 out of 12 patients became negative persistently for H C V - R N A , 3 cases became negative transiently and the other 4 cases were positive persistently for at least 12 months after therapy ended. In the effective group, serum A L T became normal in 4 of 5 cases and the other case remained showing good effect for serum A L T , because this patient drank. In the partially effective group, 3 cases showed transient effects for serum A L T level and the other case showed poor effect for serum A L T . In the ineffective group, only one case showed good effect for serum A L T and the other 3 cases showed poor effect for serum ALT.
The criterion on therapeutic efficacy of IFN for chronic hepatitis C The clinical effects of IFN therapy for chronic hepatitis C according to the results were classified (Table 3). Type I response is complete response. In this type, serum H C V - R N A became negative continuously and serum A L T became normal or nearly normal for at least 12 months afte rtherapy ended. Type II response is partial response. In this type, serum H C V - R N A became negative transiently in all cases and the effect on serum A L T level was transient or poor. Type III is non-effective. In this type, serum H C V - R N A did not become negative and the effect for serum A L T was almost poor. Discussion
In the IFN treatment for chronic hepatitis C, the therapeutic efficacy has been evaluated by the improvement of serum A L T level. Hofnagle et al. 6 reported that serum A L T levels usually improved during the treatment but their serum A L T level increased after the end of IFN therapy in many patients with non-A, non-B chronic hepatitis. In the study of Di Bisceglie et al. s, 2 out of 21 patients with anti-HCV positive chronic hepatitis became normal continuously after the end of IFN
242
T. K u r o k i et al.
therapy. In our study, the therapeutic efficacy of IFN for patients with chronic hepatitis who were positive for serum H C V - R N A was evaluated by the efficacy in terms of serum A L T level and serum H C V - R N A . In this trial, the response to IFN therapy for chronic hepatitis C was classified into 3 types. In Type I response (complete response), serum H C V - R N A became negative persistently and serum A L T became normal or nearly normal for at least one year after therapy ended. In Type II response (partial response) serum H C V - R N A became negative transiently in all cases and the effect for serum A L T level was transient or poor. In Type III response (non-effective response), serum H C V - R N A did not become negative and the effect on serum A L T level was almost poor. In patients with chronic hepatitis C who showed a Type I response, H C V - R N A disappeared persistently and the serum A L T level became normal during the therapy, remaining normal continuously and the histological findings markedly improved. These findings in Type I response suggested that the IFN therapy had cured patients with chronic hepatitis C.
Summary The efficacy of interferon therapy for chronic hepatitis C were evaluated by the changes of serum R N A of the hepatitis C virus (HCV) by the polymerase chain reaction. Before the treatment, H C V - R N A was detected in all of the 17 patients. 5 patients given IFN for 4 weeks, 12 cases given IFN by the 2 weeks/on 2 weeks off schedule (4 cases given 4 cycles and 8 given 6 cycles). Immediately after the treatment ended, the HCVR N A was not d~tected in 12 (71%) cases. Five cases were persistently positive for H C V - R N A and showed continuously abnormal level of ALT. In 7 of 12 cases who became negative for HCVR N A just after the treatment ended, H C V - R N A was detected again at first and 12th month after therapy. The A L T level were continuously abnormal in 4 of these 7 cases during and after the treatment, and became normal transiently in the other 3. In the 5 cases who became persistently
Vol. 26, Suppl. 3
negative (at least i year), A L T level decreased to normal or near-normal during follow up for more than one year. According to our results, we classified the therapeutic efficacy of IFN therapy for chronic hepatitis C. Type I response is complete response. In this type, H C V - R N A became negative persistently and A L T became normal or near-normal for at least 12 months after therapy. Type II is partial response. In this type, HCVR N A became negative transiently and A L T level was transiently normal or poor. Type III is ineffective. In this type, H C V - R N A did not become negative and the effect for A L T was poor. These results suggested that Type I response was conplete cure of the chronic H C V infection. Type I response were observed in 0 of 5 cases given IFN for 4 weeks but 1 (25%) of 4 cases given the 4 cycles of IFN and 4 (50%) of 8 cases given the 6 cycles of IFN by the 2 weeks on/2 weeks off schedule.
References 1. Grecnberg HB, Lindberg J, Lundin P, et al: Effect of human leukocyte interferon on hepatitis B viral infection in patients with chronic active hepatitis. N Engl J Med 1976;295:517-522 2. Kuroki.T, Nishiguchi S, Saito S, et al: Response of 2',5'-oligoadenylate synthetase in hepatitis Be antigen-positive chronic hepatitis B treated with interfreon. New trend in peptic ulcer and hepatitis. Part II Chronic Hepatitis Excerpta Medica, Tokyo 1986;115-120 3. Kuroki T, Nishiguchi S, Takeda T, et al: Studies on the relation between response of 2',5'-oligadenylate synthetase and efficacy of interferon therapy in chronic hepatitis B. New trend in hepatology. Excerpta Medica, Tokyo 1986;249-255 4. Nishiguchi S, Kuroki T, Otani S, et al: Relationship of the effects of interferon on chronic hepatitis B and the induction of 2',5'oligoadenylate synthetase. Hepatology 1989;10:29-33 5. Nakajima S, Kuroki T, Shintani M, et al: Changes in interferon receptor on peripheral blood mononuclear cells from patients with chronic hepatitis B being treated with interferon. Hepatology 1990;12:1261-1265 6. Hoofnagle JH, Mullen KD, Jones DB, et al: Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. N Engl J Med 1986;315:1575-1578 7. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation ofcDNA clone derived from a blood -borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362 8. Di Bisceglie, A.M, Martin P, Kassianides et al. Rcconbinant interferon alpha therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321: 1506-1610
Vol. 26, Suppl. 3 Printed in Japan
Therapeutic efficacy of interferon of HCV-RNA in chronic hepatitis C T. KUROKI t, S. NISHIGUCHI 1, T. UEDA 1, T. YABUSAKO 1, K. FUKUDA 1, T. TAKEDA 1, K. KIM 1, S. NAKAJIMA 1, S. SHIOMI 1, S. SEKI 1, K. KOBAYASHI 1, S. OTANI 2, I. YANO 3, S. YAMAMOTO 4, N. HAYASHI, and T. SHIKATA 5
1Third Department of Internal Medicine, 2Second Department of Biochemistry, and 3Department of Bacteriology, Osaka City University Medical School, Osaka, Japan; 4Osaka Socio-Medical Center, Osaka, Japan; and SDepartment of Pathology, Nihon University School of Medicine, Tokyo, Japan
Introduction
Greenberg et al. 1 treated patients with chronic hepatitis B with interferon (IFN) and reported it to be effective. The relationship between the efficacy of IFN and anti-viral systems of IFN for hepatitis B virus in patients with chronic hepatis B was studied by the authors 2-5. On the other hand, there has been no effective treatment for chronic hepatitis C, which usually leads to hepatic cirrhosis or hepatocellular carcinoma. Hoofnagle et al. 6 attempted IFN for the treatment of non-A, non-B chronic hepatitis and they found that transaminase levels improved during the treatment in many patients. We treated these patients with IFN and evaluated the results of therapy by assaying RNA of hepatitis C virus (HCV) in the serum using the polymerase chain reaction (PCR). Our purpose was to find if IFN had direct anti-viral effects on HCV. We also studied the correlation between the results of therapy evaluated in this way and the changes in the serum level of alanine aminotransferase (ALT), which has been used to evaluate the response to therapy. Patients and Methods
The subjects were 17 patients with anti-HCV (C100) antibody 7 in 23 patients diagnosed as having non-A, non-~ chronic hepatitis or hepatic cirrhosis by excluding factors such as alcoholism,
autoimmune disease, or hepatitis B virus. Before therapy, these 17 patients gave positive results for anti-HCV, and were diagnosed as having hepatitis type C. Anti-HCV in serum was measured by the ELISA test (Ortho D.S. Co). For the detection of HCV-RNA, R N A was extracted from 100/.tl of serum by the method of Chomczynski et al. and c D N A was prepared using reverse transcriptase. Primers and a probe were constructed for the NS 5 region based on sequence data for HCV. The c D N A we prepared was amplified by 40 cycles of the PCR. The product obtained was treated by electrophoresis and then by Southern blotting with a probe labeled with 32p. IFN treatment was done on one of two schedules. On one, 3 million IUs of human lymphoblastoid IFN-a (Sumitomo Pharm. Co) or human fibroblastoid IFN-/3 (Toray Co) was given daily for four weeks conservatively. Five patients were on this four-week schedule. On the other schedule, the same daily dose of IFN-a was used, but the therapy was continued for only two weeks, followed by a two-week period without therapy. This made up one cycle, and the cycles were repeated for a total of either 4 or 6 times. Twelve patients were on this 2 weeks on, 2 weeks off schedule. The background of these 17 patients is given in Table 1, together with the details about IFN therapy. Three patients were treated with IFN-/3
Gastroenterol Jpn 1991:26(Suppl 3)239-242 Address for correspondence: Tetsuo Kuroki, M.D., The Third Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545, Japan.
T. K u r o k i et al.
240
V o l . 26, S u p p l . 3
Table 1 The background of patients with HCV-RNA positive chronic hepatitis treated with IFN Case No.
Age/Sex
ALT (IU)
Histological diagnosis
Kind of IFN
Length/Cycles
Total dose (10-61U)
1 2 3 4 5
55 40 22 29 55
F M M M M
77 175 242 487 98
CAH CAH CPH CPH CPH
a a ,6 ,6 ,6
4 4 4 4 4
weeks/1 weeks/1 weeks/1 weeks/1 weeks/1
84 84 84 102 102
6 7 8 9 10 11 12 13 14 15 16 17
59 51 46 28 58 41 31 31 58 53 57 50
F F M M M M M M M M M M
187 168 183 94 223 261 235 292 263 161 81 191
CPH LC CAH CAH LC LC CPH CAH LC CAH CAH LC
a
2 2 2 2 2 2 2 2 2 2 2 2
weeks/4 weeks/6 weeks/6 weeks/6 weeks/6 weeks/4 weeks/6 weeks/6 weeks/4 weeks/4 weeks/6 weeks/6
168 252 252 252 252 168 252 252 168 168 252 252
a a a a a a a a a a a
Table 2 The effects of IFN therapy for chronic hepatitis with serum HCV-RNA Case No.
Age/Sex
Treatment for 4 weeks 1 55 F 2 40 M 3 22 M 4 29 M 5 55 M
Therapy with IFN
Histological diagnosis
Kind of IFN
CAH CAH CPH CPH CPH
a a ,6 ,/3 ,6
1 1 1 1 1
[] [] [] [] 9
Partially Partially Partially Partially Inflect.
9 Poor 9 Poor 9 Poor /k Transient 9 Poor
a a
4 6 6 6 6 4 6 6 4 4 6 6
C) Effective C) Effective 9 Effective 9 Effective O Effective [] Partially [] Partially [] Partially 9 Ineffect. 9 Ineffect. 9 Ineffect. 9 Ineffect.
(3 Complete [] Good 9 Compelte O Complete O Complete 9 Poor /k Transient A Transient [] Good 9 Poor 9 Poor 9 Poor
Treatment by the 2 weeks on 92 weeks off 6 59 F CAH 7 51 F LC 8 46 M CAH 9 28 M CAH 10 58 M LC 11 41 M LC 12 31 M CPH 13 31 M CAH 14 5~ M LC 15 53 M CAH 16 57 M CAH 17 50 M LC
Cycles
a a a a a a a
a a a
Effect on HCV-RNA
Effect on serum ALT
CPH: chronic persistent hepatitis, CAH: chronic active hepatitis, LC: liver cirrhosis
and 14 patients were treated with IFN-a. The effects on HCV-RNA by the therapy were classified 3 groups. In the effective group, HCVRNA was negative when the therapy ended and
remained negative. In the Partially effective group, HCV-RNA had become negative when the therapy ended and but reappeared, while in the ineffective group, HCV-RNA did not disappear.
July 1991
IFN treatment for chronic hepatitis C
Table 3 Classification of therapeutic efficacy for chronic hepatitis with HCV-RNA
Response Type I Type II Type III
Effect on HCV-RNA
Effect on serum ALT
No. of cases
Persistently negative Transiently negative Persistently positive
Complete Transient or poor Almost poor
5* 7 5*
*Only one case showed good response in each group
The efficacy in terms of serum A L T levels were classified 4 groups. In the complete effect group, serum A L T level decreased to normal with the therapy and remained normal during follow-up for at least 1 year. Cases in which serum A L T level decreased to nearly normal with the therapy and remained at levels less than twice the normal range during follow-up were classified as good effect. In the transient effect group, serum A L T level decreased to less than half of the pretreatment level with the therapy but increased during follow-up, while in the poor effect group, serum A L T did not decrease with therapy. Results
The therapeutic efficacy in patients given IFN for 4 weeks The effect for H C V - R N A and the efficacy for serum A L T in patients treated with IFN for 4 weeks is given in Table 2. H C V - R N A was detected immediately before therapy in all 5 patients. With IFN therapy, 4 out of 5 patients became negative for H C V - R N A when IFN therapy ended but H C V - R N A was detected 1 to 3 months later in all cases. Serum A L T became normal treansiently in one case which was partially effective for H C V - R N A when IFN therapy ended. In the other 4 cases in which treatment yolded only a poor effect, serum A L T did not decrease to less than half of the normal range.
The therapeutic efficacy in patients given IFN by the 2 weeks on~2 weeks off schedule The effect for H C V - R N A and the efficacy for
241
serum A L T in 12 patients treated with IFN by the 2 weeks on/2 weeks off schedule is given Table 2. H C V - R N A was detected immediately before therapy in all 12 patients. With IFN therapy, 5 out of 12 patients became negative persistently for H C V - R N A , 3 cases became negative transiently and the other 4 cases were positive persistently for at least 12 months after therapy ended. In the effective group, serum A L T became normal in 4 of 5 cases and the other case remained showing good effect for serum A L T , because this patient drank. In the partially effective group, 3 cases showed transient effects for serum A L T level and the other case showed poor effect for serum A L T . In the ineffective group, only one case showed good effect for serum A L T and the other 3 cases showed poor effect for serum ALT.
The criterion on therapeutic efficacy of IFN for chronic hepatitis C The clinical effects of IFN therapy for chronic hepatitis C according to the results were classified (Table 3). Type I response is complete response. In this type, serum H C V - R N A became negative continuously and serum A L T became normal or nearly normal for at least 12 months afte rtherapy ended. Type II response is partial response. In this type, serum H C V - R N A became negative transiently in all cases and the effect on serum A L T level was transient or poor. Type III is non-effective. In this type, serum H C V - R N A did not become negative and the effect for serum A L T was almost poor. Discussion
In the IFN treatment for chronic hepatitis C, the therapeutic efficacy has been evaluated by the improvement of serum A L T level. Hofnagle et al. 6 reported that serum A L T levels usually improved during the treatment but their serum A L T level increased after the end of IFN therapy in many patients with non-A, non-B chronic hepatitis. In the study of Di Bisceglie et al. s, 2 out of 21 patients with anti-HCV positive chronic hepatitis became normal continuously after the end of IFN
242
T. K u r o k i et al.
therapy. In our study, the therapeutic efficacy of IFN for patients with chronic hepatitis who were positive for serum H C V - R N A was evaluated by the efficacy in terms of serum A L T level and serum H C V - R N A . In this trial, the response to IFN therapy for chronic hepatitis C was classified into 3 types. In Type I response (complete response), serum H C V - R N A became negative persistently and serum A L T became normal or nearly normal for at least one year after therapy ended. In Type II response (partial response) serum H C V - R N A became negative transiently in all cases and the effect for serum A L T level was transient or poor. In Type III response (non-effective response), serum H C V - R N A did not become negative and the effect on serum A L T level was almost poor. In patients with chronic hepatitis C who showed a Type I response, H C V - R N A disappeared persistently and the serum A L T level became normal during the therapy, remaining normal continuously and the histological findings markedly improved. These findings in Type I response suggested that the IFN therapy had cured patients with chronic hepatitis C.
Summary The efficacy of interferon therapy for chronic hepatitis C were evaluated by the changes of serum R N A of the hepatitis C virus (HCV) by the polymerase chain reaction. Before the treatment, H C V - R N A was detected in all of the 17 patients. 5 patients given IFN for 4 weeks, 12 cases given IFN by the 2 weeks/on 2 weeks off schedule (4 cases given 4 cycles and 8 given 6 cycles). Immediately after the treatment ended, the HCVR N A was not d~tected in 12 (71%) cases. Five cases were persistently positive for H C V - R N A and showed continuously abnormal level of ALT. In 7 of 12 cases who became negative for HCVR N A just after the treatment ended, H C V - R N A was detected again at first and 12th month after therapy. The A L T level were continuously abnormal in 4 of these 7 cases during and after the treatment, and became normal transiently in the other 3. In the 5 cases who became persistently
Vol. 26, Suppl. 3
negative (at least i year), A L T level decreased to normal or near-normal during follow up for more than one year. According to our results, we classified the therapeutic efficacy of IFN therapy for chronic hepatitis C. Type I response is complete response. In this type, H C V - R N A became negative persistently and A L T became normal or near-normal for at least 12 months after therapy. Type II is partial response. In this type, HCVR N A became negative transiently and A L T level was transiently normal or poor. Type III is ineffective. In this type, H C V - R N A did not become negative and the effect for A L T was poor. These results suggested that Type I response was conplete cure of the chronic H C V infection. Type I response were observed in 0 of 5 cases given IFN for 4 weeks but 1 (25%) of 4 cases given the 4 cycles of IFN and 4 (50%) of 8 cases given the 6 cycles of IFN by the 2 weeks on/2 weeks off schedule.
References 1. Grecnberg HB, Lindberg J, Lundin P, et al: Effect of human leukocyte interferon on hepatitis B viral infection in patients with chronic active hepatitis. N Engl J Med 1976;295:517-522 2. Kuroki.T, Nishiguchi S, Saito S, et al: Response of 2',5'-oligoadenylate synthetase in hepatitis Be antigen-positive chronic hepatitis B treated with interfreon. New trend in peptic ulcer and hepatitis. Part II Chronic Hepatitis Excerpta Medica, Tokyo 1986;115-120 3. Kuroki T, Nishiguchi S, Takeda T, et al: Studies on the relation between response of 2',5'-oligadenylate synthetase and efficacy of interferon therapy in chronic hepatitis B. New trend in hepatology. Excerpta Medica, Tokyo 1986;249-255 4. Nishiguchi S, Kuroki T, Otani S, et al: Relationship of the effects of interferon on chronic hepatitis B and the induction of 2',5'oligoadenylate synthetase. Hepatology 1989;10:29-33 5. Nakajima S, Kuroki T, Shintani M, et al: Changes in interferon receptor on peripheral blood mononuclear cells from patients with chronic hepatitis B being treated with interferon. Hepatology 1990;12:1261-1265 6. Hoofnagle JH, Mullen KD, Jones DB, et al: Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. N Engl J Med 1986;315:1575-1578 7. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation ofcDNA clone derived from a blood -borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362 8. Di Bisceglie, A.M, Martin P, Kassianides et al. Rcconbinant interferon alpha therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321: 1506-1610
