Retreatment with interferon in patients with genotype II1b-related chronic hepatitis C

International Hepatology Communications

4 (1995) 126-132

ELSEVIER

Retreatment with interferon in patients with genotype II/l b-related chronic hepatitis C Tadao Okuno*, Ken Arai, Masayuki Matsumoto, Michiko Shindo Department

of Internal

Medicine,

Akashi

Municipal Hospital, Japan

1-33 Takashomachi,

Akashi,

Hyogo.

673.

Received3 April 1995;revisionreceived2 June 1995;accepted22 June 1995

Abstract

A retrospective study was undertaken to evaluate the efficacy of interferon retreatment in patients with type II/lb-related chronic hepatitis C, and also to determine the most useful predictor of a long-term response to interferon treatment. Twenty-eight patients who were positive for both anti-HCV and HCV RNA in serum, were retreated with interferon from 1989-1993. In the second course of interferon therapy, approximately 80% of patients showed a similar responsepattern to the initial interferon therapy in both serum aminotransferase and HCV RNA levels, while the remaining 20% of patients showed a different response pattern. Long-term responseoccurred in four (14.3%) of the 28 patients with type II/l b-related chronic hepatitis C. These findings suggestthat response patterns of retreatment are similar to those of the initial therapy and successrate of interferon retreatment appears to be low. They also suggest that ALT normalization with a loss of HCV RNA from serum at the end of initial interferon treatment is a useful marker for identifying patients likely to benefit from IFN retreatment. Keywords: Chronic hepatitis C; Interferon retreatment; HCV RNA

1. rntroduction

Interferon (IFN) therapy has a beneficial effect in some patients with chronic hepatitis C (l-31. The percentage of patients who have a long-term response to IFN therapy is approximately 25-30?/, with the remaining patients not responding to * Correspondingauthor, Tel.: +81 078 912 2323; Fax: +81 078 914 8374. 0928-4346i95BO9.500 1995ElsevierScienceIreland Ltd. All rights reserved SSDI

0928-4346(95)00233-Z

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therapy or relapsing after the cessation of therapy. Several groups have reported the efficacy of IFN retreatment in such patients [4-81. However, its efficacy is still inconclusive and little is known about predictors of a sustained response to retreatment with IFN. We therefore carried out a retrospective study to evaluate the efficacy of IFN retreatment in patients with chronic hepatitis C who did not respond to therapy or those who had a relapse after the initial IFN treatment, and also to determine the most important predictors of a long-term response to IFN retreatment. 2. Materials and methods Twenty-eight patients with chronic hepatitis C who did not respond to the initial IFN therapy or relapsed after the cessation of therapy were retreated with IFN from 1989 to 1993. They were 20 males and 8 females with a mean age of 50 f 11 years. All of the patients had elevated serum aminotransferase levels (at least 1.5 times the upper limit of the normal range) for at least 6 months prior to the initial IFN treatment and all had been histologically proven to have chronic hepatitis. The clinical characteristics prior to initial therapy of patients studied are shown in Table 1. All patients were positive for antibody to hepatitis C virus (anti-HCV) by radioimmunoassay (Ortho Diagnostic System, Tokyo, Japan) and were also positive for HCV RNA in serum. All patients showed genotype II/lb. All were negative for both hepatitis B surface antigen (HBsAg) and IgM anti-HAV (AUSRIA-II, HAVAB-M, respectively, Abbott Laboratory, North Chicago, IL.). All of the patients attended and had liver biochemical tests at in- or outpatient liver clinic at Akashi Municipal Hospital. Liver biopsies were performed before and at the end of IFN therapy on all patients after written informed consents was obtained. Histologic Table 1 Patients’ characteristics studied No. of patients Gender (M/F) Age (year) ALT (WI) Anti-HCV (+) Serum HCV RNA (log titer) HCV genotype II/lb Liver histology CPH CAH, moderate CAH, severe Knodell HA1 score IFN treatment 2nd course 3rd course 4th course BMean f S.D.

28 20/8 50 l 11;oa 162 f 58.2a 28 2.2 f 1.Y 28 6 14 8 9.2 f 3.2a 28 11 4

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diagnosis was made on hematoxylin-eosin and reticulin stained sections according to international standards. The paired liver biopsy specimens were reviewed by a single pathologist who was blinded to clinical materials and were graded according to the Knodell scoring system [9]. 2.1. hterferon

treatment

For the first IFN treatment, 22 patients were intramuscularly given natural interferon-a (HLBI, Sumitomo Pharmaceutical, Osaka, Japan), recombinant IFNa2a (Takeda Pharmaceutical Co., Osaka, Japan), or recombinant IFN-a2b (Schering-Plough Co., Osaka, Japan), while the remaining six were intravenously given natural interferon-8 (Toray, Tokyo, Japan). All 28 patients received a second course of interferon therapy; 22 patients were treated with interferon-o and six with interferon-p. Thereafter, 11 of the 28 patients also received a third course of treatment; ten were treated with interferon-a and one with interferon-& Finally, four of the 11 received a fourth course of interferon treatment; three patients were treated with interferon-a and one with interferon-p. The duration of interferon administration varied from 8-24 weeks. Interferon-a was given three times per week for 12-24 weeks at a dose of 6-10 million units (MU), and interferon-8 was given at a dose of 3-6 MU daily for 8 weeks. The interval between each IFN readministration varied from 6-12 months. The 28 patients were categorized into three groups according to the outcome of therapy; non-responders (serum ALT levels did not normalize during therapy), short-term responders (serum ALT levels normalized during therapy, but rose again after the cessation of therapy), and long-term responders (serum ALT levels remained normal for more than 1 year after the cessation of therapy). 2.2. HCV RNA assay HCV RNA was detected in serum using reverse transcriptase polymerase chain reaction (RT-PCR) as previously described [lo]. End-point titer of HCV RNA was estimated in a semi-quantitative fashion by testing serial lo-fold dilutions of the nucleic acids extracted from 50 ~1 of serum [lo]. HCV genotyping was performed using RT-PCR using type-specific primers according to the methods of Okamoto et al. [ll]. The entire protocol was approved by the hospital ethics committee. Written informed consent was obtained from all patients. Statistical analysis was performed using x2 test or Fisher’s exact r-test. A level of P < 0.05 was considered statistically significant. 3. Results The characteristics of patients studied are shown in Table 1. With the first course of interferon therapy, 12 (48%) of the 28 patients with type II/lb-related chronic hepatitis C were short-term responders and the remaining 16 (57%) were non-responders. AI1 of the 28 patients received a second course of interferon therapy. The 12 short-term responders with the first course of therapy all

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became short-term responders again with the second course of therapy. Only three (190/o)of the 16 non-responders became short-term responders and the remaining 13 (81%) were still non-responders. Three of the 12 short-term responders became long-term responders with the second course of therapy, while the remaining nine were still short-term responders. One of these nine patients was given a third course of IFN therapy and finally became a long-term responder. Ten of the 13 non-responders with the second course of therapy also received a third course of interferon therapy, all of whom continued to be non-responders. Furthermore, four of the ten non-responders with the third course of therapy were given a fourth course of interferon therapy with no response to therapy. Overall, with IFN retreatment a long-term response occurred in four (14%) of the 28 patients. The pretreatment serum ALT levels in the short-term and non-responders before the first and second therapy are shown in Fig. 1A. The initial ALT levels in the shortterm responders were significantly lower than those in the non-responders in both therapies (before the first therapy, 114 i 28.6 vs.1852 f 55.2 IU/L, P = 0.01, and before the second therapy, 97.1 f 25.1 vs. 172.5 f 105.8 III/L, P = 0.009). The pretreatment serum HCV RNA levels are shown in Fig. 1B. The initial HCV

Serum ALT

HCV RNA NS NS

300

y NS

200 c3 =. 2 100

NS h pKJ 1st

m

2nd IFN

1st

A

2nd IFN

1st

2nd IFN

1st

2nd IFN

B

Fig. 1 Changes in serum ALT levels (A) and HCV RNA in serum (B). HCV RNA titer was expressed by the end-point titer of HCV RNA estimated in a semi-quantitative fashion by testing serial IO-fold dilutions of the nucleic acids extracted from 50 ~1 of serum. IFN = interferon, SR = short-term responder (serum aminotransferase levels became normal during therapy, but relapsed after the cessation of therapy). NR = non-responder (serum aminotransferase levels did not become normal during therapy).

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RNA levels in the first and second courses of therapy did not differ significantly between the short-term and non-responder groups. At. the end of the initial therapy, HCV RNA became undetectable in 11 (390!) of the 28 patients, and it remained positive in the remaining 17 (61%). Subsequently, all patients again became positive for HCV RNA in serum before the start of the second course of therapy. Nine (82%) of the 11 patients with undetectable HCV RNA at the end of initial therapy again lost HCV RNA, and five (29%) of the 17 patients with detectable HCV RNA at the end of the initial therapy also lost HCV RNA at the end of the second therapy. However, the remaining 14 were still positive for HCV RNA at the end of the second course of therapy. There was no statistical difference in the initial HCV RNA levels between the short-term and non-responder groups in the first two courses of therapy (Fig. 1B). Three of the four long-term responders lost HCV RNA at the end of both the first and second courses of therapy, while the remaining responder was positive for HCV RNA at the end of the first course of therapy, but lost HCV RNA at the end of the second and third therapy. The initial log titers of HCV RNA in the four long-term responders were 1 in two patients and 3 in two patients, respectively. None of the non-responders with the second course of therapy became undetectable for HCV RNA in serum after either the third or the fourth course of therapy. The pretreatment histological activity index (HAI) scores are shown in Fig. 2A.

HAI score

Total IFN Dose

NS NS

r--=--l

NS

141312lllo’ 8 :: 5

987854-

F-l I II

X106llJ 700 -

NS

r

600 500 L8

400-

-0 t -

300200 -

32l-

ioo-

1st

2nd

1st

IFN

2nd IFN

A

1st

1st

2nd

2nd IFN

IFN

B

Fig. 2 Changes in Knodell’s histological activity index (HAI) score (A) and total dose of interferon administration (B). Abbreviations are the same as in Fig. 1.

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131 At the end of 4th IFN

LR 3 (468 MU) SR g __________. LR , (442 MU) (432 MU)

SR 12 (328 MU) Patients 28

Communications

SR3 (416 MU) NR 13 ____________________. NR 10 __________. NR 4 (382 MU) (484 MU) (432 MU)

Fig. 3 Relationship between response to each course. of IFN therapy and total IFN dose. Numbers in parentheses represent total IFN dose. LR = long-term responder, SR = short-term responder, NR = nonresponder.

Mean HA1 score did not differ statistically between the short-term and nonresponder groups in both therapies. The initial histological diagnosis of the four long-term responders was chronic persistent hepatitis (HA1 scores, 5-6) in three and chronic active hepatitis (HA1 scores, 12) in one. The total dose of IFN in the second course of therapy was greater than that in the first treatment in the two groups. However, there was no significant difference between short-term and non-responder groups or each course of therapy (Fig. 2B). Relationship between response to each course of IFN therapy and total IFN dose is shown in Fig. 3. 4. DIscussi In this study, approximately 80% of patients with chronic hepatitis C showed similar response patterns in serum ALT levels and HCV RNA levels with IFN retreatment to those of the initial therapy. The remaining 20% of patients showed different responses to IFN readministration. Long-term response occurred in four (14%) of the 28 patients retreated with IFN, which was in accordance with the previous report [8]. However, most of the non-responders with the second course of IFN therapy are still non-responders even with multiple courses of IFN therapy. Therefore, more than three courses of IFN therapy may be unnecessary. Several studies have shown that patients with type II/l b-related HCV infection and higher viral levels have little chance to respond to interferon therapy compared with those with type 111/2a or IV/2b and lower viral levels [ 12-151. However, genotype II/lb is the most prevalent type of HCV infection in Japan, and previous studies [7-81 as well as the present

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study have shown that patients with this type of infection are the most common candidates for retreatment with IFN. Our findings suggest that it is important to select patients who have a greater likelihood of a sustained response to IFN in order to achieve a higher treatment success rate. Thus, ALT normalization with a loss of HCV RNA from serum at the end of initial treatment seems to be at least a precondition for the selection of IFN retreatment candidates. References [l] [2] [3] [4] [5] [6] [7] [8] [9] [IO] [I l] [12] [13] [14] [15]

Davis GL, Balart LA, Schiff ER et al. Treatment of chronic hepatitis C with recombinant interferon-alpha. A multicenter randomized, controlled trial. N En@ J Med 1989; 321: 1501-6. DiBisceglie AM, Martin P, Karsianides C et al. Recombinant interfeon alpha therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1989; 321: 1506-10. Marcellin P, Boyer N, Giostra E et al. Recombinant human a-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology 1991; 13: 393-l. Weiland 0, Zhang Y-Y, Widell A. Serum HCV RNA levels in patients with chronic hepatitis C given a second course of interferon alpha-2b treatment after relapse following initial treatment. Stand J Infect Dis 1993; 25: 25-30. Kakumu S, Yoshioka K. Retreatment with interferon in patients with chronic hepatitis C [Letter]. J Hepatol 1994; 21: 483. Horiike N, Kurose K, Ohkura I et al. Retreatment with interferon in chronic hepatitis C. [Letter]. J Hepatol 1994; 21: 1155. Toyoda H, Nakano S, Takeda I et al. Retreatment of chronic hepatitis C with interferon. Am J Gastroenterol 1994; 89: 1453-7. Arase Y, Kumada H, Chayama K et al. Interferon retreatment of non-responders with HCV-RNApositive chronic hepatitis C. J Gastroenterol 1994; 29: 299-304. Knodell RG, Ishak KG, Black WC et al. Formulation and application of a numerical scoring system for assessing histologic activity in asymptomatic chronic active hepatitis. Hepatology 1991; I: 431-5. Shindo M, Arai K, Sokawa Y, Okuno T. Hepatic hepatitis C virus RNA as a predictive factor of a long-term response to interferon-a therapy. Ann Intern Med 1995; 122: 586-91. Okamoto H, Sugiyama Y, Okada S et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sourses. J Gen Viral 1992; 73: 673-9. Hagiwara H, Hayashi N, Mita E et al. Quantitative analysis of hepatitis C virus RNA in serum during interferon alpha therapy. Gastroenterology 1993; 104: 877-83. Kanai K, Kato M, Okamoto H. HCV genotypes in chronic hepatitis C and response to interferon [Letter]. Lancet 1992; 339: 1543. Yoshioka K, Kakumu S, Wakita et al. Detection of hepatitis C virus by polymerase chain reaction and response to interferon-a therapy: relationship to genotypes of hepatitis C virus. Hepatology 1992; 16: 293-9. Tsubota A, Chayama K, Ikeda K et al. Factors predictive of response to interferon-alpha therapy in hepatitis C virus infection. Hepatology 1994, 19: 1088-94.