Comparison of two interferon alfa treatment regimens characterized by an early virological response in patients with chronic hepatitis C

Vol. 93, No. 2, 1998 ISSN 0002-9270/98/$19.00 PI1 SOOO2-9270(97)00094-4

AMERICAN hX,RNAL OF GASTRO~ROLOGY Copyright 0 1998 by Am. Coil. of Gastroenterology Published by Elsevier Science Inc.

THE

Comparison of Two Interferon Alfa Treatment Regimens Characterized by an Early Virological Response in Patients With Chronic Hepatitis C Tatehiro Kagawa, M.D., Katsumi Hosoi, M.D., Shinji Takashimizu, M.D., Kazuya Kawazoe, M.D., Kaori Mochizuki, M.D., Mitsuru Wasada, M.D., Naruhiko Nagata, M.D., Junzo Uchiyama, M.D., Atsushi Nakano, M.D., Yasuhiro Nishizaki, M.D., Noribito Watanabe, M.D., and Shohei Matsuzaki, M.D. Department

of internal

Medicine

(III), Tokai Universify School of Medicine,

Bohseidai,

lsehara, Kanqawa,

Japan

Studies have suggestedthat the early disappearanceof serum HCV RNA during IFN therapy is associatedwith complete response(6, 7). Hino et al. (6) reported that serum HCV RNA disappearedin 80% of respondersand 3.8% of nonrespondersat the secondweek of therapy. The effects of higher dose IFN therapy and modification of the regimen basedon the virological status during treatment in nonrespondershave not been investigated. We investigated the efficacy of and the toIerance to IFN therapy using a higher total dose in patients with chronic hepatitis C in whom serumHCV RN.4 persistedafter 2 wk of IFN treatment, and also investigated whether the patient’s virological statusduring IFN treatment is useful for predicting a complete response.

Obj,ctve: We investigated the efficacy of an interferon regimen characterized by an early virological response in patients with chronic hepatitis C and evaluated whether the patient’s virological status during therapy would he useful for predicting a complete response. Methods: We treated 62 patients with chronic hepatitis C with 6 million units (MU) of human lymphoblastoid interferon daily for 4 wk. The serum HCV RNA was assayed at week 2 by the reverse transcription-polymerase chain reaction. HCV RNA-negative patients (group A) received 6 MU of interferon three times weekly for an additional 22 wk (total dose, 564 MU). HCV RNA-positive patients were randomly assigned to group B-l, which received the same regimen as group A, or to group B-2, which received 6 MU of interferon daily for 4 wk followed by 6 MU three times weekly for 18 wk (total dose, 660 MU). Results: Complete responses were achieved by 19 (63.3%) of 30 group A patients, compared with one (6.3 %) of 16 group B-l patients and none of 16 group B-2 patients. The virological response at week 2 and the pretreatment serum HCV RNA level were independent significant predictors of a complete response. Conclusion: Patients who were still HCV RNA-positive at week 2 were unlikely to achieve a complete response after interferon therapy. An increase in the total dose of interferon failed to yield further benefit in these patients. (Am J Gastroenterol 1998;93:192-196. 0 1998 by Am. Coll. of Gastroenterology)

MATERXALS

AND METHODS

Patients

We studied 62 Japanesepatients (44 men and 18 women, aged 20 to 70 yr, mean age 50.3 ? 13.0 yr) who met the following criteria: (I) the presenceof serumHCV RNA, (2) persistentlyelevated serumlevels of alanineaminotransferase (ALT) for at least 6 months,(3) histologicahy proven chronic active hepatitis,and (4) absenceof other liver diseases. IFN treatment

regimen

Each patient received a subcutaneousinjection of 6 million units (MU) of human lymphoblaatoid IFN (Wellferon; Sumitomo Pharmaceutical, Osaka, Japan) daily for 4 wk. The serumHCV RNA was assayedafter 2 wk of therapy by reverse transcription-polymerasechai a reaction (RT-PCR). An early virological responsewas defined as the disappearanceof serumHCV RNA after 2 wk of therapy. After week 2, patients were classified into groups according to their virological status during IFN treatment. Patients who exhibited an early virological responsereceived 6 MU of IFN three times weekly for an additional 22 wk (total dose, 564 MU) (group A). Patients without an early virological responsewere randomly assignedto either group B- 1, which received the sameregimen asgroup A, or group B-2, which received 6 MU of IFN daily for 4 wk followed by 6 MU

INTRODUCTION Several randomized trials (l-4) have demonstratedthat interferon (IFN) is an effective treatment for chronic hepatitis C. However, IFN treatment is associatedwith a complete responserate of only about 30% (5). Thus, studiesare needed to determine whether higher doses,a longer treatment duration, or titration of the dosebasedon the viral load will improve the efficacy rate of IFN therapy. Received Mar. 21, 1997: accepted Oct. 13, 1997. 192

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three times weekly for an additional 18 wk (total dose, 660 MU). Serum HCV RNA levels were quantified before treatment. Then, at weeks 2,4,8,26 (end of treatment), 30 (4 wk after the end of treatment), and 50 (24 wk after the end of treatment), the presence or absence of HCV RNA was determined in each patient. The pretreatment HCV genotype was also determined. A liver biopsy was obtained before the initiation of IFN treatment, and the histological stage and grade of activity were determined according to the standard criteria (8). Leukopenia and thrombocytopenia were defined as a decrease in the number of leukocytes and platelets, respectively, to less than half of the pretreatment levels. The study protocol was approved by the Institutional Review Board of Tokai University Hospital. Informed consent was obtained from all patients. Determination of serum HCV RNA and HCV genotypes The presence or absence of HCV RNA in serum was determined by nested RT-PCR using primers specific for the 5’ untranslated region of the HCV genome (9). The sensitivity of the assay was 200 copies/ml. Quantitation of HCV RNA in 50 ~1 of serum was performed by competitive RT-PCR using mutant HCV RNA as the competitor (10). Serum HCV RNA levels >l million copies/ml were considered to be high. HCV genotyping was performed according to the method of Okamoto et al. (11, 12) using RT-PCR with type-specific primers of the core gene. HCV genotypes were classified into four types (13). Evaluation of the eficacy of treatment A complete response was defined as the absence of serum HCV RNA and the sustained normalization of serum ALT levels up to week 50 (24 wk after the end of treatment). Relapse was defined as the reappearance of serum HCV RNA after the end of IFN treatment, and breakthrough as the reappearance of serum HCV RNA during IFN treatment. Patients who were HCV RNA positive throughout the study period were classified as nomesponders. Relapse, breakthrough, and no response were defined irrespective of the serum levels of ALT. Statistical evaluation Dichotomous variables were compared using the 2 test. Quantitative variables were compared using the Student’s t test (two-tailed). Variables with a p value CO.1 were included in multivariate analysis. Logistic multiple regression analysis was performed using SPSS 6.1 J for the Macintosh computer to determine the independent prognostic value of the selected variables. RESULTS Patient characteristics Of 62 patients, 30 (48.4%) lost serum HCV RNA at week 2 after the beginning of IFN treatment (group A). The

C RESPONSE

TO INTERFERON

o-J, B

w

L

I

30 weeks aftarthe aily

193

50 start of IFN treatment

TIW

lOO-

Group B-1

26

30

50

weeks aftftr the start of IFN treatment

Group B-2

weeks after the start of IFN treatment

FIG. 1. Changes in percentage of HCV RNA-negative patients. A: group A (n = 30); B: group B-l (n = 16); C: group B-2 (n = 16). Shaded rectangle, daily IF’N administration; open rectangle, three times weekly IFN adminstration.

remaining 32 patients (51.6%) were HC’V RNA-positive at week 2 (group B). There were no significant differences in age, sex, serum ALT level, or liver histology between groups. The serum HCV RNA titer was high in 11 patients (36.7%) in group A and 23 patients (7 1.9%) in group B (p < 0.02). The Ib genotype was identified in 17 patients (56.7%) in group A and 26 patients (71.2%) in group B. There were no significant differences in clinical chatacteristics between group B-l (n = 16) and group B-2 (n == 16). Virological status All patients completed IFN treatment and were followed-up for 50 wk. All 30 group A patients remained HCV RNA-negative at week 4 (Fig. 1). Breakthrough was observed in 6 patients (20%) by week 26. Therefore 24 patients (80%) were HCV RNA-negative at week 26 (end of treatment). Relapses occurred in 5 patients by week 30. There were 19 patients (63.3%), who were complete responders, who remained HCV RNA-negative throughout the follow-up period and had sustained normalization of serum ALT levels. In group B-l, seven (43.8%) of 16 patients were HCV RNA-negative at week 4. Breakthrough occurred in three

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et al. TABLE

TABLE 1 Results of IFN Treatment Outcome

Group A (n = 30)

Complete response Relapse Breakthrough No response Data represent the number *p
19 (63.3) 5 (16.7)

6 (2’3) 0 (0) (and

Pretreatment Features

Group B-l (n = 16) 1 (6.3)* 3 (18.8) 3 (18.8) 9 (56.3)*

percentage)

Group B-2 (n = 16) 0 7 2 7

c9* (43&t (12.5) (43.8)*

of patients.

(18.8%) by week 26 and 4 patients (25%) were still HCV RNA-negative by week 26. Relapses occurred in three patients by week 30. By week 50, only one patient (6.3%) remained HCV RNA-negative and had sustained normalization of the ALT level (complete response). There were nine nonresponders (56.3%) in group B-l, who remained HCV RNA-positive throughout the study period. In group B-2, five (31.3%) of 16 patients were HCV RNA-negative at week 4. By week 8, nine patients (56.3%) were HCV RNA-negative. Breakthrough was observed in two patients (12.5%), and seven patients (43.8%) were HCV RNA-negative at week 26. All seven patients relapsed by week 30. Thus, there were no complete responders and seven nonresponders (43.8%) in group B-2. None of the patients showed a loss of serum HCV RNA for the first time after switching from daily to three times weekly administration. All patients who were HCV RNAnegative at week 30 (4 wk after the end of treatment) were HCV RNA-negative at week 50 (24 wk after the end of treatment); all of these HCV RNA-negative patients showed normalization of serum ALT levels throughout the follow-up period. patients

Overall result of IFN treatment The complete response rate was significantly higher in group A than in group B-l or B-2 (Table 1). There was no significant difference in the complete response rate between groups B-l and B-2, indicating that the longer duration of daily therapy did not improve the rate of response. Despite the persistence of serum HCV RNA, sustained normal serum levels of ALT were observed in two group A patients, one group B-l patient, and one group B-2 patient. Relapse occurred more frequently in group B-2 (43.8%) than in group A (16.7%). The breakthrough rate was not significantly different among groups. In each case, breakthrough occurred after the transition from daily to three times weekly administration of IFN. No patient again became HCV RNAnegative following breakthrough. The no response rate was significantly higher in groups B- 1 and B-2 than in group A. Predictors of response There was no significant difference in age, sex, the serum ALT level, or liver histology between the complete responders and the other patients (Table 2). The serum level of HCV

2

Clinical, Biochemical, Virological. and Hisrological of Patients With and Without a Complete Response

Variable Serum HCV RNA level Low High? HCV genotype Ib Others Early virological response* Yes No

Complete Responders (n = 20)

Others* (n = 42)

Analysis Univariate

16 4

12 30

0.0004

10 10

33 9

0.05

19 1

11 31

0.00001

(p Value) Multivariate

* Relapse, breakthrough, or no response. t Serum level of HCV RNA 12 1 million copies/ml. j: Early virological response was defined as the disappearance HCV RNA at week 2. NS = not significant.

0.01

NS

0.0007

of serum

RNA was significantly lower and the Ib genotype was less frequent in the complete responders. An early virological response was observed in 19 (95%) of 20 complete responders, compared with 11 (26.2%) of 42 patients without a complete response. Surprisingly, only one of the 32 patients without an early virological response showed a complete response. The accuracy of an early virological response for prediction of a complete response was 80.6%. Multivariate analysis was performed using variables that yielded a p value
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studies have shown that the serum HCV RNA level is an independent predictor of the response to therapy (14, 15). Although univariate analysis identified the HCV genotype as a significant predictor of response, this factor was eliminated by multivariate analysis. An early virological response was so strongly associated with a complete response to IFN treatment that other factors with weaker correlations, including genotype, were eliminated. Of the 30 patients with an early virological response, 19 (63.3%) achieved a complete response. Therefore, the administration of 6 MU of IFN daily for 4 wk and three times weekly for 22 wk appeared to be satisfactory in patients who showed an early virological response after 2 wk of therapy. Administration of 6 MU of IFN daily for 2 wk did not result in the disappearance of serum HCV RNA in 5 1.6% of patients. Serum virions appear to have a short estimated half-life of 0.3 (16) or 0.7 (17) days. If viral production were completely inhibited by IFN, serum HCV RNA would be undetectable after 2 wk of treatment. Therefore, in patients who remained HCV RNA-positive at week 2, viral replication would have persisted. Lam et al. demonstrated that a single injection of IFN cleared serum virions in a dosedependent manner (16). The increase in the rate of disappearance of HCV RNA from week 4 (3 1%) to week 8 (63%) in patients who received a longer duration of daily therapy (group B-2), and the decrease in the rate of HCV RNA disappearance after patients were switched to three times weekly administration (each group), may have resulted from the dose dependency of IFN’s antiviral effect. Alternatively, viral mutation resistance to IFN may have been responsible for the latter phenomenon. Although studies have compared different IFN regimens (18 -26), it is still questionable whether an increase in the IFN dose or a longer duration of treatment would improve the incidence of a sustained response. Poynard et al. (5) performed a metaanalysis of 17 randomized IFN trials and compared the response rate obtained with the different regimens. They concluded that 3 MU of IFN three times weekly for at least 12 months was most strongly associated with a sustained response. In the present study employing a 6 month therapy, the increase in the total dose of IFN from 564 to 660 MU did not improve the overall result in patients without an early virological response. Relapses occurred in 15 (41.7%) of 36 patients who were HCV RNA-negative at the end of treatment. In some patients, prolongation of treatment may suppress a relapse. Further studies are needed to determine whether prolongation of treatment will be effective in reducing the relapse rate. Breakthrough occurred in 11 patients, and 16 patients were nonresponders. These patients would probably not have achieved a complete response even if IFN had been administered at a higher dose for at least 12 months. The present results showed that the patient’s virological status during IFN treatment was very useful for predicting the long-term response. Therefore, IFN regimens modified based on the virological status may be useful. Standard

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regimens should be considered for palients with an early virological response, and a new approach needs to be developed for those without an early response. ACKNOWLEDGMENT This work was supported in part by a grant-in-aid from the Ministry of Education, Science and Culture of Japan. Reprints requests to: Shohei Matsuzaki, M.D. Department of Medicine (III), School of Medicine, Tokai University, Kanagawa ture 259-l 1, Japan. Correspondence to: Tatehiro Kagawa, M.D., Department of Medicine (III), School of Medicine, Tokai University, Kanagawa ture 259- 11, Japan.

Internal PrefecInternal Prefec-

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