Efficacy of early retreatment with interferon β for relapse in patients with genotype Ib chronic hepatitis C

Hepatology Research 28 (2004) 36–40

Efficacy of early retreatment with interferon ␤ for relapse in patients with genotype Ib chronic hepatitis C Hideyuki Nomura a,∗ , Suketo Sou a , Takashi Nagahama a , Jun Hayashi b , Seizaburo Kashiwagi c , Hiromi Ishibashi d a

Department of Internal Medicine, Shin-Kokura Hospital, 1-3-1 Kanada, Kokurakitaku, Kita-Kyushu 803-8505, Japan b Department of Environmental Medicine and Infectious Diseases, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maedashi, Higashiku, Fukuoka 812-8582, Japan c Fukuoka Red Cross Blood Center, 232-11, Kamikoga Chikushino, Fukuoka 818-8588, Japan d Clinical Research Center, National Nagasaki Medical Center, 2-1001-1 Omura, Nagasaki 856-8562, Japan Received 28 February 2003; received in revised form 3 September 2003; accepted 24 September 2003

Abstract Background: Interferon (IFN) retreatment for hepatitis C virus (HCV) relapsers has been effective under some conditions. We conducted a randomized, controlled trial of IFN ␤ retreatment for HCV relapsers after IFN ␣. Patients and methods: We gave IFN ␤ 6MIU therapy to 43 patients who had relapse of HCV after the 24 weeks IFN ␣ monotherapy. The 43 patients were randomly assigned to two groups: Group A started retreatment within 4 weeks after relapse; and Group B started retreatment 24 weeks or more after relapse. Results: Nine patients showed sustained virological response (SR) to the retreatment. All of these patients were in a low viral load subgroup. The SR rate in Group A (8/22, 36%) was significantly higher than in Group B (1/21, 5%) (P = 0.0128). Among patients with lower viral load, the SR rate in Group A (8/10, 80%) was also significantly higher than in Group B (1/8, 13%) (P = 0.0076). Conclusion: The retreatment with IFN ␤ is effective for patients with HCV low viral load, and the sooner after the relapse the retreatment is started, the better the clinical results will be. © 2003 Elsevier B.V. All rights reserved. Keywords: Interferon ␣; Interferon ␤; Retreatment; Chronic hepatitis C; Genotype 1b

1. Introduction Chronic hepatitis due to persistent infection with the hepatitis C virus (HCV) often progresses to cirrhosis and hepatocellular carcinoma [1]. Interferon (IFN) represents an effective therapy for many patients with chronic hepatitis C [2,3]. A sustained virological response (SR) with IFN treatment depends on many factors, including viral genotype, viral load, presence of hepatic fibrosis, age, gender, and mutations in IFN susceptibility determinants in the nonstructural 5A (NS5A) region of the virus [4–7]. HCV genotype and viral load are particularly important factors in predicting treatment response [2,4,5,8]. Resistance of the HCV genotype 1b to treatment with IFN has been frequently reported in Japan [8–10]. Many ∗ Corresponding author. Tel.: +81-93-571-0553; fax: +81-93-591-1031. E-mail address: [email protected] (H. Nomura).

1386-6346/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2003.09.005

patients infected with genotype 1b fail to eliminate HCV after treatment with IFN monotherapy. In addition, many patients eliminate HCV during the treatment but can not prevent later relapse. Alberti et al. reviewed several prospective studies [11]. Their report generally described patients other than genotype 1b (genotype 1b, 11%; other, 41%), significantly higher alanine aminotransferase (ALT) levels at time of retreatment, treatment with IFN for at least 12 months, and retreatment with IFN in patients who relapsed. Recently, a combination of IFN␣2b and ribavirin has been used for retreatment of patients who relapsed after initial treatment with IFN alone. This combination has been proven more effective than IFN␣2b monotherapy [12]. However, this combination therapy is limited because ribavirin is contraindicated in many patients [13]. This study is suggesting an effective new retreatment regimen. The study evaluated differences in efficacy of reattempting therapies, one was starting immediately after the relapse and the other was starting after 24 weeks, in patients

H. Nomura et al. / Hepatology Research 28 (2004) 36–40

who relapsed after initial treatment. All patients were diagnosed as chronic hepatitis C with genotype 1b and were initially treated with natural IFN␣. Patients with relapse were then randomly assigned to two groups. One group began retreatment with a 6 week course of natural IFN␤ starting immediately after relapse. The other began retreatment with the same regimen starting 24 weeks after relapse. We now report on the significant differences in the treatment responses.

2. Patients and methods 2.1. Selection of patients The patients involved in this study were treated at ShinKokura Hospital from January 1997 to December 1999. Each patient was positive for HCV-RNA based on reverse transcription nested polymerase chain reaction (RT-nested PCR) test [14] and diagnosed as chronic hepatitis C from findings on a liver biopsy performed within 3 months. Only adult patients with HCV genotype 1b were eligible for this study. Patients with cirrhosis, autoimmune hepatitis, alcoholic liver diseases, or hepatitis B surface antigen positives by an enzymelinked immunosorbent assay (Abbott Japan, Co. Ltd., Tokyo, Japan) were also excluded. Patients ranged in age from 20 to 69 years. The study design and IFN treatment were explained, and written informed consent was obtained from all of the patients prior to enrollment. All procedures in this study were conducted in accordance with the Helsinki Declaration of 1975 (1983 revision). 2.2. Study design and treatment regimens Natural IFN␣ (Sumiferon, Sumitomo Pharmaceutical Industries Inc., Osaka, Japan) was used as the initial treatment. The dose was 6 million international units (MIU) by intramuscular injection, administered once daily for 2 weeks, followed by three times a week for 22 weeks (total dose: 480 MIU). Patients who were HCV negative at completion of the initial treatment but who later experienced relapse were randomized into one of two treatment groups by using an enveloped enrollment sheet method. In Group A, retreatment was initiated within 4 weeks after relapse. In Group B, retreatment was started 24 weeks or more after relapse. Twenty two of the 43 relapsed patients after initial treatment were assigned to Group A (low viral load: 10 patients) and the others were assigned to Group B (low viral load: 8 patients). Table 1 shows the baseline of clinical profiles of the patients. No statistically significant differences in any baseline profiles were observed between Groups A and B. Measurement of viral load prior to retreatment demonstrated low viral load in 18 of the 43 patients. The retreatment regimen was natural IFN␤ (6 MIU per day) (Feron, Toray Industries Inc., Tokyo, Japan), administered once daily by intravenous injection for 6 weeks (total dose: 252 MIU).

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Table 1 Clinical characteristics of patients receiving retreatment Group A (n = 22)

Group B (n = 21)

Total (n = 43)

Age (years) 21–49 50–69

13 9

11 10

24 19

Gender Male Female

15 7

13 8

28 15

Viral loads <100 (kcopies/ml) ≥100 (kcopies/ml)

10 12

8 13

18 25

Liver tissue Mild hepatitis Severe hepatitis

11 11

16 5

27 16

Serum ALT value <2 × ULN ≥2 × ULN

14 8

16 5

30 13

This table shows the clinical characteristics of patients before retreatment with IFN␤. Patients were randomly assigned to Group A or Group B, and classified into subgroups based on liver histology: mild hepatitis (HAI score ≤ 10) and severe hepatitis (HAI score ≥ 11). ULN: the upper limit of the normal range (40 IU/l). HAI: histological activity index.

SR was defined as serum ALT levels below the upper limits of the normal level (ULN: 40 IU/L) and negative HCV-RNA at 24 weeks after retreatment. Any clinical findings other than SR were considered nonresponse (NR). The subsequent followup period was 1 year. HCV viral load was measured just before the start of retreatment. Viral load was measured with Amplicor-HCV monitor assay (Roche Molecular Diagnostics, Tokyo, Japan) [15]. Low viral load was defined as <100 kcopies/ml, and high viral load as ≥100 kcopies/ml. Serum ALT levels, hemoglobin concentration, white blood cell count, and platelet count were measured at 4-week intervals from the start of treatment until 24 weeks after completion of retreatment. If serum ALT levels again increased to ≥2 × ULN after completion of treatment, HCV-RNA was assayed. Hepatic inflammation and fibrosis were assessed using the Knodell histological activity index (HAI). Patients were classified into two subgroups: mild hepatitis (HAI ≤ 10) and severe hepatitis (HAI ≥ 11) [16]. Treatment with IFN was discontinued if the hemoglobin concentration decreased below 9.0 g/dl, if the white blood cell count decreased below 1500 mm−3 , if the platelet count decreased below 50,000 mm−3 , or if symptoms such as severe malaise was observed. 2.3. Statistical analysis Differences between the groups were analyzed with Fisher’s exact test. In the determination of predictive factors for IFN retreatment efficacy, simple logistic regression analysis was performed. Logistic analysis was performed

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H. Nomura et al. / Hepatology Research 28 (2004) 36–40

for age (21–49 years versus 50–69 years), gender (male versus female), time of starting retreatment (Group A versus Group B), HCV-RNA level (<100 kcopies/ml versus ≥100 kcopies/ml), liver histology (HAI score 2–10 versus 11–22), and serum ALT value (< 2 × ULN versus ≥ 2 × ULN). Probability values of <0.05 stands for statistically significant.

3. Results 3.1. Relationship between predictive factors and efficacy of IFN retreatment The results of univariate analysis for predictive factors associated with SR in the 43 retreated patients were: age (P = 0.2607), gender (P = 0.2185), time of starting retreatment (P = 0.0482), viral load (P = 0.0020), hepatic histology (P = 0.3910), and serum ALT level (P = 0.6043). Both “viral load” and “time of starting retreatment” were significant predictive factors (Table 2). 3.2. Results of IFN retreatment by viral loads Table 3 shows the results of IFN retreatment by viral loads. SR was observed in nine retreated patients (21%), all of whom had low viral load prior to retreatment. The SR Table 2 Results of univariate analysis for predict factor of retreatment Factor

Chi-Square

P-value

Odd ratio

95% Confidence limits

Age Gender Time of starting retreatment Virus loads Histology Serum ALT level

1.2648 1.5039 3.9016

0.2607 0.2185 0.0482

0.385 3.356 5.970

0.073–2.034 0.488–23.084 1.014–35.147

9.5104 0.7358 0.2686

0.0020 0.3910 0.6043

18.86 1.959 1.527

2.915–125.102 0.421–9.110 0.308–7.569

Cutoff values for liver histology were HAI score of 11 and viral load of 100 kcopies/ml. Patients were divided into Group A or Group B based on time of starting retreatment. Table 3 Results of sustained virologic response rate for interferon retreatment by viral loads Group A (n = 22) SR/n (%)

Group B (n = 21) SR/n (%)

Total (n = 43) SR/n (%)

Viral loads <100 (kcopies/ml) ≥100 (kcopies/ml)

8/10 (80)∗∗ 0/12 (0)

1/8 (13)∗∗ 0/13 (0)

9/18 (50) 0/25 (0)

Total

8/22 (36)∗

1/21 (5)∗

9/43 (21)

This table summarized analysis of data from Fisher’s exact test. SR: Sustained virologic response, (%):Sustained virologic response rate. ∗∗ P < 0.01 (Group A vs. Group B). ∗ P < 0.05 (Group A vs. Group B).

rate was significantly higher in Group A (8/22, 36%) than in Group B (1/21, 5%) (P = 0.0128). Among the patients with low viral load, SR was observed in 8 of 10 patients in Group A (80%) but only in 1 of 8 patients in Group B (13%, P = 0.0076). Serum ALT at 24 weeks after retreatment was below ULN in 10 patients in Group A (45%), but only in 3 patients in Group B (14%, p = 0.0279). In evaluation after retreatment (24 weeks after completion of retreatment), among the HCV-RNA positive patients, 4 of 5 with serum ALT below ULN eventually had a rise in serum ALT to above ULN the during followup for 1 year. However, no patients with SR had a relapse during 1 year of followup after retreatment. No discontinuations or withdrawals occurred during the 6 weeks of retreatment with IFN␤. 3.3. Safety No clinically significant decreases in hemoglobin concentrations, white blood cell counts or platelet counts were observed during initial treatment and retreatment. No symptoms such as severe malaise or adverse reactions requiring discontinuation of IFN treatment were observed.

4. Discussion Our study was characterized by [1] time of starting retreatment [2], change to a different types of IFN for retreatment [3], short duration of retreatment and small total dose (252 MIU), and [4] absence of any treatment discontinuations or withdrawals. Based on data from previous studies evaluating efficacy of retreatment [11–13,17], the present study targeted retreatment in HCV relapsers after IFN therapy. Genotype 1b chronic hepatitis C is often resistant to IFN treatment. All patients in this study were initially treated with IFN␣. Only the HCV relapsers were retreated with IFN␤. For patients with low viral load, the SR rate with retreatment early after relapse (Group A) was about 80%. Unfortunately, as in previous reports [18], the response rate was poor when retreatment was initiated after 24 weeks or more from the relapse. Our data supports that retreatment should be started after HCV recurrence as soon as possible for patients with low viral load. HCV load may rise from 4 to 8 weeks after completing treatment with IFN but then decrease [19]. Retreatment in Group A was probably started at a time of decreased HCV load, thus resulting in a high SR rate. In Group B, however, retreatment was started 24 weeks or more after HCV recurrence. This resulted in a low SR rate, like those reported with other retreatment regimens. Not only IFN␣, but IFN␤ is also used for treatment of chronic hepatitis C in Japan. The IFN␤ standard regimen is daily administration for 6–8 weeks. The IFN␣ regimen is a combination of daily administration followed by intermittent administration for a total of 24 weeks. SR rates for each

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regimen are almost the same in chronic hepatitis C treatment [17]. Barbaro et al. compared IFN␤ monotherapy to a combination of IFN␣ and ribavirin for retreatment of IFN␣ nonresponders, and found that the HCV negative rate was higher with IFN␤ [21]. In another study, patients who did not convert to HCV-RNA negative during treatment with IFN␣ later did convert to HCV-RNA negative after treatment was switched to IFN␤ [22]. Thus, a switch to a different type of IFN (e.g., IFN␤) can be effective in patients with no response to IFN␣. IFN␤ demonstrates a potent antiviral effect against HCV. A short 6-week course of IFN␤ shows an HCV-RNA negative turning ratio of about 90%, but the rate of recurrence is high [20]. Therefore, a longer course of therapy has been tried in genotype 1b patients resistant to IFN [23,24]. Watanabe et al. reported that IFN␤ and IFN␣ sequential therapy has better results than IFN␣ monotherapy [25]. However, IFN␤ costs more than IFN␣ in Japan, and longterm treatment can become a considerable financial burden on patients [24]. Our results show that higher efficacy can be achieved over a short period (6 weeks) and with a small total dose (252 MIU) for patients with low viral load if retreatment is started sooner after relapse. In addition, the shorter duration of therapy increases patient quality of life and helps to reduce the financial burden from the perspective of insurance coverage. A combination of IFN and ribavirin has been used for retreatment of patients with genotype 1b HCV. However, the use of ribavirin in many patients is limited because of contraindications and adverse effects. In our study on IFN␣ and IFN␤, no clinically significant decreases in hemoglobin concentrations, white blood cell counts or platelet counts were observed, and no serious adverse reactions requiring discontinuation of treatment were noted. In this randomized controlled study, combination use of two types of IFN provided effective treatment for patients with low viral load HCV genotype 1b, if we start sooner after the relapse of HCV. Retreatment in our study was relatively short term, using a small total dose, and was highly tolerable. This retreatment regimen shows promise for effective treatment and improving quality of life in patients with low viral load HCV genotype 1b. 5. Conclusion In this study, we show that retreatment with IFN-␤ is effective in low viral load genotype 1b patients, if we start sooner after the relapse of HCV. References [1] Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671–5.

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