A multicentre randomized interferon-alpha-2a in the ...downloads.hindawi.com/journals/cjgh/1997/454395.pdftreatment of patients with chronic hepatitis C ... Hitoshi Yagisawa MD, Kanji

A multicentre randomizedcontrolled trial of recombinant

interferon-alpha-2a in thetreatment of patients with

chronic hepatitis CMasafumi Komatsu MD, Tsuyoshi Ono MD, Ko Nakajima MD, Itaru Toyoshima MD, Mitsuro Chiba MD,

Osamu Masamune MD, Shunji Ohkubo MD, Tsukasa Yoshida MD, Hitoshi Yagisawa MD, Kanji Komatsu MD,Hideki Wakamatsu MD, Nobuo Yamada MD, Hiroyuki Watanabe MD, Tsuyoshi Mukojima MD, Mitsuo Goto MD

Can J Gastroenterol Vol 11 No 7 October 1997 579

M Komatsu, T Ono, K Nakajima, et al. A multicentre random-ized controlled trial of recombinant interferon-alpha-2a in thetreatment of patients with chronic hepatitis C. Can J Gastroen-terol 1997;11(7):579-582. Sixty-one chronic hepatitis C pa-tients were randomly assigned to receive either 6x106 or 9x106 Uof recombinant interferon-alpha-2a (IFN�-2a) six days a week forthe first two weeks of treatment, followed in both cases by 6x106 Uthree days a week for the next 22 weeks. In the low dose group, 11patients showed a complete response maintained for at least sixmonths, 12 responded but then relapsed and nine did not respond;the corresponding figures in the high dose group were 10, 15 andfive patients, respectively. The differences between groups are notstatistically significant. Thus, this study provides no evidence oftherapeutic benefit from increasing the initial dose of IFN�-2a.In both treatment groups, complete responders had significantlylower pretreatment viral titres than nonresponders and were sig-nificantly more likely to be infected by type 2a versus type 1b virus.

Key Words: Chronic hepatitis C, Hepatitis C virus genotype, Hepati-

tis C virus-RNA titre, IFN�-2a

Essai clinique contrôlé randomisé multicentrique sur uninterféron-alfa-2a recombinant dans le traitement despatients atteints d’hépatite C chronique

RÉSUMÉ : Soixante-et-un patients atteints d’hépatite C chronique ontété assignés au hasard afin de recevoir soit 6 x 106 ou 9 x 106 Ud’interféron-alfa-2a recombinant (IFN�-2a) six jours par semaine,pendant les deux premières semaines de traitement, suivi dans les deux casde 6 x 106 U trois jours par semaine pendant les 22 semaines suivantes.Dans le groupe recevant la dose faible, 11 patients ont présenté une réponsecomplète qui s’est maintenue pendant au moins six mois, 12 ont répondu,puis on connu une rechute et 9 n’ont aucunement répondu. Les chiffrescorrespondant pour le groupe recevant la dose forte étaient de 10, 15 et 16patients respectivement. Les différences entre les groupes n’ont pas étéjugées cliniquement significatives. Donc, cette étude ne permet pas deprouver l’avantage thérapeutique d’une augmentation de la dose initialed’IFN�-2a dans les deux groupes traités, les personnes ayant connu uneréponse complète présentaient des titres viraux préthérapeutiquessignificativement moindres que les non-répondants et étaient beaucoupplus probablement infectés par le virus de type II-a plutôt que II-b.

First Department of Internal Medicine, Akita University School of Medicine, Akita, Japan; First Department of Internal Medicine, HirakaGeneral Hospital, Yokote, Japan; Second Department of Internal Medicine, Akita City Hospital, Akita, Japan; Department of Internal Medicine,Akita Rosai Hospital, Oodate, Japan; Department of Gastroenterology, Honjyo Daiici Hospital, Honjyo, Japan; Department of Gastroenterology,Yuri Kumiai General Hospital, Honjyo, Japan; Department of Gastroenterology, Akita Adult Disease Medical Center, Akita, Japan; SecondDepartment of Internal Medicine, Ogachi Central Hospital, Yuzawa, Japan

Correspondence and reprints: Dr Masafumi Komatsu, First Department of Internal Medicine, Akita University School of Medicine, 1-1-1,Hondo, Akita City, Japan. Telephone 81-18-834-1111, fax 81-18-836-2611

Received for publication November 13, 1996. Accepted June 3, 1997

ORIGINAL ARTICLE

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G:\GASTRO\1997\11#7\komatsu.vpFri Oct 03 15:32:39 1997

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In the United States and Europe, administration of inter-feron (IFN) for treatment of hepatitis C is usually initially

intermittent (three times a week) (1-4). In Japan, however,IFN is generally administered six times a week for the firstone to four weeks; only then is a three-times-a-week regimeninitiated and continued for the remainder of the several-month treatment period. Japanese physicians also typicallyemploy higher individual doses of IFN than those used inwestern countries, so the total IFN dose is greater.

The Japanese treatment regimen has proven effective: al-though the percentage of patients with long term normaliza-tion of transaminase levels is relatively low – about 30%(5,6) – the rarity of spontaneous recovery in hepatitis C pa-tients renders this a very significant improvement in clinicaloutcome. IFN treatment is expensive, however, and is asso-ciated with various adverse reactions. In view of these eco-nomic costs and the physical burdens placed on the patient,the efficacy rates reported to date cannot be considered satis-factory. Further study is needed to determine the optimaldose and administration schedule for IFN.

In an effort to improve the effectiveness of IFN treatmentin patients with chronic hepatitis C, we carried out a con-trolled trial using two different doses of IFN�-2a. Our hy-pothesis was that increasing the daily dose of IFN in theinitial treatment period would improve the effectiveness ofIFN therapy.

PATIENTS AND METHODSStudy design: Sixty-five patients with chronic hepatitis Cfrom eight hospitals were enrolled. In all patients, hepatitis Cvirus (HCV)-RNA was detected by polymerase chain reac-tion (PCR). All patients were positive for anti-HCV anti-body and were diagnosed histologically as having chronichepatitis. All patients had no history of IFN treatment, andtests for hepatitis B surface antigen were negative in all cases.After informed consent was obtained, the patients were ran-domly assigned to two groups: group A (n=33) and group B(n=32). In group A, 6x106 U IFN�-2a was administered sixdays per week for two weeks, followed by the same dose threedays per week for 22 weeks. The total dose of IFN was468x106 U. In group B, the initial dose was 9x106 U six daysper week for two weeks, followed by the same regimen of6x106 U three days per week for 22 weeks, as per group A. Thetotal dose of IFN was 504x106 U.

Four patients dropped out of the study due to adverse re-actions or for personal reasons. In group A, one patientdropped out after developing depression and another afterexperiencing arm numbness. In group B, one patient stoppeddue to the appearance of heart failure and another was lost tofollow-up because of a job transfer. Therefore, 61 patientswere studied, 31 in group A and 30 in group B. The twogroups did not differ in age, sex, histological type, alanineaminotransferase (ALT) value immediately before IFNtreatment, HCV-RNA titre or HCV genotype (Table 1).

For evaluation of effectiveness, patients who had ALTvalues within the normal range for six months after comple-tion of IFN treatment and in whom HCV-RNA could not be

detected at the time, were defined as complete responders.Responders who relapsed were patients who had normalALT values and negative HCV-RNA findings upon comple-tion of IFN treatment, but in whom HCV-RNA later reap-peared. All other patients were considered nonresponders.Laboratory measurements: Serum was obtained asepticallyand immediately frozen at –40 to –80°C; it was then thawedjust before testing. ALT values were measured immediatelybefore the start of IFN administration, weekly for the follow-

580 Can J Gastroenterol Vol 11 No 7 October 1997

Komatsu et al

TABLE 1Patient characteristics at entry into the trial

Clinical featuresGroup A

(468x106 U)Group B

(504x106 U)

Number of patients 31 30

Age (years)* 54.7�8.6 53.9�10.5

Sex (male:female) 18:13 16:14

ALT (IU/L)* 96.8�56.8 110.8�77.8

HCV-RNA levels(log10 copies/mL)*

7.7�1.4 7.3�1.4

HCV genotype

1b 17 16

2a 6 7

2b 2 0

Unclassified 1 1

Unknown 5 6

Liver histology

HAI score* 8.2�3.3 8.9�2.8

The difference between group A and B was not statistically significant in any

item. *Values are mean � SD. ALT Alanine aminotransferase; HAI Histologicalactivity index; HCV Hepatitis C virus

Figure 1) Serial alanine aminotransferase (ALT) levels in patients withchronic hepatitis C receiving interferon therapy. *P<0.05

2



ing month, and monthly for the remainder of the study pe-riod. Anti-HCV body was measured by ELISA (C-100-3).

HCV-RNA qualitative analysis was performed on threeoccasions – immediately before, immediately after and sixmonths following completion of IFN administration – by thereverse transcription nested PCR using the 5�-noncoding re-gion as primer (7,8). The quantitative HCV-RNA titre wasmeasured by the multicyclic PCR method using the 5�-non-coding region as primer (9).

In 50 patients whose serum was preserved before admini-stration, the viral genotype was identified by PCR using thetype-specific core region primer according to the method ofOkamoto et al (10). Types 2, 3 and 4 noted by Okamoto et alcorrespond to types 1b, 2a and 2b of Simmonds et al (11).Statistical analysis: Results are presented as mean � SD, andas percentages of total patients. Statistical analysis was per-formed using the Mann Whitney U test and Student’s t test.For multivariate analysis, a stepwise regression analysis wasused. P<0.05 was considered statistically significant.

RESULTSIn both treatment groups, IFN administration produced a de-crease in ALT values that reached statistical significance af-ter one month of treatment. This trend was also observedduring treatment and six months after cessation of admini-stration. However, there was no significant difference inALT values between groups A and B at any time (Figure 1).

The ALT values of 11 patients (35.5%) in group A and 12(40.0%) in group B remained within the normal range formore than six months after completion of IFN therapy ingroup A; this difference was not statistically significant.HCV-RNA findings, which had been positive in all patientsbefore IFN administration, became negative immediately af-ter completion of IFN administration in 16 group A patients(51.6%) and 19 group B patients (63.3%). By six months af-ter cessation of treatment, however, there was no longer anydifference between groups: 10 patients in each group hadnegative findings (32.3% of group A patients and 33.3% ofthose in group B).

Thus, group A had 10 (32.3%) complete responders, 12(38.7%) responders who relapsed and nine (29.0%) nonre-sponders; group B had 10 (33.3%) complete responders, 15(50.0%) responders who relapsed and five (16.7%) nonre-sponders. There were no statistically significant differencesbetween the two groups (Table 2).

The outcome of IFN treatment was significantly corre-lated with the amount of HCV-RNA before treatment:log10 HCV-RNA titres in complete responders –6.5�1.6 copies/mL – were significantly lower than the titresof 8.0�1.1 copies/mL in responders who relapsed and8.2�0.8 copies/mL in nonresponders.

Treatment outcome was also correlated with HCV geno-type. As shown in Table 3, among the 33 patients tested forHCV genotype, type 1b was found in six of 33 complete re-sponders (18.2%), in 18 of 33 responders who relapsed(54.5%) and in nine of 33 nonresponders (27.3%). Ex-pressed another way, 18.2% of the 33 patients known to be

infected by this genotype responded completely, 54.5% re-sponded but later relapsed and 27.3% did not respond. Bycontrast, of the 13 patients known to be infected by HCVtype 2a, six (46.2%) responded completely and seven(53.8%) responded but later relapsed; there were no nonre-sponding patients in this group. As implied by the combina-tion of these results with those in the previous paragraph, thelog10 HCV-RNA titre was significantly higher in patientsinfected by type 1b virus (7.7�1.4 copies/mL) than in thosewith infected by type 2a (6.5�1.5 copies/mL).

Stepwise regression analysis of the independent factorsthat contribute to complete response, such as sex, age, levelof serum ALT, method of IFN administration, histology,amount of serum HCV-RNA and HCV genotype, revealedthat only the amount of serum HCV-RNA was significant(P=0.0015).

DISCUSSIONFactors influencing the effectiveness of IFN treatment in pa-tients with chronic hepatitis C include: HCV-RNA titre,HCV genotype, HCV genetic diversity, histological degreeof liver injury, and the dose, administration method and pe-riod of administration of IFN.

It has been reported that the efficacy of IFN treatment in-creases with the total dose (12-14). However, the incidenceof adverse reactions also increases with the dose. It is there-fore very important to consider not only the benefits of IFNbut also its risks and costs to determine the optimum IFNdose.

In Japan, the most widely used treatment regimen is six-times-a-week IFN administration for two weeks, to providerapid, potent inhibition of viral growth, followed by inter-mittent (three times weekly) administration for a total of sixmonths. Reports suggest that, for a total dose, this regimen

Can J Gastroenterol Vol 11 No 7 October 1997 581

Recombinant interferon-alpha-2a and chronic hepatitis C

TABLE 2Response to interferon in each group

Response to interferonGroup A

(468x106 U)Group B

(504x106 U)

Number 31 30

Complete responder 10 (32.3%) 10 (33.3%)

Responder who relapsed 12 (38.7%) 15 (50.0%)

Nonresponder 9 (29.0%) 5 (16.7%)

TABLE 3Relationship between hepatitis C virus (HCV) genotypeand response to interferon

HCV genotype

1b 2a + 2b

Number 33 15

Complete responder 6 (18.2%) 7 (46.7%)

Responder who relapsed 18 (54.5%) 7 (46.7%)

Nonresponder 9 (27.3%) 1 (6.6%)

Significant difference in HCV genotype 2a + 2b group compared with genotype1b (P<0.05)

3



may be more effective than either three- or six-times-a-weekadministration throughout the entire course of IFN treat-ment (14). However, there have been few controlled studiesto determine the optimum dose in the initial treatment pe-riod.

We therefore carried out a controlled study in which allpatients were dosed according to the basic Japanese treat-ment schedule, but group A received 6x106 of IFN six daysper week through the initial two-week treatment periodwhile group B received 9x106 U; both groups then received6x106 three times a week for the remaining 22 weeks. Thetotal IFN dose was thus 468x106 U in group A and 504x106

in group B, a fairly modest difference. We hypothesized,however, that the higher initial dose would have a favour-able effect on response to treatment.

Results did not support this hypothesis. No statisticallysignificant differences between the two groups were observedin ALT levels during administration, in ALT normalizationrates immediately after administration or at later times, or inrates of HCV-RNA negativity either immediately after orsix months following cessation of treatment. Although thepercentage of nonresponders was lower in group B than ingroup A, this difference was not significant. We thereforeconclude that increasing the dose of IFN to 9x106 U duringthe initial treatment period has no advantages.

Kasahara et al (15) compared the effects of administering

IFN� three times per week for a period of either 28 or52 weeks. They reported that relapses after cessation of IFNtreatment were significantly reduced in the 52-week treat-ment group, with nonresponders amounting to 30% of thetotal patient population. In the present controlled study, thepercentage of nonresponders in group A was about the sameas that reported by Kasahara et al (15); in group B, however,the percentage of nonresponders fell to just 16%, the differ-ence accounted for by responders who relapsed. The combi-nation of our results with those of Kasahara et al (15)supports the possibility that the efficacy rate can be in-creased and relapses suppressed by extending the dosage regi-men employed in group B over a longer period.

In the present study, the HCV-RNA titres in completeresponders were significantly lower than those in nonre-sponders. We also found, as others have reported (15-18),that the percentage of complete response was lower in pa-tients with HCV genotype 1b than in those with genotype2a. However, because the viral titre was higher in patientsinfected with type 1b virus than in those infected with type2a, it is not clear whether the HCV genotype is an independ-ent virus-specific factor that influences the effectiveness ofIFN therapy. In any case, it seems clear that virus character-istics have a major effect on response to treatment. Thus, fur-ther research is required to determine how viral characteris-tics may affect the choice of IFN dosage regimen.

582 Can J Gastroenterol Vol 11 No 7 October 1997

Komatsu et al

REFERENCES1. Davis G, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C

with recombinant interferon alpha. A multicenter randomized,controlled trial. N Engl J Med 1989;321:1501-6.

2. Castillo I, Bartolome J, Navas S, et al. Virological and biochemicallong-term follow-up of patients with chronic hepatitis C treated withinterferon. Hepatology 1994;19:1342-6.

3. Serfaty L, Giral P, Loria A, et al. Factors predictive of the response tointerferon in patients with chronic hepatitis C. J Hepatology1994;21:12-7.

4. Budellon G, Cimino L, Blanco CD, et al. Long-term follow-upevaluation in HCV chronic hepatitis treated with alpha-2b. Ital JGastroenterol 1994;26:16-20.

5. Terada M, Baba T, Ota M, et al. [Interferon treatment for chronichepatitis C: Assessment of 3 regimens in patients who received morethan 500 MU interferon treatment and their effect as predictivefactors for interferon treatment using multivariate analysis with thelogistic regression model.] Jpn Gastroenterol 1995;92:56-61.

6. Toyoda H, Nakano S, Kumada T, et al. [Clinical study of efficacy ofinterferon alpha for chronic hepatitis C: evaluation according toeffectiveness and background.] Acta Hepatol Jpn 1994;35:481-7.

7. Garson J, Tedder R. Detection of hepatitis C viral sequences in blooddonations by “nested” polymerase chain reaction and prediction ofinfectivity. Lancet 1990;335:1419-22.

8. Okamoto H, Kurai K, Okada S, et al. Full-length sequence of ahepatitis C virus genome having poor homology to reported isolates:comparative study of four distinct genotypes. Virology1992;188:331-41.

9. Ishiyama N, Katayama K, Ishimi N, et al. [Multicyclic RT-PCR:a new quantitative method for hepatitis C virus and its comparisonwith modified CRT-PCR.] Acta Hepatol Jpn 1992;33:506-7.

10. Okamoto H, Sugiyama Y, Okada S, et al. Typing hepatitis C virus bypolymerase chain reaction with type-specific primers: application toclinical surveys and tracing infectious source. J Gen Virol1992;73:673-9.

11. Simmonds P, McOmish F, Yap PL, et al. Sequence variability in theIFN therapy for chronic hepatitis C 5� noncoding region of hepatitis Cvirus: identification of a new virus type and restrictions of sequencediversity. J Gen Virol 1993;74:661-8.

12. Ichida F, Matsushima T, Iino S, et al. [Dose finding trial with humanlymphoblastoid interferon in patients with chronic non-A, non-Bhepatitis.] Kan Tan Sul 1992;24:153-72.

13. Hayashi N. [Antiviral effect of natural interferon � (HLBI) forhepatitis C virus cases on prospective randomized controlled study.]Kan Tan Sul 1992;24:663-73.

14. Iino S. High dose interferon treatment in chronic hepatitis C. Gut1993;34:S114-8.

15. Kasahara A, Hayashi N, Hiramatsu N, et al. Ability of prolongedinterferon treatment to suppress relapse after cessation of therapy inpatients with chronic hepatitis C: a multicenter randomizedcontrolled trial. Hepatology 1995;21:291-7.

16. Yoshioka K, Kakumu S, Wakita T, et al. Detection of hepatitis C virusby polymerase chain reaction and response to interferon alphatherapy: relationship to genotypes of hepatitis C virus. Hepatology1992;16:293-9.

17. Hino K, Sainokami S, Shimoda K, et al. Genotypes and titers ofhepatitis C virus for predicting response to interferon in patients withhepatitis C. J Med Virol 1994;42:299-305.

18. Takada N, Takase S, Enomoto N, et al. Clinical background of thepatients having different types of hepatitis C virus genomes.J Hepatology 1992;14:35-40.

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A multicentre randomized interferon-alpha-2a in the ...downloads.hindawi.com/journals/cjgh/1997/454395.pdftreatment of patients with chronic hepatitis C ... Hitoshi Yagisawa MD, Kanji