Efficacy and safety of pegylated (40-kd) interferon α-2a compared with interferon α-2a in noncirrhotic patients with chronic hepatitis C

Efficacy and Safety of Pegylated (40-kd) Interferon ␣-2a Compared With Interferon ␣-2a in Noncirrhotic Patients With Chronic Hepatitis C K. RAJENDER REDDY,1 TERESA L. WRIGHT,2 PAUL J. POCKROS,3 MITCHELL SHIFFMAN,4 GREGORY EVERSON,5 ROBERT REINDOLLAR,6 MICHAEL W. FRIED,7 PRESTON P. PURDUM, III,8 DONALD JENSEN,9 COLEMAN SMITH,10 WILLIAM M. LEE,11 THOMAS D. BOYER,12 AMY LIN,13 SIMON PEDDER,13 AND JEAN DEPAMPHILIS13

Administration of interferon (IFN) 3 times weekly in patients with chronic hepatitis C (CHC) is associated with low sustained responses, which may be, in part, related to this regimen’s inability to maintain IFN concentrations sufficient to suppress viral replication. An enhanced IFN molecule produced by the covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN ␣-2a (PEG[40kd] IFN ␣-2a) exhibits sustained absorption, a restricted volume of distribution, and reduced clearance compared with unmodified IFN ␣-2a. One hundred fifty-nine patients with CHC participated in a randomized, ascending-dose (45 or 90, 180, 270 ␮g) study comparing PEG(40kd) IFN ␣-2a administered once weekly with 3 MIU IFN ␣-2a administered 3 times weekly for 48 weeks to determine the most appropriate PEG(40kd) IFN ␣-2a dose for subsequent clinical trials. Efficacy was assessed by measuring hepatitis C virus (HCV) RNA following a 24-week treatment-free period. Sustained virological responses for PEG(40kd) IFN ␣-2a once weekly were 10% (45 ␮g; not significant), 30% (90 ␮g; P ⴝ .009), 36% (180 ␮g; P ⴝ .0006), and 29% (270 ␮g; P ⴝ .004), compared with 3% for the 3-times-weekly 3-MIU IFN ␣-2a regimen. The types and frequencies of adverse events and laboratory abnormalities were similar among all groups. In conclusion, once-weekly PEG(40kd) IFN ␣-2a was associated with a higher number of sustained virological responses compared with IFN ␣-2a 3 times weekly in patients with CHC, but had a similar safety profile. The 180-␮g PEG(40kd) IFN ␣-2a dose appeared to be the optimal dose based on sustained

Abbreviations: IFN, interferon alfa; CHC, chronic hepatitis C; PEG(40kd) IFN ␣-2a, 40-kd pegylated interferon ␣-2a; MIU, million international units; ALT, alanine aminotransferase; HCV, hepatitis C virus; SRB, Safety Review Board; HAI, histological activity index. From the 1University of Miami School of Medicine, Miami, FL; 2VA Medical Center, San Francisco, CA; 3Scripps Clinic, La Jolla, CA; 4Medical College of Virginia, Richmond, VA; 5University of Colorado School of Medicine, Denver, CO; 6Carolinas Center for Liver Disease, Charlotte, NC; 7Emory University School of Medicine, Atlanta, GA; 8Charlotte Clinic for Gastrointestinal and Liver Disease, Charlotte, NC; 9Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL; 10Minnesota Clinical Research Center, St. Paul, MN; 11Southwestern Medical Center at Dallas, Dallas, TX; 12Emory University School of Medicine, Atlanta, GA; and 13Hoffmann-La Roche Inc., Nutley, NJ. Received May 24, 2000; accepted November 9, 2000. Dr. Fried is now with the University of North Carolina, Chapel Hill, NC. Supported by a grant from F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Address reprint requests to: K. Rajender Reddy, M.D., Center for Liver Diseases, 1500 NW 12th Ave., Suite 1101, Miami, FL 33136. E-mail: [email protected]; fax: 305243-6681. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3302-0016$35.00/0 doi:10.1053/jhep.2001.21747

virological response and its associated side-effect profile. (HEPATOLOGY 2001;33:433-438.) Interferon ␣ (IFN) is an essential component of therapy for patients with chronic hepatitis C (CHC) virus infection; however, 3 MIU IFN ␣-2b administered 3 times weekly for 48 weeks produces low sustained virological responses (13%-19%).1,2 Previously, attempts at improving responses to IFN ␣-n3 monotherapy through daily administration met with limited success, because a trend for improved response was only observed in patients with hepatitis C virus (HCV) genotype non-1 infections.3 More recently, the addition of ribavirin to the standard IFN regimen has resulted in improved sustained virologic responses (38%-43%), but at the cost of additional toxicity.1,2 IFN has a half-life of approximately 8 hours, and, consequently, a 3-times-weekly dosing schedule may be insufficient to maintain adequate serum concentrations.4 Pegylated interferon ␣-2a (PEG[40kd] IFN ␣-2a) was developed in an attempt to improve the pharmacological profile of IFN ␣-2a. Covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN ␣-2a results in more sustained absorption (time to peak plasma concentration increased ⬎7-fold), reduced clearance (10-fold), and a smaller volume of distribution (4-fold), thereby permitting once-weekly dosing.5,6 This study evaluated the safety and efficacy of 4 doses of once-weekly PEG(40kd) IFN ␣-2a administered for 48 weeks compared with 3 MIU IFN ␣-2a 3 times weekly in the treatment of patients with CHC. The primary intention of the study was to establish the most appropriate dose of PEG(40kd) IFN ␣-2a for subsequent, larger trials. MATERIALS AND METHODS Patient Selection. The target population comprised patients with CHC but without associated bridging fibrosis or cirrhosis (fibrosis score 3 and 4)7 on pretreatment liver biopsies, who had not previously been treated with IFN therapy. The definition of CHC required documentation of persistently abnormal serum alanine aminotransferase (ALT) activity (2 occasions ⱖ14 days apart), a positive antiHCV antibody (anti-HCV–EIA version 2), a pretreatment liver biopsy obtained within 12 months before study treatment consistent with chronic hepatitis (as determined by a central pathologist), and detectable pretreatment HCV RNA by a polymerase chain reaction assay (AMPLICOR HCV MONITOR™ version 1.0, Roche Diagnostics, Branchburg, NJ; lower limit of quantitation of 2,000 copies/mL) within 35 days before the first dose of study medication. Patients were excluded during screening for any of the following reasons: liver disease from causes other than CHC; white blood cell count ⬍1,500/mm3; platelet count ⬍90,000/mm3; serum creatinine

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⬎1.5 times the upper limit of normal; history of pre-existing medical conditions such as severe psychiatric illness, retinopathy, neoplasm (active or likely to recur), seizure disorder, unstable thyroid dysfunction, and cardiac or renal disease; current pregnancy or breastfeeding of infants; alcohol/drug dependence within the previous 12 months; therapy with systemic antineoplastic or immunomodulatory agents within the past 6 months, or the administration of antiviral or investigational compounds within the past 3 months. Study Design. This multicenter, open-label, randomized, ascending-dose trial was conducted in the United States between February 1997 and March 1999. An institutional review board at each center approved and administered the protocol in conformance with the principles of the Declaration of Helsinki. Informed consent was obtained from each patient participating in the study. Patients who met the entry criteria were randomized to receive either PEG(40kd) IFN ␣-2a (Pegasys威, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) or IFN ␣-2a (Roferon-A威, F. Hoffmann-La Roche, Ltd.) subcutaneously for 48 weeks in a 4:1 ratio, on an outpatient basis. The first cohort of patients received 45 or 90 ␮g PEG(40kd) IFN ␣-2a or 3 MIU IFN ␣-2a. Following review of safety data collected during the initial 8 weeks of therapy by an independent Safety Review Board (SRB) (see Appendix for members), a second cohort was enrolled and randomized to 180 ␮g PEG(40kd) IFN ␣-2a or 3 MIU IFN ␣-2a. Finally, after an assessment of initial safety data from the second cohort by the SRB, a third cohort was randomized to 270 ␮g PEG(40kd) IFN ␣-2a or 3 MIU IFN ␣-2a. Ten patients from each PEG(40kd) IFN ␣-2a dose group and 9 control patients constituted the safety population whose data were intensively reviewed by the SRB before subsequent dose escalations. This sample size allowed the SRB to identify adverse events expected to occur with an incidence of 20% or more in larger populations. Patients were evaluated at weeks 1, 2, 4, 6, and 8, and every 4 weeks thereafter. Once fully enrolled, each cohort was treated for 48 weeks and followed during a 24-week treatment-free period. Originally, the protocol specified that doses be administered as assigned or completely withheld; no dose reductions were allowed. As the study proceeded, however, the protocol was amended (May 1997) to allow investigators to reduce doses, as necessary. Assessments. Virological response was defined as undetectable plasma HCV RNA using the AMPLICOR HCV MONITOR™ version 1.0 (lower limit of quantitation of 2,000 copies/mL). All samples

without detectable HCV RNA at week 72 were retested with the newly available AMPLICOR HCV MONITOR™ version 2.0 (with the sensitivity of 100 copies/mL; Roche Diagnostics). Biochemical response was defined as normalization of serum ALT activity. All virological and biochemical assays were performed at a central laboratory (Covance, Indianapolis, IN). Viral genotype was determined through analysis of polymerase chain reaction–amplified viral 5⬘ untranslated region sequences8 at Roche Molecular Systems (Branchburg, NJ). The primary efficacy parameter was defined as the sustained virological response (i.e., the proportion of patients with ⬍100 copies/mL HCV RNA) at week 72. Secondary measures of efficacy included the sustained biochemical response at week 72, virological and biochemical responses at the end of treatment (week 48), and histological response. Histological response was defined as a (ⱖ2-point decrease in the total histological activity index (HAI) between biopsies obtained at baseline and week 72, as determined by a central pathologist reviewing slides in a coded, blinded fashion. Safety was assessed through monitoring of adverse events and laboratory abnormalities. Adverse events, graded as either mild, moderate, severe, or life-threatening and either spontaneously reported or detected during scheduled safety assessment time points, were evaluated for duration, severity, and relationship to study medication. A centralized laboratory performed all hematological and biochemical tests (Covance). The SRB and the sponsor evaluated all safety data throughout the study on a continual basis. Statistical Analysis. The final efficacy analyses included all randomized patients (intent-to-treat population), including 3 patients in the 3-MIU IFN ␣-2a group and 1 patient in the 270-␮g PEG(40kd) IFN ␣-2a group who were not treated. The safety analysis included all patients who received at least 1 dose of study medication and had at least 1 postbaseline safety assessment. Fisher’s exact test was used to compare biochemical, virological, and histological responses between each PEG(40kd) IFN ␣-2a dose group and the IFN ␣-2a control group. RESULTS Baseline Patient Characteristics. The 5 treatment groups were

fairly well balanced with respect to baseline demographic and disease characteristics (Table 1). Mean ALT activities were similar between the PEG(40kd) IFN ␣-2a and IFN ␣-2a

TABLE 1. Baseline Demographics and Disease Characteristics IFN ␣-2a

PEG(40 kd) IFN ␣-2a

Characteristic

3 MIU (n ⴝ 33)

45 ␮g (n ⴝ 20)

90 ␮g (n ⴝ 20)

180 ␮g (n ⴝ 45)

270 ␮g (n ⴝ 41)

Age (yr ⫾ SD) Sex (% male) Weight (kg ⫾ SD) Body surface area (m2 ⫾ SD) Race, n (%) White Black Oriental Other Mean ALT (U/L ⫾ SD)* Mean HCV RNA (106 copies/mL ⫾ SD) Noncirrhosis, n (%)† Bridging fibrosis,† n (%) Mean HAI score† HCV genotype, n (%) 1 Non-1 Missing

41.8 ⫾ 5.9 79 86.8 ⫾ 15.5 2.0 ⫾ 0.2

41.9 ⫾ 4.8 65 82.8 ⫾ 20.5 2.0 ⫾ 0.3

43.1 ⫾ 6.7 70 87.6 ⫾ 18.1 2.0 ⫾ 0.3

42.0 ⫾ 6.4 82 87.5 ⫾ 16.6 2.0 ⫾ 0.2

41.6 ⫾ 5.7 85 85.9 ⫾ 20.2 2.0 ⫾ 0.3

26 (79) 4 (12) 1 (3) 2 (6) 95 ⫾ 47

18 (90) 2 (10) 0 0 111 ⫾ 102

19 (95) 0 1 (5) 0 80 ⫾ 27

40 (89) 4 (9) 0 1 (2) 98 ⫾ 50

36 (88) 4 (10) 0 1 (2) 97 ⫾ 35

3.1 ⫾ 3.1 27 (82) 6 (18) 10.8

1.7 ⫾ 1.6 17 (85) 3 (15) 11.7

1.2 ⫾ 1.5 19 (95) 1 (5) 10.6

2.3 ⫾ 2.0 41 (91) 4 (9) 10.7

2.8 ⫾ 3.2 40 (98) 1 (2) 10.0

27 (82) 5 (15) 1 (3)

15 (75) 5 (25) 0

14 (70) 6 (30) 0

35 (78) 10 (22) 0

26 (63) 12 (29) 3 (7)

* Average of the 2 ALT measurements that qualified each patient for entry into study. † Based on blinded reading of all patients with a pretreatment biopsy by central pathologist at week 72.

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TABLE 2. Biochemical and Virological Responses at Weeks 48 and 72 (Intent-to-Treat Population) IFN ␣-2a Parameter ⴚ n (%)

Week 48 end of treatment Biochemical response Virological response Week 72 end of follow-up Biochemical response Virological response

PEG(40 kd) IFN ␣-2a

3 MIU (n ⴝ 33)

45 ␮g (n ⴝ 20)

90 ␮g (n ⴝ 20)

180 ␮g (n ⴝ 45)

270 ␮g (n ⴝ 41)

5 (15) 4 (12)

4 (20) 6 (30)

4 (20) 9 (45)†

17 (38)* 27 (60)‡

11 (27) 23 (56)§

3 (9) 1 (3)

2 (10) 2 (10)

5 (25) 6 (30)¶

17 (38)㛳 16 (36)**

11 (27) 12 (29)㛳

All P values are vs. IFN ␣-2a: * P ⫽ .04, † P ⫽ .01, ‡ P ⫽ .00002, § P ⫽ .00009, 㛳 P ⫽ .004, ¶ P ⫽ .009, ** P ⫽ .0006.

groups. Most patients were infected with HCV genotype 1, with the control group demonstrating the highest proportion. The control group also had a somewhat higher mean HCVRNA concentration than any of the PEG(40kd) IFN ␣-2a groups. Although patients with bridging fibrosis were to be excluded from the study, a total of 15 patients (9%) with this degree of baseline liver disease were inadvertently enrolled. The percentage of patients demonstrating pretreatment bridging fibrosis was slightly higher in the IFN ␣-2a group than in the 4 PEG(40kd) IFN ␣-2a groups. No patient with cirrhosis on pretreatment liver biopsy was enrolled. Efficacy. Of the 159 randomized patients, 122 completed the 48 weeks of treatment. A majority of the 180- and 270-␮g PEG(40kd) IFN ␣-2a dose group patients achieved virological responses at week 48. Biochemical responses in these groups were 38% and 27%, respectively, at end of treatment. Sustained virological responses were significantly higher in the 90-, 180-, and 270-␮g PEG(40kd) IFN ␣-2a dose groups as compared with the IFN ␣-2a group and the 45-␮g PEG(40kd) IFN ␣-2a dose group (Table 2). Sustained virological responses increased in a dose-dependent manner between 45 and 180 ␮g PEG(40kd) IFN ␣-2a, with no further increase in response at the 270-␮g dose. Patients with HCV genotype non-1 exhibited higher proportions of sustained virological responses than patients with HCV genotype 1 (Table 3). Sustained biochemical responses increased in a dose-dependent fashion for the 45-, 90-, and 180-␮g PEG(40kd) IFN ␣-2a groups. As with sustained virological response, no further increase in sustained biochemical response was observed with 270 ␮g PEG(40kd) IFN ␣-2a. The 180-␮g PEG(40kd) IFN ␣-2a group achieved a significantly greater sustained biochemical response compared with the IFN ␣-2a group (38% vs. 9%; P ⫽ .004). The percentage of patients with virological responses at the end of treatment with PEG(40kd) IFN ␣-2a was higher than those with biochemical responses (Table 2). In these patients, however, median ALT levels were consistently lower than baseline median ALT levels or remained within the normal range or slightly above the normal range during treatment. Most patients (n ⫽ 94 of 159) who achieved a virological response did so within the first 16 weeks of treatment, partic-

ularly those in the 180- and 270-␮g PEG(40kd) IFN ␣-2a groups (78% and 73%, respectively). Furthermore, more patients in the 2 higher-dose PEG(40kDa) IFN ␣-2a groups who ultimately had a virological response did so by week 4 compared with the lower-dose groups (65% vs. 40%, respectively). Separate analysis of sustained virological response excluding patients with bridging fibrosis was performed; the overall response relationships remained unchanged (data not shown). The proportions of patients achieving histological responses were similar in all groups (Table 4). The mean and median improvements from baseline were greatest in the PEG(40kd) IFN ␣-2a 180-␮g group. Of the patients with paired biopsies who achieved sustained virological responses, all but 2 (both in the PEG[40kd] IFN ␣-2a 270-␮g group) also achieved histological responses, regardless of whether their serum ALT had normalized during treatment. Among the 88 patients with paired biopsies who did not have a sustained virological response, between 42% and 60% in the PEG(40kd) IFN ␣-2a dose groups and 55% in the IFN ␣-2a group achieved a histological response. Safety. Patients in both the PEG(40kd) IFN ␣-2a and the IFN ␣-2a groups experienced similar incidences of adverse events commonly associated with IFN ␣-2a treatment (Table 5). Exceptions were depression, pruritus, and irritability, which were reported in a higher percentage of patients in PEG(40kd) IFN ␣-2a groups compared with IFN; conversely, the incidences of dizziness and myalgia were higher in the IFN ␣-2a group as compared with the PEG(40kd) IFN ␣-2a– treated groups. No apparent dose-dependent effect was observed for any adverse event in the PEG(40kd) IFN ␣-2a dose groups except rigors. Most adverse events were mild to moderate in intensity. The percentage of adverse events reported as severe was similar in the IFN ␣-2a (10%) and all PEG(40kd) IFN ␣-2a groups (7%, 2%, 10%, and 7%). Median values for hematological parameters were all within the normal range at baseline, and most decreased within the first 2 weeks of therapy across all regimens. Although PEG(40kd) IFN ␣-2a treatment was associated with mild, dose-dependent decreases in hemoglobin (⬍12 g/dL), median hemoglobin concentrations remained within the normal

TABLE 3. Sustained Virological Responses by HCV Genotype IFN ␣-2a

PEG(40 kd) IFN ␣-2a

HCV Genotype

3 MIU

45 ␮g

90 ␮g

180 ␮g

270 ␮g

Non-1 1

0/4 (0) 1/25 (4)

1/5 (20) 1/15 (7)

4/6 (67) 2/14 (14)

5/10 (50) 11/35 (31)

8/12 (67) 3/26 (12)

NOTE. Values represent the number of patients with sustained virological response/total (%) in each cohort.

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Findings and Treatment

Patients with paired biopsies/patients randomized Baseline mean total HAI score ⫾ SEM Change from baseline mean total HAI score ⫾ SEM Baseline median total HAI score Change from baseline median total HAI score No. (%) histological responders

PEG(40 kd) IFN ␣-2a

3 MIU

45 ␮g

90 ␮g

180 ␮g

270 ␮g

23/33 10.7 ⫾ 0.4 ⫺2.0 ⫾ 0.6 11.0 ⫺2.0 13 (57)

15/20 11.6 ⫾ 0.8 ⫺0.9 ⫾ 0.8 12.0 ⫺1.0 7 (47)

17/20 10.5 ⫾ 0.6 ⫺2.6 ⫾ 1.0 11.0 ⫺2.0 10 (59)

30/45 10.9 ⫾ 0.4 ⫺2.8 ⫾ 0.6 11.0 ⫺3.0 19 (63)

29/41 9.0 ⫾ 0.7 ⫺2.5 ⫾ 0.7 10.0 ⫺2.0 19 (66)

NOTE. HAI score represents all patients with both a baseline biopsy and end of follow-up biopsies (paired). Histological response is defined as a ⱖ2-point improvement in the HAI score.

range throughout the treatment period, and no patients discontinued treatment because of anemia. Median platelet counts decreased in a dose-dependent manner, with the decreases being slightly larger and occurring earlier with higher PEG(40kd) IFN ␣-2a doses. Median platelet counts reached a plateau by weeks 8 to 12 of treatment and returned to normal by week 52 in all groups. In addition, a dose-dependent decrease in median neutrophil counts was observed; however, these counts remained within the normal range in all but the 270-␮g PEG(40kd) IFN ␣-2a group. The percentage of patients who had dose modifications (withheld or reduced) for adverse events or laboratory abnormalities was similar across all groups, with the exception of the 270-␮g PEG(40kd) IFN ␣-2a dose group, in which 5 patients (12%) received dose reductions of 25% to 50% and 15 (37%) received dose reductions of 50% or more at some time during treatment. Seventeen of these patients (42%) received a dose ⱕ 180 ␮g at some time during treatment. More patients in the PEG(40kd) IFN ␣-2a groups than the IFN ␣-2a group (9%) were prematurely withdrawn from the trial because of

adverse events or laboratory abnormalities (10%, 0%, 22%, and 20%). DISCUSSION

The primary objectives of this study were to compare the efficacy and safety of 4 doses of PEG(40kd) IFN ␣-2a to a standard regimen of unmodified IFN ␣-2a, and to establish the most appropriate dose of PEG(40kd) IFN ␣-2a for larger clinical trials. Although in this study, HCV genotype and HCV viral load differences existed between the IFN ␣-2a and PEG(40kd) IFN ␣-2a groups, they were small and unlikely to account for the large differences in response between the groups; however, they may have contributed to the lowerthan-expected response observed with IFN ␣-2a treatment. Patients with HCV genotype non-1 had better responses compared with patients with HCV genotype 1, across all treatment arms, as has been observed in other trials of IFN-based therapy.1,2,6,9-11 This study demonstrated that PEG(40kd) IFN ␣-2a is superior to IFN ␣-2a in the treatment of patients with CHC. The

TABLE 5. Incidence of Adverse Events IFN ␣-2a

PEG(40 kd) IFN ␣-2a

Adverse Event No. (%)

3 MIU (n ⴝ 30)

45 ␮g (n ⴝ 20)

90 ␮g (n ⴝ 20)

180 ␮g (n ⴝ 45)

270 ␮g (n ⴝ 40)

General Events Fatigue Headache Myalgia Rigors Nausea Depression Diarrhea Irritability Injection-site inflammation Insomnia Arthralgia Pyrexia Alopecia Upper abdominal pain Dizziness Impaired concentration Dermatitis Pain Decreased appetite Back pain Pain in limb Vomiting Pruritus

21 (70) 18 (60) 19 (63) 14 (47) 14 (47) 3 (10) 6 (20) 4 (13) 6 (20) 7 (23) 7 (23) 9 (30) 6 (20) 5 (17) 7 (23) 2 (7) 2 (7) 4 (13) 2 (7) 5 (17) 4 (13) 5 (17) 1 (3)

14 (70) 8 (40) 8 (40) 1 (5) 9 (45) 6 (30) 5 (25) 7 (35) 7 (35) 5 (25) 4 (20) 3 (15) 1 (5) 6 (30) 2 (10) 2 (10) 3 (15) 4 (20) 3 (15) — 3 (15) 4 (20) 2 (10)

17 (85) 7 (35) 13 (65) 4 (20) 3 (15) 7 (35) 5 (25) 4 (20) 6 (30) 1 (5) 8 (40) 2 (10) 6 (30) 2 (10) 4 (20) 4 (20) 0 0 4 (20) 3 (15) 5 (25) 0 3 (15)

30 (67) 26 (58) 14 (31) 21 (47) 20 (44) 12 (27) 14 (31) 13 (29) 11 (24) 15 (33) 8 (18) 11 (24) 10 (22) 8 (18) 6 (13) 3 (7) 6 (13) 9 (20) 7 (16) 7 (16) 4 (9) 7 (16) 5 (11)

28 (70) 19 (48) 19 (48) 20 (50) 12 (30) 15 (38) 13 (33) 13 (33) 10 (25) 12 (30) 12 (30) 11 (28) 10 (25) 11 (28) 7 (18) 12 (30) 11 (28) 5 (13) 5 (13) 6 (15) 3 (8) 1 (3) 5 (13)

NOTE. Events observed in at least 10% of patients are included.

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180-␮g PEG(40kd) IFN ␣-2a dose was associated with the highest sustained virological and biochemical responses (36% and 38%, respectively). These responses were statistically higher than those observed with IFN ␣-2a monotherapy (3% and 9%, respectively, for virological and biochemical responses) and are in the range of those reported for combination IFN ␣-2a ribavirin therapy.12 However, a direct comparison of the efficacy and safety of PEG(40kd) IFN ␣-2a with combination therapy must await the results of ongoing trials. The 180-␮g PEG(40kd) IFN ␣-2a dose appears to be the optimal dose in CHC. Virological and biochemical responses increased in a dose-dependent manner for PEG(40kDa) IFN ␣-2a doses up to 180 ␮g. However, the 270-␮g PEG(40kd) IFN ␣-2a dose was associated with a greater need for dose modification compared with the 180-␮g dose (53% vs. 31%), perhaps preventing further improvements in response. Conversely, although the 90-␮g PEG(40kd) IFN ␣-2a group achieved a relatively large percentage of sustained virological responses (30%), this group may not have been comparable with the 180-␮g PEG(40kd) IFN ␣-2a group, because it contained lower proportions of patients infected with HCV genotype 1 or with baseline bridging fibrosis, and as a group, demonstrated a lower median baseline HCV-RNA concentration. Although the number of patients who achieved a histological response was similar across groups, the 180-␮g PEG(40kd) IFN ␣-2a group had the greatest improvement in median HAI scores (⫺3.0). As previously reported,13 a large percentage of patients who did not achieve a virological response had a ⱖ2-point improvement in the HAI score, indicating a benefit from treatment with PEG(40kd) IFN ␣-2a or IFN, regardless of end-of-treatment or sustained virological responses. In general, the 180-␮g PEG(40kd) IFN ␣-2a group achieved earlier responses than the 45- and 90-␮g PEG(40kd) IFN ␣-2a groups. Sixty-five percent of the sustained virological responders in the 180-␮g PEG(40kd) IFN ␣-2a group had undetectable HCV RNA by week 4, which supports previous reports of early viral clearance being predictive of sustained response to IFN monotherapy.14-16 At the end of treatment, biochemical responses were somewhat lower than virological responses in the PEG(40kd) IFN ␣-2a dose groups. These responses converged, however, during treatment-free follow-up. The discordance between virological and biochemical responses at the end of treatment reflected ALT values that had decreased from baseline but had not totally normalized in a number of patients with undetectable HCV RNA. For patients maintaining their virological response through week 72, serum ALT values rapidly normalized, generally by weeks 52 or 56. Mild elevations in ALT during IFN therapy have been well described, particularly at more intensive doses.17-19 It is not clear if the mechanisms underlying these observations are also responsible in the current circumstance. However, regardless of the mechanism, failure of end-of-treatment virological responders to normalize ALT did not adversely affect chances for achieving either sustained virological response or histological response. Moreover, it is important to note that median ALT values during treatment were consistently lower than baseline values in both virological responders and nonresponders treated with PEG(40kd) IFN ␣-2a. The adverse-event profile of PEG(40kd) IFN ␣-2a was similar to that of IFN,20 with no clear dose-related patterns to the incidence or severity of adverse events. Changes in several

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hematological parameters were dose-related, but the effects were generally mild and transient, and required treatment withdrawal in only a small proportion of patients. In this small trial, the 180- and 270-␮g PEG(40kd) IFN ␣-2a groups had a somewhat higher proportion of premature withdrawals for adverse events or laboratory abnormalities than the control group. This finding might be at least partially explained by investigators exercising particular caution in this study, because this represented the first patient experience with PEG(40kd) IFN ␣-2a. Also, detailed dose-modification schemes were not put in place for the PEG(40kd) IFN ␣-2a treatment arms until several months after the start of the study. As investigators gained more clinical experience, they were more likely to reduce or withhold doses, rather than to discontinue therapy. Of note, in a subsequent, recently completed Phase II/III trial involving only patients with cirrhosis or advanced fibrosis, the safety-related premature withdrawal frequencies between PEG(40kd) IFN ␣-2a–treated patients and IFN ␣-2a controls were similar (11%-14%).21 Based on the results of this trial, a once-weekly regimen of PEG(40kDa) IFN ␣-2a offers superior efficacy and a similar safety profile to a 3-times-weekly regimen of IFN ␣-2a. However, caution should be emphasized when interpreting these data because of the relatively small number of patients evaluated. Overall, the 180-␮g dose of PEG(40kd) IFN ␣-2a is associated with the best efficacy and an acceptable safety profile. Therefore, this dose was selected as the most appropriate for larger, subsequent trials. APPENDIX Safety Review Board Members: Luis Balart, Memorial Medical Center, New Orleans, LA; Robert Carithers, University of Washington Medical Center, Seattle, WA; E. Jenny Heathcote, Toronto Hospital–Western Division, Toronto, Ontario, Canada. REFERENCES 1. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZC, et al., and the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-1492. 2. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, et al., and the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alpha 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:14261432. 3. Chemello L, Cavalletto L, Bernardinello E, Boccato S, Casarin P, Cavinato F, Urban F, et al. Comparison of thrice weekly vs daily leucocyte interferon-alpha therapy for chronic hepatitis C. J Viral Hepat 1999;6: 321-327. 4. Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet 1990;19:390-399. 5. Xu Z-X, Patel I, Joubert P. Single-dose safety/tolerability and pharmacokinetic/pharmacodynamics (PK/PD) following administration of ascending subcutaneous doses of pegylated-interferon (PEG-IFN) and interferon ␣-2a (IFN␣-2a) to healthy subjects [Abstract]. HEPATOLOGY 1998; 28(Suppl):702. 6. Reddy KR. Controlled-release, pegylation, liposomal formulations: new mechanisms in the delivery of injectable drugs. Ann Pharmacother 2000; 34:915-923. 7. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22:696-699. 8. Germer JJ, Rys PN, Thorvilson JN, Persing DH. Determination of hepatitis C virus genotype by direct sequence analysis of products generated with the Amplicor HCV test. J Clin Microbiol 1999;37:2625-2630.

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