Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

GASTROENTEROLOGY 2008;135:451– 458

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response PETER FERENCI,* HERMANN LAFERL,‡ THOMAS–MATTHIAS SCHERZER,* MICHAEL GSCHWANTLER,§ ANDREAS MAIERON,储 HARALD BRUNNER,¶ RUDOLF STAUBER,# MARTIN BISCHOF,** BERNHARD BAUER,‡‡ CHRISTIAN DATZ,§§ KARIN LÖSCHENBERGER,储 储 ELISABETH FORMANN,§ KATHARINA STAUFER,* and PETRA STEINDL–MUNDA* for the Austrian Hepatitis Study Group

See CME exam on page 700.

Background & Aims: This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 ␮g/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. Methods: NonRVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). Results: A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level <400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted SVR. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9 – 86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%–96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/ 113; 95% CI, 70.1%– 85.9%; intent to treat: 89/120; 74.2%; 65.4 – 81.7%). Treatment was well tolerated. Conclusions: This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

T

he combination of pegylated interferon (peginterferon) plus ribavirin is the treatment of choice for patients with chronic hepatitis C and is likely to remain the backbone of treatment for this condition in the foreseeable future.1,2 The probability of eradicating hepatitis C virus (HCV) varies by HCV genotype, with genotype 1 the most difficult to cure among known genotypes. Sustained virological response rates were significantly higher in patients treated for 48 weeks as compared with 24 weeks and in those treated with a higher dosage of ribavirin (ie, 1000/ 1200 mg/day rather than 800 mg/day) in a large randomized international study.3 On this basis, more intensive therapy with a higher dosage of ribavirin and a longer duration of treatment is generally recommended as initial therapy for treatment of HCV genotype 1.1 Eradication rates of approximately 50% are achievable with the recommended regimen in patients with HCV genotype 1.3– 6 It has recently been recognized that some patients with genotype 1 infection are “easier to cure” than others and that the key to identifying these individuals is a rapid virological response (RVR), defined as undetectable HCV RNA after 4 weeks of treatment with the combination of peginterferon plus ribavirin.7 A retrospective analysis of data from the trial by Hadziyannis et al3 showed that among patients with an RVR at week 4, the rate of sustained virological response was 89%–90% after 24 or 48 weeks of treatment.7 The prospect of shorter treatAbbreviations used in this paper: CI, confidence interval; EVR, early virological response; OR, odds ratio; PCR, polymerase chain reaction; peginterferon, pegylated interferon; RVR, rapid virological response. © 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2008.04.015

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*Department of Internal Medicine III, Medical University, Vienna; ‡Department of Internal Medicine, Kaiser-Franz-Josef-Spital, Vienna; §Department of Internal Medicine IV, Wilhelminenspital, Vienna; 储Department of Internal Medicine, Elisabethinen Hospital, Linz; ¶Department of Internal Medicine I, Hospital Hietzing, Wien; #Department of Internal Medicine, Medical University, Graz; **Department of Internal Medicine IV, Rudolfshospital, Vienna; ‡‡LKH Hörgas-Enzenbach, Gratwein; §§Krankenhaus, Oberndorf; and 储 储Roche Austria, Vienna, Austria

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ment for HCV genotype 1 is appealing because the overall tolerability is likely to be better and the costs lower with an abbreviated treatment regimen. With the exception of Egypt, infection with HCV genotype 4 infection is much less common than infection with HCV genotype 1. Available data suggest that infection with these 2 entities is broadly similar. Thus, treatment recommendations are identical for patients infected with either of these 2 genotypes.1,2 Consistent with the hypothesis of Jensen et al,7 a recent Egyptian trial has confirmed that patients with HCV genotype 4 and an RVR have higher rates of sustained virological response than those without an RVR.8 This study was initiated to investigate the impact of rapidity of viral response on the duration of peginterferon/ribavirin combination therapy. We incorporated an abbreviated treatment strategy for HCV genotypes 1 and 4 based on RVR status into this large, prospective, randomized comprehensive study that has as its overall objective the optimization of combination therapy in patients infected with HCV genotype 1 or 4. Patients without an RVR but with early virological response (EVR) were randomized to receive either 48 or 72 weeks of therapy. This study is still ongoing. The results of this analysis are important because of the potential benefit of abbreviated regimens for patients with HCV genotype 1 and 4 infection. Abbreviated regimens are more convenient for patients and less expensive. Moreover, the incidence of adverse events is lower with shorter durations of therapy.3,8 The objective of this paper is to report the final results in patients infected with HCV genotype 1 or 4 who were assigned to an abbreviated 24-week regimen after achieving an RVR at week 4.

Patients and Methods Patients Treatment-naive adults aged 18 – 65 years with chronic HCV genotype 1 or 4 infection were eligible for enrollment in the trial. Patients were required to have serologic evidence of HCV infection documented by a positive anti-HCV antibody test, quantifiable HCV RNA in serum by polymerase chain reaction (PCR) assay (COBAS Amplicor HCV Monitor Test, version 2.0; Roche Diagnostics, Branchburg, NJ; limit of quantitation, 600 IU/mL), and elevated alanine aminotransferase levels at baseline, as well as histologic findings consistent with the diagnosis of chronic hepatitis C as evidenced by liver biopsy results obtained within the previous 6 months. Patients with a histologic diagnosis of cirrhosis or transition to cirrhosis (METAVIR stage 3 or 4) were eligible provided that they had compensated liver disease (Child–Pugh class A). Patients were required to have a neutrophil count ⬎3.0 ⫻ 109/L, a platelet count ⬎100 ⫻ 109/L, a hemoglobin level ⬎120 g/L in women and ⬎130

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g/L in men, a serum creatinine level ⱕ1.5 times the upper limit of normal, and a thyroid-stimulating hormone level within normal limits. Patients were excluded if they had a history or evidence of a medical condition associated with chronic liver disease other than HCV, evidence of infection with human immunodeficiency virus or hepatitis B virus, and received previous drug therapy for chronic hepatitis C at any time or systemic immunomodulatory or antineoplastic therapy within the previous 6 months. Patients with diabetes mellitus receiving insulin, severe psychiatric disorders, especially depression, a history of immunologically mediated disease, or any other severe chronic or uncontrolled disease were excluded. Pregnant or breast-feeding women and men with pregnant partners were also excluded. All fertile patients enrolled in the trial were required to use 2 forms of effective contraception during treatment and for 6 months after the end of treatment.

Study Design All patients received subcutaneous peginterferon alfa-2a (Pegasys; Roche, Basel, Switzerland) 180 ␮g/wk in combination with oral ribavirin (Copegus 200 mg tablets; Roche) 1000 or 1200 mg/day during the trial. The duration of treatment was determined on the basis of a qualitative HCV RNA test after 4 weeks of treatment and/or a quantitative HCV RNA test after 12 weeks of treatment. Patients with an RVR, defined as undetectable HCV RNA (⬍50 IU/mL) after 4 weeks of treatment, were assigned to complete a total of 24 weeks of combination therapy. Those without an RVR continued treatment until week 12, at which time HCV RNA levels were reassessed. Those with an EVR, defined as undetectable HCV RNA (⬍50 IU/mL by qualitative PCR assay; COBAS Amplicor HCV Test, version 2.0, Roche Diagnostics) or ⱖ2log10 decrease (by the quantitative PCR assay) in HCV RNA level as compared with baseline, were randomly assigned to complete either 48 or 72 weeks of combination therapy. Patients without an EVR (ie, those with detectable HCV RNA and ⬍2-log10 decrease in HCV RNA level as compared with baseline) were assigned to complete 72 weeks of combination therapy. Thus, there were 4 treatment groups. Dose modifications of peginterferon alfa-2a and ribavirin for adverse events and laboratory abnormalities were performed in a stepwise manner as defined in the study protocol. The weekly dose of peginterferon alfa-2a could be decreased in a sequential manner in 45-␮g decrements from 180 ␮g to 135 ␮g, 90 ␮g, and 45 ␮g. The daily dosage of ribavirin was to be decreased by 200 mg/day in any patient experiencing a decrease in hemoglobin level to ⬍100 g/L or in the event of a ⬎20g/L decrease in hemoglobin level during any 4-week interval during treatment in patients with clinically significant cardiovascular disease. The use of erythropoietin was left to the discretion of the investigator.

Ribavirin was withheld from any patient if the hemoglobin level decreased to ⬍85 g/L, or in the event of a decrease in hemoglobin level to ⬍120 g/L despite 4 weeks of treatment at 600 mg/day, in patients with clinically significant cardiovascular disease. Therapy with erythropoietin (NeoRecormon; Roche) was permitted if the hemoglobin level decreased to ⬍105 g/L. If ribavirin was withheld a patient could continue to receive peginterferon alfa-2a, but monotherapy with ribavirin was not permitted. When the precipitating event had resolved, the dosage of either study drug could subsequently be adjusted upward (or reinstituted) at the discretion of the investigator. Patients returned unused prefilled syringes and unused tablets at each clinic visit. Patient adherence was assessed by pill counts and by maintaining records of drugs dispensed and returned.

Assessment and End Points Among patients assigned to complete 24 weeks of combination therapy, the serum HCV RNA level was determined at baseline; at weeks 4, 12, and 24 during treatment; and after 12 weeks (week 36) and 24 weeks (week 48) of follow-up by the qualitative PCR assay (COBAS Amplicor HCV Test, version 2.0; limit of detection, 50 IU/mL). Samples with detectable HCV RNA were retested with the quantitative PCR assay (COBAS Amplicor HCV Monitor, version 2.0; limit of quantitation, 600 IU/mL). The primary efficacy end point in the trial was sustained virological response, defined as undetectable HCV RNA in serum by qualitative PCR at the end of 24 weeks of untreated follow-up (ie, study week 48 in patients assigned to complete 24 weeks of combination therapy).

PEGINTERFERON ALFA-2A/RBV IN PATIENTS WITH RVR

5% with a statistical power of 80%. In the original sample size calculation, it was assumed that 15% of patients would have undetectable HCV RNA at week 4 and that 80% of patients would have undetectable HCV RNA or a ⱖ2-log10 decrease in HCV RNA level by week 12. On this basis, the original plan specified a planned enrollment of 440 patients to ensure randomization of an adequate number of patients at week 12. In a planned interim analysis after enrolling 100 patients in group D (patients with an RVR), the proportion of patients with an RVR exceeded the number anticipated in the sample size calculation. For this reason, the plan was revised. The revised plan envisaged a rapid virological response rate of 30%; thus, the planned enrollment was revised upward to a total of 558 to ensure that sufficient patients will be randomized at week 12. No more than 20% of the patients enrolled in the trial were allowed to have cirrhosis. All patients who received at least one dose of study drug were included in the efficacy analyses. The safety sample comprised patients who received at least one dose of either study medication and had at least one safety assessment postbaseline.

Study Conduct The study was conducted at 13 centers in Austria. Institutional review boards of participating centers ap-

Safety Assessments Safety was assessed at scheduled clinic visits by physical examinations, laboratory tests, and reports of clinical adverse events.

Statistical Analysis As noted previously, the primary measure of efficacy in patients treated for 24 weeks was sustained virological response in patients who completed 24 weeks of treatment. Patients without an end of follow-up HCV RNA test result were considered not to have achieved a sustained virological response. The primary efficacy end point in the overall study was the difference in the virological relapse rates among patients randomized to 48 or 72 weeks of treatment. The sample size calculation was based on this end point. The relapse rate is defined as the difference between the end-of-treatment virological response rate and the sustained virological response rate. Assuming relapse rates of 30% in patients randomized to 48 weeks of treatment and 15% in patients randomized to 72 weeks, a total of 242 patients would have to be randomized to show a 2-sided significant difference of

453

Figure 1. Flow of patients through the trial.

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Table 1. Baseline Characteristics of Patients Enrolled in the Trial According to Treatment Group Assignment Patients with an RVR Patients with an EVR (group D) (groups A and B) Total patients, n (%) Male, n (%) Age (y), mean ⫾ SD Weight (kg), mean ⫾ SD Alanine aminotransferase level (IU), mean ⫾ SD Fibrosis grade 0–2, n (%) Fibrosis grade 3–4, n (%) Genotype 1, n (%) Genotype 4, n (%) HCV RNA level (IU/mL) ⫻ 106, median (range) HCV RNA level ⬍400,000 IU, n (%) HCV RNA level 400,000–800,000 IU, n (%) HCV RNA level ⬎800,000 IU, n (%)

150 (29) 96 (64) 40.5 ⫾ 11.5 75.1 ⫾ 15.6 127.1 ⫾ 120 126 (84) 24 (16) 120 (80.0) 30 (20.0) 0.38 (0.04–17.6) 74 (49.4) 47 (31.3) 29 (19.3)

289 (56) 190 (66) 44.6 ⫾ 10.4 77.7 ⫾ 13.3 91 ⫾ 63 231 (79.9) 58 (20.1) 261 (90.3) 28 (9.7) 0.69 (0.01–7.23) 75 (26.1) 97 (33.7) 116 (40.2)

NR (group C)

RVR (D) vs EVR RVR (D) vs (A ⫹ B)a NR (C)a

77 (15) 55 (71) 46.6 ⫾ 9.1 76.7 ⫾ 11.9 92 ⫾ 56 52 (65.3) 25 (33.7) 69 (89.6) 8 (10.5) 0.7 (0.01–24.6) 14 (18.8) 34 (44.1) 29 (37.6)

.001 .003 ⬎.1

.003 .03 .007

.003 ⬍.001 ⬍.001

⬎.1 ⬍.001 ⬍.001

RVR, rapid virological response defined as HCV RNA level ⬍50 IU/mL at week 4; EVR, early virological response defined as detectable serum HCV RNA at week 4 (⬎50 IU/mL) and either undetectable HCV RNA (⬍50 IU/mL) or ⱖ2-log10 decrease in serum HCV RNA level at week 12; NR, nonresponse defined as detectable serum HCV RNA level at week 4 (⬎50 IU/mL) and ⬍2-log10 decrease in serum HCV RNA level at week 12. aUnivariate analysis, Wilcoxon 2-sample test. CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

proved the protocol, and all patients provided written informed consent. The study was conducted according to the guidelines of the Declaration of Helsinki. The study was sponsored by Roche (Vienna, Austria).

Results The first patient was enrolled in March 2003, recruitment ended in July 2006, and the last patient is due to complete follow-up in August 2008. Of the 552 recruited patients, 516 patients were eventually assigned to one of the treatment arms. Thirty-six individuals dropped out before week 4. Of the 516 patients, a total of 150 (29%) had undetectable HCV RNA (⬍50 IU/mL) after 4 weeks of treatment and were assigned to complete a total of 24 weeks of combination therapy (Figure 1). Seven of these individuals withdrew before completing 24 weeks of treatment (4 because of depression and one each for intercurrent bronchitis, recurrent fever, and noncompliance). Patients with an RVR differed significantly from those without an RVR (Table 1). A stepwise logistic regression analysis that compared the baseline characteristics of patients with an RVR (group D) with those of patients with an EVR (groups A and B) revealed significant differences in body weight (odds ratio [OR], 0.963; 95% confi-

dence interval [CI], 0.945– 0.980), genotype distribution (OR, 0.295; 95% CI, 0.157– 0.555), the proportion of patients with a low baseline serum HCV RNA level (OR, 0.260; 95% CI, 0.164 – 0.414), and baseline alanine aminotransferase level (OR, 1.007; 95% CI, 1.004 –1.010). A higher proportion of patients infected with HCV genotype 4 (30 of 66; 45.4%) had an RVR than those infected with HCV genotype 1 (120/450; 26.7%). The baseline characteristics of patients with an RVR are presented according to genotype in Table 2.

Efficacy: Virological Response A total of 143 of 150 patients (95%) with an RVR completed 24 weeks of treatment and 7 individuals (5%) stopped treatment between weeks 12 and 24. The overall rate of sustained virological response was 76.7% (115/ 150; 95% CI, 69.1– 83.2) when all patients with an RVR are considered in the analysis and 80.4% (115/143; 95% CI, 72.9 – 86.6) when the 7 patients who withdrew prematurely are excluded (Table 3). Of the 28 patients with an RVR who completed treatment but did not have an SVR, 15 experienced a relapse between the end of treatment and end of follow-up and 13 were lost to follow-up. One of the patients who experienced a relapse resumed using intravenous drugs while

Table 2. Baseline Characteristics of Patients With an RVR at Week 4 Characteristic

Patients with genotype 1

Patients with genotype 4

All patients

Total patients, n (%) Male, n (%) Age (y), mean ⫾ SD Weight (kg), mean ⫾ SD Alanine aminotransferase level (IU), mean ⫾ SD Patients with bridging fibrosis/cirrhosis, n (%) HCV RNA level (IU/mL) ⫻ 106, median (range) HCV RNA level ⬎400,000 IU/mL, n (%)

120 (81) 73 (60.3) 40.7 ⫾ 12.2 74.6 ⫾ 15.8 119.2 ⫾ 105.8 21 (17.3) 0.324 (0.04–14.4) 66 (54.5)

30 (19) 23 (79.3) 40.4 ⫾ 8.7 77.0 ⫾ 14.9 125.4 ⫾ 96.0 3 (10.3) 0.572 (0.06–17.6) 9 (31.0)

150 (100) 96 (64) 40.5 ⫾ 11.5 75.1 ⫾ 15.6 120 ⫾ 103.6 24 (16) 0.38 (0.04–17.6) 75 (50)

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Table 3. Rate of Sustained Virological Response in 143 Patients With an RVR Who Completed 24 Weeks of Therapy Genotype 1, n/N (%; 95% CI)

Genotype 4, n/N (%; 95% CI)

All patients, n/N (%; 95% CI)

89/113 (78.8; 70.1–85.9) 52/64 (81.3; 69.5–89.9) 25/31 (80.6; 62.5–92.5) 12/18 (66.7; 41.0–86.6) 74/93 (79.6; 70.0–87.2) 15/20 (75; 50.9–91.3)

26/30 (86.7; 69.3–96.2) 9/10 (90) 12/14 (85.7; 57.2–98.2) 5/6 (83.3; 35.9–99.6) 23/26 (88.5; 69.8–97.6) 3/4 (75)

115/143 (80.4; 72.9–86.6) 61/74 (86.5; 76.5–93.3) 37/45 (82.2; 67.9–92.0) 17/24 (70.8; 48.9–87.4) 97/119 (81.5; 74.3–88.0) 18/24 (75.0; 53.3–90.2)

on follow-up and was apparently de novo infected (with genotype 3a). The intention-to-treat rate of sustained virological response was somewhat higher in patients infected with HCV genotype 4 (26/30 [86.7%]; 95% CI, 69.3%–96.2%) than in those infected with HCV genotype 1 (89/120 [74.2%]; 95% CI, 65.4 – 81.7%; not significant). The rate of sustained virological response was affected by baseline HCV RNA level, although this effect differed by genotype. Among patients infected with HCV genotype 1, the rate of sustained virological response was higher in patients with a baseline HCV RNA level ⱕ400,000 IU/mL (52/64 [81.3%]; 95% CI, 69.5%– 89.9%) as compared with ⬎800,000 IU/mL (12/18 [66.6%]; 95% CI, 41.0%– 86.7%; not significant). The trend was not observed among patients infected with HCV genotype 4, because all patients with a baseline HCV RNA level of ⱕ400,000 or ⬎800,000 IU/mL achieved a sustained virological response. The presence of advanced fibrosis (METAVIR stage 3 or 4) at baseline did not affect either the rate of relapse or sustained virological response in patients infected with HCV genotype 1 or 4 (Table 3).

Safety The adverse event profile was similar to that previously reported for the combination of peginterferon alfa-2a plus ribavirin. No patients withdrew from treatment because of a severe adverse event or laboratory abnormality. There were no life-threatening adverse events or patient deaths during the study. The incidence of adverse events is presented in Table 4. Three serious adverse events were considered to be remotely, possibly, or probably related to treatment by investigators, these being depression, suicidal depression, and vomiting, each of which occurred in 1 patient. The dosage of peginterferon alfa-2a and/or ribavirin was decreased in a total of 39 patients (26%) because of adverse events or laboratory abnormalities during treatment (Table 4). The dosage of ribavirin was reduced in 22 patients, among whom 16 achieved a sustained virological response, 3 experienced a virological relapse during follow-up, 1 was lost to follow-up, and 1 withdrew because of an adverse event (drug overdose) (Table 5). Nine patients (6%) experienced grade 4 neutropenia (neutrophils ⬍0.5 ⫻ 109/L) during the study, but no patients experienced a serious infection. The mean max-

imum decrease in hemoglobin level during treatment and follow-up was 33.4 ⫾ 13 g/L; 4 patients experienced a decrease in hemoglobin level to ⬍85 g/L. No patients experienced grade 4 thrombocytopenia (platelets ⬍20 ⫻ 109/L) during treatment and follow-up.

Discussion The key finding of this analysis is the overall 80.4% rate of sustained virological response in HCV geTable 4. Incidence of AEs and Laboratory Abnormalities

Event Any AE Treatment-related AEa Serious AE Treatment-related serious AEa Premature withdrawal for AE or laboratory abnormality Dose modifications for AE or laboratory abnormality Incidence of individual AEsc Fatigue Influenza-like illness Depression Alopecia Headache Rash Anemia Cough Dry skin Leukopenia Upper abdominal pain Anorexia Pruritus Nausea Hypertriglyceridemia Laboratory abnormalities Neutrophil count ⬍0.5 ⫻ 109/L Platelet count ⬍50 ⫻ 109/L and ⱖ20 ⫻ 109/L Hemoglobin level ⬍85 g/L

Patients experiencing an event, n (%) 146 (97.3) 143 (95.3) 12b (8.0) 3 (2.0) 0 39 (26.0)

66 (44.0) 59 (39.3) 28 (18.7) 25 (16.7) 24 (16.0) 23 (15.3) 22 (14.7) 19 (12.7) 18 (12.0) 18 (12.0) 18 (12.0) 17 (11.3) 17 (11.3) 15 (10.0) 15 (10.0) 9 (6.0) 4 (2.7) 4 (2.7)

NOTE. Individual AEs reported in ⱖ10% of patients. AE, adverse event. aRemotely, possibly, or probably related to treatment in the opinion of the investigator. bThirteen serious AEs were reported in 12 patients, including abdominal pain, vomiting, pregnancy (2 patients), depression, suicidal depression, pregnancy of partner (2 patients), pericarditis, hepatotoxicity, diabetes mellitus, dyspnea, and thrombophlebitis. cIndividual adverse events reported in ⱖ10% of patients.

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Overall HCV RNA level ⱕ400,000 IU/mL HCV RNA level 400,000–800,000 IU HCV RNA level ⬎800,000 IU METAVIR F0–2 METAVIR F3–4

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Table 5. Patients With Ribavirin Dosage Modifications: Timing and Extent of Dose Reduction and Treatment Outcome

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Initial ribavirin dosage (mg/day)

Week of first ribavirin dosage reduction

Lowest ribavirin dosage (mg/day)

Dose subsequently increased?

Total dose administered (mg)

Percent of planned dose administered

Mean dosage (mg · kg⫺1 · day⫺1)

1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1200 1200 1200 1200 1200 1000 1000 1200 1000 1000 1000

17 20 14 9 8 3 8 4 13 21 8 8 11 8 4 4 8 3 15 1 9 16

600 600 600 600 800 0 600 600 0 800 600 1000 0 1000 400 600 400 400 1000 0 0 0

No No Yes Yes No No No No Yes No No No No Yes No No Yes No No Yes No No

156,800 151,200 154,000 159,600 144,200 98,000 120,400 109,200 137,200 162,400 138,600 177,800 149,800 190,400 109,200 131,600 126,000 71,400 187,600 154,000

93.3 90.0 91.7 95.0 85.8 58.3 71.7 65.0 81.7 96.7 82.5 84.4 71.1 90.4 51.9 62.5 75.0 42.5 89.1 91.7

16.67 15.00 15.28 15.83 13.62 9.11 11.03 9.85 12.01 13.81 11.79 14.11 11.89 12.73 7.07 7.46 14.71 6.85 12.98 16.08

Outcome SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR SVR Relapse Relapse Relapse Lost to follow-up Withdrew Withdrew

NOTE. All patients had an RVR (HCV RNA level ⬍50 IU/mL) at week 4. Patients weighing ⬍75 kg received ribavirin 1000 mg/day as their initial dosage; those weighing ⱖ75 kg received ribavirin 1200 mg/day as their initial dosage. The planned ribavirin dose (administered over 24 weeks) was 168,000 mg in patients weighing ⬍75 kg and 210,600 in patients weighing ⱖ75 kg. SVR, sustained virological response.

notype 1 and 4 patients who had an RVR (HCV RNA level ⬍50 IU/mL) and completed 24 weeks of therapy with the combination of peginterferon alfa-2a plus ribavirin (1000/1200 mg/day). Younger patients, leaner patients, and those with a low baseline serum HCV RNA level and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor was a significant predictor of sustained virological response. There was a trend toward a lower probability of sustained virological response in genotype 1 patients with a baseline HCV RNA level ⬎800,000 IU/mL, but this was not statistically significant. Of note, the presence of advanced fibrosis, defined as METAVIR stage 3 or 4, did not appear to modify the probability of sustained virological response in patients with an RVR. Sixteen of 19 patients (84%) for whom the outcome of treatment is known achieved a sustained virological response after having the dosage of ribavirin reduced; thus, the ribavirin dosage reduction strategy used in the study (200-mg/day decrements) did not adversely affect treatment outcomes. The overall outcomes in patients with genotype 1 and 4 were similar; however, there were some notable differences in the pattern of responses between patients infected with HCV genotype 1 and 4, although the number of patients on which this conclusion is based is small. Virological relapse after the end of follow-up occurred only in 1 patient with genotype 4 infection and in a small number of patients infected with genotype 1. In patients

with genotype 4 infection, the baseline HCV RNA level did not modify the probability of achieving a sustained virological response. Overall, the number of patients with a baseline HCV RNA level ⬎800,000 IU/mL who achieved an RVR tended to be lower than in patients with a baseline HCV RNA level ⬍800,000 IU/mL. The proportion of genotype 1 patients achieving an RVR after 4 weeks of treatment with peginterferon alfa-2a plus ribavirin has ranged from 12% to 22% in large clinical trials.7,9 –11 The 29.1% RVR rate in this study is substantially higher and encouraged us to conduct a separate analysis in these patients. The final results of the randomized prospective trial comparing the outcome of patients without RVR treated for 48 or 72 weeks will be available by the end of 2008. The results in genotype 1 patients with an RVR in this study are consistent with 2 previous reports and thus confirm that abbreviated treatment is a reasonable strategy in this subgroup.7,12 Overall sustained virological response rates of 89% were obtained in the other studies, one of which enrolled only patients with low HCV RNA levels (ⱕ600,000 IU/mL).12 Retrospective analysis of data from a large, randomized, international, phase 3 study showed that in the subgroup of patients with an RVR, sustained virological response rates were almost identical in those who received 24 weeks of treatment with peginterferon alfa-2a plus ribavirin 800 mg/day (89%) and those who received

48 weeks of treatment with peginterferon alfa-2a plus ribavirin 1000 or 1200 mg/day (91%).7 In the analysis by Jensen et al,7 the rate of relapse during follow-up was 9% among 33 patients treated for 24 weeks with peginterferon alfa-2a plus ribavirin 1000 or 1200 mg/day and 2% among 55 patients treated for 48 weeks with peginterferon alfa-2a plus ribavirin 1000 or 1200 mg/day. Because this was a retrospective analysis based on a small number of patients, the statistical significance of this difference cannot be determined. The most important limitation of our study is the absence of a control group with which to compare the rate of relapse. Our observed relapse rate of 10.7% (14 of 130 patients) in genotype 1 patients is consistent with that reported by Jensen et al.7 Abbreviated therapy has been extensively studied in patients with HCV genotype 2 or 3 infection.13 Abbreviated 12- to 16-week regimens of peginterferon plus ribavirin have been compared with 24 weeks of combination therapy in this setting. Several small studies concluded that abbreviated treatment was as effective as the standard regimen in patients with an RVR at week 4.14 –16 However, the results of 2 large studies clearly show that the rate of SVR is significantly lower in patients randomized to abbreviated regimens, including patients with an RVR, because of a higher rate of virological relapse during untreated follow-up.17,18 Collectively, the results of these studies show that patients with an RVR have a high probability of achieving a sustained virological response, regardless of treatment duration, but that the risk of relapse increases with abbreviated treatment. For this reason, abbreviated regimens can only be recommended for genotype 2 or 3 patients with favorable prognostic characteristics at baseline such as a low baseline HCV RNA level and the absence of advanced fibrosis.17 It may be prudent to consider these points when contemplating the potential benefits and risks of abbreviated therapy for a specific patient with genotype 1 infection and an RVR. Abbreviated therapy with peginterferon plus ribavirin has been evaluated in Egyptian patients infected with HCV genotype 4. Among patients randomized to different treatment durations at baseline, the rate of sustained virological response after 24 weeks of treatment (29%) was inferior to that after treatment for 36 weeks (66%) or 48 weeks (69%).19 In a subsequent study, patients randomized to a “variable duration strategy” were assigned to complete 24 weeks of treatment with peginterferon alfa-2b plus ribavirin if they had an RVR at week 4.8 The 86% rate of sustained virological response in patients with an RVR is consistent with our results, although the 22% rate of RVR in genotype 4 patients is considerably lower than that obtained in the present study (45%). Kamal et al8 reported an SVR rate of 76% after 36 weeks of treatment in genotype 4 patients who had detectable HCV RNA at week 4 and undetectable HCV RNA at week 12, and an SVR rate of 56% after 48 weeks of treatment in genotype 4 patients who had detectable HCV RNA at

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week 12. The results of the study by Kamal et al8 and the overall results of our trial will be useful in devising an overall response-guided management strategy for patients infected with HCV genotype 4. In conclusion, the results of this prospective study confirm that an abbreviated 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with low baseline HCV RNA levels who achieve an RVR by week 4 of combination therapy. In genotype 1 patients, abbreviated therapy is best suited to those with a baseline HCV RNA level ⬍800,000 IU/mL. Select individuals with a high viral load who are unable to tolerate combination therapy may nonetheless be candidates for abbreviated therapy, provided they have an RVR at week 4. References 1. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 2006;130:225–230. 2. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147– 1171. 3. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346 –355. 4. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958 –965. 5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982. 6. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971–981. 7. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43:954 – 960. 8. Kamal SM, El Kamary SS, Shardell MD, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2007;46:1732–1740. 9. Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005;43:425– 433. 10. Berg T, von WM, Nasser S, Sarrazin C, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006;130:1086 –1097. 11. Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferonalfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006;131:451– 460. 12. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97–103. 13. Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008;46:78 – 84.

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14. Dalgard O, Bjoro K, Hellum KB, et al. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004;40:1260 –1265. 15. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609 –2617. 16. von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129:522– 527. 17. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124 –134. 18. Dalgard O, Bjoro K, Ring-Larsen H, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008;47:35– 42. 19. Kamal SM, El Tawil AA, Nakano T, et al. Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response. Gut 2005;54:858 – 866.

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Received November 29, 2007. Accepted April 10, 2008. Address requests for reprints to: Peter Ferenci, Professor of Medicine, Univ Klinik für Innere Medizin III, AKH Wien, Waehringer Guertel 18 –20, A 1090 Wien/Austria. e-mail: peter.ferenci@meduniwien. ac.at; fax: (43) 1 40400 4735. Supported by an unrestricted grant by Roche Austria. Roche Austria had no role in the study design; in the collection, analysis, and inter-

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pretation of data; and in the decision to submit the report for publication. The Main Association (Hauptverband) of the Austrian Health Insurers paid for the study medication. P.F. serves on advisory boards and as a speaker and investigator for and has also received research grants from F. Hoffmann-La Roche. M.G., H.B., and P.S.-M. each serve as a speaker for F. Hoffmann-La Roche. K.L. is an employee of F. Hoffmann-La Roche. H.L., T.-M.S., A.M., R.S., M.B., B.B., C.D., E.F., and K.S. have no conflicts of interest to disclose. Members of the Austrian Hepatitis Study Group—Graz: Bernhard Bauer, Nicole Hueter, Günther J. Krejs, Csilla Putz-Bankuti, Rudolf Stauber, Barbara Sutter, and Gernot Zollner; Innsbruck: Wolfgang Jessner, Karin Nachbaur, Bernhard Nilica, and Wolfgang Vogel; Krems: Hartwig Bognar; Linz: Franz Hackl, Rainer Hubmann, Andreas Maieron, Susanne Mild, Andreas Raml, and Sabine Metz; Ried: Björn Jagdt and Fritz Renner; Oberpullendorf: Felix Stockenhuber; Salzburg: Christian Datz, Hildegard Doppelmayr, and Michael Strasser; Vienna: Susanne Bach, Martin Bischof, Harald Brunner, Barbara Bognar, Ulrike Bergholz, Daniela Ferenci-Foerster, Peter Ferenci, Elisabeth Formann, Alfred Gangl, Michael Gschwantler, Calin Gurguta, Gerold Hartmann, Brigitte Hellmich, Harald Hofer, Hermann Laferl, Karin Mittischek, Christian Müller, Parnaz Ordubadi, Ali Reza Pourbyiabani, Markus Peck-Radosavljevic, Marianne Rosenbeiger, Kurt Schütze, ThomasMatthias Scherzer, Katharina Staufer, Petra Steindl-Munda, Anika Stückler, and Christoph Wenisch; Villach: Rudolf Foditsch; Wels: Peter Knoflach and Bernhard Stadl. The authors thank Blair Jarvis (Health Interactions Ltd, London, United Kingdom), who provided editorial support on behalf of Roche.