Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: A pilot study

Authors


Abstract

The aim of this study was to determine the efficacy of 14 weeks of treatment in patients infected with hepatitis C virus (HCV) genotype 2 or 3 who achieve early virological response (EVR). In a noncontrolled multicenter trial, 122 treatment-naive patients received 1.5 μg/kg pegylated interferon alfa-2b subcutaneously once weekly and 800 to 1,400 mg/d ribavirin based on body weight. Treatment was stopped at week 14 in patients with EVR, defined as undetectable HCV RNA at weeks 4 and 8. Patients without EVR were assigned to 24 weeks of treatment. The primary end point was sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after end of treatment. Among the 122 patients, 95 (78%) had EVR and received 14 weeks of treatment. The remaining 27 (22%) were treated for 24 weeks. SVR was obtained in 85 (90%) of 95 patients in the 14-week treatment group and 15 of (56%) 27 in the 24-week treatment group. Altogether, SVR was obtained in 100 of 122 patients (82%; 95% CI, 75%-89%). SVR after 14 weeks of treatment was achieved more frequently among genotype 3a patients with low viral load compared with high viral load (98% vs. 79%; P = .019). Logistic regression analysis showed that absence of bridging fibrosis/cirrhosis was the only independent predictor of SVR. In conclusion, patients with genotype 2 or 3 and EVR obtained a high SVR after 14 weeks of treatment. The results need to be confirmed in a randomized, controlled study before this treatment approach can be recommended, particularly for patients with genotype 3 and high viral load or severe fibrosis. (HEPATOLOGY 2004;40: 1260–1265.)

Treatment of chronic hepatitis C virus (HCV) infection with pegylated interferon alfa (IFN-α) in combination with ribavirin induces sustained virological response (SVR) in more than 50% of cases.1–3 However, side effects are common and sometimes serious, leading to premature termination of treatment in a significant number of patients.4 Furthermore, HCV treatment is expensive; a 24-week treatment course costs approximately $20,000.5

HCV genotype is an important predictor of treatment response; more than 80% of individuals who are infected with genotype 2 or 3 obtain a SVR.1, 2, 6 Trials with pegylated IFN-α and ribavirin have shown that 24-week treatment regimens are just as effective as 48-week regimens in these patients.1, 3, 7 The response rate to even shorter treatment duration is not known, but viral kinetic studies and published case reports suggest that at least a subgroup of HCV patients may respond to such regimens.8–11

The objective of this study was to assess the efficacy of 14 weeks of combination treatment in patients with HCV genotype 2 or 3 infection who became HCV RNA negative within 4 weeks.

Abbreviations:

HCV, hepatitis C virus; EVR, early virological response; SVR, sustained virological response; IFN-α, interferon alfa.

Patients and Methods

Patient Selection.

In a Norwegian nonrandomized pilot trial comprising 20 hospitals, 122 HCV treatment-naive patients were included between October 2001 and February 2003. Patients were eligible for inclusion if they were HCV RNA positive, had HCV genotype 2 or 3, and had raised alanine aminotransferase levels at least twice during the previous 6 months. Patients were excluded if they had injected drugs or abused alcohol within the previous 6 months, had poorly controlled psychiatric illnesses, decompensated cirrhosis, were hepatitis B surface antigen– or anti–human immunodeficiency virus–positive, or suffered from other significant concurrent medical conditions including chronic liver diseases.

The study was approved by the regional committee for ethnics in medical research, Eastern Norway, and all patients gave written, informed consent.

Study Design.

All patients were treated with 1.5 μg/kg pegylated IFN-α-2b (PegIntron, Schering Plough, Kenilworth, NJ) subcutaneously once weekly and ribavirin (Rebetol, Schering Plough) 800 to 1,400 mg/d based on body weight (<65 kg, 800 mg/d; 65-85 kg, 1,000 mg/d; 86-105 kg, 1,200 mg/d; >105 kg, 1,400 mg/d). Patients with EVR were treated for a total of 14 weeks; those without EVR received 24 weeks of treatment.

Assessments.

Early virological response (EVR) was defined as undetectable HCV RNA at weeks 4 and 8 after initiation of treatment. Treatment response was evaluated according to an intention-to-treat analysis. The primary end point was SVR defined as undetectable HCV RNA in serum 24 weeks after end of treatment. All other patients were recorded as nonresponders.

Safety was evaluated according to adverse events as reported by the patients (0 = none, 1 = slight, 2 = moderate, 3 = grave), laboratory tests (blood chemistry, hematology), and vital signs (blood pressure, pulse, and temperature).

Virology.

Qualititative HCV RNA analysis was performed with a Cobas Amplicor HCV monitor test, version 2.0 (Roche Diagnostics, Indianopolis, IN); the lower detection limit was 50 IU (135 copies) per mL. Viral load was measured using a branched DNA technique (Quanitiplex 2.0, Chiron, Emeryville, CA).12 Viral genotype was determined using a hybridization technique (Inno-Lipa HCV, Innogenetics, Ghent, Belgium).13

Genotyping and determination of viral load was performed before treatment and qualititative HCV RNA analyses were performed at weeks 2, 4, 8, 14, 18, 24, 28, and 38 after the start of treatment. Patients who received 24 weeks of treatment were also tested at week 48.

Liver Biopsy.

A liver biopsy showing changes compatible with chronic HCV infection and taken within 2 years prior to the study was obtained in the majority of the patients. In 29 patients, a liver biopsy was not available because of a bleeding disorder (n = 2) or because the patient declined to have a biopsy taken (n = 27). One single pathologist who was blinded to the identity of the patients assessed all biopsies. The biopsies were scored according to the Knodell histological activity index.14 Steatosis was scored according to the percentage of hepatocytes having lipid droplets in the cytoplasm (0 = 0%, 1 = 1%-10%, 2 = 11%-25%, 3 = >25%).

Statistical Analysis.

All patients who received at least one dose of medication were included in the efficacy analysis. The analysis was conducted using the SPSS v.11.0 software package. Following a descriptive analysis, a unvariate analysis was used for comparison between groups. When comparing proportions, Pearson's chi-square test or paired t test was used as appropriate. Finally, a multivariate logistic regression was performed with SVR as the dependent variable and genotype, viral load, sex, age, treatment per protocol, HCV RNA at week 4, steatosis, and fibrosis as independent variables. A two-tailed P value of less than .05 was considered significant.

Results

Patient Characteristics

The study included 122 patients, 95 (78%) of whom achieved an EVR and were treated for 14 weeks; the other 27 (22%) did not achieve an EVR and thus were assigned to 24 weeks of treatment. The characteristics of the two groups of patients are presented in Table 1. It appears from the table that the majority of patients were relatively young (median age, 37 years) with a mean Knodell score of 5.7. The majority (77%) had no or minimal fibrosis. Patients achieving EVR had a lower viral load compared with those who did not achieve an EVR.

Table 1. Basic Characteristics of 122 Patients Included in the Present Trial
CharacteristicsAll Patients (n = 122)EVR (n = 95)No EVR (n = 27)P Value
  • NOTE. EVR was defined as HCV RNA being undetectable at weeks 4 and 8 after initiation of treatment.

  • Abbreviations: BMI, body mass index; ND, not determined.

  • *

    Viral load was unavailable from one patient.

  • Steatosis was not assessed in 1 of the 93 biopsies.

Sex   .430
 Male79 (65%)59 (62%)19 (70%) 
 Female43 (35%)36 (38%)8 (30%) 
Median age (range)37 (20–56)37 (20–56)39 (27–52).290
Median BMI (range)25 (18–59)24 (18–47)25 (25–59).411
Median weight in kg (range)76 (49–171)76 (49–153)77 (58–171).848
Route of transmission   .820
 Intravenous drug use77 (63%)62 (65%)15 (56%) 
 Transfusion4 (3%)4 (4%)0 (0%) 
 Sexual activity4 (3%)3 (3%)1 (4%) 
 Tatooing5 (4%)4 (4%)1 (4%) 
 Unknown32 (26%)22 (23%)7 (37%) 
Genotype   .085
 399 (76%)74 (78%)25 (93%) 
 223 (24%)21 (22%)2 (7%) 
Viral load*   .014
 Low (<600,000 IU/mL)61 (50%)53 (56%)8 (30%) 
 High (>600,000 IU/mL)60 (50%)41 (44%)19 (70%) 
Mean Knodell score (range)5.7 (1–13)5.6 (1–13)5.9 (1–13).768
Fibrosis   .148
 None or minimal72 (77%)56 (80%)16 (67%) 
 Bridging fibrosis/cirrhosis21 (23%)14 (20%)7 (33%) 
 ND29   
Steatosis   .199
 None62 (67%)51 (72%)11 (52%) 
 >10%30 (33%)20 (28%)10 (48%) 
 ND30   

Virological Response

In the 14- and 24-week treatment groups, 85 (90%) of 95 patients and 15 (56%) of 27 patients, respectively, obtained a SVR. In both groups combined, 100 of 122 patients (82%; 95% CI, 75%-89%) obtained SVR (Fig. 1, Table 2).

Figure 1.

Intention to treat analysis: percentage of patients with sustained response (black bars), relapse (white bars), and nonresponse (gray bars) to 14 and 24 weeks of pegylated IFN-α-2b in patients with genotype 2 or 3 (those who had EVR received 14 weeks of treatment; the remainder received 24 weeks of treatment).

Table 2. Viral Response Rates in the 14- and 24-Week Treatment Groups According to Genotype, Viral Load and Stage of Fibrosis
 nPatients With EVR: 14 Weeks' TreatmentPatients Without EVR: 24 Weeks' Treatment
End of Treatment Response*SVREnd of Treatment Response*SVR
  • NOTE. EVR was defined as HCV RNA being undetectable at weeks 4 and 8 after initiation of treatment. None of the patients experienced a breakthrough, so end of treatment response was 100%.

  • *

    A biopsy was available from 93 patients.

  • P = .019 as compared with genotype 3 and high viral load.

  • P = .010 as compared with bridging fibrosis/cirrhosis.

Genotype 39974/7466/74 (89%)21/25 (84%)14/25 (56%)
 Viral load ≥600,000 IU/mL5133/3326/33 (79%)17/18 (94%)10/18 (56%)
 Viral load <600,000 IU/mL4740/4039/40 (98%)4/7 (57%)4/7 (57%)
Genotype 22321/2119/21 (91%)1/21/2 (50%)
 Viral load ≥600,000 IU/mL98/87/8 (88%)1/11/1
 Viral load <600,000 IU/mL1413/1312/13 (92%)0/10/1
No or minimal fibrosis*7256/5653/56 (95%)14/16 (88%)11/16 (69%)
Bridging fibrosis/cirrhosis*2114/1410/14 (71%)5/7 (71%)4/7 (57%)

Treatment per protocol (defined as receiving at least 80% of the ribavirin and pegylated IFN-α dosage at least 80% of the planned time and with an HCV RNA performed at least 6 months after end of treatment) was administered to 92 (75%) of the 122 patients. Of these 92 patients, SVR was obtained in 79 (86%), compared with 21 (70%) of 30 patients who were not treated per protocol (P = .05) (Fig. 2).

Figure 2.

Treatment per protocol analysis (80% of IFN and ribavirin dose 80% of the prescribed time and an available HCV RNA result at least 24 weeks after end of treatment): percentage of patients with sustained response (black bars), relapse (white bars), and nonresponse (gray bars) to 14 and 24 weeks of pegylated IFN-α-2b in patients with genotype 2 or 3 (those who had EVR received 14 weeks of treatment; the remainder received 24 weeks of treatment).

A total of 36 patients were HCV RNA negative at weeks 2, 4, and 8 and received 14 weeks treatment. All 36 patients had a SVR.

Virological relapse after end of treatment response was observed in 10 (10%) of 95 patients in the 14-week treatment group and in 7 (32%) of 22 patients in the 24-week treatment group. In the 14-week treatment group, all but one of the relapses occurred within 10 weeks (6 within 4 weeks and 3 between 4 and 10 weeks; 1 patient was lost to follow-up). Characteristics of the 10 patients who relapsed in the 14-week treatment group are presented in Table 3.

Table 3. Characteristics of 9 Early Virological Responders Who Received 14 Weeks of Treatment and Had a Virological Relapse (HCV RNA Positive Within 6 Months After Cessation of Therapy)
No. of PatientsGenotypeHigh Viral Load*SexBridging Fibrosis/Cirrhosis
  • NOTE. One patient was lost to follow-up after obtaining an end of treatment response to 14 weeks of treatment and is not presented in the table.

  • Abbreviations: M, male; ND, not determined; F, female.

  • *

    >600,000 IU/mL at baseline.

1162bYesMND
242bNoMYes
83aYesMNo
183aYesMNo
93aYesMYes
1143aYesMYes
213aYesMND
673aYesMND
1063aNoFYes

Among 7 relapsers in the 24-week treatment group, 3 relapsed within 4 weeks, 2 relapsed between 4 and 14 weeks, and 1 relapsed between 14 and 24 weeks. In addition, 1 patient was lost to follow-up.

Relapse after 14 weeks of treatment occurred in 4 (29%) of 14 patients diagnosed with bridging fibrosis or cirrhosis compared with 3 (5%) of 56 patients with no or minimal fibrosis (P = .010). (No biopsy was available in 25 patients in the 14-week treatment group.) Furthermore, 8 (20%) of 40 patients with a high viral load (600,000 IU/mL) at baseline and 2 (4%) of 54 patients with a low viral load relapsed after 14 weeks of treatment (P = .014). Relapse after 14 weeks of treatment was independent of genotype, because 2 (10%) of 21 patients with genotype 2 and 8 (11%) of 74 patients with genotype 3 relapsed.

Predictors of Response

SVR.

Both univariate and multivariate analyses to identify predictors of SVR were performed, including all patients with a biopsy available irrespective of treatment length (Table 4). The only independent predictor of SVR identified was absence of bridging fibrosis or cirrhosis (odds ratio [OR], 0.16; 95% CI, 0.04-0.69). However, 29 patients had no available liver biopsy and were therefore not included in the analysis.

Table 4. Univariate and Multivariate Analyses Identifying Predictors of SVR
CharacteristicUnivariable ModelAdjusted Multivariable Model
Odds Ratio (95% CI)P ValueOdds Ratio (95% CI)P Value
  • NOTE. All 122 patients are included in the univariate analyses. In the multivariate analysis, only the 93 patients with an available liver biopsy are included.

  • *, †

    Received ≥80% of both drugs ≥80% of planned time.

  • A biopsy was not available from 29 patients.

Sex (male vs. female)2.17 (0.74–6.34)0.157
Age (40 yr vs. ≥40 yr)0.37 (0.15–0.96)0.0400.26 (0.06–1.12).072
Treatment (Per protocol* vs. not per protocol)0.28 (0.11–0.74)0.0100.24 (0.06–1.01).052
HCV RNA week 4 (positive vs. negative)0.17 (0.06–0.47)0.0010.52 (0.116–2.34).397
Genotype (2 vs. 3)0.632 (0.17–2.35)0.493
Viral load (<600,000 IU/mL vs. ≥600,000 IU/mL)0.30 (0.11–0.83)0.0210.28 (0.06–1.34).113
Steatosis (<10% vs. ≥10%)1.04 (0.32–3.37)0.948
Fibrosis (no bridging vs. bridging or cirrhosis)0.19 (0.06–0.62)0.0060.16 (0.04–0.69).014

A second multivariate analysis omitting liver biopsy data and including all 122 patients was performed. Factors entered into this analysis were age, treatment according to protocol, viral load, and HCV RNA at week 4. All of these factors were found to be independent predictors of SVR: age less than 40 years (OR, 0.31; 95% CI, 0.10-0.96), receiving both drugs 80% or more of the planned time (OR, 0.29; 95% CI, 0.09-0.94), viral load less than 600,000 IU/mL (OR, 0.19; 95% CI, 0.05-0.71), and being HCV RNA negative at week 4 (OR, 0.24; 95% CI, 0.08-0.75).

EVR (Week 4).

Predictors of EVR were also identified via univariate and multivariate analysis. Factors entered into this regression analysis were the same as those in the model predicting SVR (age, sex, treatment received, viral load, genotype, fibrosis, and steatosis), except that week-4 HCV RNA was substituted with week-2 HCV RNA (positive vs. negative). Univariate analysis identified the following predictors of EVR: viral load less than 600,000 IU/mL (OR, 0.26; 95% CI, 0.09-0.71; P = .02) and absence of bridging fibrosis or cirrhosis (OR, 0.28; 95% CI, 0.10-0.81; P = .19). Only the absence of bridging fibrosis or cirrhosis was an independent predictor of EVR in the multivariate logistic regression analysis. However, 29 patients without a biopsy were excluded from this analysis.

Safety

Incidence rates for most adverse events were similar between the 14- and 24-week treatment group. The most frequent adverse events are presented in Table 5.

Table 5. Incidence of Adverse Events, Grade 2 or 3
Adverse Event14-Week Treatment Group (n = 95)24-Week Treatment Group (n = 25*)
  • *

    Two patients who were lost to follow-up after the first injection are not included.

Fatigue46 (48%)10 (40%)
Nausea19 (20%)2 (8%)
Depression21 (22%)5 (20%)
Irritability27 (28%)7 (28%)
Alopecia20 (21%)6 (24%)
Influenza-like symptoms62 (65%)13 (52%)
Itching28 (30%)3 (12%)
Exanthema16 (17%)2 (8%)
Anemia (hemoglobin < 10 g/dL)8 (8%)1 (4%)
Neutropenia (0.75 × 10−6/L)9 (10%)1 (4%)

Treatment was stopped early (<80% of the planned treatment time) in 7 (6%) of 122 patients. In addition, the dose of pegylated IFN-α, ribavirin, or both was reduced in 24 (20%) of 122 patients. Reasons for early treatment cessation or reduction of dose were neutropenia (n = 10), anemia (n = 4), depression (n = 3), fatigue (n = 3), diabetes mellitus (n = 1), and other side effects (n = 10).

Treatment dose was reduced or terminated early in 23 (24%) of 95 patients assigned to 14 weeks of treatment and 6 (24%) of 25 patients assigned to 24 weeks of treatment (P = .936). (Patients who were treated for less than 4 weeks were excluded from this analysis [n = 2].)

Discussion

The current standard therapy for patients with HCV genotype 2 or 3 is 24 weeks with pegylated IFN-α (2a or 2b) in combination with ribavirin. Increasing the duration of treatment from 24 to 48 weeks does not seem to increase the sustained response rate.1, 3, 7 Short-term treatment of HCV infection has only been studied to a very limited extent.15, 16 We therefore investigated the effect of a 14-week combination treatment for patients with HCV genotype 2 or 3 who were early virological responders and found that 90% of the patients had a SVR. Patients who did not have EVR were treated for 24 weeks, and the SVR rate in this group was 56%. This difference in SVR is expected, because EVR is a strong predictor of sustained response.8, 11, 17

Altogether, 82% of the 122 included patients obtained SVR. This SVR rate is comparable to the results in large HCV treatment trials with pegylated IFN-α and ribavirin. These studies have reported SVR in the range of 79% to 84% in patients with genotype 2 or 3 treated for 24 to 48 weeks.1, 3, 7

Case reports have suggested that SVR may be obtained after only 4 to 16 weeks of HCV treatment.8, 9 In a small study from Japan, a SVR of 76% was reported among a group of 21 patients with HCV genotype 2 and low viral load (<20,000 IU/mL) receiving 10 weeks of monotherapy with IFN-α.15 In another Japanese study, 32% of 50 patients and 52% of 21 genotype 2 patients obtained SVR following 16 weeks of IFN-α monotherapy.16

In the present trial, a biopsy showing no or minimal fibrosis predicted SVR. The study conducted by Manns et al.1 also showed fibrosis to be an important predictor of SVR. However, Fried et al.2 and Zeuzem et al.7 were not able to reproduce this. In the latter trial, which included 224 patients with genotype 2 or 3, low viral load or HCV genotype 2 and absence of steatosis were independent predictors of SVR.7 Our data partially support this finding, because patients with genotype 3 and low viral load had a significantly lower risk of relapsing after 14 weeks compared with those with genotype 3 and a high viral load. The power of the analysis performed is somewhat limited, however, because a liver biopsy was lacking in one quarter of our patients and the number of patients with genotype 2 was limited.

We chose HCV RNA negativity at week 4 as a criterion for assignment to 14 weeks of HCV treatment. This decision was based on the knowledge that EVR is a predictor of SVR independent of genotype.8, 10 Seventy-five percent of our patients had become HCV RNA–negative by week 4. In comparison, 84% of genotype 2 or 3 patients became HCV RNA negative within four weeks of combination treatment in a Spanish trial.18

Although the numbers are small, it is noteworthy that 4 out of 7 relapsers after 14 weeks of treatment with an available biopsy had bridging fibrosis or cirrhosis. Consequently, short-term treatment should probably be restricted to patients infected with genotype 2 or 3 who do not exhibit bridging fibrosis or cirrhosis.

Shortening the treatment period for chronic HCV infection is of major importance, because this will reduce costs for both the patient and the society. By using our approach of 14 weeks' treatment in patients with EVR, a 32% reduction of drug exposure and cost is achieved—even when including 24 weeks of retreatment in those patients with EVR but not SVR. Improving our ability to predict SVR will further increase this savings.

Side effects due to interferon–ribavirin combination therapy appear within a few weeks after the start of treatment. Thus, it is not surprising that the incidence of side effects was similar between the two groups of patients. Still, it is quite obvious that the great majority of patients will prefer a shorter treatment if the response rate does not decline.

In summary, patients with genotype 2 or 3 and EVR obtained a high SVR after only 14 weeks of combination treatment. The results need to be confirmed in a randomized, controlled study before such a treatment approach can be recommended, particularly for patients with genotype 3 and a high viral load or severe fibrosis.

KBC Study Group.

Patients were treated at the following hospitals: Aker University Hospital (H. Bell, O. Dalgard), Akershus University Hospital (A. Eskesen, K. B. Hellum), Arendal Hospital (K. Kaasen Jørgensen), Buskerud Hospital (S. Ritland), Bærum Hospital (E. J. Rønningen), Diakonhjemmet Hospital (A. Bucher, N. Stray, R. Weberg), Haukeland University Hospital (P. E. Akselsen, A. M. Dyrhol-Riise, S. I. Fylkesnes, R. Leiva, S. Lund-Tønnessen, K. Mørch), Gjøvik Hospital (E. Reinertsen), Hamar Hospital (A. Torp), Kristiansand Hospital (A. Sundøy), Lillehammer Hospital (I. J. Hagen), Nord Norge University Hospital (J. Florholmen), Rikshospitalet (K. Bjøro), Rogaland Hospital (B. Døskeland, L. Karlsen, S. Størset), St. Olavs Hospital (A. Henriksen, B. Viggen), Telemark Hospital (J. Paulsen), Ullevål University Hospital (A. Mæland, A. Maagaard, B. vd Lippe Ullevål) and Østfold Hospital (I. Ringstad, P. Sandvei).

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