Digestive Diseases and Sciences

, Volume 56, Issue 8, pp 2439–2448 | Cite as

Retreatment of Hepatitis C with Consensus Interferon and Ribavirin After Nonresponse or Relapse to Pegylated Interferon and Ribavirin: A National VA Clinical Practice Study

  • Helen S. Yee
  • Sue L. Currie
  • Kathryn Tortorice
  • Myrna Cozen
  • Hui Shen
  • Summer Chapman
  • Fran Cunningham
  • Alexander Monto
Original Article

Abstract

Background

Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care.

Aims

The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed ≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006.

Results

A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P < 0.0001). A 2-log10 or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV.

Conclusions

CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log10 or greater decline than in nonresponders.

Keywords

Consensus interferon Hepatitis C virus Nonresponders Pegylated interferon/ribavirin Retreatment 

Abbreviations

CIFN

Consensus interferon

DIRECT

Daily-dose consensus interferon and ribavirin: Efficacy of combined therapy

HCV

Hepatitis C virus

PEG-IFN

Pegylated interferon alfa

IFN

Interferon

PBM

Pharmacy Benefits Management

RBV

Ribavirin

SVR

Sustained virologic response

HCV RNA

Hepatitis C virus ribonucleic acid level

VA

Veterans Affairs

ICD-9

International classification of diseases, ninth revision

NPF

National Patient Files

CPT-4

Coding for procedures performed, fourth revision

HIV

Human immunodeficiency virus

Introduction

Approximately 3.2 million people in the United States and over 170 million people worldwide are chronically infected with the hepatitis C virus (HCV) [1, 2]. HCV is a leading cause of chronic liver disease and liver transplantation. The goals of antiviral therapy are to eradicate HCV RNA and to slow the progression of liver disease. More than 50% of HCV genotype 1-infected patients are unable to achieve sustained virologic response (SVR) following treatment with the recent standard of care—pegylated interferon alfa plus ribavirin (PEG-IFN/RBV) [3, 4, 5]. Patients who fail antiviral treatment are at continued risk for the development of clinical complications of longstanding HCV infection, including cirrhosis and hepatocellular carcinoma [6, 7].

Limited options have been available for the retreatment of PEG-IFN/RBV nonresponders or relapsers, i.e. those who fail to clear the virus or who have recurrent viremia following initial treatment-induced viral clearance, respectively. Retreatment strategies in these patients have included PEG-IFN/RBV at higher doses and for longer durations. Only 7–16% of prior nonresponders achieved SVR using these retreatment approaches in a recently reported randomized, controlled trial [8].

Consensus interferon (CIFN, Infergen®) in combination with RBV was approved by the FDA in July 2010 for retreatment of PEG-IFN/RBV failures. Some studies suggest subtle differences in signal transduction induced by CIFN compared to interferon (IFN) α-2a and IFNα-2b, possibly resulting in enhanced in vitro antiviral effects [9, 10, 11, 12]. Small, single-center, open-label studies demonstrated SVR in 23–37% of patients who were retreated with CIFN/RBV after failing PEG-IFN/RBV. Variations in retreatment strategies have included the use of high-dose CIFN (15–27 mcg daily), extending the CIFN/RBV treatment duration to 72 weeks, and switching to CIFN/RBV immediately upon failure of PEG-IFN/RBV therapy [13, 14, 15, 16]. Retreatment response to CIFN/RBV was particularly low in one study of PEG-IFN/RBV nonresponders with advanced liver disease, only 18% of whom achieved SVR [17]. Early discontinuation rates were low at 3–14% across these studies [13, 14, 15].

The most rigorous study to date of CIFN/RBV retreatment of PEG-IFN/RBV nonresponders is a prospective, multicenter, randomized trial (DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy), in which CIFN at 9 or 15 mcg daily plus RBV 1,000–1,200 mg daily for 48 weeks achieved SVR in only 9% overall [18]. No significant difference in SVR rates between the 15 mcg/day and 9 mcg/day arms was observed (11 and 7%, respectively). Treatment was discontinued due to adverse effects in 18% of patients.

Although daily CIFN/RBV has been heralded as a viable option to retreat patients who fail PEG-IFN/RBV, marked variability in SVR rates and drug tolerability have been reported [13, 14, 15, 16, 17, 18]. In contrast to results from earlier open-label retreatment studies using CIFN/RBV, SVR rates in the DIRECT trial were similar to PEG-IFN/RBV retreatment [8, 18]. To further clarify these disparate results, we examined the use and efficacy of CIFN/RBV in clinical practice within the Department of Veterans Affairs (VA) Healthcare System, the largest national, integrated system for hepatitis C care. The primary study aims were to determine rates and factors associated with SVR following CIFN/RBV retreatment of PEG-IFN/RBV failures. Secondary aims were to evaluate CIFN/RBV dosing regimens, treatment duration, and the use of concomitant growth factors.

Methods

Study Design

This study was a retrospective review of national VA Healthcare System data in patients with chronic HCV who failed ≥12 weeks of prior PEG-IFN/RBV treatment and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006. The protocol was approved by the Institutional Review Board at the University of California, San Francisco and the Department of Veterans Affairs Medical Center, San Francisco. Patients with an International Classification of Diseases, 9th revision code (ICD-9) diagnosis of chronic HCV who received at least one prescription for CIFN within the VA Healthcare System during the study period were included in the initial data collection. Only patients with documentation of a failed prior course of PEG-IFN/RBV for ≥12 weeks were included in the outcome analysis. Nonresponders to PEG-IFN/RBV were defined as those with detectable HCV RNA at ≥12 weeks during treatment. Relapsers were defined as those with undetectable HCV RNA at the end of treatment but detectable HCV RNA following discontinuation of PEG-IFN therapy. Patients in this study had not previously failed CIFN, nor were they enrolled in clinical trials of CIFN.

SVR following retreatment with CIFN/RBV was the primary outcome measure of the study. If HCV RNA was detected at any time after completion of CIFN/RBV, patients were considered treatment failures. If HCV RNA values were undetectable at or after 24 weeks post-treatment, patients were considered to have achieved SVR. If no such HCV RNA levels were available, patients were excluded from the outcome analysis.

All quantitative and qualitative HCV RNA results which were available in patients’ medical records between January 1, 1997 and December 31, 2007 were collected and evaluated, including those taken prior to, during, and after PEG-IFN/RBV and CIFN/RBV treatments. Quantitative HCV RNA levels prior to CIFN/RBV treatment were assessed, and high HCV RNA levels were defined as ≥800,000 IU/ml or ≥2 million copies/ml. The lower limits of detection for quantitative HCV RNA levels ranged from <10 to <615 IU/ml and <50 to <600 copies/ml, depending on the assay used within each facility. In rare cases in which a recorded value for HCV RNA was less than 10 IU/ml, this was considered undetectable.

Data Sources

VA Pharmacy Benefits Management (PBM) databases (designated PBM v 4.0) and VA National Patient Files (NPF) were utilized for the study. The PBM v 4.0 national prescription database contains extensive information including: product name, dosing instructions, and days of supply for patients who obtain their prescriptions in the VA system. The VA NPF contains demographic and clinical information; coding for procedures performed, fourth revision (CPT-4); and diagnoses (ICD-9 codes) associated with care. HCV genotype could not be obtained from these files and thus was unavailable for this study. Patient files were de-identified prior to transfer to investigators.

Variables Collected

The following data elements were collected: (1) demographic characteristics (age, gender, race); (2) duration of prior treatment with PEG-IFN/RBV; (3) PEG-IFN formulation (alfa- 2a or -2b) and dose; (4) time interval between last PEG-IFN dose and CIFN initiation; (5) CIFN dose, frequency and duration of therapy; (6) RBV dose; (7) HCV RNA levels; and (8) growth factor use during CIFN treatment. A patient was defined as having cirrhosis if one or more of the following ICD-9 codes were present prior to September 30, 2008: 571.2 (cirrhosis, alcoholic); 571.5 (cirrhosis, unspecified); 572.2 (encephalopathy); 789.5 (ascites); 572.3 (portal hypertension); 456.21 (varices, non-bleeding); 456.20 (varices, bleeding). HIV positivity was confirmed by the presence of anti-HIV-1 antibodies and/or a prescription for HIV antiretroviral medications between October 1, 2000 and September 30, 2006.

Statistical Analysis

Descriptive statistics were generated for continuous variables (mean, standard deviation) and for categorical variables (frequencies and percents). Percentages were calculated using the total number of patients without missing data as the denominator, except for the four predictor variables for which more than 5% of values were missing or unknown: race/ethnicity, HIV status, HCV RNA levels prior to CIFN/RBV, and prior PEG-IFN/RBV response (i.e. treatment relapse or nonresponse). For each of these variables, a category named “unknown” was created and included in the analysis, rather than leaving those values as missing. Analysis of categorical variables was performed using the chi-square or Fisher’s exact test, as appropriate. The Student’s t-test or Wilcoxon rank sum test was used to compare continuous variables. Logistic regression modeling was used to conduct univariate analyses. Treatment outcome, expressed as SVR or no SVR, was the major outcome variable. Logistic regression modeling was used to conduct outcome analysis. SAS version 9.2 (SAS Institute, Cary, NC) was used to perform all statistical analyses.

Results

CIFN was prescribed to 774 HCV-infected patients from 73 of 134 VA medical facilities (54%) during the study period. Centers treated from one to 56 patients, with a median of six. Among these patients, 597 had documented treatment failure following ≥12 weeks of PEG-IFN/RBV prior to receiving CIFN/RBV therapy and were included in this study.

Patient Characteristics

Baseline characteristics of the 597 patients are described in Table 1. Those for whom treatment outcome could be ascertained are presented separately. The mean age of patients was 55 years. Typical of the VA population, nearly all were male (96%). Most patients were either Caucasian (40%) or African American (28%), although in 27% race/ethnicity was unavailable. An ICD-9 diagnosis of cirrhosis was present in 33%, and HIV/HCV coinfection was confirmed in 14%. Quantitative HCV RNA values drawn between the cessation of PEG-IFN/RBV and the initiation of CIFN/RBV treatment were available in 297 patients, and were almost evenly divided between those with high and low levels. Qualitative HCV RNA determinations between the cessation of PEG-IFN/RBV and the start of CIFN/RBV were available in an additional 30 patients.
Table 1

Clinical characteristics of patients treated with consensus interferon (CIFN) and ribavirin (RBV)

Variable

Total (N = 597)

Known treatment outcome (N = 385)

Unknown treatment outcome (N = 212)

P-value

Age, years

 Mean ± SD

55.3 ± 5.0

55.5 ± 5.5

55.2 ± 5.4

0.74a

Gender

 Male

571 (95.6%)

367 (95.3%)

204 (96.2%)

0.61

 Female

26 (4.4%)

18 (4.7%)

8 (3.8%)

Race/ethnicity

 Caucasian

240 (40.2%)

150 (39.0%)

90 (42.5%)

0.007b

 African American

169 (28.3%)

126 (32.7%)

43 (20.3%)

 

 Hispanic

26 (4.4%)

13 (3.4%)

13 (6.1%)

 

 Asian/Pacific Islander/Native American

1 (0.2%)

1 (0.3%)

0 (0.0%)

 

 Unknown

161 (27.0%)

95 (24.7%)

66 (31.1%)

 

Known HIV positive (n = 144)

84 (14.1%)

53 (13.8%)

31 (14.7%)

0.001

Cirrhosis

200 (33.5%)

138 (35.8%)

62 (29.2%)

0.10

Baseline HCV RNA (n = 297)

84 (58.3%)

53 (67.1%)

31 (47.7%)

 

 ≥800,000 IU/ml or ≥2 million copies/ml

151 (50.8%)

110 (52.1%)

41 (47.7%)

0.49

 <800,000 IU/ml or <2 million copies/ml

146 (49.2%)

101 (47.9%)

45 (52.3%)

 

Courses of prior PEG-IFN/RBV therapy

 One course

487 (81.6%)

310 (80.5%)

177 (83.5%)

0.37

 Two courses

110 (18.4%)

75 (19.5%)

35 (16.5%)

Duration of prior PEG-IFN/RBV, longest course

 12–24 weeks

195 (32.7%)

126 (32.7%)

69 (32.5%)

0.93

 25–47 weeks

265 (44.4%)

169 (43.9%)

96 (45.3%)

 ≥48 weeks

137 (22.9%)

90 (23.4%)

47 (22.2%)

Interval between PEG-IFN/RBV and CIFN/RBV

 ≤4 weeks

90 (16.2%)

56 (15.4%)

34 (17.6%)

0.57

 5–24 weeks

141 (25.4%)

88 (24.2%)

53 (27.5%)

 25–48 weeks

113 (20.3%)

79 (21.8%)

34 (17.6%)

 >48 weeks

212 (38.1%)

140 (38.6%)

72 (37.3%)

CIFN consensus interferon, RBV ribavirin, PEG-IFN pegylated interferon alfa

P-values were calculated using Chi-square test for categorical variables and Student’s t-test for continuous variables unless otherwise marked

aP-values were calculated using Wilcoxon test

bP-values were calculated using Fisher’s exact test

Eighteen percent of patients had previously received two or more courses of PEG-IFN/RBV therapy. Sixty percent of patients were treated with PEG-IFN α-2a, with the majority receiving doses of 180 mcg per week. The remaining 40% were treated with PEG-IFNα-2b, generally at doses of 120–150 mcg per week. The mean duration of the longest PEG-IFN/RBV treatment course was 43 weeks, with 23% of patients having received ≥48 weeks of therapy. The mean interval between the end of PEG-IFN/RBV and the initiation of CIFN/RBV was 43 weeks. Approximately 22% of patients initiated CIFN within 4 weeks of the discontinuation of PEG-IFN/RBV therapy.

Dosing and Duration of CIFN/RBV

The CIFN/RBV treatment course is described in Table 2. The majority of patients (71%) received an initial CIFN dose of 15 mcg daily, and 88% of these patients remained on this dose until their treatment was discontinued (data not shown). Among all patients, approximately 10% required CIFN dose reductions and 10% had their dose increased during therapy. Ninety-five percent of patients treated with CIFN received concomitant RBV therapy. Most (87%) were prescribed an initial RBV dose of 1,000–1,400 mg/day, and 70% remained on their initial RBV dose until the cessation of treatment (data not shown). The mean treatment duration was 21 weeks. Treatment was discontinued within 4 weeks of initiation in 24% of patients and within 5–12 weeks in another 21%. Overall, 92% of patients did not complete 48 weeks of therapy, leaving 8% who were treated for ≥48 weeks.
Table 2

Consensus interferon (CIFN) and ribavirin (RBV) treatment course

Variable

Total (N = 597)

Known treatment outcome (N = 385)

Unknown treatment outcome (N = 212)

P-value

Initial CIFN dose

 <15 mcg/day

166 (28.0%)

96 (25.1%)

70 (33.3%)

0.07a

 15 mcg/day

422 (71.2%)

283 (73.9%)

139 (66.2%)

 

 >15 mcg/day

5 (0.8%)

4 (1.0%)

1 (0.5%)

 

CIFN dose modification during treatment

 Dose decreased

59 (9.9%)

40 (10.4%)

19 (9.0%)

0.78

 No dose adjustment

478 (80.1%)

308 (80.0%)

170 (80.2%)

 

 Dose increased

60 (10.1%)

37 (9.6%)

23 (10.8%)

 

Duration of CIFN/RBV treatment

 ≤4 weeks

143 (24.0%)

77 (20.0%)

66 (31.1%)

0.02

 5–12 weeks

126 (21.1%)

88 (22.9%)

38 (17.9%)

 

 13–24 weeks

121 (20.3%)

83 (21.6%)

38 (17.9%)

 

 25–48 weeks

160 (26.8%)

110 (28.6%)

50 (23.6%)

 

 >48 weeks

47 (7.9%)

27 (7.0%)

20 (9.4%)

 

Concomitant RBV

565 (94.6%)

369 (95.8%)

196 (92.5%)

0.08

Initial RBV dose

 <1,000 mg/day

74 (13.1%)

46 (12.5%)

28 (14.4%)

0.52

 1,000–1,200 mg/day

466 (82.6%)

305 (82.7%)

161 (82.6%)

 

 >1,200 mg/day

24 (4.3%)

18 (4.9%)

6 (3.1%)

 

Growth factor use

291 (48.7%)

195 (50.6%)

96 (45.3%)

0.21

 Epoetin or Darbepoetin only

189 (31.7%)

131 (34.0%)

58 (27.4%)

0.35

 Filgrastim or pegfilgrastim only

44 (7.4%)

26 (6.8%)

18 (8.5%)

 

 Both growth factors

58 (9.7%)

38 (9.9%)

20 (9.4%)

 

CIFN consensus interferon, RBV ribavirin, PEG-IFN pegylated interferon alfa

P-values were calculated using Chi-square test for categorical variables unless otherwise marked

aP-values were calculated using Fisher’s exact test

Growth Factor Use

Nearly half (49%) of CIFN/RBV-treated patients were prescribed growth factors during therapy. Thirty-two percent received either epoetin alfa or darbepoetin alfa, and 7% received filgrastim or pegfilgrastim. Approximately 10% of patients received both an erythropoietic agent and a colony stimulating factor.

Treatment Outcomes

Response to CIFN/RBV therapy was available in 385 patients. HCV RNA levels were available during therapy in 19% (15/77) of patients treated with CIFN/RBV for 4 weeks or less, and in 41% (36/88) of patients treated for 4–12 weeks (Table 2). This figure rose to 45% (37/83) for those treated for 12–24 weeks.

Data on response to CIFN/RBV was more likely to be available for: (1) African Americans (compared to known non-African Americans, P = 0.003); (2) HIV/HCV co-infected patients (compared to HCV-infected patients who were HIV negative, P = 0.02); and (3) patients treated with CIFN/RBV for ≥5 weeks (compared to patients treated with CIFN/RBV for ≤4 weeks, P = 0.05). There were no other differences between patients for whom treatment outcome was available and those for whom it was not. Specifically, the presence of cirrhosis, CIFN dose, RBV dose, or growth factor use did not differ significantly between groups (Tables 1, 2).

SVR was achieved in 11% (42/385). In the 42 patients who achieved SVR, there were 133 HCV RNA levels performed; the lower limit of detection (LLD) of the assay was 615 IU/ml in five, 600 copies/ml in 13, and 50 IU/ml in the remaining 115. The mean duration of CIFN/RBV among SVR patients was 34 weeks. HCV RNA levels were undetectable at the end-of-treatment with CIFN/RBV in 19% (74/385) of patients; however, 43% (32/74) of these patients were documented to experience viral relapse following treatment. Eleven (26%) SVR patients were cirrhotic, which did not differ from the cohort overall.

Data on response to prior PEG-IFN/RBV treatment were available in 80% (306/385) of patients overall. Of those, 17% (52/306) were relapsers and 83% (254/306) were nonresponders (Table 3). SVR occurred in 31% (16/52) of prior PEG-IFN relapsers and 6% (15/254) of prior nonresponders (OR 7.1, 95% CI 3.23–15.56; P < 0.0001). In addition, SVR was achieved more frequently in all patients who previously had ≥2-log10 decline at week 24 while on PEG-IFN/RBV (P = 0.002). SVR did not differ in patients who previously achieved early virologic response (EVR), including those who achieved partial EVR (≥2 log decline in HCV RNA but detectable at week 12) or complete EVR (undetectable HCV RNA at week 12) while on PEG-IFN/RBV. The patient group who initiated CIFN/RBV treatment ≥5 weeks after PEG-IFN/RBV contained a higher proportion of prior relapsers than nonresponders (P = 0.03) and were significantly more likely to achieve SVR (OR 5.60, 95% CI 1.32–23.69, P = 0.02). Results of other univariate models to evaluate variables associated with SVR are presented in Table 4. Multivariable analyses did not yield significant results.
Table 3

Clinical characteristics of patients with known post-treatment outcome

Variable

Total (N = 385)

Prior nonresponder (N = 254)

Prior relapser (N = 52)

Unknown response to prior Tx (N = 79)

P-value

Age, years

 Mean ± SD

55.51 ± 5.47

55.13 ± 5.06

55.25 ± 3.62

56.90 ± 7.28

0.11a

Gender

 Female

18 (4.7%)

11 (4.3%)

2 (3.8%)

5 (6.3%)

0.76b

 Male

367 (95.3%)

243 (95.7%)

50 (96.2%)

74 (93.7%)

 

Ethnicity

 Caucasian

150 (39.0%)

97 (38.2%)

28 (53.8%)

25 (31.6%)

0.16

 African-American

126 (32.7%)

83 (32.7%)

9 (17.3%)

34 (43.0%)

 

 Hispanic

13 (3.4%)

10 (3.9%)

1 (1.9%)

2 (2.5%)

 

 Asian/Pacific Islander/Native American

1 (0.3%)

1 (0.4%)

0 (0.0%)

0 (0.0%)

 

 Unknown

95 (24.7%)

63 (24.8%)

14 (26.9%)

18 (22.8%)

 

Known HIV positive (n = 79)

 Negative

26 (32.9%)

17 (30.4%)

6 (60.0%)

3 (23.1%)

0.13b

 Positive

53 (67.1%)

39 (69.6%)

4 (40.0%)

10 (76.9%)

 

Baseline HCV RNA (n = 211)

 <800,000 IU/ml

101 (47.9%)

81 (51.6%)

12 (37.5%)

8 (36.4%)

0.18

 ≥800,000 IU/ml

110 (52.1%)

76 (48.4%)

20 (62.5%)

14 (63.6%)

 

Cirrhosis

 No

247 (64.2%)

168 (66.1%)

29 (55.8%)

50 (63.3%)

0.36

 Yes

138 (35.8%)

86 (33.9%)

23 (44.2%)

29 (36.7%)

 

12-week VL decline on PEG-IFN/RBV (n = 118)

 ≥2 log drop

29 (24.6%)

17 (18.1%)

11 (61.1%)

1 (16.7%)

0.0009b

 <2 log drop

89 (75.4%)

77 (81.9%)

7 (38.9%)

5 (83.3%)

 

24-week VL decline on PEG-IFN/RBV (n = 209)

 ≤2 log drop

71 (34.0%)

38 (23.3%)

29 (80.6%)

4 (40.0%)

<0.0001

 <2 log drop

138 (66.0%)

125 (76.7%)

7 (19.4%)

6 (60.0%)

 

Duration of PEG-IFN/RBV (longest course)

 12–24 weeks

126 (32.7%)

95 (37.4%)

8 (15.4%)

23 (29.1%)

0.01

 25–48 weeks

169 (43.9%)

102 (40.2%)

26 (50.0%)

41 (51.9%)

 

 ≥48 weeks

90 (23.4%)

57 (22.4%)

18 (34.6%)

15 (19.0%)

 

Duration of CIFN/RBV

 ≤4 weeks

77 (20.0%)

50 (19.7%)

12 (23.1%)

15 (19.0%)

0.01

 5–12 weeks

88 (22.9%)

60 (23.6%)

6 (11.5%)

22 (27.8%)

 

 13–24 weeks

83 (21.6%)

64 (25.2%)

4 (7.7%)

15 (19.0%)

 

 25–48 weeks

110 (28.6%)

65 (25.6%)

23 (44.2%)

22 (27.8%)

 

 >48 weeks

27 (7.0%)

15 (5.9%)

7 (13.5%)

5 (6.3%)

 

SVR to CIFN/RBV

 No SVR

343 (89.1%)

239 (94.1%)

36 (69.2%)

68 (86.1%)

<0.0001

 SVR

42 (10.9%)

15 (5.9%)

16 (30.8%)

11 (13.9%)

 

SD standard deviation, CIFN consensus interferon, RBV ribavirin, PEG-IFN pegylated interferon alfa

P-values were calculated using Chi-square test for categorical variables and ANOVA for continuous variables unless otherwise marked

aVariable was rank transformed

bP-values were calculated from Fisher’s exact test

Table 4

Univariate analyses assessing predictors of sustained virologic response (SVR) (N = 385)

Variable

SVR (N = 42)

No SVR (N = 343)

OR of achieving SVRa (95% CI)

P-value

Age, years

 Mean ± SD

56.87 ± 8.99

55.35 ± 4.90

1.04 (0.99–1.10)

0.11

Gender

 Male

41 (11.2%)

326 (88.8%)

2.14 (0.28–16.49)

0.47

 Female

1 (5.6%)

17 (94.4%)

1.00

 

Race/Ethnicity

 African American

9 (7.1%)

117 (92.9%)

0.47 (0.21–1.06)

0.07

 Non-African American

23 (14.0%)

141 (86.0%)

1.00

 

 Unknown

10 (10.5%)

85 (89.5%)

0.72 (0.33–1.59)

0.42

HIV positive

 Positive

4 (9.5%)

49 (14.4%)

0.98 (0.17–5.73)

0.98

 Negative

2 (4.8%)

24 (7.0%)

1.00

 

 Unknown

36 (85.7%)

268 (78.6%)

1.61 (0.37–7.11)

0.53

Cirrhosis

 Yes

11 (8.0%)

127 (92.0%)

0.60 (0.29–1.24)

0.17

 No

31 (12.6%)

216 (87.4%)

1.00

 

Baseline HCV RNA

 <800,000 IU/ml or <2 million copies/ml

9 (8.9%)

92 (91.1%)

1.00

 

 ≥800,000 IU/ml or ≥2 million copies/ml

12 (10.9%)

98 (89.1%)

1.25 (0.50–3.11)

0.63

 Unknown

21 (12.1%)

153 (87.9%)

1.40 (0.62–3.19)

0.42

2 or more courses of PEG/RBV treatment

 Yes

5 (6.7%)

70 (93.3%)

0.53 (0.20–1.39)

0.20

 No

37 (11.9%)

273 (88.1%)

1.00

 

Duration of prior PEG-IFN/RBV, longest course

 12–24 weeks

7 (5.6%)

119 (94.4%)

0.47 (0.17–1.29)

0.14

 25–47 weeks

25 (14.8%)

144 (85.2%)

1.39 (0.64–3.04)

0.41

 ≥48 weeks

10 (11.1%)

80 (88.9%)

1.00

 

12-week VL decline on PEG-IFN/RBV (n = 118)

 ≥2 log decline

1 (3.4%)

28 (96.6%)

0.60 (0.07–5.36)

0.65

 <2 log decline

5 (5.6%)

84 (94.4%)

Ref

 

24-wk VL decline on PEG-IFN/RBV (n = 209)

 ≥2 log decline

14 (19.7%)

57 (80.3%)

4.60 (1.76–11.99)

0.002

 <2 log decline

7 (5.1%)

131 (94.9%)

Ref

 

Interval between PEG-IFN/RBV and CIFN/RBV

 ≤4 weeks

2 (3.6%)

54 (96.4%)

1.00

 

 >4 weeks

40 (13.0%)

267 (87.0%)

5.60 (1.32–23.69)

0.02

Initial CIFN dose

 <15 mcg/day

9 (9.4%)

87 (90.6%)

1.00

 

 ≥15 mcg/day

33 (11.5%)

254 (88.5%)

1.26 (0.58–2.73)

0.57

Initial RBV dose

 <1,000 mg/day

6 (13.0%)

40 (87.0%)

1.16 (0.46–2.93)

0.76

 1,000–1,200 mg/day

35 (11.5%)

270 (88.5%)

1.00

 

 >1,200 mg/day

1 (5.6%)

17 (94.4%)

0.45 (0.06–3.52)

0.45

Growth factors

 Epoetin or darbepoetin only

19 (14.5%)

112 (85.5%)

1.62 (0.82–3.22)

0.17

 Filgrastim or pegfilgrastim only

3 (11.5%)

23 (88.5%)

1.25 (0.34–4.56)

0.74

 Both growth factors

2 (5.3%)

36 (94.7%)

0.53 (0.12–2.39)

0.41

 None

18 (9.5%)

172 (90.5%)

1.00

 

Outcome of prior PEG-IFN/RBV

 Nonresponse

15 (5.9%)

239 (94.1%)

1.00

 

 Relapse

16 (30.8%)

36 (69.2%)

7.08 (3.23–15.56)

<0.0001

 Unknown

11 (13.9%)

68 (86.1%)

2.58 (1.13–5.87)

0.02

SD standard deviation, SVR sustained virologic response, CIFN consensus interferon, RBV ribavirin, PEG-IFN pegylated interferon alfa

aOdds ratio for SVR versus no SVR

Discussion

The current study comprises a retrospective analysis of CIFN/RBV salvage therapy in HCV patients who have failed PEG-IFN/RBV. The VA Healthcare System is the largest integrated provider of HCV care in the United States, and these data describe a real-world experience with CIFN in a national cohort from a clinical practice setting. SVR was achieved in only 11% of patients following CIFN/RBV retreatment, an outcome that is similar to the DIRECT trial (9%). We found that SVR was significantly higher in PEG-IFN/RBV relapsers (31%) compared to nonresponders (6%). As is the case with PEG-IFN/RBV retreatment, CIFN/RBV treatment of PEG-IFN/RBV failures appears to be more effective in prior relapsers than in nonresponders [19, 20, 21]. Interim results from a prospective study of the retreatment of PEG-IFN/RBV relapsers with either daily CIFN/RBV for 48 weeks or PEG-IFN/RBV for 72 weeks also found high SVR rates at 47 and 50%, respectively [22].

Similar to the DIRECT trial, HCV RNA decline on PEG-IFN/RBV was associated with subsequent response to CIFN/RBV. In a subanalysis of the DIRECT trial, CIFN/RBV retreatment achieved SVR in 30% of noncirrhotic patients who previously had a >2 log10 reduction in HCV RNA during prior PEG-IFN/RBV treatment [18]. Although our study included 17% PEG-IFN/RBV relapsers whereas the DIRECT trial enrolled only PEG-IFN/RBV nonresponders, a ≥ 2 log10 HCV RNA decline during PEG-IFN/RBV treatment was also a predictor of CIFN/RBV treatment success in this study. SVR to CIFN/RBV did not differ based on prior partial EVR or complete EVR to PEG-IFN/RBV; however, HCV RNA levels at week 12 of PEG-IFN/RBV were not consistently performed.

Retreatment with CIFN/RBV was used by providers in 54% of VA medical centers during this time period. Several factors may have contributed to CIFN/RBV use, despite lack of conclusive evidence for its efficacy. These include the absence of effective alternative therapies, patient motivation, tolerability of prior PEG-IFN/RBV, severity of liver disease and perceived risk of disease progression, and variations in the availability of this therapy between VA facilities. CIFN was dosed almost exclusively as 15 mcg subcutaneous daily with RBV, the doses which tended to be used in the single center trials [13, 14, 15, 16]. The use of erythropoietic growth factors and/or granulocyte colony stimulating factors in 49% of patients reflects both the hematological toxicity of this therapy, as well as the clinical judgment by providers that continuation of CIFN/RBV was important enough to warrant the use of these agents. Nonetheless, patients were only treated with CIFN/RBV for an average of 21 weeks, a shorter duration than in other published studies [13, 15, 16, 17, 18]. Twenty four percent of patients discontinued CIFN/RBV within 4 weeks of its initiation. Only 8% of patients received a ≥48 week course of treatment. The more intensive support provided to patients in clinical trials may help to explain why early discontinuation rates in those settings, 3–18%, were so much lower than those seen in the current study [13, 15, 16, 17, 18].

Clinical practice clearly involves a different set of therapeutic considerations than are employed in clinical trials. HCV RNA levels were obtained during CIFN/RBV therapy in many patients and likely contributed to some clinical decision-making about continuing therapy. Although early virological responses may have influenced treatment decisions, HCV RNA levels were available from our data sources in less than 50% of patients who stopped CIFN/RBV therapy prior to 24 weeks. These data suggest that many early discontinuations were not guided by viral load responses, but instead by patient tolerability of therapy.

In patients who achieved SVR, the majority (86%) had HCV RNA levels measured using an assay with a LLD of ≤50 IU/ml. The low SVR observed in this study likely reflects the high proportion of PEG-IFN/RBV nonresponders rather than relapsers, as well as the low completion rates of CIFN therapy. Although HCV genotype was not available in this analysis, it is likely that the majority of patients were infected with genotype 1, as this is the predominant genotype in PEG-IFN/RBV treatment failures and in VA patients overall [3, 4, 5, 15, 18, 23]. Additional factors that may have contributed to the low SVR include a relatively high proportion of patients who were African American (28%), cirrhotic (34%), or HIV/HCV co-infected (14%), groups which have impaired responses to PEG-IFN/RBV, although these groups were not found to have statistically significantly lower SVR rates in this study [3, 4, 19, 24]. The lack of an association with variables that are traditionally believed to predict response may be explained partly by the small number of patients who achieved SVR in this study, although patient-specific characteristics predictive of CIFN/RBV response have been incompletely described [14, 15, 19, 20, 21, 25]. SVR was not associated with the initiation of CIFN within 4 weeks of concluding PEG-IFN/RBV in this study, a “roll-over” strategy which was employed in one study of prior PEG-IFN/RBV failures [15]. In fact, SVR rates were significantly higher in patients who delayed retreatment with CIFN/RBV, likely due to an increased proportion of PEG-IFN/RBV relapsers compared to nonresponders in this group.

VA databases provide access to a large national cohort from a clinical practice setting, which is a principal strength of this study. Weaknesses of this study include the fact that data were retrieved from administrative or clinical records, and hence variables including HCV genotype and reasons for treatment discontinuation were incompletely captured or unavailable. Also, data were only available if they were obtained as part of routine medical care; thus, pertinent tests such as HCV RNA levels often were not obtained at standard timepoints and were often missing. This is in contrast to clinical trials, in which standard testing is nearly universally available. Finally, as this cohort consists of predominantly male veterans, the study findings may not be fully generalizable to other patient groups.

CIFN is a synthetic IFNα containing commonly occurring amino acid substitutions from numerous naturally occurring type I IFN molecules. Compared to the naturally occurring cytokines IFNα-2a and IFNα-2b, CIFN binds to the same type I IFN receptors with a similar avidity, but in vitro studies suggest that CIFN and naturally occurring IFNα may trigger subtle differences in immune stimulation [9, 10, 11, 12]. Whether CIFN has greater in vivo anti-HCV activity than pegylated IFN-α remains controversial.

In this large VA observational study, we find that CIFN/RBV retreatment achieves SVR in only 6% of prior PEG-IFN/RBV nonresponders and 31% of prior relapsers. Based upon these findings and the results of DIRECT trial, CIFN/RBV cannot be clearly recommended for retreatment of prior PEG-IFN/RBV nonresponders. There may be a role for CIFN/RBV retreatment in PEG-IFN/RBV partial responders and relapsers but this needs to be better defined. The role of HCV protease and/or polymerase inhibitors combined with different types of interferon and ribavirin in PEG-IFN/RBV treatment failures will be an important area for further study and may provide additional options for this treatment-refractory population.

Notes

Acknowledgments

This study was performed with support from the Department of Veterans Affairs Hepatitis C Resource Center Program, VA Merit grant I01 CX000295, and an unrestricted grant from Valeant Pharmaceuticals International. The concept, study design, study preparation, data gathering, data analysis, and manuscript preparation were performed exclusively by the investigators. The authors would like to thank Daniel Tracy, Teresa L. Wright, and James C. Ryan for their assistance in the preparation of the manuscript.

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Copyright information

© Springer Science+Business Media, LLC (Outside the USA) 2011

Authors and Affiliations

  • Helen S. Yee
    • 1
    • 2
  • Sue L. Currie
    • 3
  • Kathryn Tortorice
    • 4
  • Myrna Cozen
    • 1
    • 2
  • Hui Shen
    • 1
    • 2
  • Summer Chapman
    • 4
  • Fran Cunningham
    • 4
  • Alexander Monto
    • 1
    • 2
  1. 1.Gastroenterology SectionDepartment of Veterans Affairs Medical Center (VAMC)San FranciscoUSA
  2. 2.University of California, San FranciscoSan FranciscoUSA
  3. 3.Clinical Care OptionsRestonUSA
  4. 4.Department of Veterans Affairs Pharmacy Benefits Management ServicesHinesUSA

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