Digestive Diseases and Sciences

, Volume 52, Issue 3, pp 732–736

Pegylated Interferon and Ribavirin Failures: Is Retreatment an Option?

Authors

  • Rekha Cheruvattath
    • Transplant MedicineMayo Clinic
  • Marianne J. Rosati
    • Transplant MedicineMayo Clinic
  • Manjushree Gautam
    • Transplant MedicineMayo Clinic
  • Hugo E. Vargas
    • Transplant MedicineMayo Clinic
  • Jorge Rakela
    • Transplant MedicineMayo Clinic
  • Vijayan Balan
    • Transplant MedicineMayo Clinic
    • Division of Gastroenterology and Hepatology, Transplant MedicineMayo Clinic
Original Article

DOI: 10.1007/s10620-006-9457-x

Cite this article as:
Cheruvattath, R., Rosati, M.J., Gautam, M. et al. Dig Dis Sci (2007) 52: 732. doi:10.1007/s10620-006-9457-x

Abstract

Currently, there are limited therapeutic options available for chronic hepatitis C (HCV) patients who fail treatment with peginterferon α (PEG IFN) + ribavirin (RBV). An option is retreatment with a second course PEG-IFN + RBV. However, the virologic clearance with this option is unknown. Thus, we evaluated the outcome of our cohort of patients with chronic HCV who achieved a sustained viral response when retreated with PEG IFN plus RBV after having no response to an initial course of PEG IFN plus RBV. Nonresponse to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of PEG-IFN + RBV therapy. Twenty patients (12 [60%] men; 8 [40%] women) were treated with PEG IFN α-2b plus RBV and PEG IFN α-2a plus RBV. The mean age of the patients was 50 years, 85% were white, 95% had genotype 1, and 35% had cirrhosis. Prior to the first course of PEG IFN plus RBV, 12 (60%) of 20 patients had no prior treatment for Hepatitis C. After the second course of PEG IFN plus RBV, 2 (10%) of 20 patients achieved a sustained virologic response. These results suggest marginal benefit of retreatment of patients with chronic HCV with another course of PEG IFN plus RBV after they have not responded to an initial course of PEG IFN plus RBV.

Keywords

Hepatitis CChronicInterferonPeginterferonRetreatmentRibavirin

The current standard of treatment for chronic hepatitis C virus (HCV) is a combination of pegylated interferon (peginterferon [PEG IFN]) and ribavirin (RBV), which has greatly improved the percentage of patients who achieve a sustained virologic response (SVR). Nevertheless, after this combination therapy, an SVR is not achieved in 40–50% of patients with genotype 1 chronic HCV and in about 30% of patients with genotype 2 or 3 chronic HCV [1]. Recent data have shown that about 18% of all patients with a previous lack of response to standard IFN therapy with or without RBV attain an SVR when retreated with PEG IFN and RBV [2]. However, there are limited therapeutic options available for patients with chronic HCV who do not respond to treatment with PEG IFN α and RBV. One approach has been to retreat the patients with another course of PEG IFN and RBV.

The decision to retreat a nonresponder should take into account the proportion of patients who are likely to achieve an SVR after retreatment. To our knowledge, there are no published reports of studies to date that specifically address HCV clearance rates in patients who are being treated with PEG IFN and RBV after not responding to a prior course of PEG IFN and RBV. We therefore undertook the present study to review our cohort of HCV patients who did not respond to an initial course of PEG IFN and RBV and who were subsequently retreated with a second course of PEG IFN and RBV.

Methods

Patients

We reviewed the records of all patients with chronic HCV in our institutional database who did not respond to an initial course of PEG IFN plus RBV and were subsequently retreated with another course of PEG IFN plus RBV. Nonresponse to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of PEG-IFN + RBV therapy. These included patients with a <1 log10 reduction in HCV RNA at week 4, <2 log10 decline in HCV RNA at week 12, positive HCV RNA at week 24 or 48, or detectable HCV RNA during the 24-week follow-up after completion of therapy with PEG IFN plus RBV. Patients whose therapy was discontinued during their first course of PEG IFN plus RBV for adverse events were not included.

Twenty patients met the inclusion criteria for analysis. Medical records were reviewed and the information collected included demographic information, HCV genotype, duration of first course and second course of PEG IFN plus RBV therapy. HCV viral loads during both courses of therapy were also collected. All 20 patients were treated initially with PEG IFN α-2b and RBV but did not respond to that treatment; they were subsequently treated with PEG IFN α-2a and RBV. PEG IFN α-2b was given weekly in a weight-based dose starting at 1.5 μg/kg per week and PEG IFN α-2a was started at 180 μg/week. The dose of RBV was based on body weight (1000–1200 mg/day). Dose changes took into consideration hemoglobin levels and neutrophil and platelet counts.

Virologic assay

Virologic assessment was determined by branched DNA-based VERSANT HCV RNA 3.0 assay (Bayer Diagnostics, Berkeley, CA) for quantitative assay and the COBAS AMPLICOR HCV Test 2.0 (Roche Diagnostics, Basel, Switzerland) for qualitative results.

Statistics

Continuous variables were presented as mean values with standard deviation. Categorical variables are expressed as percentages. The significance of differences between the 2 groups was determined by the 2-tailed Student t-test. P < .05 was considered statistically significant. We calculated 95% confidence intervals for proportions. The actual cumulative dose for the study cohort was calculated by obtaining the average dose of PEG IFN and RBV at the following time points: weeks 4, 8, 12, 24, 36, and 48 of treatment. Expected dose was the ideal dose that the patients would have received with no dose reductions or interruptions and was calculated at the same time points. Next, the area under the curve (AUC) was calculated using the trapezoid rule using Microsoft® Excel 2003. AUC was used to compare the expected and the actual doses received during the 2 courses of treatment and were expressed as a percentage.

Results

Demographics

Twenty patients who were treated with both PEG IFN α-2b plus RBV and PEG IFN α-2a plus RBV were included (Table 1). Of the 20 patients, 12 (60%) were men and 17 (85%) were white. The mean age was 50 years. Most patients (95%) had genotype 1 HCV. Seven patients (35%) had a fibrosis score of 6 according to the Knodell Histology Activity Index [3]. Before the first course of PEG IFN plus RBV, 12 of the 20 patients (60%) were naïve to treatment. Eight patients were treated with standard IFN or a combination of IFN and RBV (mean duration of prior treatment, 56 weeks; range, 24–120 weeks) before being treated with PEG IFN and RBV. Mean duration of the first course of treatment with PEG IFN and RBV was 38.7 weeks and of the second course was 33.7 weeks. Reasons for stopping therapy earlier are summarized in Table 2.
Table 1

Baseline characteristics of 20 patients with chronic hepatitis C retreated with pegylated interferon plus ribavirin

Characteristic

Patients (%)*

Gender

 

Male

12 (60)

Female

8 (40)

Race

 

White

17 (85)

African American

1 (5)

Hispanic

2 (10)

Mean age ± SD (range) (yrs)

50.2 ± 6.1 (44–66)

Mean BMI ± SD (range) (kg/m2)

30.3 ± 5.1 (23–40)

HCV genotype

 

Genotype 1

19 (95)

Genotype 2

1 (5)

Mean HCV RNA level (log 10 ± SD)

 

 Prior to first course

5.9 ± 6.09

 Prior to second course

6.07 ± 6.63

Mean baseline ALT (expressed as times upper limit of normal)

2.3 ±1.5

 Prior therapy

8 (40)

Mean duration of treatment

 

Prior therapy ± SD (range) (wk)

56 ± 30.4 (24–120)

First course (wk)

38.7 ± 22.7

Second course (wk)

33.7 ± 31.6

Abbreviations: ALT: alanine transaminase; BMI: body mass index; HCV: hepatitis C virus.

*Values are number (percentage) unless indicated otherwise.

Table 2

Reasons for stopping therapy

 

PEG IFN plus RBV

Reason

First course No. (%)

Second course No. (%)

Positive HCV RNA

  

At ≥24 weeks

11 (55)

7(35)

At 24 weeks

4 (20)

5 (25)

At 48 weeks

5 (25)

1(5)

At 72 weeks

2 (10)

1 (5)

<2 log10 decline at 12 weeks

4 (20)

6 (30)

<1 log10 decline at 4 weeks

3 (15)

4 (20)

Positive HCV RNA after stopping therapy

2 (10)

0 (0)

Adverse effects

0 (0)

1 (5)

SVR

0 (0)

2 (10)

Abbreviations: HCV: hepatitis C virus; IFN: interferon; PEG: pegylated; RBV: ribavirin; SVR: sustained virologic response.

Virology

After the first course of PEG IFN plus RBV, 11 patients (55%) still had detectable HCV RNA at 24 weeks. Five of these 11 were treated for an additional 24 weeks and 2 were treated for a total of 72 weeks. Four (20%) of the 20 patients had <2 log10 decline in HCV RNA at week 12; 3 patients (15%) had <1 log10 reduction in HCV RNA at week 4. Two of the 20 patients had detectable HCV RNA after completion of therapy. After the second course of PEG IFN and RBV, 2 patients (10%) achieved an SVR. These 2 patients had been treated for a total of 68 and 72 weeks during the second course of therapy with PEG IFN plus RBV, including 48 weeks after their HCV RNA became negative.

One (5%) patient was treated for 48 weeks; the other (5%) was treated for 72 weeks for persistent viremia at the end of treatment. Five patients (25%) stopped therapy after testing positive at 24 weeks. Six patients (30%) stopped treatment because they did not have a 2 log10 decrease in HCV RNA at week 12, and 4 patients (20%) stopped treatment because they had <1 log10 decline in HCV RNA. One patient had to stop treatment at week 12 because of a severe rash. When patients who did not show <1 log10 reduction in HCV RNA at week 4 were excluded, SVR was 12.5%.

Exposure to pegylated interferon and ribavirin

The actual cumulative dose and the expected dose were calculated for both PEG IFN and RBV during both courses of treatment. Next, the AUC was used to compare these 2 doses. Figure 1 shows the actual cumulative dose as a percentage of the expected cumulative dose. During the first course, patients received 85.3% of the expected dose of PEG IFN compared to 83.8% during the second course (P = NS). Regarding the dose of RBV, patients received 91.2% of the expected dose and 88.1% during the first and second courses of treatment respectively (P = NS).
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-006-9457-x/MediaObjects/10620_2006_9457_Fig1_HTML.gif
Fig. 1

Cumulative doses of pegylated interferon and ribavirin during the first and second courses of treatment as a percentage of expected dose. 1st course: pegylated interferon 85.3%; ribavirin 91.2%. 2nd course: pegylated interferon 83.8%; ribavirin 88.1%

Use of growth factors

The use of erythropoietin or granulocyte-colony stimulating factor (G-CSF) or both was about the same in both groups of patients. Sixteen patients (80%) used erythropoietin in the first course, and 8 patients (40%) used G-CSF. During the second course, 17 patients (85%) used erythropoietin and 11 patients (55%) used G-CSF.

Details of responder patients

Patient 1 was a 45-year-old Caucasian male, previous nonresponder to interferon plus ribavirin treatment, with a BMI of 24, pretreatment viral load of >600,000 IU/mL, and minimal fibrosis on liver biopsy. This patient was treated with PEGIFN α-2b 1.5 μg/kg and RBV 1000 mg/d. During the first course of PEG IFN therapy, this patient received 100% of the expected dose of PEG IFN plus RBV without any dose reductions. At week 12, the HCV RNA was nondetectable but the HCV PCR was positive. However at week 24, the HCV-RNA levels increased to 3690 IU/mL. At the end of treatment at 48 weeks, the patient did become HCV PCR negative, but subsequently at week 12 follow-up became HCV RNA positive. The second course of therapy was with PEG IFN α-2a 180 μg/week and RBV 1000 mg/d for 68 weeks. The patient was treated for 48 weeks after the HCV RNA became negative during this course. The patient has been followed for 72 weeks after completion of treatment and remains HCV RNA negative.

Patient 2 was a 47-year-old African American female who was naïve to any previous HCV therapy, with a BMI of 25 and a pretreatment viral load of 5,178,500 IU/mL. Fibrosis on liver biopsy was 3 out of 6 by the modified hepatic activity index. This patient was treated with PEG IFN α-2b 1.5 μg/kg/week and RBV 800–1000 mg/d. During this first course of PEG IFN therapy, this patient received 89.6% of the expected dose of RBV and 81.3% of the expected dose of PEG IFN. At week 12, the patient had a <2 log drop in HCV RNA (74,728 IU/mL) and remained HCV PCR detectable at week 24. The second course of therapy was with PEG IFN α-2a 180 μg/week and RBV 1000 mg/d for 72 weeks. The patient was treated for 48 weeks after HCV RNA became negative during this course. The patient has been followed for 48 weeks after completion of treatment and remains HCV RNA negative

Discussion

Currently, there are limited therapeutic options available for patients with chronic HCV whose treatment with PEG IFN-α and RBV proves unsuccessful. One approach has been to retreat patients with another course of PEG IFN and RBV. We did not notice any significant benefit in our cohort of patients who were treated with another course of PEG IFN and RBV; the response rate was only 10%.

During the past 2 decades, there has been an evolution in the treatment of hepatitis C. The retreatment of IFN nonresponders has been challenging, and various attempts using different types of treatment with IFN and RBV have been made. However, there has not been a substantial improvement in the response rate for retreatment of patients whose prior treatment failed. For example, the retreatment with IFN of patients after IFN failure resulted in an SVR of about 2% (10 of 443; 95% confidence interval, 1–4%) [4]. Patients retreated with a different form of IFN showed a higher response rate (13.0–18.6%) [5, 6]. When IFN nonresponders were treated with a combination of IFN and RBV, the resulting SVR was 13–21% [4, 7] (higher with a 48-week treatment and higher in patients who were non–type 1 genotypes). The SVR increased to 25–40% when PEG IFN and RBV were used [1, 8]. When failures occurred in patients with the standard IFN and RBV treatment and they were retreated with PEG IFN plus RBV combination therapy, an SVR was noted in only 6–10% of the patients [8, 9]. In 1 study that evaluated on-treatment responses, an SVR was achieved only in patients who were partial responders [8]. There was no SVR in nonresponders.

This report describes the experience in a practice-based setting on the outcome of retreatment of HCV with PEG IFN plus RBV after failure of an initial course of PEG IFN and RBV. As this is a review of this treatment experience and treatments were discontinued for various reasons, we wanted to ensure that true failures were included for this analysis. The currently well accepted criteria of non-response to treatment such as failure to achieve a 2 log10 decline in HCV RNA at week 12 or detectable HCV RNA at week 24, or at end of treatment or after completion of therapy with PEG IFN plus RBV were used. In addition, we also used the criteria of failure to have <1 log10 reduction in HCV RNA at week 4. Indeed, several studies have shown the utility of early testing at week 4 for HCV viremia as a predictive factor of sustained response during treatment for HCV [1012]. When patients who did not show <1 log10 reduction in HCV RNA at week 4 were excluded, SVR was still only 12.5%.

A limitation of our study is that it is retrospective. However, to our knowledge, this is the first published report on the experience in a real-life, practice-based setting of retreatment of HCV with PEG IFN plus RBV after failure of an initial course of PEG IFN and RBV. We believe that this study provides a valuable tool for designing future studies to investigate the treatment options for nonresponse.

An important point regarding the 2 patients who did achieve SVR is that they were treated for >48 weeks. They were treated for a total of 68 and 72 weeks (for 48 weeks after HCV RNA became negative) during the second course of PEG IFN plus RBV. These patients were treated for a longer period of time because they demonstrated fluctuating levels of viremia, including positive HCV RNA following periods of undetectable RNA. This finding suggests that the standard 48-week treatment is insufficient and that an extended course of treatment may be necessary.

The American Association for the Study of Liver Diseases guidelines currently do not recommend retreatment with PEG IFN plus RBV with the aim of eradicating HCV in patients who have failed to respond to a prior course of PEG IFN plus RBV, even if a different type of PEG IFN is administered [13]. While we await newer treatment modalities for this patient population, use of consensus interferon may be an option. In a recent report by Cornberg et al. [14], the use of daily dosing of consensus interferon plus RBV appeared to be a promising concept for selected nonresponder HCV patients.

In conclusion, HCV patients who fail PEG plus RBV may represent a highly resistant group of patients who need more effective treatment strategies, preferably with multidrug combinations. Retreatment of these patients with another course of PEG IFN plus RBV after they have not responded to an initial course of PEG IFN plus RBV is of marginal benefit.

Copyright information

© Springer Science&#x002B;Business Media, Inc. 2006