Erythropoietic Response to Anemia is Decreased in Patients Infected With Hepatitis C Virus (HCV) Receiving Combination Ribavirin and PEG-Intron (peginterferon alfa-2b) Therapy

Studies in anemic patients (pts) with cancer and HIV infection show that the inverse relationship between serum erythropoietin (sEPO) and hemoglobin (Hb) seen in control pts with iron deficiency anemia (IDA) is decreased, suggesting that these pts have a blunted erythropoietic response (Spivak et al, JAMA 1989; Miller et al, NEJM 1990).

The present study was conducted to describe the patterns of change in Hb, sEPO, and reticulocytes (retics) to evaluate if HCV-infected pts treated with ribavirin and pegylated interferon (RBV/PEG-IFN) therapy (tx) also show a diminished erythropoietic response to anemia. Historic control pts with IDA were used as a comparator.

A multicenter, observational, 8-week (wk) study is being conducted in 100 HCV-infected pts scheduled to receive their initial course of RBV/PEG-IFN tx. Laboratory parameters are measured weekly for 8 wks or until early withdrawal (endpoint). Primary variables include changes in Hb, sEPO, and retics. Interim results are presented.

The interim analysis included 65 pts (mean age, 46.9 yrs; 37.3% men). Mean Hb decreased by 2.7 ± 1.4 g/dL from Day 1 (D1) to endpoint. Mean sEPO and retics increased from D1 to endpoint; however, regression analysis showed that the estimated erythropoietic response (defined as the slope of the relation between sEPO and Hb) was lower (sEPO = -18.3 Hb + 264 [r = -0.51]) than in historic control pts with IDA (sEPO = -25.8 Hb + 316 [r = -0.90], sEPO = -45.0 Hb + 518 [r = -0.71]).

The mean initial dose of RBV was 982 mg/day versus 906 mg/day at endpoint. A total of 9.2%, 9.2% and 1.5% of pts had 200, 400, and 600 mg/day RBV dose reductions, respectively, from D1 and at Wk 8. There was no change in mean PEG-IFN doses from D1 (1.54 mcg/kg) to Wk 8 (1.49 mcg/kg). There were 7 pt withdrawals due to side effects of HCV tx.

Conclusion: Similar to other pt groups, HCV-infected pts treated with RBV/PEG-IFN showed diminished production of endogenous sEPO for their degree of anemia when compared with historic control pts with IDA.

These data point to a multifactorial etiology for the anemia seen with combination HCV tx, which, as shown in preliminary studies (Dieterich et al, AASLD 2002; Sulkowski et al, AASLD 2001), could be responsive to treatment with recombinant human erythropoietin (rHuEPO).

05/19/03

Reference
V Balan and others. Erythropoietic Response to Anemia is Decreased in Patients Infected With Hepatitis C Virus (HCV) Receiving Combination Ribavirin and Pegylated Interferon (RBV/PEG-IFN) Therapy. Abstract M1417 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

PEG-Interferon Alfa-2b Plus Ribavirin for Treatment of CHC Patients Who Failed or Relapsed Following Interferon-based Therapy

The role of PEG-Intron (pegylated interferon alfa-2b/ PEG) and ribavirin (RBV) therapy for patients (pts) with chronic Hepatitis C (HCV) who have previously failed interferon (IFN)-based therapies is not fully known.

The objective of the current study was to compare the safety and efficacy of continuous weight-based (CONT) vs. Categorical weight-based (CAT) PEG-IFN alfa-2b/RBV in pts who have failed to achieve sustained virologic response after previous IFN/RBV treatment.

This is an open-label, multi-center, randomized clinical trial of CONT vs. CAT PEG/RBV. Pts were randomized to receive 800mg RBV QD with either Continuous weight adjusted PEG-IFN aldfa-2b (1.5 mcg/kg) QW (n=259) or Categorical weight adjusted PEG-IFN alfa-2b (100 mcg if < 80kg, 150 mcg if > 80kg) for 48 weeks. HCV RNA was evaluated at baseline (BL), week 12 (EVR), and end of treatment (EOT). Intent-to-treat response rates were compared using Fischer's Exact Test and logistic regression.

517 pts were enrolled and took at least one dose of drug. The median age was 47 years, and the pts were 64.8% male, 76.8% Caucasian, 13.5% Black and 8.3% Asian. HCV Genotype 1, 90.5% and 2 or 3, 9.5%.

207 pts completed 48 weeks of treatment. 278 pts withdrew before EOT; the primary reason for withdraw was viral non-response.

No differences were observed in AEs between treatment groups, including neutropenia (p=0.7). EVR/EOT for CONT and CAT were 40.0%/24.3% and 31.0%/25.6%, respectively (p=0.47 and 0.64)). EVR/EOT for relapsers and non-responders were 50.6%/34.9% and 23.9%/20.3%, respectively (p < .0003). EOT response was 23.8% in genotype 1 and 36.7% in genotype 2/3(p=0.046).

Conclusions: Continuous and Categorical weight-based dosing of PEG-IFN alfa-2b/RBV had similar safety and efficacy in the re-treatment of pts who failed or relapsed after original IFN-based therapy for HCV.

Among non-responders to prior therapy, the EOT response was more than 20%; as expected the EOT was higher among relapsers.

These data suggest that PEG-IFN alfa-2b/RBV may be effective in persons who initially failed to respond to or relapsed after previous IFN/RBV treatment.

05/23/03

Reference
M Sulkowski and others. PEG-Interferon alfa-2b + Ribavirin for Treatment of Patients with Chronic Hepatitis C Who Have Previously Failed to Achieve a Sustained Virologic Response Following Interferon alfa or Interferon a-2b + Ribavirin Therapy. Abstract T1292 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Use of Carotenoid-based Functional Food Minimizes the Severity of Ribavirin-related Anemia

Oxidative stress plays a major role in the physiopathology of hemolytic anemia during ribavirin therapy. The efficacy of antioxidant supplementation (vitamin C and E as pure compounds) is still controversial.

Italian researchers conducted a study to verify if the supplementation with an antioxidant-rich tomato-based functional food (FF) reduces the anemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy for chronic hepatitis C (CHC).

A functional food with high content of natural antioxidants and demonstrated high carotenoid bioavailability was developed.

The investigators enrolled 92 patients (70M/22F) with CHC, treated with standard combination therapy. 46 of them received a daily dose (100g.) of FF (group 1), and 46 did not (group 2).

At baseline, the groups were similar for demographics (M/F, body weight, age); mean hemoglobin (Hb) levels (15.09 vs 14.9 g/dl, p= ns), and both groups received a similar mean dose of RBV (13.51, +/- 1.09 vs 13.39 +/- 1.52 mg/kg, p=ns).

The effect of antioxidant activity was assessed comparing the compliance to the start dose of RBV and the Hb levels during the first three months of treatment.

Only 4/46 (8.7%) patients of group1 had to reduce daily RBV dose, while RBV reduction was necessary for 14/46 (30.4%) in group 2 (p= 0.09). Hb levels during the observation time are reported in the table.

The authors conclude “ The results demonstrated that our antioxidant-rich tomato-based functional food limit the severity of ribavirin-related anemia and improve the tolerance to the initial dose of ribavirin in patients with chronic hepatitis C.”

 Mean Hemoglobin levels

05/23/03

Reference
F Morisco and others. Use of Carotenoid-Based Functional Food Minimizes the Severity of Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C: a Randomized Study. Abstract 234 (topic forum). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

Reasons for Discontinuation for Treatment of Chronic Hepatitis C: Interim Analysis of the Frontier Trial

Treatment with pegylated interferon and ribavirin may be an option for patients with chronic hepatitis C who have failed Rebetron combination therapy (Reb) and/or interferon monotherapy (IFN). However, a major obstacle to attaining a positive treatment outcome is whether or not patients can complete their full course of therapy.

Two hundred thirteen patients with chronic hepatitis C who have failed Reb and/or IFN were randomized to treatment with Peg-Intron and ribavirin (P+R) for 24, 36, or 48 weeks. Patients were enrolled and treated at one of six academic institutions (AI) or one of twelve community practices (CP).

All received Peg-Intron 1.5 mcg/kg/weekly and ribavirin 800 mg/d. This is an interim report of the first 146 patients treated. Reason for discontinuation of treatment was assessed for each patient who did not complete his or her assigned therapy.

Of the 146 patients, 60 were treated at AI and 86 were treated at CP. Eighty-eight of the 146 patients completed the full course of treatment to which they were randomized: 45 of 60 at AI (75%) and 43 of 86 at CP (50%; p vs. AI= 0.002).

Of the 58 patients that did not complete the full course of treatment, 40 patients chose to drop out of the study: 9 of 60 at AI (15%) and 31 of 86 at CP (36%; p vs. AI= 0.005). Twelve patients in CP and 4 in AI dropped out of the study within the first twelve weeks (p = 0.18).

The most common reasons cited for dropping out were related to the usual flu-like and neuro-psychiatric side effects of therapy in 13 cases (4 in AI vs. 9 in CP; p= 0.55), not recorded (9, all in CP), and non-compliance with the protocol (1 in AI vs. 5 in CP).

Eighteen serious adverse events led to treatment termination (6 in AI and 12 in CP) and included

- complaints of chest pain (3),

- suicidal ideation (2),

- severe depression (2), and

- irritability/aggressiveness (2).

No significant effect of age, gender, BMI, or race was seen on adherence rates.

Adherence to therapy during the first 12 weeks of pegylated interferon and ribavirin therapy and then throughout the remainder of the treatment course has been associated with successful treatment outcome.

This data shows a disparity between academic and community institutions regarding the rates of patient-initiated discontinuation of treatment (i.e. dropouts), and suggests that treatment response rates and rates of compliance typically reported in the literature may not accurately depict rates of success that can realistically be expected.

05/23/03

Reference
M Nichols and others. Reasons for Discontinuation of Treatment of Chronic Hepatitis C: An Interim Analysis of the Frontier Trial. Abstract 235 (topic forum). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

 

Interferon and Interferon Plus Ribavirin in Prevention of Hepatocellular Carcinoma

IFN prevents hepatocellular carcinoma (HCC) development in patients with HCV-related cirrhosis. The effect is modest and seems more pronounced among sustained responders. Data on the preventive effect of more powerful therapeutic regimens on HCC development are lacking.

A total of 101 patients (62 males and 39 females, mean age 55.1 +/- 1.4) with histologically proven HCV-related liver cirrhosis and compatible biochemistry and ultrasonography were enrolled in this Italian study. Ultrasonography was performed every 6 months. Liver biopsy was performed on all focal lesions detected by ultrasound. Follow-up after treatment lasted an average of 6 years.

To evaluate hepatocyte proliferation, Ag-NOR proteins were measured in hepatocyte nuclei present in 50 consecutive microscopic fields using a specific computer-assisted imaging system. The percentage of hepatocytes with an AgNOR area > 7 square micrometers (indicative of a proliferative state) was expressed as AgNOR-PI (AgNOR-Proliferative Index) (cut-off=25).

41 patients (27 m, 14 f) were only followed up after the end of a year of treatment with IFN-alpha2b (6 MU/day for 30 days followed by 3 MU/day for 11 months) (Old Treatment Control Group = OTCG).

60 naives patients (35 m, 25 f) were stratified according to sex and AgNOR-PI and then randomized in two groups: 30 were treated with IFN-alpha2b (6MU/day for a month then 3 MU/day for 11 months) +Ribavirin (1 g/day for 11 months) (Treatment Group = TG) and the remaining served as controls (Control Group = CG).

Non responders or relapsers in the TG received further IFN/ribavirin treatments after 6 mo withdrawal.

The AgNOR-PI was significantly lowered by IFN; 9 patients (26%) out of 35 with basal AgNOR-PI higher than 25 developed HCC, while 2 (3%) out of 66 with basal AgNOR-PI lower than 25 developed tumors (p<001). Two patients of OTCG (both non responders) developed HCC during 6 yrs of follow-up after about 50 months from IFN withdrawal.

None of the 30 patients in the TG developed HCC, while 9 (30%) patients in the CG developed HCC during follow-up. The Kaplan-Mayer survival curves showed statistically significant differences among OTCG vs CG (p<0.004) and TG vs CG (p<0.003). The HCC annual rate of incidence in the CG was 5%.

Conclusion: IFN/ribavirin treatment associated with re-treatment courses of non responder patients seems to produce the best results in terms of HCC prevention. AgNOR-PI is a useful marker of possible HCC development.

05/23/03

Reference 
F Azzaroli and others. Interferon and Interferon Plus Ribavirine in Hepatocellular Carcinoma Prevention: A Prospective Study on Patients with HCV-Related Cirrhosis. Abstract 233 (topic forum). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

Pegylated Interferon Alfa-2b Plus Ribavirin for Prior Nonresponders and Relapsers

Pegylated interferon (PEG IFN) has proven superior to standard interferon (IFN) as monotherapy for chronic hepatitis C and, more recently, in combination with ribavirin (RBV) in treatment naive patients.

The objective of this study was to compare the efficacy of two dose regimens of PEG-Intron (peginterferon alfa-2b) plus ribavirin in patients with prior nonresponse to IFN monotherapy or combination therapy, or with relapse after combination therapy. We present final data from this study.

Patients in the three categories were randomized to receive

(1)     peginterferon alfa-2b 1.0 microgram/kg plus RBV 1000-1200 mg/d (Group 1), or

(2)     peginterferon alfa-2b 1.5 µ/kg plus RBV 800 mg/d (Group 2).

Prior therapy must have been stopped at least three months prior to entry. Patients were treated for 48 weeks with cessation of therapy if HCV RNA PCR (Roche Amplicor) was positive at 24 weeks.

Of 321 patients enrolled in the study, 161 were randomized to Group 1 and 160 were randomized to Group 2. Overall, the sustained response (SR) rate was 15% across the three categories. SR rates for the different treatment groups are given in the table.

Among the combination non responders, patients with genotype 1 had lower SR rates than non-genotype 1 patients (5-9% vs. 13-25%). Patients with normal ALT respond as well as those with an elevated ALT at onset of therapy (21% vs. 14%, p=0.54).

Patients with advanced fibrosis (Metavir stage 3-4) tend to respond better with the higher dose of PEG IFN (25% vs. 5%, p=0.44)

Conclusions:

(1)     SR rates are highest in combination relapsers (range 32-47%) and lowest in genotype 1 combination non responders (range 5-9%).

(2)     Breakthrough and relapse are more common than in naive patients; the concept of treatment for more than 12 months warrants further study.

(3)     Higher dose of PEG IFN may be better in patients with fibrosis.

(4)     Normal ALT does not adversely affect response.

Quantitative PCR <1000 cop/ml at follow-up week 24

05/23/03

Reference
IM Jacobson and others (PEG-Intron Study Group). Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: Final Results. Abstract 504 (plenary session). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.