Addition of Amantadine to Peginterferon and Ribavirin Does Not Increase the Efficacy of this Regimen

The results of several studies have suggested that the addition of amantadine (AMANT) to interferon (IFN) plus ribavirin (RIBA) may enhance the efficacy of this anti-viral regimen for chronic hepatitis C. Other studies have concluded no benefit from the triple combination of amantadine/ interferon/ribavirin.

The safety and efficacy of the triple combination of PEG-Intron (peginterferon alfa-2b / PEG-IFN) and ribavirin were assessed in a multi-center clinical trial.

Patients with chronic hepatitis C [elevated ALT, HCV RNA (+) by PCR] were enrolled [67 treatment naive and 101 without previous sustained virologic response (SVR)].

Patients were started on PEG-IFN at a dose of 1.5 mcg/kg weekly with RIBA 1000-1200 mg/d and AMANT 200 mg/d for 4 weeks, followed by PEG-IFN 0.5 mcg/kg weekly, RIBA 1000-1200 mg/d and AMANT 200 mg/d for another 20 weeks.

Patients with undetectable HCV RNA at week 24 continued this regimen for 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow up were considered to have SVR. Intention-to-treat analysis is being reported.

Of 168 patients enrolled, 74% were male, age 47.26±5.73, BMI 28.87±5.02, 79.2% were white, 84% had genotype 1 and 4, 16% genotype 2 and 3, and 36% with cirrhosis.

Their baseline HCV RNA was 689,242±698,030 IU/mL with a baseline ALT of 107.25±79.09. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow up.

Significant anemia (hemoglobin<10 g/dL) occurred in 19% (32/168) while severe anemia (hemoglobin<8.5 g/dL) occurred in 0.6% (1/168).

For the entire cohort, early virologic response after 24 weeks of therapy (ER) was 40.5%, with an end-of-treatment virologic response (ETR) of 35.7% and a SVR of 25%. This response was higher in patients who were treatment naive than those who were non-responders to previous treatment. Additionally, those with genotype 1 and 4 had lower response rates than those with genotype 2 and 3.

Patients with advanced fibrosis (METAVIR stage 3 and 4) had lower response rates than those with minimal or mild fibrosis (METAVIR stage 0-2).

African-American patients had lower response rates than Caucasians or other ethnic groups BMI, gender and age did not affect SVR.

Conclusion: The dddition of AMANT to PEG-IFN and RIBA does not increase the efficacy of this anti-viral regimen.

05/21/03

Reference
ZM Younossi and others. Triple Combination of Pegylated Interferon Alpha 2b, Ribavirin and Amantadine for Treatment of Chronic Hepatitis C. Abstract T1280 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

 

Procrit (epoetin alfa) Treatment of Anemic HCV Patients Allows for Maintenance of Ribavirin Dose, Increases Hemoglobin Levels, and Improves Quality of Life

Combination therapy for chronic HCV infection--ribavirin (RBV)/interferon alfa (IFN) or RBV/pegylated IFN alfa (PEG-IFN)--induces anemia that may compromise the ability to achieve a sustained virologic response (SVR) by prompting RBV dose reduction or cessation.

Treatment (tx) adherence is critical for achieving an SVR, and studies suggest that maintaining higher RBV doses (1000/1200 mg/day vs 800 mg/day) is more effective (Hadziyannis et al., EASL. 2002; Manns et al., Lancet. 2001; McHutchison, Hepatology. 2000).

Researchers assessed whether epoetin alfa (EPO) tx of anemic (Hb < or = 12 g/dL) HCV-infected patients (pts) could maintain RBV dose, increase hemoglobin (Hb) levels, and improve quality of life (QOL).

HCV pts (N=186) who developed anemia while being treated with RBV/IFN or RBV/PEG-IFN for an anticipated period of > or = 16 weeks (wks) were randomized to receive 40,000—60,000 IU, SC QW EPO or matched placebo (PL) with titration for 8 wks (double-blind phase [DBP]). Following the DBP, eligible pts received open-label EPO for the remainder of their HCV therapy.

After HCV therapy cessation, pts were followed at 4, 12, and 24 wks. The primary efficacy endpoint (assessed at the end of Wk 8) was RBV dose success—a Wk 8 RBV dose > or = study entry RBV dose.

Secondary efficacy endpoints assessed at Wks 9 and 17 were RBV dose, change in Hb levels, and QOL self-assessments (Linear Analog Scale Assessment [LASA] and Medical Outcomes Study Short Form-36v2 [SF-36v2]).

The investigators reported the preliminary results of the DBP. 

Pts (n=95 [EPO], n=91 [PL]) had similar baseline (BL) characteristics. RBV dose success was achieved in 88% of pts on EPO vs 60% on PL (P<.001). Mean RBV doses at the end of the DBP were 944 ± 217 mg/day (EPO) and 855 ± 241 mg/day (PL) (P<.001).

At 8 wks, 80% of EPO-treated pts had a RBV dose > or = the dose at the start of HCV therapy vs 49% of pts on PL (P<.0001). Mean Hb levels at the end of the DBP were 13.0 ± 1.3 g/dL (EPO) vs 10.8 ± 1.0 g/dL (PL) (P<.001); mean changes from BL Hb were +2.2 ± 1.3 g/dL (EPO) and 0 ± 1.0 g/dL (PL).

Mean scores on the LASA and selected SF-36v2 domains improved significantly from BL with EPO vs PL (P<.001—.003). EPO appeared safe and well tolerated.

Conclusion: In anemic HCV-infected pts on RBV/IFN or RBV/PEG-IFN, EPO maintains RBV dose and significantly improves anemia and QOL. EPO has the potential to improve adherence rates, which may in turn improve SVRs.

05/21/03

Reference
NH Afdhal and others. Epoetin alfa Treatment of Anemic HCV-infected Patients Allows for Maintenance of Ribavirin Dose, Increases Hemoglobin Levels, and Improves Quality of Life Vs Placebo: a Randomized, Double-blind, Multicenter Study. Abstract 505 (plenary session). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Aggressive Psychiatric Intervention Based on Clinical Suspicion, Not Standardized Depression Scores, Increases Adherence to Pegylated Interferon and Ribavirin Therapy

Neuropsychiatric side effects of pegylated interferon often lead to dose reductions or discontinuation of therapy for HCV. Depression is the most common reason for treatment discontinuation. Early treatment of depression may increase the efficacy of interferon-based therapy.

The objective of this study was to investigate the utility of standard depression scores (Beck Depression Index (BDI) and Center for Epidemiologic Studies-Depression (CES-D) for predicting depression and of early psychiatric intervention on adherence to pegylated interferon and ribavirin therapy.

55 treatment naive HCV patients at one site were entered into WINR-R, a study comparing standard ribavirin 800mg qd to weight based ribavirin, 800-1400mg qd, both with PEG-Intron 1.5 microgram/kg q wk.

The investigators reported on 39 patients with complete follow-up. BDI and CES-D surveys were completed at weeks 0,4,12,24,48 and 24 weeks post-therapy; investigators were blinded to results.

Psychiatric evaluation was performed by 1 psychiatrist if there was current (+ad, n=6) or prior (+hx, n=8) depression, or if they reported depression on routine questioning. Data on psychotropic medication and outcomes was collected.

30 of 39 patients completed surveys. During therapy, 40 (20% at entry), 30, and 6% used antidepressants, sleeping medications, and benzodiazepines respectively. 30% used no psychotropic medications.

There were no dose reductions for psychiatric side effects.

The 2 surveys were analyzed individually, and were normalized to produce 1 data set. Patients requiring antidepressants had mean maximum scores of 19 (BDI), 27 (CES-D), and 12 (normalized) compared to 10, 13, and 6 respectively for those not requiring antidepressants (p<0.05).

Mean scores for patient groups are shown in the figure. BDI and CES-D scores increased at wk 4, were higher at wk 48, and remained elevated 6 months after therapy.

Conclusions: Aggressive psychiatric intervention led to a 0% need for discontinuation of therapy for psychiatric side effects. Clinical assessment achieved this high adherence rate, as individual BDI and CES-D scores were too variable to predict the need for antidepressants.

Six months after end of therapy, patients did not resume their baseline psychiatric profile.

05/21/03

Reference 
J Moss and others. Aggressive Psychiatric Intervention Based on Clinical Suspicion, Not Standardized Depression Scores, Increases Adherence to Pegylated Interferon and Ribavirin Therapy for Hepatitis C. Abstract 216. Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Pegasys (peginterferon alfa-2a) Monotherapy Appears Safe and Effective for Children with Chronic Hepatitis C

Sponsored by the American Association for the Study of Liver Diseases (AASLD) and others, the annual Digestive Disease Week (DDW) conference, is one of the premiere liver meetings of the year. During the next two weeks, HIV and Hepatitis.com will report on selected treatment highlights, with a special focus on the pegylated interferons, presented at Digestive Disease Week 2003, now under way in Orlando, FL.

One presentation of particular interest on Monday morning (5/19/03) concerned the evaluation of Pegasys (peginterferon alfa-2a) for treatment of chronic hepatitis C in children.

While Pegasys monotherapy and in combination with ribavirin has been shown safe and effective in the treatment of adults with chronic hepatitis C (CHC) infection, there is not yet any published data on the safety and efficacy of peginterferon use in the treatment of children.

Some studies have concluded that standard interferon, with and without ribavirin, is safe and effective in children with CHC. The primary objective of the current study was to evaluate the safety, efficacy and pharmacokinetics (PK) of Pegasys in children with CHC.

This is a multicenter, open-label study of treatment-naïve children with established CHC. Children received Pegasys once weekly for 48 weeks with a 24-week post-treatment follow-up.

The dose was normalized for patient body surface area (BSA). Multiple blood samples were obtained to determine single-dose and multiple-dose PK. Adverse events (AEs) were assessed by clinical exam. HCV RNA was measured at weeks 12, 24, 48 and 72 using the Roche AMPLICOR MONITOR^TM HCV Test v. 2.0.

Fourteen patients, 8 males, 6 females, aged 2-8 (median = 3.5) years were enrolled; majority (13/14) were Caucasian and genotype 1 (12/13). CHC was acquired by vertical transmission in 11 patients.

After administration of the first PEgasys dose, there was rapid and sustained absorption with mean concentrations of 22.3 ± 8.2 nanogram/ml and 19.0 +/- 8.4 nanogram/ml at 24 and 96 hours post-dose. Mean steady-state trough concentrations were 24.3 ± 13.7 nanogram/ml. Pegasys concentrations increased 1.5- 2.5-fold before reaching steady state by week 12.

At weeks 24, 48, and 72, 57% (8/14), 43% (6/14) and 38% (5/13) of patients, respectively, were HCV RNA negative.

The most frequently reported AEs were pyrexia, headache, vomiting, anorexia and abdominal pain; no serious AEs were observed. The majority of these AEs were mild in intensity.

Four patients were withdrawn from therapy (1 due to lack of viral response at week 24; 2 due to elevated transaminases; 1 due to exacerbation of baseline hypertriglyceridemia). Five patients required dose reductions due to neutropenia.

Conclusions: Pegasys (peginterferon alfa-2a) was well tolerated. Exposure to peginterferon alfa-2a in pediatrics is slightly higher than in adults following a fixed 180 microgram dose.

The efficacy of Pegasys monotherapy in children appears higher than that reported for adults and approaches that for standard interferon+  ribavirin in children. These results support further study of Pegasys, with and without ribavirin, in children with CHC.

05/19/03

Reference
K B Schwarz and others. The Safety, Efficacy and Pharmacokinetics of Peginterferon Alfa-2a (40KD) In Children With Chronic Hepatitis C. Abstract 215. Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

Pharmacokinetics, Pharmacodynamics and Antiviral Response in Patients with Chronic Hepatitis C Infection on Methadone Maintenance Therapy Receiving Pegasys (peginterferon alfa-2a)   The majority of injection drug users (IDUs) are infected with hepatitis C virus (HCV) and are often treated with methadone maintenance therapy (MMT). Data suggests that methadone may suppress interferon-mediated antiviral activity. Studies are needed to evaluate the clinical and pharmacological interaction of Pegasys (peginterferon (40KD) alfa-2a/PEG-IFN) and methadone. The primary objective of the present study was to evaluate the potential for pharmacokinetic (PK), pharmacodynamic (PD) and clinical drug interactions with the concomitant use of 180 microgram PEG-IFN and methadone in CHC patients on MMT. The PK and PD of PEG-IFN were evaluated after single and multiple weekly 180 microgram doses in 24 CHC patients on MMT. PEG-IFN's effect on methadone pharmacokinetics was assessed by the comparison of methadone's PK before and after multiple doses of PEG-IFN. The PD effects of PEG-IFN were assessed by measuring 2',5'-oligoadenylate synthetase (2',5'-OAS) serum activity and HCV kinetics. Non-compartmental PK and PD analyses, including descriptive statistics and an ANOVA, were completed. The majority of patients enrolled were male (63%), Caucasian (63%), 50 to 124 kg, and 34 to 57 years old. Patients received stable daily methadone doses of 30 to 150 mg. PEG-IFN PK at week 1 and week 4 was similar to PEG-IFN PK determined from historic data in CHC patients not receiving MMT. Methadone PK was similar at baseline and after 4 weeks of PEG-IFN treatment. PEG-IFN-induced 2',5'-OAS activity after a single dose was similar to that seen in healthy subjects. Twelve of 20 (60%) patients demonstrated a virological response (undetectable [<600 IU/mL] or a 2-log10 drop in HCV RNA serum concentrations) by treatment week 4. The most frequently reported adverse events included headache, myalgia, pyrexia, fatigue and anorexia; most were mild or moderate in intensity. No signs of opioid withdrawal were observed. No patient modified methadone or PEG-IFN doses during the study. One subject withdrew prematurely due to poor venous access. Conclusions: - PEG-IFN monotherapy is well tolerated by CHC patients receiving MMT; - PEG-IFN and methadone do not significantly alter the PK of each respective therapy; - Biologic response as assessed by 2',5'-OAS activity was similar to that in healthy subjects; - HCV RNA decline was similar to that seen in CHC patients not receiving MMT; - These data suggest that MMT does not impair the antiviral activity of PEG-IFN. 05/19/03 Reference MS Sulknowsi and others. Pharmacokinetics, Pharmacodynamics and Antiviral Response in Patients with Chronic Hepatitis C Infection on Methadone Maintenance Therapy Receiving Peginterferon (40KD) Alfa-2a (Pegasys®). Abstract 231. Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.

Treatment of Recurrent Hepatitis C After Liver Transplantation with PEG-Intron (peginterferon alfa-2b) Plus Ribavirin: A Preliminary Analysis

Recurrent HCV is a significant cause of graft dysfunction and loss post orthotopic liver transplantation (OLT). Sustained virologic response rates to previous therapies were disappointing. Preliminary data on combination therapy with Peg-Intron (pegylated interferon alfa-2b/ PEG IFN alfa-2b) plus ribavirin are promising.

The aim of this study, presented at an AASLD topic forum, is to evaluate the safety, tolerability and efficacy of treatment with 2 different doses of PEG IFN alfa-2b plus 800 mg/day ribavirin in patients with recurrent HCV post OLT.

This multi-center, randomized clinical trial of OLT patients with recurrent HCV started with PEG IFN alfa-2b 0.5 microgram/kg/week plus ribavirin at 600 mg/day. At week 4, patients tolerating therapy were increased to ribavirin 800 mg/day and randomized to remain (low dose arm) or increase to 1.5 mcg/kg/week (high dose arm).

Therapy continued for 48 more weeks unless HCV RNA was positive at week 24. Growth factors were used to decrease needed dose reductions.

Enrollment included 30 patients (ages 38-67 years; mean 51.8, SD 6.9) (13 females; 17 males) with a range of 0.3-5.0 years since OLT (mean 1.67 ± 1.2). HCV was genotype 1 in 23 (77%) of patients.

Mean baseline HCV RNA was 4.2 million IU/mL (± 3.2; range 0.04-13.30 million IU/mL). Nine patients have not started therapy; 21 patients on therapy have completed 3-37 weeks (mean 18.4 ± 11.2 weeks).

In 11 patients completing >12 weeks, HCV RNA with high dose versus low dose was negative in 3/5 (60%) and 1/6 (17%), >2 log drop in 3/5 (60%) and 2/6 (33%), and >1 log drop in 3/5 (60%) and 4/6 (67%), respectively.

Four patients have completed 24 weeks; HCV RNA was negative in 2/2 on high dose; both patients on low dose were withdrawn due to positive HCV RNA.

Normalization of ALT occurred in 8/10 (80%) on high dose and 7/11 (64%) on low dose. Dose reductions occurred in high and low dose arms (1/10 and 3/11 for PEG INF alfa-2b; 4/10 and 5/11 for ribavirin, respectively).

One patient on low dose required a liver biopsy during therapy revealing possible mild rejection.

Conclusions: Preliminary analysis of recurrent HCV in OLT patients showed PEG IFN alfa-2b 1.5 mcg/kg/week plus ribavirin 800 mg/day (high dose arm) and PEG IFN alfa-2b at 0.5 mcg/kg/week plus ribavirin 800 mg/day (low dose arm) are effective at week 12 in clearing virus (60% and 17%, respectively) and >2 log drop in virus (60% and 33%, respectively).

Most patients normalized their ALT during therapy with no clinically significant episodes of rejection. High dose therapy was more effective than low dose therapy in early virologic clearance without added toxicity.

05/19/03

Reference
RH Ghalib and others. Treatment of Recurrent Hepatitis C after Liver Transplantation with Pegylated Interferon alfa-2b plus Ribavirin. Preliminary Analysis. Abstract 51 (oral). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL, USA.