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  The Digestive Disease Week 2003 Conference
Orlando, Florida May 17-23, 2003
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Retreatment with PegIntron plus Ribavirin for Nonresponders & Relapsers to Prior HCV Therapy
Reported by Jules Levin
  "Pegylated Interferon alfa-2b plus Ribavirin in Patients with Chronic C: a Trial in Prior Nonresponders to Interferon Monotherapy or Combination Therapy and in Combination Therapy Nonresponders" abstract 504
Although the conference is not over, there are no more hepatitis presentations, so I'm through. Additional reports of information and study results from this conference is forthcoming. All reports are archived on the NATAP website at in addition to the email reports.
Ira Jacobson, MD, (Cornell Hospital, NYC) reported the final results of the this Study, which examines retreatment with PegIntron plus ribavirin using two different dosing combinations for 320 patients who had prior therapy but did not achieve sustained viral responses.
In brief, this study found that patients who were prior nonresponders to standard interferon plus ribavirin can respond to pegylated interferon plus ribavirin, but the overall response rates were disappointingly low. Patients who were previoulsy treated and relapsed at the end of treatment showed a better response to PegIntron plus ribavirin than nonresponders. Patients who were previously treated with standard interferon alone (without ribavirin) showed a better response to PegIntron plus ribavirin than patients who were non-responders to prior combination therapy, but not as well as patients who relapsed at the end of treatment with combination therapy with standard interferon: combination relapsers>IFN NR>combination NR. The actual data and details from the study follows. At the end of this report is a discussion of additional treatment options for nonresponders.
The study compared the efficacy of two regimens of pegylated interferon alfa-2b (PegIntron) and ribavirin:
GROUP 1: PEG IFN alfa-2b 1.0 mcg/kg + RBV 1000-1200 mg/day
Or Group 2: PEG IFN alfa-2b 1.5 mcg/kg + RBV 800 mg/day
Group 2 received the higher dose of peginterferon with the lower dose of ribavirin. These 3 patient groups were treated:
--combination therapy nonresponders (viral load was not undetectable at the end of treatment)
--combination therapy relapsers (viral load rebounds at the end of treatment after being undetectable on treatment)
--interferon monotherapy nonresponders
To qualify for this study patients had compensated liver disease, they did not have decompensated cirrhosis. They did not have not concmitant liver disease. They were HCV RNA positive. There was no ALT restriction. They had to have a liver biopsy within 3 years. Patients were treated for 48 weeks in the WIN-R Study. They were discontinued at week 24 if they were PCR positive.
The patient characteristics were comparable between the two study treatment groups. Age- 49; 75% male; mean ALT 100; 90% genotype 1; 8% genotype 2; mean stage of fibrosis (Metavir 2.2). About 60% of patients had stage 02 liver disease (histology), about 40% had stage 3-4. About 28% had <1 million copies/ml of viral load and about 70% had >1 million. 321 patients were randomized. In Group 1 (n=161) 114 were combination non-responders, 25 were combination relapsers, and 22 were interferon nonresponders. In Group 2 (n=160), 105 patients were combination non-responders, 30 were combination relapsers, and 25 were interferon nonresponders.
Sustained Viral Response: overall results
--42% of combination relapsers achieved SVR
--21% of IFN nonresponders had SVR
--8% of combination nonresponders had SVR
Combination Nonresponders
--at week 24, 30% in group 2 were HCV RNA negative vs 18% in group 1
--at week 48, 24% in group 2 were HCV RNA negative vs 12% in group 1
--at week 72 (24 weeks after the end of treatment), 10% in group 2 vs 6% in group 1 were HCV RNA negative (this difference was not significantly different)
You can see the difference between week 48 and week 72, the relapse rate in this study for nonresponders is high.
I found 3 additional studies at the conference on this subject presented in posters. Two of the studies had similar results. The third presented by Paul Gaglia (Columbia-Presbyterian Hospital, NY) examined 462 patients in New Orleans and showed better responses to therapy: 21% of combination nonresponders achieved SVR; 17% of Caucasians with genotype 1 and 50% of Caucasians with genotype 2/3; interesting Gaglia reported 19% of Blacks had SVR, as Blacks usuyally do not respond as well to therapy. The first 250 patients who enrolled in this study received PegIntron 1.5 mcg/kg plus ribavirin 800mg/day. The remaining patients enrolling received PegIntron 1.5 mcg/kg plus weight-based dosed ribavirin (800-1400 mg/day).
Back to the WIN-R Study.
Combination Nonresponders: genotype 1
--at week 48, 24% in group 2 and 9% in group 1 were HCV RNA negative --at week 72, 9% in group 2 and 5% in group 1 were HCV RNA negative (the difference between groups 1 & 2 were not significant) Again a high relapse rate.
Combination Relapsers
These patients had much better response rates.
--at week 48 (end of treatment), 77% in group 2 and 60% in group 1 were HCV RNA negative --at week 72, 50% in group 2 and 32% in group 1 had SVR (the difference between groups was not significant)
Interferon Nonresponders
--at week 48, 40% in group 2 and 32% in group 1 were HCV RNA negative
--at week 72, 16% in group 2 and 27% in group 1 had SVR (the difference was not significant)
SVR: genotype 2/3
The numbers of patients were small.
--3/16 (19%) of combination nonresponders had SVR
--5/8 (63%) of combination relapsers had SVR
--2/7 (28%) of interferon nonresponders had SVR
--47% (42/88) of patients experienced relapse (return of HCV RNA after being undetectable at the end of 48 weeks treatment)
--9% (11/116) of patients had breakthrough (HCV RNA positive at week 48 after being HCV RNA negative at week 24 during treatment)
Sustained Response and Fibrosis
  Apparently, the higher peginterferon dose in group 2 was more effective in stage 3-4 fibrosis.
Patients with normal ALT at study entry had 21% SVR and patients with elevated SVR had 14% SVR.
African-Americans (n=48) did more poorly than Caucasians (n=224). 4% of African-Americans had a 4% SVR regardless of being in group 1 or 2. Caucasians in group 2 had 23% SVR, Caucasians in group 1 had 14% SVR.
Combination nonresponders with low viral load (<100,000 copies/ml) at the end of treatment when they were previously treated had better response rates than patients with >100,000 copies/ml viral load at the end of their previous treatment (21% vs 5%; p=0.002).
Predictive Value of HCV RNA at 12 Weeks
This held up in the study.
41 combination nonresponders with SVR or relapse and week 12 viral load test results were available for analysis.
--23 sustained responders: all were HCV RNAnegative at week 12
--18 relapsers: 10/18 were HCV RNA positive at week 12, and negative at week 24; 8/18 were HCV RNA negative at week 12
Adverse Events
Serious adverse events: 11% in group 1; 8% in group 2
Discontinuations for AE: 11% in group 1 and 13% in group 2
Dose Modifications
  Jacobson summarized:
--SVR rates: combination relapsers>IFN NR>combination NR
--higher relapse rates than in treatment-na•ve patients
--higher PEG IFN dose better with advanced fibrosis
--poor response in African-Americans
--normal ALT does not impair SVR
--all SVRs with 12 weeks PCRs were negative
--in combination NR, low viral load at prior end-of-treatment associated with SVR
Jacobson concluded by suggesting further study of higher doses of peginterferon for nonresponders. He also suggested study of longer duration therapy.
Editorial note from Jules Levin: so what additional treatment options do nonresponders and relapsers have to potentially increase their chance for better response rates? A dose of 3.0 PegIntron is currently in study and preliminary results suggest improved response rates while tolerability so far seems acceptable. New antiviral drugs are in early stages of treatment: polymerase and protease inhibitors. A pilot study of a protease inhibitor in HCV+ patients showed potency. Maintenance therapy with half-dose peginterferon may slow disease progression. A small pilot study using high-dose Consensus Interferon in nonresponders was presented at this conference showed promising and improved response rates, I'll be reporting the study results in a soon forthcoming email report, hopefully by tomorrow.