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New Strategies for the Treatment and Supportive Care of Veterans with Hepatitis C Conference
San Francisco, California. January 16-18, 2002

Alan Franciscus
Editor-in-Chief
HCV Advocate

Part 2

Session Two

“Chronic Hepatitis C Virus Infection: Therapeutic Options for Relapsers and Non-Responders” Dr. Steven L. Flamm, Medical Director of Liver Transplantation, Northwestern Memorial Hospital

Dr. Flamm opened his session by defining the difference between a hepatitis C patient who relapses after therapy and a hepatitis C patient who has a non-response to therapy. He defined the terms ‘relapse’ and ‘non-response’ as follows:

Relapse – HCV RNA positivity in the follow up period after completion of an HCV treatment regimen during which HCV RNA was undetectable at the end of therapy. HCV RNA testing by PCR should be as sensitive as possible(<100 copies/ml).
Non-Response – HCV RNA positivity after completion of an HCV treatment regimen of at least 12 weeks using sensitive HCV RNA testing by PCR(<100 copies/ml)

Next Dr. Flamm discussed what the scope of the problem is regarding treating hepatitis C in patients that have either relapsed after therapy or are non-responders to therapy.

Firstly, with a 12 month course of interferon alpha monotherapy, approximately 25% of naïve patients will relapse and approximately 60% of patients will not respond. When that is compared with combination therapy of interferon alpha and ribavirin, approximately 20% of naïve patients will relapse and 40% will not respond. Finally, with the pegylated interferon alpha and ribavirin, Dr. Flamm said that approximately 10% of naïve patients will relapse and approximately 35% of patients will not respond.

Dr. Flamm then posed a question. “What should be done in the management of patients with hepatitis C who relapse or do not respond and attain a sustained virologic response with currently available therapy? Is maintenance therapy beneficial for these patients who relapse or do not respond?”

To date there are very few published articles in this area but Dr. Flamm shared the following information that is available :

Relapse

According to Dr. Flamm, the predictors of relapse for patients with hepatitis C are:

  • Genotype 1
  • Shorter treatment course
  • Advanced liver disease, which includes stage 3 and 4 fibrosis
  • HCV RNA detectable in the hepatocytes (keep in mind that it is very difficult to perform tissue PCR)

Dr. Flamm firstly went over the data that is available regarding the re-treatment of relapsers to interferon alpha monotherapy.

Patients that were relapsers to a course on interferon alpha monotherapy

  • Patients who relapsed after a 6 month course of interferon alpha with standard interferon alpha monotherapy when retreated with interferon alpha monotherapy for 12 months yielded an SVR of 56%. (This data was published by Alberti in Hepatology 1997;26 (suppl 1): 137S-142S)
  • Patients who relapsed after a 6 month course of interferon alpha when retreated with high dose consensus interferon monotherapy for 12 months yielded an SVR of 58% (This data was published by Keefe in Hepatology 1997; 26 (suppl 1);101S-107S)

Patients that were relapsers to a course of interferon alpha + ribavirin (combination therapy)

  • Patients who relapsed after a 6 month course of interferon alpha with interferon alpha (3MU tiw) + ribavirin (1000/1200mg/day) when retreated with the combination for 6 months yielded an end of treatment response (ETR) of 82% and a SVR of 49%. (This data was published in by Davis in the New England Journal of Medicine 1998; 339:1493-1499).

In this study the following was noted:

  • Histological improvement was noted in 63% of patients in the combination therapy group, with a mean decrement in the inflammatory scores of 2.6

    Dr. Flamm posed a few questions that are still unanswered based upon the Dr. Davis study.

    “Would 12 months of combination therapy increase the sustained virologic response?”
    “Would even longer courses of therapy be required for patients who relapsed after a 12 month course of interferon alpha monotherapy who responded to initial therapy (‘late relapsers’ such as those patients that relapsed after week 24) or those patients who have other adverse prognostic indicators such as genotype 1 or advanced liver disease?”

  • Patients who relapsed after 6 months of interferon alpha + ribavirin were re-treated with 2 different doses of pegylated interferon alpha 2b + ribavirin. Preliminary 12 week treatment results have been revealed and 37% of patients have undetectable HCV RNA (This data was presented by Sulkowski at AASLD and is shown below in abstract form – Abstract 987)

    987


    PEG-INTERFERON a-2B PLUS RIBAVIRIN FOR TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C WHO HAVE PREVIOUSLY FAILED TO ACHIEVE A SUSTAINED VIROLOGIC RESPONSE FOLLOWING INTERFERON a OR INTERFERON a-2B PLUS RIBAVIRIN THERAPY

    Mark Sulkowski, Johns Hopkins Med Institutions, Baltimore, MD; Kenneth D Rothstein, Albert Einstein Med Ctr, Philadelphia, PA; Lawrence Stein, Florham Park, New Jersey, Florham Park, NJ; Eliot Godofsky, Bradenton, Florida, Bradenton, FL; David Shoultz, PPD Development and Univ of Washington, Seattle, WA; Russ Hudnall, Mary Huff, Hepatitis Resource Network, Tacoma, WA; Douglas Dieterich, New York Univ Sch of Medicine, New York, NY

    Background: The effectiveness of re-treatment with pegylated (PEG)-interferon (IFN) a-2b plus ribavirin (RBV) of patients who failed prior IFN-based therapies is unknown. Objective: To evaluate the anti-viral efficacy and safety of PEG-interferon a-2b (fixed dose versus weight-based) plus ribavirin among patients who failed to respond to prior interferon-based therapy (non-response or relapse). Methods: This is an open-label, multi-center, randomized clinical trial. Patients were randomized to receive RBV (800 mg/d) with body-weight adjusted PEG-interferon a-2b (1.5 mcg/kg) QW (N= 183) or fixed dose PEG-interferon a-2b (100 mcg or 150 mcg) QW (N= 182) X 48weeks. Early virologic response (EVR) was defined as undetectable HCV RNA < 1000 IU/mL at treatment week 12. Results: As of 5/31/01, 365 patients have enrolled with the following characteristics: median age was 47 years (range, 20-75); 67% were male; ethnicity - Caucasian, 78%, Black, 11%, Hispanic, 10.4%; HCV genotype - 1, 89%, 2 or 3, 10%, 4, 1%. Prior IFN/RBV response pattern was Non-response (NR), 67% and Relapse (R), 33%. Cirrhosis (by liver biopsy) was identified in 39 (10.6%) patients. Currently, 162 patients have had HCV RNA determined at week 12 and 46 patients stopped treatment prior to week 12 (43% of weight-based and 57% of fixed dose patients). Among those with week 12 EVR data available, 43% (69/162 patients) had HCV RNA < 1000 IU/mL. The week 12 EVR rate among previous non-responders was 46% (47/102) and among previous relapsers was 37% (22/60). The week 12 EVR among fixed dose group was 38% (31/82) and among the weight-based group was 43% (34/80). Among those patients with week 24 EVR data available, 54.6% (35/64) had HCV RNA < 1000 IU/mL. Dose modifications of PEG-interferon a-2b occurred in 12.6% of fixed dose and 11.5% of weight-based dose patients. Observed adverse events were similar in the treatment groups. Conclusions: Based on early virologic response data, PEG-interferon a-2b plus RBV may be effective for the treatment of patients who previously failed to respond to IFN/RBV therapy. Week 24 response data will be presented.

    Dr. Flamm stated that there is a lot of on-going research that needs to be done in this area to be able to definitively make recommendations as to how to handle the hepatitis C patient that relapses after treatment or is a non-responder to treatment

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    Non-Response

    Patients that were non-responders to a course of interferon alpha monotherapy

    • Patients who did not respond to interferon alpha monotherapy when retreated with various doses of interferon alpha + ribavirin yielded an SVR of approximately 15-25% (numerous abstracts, but no published papers at this time)
    • Patients with advanced fibrosis or cirrhosis who did not respond to interferon alpha monotherapy are retreated with pegylated interferon alpha 2a (180µg/week) + ribavirin (1000mg/1200mg/day) in the HALT-C trial. Preliminary 24-week treatment results have revealed 35% of patients with undetectable HCV RNA (This was presented by Shiffman in abstract and during a plenary session at AASLD – abstract # 279)

      279


      RETREATMENT OF INTERFERON AND INTERFERON-RIBAVIRIN NON-RESPONDERS WITH PEGINTERFERON-ALPHA-2A AND RIBAVIRIN: INITIAL RESULTS FROM THE LEAD-IN PHASE OF THE HALT-C TRIAL

      Mitchell L Shiffman, Virginia Commonwealth Univ Health Sys, Richmond, VA; For the HALT-C (Hepatitis C antiviral long-term treatment against cirrhosis) Trial Investigators

      The HALT-C trial was designed to determine if long term maintenance interferon therapy, administered over 4 years, could prevent histologic progression, reduce the development of hepatocellular carcinoma and the need for hepatic transplantation in patients with chronic HCV and advanced fibrosis or cirrhosis who remain HCVRNA (+) despite therapy. Since peginterferon plus ribavirin is more effective than standard interferon/ribavirin for treatment of chronic HCV all patients enrolled in the HALT-C trial were first treated with peginterferon plus ribavirin during the lead-in phase of this trial. The SPECIFIC AIMS of this evaluation were to document the rate of virologic response to peginterferon plus ribavirin in patients who were non-responders to previous interferon or interferon/ribavirin therapy. METHODS: All patients were anti-HCV (+), had an elevation in serum ALT within the previous 6 months, were HCV-RNA (+), had advanced fibrosis or cirrhosis (Ishak fibrosis stage >3) on liver biopsy performed within the previous 6 months, and were non-responders to their most recent course of therapy for chronic HCV; either interferon monotherapy (at least 3 MU tiw) or interferon plus ribavirin. Non-response to this previous treatment was defined as being either HCVRNA (+) after receiving at least 12 weeks of therapy or, if HCVRNA testing was not performed, having a persistent elevation in serum ALT prior to, during and after completion of this previous course of therapy. Patients were excluded if they had any other form of co-existent liver disease, had decompensated cirrhosis (Child-Pugh score of 7 points of greater), previous variceal hemorrhage, a platelet count < 75,000/ml, neutrophil count < 1,500/ml or hemoglobin < 11 gm/dl, were HIV (+), had received an organ transplant or had significant underlying cardiac, pulmonary, renal, hematologic or active psychiatric disease. All patients were treated for 24 weeks with peginterferon-alpha-2a 180 mcg/wk plus ribavirin 1,000 mg/day (1,200 mg/day for patients weighing > 75 kg). Virologic response was assessed by the Amplicor PCR assay (lower limit of detection 50 IU/ml). Patients who achieved a virologic response continued therapy for 48 weeks. Patients who remained HCVRNA (+) by treatment week 20 were considered non-responders and eligible to enter the HALT-C trail. RESULTS: 146 patients began treatment prior to 1/1/2001 and could have received 20 weeks of therapy to date. Of these patients, 8 (5%) dropped-out of the protocol secondary to fatigue, thrombocytopenia, neutropenia, anemia and depression. Of the remaining 138 patients, 59 (43%) achieved a virologic response. Patients who were non-responders to previous treatment with interferon monotherapy had a significantly (p=0.02) increased rate of virologic response during re-treatment with peginterferon-alpha-2a plus ribavirin (56%) compared to patients previously treated with interferon/ribavirin combination therapy (35%). Mean age was also significantly (p=0.01) lower in responders (47 years) than in non-responders (50 years). Only 1/8 (12.5%) African Americans achieved virologic response during re-treatment and this was lower than the response rate observed for patients of all other racial groups (45%). No significant differences existed between responders and non-responders with respect to gender (71 vs. 72% males), body weight (88 vs. 90 kg), body mass index (29 vs. 30), cirrhosis on liver biopsy (32 vs. 43%), serum ALT (125 vs. 120 U/l) or baseline HCVRNA titer (4.4 x 106 vs. 4.3 x 106 IU/ml). CONCLUSIONS: Re-treatment of previous non-responders with peginterferon-alpha-2a plus ribavirin is well tolerated and associated with a significant rate of virologic response (43%). The likelihood of achieving a virologic response was significantly greater in those patients previously treated with standard interferon monotherapy (56%) compared to interferon/ribavirin combination therapy (35%).

    • Patients who did not respond to interferon alpha monotherapy were retreated with phlebotomy or phlebotomy + interferon alpha and although yielded little in the way of SVR did gain improvement in biochemical parameters and histological improvement. (This data was presented by Di Bisceglie in Hepatology 2000;32 (1):135-138)

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    Patients that were non-responders to a course of interferon alpha + ribavirin

    • Patients with advanced fibrosis or cirrhosis who failed standard combination therapy are being retreated with pegylated interferon alpha 2a (180µg/week) + ribavirin (1000mg/1200mg/day) in the HALT-C trial. Preliminary 24-week treatment results have revealed 56% of patients with undetectable HCV RNA (This was presented by Shiffman in abstract and during a plenary session at AASLD – abstract # 279) * SEE ABOVE
    • Patients with advanced liver disease (42%) who failed standard combination therapy are being retreated with pegylated interferon alpha 2b (2 different dosing regimens) + ribavirin. Preliminary 24-week treatment results have revealed 38%/33% of patients with undetectable HCV RNA (This was presented by Lawitz at AASLD – abstract # 664).

      664


      PEGYLATED INTERFERON ALFA 2B (PEG-IFN) AND RIBAVIRIN FOR HEPATITIS C PATIENTS WHO WERE PREVIOUS NONRESPONDERS TO STANDARD COMBINATION THERAPY: 24 WEEK VIRAL CLEARANCE

      Eric J Lawitz, Brooke Army Med Ctr, SanAntonio, TX; Mark A Jeffries, Wilford Hall USAF Med Ctr, SanAntonio, TX; Norma S Cantu, Shailesh C Kadakia, The Alamo Study Group, Brooke Army Med Ctr, SanAntonio, TX

      Background: Standard combination therapy results in about a 41% sustained response rate in patients with hepatitis C. There are currently no accepted treatment options for standard combination therapy nonresponders. Viral kinetics studies have shown an initial dose dependent clearance of HCV-RNA. Previous studies have shown no benefit with the use of induction dosing, however these studies have not used continuous interferon for the entire 48 weeks. PEG-IFN allows continuous delivery of interferon possibly making the induction strategy more successful. Aim: To evaluate the efficacy of induction PEG-IFN and ribavirin compared to fixed dose PEG-IFN and ribavirin in previous standard combination therapy nonresponders. Methods: Participants were randomized to receive either PEG-IFN 1.5 mcg/kg/wk + Ribavirin 1000-1200mg daily x 12 weeks then PEG-IFN 1.0mcg/kg/wk + Ribavirin 800mg x 36 weeks or PEG-IFN 1.0 mcg/kg/wk + Ribavirin 800 mg for 48 weeks. HCV-RNA was measured at week 0, 24, & 48 of treatment and 24 weeks post treatment. Results: Five hundred and fifty adult participants with compensated liver disease have been enrolled to date. Baseline characteristics include: Genotype 1-81%, African Americans-17%, advanced liver disease-42%. Fifty-three participants have completed 24 weeks of therapy. Induction dosing achieved viral clearance in 38% (11/29), while fixed dose achieved viral clearance in 33% (8/24) at 24 weeks of therapy(p>.05). PEG-IFN was reduced in 5% (neutropenia) while ribavirin was reduced in 2% (anemia). Therapy has been discontinued in 3% of participants. Conclusion: Twenty-four week viral clearance for over 400 participants including a multivariate analysis regarding African Americans (70 participants) response to therapy will be available for the annual meeting.
    • Patients who had previously failed standard combination therapy were retreated with 4 different treatment regimens and obtained SVRs of approximately 30% in each of the following groups: pegylated interferon alpha 2a (180µg/week) + ribavirin, ribavirin + amantadine, or mycophenolate mofetil (an anti-rejection agent). (This was presented by Afdahl at AASLD both in a plenary session as well as in abstract form – abstract # 277).

      277


      ANALYSES OF 40 KDA PEGINTERFERON ALFA-2A (PEGASYS) IN COMBINATION WITH RIBAVIRIN, MYCOPHENOLATE MOFETIL, AMANTADINE, OR AMANTADINE PLUS RIBAVIRIN IN PATIENTS THAT RELAPSED OR DID NOT RESPOND TO REBETRON THERAPY: A REPORT OF TWO RANDOMIZED, MULTICENTER, EFFICACY AND SAFETY STUDIES

      Nezam Afdhal, Beth Israel Deaconess Med Ctr and Harvard Med Sch, Boston, MA; Steven Flamm, Northwestern Memorial Hosp, Chicago, IL; Joanne C Imperial, Stanford Univ Sch of Medicine, Palo Alto, CA; Peter F Malet, Univ of Texas Southwestern Med Ctr, Dallas, TX; Myron Tong, Huntington Hosp Liver Ctr, Pasadena, CA; Steven K Herrine, Thomas Jefferson Univ Hosp, Philadelphia, PA; Robert Brown Jr., Columbia Presbyterian Med Ctr, New York, NY; Stephen Esposito, Hepatobiliary Assoc of New York, Bayside, NY; David E Bernstein, North Shore Univ Hosp, Manhasset, NY; Jennifer L Campagna, Roche Labs Inc, Nutley, NJ

      Background: About 60% of patients with chronic hepatitis C (CHC) do not achieve a sustained virological response (SVR) with combination therapy using interferon a-2b plus ribavirin (IFN/RBV). Treatment success may be possible in these patients by combining 40 kDa peginterferon alfa-2a with other antiviral and immunomodulatory agents, including ribavirin, amantadine, and mycophenolate mofetil. Objective: To investigate the efficacy and safety of 40 kDa peginterferon alfa-2a when used in combination with other antiviral and immunomodulatory agents in patients with CHC who have relapsed, or who have not responded, to ³12 weeks of treatment with IFN/RBV. Methods: Patients were randomized into 1 of 4 treatment arms: (A) 40 kDa peginterferon alfa-2a + ribavirin; (B) 40 kDa peginterferon alfa-2a + mycophenolate mofetil; (C) 40 kDa peginterferon alfa-2a + amantadine; (D) 40 kDa peginterferon + amantadine + ribavirin. Patients were stratified according to HCV genotype (1 vs. non-1) and viral load (HCV RNA <1x106 IU/mL [low] vs. >1x106 IU/mL [high]). Treatment was for 48 weeks with 24 weeks of follow-up. Outcome of therapy was assessed as virological response (HCV RNA <50 IU/mL (undetectable) and >2-log drop from baseline using the AMPLICOR HCVä Test v 2.0) or biochemical response (normalization of serum ALT) assessed at weeks 4, 12, 24, 48, 60, 68, and 72. Results: For patients who relapsed, baseline characteristics were as follows: mean age 47 ± 7.2 years; 68% (83) male; mean ALT 105 ± 76 U/L; 58% (71) had high viral load 71; 81% (99) had HCV genotype 1. Twenty-one patients have discontinued therapy: 11 patients due to expected adverse events (AEs), 6 patients due to insufficient therapeutic response, and 4 patients due to other reasons. For non-responders, baseline characteristics were as follows: mean age 47 ± 6.4 years; 75% (88) male; mean ALT 109 ± 77.2 U/L; 67% (79) had high viral load; 90% (106) had HCV genotype 1. Thirty-six patients have discontinued therapy: 4 patients due to expected AEs, 25 patients due to insufficient therapeutic response, and 7 patients due to refusal of treatment or failure to return. No unexpected AEs have been noted. All ongoing patients have completed ³24 weeks of treatment. The response to therapy is summarized in the table below. Conclusions: These interim analyses reveal that all three 40 kDa peginterferon alfa-2a combinations are associated with appreciable virological response rates in patients who relapsed or who did not respond to therapy with IFN/RBV (week 24 HCV RNA negative 32-81% and 30-38% for relapsers and non-responders, respectively). These results support continuing the present studies of efficacy and safety and suggest that IFN/RBV relapsers or nonresponders may benefit from treatment with 40 kDa peginterferon alfa-2a in combination with other agents.

      Arm Relapser Study Non Responder Study
        HCV-RNA>2 HCV-
      RNA
      HCV-RNA>2 HCV-
      RNA
        Drop week 24 Neg. week 24 Drop week 24 Neg. week 24
      A 28/32 (88%) 22/32 (69%) 14/30 (47%) 9/30 (30%)
      B 24/29 (83%) 21/29 (72%) 17/29 (59%) 9/29 (31%)
      C 20/31 (65%) 10/31 (32%) 9/28 (32%) 5/28 (18%)
      D 27/31 (87%) 25/31 (81%) 18/31 (58%) 12/31 (38%)
      A = 40kDa peginterferon alpha 2a + ribavirin
      B = 40kDa peginterferon alpha 2a + Cellcept®
      C = 40kDa peginterferon alpha 2a + amantadine
      D = 40kDa peginterferon alpha 2a + amantadine + ribavirin
    • There is also a large national trial currently enrolling patients examining interferon alpha 2b (1.5mcg/kg/wk vs. 3.0mcg/kg/wk) + ribavirin for patients who have previously failed standard combination therapy.

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    Dr. Flamm then discussed what the role of maintenance therapy is in managing patients with hepatitis C. He felt that the following position should be taken:

    • The role of maintenance therapy in patients who have relapsed or not responded to a previous course of therapy for chronic hepatitis C is unclear. There are, according to Dr. Flamm the following potential benefits:
    • Decrease the rate of fibrosis progression
    • Decrease the rate of development of complications of end stage liver disease and thereby decrease the liver transplantation rate
    • Decrease the rate of hepatocellular carcinoma
    • Increase survival
    • Interferon alpha 2b (3MU tiw) was administered for 2 years to patients who did not respond to a previous course of interferon alpha monotherapy. Only patients who had a histological improvement after the initial course were selected were randomized to receive long-term therapy versus no therapy. Inflammation and fibrosis returned to baseline in patients who received no therapy. Inflammation and fibrosis were significantly lower in the group that received the maintenance therapy (This data was presented by Shiffman in Gastroenterology 1999;117:1164-1172)
    • There are 2 large trials currently ongoing designed to examine these issues in patients with extensive fibrosis or cirrhosis.
    • HALT-C (Hepatitis C Antiviral Long-Term Treatment against Cirrhosis) trial, sponsored by the NIH, in which patients are treated with pegylated interferon alpha 2a + ribavirin for 24 weeks. Patients who respond will continue on combination therapy for 48 weeks in order to maximize chances -alpha 2a (90µg/week) vs. placebo for 36 months
    • COPILOT (Colchicine vs. Peg Intron Long term), in which patients are randomized to receive either colchicines (0.6mg bid) or pegylated interferon alpha 2b (0.5µg/kg/week) for 48 weeks

    Dr. Flamm recommended that clinicians consider maintenance therapy in patients who have advanced fibrosis or cirrhosis, who have had an excellent virological response to the medication which he defined as a 2 log drop from baseline in viral titer and who are tolerating the medication reasonably well. Dr. Flamm followed up by stating that the data does not support high dose induction therapy with interferon alpha, changing interferon alpha medications as well as use of Amantadine or Thymosine.

    Dr. Flamm concluded his presentation on “Chronic Hepatitis C Virus Infection: Therapeutic Options for Relapsers and Non-Responders” by making the following concluding comments:

    • It is unclear what the best approach is for patients who have relapsed or have not responded to a course of interferon alpha based medical regimen. It seems prudent that pegylated interferon alpha + ribavirin should be attempted, particularly in patients who have aggressive histological liver disease (moderate to sever inflammation and/or presence of fibrosis)
    • If a sustained virologic response is not achieved with pegylated interferon alpha + ribavirin, maintenance therapy should be considered for patients who have advanced fibrosis/cirrhosis, have had an excellent virologic response and who have been tolerating the medications reasonably well.

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