Amantadine therapy for chronic hepatitis C: a dose escalation study

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Group: 2004
Subgroup: Volume 4, Issue 7, Summer
Date: July 2004
Type: Commentary
Start Page: 83
End Page: 84

Authors:

Abstract:


OBJECTIVES: Amantadine reduces liver transaminase levels in some patients with chronic hepatitis C at doses of 200 mg daily and may improve the sustained virological response (SVR) when given with interferon and ribavirin. The primary purpose of the present investigation was to study the safety and toxicity of higher doses of amantadine in subjects who previously failed or were intolerant to interferon. The secondary aim was to test the efficacy of higher dose of amantadine against hepatitis C.

METIIODS: An open-labeled prospective study was conducted starting with amantadine 200 mg daily and increasing to 500 mg daily while monitoring for safety, tox icity, and efficacy. An amantad ine blood level exceeding 1,600 ng/ml was considered toxic requiring dose reduction. The patient's symptoms, laboratory tests, and quality of life were monitored .

RESULTS: One hundred patients enrolled in th e s tud y. Normalization of alanine aminotransferase (ALT) for each dose was as follows: 200 mg (35%), 300 mg (49%), 400 mg (53%), and 500 mg (56%). The incidence of toxic amantadine plasma levels increased with dose, i.e ., 200 mg (0%), 300 mg (6%),400 mg (27%), and 500 mg (49%). The frequency and severity of arthralgia and fatigue improved at all dosages administered. No changes in the occurrence or severity of headache, insomnia, or depression were reported. Serious adverse events included myocardial infarction and suicide attempt. Other side effects in cluded impotence, confusion, alopec ia, and hoarseness.

CONCLUSIONS: Amantadine given at a dose of300 mg daily is safe, and sign ificantly lowers AL T blood levels more than 200 mg daily. The enzyme response rate does not significantly improve above 300 mg, but toxicity increases.

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Hepatitis Monthly Editorial Board Comment

The Amantadine story in the treatment of HCU:a mouing pendulum

 

Amantadine (AMA) is an effective antiviral in the prevention of influenza A.1 In early 1990s reports showed its potential benefit in the treatment of hepatitis C2, 3 , but the AMA's mechanism of antiviral action in HCV is still unclear2 In 1997 several studies suggested the combination of Interferon alfa (IFN alfa) and AMA for treatment of HCV 4, 5 , but in the subsequent years Khalili et al. demonstrated the lack of efficacy of dual therapy with interferon and AMA for interferon nonresponders 6 and in conjunction with the majority of abstracts presented at the Digestive Disease Week (DOW) 2000 , it was confirmed that there was no role for dual therapy with IFN alfa lAMA in the treatment of hepatitis C, both in IFN alfa nonresponders and naive patients?-9 The storyTwas temporarily abundant while Mangia et ai, in a well-designed multicenter randomized study showed the superiority of IFN alfa and AMA combination over IFN alta monotherapy.10 So the pendulum moved again to the opposite side, and the pendulum continued swinging till Mangia et ai, in a recent meta-analysis showed that therapy with AMA and IFN alfa is effective and may be an alternative to IFN alfa and ribavirin (RBV) in patients who cannot to lerate RBV.1 1 All the studies discussed above used the usual anti-Influenza dos of 200 mg/d of AMA but the current study of Smith JP 12 was the fi rst toxicologic and dose escalation study upon AMA which showed that 300 mg/d is well tolerated and lowers AL T more than 200 mg/d. This makes one eager of knowing the efficacy of the AMA 300 mg/d in combination with IFN alfa in future tudies. Looking from another pOint of view, triple therapy of AMA, IFN alfa and RBV has r cently been shown to be effective in IFN alfa plus RBV nonresponders.13? 14 In summary, after several swings of the AMA pendulum during the last 10 years it seems that at present AMA has a lot to say with 300 mg daily dose in combination with IFN If a ± RBV specially for a group of HCV infected patients unresponsive to standard IFN alfa plus RBV treatment or those with hemoglob olinopathies in whom RBV is contraindicated.

References: (14)

  1. Nicholson KG, Wiselka MJ. Amantadine for influenza A. Br MedJ 1991;302:425- 6.
  2. Smith JP. Treatment of chronic hepati tis C with amantadine. DigDis Sci 1997; 42:1681-7.
  3. Brillanti S, Foli M, Di Tomasi M, et aL Pilot study of triple therapyfor chronic hepatitis C in interferon alpha non-responders.ltal J Gastroenterol Hepatol 1993; 31:130-4.
  4. Findor JA, Daruich JR, Bruch Igartua E, et a/. Amantadine HCL alone, and associated with recombinant alpha IFN 2a during a short term herapy in chronic HCV infection. Hepatology 1997; 26:217 A.
  5. Fang JC, Hespenheide EE, Driscoll CJ, et aL Amantadine-HCL treatment of chronic hepatitis C.Hepatology 1997;26:217 A.
  6. Khall /i M, Denham C, Perrillo R. Interferon an ribavirin versusinterferon and amantadine in interferon non respon ders with c hro nic hepatitis C. Am J Gastroenterol 20 00 ;95:1284 - 9.
  7. Yang S-S, Tu T-C, Wu C-H. Combination of interferon alfa-2a and amantadine does not improve the efficacy of interferon therapy in patients with chronic hepatitiS C. Hepa 01 gy 1999; 30:369A.
  8. Zeuzam S, Teuber G. Naumann U, et aL Randomised, doubleblind, controlled trial interferon-alfa with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 1999;30:200A.
  9. Brown PJ, Neuman MG. Digestive Disease Week 2000 conference report: New treatments for chronic hepatitis C. Can J Clin PharmacoL 2001 Summer;8(2):67-71.
  10. Mangia A, Minerva N, Annese M, Leandro G, Villani MR, SantoroR, Carretta V, Bacca D. Glangaspero A, Bisceglia M, Ventrella F, Dell'Erba G, Andriulli A A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C. Hepatology. 2001 Apr;33(4):989-93.
  11. Mangia A, Leandro G, Helbling B, Renner EL, Tabone M, SidoliL, Caronia S, Foster GR, Zeuzem S, Berg T, 01 Marco V, Cino N, Andriu lli A Combination therapy with amantadine and in terferon in naive patients with chronic hepatitis C: meta-analysis of individual patient data from six clinical trials. J HepatoL 2004 Mar;40(3):478-83
  12. Smith JP, Riley TR 3rd, Bingaman S, Mauger DT. Amantadine therapy for chronic hepatitis C: a dose escalation study. Am J Gastroenterol. 2004 Jun;99(6):109S-104.
  13. Teuber G, Pascu M, Berg T, Lafrenz M, Pausch J, KulimannF, Ramadori G, Arnold R, Weidenbach H, Musch E. Junge U, Wiedmann KH, Herrmann E, Zankel M, Zeuzem S. Randomized. controlled trial with IFN-alpha combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C. J Hepatol. 2003 Oct;39(4):606-13.
  14. Thuluvath PJ, Maheshwari A, Mehdi J, Fairbanks KD. Wu LL,Gelrud LG. Ryan MJ, Anania FA.Lobis IF, Black M. Randomised, double blind , placebo controlled trial of interferon. ribavirin . and amantadine versus interferon, ribavirin , and placebo in treatment naive patients with chronic hepatitis C. Gut 2004 Jan; 53(1 ):130-5.