Does Amantadine Help Response to HCV Therapy?

Pegasys Combinations With Amantadine, Ribivarin + Amantadine, and Mycophenolate Acid

Various studies have produced mixed results on whether combining amantadine improves standard HCV therapy. Some studies suggested amantadine may be affective in combination with IFN and RBV while other studies showed it did not help. A number of researchers have concluded amantadine is not helpful. At this year's AASLD, the same mixed results were reported from several studies. But when considering the AASLD studies together I think they tend to suggest amantadine may have benefit, and deserves a continuing look. These reports are mostly from the AASLD program abstract booklet.

Amantadine Appears Helpful in Non-Responders Receiving Interferon+Ribivarin
     (Adinolfi, abstract 770)

This first one-year randomized controlled pilot study in 65 persons with chronic HCV took place in non-responders to previous therapy with IFN 5-6 MU 3 times per week. The study compared three regimens: group C received IFN 3 MU daily for 1 month, then 3MU tiw (3x/wk) plus ribivarin, plus amanatadine 200 mg daily. Group B received the same IFN/RBV regimen without amantadine. And Group A received standard therapy: IFN 3MU tiw plus RBV 1000 mg daily. Study investigators reported: "in a 6th month follow-up post treatment, sustained response was observed in 0% of patients in Groups A & B, and all relapsed within the 2nd month after therapy. In the triple therapy Group C, response was 38% at 4th-6th month of follow-up". Authors reported triple therapy was safe and side effects were similar to those observed on Groups A & B. The authors reported 38% in Group C had cirrhosis and their response rate at the end of treatment was 75% compared to 0% and 14% in Groups A & B, respectively.

Randomization to Groups A, B and C was 26:26:13, respectively. Prior to starting study therapy, no differences were observed between Groups A, B, and C with respect to age (median 51, 51 and 50, respectively), cirrhosis (26%, 25%, and 38%, respectively), genotype 1 (69%, 73%, and 69%, respectively), and levels of viral load. The response end-point was ALT normalization and HCV viral clearance. At the end-of-treatment, response rate was for Group A 27%, Group B 27%, and for Group C 69% (p<0.03). The response with respect to chronic HCV and cirrhosis was for Group A (28% and 0%), B 32% and 14%), and C 67% and 75%). Patients with Genotype 1 showed a response rate of 28%, 32%, and 56% for Groups A, B, and C, respectively. Response was observed between 3 & 8 months in Groups A & B, whereas in Group C, 44% of patients responded within the first month of therapy. Again, 6 months after treatment stopped (sustained response rate) 0% responders in Groups A & B, and all relapse occurred in 2nd month post therapy. In the amantadine triple therapy group response was 38% at 4-6 months of follow-up.

Amantadine Was Not Effective In This Small Study of Non-Responders Receiving Interferon Without Ribivarin
     (Tueber, abstract 778)

55 previous IFN non-responders with chronic HCV received IFN 6 MU tiw for 24 weeks followed by 3 MU for an additional 24 weeks. Amantadine sulfate (n=26) or a matched placebo (n=29) was given orally twice daily for 48 weeks. Because of an initial low response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN dose was reduced , a virologic end-of-treatment response with undetectable HCV viral load (<100 copies/ml) was achieved in only 5 patients (1 receiving IFN+amantadine, and 4 receiving IFN+placebo). After 24 weeks follow-up a sustained virologic response was observed in only 2 patients receiving IFN and placebo. Health and quality of life analysis revealed a substantial improvement of the Profile of Mood States scale (POMS) concerning the parameters fatigue  (p<0.05) and vigor (p<0.05) in patients receiving combined IFN+amantadine compared to patients receiving IFN alone. But since RBV was not used these health & quality of life results appear tentative to me. Authors reported IFN+amantadine combination was well tolerated without any serious adverse events. The author concluded IFN+amantadine does not increase low sustained virologic response rate of IFN therapy in non-responders, but  it may lead to improved health-related quality of life.

Long-Term Response to Interferon+Amantadine is Significantly Higher Than to Interferon Alone in Chronic HCV Treatment Nave
    
(Mangia, abstract 636)

This multi-center controlled study of 194 patients compared the long-term efficacy of IFN monotherapy to IFN+amantadine in treatment nave patients with chronic HCV without cirrhosis. Patients were randomized to IFN 6 MU tiw plus amantadine (200 mg/day), or to IFN monotherapy for 48 weeks treatment. The main end-point was sustained undetectable HCV viral load 6 months after the end of treatment. The secondary study end-point was ALT normalization and HCV viral load at the end of treatment (ETR).

ETR was seen in 41% in amantadine+IFN group vs 22.3% in IFN group (p<0.007). Relapse rates were about the same (26.8% vs 28.5%). Sustained virologic response was 30% in amantadine group and 16% in IFN alone group (p=0.02).

Daily Induction 18 MU Interferon + Ribivarin + Amantadine in Relapsers: viral kinetics & tolerability
    
(Weegink, abstract 1135)

28 patients with chronic HCV who had a virologic relapse were retreated with IFN alfa-2a 6 MU every 8 hours for 2 weeks in combination with ribivarin 1000-1200 mg/day and amantadine 100 mg per day (8 genotype 1 and 20 patients had genotype non-1). This study explored HCV viral kinetics and adverse events. 5 patients had previously been treated with IFN/ribivarin. Before treatment and after 1 and 2 weeks after the start of treatment viral load was monitored using the qualitative Roche HCV 2.0 Assay (lower limit of detection 50 IU/ml), and by the quantitative Roche Monitor version 2.0 assay (lower limit of detection 600 IU/ml).

All 28 patients completed the 2 week high dose induction treatment. Tiredness, flu-like symptoms, sleeping disorders, ittitability, and loss of appetitie were the most common side effects, occurring in almost all patients. Authors reported, however, that the severity of the side effects were similar to those occurring during initial treatment with 3-6 MU OFN tiw. At week 1 7/28 and at week 2 14/28 had undetectable HCV by the qualitative test (<50 IU/ml). At week 1 and 2 19/28 and 25/28, respectively, had undetectable viral load using the quantitative test (<600 IU/ml). By week 1 the viral load had declined in all patients, in 17/28 by 3-5 logs and 11/28 by 1-2 logs. At week 2, the qualitative PCR was negative in 2/8 patients with genotype 1 and in 10/20 patients with genotype non-1.

The authors concluded high dose IFN induction retreatment for 2 weeks, in combination with RBV+amantadine, in chronic HCV, who had a virologic relapse, is well tolerated and is associated with a rapid decline in viral load. After two weeks, 89% of patients had a viral load <600 IU/ml and the qualitative PCR was undectable <50 IU/ml in 50% of patients. I think its important to bear in mind that a number of viral kinetics studies have been conducted using high dose induction therapy, and it is my opinion that it has yet to be firmly established that very early high viral load decline rates produces higher sustained virologic response rates.

The previous high-dose induction study nicely transitions into preliminary study data reported using Pegasys plus amantadine.

Pegasys In Combination with Amantadine and Various other Drugs
     ( Di Bisceglie, abstract 1139)

For background purposes IFN monotherapy in untreated patients yields between 10 to 18% sustained virologic response rates in various studies, while Pegasys monotherapy studies have shown about a 35% sustained virologic response rate. In this study patients were randomized in a 3:3:1:1 ratio as:

Patients were stratified according to genotype 1 vs non-1, and viral load (<1 x 106  IU/mL [low] vs >1 x 106  IU/mL [high]). Treatment is for 48 weeks with 24 weeks follow-up. Outcome was assessed as virologic response (HCV RNA <50 IU/ml and >2 log drop from baseline using the Amplicor HCV test version 2.0) or biochemical response (normalization of serum ALT) assessed at weeks 4, 12, 24, 48, 60, 68, and 72. 153 patients were enrolled and 149 have completed at least 4 weeks of treatment, 148 patients at least 12 weeks treatment and 104 patients at least 24 weeks of treatment. 5 patients were discontinued due to expected adverse events, 3 patients have discontinued for non-safety reasons, and 7 dropped out after randomization without taking any study medications.

BASELINE CHARACTERISTICS

Week 24: HCV-RNA <50 IU/ml & ALT & >2 Log Drop

  HCV-RNA Normal ALT >2 log drop
A 21/37 56% 27/37 73% 23/37 62%
B 21/41 51% 21/39 54% 28/40 70%
C   9/13 69%   7/13 54% 12/13 92%
D   8/13  61%   9/13 69% 11/13 84%

Roche researchers concluded that these early findings over weeks 4, 12 and 24 show a trend to similar or greater benefit using the new therapies compared to current standard of care, and similar safety profile was displayed across all treatment arms. Additionally, they concluded these early findings could show new therapies revealing greater response rates or for those who cannot tolerate standard IFN+RBV therapy. These results support continuing the present study and starting larger phase III studies to test antiviral efficacy.

Amantadine Plus IFN+RBV in Previous Non-Responders
     (Younossi, abstract 1140)

This open-label pilot study treated 20 previous non-responders with IFN+RBV+amanatadine. Patients had previous treatment with IFN monotherapy followed by combination IFN (Intron A 3 MU) tiw + ribivarin 800 mg/day (n=10), or Intron A 3 Mu tiw + amantadine 200 mg/day (n=10). One month following discontinuation of these regimens patients received Intron A 3 MU + RBV 1000-1200 mg/day + amantadine 200 mg /day. ALT, HCV-RNA by PCR, and Health Related Quality of Life (CLDQ and SF-36) were evaluated. For patients with a undetectable HCV viral load at the end of 24 weeks of therapy, a complete 48 week course of triple therapy was given. The analysis is reported as intent-to-treat.

Of the 20 patients enrolled, 4 (20%) discontinued due to side effects but 15 have completed the regimen. 12, 24 and 48 week viral eradication (undetectable HCV viral load by PCR) was achieved by 6 (30%), 5 (25%), and 3 (15%) of the patients, respectively. The last patient is on week 35 of the regimen with undetectable HCV RNA. Of 3 patients with end-of-treatment viral negativity, 2 have follow-up HCV-RNA and both remain negative (median follow-up is 6 weeks). Study authors report that this early viral clearance was equally divided among those previously treated with IFN+RBV or IFN/amantadine.

The authors concluded that in this group of previous non-responders, triple amantadine therapy was associated with significant early viral undetectability, and durability is being followed.