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Review
. 2014 May 3;2014(5):CD010125.
doi: 10.1002/14651858.CD010125.pub2.

Aminoadamantanes for chronic hepatitis C

Mieke H Lamers  1 , Mark Broekman, Joost P H Drenth, Christian Gluud
Affiliations
Review

Aminoadamantanes for chronic hepatitis C

Mieke H Lamers et al. Cochrane Database Syst Rev. .

Abstract

Background: Around 3% of the world's population (approximately 160 million people) are chronically infected with hepatitis C virus. The proportion of infected people who develop clinical symptoms varies between 5% and 40%. Combination therapy with pegylated interferon-alpha plus ribavirin eradicates the virus from the blood six months after treatment (sustained virological response) in approximately 40% to 80% of infected patients, depending on the viral genotype. New antiviral agents, such as boceprevir and telaprevir, in combination with standard therapy, can increase sustained virological response in genotype 1 infected patients to at least 70%. There is therefore an unmet need for drugs that can achieve a higher proportion of sustained virological response. Aminoadamantanes are antiviral drugs used for treatment of patients with chronic hepatitis C.

Objectives: To assess the beneficial and harmful effects of aminoadamantanes for patients with chronic hepatitis C infection by conducting a systematic review with meta-analyses of randomised clinical trials, as well as trial sequential analyses.

Search methods: We conducted electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11 of 12 (1995 to December 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013 and checked the reference lists of identified publications.

Selection criteria: Randomised clinical trials assessing aminoadamantanes in patients with chronic hepatitis C infection.

Data collection and analysis: Two authors independently extracted data. We assessed for risks of systematic errors ('bias') using the 'Risk of bias' tool. We analysed dichotomous data with risk ratio (RR) and continuous data with mean difference (MD) or standardised mean difference (SMD), both with 95% confidence intervals (CI). We used trial sequential analysis to assess the risk of random errors ('play of chance'). We assessed quality using the GRADE system.

Main results: We included 41 randomised clinical trials with 6193 patients with chronic hepatitis C. All trials had high risk of bias. All included trials compared amantadine versus placebo or no intervention. Standard antiviral therapy was administered equally to the intervention and the control groups in 40 trials. The standard antiviral therapy, which was administered to both intervention groups, was interferon-alpha, interferon-alpha plus ribavirin, and peg interferon-alpha plus ribavirin, depending on the time when the trial was conducted.When we meta-analysed all trials together, the overall results demonstrated no significant effects of amantadine, when compared with placebo or no intervention, on our all-cause mortality or liver-related morbidity composite outcome (5/2353 (0.2%) versus 6/2264 (0.3%); RR 0.90, 95% CI 0.38 to 2.17; I² = 0%; 32 trials; very low quality). There was also no significant effect on adverse events (288/2869 (10%) versus 293/2777 (11%); RR 0.98, 95% CI 0.84 to 1.14; I² = 0%; 35 trials; moderate quality). We used both fixed-effect and random-effects meta-analyses. Amantadine, when compared with placebo or no intervention, did not significantly influence the number of patients who failed to achieve a sustained virological response (1821/2861 (64%) versus 1737/2721 (64%); RR 0.98, 95% CI 0.95 to 1.02; I² = 35%; 35 trials; moderate quality). However, in the subgroup using interferon plus ribavirin, amantadine decreased the number of patients who failed to achieve a sustained virological response (422/666 (63%) versus 447/628 (71%); RR 0.89, 95% CI 0.83 to 0.96; I² = 41%; 11 trials; low quality). Similar results were found for failure to achieve an end of treatment virological response. Amantadine, when compared with placebo or no intervention, significantly decreased the number of patients without normalisation of alanine aminotransferase (ALT) serum levels at the end of treatment (671/1141 (59%) versus 732/1100 (67%); RR 0.88, 95% CI 0.83 to 0.94; I² = 47%; 19 trials; low quality). Amantadine, when compared with placebo or no intervention, did not significantly influence the end of follow-up biochemical response (1133/1896 (60%) versus 1151/1848 (62%); RR 0.95, 95% CI 0.91 to 1.00; I² = 49%; 21 trials; low quality).The observed beneficial effects could be true effects but could also be due to both systematic errors (bias) and random errors (play of chance). The latter is due to the fact that trial sequential analyses could not confirm or refute our findings. We were not able to perform meta-analyses for failure of histological improvement or quality of life due to a lack of valid data.

Authors' conclusions: This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct-acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine.

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Conflict of interest statement

M.H. Lamers: no declarations of interest. Mark Broekman: no declarations of interest. Joost PH Drenth: no declarations of interest. Christian Gluud: no declarations of interest.

Figures

1
1
Flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 4 Subgroup: trials at lower risk versus high risk of bias. Outcome: 4.1 All‐cause mortality or liver‐related morbidity.
5
5
Trial sequential analysis of the random‐effects meta‐analysis of the effect of amantadine versus placebo or no intervention on all‐cause mortality or liver‐related morbidity in patients with chronic hepatitis C infection. The trial sequential analysis is performed with a type 1 error of 5% (two‐sided), a power of 80%, an assumed control proportion of death or liver‐related morbidity of 2%, and an anticipated relative risk reduction (RRR) of 20%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 20%, with a between‐trial heterogeneity of 0%, is estimated at 34,685 participants. The number of participants actually accrued is 2196, which is only 6% of the required information size. The blue cumulative Z‐curve does not cross the red trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support or refute the assumption that amantadine influences all‐cause mortality or liver‐related morbidity. The cumulative Z‐curve does not reach the futility area (which is not even drawn by the program), demonstrating that further randomised trials may be needed.
6
6
Trial sequential analysis of the random‐effects meta‐analysis of the effect of amantadine versus placebo or no intervention, in chronic hepatitis C‐infected patients, on the number of patients experiencing a serious adverse event or the number of patients who had to discontinue treatment due to an adverse event. The trial sequential analysis is performed with a type 1 error of 5% (two‐sided), a power of 80%, an assumed control proportion of number of patients experiencing a serious adverse event or who had to discontinue treatment due to an adverse event of 10%, and an anticipated relative risk reduction (RRR) of 20%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 20%, with a between‐trial heterogeneity of 0%, is estimated at 5787 participants. The number of participants actually accrued is 5272, which is 91% of the required information size. The blue cumulative Z‐curve does not cross the red trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support the assumption amantadine influences the number of patients experiencing a serious adverse event or who have to discontinue treatment due to an adverse event. The cumulative Z‐curve does cross the trial sequential beta‐spending monitoring boundaries and reach the futility area, demonstrating that no further randomised trials may be needed.
7
7
Funnel plot of comparison: 4 Subgroup: trials at lower risk versus high risk of bias. Outcome: 4.2 Adverse events.
8
8
Funnel plot of comparison: 4 Subgroup: trials at lower risk versus high risk of bias. Outcome: 4.3 Failure of sustained virological response.
9
9
Trial sequential analysis of the random‐effects meta‐analysis of the effect of amantadine versus placebo or no intervention on the number of patients with chronic hepatitis C virus infection who failed to achieve a sustained virological response (SVR). The trial sequential analysis is performed with a type 1 error of 5% (two‐sided), a power of 90%, an assumed control proportion of number of patients who failed to achieve a SVR of 64%, and an anticipated relative risk reduction (RRR) of 7%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 7%, with a between‐trial heterogeneity of 35%, is estimated at 7609 participants. The number of participants actually accrued is 5328, which is 70% of the required information size. The blue cumulative Z‐curve does not cross the red trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support the assumption that amantadine influences the number of patients who fail to achieve a SVR and it is likely that a 7% RRR in the number of patients who fail to achieve a SVR can be rejected with the chosen error risks. The cumulative Z‐curve does reach the futility area, demonstrating that no further randomised trials may be needed.
10
10
Trial sequential analysis of the random‐effects subgroup meta‐analysis of the effect of amantadine plus interferon‐alpha and ribavirin versus placebo or no intervention plus interferon‐alpha and ribavirin on the number of patients with chronic hepatitis C virus infection who failed to achieve a sustained virological response (SVR). The trial sequential analysis is performed with a type 1 error of 5% (two‐sided), a power of 90%, an assumed control proportion of number of patients who failed to achieve a SVR response of 71%, and an anticipated relative risk reduction (RRR) of 7%. The diversity‐adjusted required information size (DARIS) to detect or reject a RRR of 7%, with a between‐trial heterogeneity of 12%, is estimated at 4171 participants. The number of participants actually accrued is 1294, which is only 31% of the required information size. The blue cumulative Z‐curve does not cross the red inward sloping trial sequential alpha‐spending monitoring boundaries for benefit or harm. Therefore, there is no evidence to support the assumption that amantadine influences number of patients who fail to achieve a SVR and it is likely that a 7% RRR in the number of patients who fail to achieve a SVR on treatment with amantadine plus interferon‐alpha and ribavirin can be rejected with the chosen error risks. The cumulative Z‐curve does not reach the futility area (which is not even drawn by the program), demonstrating that further randomised trials may be needed.
1.1
1.1. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 1 All‐cause mortality or liver‐related morbidity.
1.2
1.2. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 2 Adverse events.
1.3
1.3. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 3 Failure of end of treatment virological response.
1.4
1.4. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 4 Failure of sustained virological response.
1.5
1.5. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 5 Failure of histological response.
1.6
1.6. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 6 Failure of normalisation of ALT at end of treatment.
1.7
1.7. Analysis
Comparison 1 Amantadine versus placebo or no intervention, Outcome 7 Failure of normalisation of ALT at end of follow‐up.
2.1
2.1. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 1 Mortality or liver‐related morbidity.
2.2
2.2. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 2 Adverse events.
2.3
2.3. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 3 Failure of sustained virological response.
2.4
2.4. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 4 Failure of end of treatment virological response.
2.5
2.5. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 5 Failure of histological response.
2.6
2.6. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 6 Failure of normalisation of ALT at end of treatment.
2.7
2.7. Analysis
Comparison 2 Subgroup: naives, relapsers, non‐responders, Outcome 7 Failure of normalisation of ALT at end of follow‐up.
3.1
3.1. Analysis
Comparison 3 Subgroup: genotype 1 compared to genotype non‐1, Outcome 1 Failure of sustained virological response.
4.1
4.1. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 1 All‐cause mortality or liver‐related morbidity.
4.2
4.2. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 2 Adverse events.
4.3
4.3. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 3 Failure of sustained virological response.
4.4
4.4. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 4 Failure of end of treatment virological response.
4.5
4.5. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 5 Failure of histological response.
4.6
4.6. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 6 Failure of normalisation of ALT at end of treatment.
4.7
4.7. Analysis
Comparison 4 Subgroup: trials at lower risk of bias compared to trials at high risk of bias, Outcome 7 Failure of normalisation of ALT at end of follow‐up.
5.1
5.1. Analysis
Comparison 5 Subgroup: sensitivity analysis, Outcome 1 Failure of sustained virological response.
5.2
5.2. Analysis
Comparison 5 Subgroup: sensitivity analysis, Outcome 2 Failure of end of treatment virological response.
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References

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Mangia 2001 {published data only}
    1. Mangia A, Minerva N, Annese M, Leandro G, Villani MR, Santoro R, et al. A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C. Hepatology 2001;33(4):989‐93. [PUBMED: 11283865] - PubMed
    1. Mangia A, Santoro R, Villani MR, Soccio T, Cela O, Annese M, et al. Long term response to amantadine + interferon is significantly higher than that to interferon alone in chronic hepatitis C: final report of a randomized clinical trial. Hepatology 2000;32:318A.
Maynard 2006 {published data only}
    1. Maynard M, Ahmed SNS, Bailly F, Rozier F, Benmakhlouf N, Bourne‐Branchu V. Retreatment of IFN/ribavirin non‐responder hepatitis C patients: benefit of peg‐interferon/ribavirin/amantadine. Hepatology 2004;40:398A.
    1. Maynard M, Pradat P, Bailly F, Rozier F, Nemoz C, Si Ahmed SN, et al. Amantadine triple therapy for non‐responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). Journal of Hepatology 2006;44(3):484‐90. [PUBMED: 16426697] - PubMed
Mendez‐Navarro 2010 {published data only}
    1. Mendez‐Navarro J, Chirino RA, Corey KE, Gorospe EC, Zheng H, Chung R, et al. Assessment and prediction of sustained virological response among treatment‐naive Latinos with, genotype 1 HCV treated with standard double versus triple therapy with amantadine. Hepatology 2009;50:707A.
    1. Mendez‐Navarro J, Chirino RA, Corey KE, Gorospe EC, Zheng H, Moran S, et al. A randomized controlled trial of double versus triple therapy with amantadine for genotype 1 chronic hepatitis C in Latino patients. Digestive Diseases and Sciences 2010;55(9):2629‐35. [PUBMED: 19960257] - PMC - PubMed
Pessoa 2012 {published data only}
    1. Cheinquer H, Pessoa M, Almeida P, Silva G, Patelli M, Parana R, et al. Prospective randomized study of peginterferon alpha‐2a plus ribavirin, in hepatitis C patients non‐responders or relapsers to interferon‐alpha and ribavirin. Journal of Hepatology 2006;44:S209.
    1. Pessoa MG, Cheinquer H, Almeida PR, Silva GF, Lima MP, Parana R, et al. Re‐treatment of previous non‐responders and relapsers to interferon plus ribavirin with peginterferon alfa‐2a (40KD), ribavirin +/‐ amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial. Annals of Hepatology 2012;11(1):52‐61. [PUBMED: 22166561] - PubMed
Piai 2003 {published data only}
    1. Piai G, Rocco P, Tartaglione MT, Ciarleglio A, Focareta R, Grimaldi E, et al. Triple (interferon, ribavirin, amantadine) versus double (interferon, ribavirin) re‐therapy for interferon relapser genotype 1b HCV chronic active hepatitis patients. Hepatology Research 2003;25(4):355‐63. [PUBMED: 12699845] - PubMed
Salmeron 2007 {published data only}
    1. Salmeron J, Diago M, Andrade R, Perez R, Sola R, Romero M, et al. Induction doses of interferon‐alpha‐2a in combination with ribavirin and/or amantadine for the treatment of chronic hepatitis C in non‐responders to interferon monotherapy: a randomized trial. Journal of Viral Hepatitis 2007;14(2):89‐95. [PUBMED: 17244248] - PubMed
Sax 2001 {published data only}
    1. Sax H, Friedl A, Renner E, Steuerwald MH, Weber R. Pilot study of interferon‐alpha with and without amantadine for the treatment of hepatitis C in HIV coinfected individuals on antiretroviral therapy. Infection 2001;29(5):267‐70. [PUBMED: 11688904] - PubMed
Shakil 2000 {published data only}
    1. Ahmad J, Vargas H, Balan V, Rakela J, Shakil AO. A randomized, double‐blind, placebo‐controlled trial of interferon‐alpha and amantadine versus interferon‐alpha alone in the treatment of patients with chronic hepatitis C. Digestive Diseases and Sciences 2002;47(7):1655‐6. - PubMed
    1. Shakil AO, Balan V, Vargas H, Gartner K, Rakela J. A randomized, double‐blind, placebo controlled trial of interferon‐alfa and amantadine versus interferon‐alfa alone in the treatment of chronic hepatitis C. Gastroenterology 2000;118:A1487. - PubMed
Smith 2004 {published data only}
    1. Smith JP, Riley TR 3rd, Devenyi A, Bingaman SI, Kunselman A. Amantadine therapy for chronic hepatitis C. Journal of General Internal Medicine 2004;19(6):662‐8. [PUBMED: 15209605] - PMC - PubMed
    1. Smith JP, Riley TR 3rd, Devenyi A, Bingaman SI, Kunselman A. Amantadine therapy for chronic hepatitis C: a randomized double‐blind placebo controlled trial. Gastroenterology 2002;122(S4):A‐627.
Tabone 2001 {published data only}
    1. Tabone M, Delmastro B, Bonardi R, Andreoni M, Manca A, Calleri G, et al. Combination therapy interferon plus amantadine in chronic active hepatitis C. A multicentric randomised study: preliminary reports. Hepatology 1999;30:628A.
    1. Tabone M, Laudi C, Delmastro B, Biglino A, Andreoni M, Chieppa F, et al. Interferon and amantadine in combination as initial treatment for chronic hepatitis C patients. Journal of Hepatology 2001;35(4):517‐21. [PUBMED: 11682037] - PubMed
Teuber 2001 {published data only}
    1. Teuber G, Berg T, Naumann U, Raedle J, Brinkmann S, Hopf U, et al. Randomized, placebo‐controlled, double‐blind trial with interferon‐alpha with and without amantadine sulphate in primary interferon‐alpha nonresponders with chronic hepatitis C. Journal of Viral Hepatitis 2001;8(4):276‐83. [PUBMED: 11454179] - PMC - PubMed
    1. Teuber G, Naumann U, Berg T, Dreher A, Hopf U, Zeuzem S. Randomized, placebo‐controlled, double‐blind trial with interferon‐A (IFN A) with and without amantadin‐sulfat in primary IFN‐A non‐responders with chronic hepatitis C. Hepatology 2000;32:354A.
    1. Teuber G, Naumann U, Berg T, Raedle J, Dreher A, Hopf U, et al. Multicenter, randomized, double‐blind, placebo‐controlled trial of interferon‐A (IFN‐A2A) with and without amantadine as treatment for IFN‐A non‐responders with chronic hepatitis C. Gastroenterology 2000;118:A1494.
Teuber 2002 {published data only}
    1. Teuber G, Pascu M, Lafrenz M, Weidenbach H, Schoelmrich J, Wietske‐Braun P, et al. Randomized, controlled trial with interferon‐alfa plus ribavirin with and without amantadine sulphate in patients with chronic hepatitis C relapsing after primary successful antiviral treatment. Hepatology 2001;34:579A.
    1. Teuber G, Pascu M, Lafrenz M, Weidenbach H, Schoelmrich J, Wietske‐Braun P, et al. Randomized, controlled trial with interferon‐alpha plus ribavirin with and without amantadine sulphate in patients with chronic hepatitis C relapsing after previous successful antiviral treatment. Journal of Hepatology 2002;36:132.
Teuber 2003 {published data only}
    1. Teuber G, Berg T, Lafrenz M, Weidenbach H, Schoelmerich J, Wietzke‐Braun P, et al. Randomized, controlled trial with interferon‐alpha (IFN‐alpha) combined with ribavirin with and without amantadine sulfate in primary IFN‐alpha nonresponsive patients with chronic hepatitis C. Journal of Hepatology 2001;34(1):23.
    1. Teuber G, Berg T, Lafrenz M, Weidenbach H, Schoelmerich J, Wietzke‐Braun P, et al. Randomized, controlled trial with interferon‐α (IFN‐α) combined with ribavirin with and without amantadinsulfat in primary IFN‐α non‐responders with chronic hepatitis C. Hepatology 2001;120:A381.
    1. Teuber G, Pascu M, Berg T, Lafrenz M, Pausch J, Kullmann F, et al. Randomized, controlled trial with IFN‐alpha combined with ribavirin with and without amantadine sulphate in non‐responders with chronic hepatitis C. Journal of Hepatology 2003;39(4):606‐13. [PUBMED: 12971972] - PubMed
Thuluvath 2004 {published data only}
    1. Thuluvath PJ, Maheshwari A, Mehdi J, Fairbanks KD, Wu LL, Gelrud LG, et al. 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;53(1):130‐5. [PUBMED: 14684587] - PMC - PubMed
van Soest 2010 {published data only}
    1. Soest H, Schaar PJ, Koek GH, Vries RA, Ooteghem NA, Hoek B, et al. No beneficial effects of amantadine in treatment of chronic hepatitis C patients. Digestive and Liver Disease 2010;42(7):496‐502. [PUBMED: 20018575] - PubMed
Vardar 2001 {published data only}
    1. Vardar R, Karasu Z, Gunsar F, Akarca U, Ersoz G, Batur Y. Interferon plus amantadine has no superiority to IFN monotherapy in naive patients with chronic hepatitis C. Journal of Hepatology 2001;34:178.
von Wagner 2008 {published data only}
    1. Wagner M, Hofmann WP, Teuber G, Berg T, Goeser T, Spengler U, et al. Placebo‐controlled trial of 400 mg amantadine combined with peginterferon alfa‐2a and ribavirin for 48 weeks in chronic hepatitis C virus‐1 infection. Hepatology 2008;48(5):1404‐11. [PUBMED: 18846541] - PubMed
    1. Wagner M, Hofmann WP, Teuber G, Berg T, Goeser T, Spengler U, et al. Randomized, double‐blind, placebo‐controlled trial of peginterferon alfa‐2a (40KD) and ribavirin with and without 400 mg amantadine‐sulphate for 48 weeks in treatment naive HCV genotype 1‐infected patients. Hepatology 2007;46:342A‐3A.
    1. Wagner M, Hofmann WP, Teuber G, Berg T, Goeser T, Spengler U, et al. Sustained virologic response is associated with worse QoL during and improved QoL after treatment with peginterferon alfa‐2a and ribavirin. Hepatology 2008;48:886A‐7A. - PubMed
Wenger 2007 {published data only}
    1. Wenger C, Bischof T, Gonvers JJ, Renner EL, Mullhaupt B. Interferon and ribavirin with or without amantadine for interferon non‐responders with chronic hepatitis C. A randomized, controlled pilot study. Swiss Medical Weekly 2007;137(29‐30):418‐23. [PUBMED: 17705104] - PubMed
Yang 2003 {published data only}
    1. Yang SS, Tu TC, Wu CH, Chen DS. Combination of interferon alfa‐2a and amantadine does not improve the efficacy of interferon therapy in patients with chronic hepatitis C. Hepato‐Gastroenterology 2003;50(53):1575‐8. [PUBMED: 14571789] - PubMed
    1. Yang SS, Tu TC, Wu CH, Chen DS. Combination of interferon alfa‐2a and amantadine does not improve the efficacy of interferon therapy in patients with chronic hepatitis C. Hepatology 1999;30:369A. - PubMed
Zeuzem 2000 {published data only}
    1. Zeuzem S, Teuber G, Naumann U, Berg T, Raedle J, Hartmann S, et al. Randomised, double‐blind, placebo‐controlled trial of interferon‐alfa with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 1999;30:200A. - PMC - PubMed
    1. Zeuzem S, Teuber G, Naumann U, Berg T, Raedle J, Hartmann S, et al. Randomized, double‐blind, placebo‐controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 2000;32(4 Pt 1):835‐41. [PUBMED: 11003631] - PMC - PubMed

References to studies excluded from this review

Buggisch 2009 {published data only}
    1. Buggisch P, Zeuzem S, Teuber G, Möller B, Ehrhardt A, Gelbmann C, et al. Treating relapse with peginterferon alfa‐2a plus ribavirin and amantadin for either 72 or 48 weeks (in patients with HDV‐type 1/3 infection): results from the TRELA‐study. Journal of Hepatology 2009;50(S1):S382.
Di Bisceglie 2001 {published data only}
    1. Bisceglie AM, Bernstein DE, Rustgi VR, Gitlin N, Jeffers LJ, Simon D, et al. Pegylated (40 KDA) interferon alfa‐2a (Pegasys®) in new combination therapies: a report of a randomized, multicenter efficacy and safety study. Journal of Hepatology 2001;34:143.
Mendez‐Navarro 2010a {published data only}
    1. Mendez‐Navarro J, Chirino RA, Corey KE, Gorospe EC, Zheng H, Moran S, et al. Erratum: a randomized controlled trial of double versus triple therapy with amantadine for genotype 1 chronic hepatitis C in Latino patients. Digestive Diseases and Sciences 2010;55(10):3010. - PMC - PubMed
Nakamura 2003 {published data only}
    1. Nakamura H, Uyama H, Enomoto H, Kishima Y, Yamamoto M, Yoshida K, et al. The combination therapy of interferon and amantadine hydrochloride for patients with chronic hepatitis C. Hepato‐Gastroenterology 2003;50(49):222‐6. [PUBMED: 12630027] - PubMed
Popovic 2000 {published data only}
    1. Popovic A, Vian A, Lorenzoni U, Lobello S, Pevere S, Silverij E, et al. Daily interferon monotherapy versus daily interferon plus amantadine in the treatment of naive chronic hepatitis C patients: short‐term response. Journal of Hepatology. 2000; Vol. 32:195.
Quarantini 2006 {published data only}
    1. Quarantini LC, Miranda‐Scippa A, Schinoni MI, Sampaio AS, Santos‐Jesus R, Bressan RA, et al. Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study. Clinical Neuropharmacology 2006;29(3):138‐43. [PUBMED: 16772812] - PubMed
Schories 2003 {published data only}
    1. Schories M, Kallinowski B, Goeser T, Maier KP, Lutterer A, Wietzke‐Braun V, et al. Randomized placebo controlled double blind study in patients with chronic hepatitis C who did not respond to interferon therapy: comparison between interferon A, ribavirin +/‐ amantadine. Journal of Hepatology 2003;38:164.
    1. Schories M, Kallinowski B, Goeser T, Maier KP, Wietzke‐Braun V, Lutterer A, et al. Randomized placebo controlled double blind study in interferon nonresponder chronic hepatitis C patients with interferon A, ribavirin, amantadine in comparison to interferon A and ribavirin. Hepatology 2002;36(4):572A.
Torre 1999 {published data only}
    1. Torre F, Brizzolara R, Giusto R, Grasso A, Sinelli N, Campo N, et al. HCV‐RNA dynamics in the first month of treatment with IFN daily therapy alone versus combinations with amantadine or ribavirin. Journal of Hepatology 1999;30:128.
Zilly 2002 {published data only}
    1. Zilly M, Lingenauber C, Desch S, Vath T, Klinker H, Langmann P. Triple antiviral re‐therapy for chronic hepatitis C with interferon‐alpha, ribavirin and amantadine in nonresponders to interferon‐alpha and ribavirin. European Journal of Medical Research 2002;7(4):149‐54. [PUBMED: 12010649] - PubMed

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