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Aminoadamantanes versus other antiviral drugs for chronic hepatitis C

  1. Mieke H Lamers1,2,*,
  2. Mark Broekman1,
  3. Joost PH Drenth1,
  4. Christian Gluud2

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 17 JUN 2014

Assessed as up-to-date: 28 MAY 2014

DOI: 10.1002/14651858.CD011132.pub2


How to Cite

Lamers MH, Broekman M, Drenth JPH, Gluud C. Aminoadamantanes versus other antiviral drugs for chronic hepatitis C. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD011132. DOI: 10.1002/14651858.CD011132.pub2.

Author Information

  1. 1

    Radboud University Medical Center Nijmegen, Department of Gastroenterology and Hepatology, Nijmegen, Netherlands

  2. 2

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark

*Mieke H Lamers, m.lamers@mdl.umcn.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 17 JUN 2014

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

 
Summary of findings for the main comparison.

Aminoadamantanes compared with ribavirin for chronic hepatitis C

Patient or population: patients with chronic hepatitis C.

Settings: mainly outpatients in tertiary and teaching hospitals.

Intervention: aminoadamantanes.

Comparison: ribavirin.

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

RibavirinAminoadamantanes

All-cause mortality or liver-related morbidity

Follow-up: 12-24 months
Study populationRR 0.98

(0.00 to 248.89)
427
(4 trials)
⊕⊝⊝⊝
very low1

0 per 10000 per 1000
(0 to 0)

Adverse events

Follow-up: 12-24 months
Study populationRR 0.56

(0.27 to 1.16)
427
(4 trials)
⊕⊝⊝⊝
very low1

86 per 100047 per 1000
(23 to 98)

Failure of sustained virological response

Absence of clearance of HCV RNA from the blood 6 months after treatment

Follow-up: 12-24 months
Study populationRR 1.14

(1.07 to 1.22)
427
(4 trials)
⊕⊕⊕⊝
low2

835 per 1000954 per 1000
(896 to 1021)

Failure of end of treatment virological response

Absence of clearance of HCV RNA from the blood at end of treatment

Follow-up: 12-24 months
Study populationRR 1.20

(1.05 to 1.36)
309

(3 trials)
⊕⊕⊝⊝
low2

678 per 1000816 per 1000
(714 to 925)

Failure of normalisation of ALT at end of treatment

Follow-up: 12-24 months
Study populationRR 2.02

(1.07 to 3.82)
29
(1 trial)
⊕⊝⊝⊝
very low1

429 per 1000867 per 1000
(460 to 1640)

Failure of normalisation of ALT at end of follow-up

Follow-up: 12-24 months
Study populationRR 1.31

(1.05 to 1.63)
92
(2 trials)
⊕⊝⊝⊝
very low1

674 per 1000892 per 1000
(715 to 1110)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ALT: alanine aminotransferase; CI: confidence interval; HCV: hepatitis C virus; RNA: ribonucleic acid; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. Quality of the evidence was downgraded based on the risk of bias, imprecision of results, inconsistency of results.
2. Quality of the evidence was downgraded based on the risk of bias and inconsistency of results.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Description of the condition

Hepatitis C virus was first described in 1989 (Choo 1989). It affects around 3% of the world population, thus affecting approximately 160 million people (Sy 2006; Lavanchy 2011). Hepatitis C virus is a leading cause of mortality and liver-related morbidity with hepatic fibrosis, liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae (Sy 2006). Hepatocellular carcinoma occurs in 3 per 100,000 persons in the United States of America (El-Serag 2003). Hepatitis C virus is responsible for one-third of these hepatocellular carcinomas (El-Serag 2003). In cirrhotic hepatitis C virus patients, the annual occurrence of hepatocellular carcinoma is 1% to 4% (Lauer 2001). Furthermore, hepatitis C virus infection is the most common indication for orthotopic liver transplantation (Kim 2009).

Chronic hepatitis C virus progresses slowly, over a time frame of 15 years to 50 years. Prospective and retrospective studies following cohorts of patients for decades suggested that less than 10% of all infected individuals would develop end-stage liver disease. However, there are also publications reporting on patients who had developed cirrhosis two or three decades after infection with a range of 0.5% to 39% (Koretz 1993; Kenny-Walsh 1999; Rodger 2000; Wiese 2000; Thein 2008; Seeff 2009).

Hepatitis C virus is divided into six genotypes (from 1 to 6) (Simmonds 2005). Genotypes 1 to 4 are the most common genotypes (Simmonds 2005). Several factors have an influence on achieving a sustained virological response to antiviral drugs (that is, undetectable hepatitis C virus ribonucleic acid (RNA) in serum by sensitivity testing six months after the end of treatment); genotype is one of these factors (Asselah 2010). Genotypes 2 and 3 respond better to treatment than genotypes 1 and 4 (Asselah 2010).

In 1990, interferon-alpha, an antiviral drug, was approved for the treatment of chronic hepatitis C virus as monotherapy (Tine 1991). Interferon-alpha was administered subcutaneously in doses of equal to or more than three million units (MU) in the induction phase (during one to three months) and less than three MU in the maintenance phase (Tine 1991). Results of studies showed that only 10% to 17% of patients responded to interferon-alpha monotherapy in achieving a sustained virological response compared with 1% to 3% of participants on no intervention (Davis 1989; Myers 2002).

Antiviral drugs for patients with hepatitis C virus-related liver disease have improved considerably during the past two decades (Ghany 2009). In 1998, trials assessed the combination of interferon-alpha and ribavirin compared with interferon alpha alone (Davis 1998; McHutchison 1998; Poynard 1998). This combination treatment resulted in an improved antiviral response in naive, chronic hepatitis C virus-infected patients compared with interferon-alpha alone (Brok 2010), and in previously treated patients who had failed to respond to interferon-alpha monotherapy (Brok 2010).

The success of antiviral therapy is usually defined as the proportion of patients who achieve sustained virological response, that is, clearance of hepatitis C virus RNA from the blood six months after treatment. Observational studies have suggested that people with sustained virological response have less disease progression and less risk of hepatocellular carcinoma (Ueno 2009). However, following a systematic review of meta-analyses with randomised clinical trials comparing ribavirin plus interferon-alpha versus interferon-alpha alone, this drug therapy combination seemed to result in more patients with a sustained virological response, but no conclusion could be made if this combination results in less mortality or morbidity (Brok 2010). Sustained virological response is still a non-validated putative surrogate outcome measure (Gluud 2007).

A recent trial showed that there was an increased mortality in patients who were retreated with interferon-alpha compared with non-treated patients (Di Bisceglie 2011) and that was supported in a Cochrane systematic review (Koretz 2013).

The current standard of treatment for chronic hepatitis C virus infection, according to guidelines, is a combination of pegylated interferon-alpha (peg interferon-alpha) and ribavirin (Ghany 2009; EASL 2014). The regimen can include either peg interferon-alpha-2b (Peg-Intron®, Schering Plough Corp., Kenilworth, NJ) or peg interferon-alpha-2a (Pegasys®, Hoffmann-La Roche, Nutley, NJ), both of which are administered subcutaneously (Awad 2010). The optimal dose of peg interferon-alpha-2b is 1.5 µg/kg/week (Awad 2010; Hauser 2014a). Peg interferon-alpha-2a is administered at a fixed dose of 180 µg weekly (Awad 2010). Ribavirin is an oral therapy with weight-based total daily doses between 800 mg to 1200 mg administered twice per day (Brok 2009). Between 40% and 80% of chronic hepatitis C virus patients without co-infection with hepatitis B virus or human immunodeficiency virus (HIV) will achieve a sustained virological response after treatment with peg interferon-alpha and ribavirin (Simin 2007; Awad 2010; Hauser 2014; Hauser 2014a).

Recently, a new class of antiviral drugs for hepatitis C virus have emerged on the market. These antiviral agents act directly, inhibiting the non structural (NS) NS3/N4A serine protease and NS5B polymerase inhibitors of hepatitis C virus. The direct acting antivirals can alone, or in concert with peg interferon-alpha and ribavirin (triple therapy) increase sustained virological response proportions to 80% or above (Bacon 2011; Jacobson 2011; Poordad 2011; Sherman 2011; Zeuzem 2011; Lawitz 2013; Lawitz 2014; Sulkowski 2014). The effects they show on sustained virological response will hopefully lead to comparable clinical responses.

 

Description of the intervention

Aminoadamantanes is another antiviral drug group which includes amantadine and rimantadine. The drugs have been investigated in several studies for treatment of patients with chronic hepatitis C virus (Brillanti 1999; Smith 2004). These aminoadamantanes were investigated as oral monotherapy, administered mostly as 100 mg twice a day, and also in combination with interferon-alpha or ribavirin, or both. The benefits and harms of aminoadamantanes compared with placebo in patients with chronic hepatitis C virus infection have been explored in a meta-analysis by Deltenre 2004 and in a recent Cochrane systematic review (Lamers 2014).

 

How the intervention might work

Aminoadamantanes have been used for many years to prevent infection with influenza and have been shown to have activity against Flaviviridae, a family of viruses, encompassing hepatitis C virus infection (Koff 1980). Known mechanisms of action of aminoadamantanes include inhibition of an early step in viral replication, most likely viral uncoating and interaction with the influenza A viral matrix protein (M2), which is important in virion budding (De Clercq 2001). The aminoadamantane such as amantadine acts similar to ribavirin; ribavirin in monotherapy often improves liver biochemistry (Reichard 1991; Reichard 1993), but seems to have no major effect in the course of hepatitis C virus infection on its own (Brok 2009). However, it is unclear whether aminoadamantanes may reduce the hepatitis C virus viral load or improve liver biochemistry (Lamers 2014).

 

Why it is important to do this review

The combination therapy of peg interferon-alpha and ribavirin yields sustained virological response in approximately 40% to 80% of treated patients (Simin 2007; Awad 2010). This indicates an unmet need for drugs in order to reach higher proportions of sustained virological response. With the new direct antiviral agents, higher proportions can be achieved (Bacon 2011; Jacobson 2011; Poordad 2011; Sherman 2011; Zeuzem 2011). Several studies have been published regarding the effect of aminoadamantanes. Our systematic review is aimed at assessing the benefits and harms of aminoadamantanes versus other antiviral drugs. This systematic review may have practical implications on the way patients with chronic hepatitis C virus should be treated.

The benefits and harms of aminoadamantanes compared with placebo and other antiviral drugs in patients with chronic hepatitis C virus infection have been explored earlier in a meta-analysis by Deltenre 2004. A recent Cochrane systematic review compared aminoadamantanes with placebo for chronic hepatitis C (Lamers 2014). We found no significant effect of amantadine when compared with placebo or no intervention on sustained virological response or clinical outcomes (Lamers 2014).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

To explore the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection in a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Criteria for considering studies for this review

 

Types of studies

Randomised clinical trials assessing aminoadamantanes compared with other antiviral drugs in participants with chronic hepatitis C virus infection irrespective of duration of treatment, language, publication type and status, and blinding. Quasi-randomised studies or other observational studies captured during the search process were excluded for the report of benefit but were reported in a narrative way for the data on harm from such studies.

 

Types of participants

We included participants with chronic hepatitis C virus. The diagnosis was based on the presence of serum hepatitis C virus RNA (HCV RNA) plus elevated transaminases for more than six months, or chronic hepatitis documented on liver biopsy. We also included participants diagnosed with ’non-A, non-B’ chronic hepatitis as some trials may have been conducted before HCV RNA analyses were widely available.

Based on the existence of, and response to previous antiviral treatment, we classified the included participants as naive (not previously treated with antivirals), relapsers (participants with a transient serological viral response to previous treatment with antivirals), or non-responders (patients without serological viral response to previous treatment with antivirals).

We excluded participants who had undergone liver transplantation.

 

Types of interventions

Aminoadamantanes versus other antiviral drugs.

Co-interventions were allowed if administered equally to the intervention groups being compared.

 

Types of outcome measures

 

Primary outcomes

1. All-cause mortality or liver-related morbidity as a composite outcome: number of patients who died or who developed, for example, cirrhosis, ascites, hepatic encephalopathy, or hepatocellular carcinoma.
2. Adverse events: number of patients with either serious adverse events or treatment discontinuation due to any adverse event. Serious adverse events are defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice as "any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in persistent or significant disability or incapacity, or was a congenital anomaly/birth defect, or any medical event that might have jeopardised the patient, or required intervention to prevent it" (ICH-GCP 1997). All other adverse events (that is, any medical occurrence not necessarily having a causal relationship with the treatment but that did, however, cause a dose reduction or discontinuation of the treatment) were considered as being non-serious (ICH-GCP 1997).
3. Quality of life (as reported in the trials).

 

Secondary outcomes

1. Failure of serum (or plasma) sustained virological response: number of patients with detectable HCV RNA at least six months after treatment.
2. Failure of end-of treatment virological response: number of patients with detectable HCV RNA at the end of treatment.
3. Failure in histological response: number of patients without improvement of histology (inflammation score (grading) or fibrosis score (staging) as defined by the individual trials).
4. Number of participants without normalisation of alanine aminotransferase (ALT) or aspartate transaminase (AST) serum levels or both (defined by the individual trials) at end of treatment and end of follow-up.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013) (Gluud 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), and Science Citation Index EXPANDED (1900 to December 2013) (Royle 2003). We also searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm. We have given the search strategies in Appendix 1 with the time spans of the searches.

 

Searching other resources

We identified further trials by reading the reference lists of the identified studies. We checked review articles and meta-analyses in order to find randomised trials not identified by the electronic searches. We searched for abstracts from various gastrointestinal meetings. We wrote to the principal authors of the identified randomised trials and to the researchers active in the field to enquire about additional randomised trials they might know of. In order to obtain unpublished trials, we contacted pharmaceutical companies involved in the production and assessment of aminoadamantanes.

 

Data collection and analysis

 

Selection of studies

Two review authors (ML, MB) independently inspected each reference identified by the searches and applied the inclusion criteria. For possible relevant publications, or in cases of disagreement between the two review authors, the full article was obtained and inspected independently by the two authors. If the two review authors still disagreed, a third review author (CG) was consulted.

 

Data extraction and management

Two review authors (ML, MB) independently extracted data. In case of disagreement between the two review authors, a third review author (CG) arbitrated. The data extraction was discussed, decisions documented, and, where necessary, we contacted trial authors for clarification. Trials were identified by the name of the first author and year in which the study was published in full and ordered chronologically.

The following data were extracted, checked, and recorded.

  • Characteristics of trials: date, location and setting; publication status; sponsor (specified, known or unknown); duration of follow-up; bias-domains; sample size calculation.
  • Characteristics of participants: number of participants in each group; age; sex; ethnicity; weight or body mass index; viral load at the beginning of treatment; degree of fibrosis at the beginning of treatment.
  • Characteristics of interventions: dose and duration of aminoadamantanes and any co-interventions.
  • Characteristics of outcome measures: whenever possible, the number of events previously listed under 'outcome measures' were recorded in each group of the trial; information about harms were extracted in observational studies.

 

Assessment of risk of bias in included studies

According to empirical evidence (Schultz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), risk of bias in a trial can be assessed using 'Risk of bias' domains. We have used the following domains with definitions to assess the risk of bias of the trials included in the review.

 

Allocation sequence generation

  • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent person not otherwise involved in the trial.
  • Uncertain risk of bias: the method of sequence generation was not specified.
  • High risk of bias: the sequence generation method was not random.

 

Allocation concealment

  • Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (for example, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
  • Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
  • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

 

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
  • Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
  • High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.

 

Incomplete outcome data

  • Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
  • Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
  • High risk of bias: the results were likely to be biased due to missing data.

 

Selective outcome reporting

  • Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
  • Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.
  • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For a trial to be assessed with low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, for example published in a paper journal. In the case where the trial was run and published in the years when trial registration was not required, we carefully scrutinised all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives were provided in the publication's results section, then the trial can be considered low risk of bias in the 'Selective outcome reporting' domain.

 

For-profit bias

  • Low risk of bias: the trial appeared to be free of industry sponsorship or other kind of for-profit support that might have result in manipulation of the trial design, conduct, or results of the trial.
  • Uncertain risk of bias: the trial might or might not be free of for-profit bias as no information on clinical trial support or sponsorship is provided.
  • High risk of bias: the trial was sponsored by industry or had received other kinds of for-profit support.

All trials were assessed for risk of bias. If the risk of bias in a trial was judged as 'low' in all the above listed domains, then the trial was considered at 'low risk of bias'. If the risk of bias was judged as 'uncertain' or 'high', then the trial was considered at 'high risk of bias'.

Reporting bias was handled following the recommendations of The Cochrane Collaboration (Higgins 2011). Subgroup analyses (see below) and funnel plot asymmetry were assessed (Higgins 2011), even though asymmetric funnel plots are not necessarily caused by publication bias and publication bias does not necessarily cause asymmetry in a funnel plot (Egger 1997).

 

Measures of treatment effect

The treatment effects in this meta-analysis are dichotomous or continuous. The dichotomous data were expressed with risk ratio (RR) and 95% confidence intervals (CI). The number needed to treat (NNT) was derived from the risk difference (RD), in case the intervention effect was considered significant and valid. For continuous data, we planned to use the mean difference when outcomes of the trials were measured in the same way. Where appropriate, we would have used the standardised mean difference to combine trials that measured the same outcome but used different methods.

 

Unit of analysis issues

We used the intervention groups of participants in randomised clinical trials as our unit of analysis. Three included trials used a two-armed parallel group design; the other three trials used a multiple-armed parallel group design. We present those additional treatment arms in the 'Summary of characteristics of included studies', see  Table 1. Where the additional treatment arms were not relevant, we did not use these data.

 

Dealing with missing data

We contacted the original investigators to request missing data that we expected to have been measured but were not reported.

We performed all analyses according to the intention-to-treat method, including all participants irrespective of compliance or follow-up.

Regarding our primary outcomes, we included patients with incomplete or missing data in sensitivity analyses by imputing them according to the following two extreme scenarios (Hollis 1999; Gluud 2014).

  • Extreme case analysis favouring the experimental intervention ('best-worse' case scenario): none of the dropouts/participants lost from the experimental arm, but all of the dropouts/participants lost from the control group experienced the outcome, including all randomised participants in the denominator.
  • Extreme case analysis favouring the control ('worst-best' case scenario): all dropouts/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomised participants in the denominator.

 

Assessment of heterogeneity

We assessed heterogeneity using the chi-squared statistic test of heterogeneity and quantity of heterogeneity by the I2 measure of inconsistency (Higgins 2011). In case of substantial heterogeneity as measured by a chi-square test P value less than 0.1 or an I2 measure greater than 70%, we considered not to conduct the meta-analysis. We assessed sources of clinical, methodological, and statistical heterogeneity in subgroup analyses.

 

Assessment of reporting biases

Described under 'Assessment of risk of bias in included studies'.

 

Data synthesis

 

Meta-analysis

For the statistical analyses, we used Review Manager 5.2 (RevMan 2012). We meta-analysed the data with both a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987) to ensure robustness of the results. In case of statistically significant differences of the results that the two methods produced, we presented the results with both methods. If there were no differences in the results, we presented the results of the fixed-effect model only (Higgins 2011). If there was considerable variation in the results, and particularly if the direction of effect was inconsistent, it may be misleading to quote the average value for the intervention effect; we therefore interpreted the meta-analyses with utmost care.

 

Trial sequential analysis

We applied trial sequential analysis (CTU 2011; Thorlund 2011) as cumulative meta-analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2008; Wetterslev 2008; Brok 2009). To minimise random errors, we calculated the required information size (i.e., the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) (Wetterslev 2008). The required information size calculation should also account for the heterogeneity or diversity present in the meta-analysis (Wetterslev 2008; Wetterslev 2009). In our meta-analysis, the diversity-adjusted required information size was based on the event proportion in the control group; assumption of a plausible RR reduction of 20% or the RR reduction observed in the included trials with low risk of bias; a risk of type I error of 5%; a risk of type II error of 20%; and the assumed diversity of the meta-analysis (Wetterslev 2009). We added the trials according to the year of publication, and if more than one trial was published in a year, trials were added alphabetically according to the last name of the first author. On the basis of the required information size, trial sequential monitoring boundaries were constructed (Lan 1983; Wetterslev 2008; Thorlund 2011). These boundaries determine the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size; if the trial sequential monitoring boundary for benefit or harm is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. This can be determined by assessing if the cumulative Z-curve crosses the trial sequential boundaries for futility. If futility boundaries are crossed, then further trials may be unnecessary (CTU 2011).

We conducted trial sequential analyses using software from The Copenhagen Trial Unit (CTU 2011).

 

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were performed to compare the following.

  • Trials with low risk compared to trials with high risk of bias.
  • Type of patients regarding previous antivirals: naives, relapsers, and non-responders.
  • Type of patients regarding genotype: genotype 1 compared to genotype non-1.
  • Type of patients regarding degree of liver disease (inflammation score (grading) or fibrosis score (staging)).
  • Type of patients regarding HIV or hepatitis B co-infection.
  • Type of patients regarding age: children compared to adults.
  • Intervention: according to the type, dose and duration of aminoadamantanes, and other viral drugs.

Subgroups were compared with test of interaction (Altman 2003).

 

Sensitivity analysis

Suitable sensitivity analyses were identified during the review process, e.g., a sensitivity analysis was used when imputing missing data with replacement values.

Data analysis in included trials: according to intention-to-treat principle as well as 'as treated' (per protocol) analysis.

 

'Summary of findings' table

We used the principles of the GRADE system to assess the quality of the body of evidence associated with all outcomes mentioned in our review and constructed 'Summary of findings' table using the GRADE software (ims.cochrane.org/revman/gradepro).

We assessed five factors referring to limitations in the study design and implementation of available studies suggesting high likelihood of bias; indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results (wide confidence intervals); and high probability of publication bias.

We defined the levels of evidence as:

  • high-quality evidence when all bias domains were assessed with low risk of bias and there were consistent findings that were generalisable to most of the population of interest; there were sufficient data, with narrow confidence intervals; there were no known or suspected reporting biases; in such a case, "further research is very unlikely to change our confidence in the estimate of effect";
  • moderate-quality evidence when "further research is likely to have an important impact on our confidence in the estimate of effect, and may change the estimate";
  • low-quality evidence when the following statement applies: "further research is very likely to have an important impact on our confidence in the estimate of effect, and is likely to change the estimate";
  • very low-quality evidence when the following statement applies: "we are very uncertain about the estimate".

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search  

We identified 639 references through the electronic searches. After filtering for duplicates, 290 publications remained. Of the remaining 290 publications, 281 were excluded after screening the title and abstract, among others because they were reviews or because they did not describe a randomised clinical trial investigating the effect of aminoadamantanes in patients with chronic hepatitis C virus. The remaining nine references described six unique randomised clinical trials (Figure 1).

 FigureFigure 1. Flow diagram.

Two of these six included trials were published in more than one publication (Khalili 2000; Younossi 2001). All six trials were published in full paper articles (Khalili 2000; Younossi 2001; Bacosi 2002; Herrine 2005; Salmeron 2007; Abbas 2012).

When necessary, the primary or last authors were contacted for further information and data relating to the trials.

We did not identify any registered ongoing or planned trials when we searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm.

 

Included studies  

We included six trials in total. Three trials were conducted in the USA (Khalili 2000; Younossi 2001; Herrine 2005). The other three trials were conducted each in different countries: Italy (Bacosi 2002), Pakistan (Abbas 2012), and Spain (Salmeron 2007) (see Characteristics of included studies).

The included trials were published from 2000 (Khalili 2000) to 2012 (Abbas 2012). Three trials had a parallel group design with two intervention groups (Khalili 2000; Younossi 2001; Abbas 2012). One trial included three intervention groups (Bacosi 2002) and two trials included four intervention groups (Herrine 2005; Salmeron 2007).

The six randomised clinical trials randomised 581 patients with chronic hepatitis C virus to amantadine versus control. The control arms consisted of ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma.

Three trials compared amantadine plus interferon-alpha versus ribavirin plus interferon-alpha (Khalili 2000; Younossi 2001; Salmeron 2007). One trial compared amantadine monotherapy with interferon-alpha without additional antiviral drugs (Bacosi 2002). One trial reported on amantadine plus interferon-alpha plus ribavirin versus interferon-gamma plus interferon-alpha plus ribavirin (Abbas 2012). Another trial compared amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha (Herrine 2005). This trial also reported on the comparison of amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha (Herrine 2005).

Amantadine dose was the same in each trial, 200 mg daily. The treatment duration of the trials varied from six to 12 months. A six-month post-treatment duration of follow-up was used in all trials, except for one trial which applied 12 months of post-treatment follow-up (Bacosi 2002). The details are displayed in  Table 1.

All publications reported the sex of the participants; more than 67% were men. All trials included adult patients. None of the trials included patients co-infected with HIV or hepatitis B virus infection.

 

Excluded studies  

The eight excluded studies are listed under 'Characteristics of excluded studies', and the reasons for exclusion are given there.

 

Risk of bias in included studies

Risk of bias was assessed according to six domains: allocation sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; handling of incomplete outcome data; selective outcome reporting; and for-profit bias. All included trials were considered to have high risk of bias. Our statistical analysis are, therefore, based on trials with a high risk of bias. For details of the judgements made for the individual trials, please see Figure 2 and Figure 3.

 FigureFigure 2. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation (selection bias)  

The generation of the allocation sequence was adequately described in only one trial (Younossi 2001). The remaining five trials were described as randomised, but the method or performing random sequence generation was not described or the randomisation was done by the principle investigator (Characteristics of included studies).

The method used to conceal allocation was adequately described in three trials (Younossi 2001; Salmeron 2007; Abbas 2012). The method of performing allocation concealment was judged as unclear in two trials (Khalili 2000; Herrine 2005) and judged as high risk in one trial (Bacosi 2002).

 

Blinding (performance bias and detection bias)  

The method of blinding of participants and personnel was adequately described in only one trial (Younossi 2001). The other five trials were considered to have a high risk of bias in the blinding of participants and personnel domain (Characteristics of included studies). None of the trials adequately described the method of blinding of outcome assessment; thus, six trials were considered as high risk of bias (Characteristics of included studies). This also means that none of the included trials had a low risk of bias according to both blinding of participants and personnel and blinding of outcome assessments (Characteristics of included studies).

 

Incomplete outcome data (attrition bias)  

Incomplete data were addressed adequately in two trials (Khalili 2000; Abbas 2012). In the other four trials, there were risks of incomplete outcome data (Characteristics of included studies).

 

Selective reporting (reporting bias)  

There were risks of selective reporting of outcomes in all six trials (Characteristics of included studies).

 

Other potential sources of bias  

Only one trial did not receive funding or other for-profit support and was therefore of low risk of bias regarding for-profit domain (Abbas 2012). Three trials received funding from the medical industry (Younossi 2001; Herrine 2005; Salmeron 2007). It was unclear whether the remaining two trials received funding from the medical industry or other for-profit support (Khalili 2000; Bacosi 2002) (Characteristics of included studies). We considered these last five trials as having high risk of bias for the for-profit bias domain (Figure 3).

There were no baseline differences in any of the trials, except for one in which there was baseline imbalance regarding age (Khalili 2000). One trial stopped early due to poor results (Salmeron 2007).

 

Effects of interventions

See:  Summary of findings for the main comparison

 

Amantadine versus ribavirin

Three trials compared amantadine plus interferon-alpha versus ribavirin plus interferon-alpha; one trial compared amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha.

Primary outcomes

The composite outcome of all-cause mortality or liver-related morbidity

Four trials provided information on all-cause mortality or liver-related morbidity. The combined outcome measure was zero in both the 216 participants in the amantadine group and the 211 patients in the ribavirin group ( Analysis 1.1). We were not able to perform meta-analyses on these data in RevMan, but with trial sequential analysis and a continuity correction of 0.5, we found no significant differences (fixed-effect model: risk ratio (RR) 0.98; 95% confidence interval (CI) 0.00 to 248.89). The required information size to detect or reject a relative risk reduction (RRR) of 20% with a between-trial heterogeneity of 0% is estimated to be 140,645 patients. The actually accrued number of patients was 427, which was only 0.3% of the required information size.

Adverse events

We classified adverse events into two groups: number of patients with serious adverse events and number of patients with treatment discontinuation due to any adverse event.

Ten patients of 216 (5%) in the amantadine group versus 18 patients of 211 patients (9%) in the ribavirin group were reported with either serious adverse events or treatment discontinuation due to any adverse event ( Analysis 1.2). Meta-analyses showed no statistically significant difference (fixed-effect model: RR 0.56; 95% CI 0.27 to 1.16; I² = 20%) ( Analysis 1.2).

As there were no trials with low risk of bias, we performed trial sequential analysis on all included trials reporting on adverse events. Trial sequential analysis of these data showed there was too little information to draw any firm conclusions (Figure 4).

 FigureFigure 4. Trial sequential analysis of the random-effects meta-analysis of the effect of amantadine versus ribavirin in chronic hepatitis C-infected patients on number of patients experiencing a serious adverse event or 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 events or who had to discontinue treatment due to an adverse event of 11%, 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 to be 7214 participants. The actually accrued number of participants is 398, which is only 6% of the DARIS. 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 that amantadine influences number of patients experiencing a serious adverse event or who had to discontinue treatment due to an adverse event. 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.

Quality of life

Only one trial reported on quality of life (Younossi 2001). Health-related quality of life (HRQL) was assessed at baseline and every three months using the medical outcome study Short Form-36 (SF-36) and a validated liver disease-specific instrument, Chronic Liver Disease Questionnaire (CLDQ). We were not able to perform meta-analyses on quality of life due to a lack of valid data. Overall, we found no significant differences between treatment with amantadine versus ribavirin in this trial.

Secondary outcomes

Failure of serum (or plasma) sustained virological response

Four trials provided information on patients who failed to achieve a sustained virological response. In the amantadine group, 206 of 216 patients (95%) did not achieve sustained virological response versus 176 of 211 patients (83%) in the ribavirin group. Meta-analysis with the fixed-effect model showed an effect on failure to achieve sustained virological response favouring the ribavirin group: RR 1.14; 95% CI 1.07 to 1.22. This estimated RR with a random-effects model was similar, with marginally wider confidence intervals including the null: RR 1.15; 95% CI 0.99 to 1.32; I² = 78%) ( Analysis 1.3).

Three trials reported on failure to achieve sustained virological response in patients treated with amantadine plus interferon-alpha versus ribavirin plus interferon-alpha ( Analysis 1.3). One-hundred and seventy-eight participants of 185 participants (96%) in the amantadine group versus 156 participants of 179 participants (87%) in the ribavirin group failed to achieve sustained virological response. This negative effect of amantadine plus interferon-alpha compared with ribavirin plus interferon-alpha, shown by the fixed-effect meta-analysis was not observed in the random-effects model analysis (fixed-effect model: RR 1.10; 95% CI 1.04 to 1.18; random-effects model: RR 1.09; 95% CI 0.98 to 1.21; I² = 78%) ( Analysis 1.3).

Sixty-three patients were treated in one trial with amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha ( Analysis 1.3). Twenty-eight of 31 participants (90%) treated in the amantadine group compared with 20 of 32 participants (63%) in the ribavirin group failed to achieve sustained virological response. Risk ratio for this event was statistically significant comparing amantadine plus peg interferon-alpha therapy with ribavirin plus peg interferon-alpha (fixed-effect model: RR 1.45; 95% CI 1.08 to 1.94) ( Analysis 1.3).

Analysing the missing data as the best-worst case scenario in all the four trials comparing amantadine with ribavirin (assuming that participants with unknown status of achieving sustained virological response receiving amantadine did achieve sustained virological response, and that all participants from the ribavirin group with unknown status of achieving sustained virological response did not achieve sustained virological response) reveals no statistically significant differences in effect of amantadine versus ribavirin (fixed-effect model: RR 0.94; 95% CI 0.86 to 1.03; 427 participants, four trials). Analysing the missing data as the worst-best case scenario (assuming that participants with unknown status of achieving sustained virological response receiving amantadine did not achieve sustained virological response and that all participants from ribavirin group with unknown status of achieving sustained virological response achieved sustained virological response) shows an effect favouring ribavirin (fixed-effect model: RR 1.58; 95% CI 1.41 to 1.77; 427 participants, four trials).

We performed trial sequential analysis on all the trials. The trial sequential analysis of the combined data supports the finding that ribavirin is superior to amantadine with less failure to achieve sustained virological response (Figure 5). The result of the trial sequential analysis is shown by the cumulated Z-curve (blue curve) which crosses the trial sequential boundary (red inward sloping curve).

 FigureFigure 5. Trial sequential analysis of the random-effects meta-analysis of the effect of amantadine versus ribavirin on 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 80%, an assumed control proportion of number of patients who failed to achieve an SVR of 83%, 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 78% is estimated to be 981 participants. The actually accrued number of participants is 427, which is 44% of the DARIS. The blue cumulative Z-curve crosses the red trial sequential monitoring boundary for harm. Therefore, there is evidence to support that ribavirin is superior compared with amantadine.

Failure of end-of treatment virological response

Three trials provided data on participants who failed to achieve end-of treatment virological response and could be included in the analyses ( Analysis 1.4). In the amantadine group, 128 of 157 participants (82%) did not achieve end-of treatment virological response versus 103 of 152 participants (68%) in the ribavirin group. Meta-analysis showed that amantadine showed more failure to achieve end-of treatment virological response compared to ribavirin (fixed-effect model: RR 1.20; 95% CI 1.05 to 1.36; I² = 32%) ( Analysis 1.4).

We performed trial sequential analysis on all the three trials. There is no evidence to support that amantadine influences the number of participants who failed to achieve an end-of treatment virological response (Figure 6).

 FigureFigure 6. Trial sequential analysis of the random-effects meta-analysis of the effect of amantadine versus ribavirin on number of patients with chronic hepatitis C virus infection who failed to achieve an end-of treatment virological response. 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 who failed to achieve an SVR of 68%, 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 32% is estimated to be 594 participants. The actually accrued number of participants is 309, which is 52% of the DARIS. The blue cumulative Z-curve does not cross the red trial sequential monitoring boundaries for benefit or harm. Therefore, we cannot exclude random error.

Analysing the data in the best-worst case scenario regarding missing data (assuming that participants with unknown status of achieving end-of treatment virological response receiving amantadine did achieve end-of treatment virological response, and that all participants from the ribavirin group with unknown status of achieving end-of treatment virological response did not achieve end-of treatment virological response) reveals no differences in effect estimate; thus, no negative effect of amantadine (fixed-effect model: RR 0.91; 95% CI 0.78 to 1.07; 309 participants, three trials). Analysing the data in the worst-best case scenario regarding missing data (assuming that participants with unknown status of achieving end-of treatment virological response receiving amantadine did not achieve end-of treatment virological response, and that all participants from control group with unknown status of achieving end-of treatment virological response did achieve end-of treatment virological response) reveals a stronger effect favouring ribavirin (fixed-effect model: RR 2.01; 95% CI 1.64 to 2.46; 309 participants, three trials).

Failure in histological response

None of the included trials provided information on the number of participants without improvement of histology.

Failure of normalisation of serum ALT levels at end-of treatment and at end-of follow-up

All trials that reported on biochemical response, only reported on ALT levels.

Only one trial provided information on failure of normalisation of end-of treatment biochemical response. In the amantadine group, 13 of 15 participants (87%) did not achieve end-of treatment biochemical response versus 6 of 14 participants (43%) in the ribavirin group. Meta-analyses showed that amantadine resulted in more participants without normalisation of ALT serum levels at end-of treatment compared with ribavirin (fixed-effect model: RR 2.02; 95% CI 1.07 to 3.82) ( Analysis 1.5).

In two trials, 41 participants of 46 participants (89%) treated with amantadine compared with 31 of 46 participants (67%) in the ribavirin group failed to achieve end-of follow-up biochemical response ( Analysis 1.6). Meta-analysis (fixed-effect model; RR 1.31; 95% CI 1.05 to 1.63; I² = 12%) showed that amantadine more often failed to achieve end-of follow-up biochemical response compared to ribavirin ( Analysis 1.6).

 

Amantadine versus mycophenolate mofetil

Only one trial provided information on the comparison amantadine versus mycophenolate mofetil (Herrine 2005). The included trial reported on 31 participants in the amantadine group versus 29 participants in the mycophenolate mofetil group.

The all-cause mortality or liver-related morbidity was zero in both intervention arms ( Analysis 2.1).

Five participants of 31 (16%) in the amantadine group versus five participants of 29 participants (17%) in the mycophenolate mofetil group were reported with either serious adverse events or treatment discontinuation due to any adverse event ( Analysis 2.2). There were no significant differences between the groups (fixed-effect model: RR 0.94; 95% CI 0.30 to 2.90) ( Analysis 2.2). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 14% is estimated to be 4093 participants. The actually accrued number of participants is 60, which is only 1% of the required information size.

Twenty-eight participants (90%) failed to achieve sustained virological response in the amantadine group versus 24 participants (83%) in the mycophenolate mofetil group. There was no significant difference in effect (fixed-effect model: RR 1.09; 95% CI 0.89 to 1.34) ( Analysis 2.3). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 87% is estimated to be 1661 participants. The actually accrued number of participants is 60, which is only 4% of the required information size.

There was a significant negative effect of amantadine on failure to achieve end-of treatment virological response (fixed-effect model: RR 2.10; 95% CI 1.09 to 4.08). In the amantadine group, 18 of 31 participants (58%) did not achieve end-of treatment virological response versus 8 of 29 participants (28%) in the mycophenolate mofetil group ( Analysis 2.4). Trial sequential analysis showed a required information size of 4017 participants. The actually accrued number of participants is 60, which is only 1% of the required information size.

The included trial did not provide information on quality of life, histological response, and normalisation of ALT at end-of treatment.

Twenty-six participants treated with amantadine (84%) compared with 23 participants treated with mycophenolate mofetil (79%) failed to achieve end-of follow-up biochemical response ( Analysis 2.5). Meta-analyses showed no statistically significant difference (fixed-effect model: RR 1.06; 95% CI 0.83 to 1.35) ( Analysis 2.5).

Due to the limited number of participants, we were unable to perform any of the remaining planned sensitivity analysis or funnel plot analysis.

 

Amantadine versus interferon-alpha

One trial reported on the comparison amantadine versus interferon-alpha (Bacosi 2002). The included trial reported on 42 participants in the amantadine group versus 39 participants in the interferon-alpha group.

The included trial did not provide information on all-cause mortality, liver-related morbidity, quality of life, or histological response.

Zero participants of 42 (0%) in the amantadine group versus 3 participants of 39 participants (8%) in the interferon-alpha group were reported with either serious adverse events or treatment discontinuation due to any adverse event ( Analysis 3.1). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 0% is estimated to be 8539 participants. The actually accrued number of participants is 81, which is only 1% of the required information size.

Thirty-five participants (83%) failed to achieve sustained virological response in the amantadine group versus 30 participants (77%) in the interferon-alpha group, which showed no significant difference in effect (fixed-effect model: RR 1.08; 95% CI 0.87 to 1.35) ( Analysis 3.2). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 81% is estimated to be 1484 participants. The actually accrued number of participants is 81, which is only 5% of the required information size.

Regarding failure to achieve end-of treatment virological response, there were no significant differences in effect between amantadine and interferon-alpha (fixed-effect model: RR 1.25; 95% CI 0.96 to 1.62). In the amantadine group, 35 of 42 participants (83%) did not achieve end-of treatment virological response versus 26 of 39 participants (67%) in the interferon-alpha group ( Analysis 3.3). Trial sequential analysis showed a required information size of 1745 participants. The actually accrued number of participants is 81, which is only 5% of the required information size.

In the amantadine group, 21 of 42 participants (50%) did not achieve end-of treatment biochemical response versus 22 of 39 participants (56%) in the interferon-alpha group. Meta-analyses showed no significant difference in the number of participants without normalisation of ALT serum levels at end-of treatment compared amantadine with interferon-alpha (fixed-effect model: RR 0.89; 95% CI 0.59 to 1.33) ( Analysis 3.4). Trial sequential analysis showed a required information size of 1252 participants. The actually accrued number of participants is 81, which is only 6% of the required information size.

Twenty-five participants (60%) treated with amantadine compared with 26 participants (67%) in the interferon-alpha group failed to achieve end-of follow-up biochemical response ( Analysis 3.5). Meta-analyses showed no statistically significant difference (fixed-effect model: RR 0.89; 95% CI 0.64 to 1.25) ( Analysis 3.5). Trial sequential analysis showed a required information size of 1074 participants. The actually accrued number of participants is 81, which is only 8% of the required information size.

Due to the limited number of participants, we were unable to perform any of the remaining sensitivity analysis, or funnel plot analysis.

 

Amantadine versus interferon-gamma

One trial provided information on the comparison amantadine versus interferon-gamma (Abbas 2012). This trial reported on 22 participants in both the amantadine group and the interferon-gamma group.

The all-cause mortality or liver-related morbidity was zero in both intervention arms ( Analysis 4.1). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 0% is estimated to be 70,005 participants. The actually accrued number of participants is 44, which is only 0.06% of the required information size.

Two participants in the amantadine group (9%) versus zero participants (0%) in the interferon-gamma group were reported with either serious adverse events or treatment discontinuation due to any adverse event ( Analysis 4.2). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 50% is estimated to be 140,010 participants. The actually accrued number of participants is 44, which is only 0.03% of the required information size.

Sixteen participants failed to achieve sustained virological response in the amantadine group versus 11 participants in the interferon-gamma group. There was no significant effect of amantadine compared with interferon-gamma (fixed-effect model: RR 1.45; 95% CI 0.89 to 2.37) ( Analysis 4.3). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 66% is estimated to be 2288 participants. The actually accrued number of participants is 44, which is only 2% of the required information size.

Also, there was no significant effect of amantadine compared with interferon-gamma on failure to achieve end-of treatment virological response (fixed-effect model: RR 1.36; 95% CI 0.82 to 2.26). In the amantadine group, 15 participants (68%) did not achieve end-of treatment virological response versus 11 participants (50%) in the interferon-gamma group ( Analysis 4.4). The required information size to detect or reject a RRR of 20% with a between-trial heterogeneity of 63% is estimated to be 2102 participants. The actually accrued number of participants is 44, which is only 2% of the required information size.

The included trial did not provide information on the outcome measures: quality of life and histological response.

In the amantadine group, 15 participants (68%) did not achieve end-of treatment biochemical response versus 11 participants (50%) in the interferon-gamma group. Meta-analyses showed no significant difference in effect comparing amantadine with interferon-gamma (fixed-effect model: RR 1.36; 95% CI 0.82 to 2.26) ( Analysis 4.5). Again, trial sequential analysis showed a required information size of 2102 participants. The actually accrued number of participants is 44. This is only 2% of the required information size.

Sixteen participants (73%) treated with amantadine compared with 11 participants (50%) in the interferon-gamma group failed to achieve end-of follow-up biochemical response ( Analysis 4.6). Meta-analyses showed no differences (fixed-effect model: RR 1.45; 95% CI 0.89 to 2.37) ( Analysis 4.6). Trial sequential analysis showed a required information size of 2288 participants. The actually accrued number of participants is 44, which is only 2% of the required information size.

Due to the limited number of participants, we were unable to perform any of the remaining planned trial sequential analysis, sensitivity analysis, or funnel plot analysis.

 

Amantadine versus other antiviral-drugs

For completeness we have also meta-analysed data from all comparisons together in order to answer the question: which is best, amantadine or other antivirals? The heterogenous group of other antivirals seemed superior.

 

Summary of findings    [Explanations]

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) 'Summary of findings' table (Guyatt 2008) is shown in  Summary of findings for the main comparison.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Summary of main results  

We included six randomised clinical trials with 581 participants that assessed the benefits and harms of amantadine versus other antiviral drugs for the treatment of chronic hepatitis C virus. Amantadine was compared with four other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. The effect of amantadine was evaluated in four different treatment strategies: monotherapy of amantadine, combination therapy of amantadine with interferon-alpha, combination therapy of amantadine plus interferon-alpha and ribavirin, and combination therapy of amantadine plus peg interferon-alpha. All trials had high risks of bias.

This systematic review did not show any benefit of amantadine on all-cause mortality or liver-related morbidity.

Furthermore, our systematic review also showed that amantadine for participants with chronic hepatitis C virus is not associated with an increase or a reduction of adverse events, defined by the number of participants who experienced a serious adverse event or who had to discontinue treatment due to an adverse event. These results are confirmed by trial sequential analyses.

When comparing amantadine versus ribavirin, amantadine seems inferior as the proportion of participants who failed to achieve sustained virological response was larger in the amantadine group. This finding was confirmed by a trial sequential analysis. However, when comparing amantadine with the other three antiviral drugs, we did not demonstrate that participants treated with amantadine had more failure in achieving sustained virological response. These findings could be due to type II errors or bias. Moreover, amantadine did not show to have decreased the overall proportion of participants who failed to achieve end-of treatment virological response. Again, type II errors or bias should be considered.

Unfortunately, we were not able to identify any benefits of amantadine on quality of life and histology because none of the included trials reported on quality of life or failure of histological improvement. We found a disadvantage of amantadine compared with ribavirin on biochemical end-of treatment and on end-of follow-up responses.

 

Overall completeness and applicability of evidence  

This systematic review examined the evidence from six included randomised clinical trials for the use of treatment of hepatitis C virus. Despite efforts to obtain additional information from the trial authors, we could not obtain all relevant data, hence not all trials reported on all of our predefined outcomes.

Due to the limited number of included trials and participants, we were not able to perform subgroup analyses according to whether a patient had already received a previous antiviral therapy for hepatitis C virus, e.g., naive participants, relapsers, or non-responders, and if so, which treatment he/she had received. Five trials reported adequately on all-cause mortality or liver-related morbidity, and all six trials reported on serious adverse events and treatment discontinuation due to an adverse event. None of the included trials provided information on quality of life. Six trials reported on our first secondary outcome: failure of achieving sustained virological response. Five trials reported on failure of end-of treatment virological response. No trial provided information on failure in histological improvement, three trials reported on failure of biochemical response at end-of treatment, and four trials reported on failure of biochemical response at end-of follow-up.

It is questionable whether the included participants are representative for the current practice. All trials included participants with positive serum HCV RNA. However, there is heterogeneity among trials due to different disease severity of participants at entry, differences according to genotype (five trials included a mixture of genotypes), and differences regarding previous antiviral treatment. Concerning sex and age, the trials seem representative for current clinical care; more than 67% of the included participants were men and all trials included adult participants. None of the trials included participants with hepatitis B virus or HIV co-infection. Accordingly, we lack data on co-infected patients.

 

Quality of the evidence  

We conducted this review according to The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). The results of our meta-analysis, however, are only as strong as the quality of primary trials included.

The main limitation in the design and implementation is the lack of clarity of the generation of allocation sequence, concealment of allocation, and blinding. Of the included trials, only one (17%) reported adequate allocation sequence generation; only three (50%) adequately reported on allocation concealment; and none reported blinding. Two trials (33%) adequately addressed incomplete data, but none of the trials reported on all clinically relevant and reasonably expected outcomes. Also, one trial (17%) appeared to be free of other components that could put them at risk of bias. Accordingly, all trials were with high risk of bias. It is surprising to see that none of the trials were considered as having low risk of bias, in spite of the repeated calls for improved trial quality both within and outside hepatology (Schultz 1995; Gluud 1998; Kjaergard 1999; Needleman 1999; Kjaergard 2001; Wood 2008; Savović 2012). Also, other bias domains had high risk of bias. Patients, patient organisations, and other stakeholders do not get unbiased research before the several calls for unbiased clinical research is followed by physicians, regulatory authorities, and industry.

Regarding precision of our results, some outcomes of the included trials in our meta-analysis include few participants and few events, and thus the confidence intervals around the estimate of effect are large.

All trials measured sustained virological response which is currently the most commonly used surrogate outcome measure of benefit. Recent large cohort studies showed a positive correlation between the presence of viraemia and mortality (Butt 2009; Uto 2009). However, sustained virological response is still only a putative (unvalidated) surrogate outcome for the patient-relevant intervention effect of antivirals (Gluud 2007; Gurusamy 2013; Koretz 2013). Because randomised clinical trials need to inform clinical practice, clinical outcomes such as the risk of liver failure, hepatocellular carcinoma, mortality, and quality of life would be of greater interest to patients and clinicians. Such measures nevertheless require a follow-up of maybe up to five years. Currently, no randomised clinical trials assessing aminoadamantanes are of such long duration.

 

Potential biases in the review process  

In this systematic review, a comprehensive literature search was performed. As far as we know, we have found all the evidence available. A potential limitation of our literature search may be that we have not specifically searched for trials in the grey literature which may have introduced a slight risk of bias into our meta-analysis (Egger 2003). However, the bias is unlikely to influence our results in a beneficial way as trials found in grey literature rarely report beneficial effects (Hopewell 2007).

We only included six trials, in which four different antiviral regimens (ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma) were used as comparator drugs. Also, most of the included trials are of a relatively small size. This increases the risk of providing a more unrealistic estimate of the intervention effects due to bias (systematic errors) or chance (random errors) (Keus 2010). Risk of bias is known to have an impact on the estimated intervention effect, with trials with high risk of bias tending to overestimate beneficial intervention effects and underestimating harmful effects (Schultz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a). We could not divide the analysis for all outcomes into high risk of bias trials and low risk of bias trials to reveal any influence of bias on the effect estimates of our outcomes, because all six trials were considered to have high risk of bias.

No statistical signs of publication bias and other bias were observed.

This review meta-analysed data for all-cause mortality or liver-related morbidity from five trials involving 500 participants. We also meta-analysed data for serious adverse events or treatment discontinuation due to an adverse event from six trials involving 581 participants. The median length of trial duration was 12 months (two trials had a trial duration of six months), the median length of follow-up was six months (one trial had a follow-up of 12 months). For our primary outcome all-cause mortality or liver-related morbidity, this is not sufficiently long considering that the estimated median time in which hepatitis C virus progresses to cirrhosis is 15 years to 50 years (Koretz 1993; Kenny-Walsh 1999; Seeff 2009). Therefore, it is difficult to detect a significant difference on all-cause mortality and liver-related morbidity based on these trials. If aminoadamantanes should have an effect on morbidity and mortality, one prerequisite would be that it significantly affected virological load. However, we were unable to extract viral data to show that this was the case.

We used trial sequential analysis (CTU 2011; Thorlund 2011) to control the risk of random errors which is higher when data come from trials with small sample sizes (Wetterslev 2008). The trial sequential analysis on the outcome serious adverse events or treatment discontinuation due to an adverse event showed no significant effect estimate applying both the random-effects and fixed-effect models in participants treated with amantadine. The trial sequential analysis on the secondary outcome measure sustained virological response applied for amantadine compared with ribavirin demonstrated a negative effect on the number of participants who failed to achieve sustained virological response in participants treated with amantadine. Thus, random errors seem to have been excluded for this comparison, but systematic errors may remain.

Heterogeneity among trials might be due to differences in dose, duration and type of interferon-alpha, or peg interferon-alpha. The inclusion of interferon-alpha as well as peg interferon-alpha with pharmacokinetic differences might have influenced the observed outcomes and comparability of results with earlier publications. Also, different definitions of non-responders were used, such as non-responder to previous interferon-alpha therapy alone or non-responder to combination therapy of interferon-alpha with ribavirin. Furthermore, there could be heterogeneity among trials due to disease severity of participants at entry and differences according to genotype, both of which can affect the sustained virological response rates. To reflect our concern about heterogeneity, we conducted all analyses using both the fixed-effect model and random-effects model. We only presented the results of the fixed-effect model if the results of the two models did not differ. Subgroup analyses of the pre-defined covariates trial risk of bias, genotype distribution, previous antiviral treatment, and degree of liver disease could not be performed because of the lack of trials that reported on these variables.

 

Agreements and disagreements with other studies or reviews  

Less than about 10% of all hepatitis C virus infected patients will develop end-stage liver disease. Overall, we found that amantadine did not show any benefit on all-cause mortality or liver-related morbidity. Most trials report on the surrogate outcome sustained virological response, but as already mentioned, we do not know if sustained virological response results in less mortality or morbidity (Gluud 2007; Brok 2009; Gurusamy 2013; Koretz 2013; Hauser 2014; Hauser 2014a).

Also, considering failure in achieving sustained virological response, we found that amantadine did not show any benefit. On the contrary, amantadine showed less effect compared with ribavirin, a finding which was supported by the trial sequential analyses. This result is in accordance with the main findings of a published meta-analysis (Chen 2012) which suggests that there is no beneficial effect of adding amantadine to peg interferon-alpha plus ribavirin in naive hepatitis C virus genotype 1 patients. Our findings are contrary to the main findings of another meta-analyses (Deltenre 2004) which suggested a role for amantadine in non-responder patients. Furthermore, our results are also in contrast with another review which suggests that there may be a limited role for combination therapy in naive patients (Lim 2005).

We have no evidence from randomised trials on long-term (> one year) effects of amantadine on our primary outcomes. Long-term effects would in particular be relevant for outcomes like all-cause mortality or liver-related morbidity.

Amantadine was generally well tolerated. We observed that amantadine was associated with non-serious adverse events and almost all trials reported in general similar frequencies and severities of adverse events in both amantadine groups versus control groups. This result is in accordance with a Cochrane review about amantadine and rimantadine for influenza A in children and the elderly (Alves Galvao 2012). This result is also somewhat comparable to two other Cochrane reviews. The review on amantadine and rimantadine in influenza A in adults showed significantly more adverse effects in patients receiving amantadine compared to placebo, but no increased risk of serious adverse events (Jefferson 2012). The second review reported on amantadine in Parkinson's disease and found that there is not enough evidence from trials about the effects of amantadine for people with Parkinson’s disease, and that adverse events in trials so far have not been severe (Crosby 2009). In our analysis, amantadine was administered with interferon-alpha or peg interferon-alpha with or without ribavirin, except for one trial. Interferon-alpha-based therapy is typically associated with haematologic complications (i.e., neutropenia, thrombocytopenia), neuropsychiatric complications (i.e., memory and concentration loss, visual disturbances, headaches, depression, irritability), flu-like symptoms, hormonal complications (i.e., hypothyroidism, hyperthyroidism), gastrointestinal complications (i.e., nausea, vomiting, weight loss), and dermatologic complications (i.e., eczema, alopecia). The most well-known adverse effect of ribavirin is a dose-dependent haemolytic anaemia, but gastrointestinal adverse effects such as nausea are also reported (Chutaputti 2000; Soza 2002; Sulkowski 2004). In conclusion, both interferon-alpha and ribavirin have a variety and severity of adverse events, which may make it hard to detect less severe adverse events of amantadine. We cannot exclude less severe adverse events from amantadine, for example gastro-intestinal symptoms and insomnia.

Regarding tolerance of amantadine, we have to take into consideration the doses of amantadine. All included trials used an amantadine dose of 200 mg per day. One randomised trial that evaluated the safety and toxicity of amantadine in patients with chronic hepatitis C virus also investigated the maximum tolerable dose of amantadine (Smith 2004a). They reported an increase in biochemical response with higher daily doses of amantadine from 200 mg per day up to 500 mg per day in monotherapy. However, no statistically difference was found in ALT values between those receiving 300 mg of amantadine or those receiving higher doses of amantadine. Also, increasing the amantadine dose did not result in more patients achieving sustained virological response comparing 200 mg per day with 300 mg to 500 mg per day (Smith 2004a).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

 

Implications for practice

This review shows that there seems to be no significant benefit of amantadine on hepatitis C virus-infected patients for all-cause mortality or liver-related morbidity, or on adverse events in hepatitis C-infected patients; although the timeframe for measuring the composite outcome was insufficient in the included randomised clinical trials. Furthermore, amantadine did not decrease the proportion of patients with failure to achieve sustained virological response compared with ribavirin. In the absence of convincing evidence of benefit, the use of amantadine seems only justified in the context of randomised clinical trials assessing the effects of combination therapy with peg interferon-alpha and ribavirin. We found no randomised clinical trials assessing other aminoadamantanes.

 
Implications for research

Given the results of our analysis, we cannot conclude whether new randomised clinical trials will or will not find any beneficial effect of amantadine on patients' survival in chronic hepatitis C patients. We found no evidence for other aminoadamantanes. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits. Therefore, it is probably better to focus on the assessments of other direct acting antiviral drugs. To our knowledge, no ongoing trials investigate the effects of amantadine in hepatitis C-infected patients. Any further trials ought to be conducted and reported according to the SPIRIT and CONSORT guidelines (Schulz 2012).

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

We thank Dimitrinka Nikolova, Bianca Hemmingsen, Maria Skoog, Jane Lindschou, and Luit Penninga from The Cochrane Hepato-Biliary Group and The Copenhagen Trial Unit for helpful discussions and comments. Furthermore, we thank Sarah Louise Klingenberg from The Cochrane Hepato-Biliary Group for helping developing the searches strategies and running the searches. We also thank the peer reviewers for their contribution to the protocol.

Peer reviewers: Sarah Louise Klingenberg, Denmark; Jane Lindschou, Denmark.
Contact editor: Janus Christian Jakobsen, Denmark.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
Download statistical data

 
Comparison 1. Amantadine versus ribavirin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality or liver-related morbidity4427Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events4427Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.27, 1.16]

    2.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.14, 1.03]

    2.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.33, 3.22]

 3 Failure of sustained virological response4427Risk Ratio (M-H, Fixed, 95% CI)1.14 [1.07, 1.22]

    3.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)1.10 [1.04, 1.18]

    3.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.08, 1.94]

 4 Failure of end of treatment virological response3309Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.05, 1.36]

    4.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
2246Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.32]

    4.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.85, 2.39]

 5 Failure of normalisation of ALT at end of treatment129Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.07, 3.82]

    5.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
129Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.07, 3.82]

 6 Failure of normalisation of ALT at end of follow-up292Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.05, 1.63]

    6.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
129Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.91, 1.48]

    6.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.02, 1.96]

 
Comparison 2. Amantadine versus mycophenolate mofetil

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality or liver-related morbidity160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.1 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events160Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.30, 2.90]

    2.1 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.30, 2.90]

 3 Failure of sustained virological response160Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.89, 1.34]

    3.1 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.89, 1.34]

 4 Failure of end of treatment virological response160Risk Ratio (M-H, Fixed, 95% CI)2.10 [1.09, 4.08]

    4.1 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)2.10 [1.09, 4.08]

 5 Failure of normalisation of ALT at end of follow-up160Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.83, 1.35]

    5.1 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.83, 1.35]

 
Comparison 3. Amantadine versus interferon-alpha

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse events181Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.49]

    1.1 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.49]

 2 Failure of sustained virological response181Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.87, 1.35]

    2.1 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.87, 1.35]

 3 Failure of end of treatment virological response181Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.96, 1.62]

    3.1 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.96, 1.62]

 4 Failure of normalisation of ALT at end of treatment181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.33]

    4.1 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.33]

 5 Failure of normalisation of ALT at end of follow-up181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.64, 1.25]

    5.1 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.64, 1.25]

 
Comparison 4. Amantadine versus interferon-gamma

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality or liver-related morbidity144Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events144Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 98.52]

    2.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 98.52]

 3 Failure of sustained virological response144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

    3.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

 4 Failure of end of treatment virological response144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

    4.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

 5 Failure of normalisation of ALT at end of treatment144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

    5.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

 6 Failure of normalisation of ALT at end of follow-up144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

    6.1 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

 
Comparison 5. Amantadine versus other antiviral drugs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality or liver-related morbidity5531Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   1.4 Amantadine versus interferon-alpha
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events6612Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.37, 1.15]

    2.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.14, 1.03]

    2.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.33, 3.22]

    2.3 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.30, 2.90]

    2.4 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.49]

    2.5 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 98.52]

 3 Failure of sustained virological response6612Risk Ratio (M-H, Fixed, 95% CI)1.14 [1.07, 1.22]

    3.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
3364Risk Ratio (M-H, Fixed, 95% CI)1.10 [1.04, 1.18]

    3.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.08, 1.94]

    3.3 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.89, 1.34]

    3.4 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.87, 1.35]

    3.5 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

 4 Failure of end of treatment virological response5494Risk Ratio (M-H, Fixed, 95% CI)1.27 [1.13, 1.42]

    4.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
2246Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.32]

    4.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.85, 2.39]

    4.3 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)2.10 [1.09, 4.08]

    4.4 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.96, 1.62]

    4.5 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

 5 Failure of normalisation of ALT at end of treatment3154Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.90, 1.58]

    5.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
129Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.07, 3.82]

    5.2 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.33]

    5.3 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.82, 2.26]

 6 Failure of normalisation of ALT at end of follow-up4277Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.99, 1.32]

    6.1 Amantadine plus interferon-alpha versus ribavirin plus interferon-alpha
129Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.91, 1.48]

    6.2 Amantadine plus peg interferon-alpha versus ribavirin plus peg interferon-alpha
163Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.02, 1.96]

    6.3 Amantadine plus peg interferon-alpha versus mycophenolate mofetil plus peg interferon-alpha
160Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.83, 1.35]

    6.4 Amantadine versus interferon-alpha
181Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.64, 1.25]

    6.5 Amantadine plus interferon-alpha and ribavirin versus interferon-gamma plus interferon-alpha and ribavirin
144Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.89, 2.37]

 
Comparison 6. Sensitivity analysis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure of sustained virological response4854Risk Ratio (M-H, Fixed, 95% CI)1.21 [1.13, 1.30]

    1.1 Best-worst: Amantadine versus ribavirin
4427Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.86, 1.03]

    1.2 Worst-best: Amantadine versus ribavirin
4427Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.41, 1.77]

 2 Failure of end of treatment virological response3618Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.17, 1.50]

    2.1 Best-worst: Amantadine versus ribavirin
3309Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.07]

    2.2 Worst-best: Amantadine versus ribavirin
3309Risk Ratio (M-H, Fixed, 95% CI)2.01 [1.64, 2.46]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Appendix 1. Search strategies


DatabaseTime spanSearch strategy

Cochrane Hepato-Biliary Group Controlled Trials Register1996 to December 2013(adaman* OR amantadin* OR symmetrel OR symandin* OR rimantadin* OR flumadin* OR methenamin*) AND ('hepatitis C' OR 'hep C' OR HCV)

Cochrane Central Register of Controlled Trials (CENTRAL)Issue 11 of 12, 2013#1 MeSH descriptor: [Adamantane] explode all trees

#2 adaman* OR amantadin* OR symmetrel OR symandin* OR rimantadin* OR flumadin* OR methenamin*

#3 (#1 OR #2)

#4 MeSH descriptor: [Hepatitis C] explode all trees

#5 hepatitis C OR hep C OR HCV

#6 (#4 OR #5)

#7 (#3 AND #6)

MEDLINE (Ovid SP)1946 to December 20131. exp Adamantane/

2. (adaman* or amantadin* or symmetrel or symandin* or rimantadin* or flumadin* or methenamin*).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

3. 1 or 2

4. exp Hepatitis C/

5. (hepatitis C or hep C or HCV).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

6. 4 or 5

7. 3 and 6

8. (random* or blind* or placebo* or meta-analys*).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

9. 7 and 8

EMBASE (Ovid SP)1974 to December 20131. exp amantadine/

2. exp rimantadine/

3. (adaman* or amantadin* or symmetrel or symandin* or rimantadin* or flumadin* or methenamin*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

4. 1 or 2 or 3

5. exp hepatitis C/

6. (hepatitis C or hep C or HCV).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

7. 5 or 6

8. 4 and 7

9. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

10. 8 and 9

Science Citation Index Expanded1900 to December 2013# 5 #4 AND #3

# 4 TS=(random* or blind* or placebo* or meta-analys*)

# 3 #2 AND #1

# 2 TS=(hepatitis C or hep C or HCV)

# 1 TS=(adaman* or amantadin* or symmetrel or symandin* or rimantadin* or flumadin* or methenamin*)



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

ML, MB, JD, and CG were involved in the study concept and design.
ML and MB screened the literature, selected publications for inclusion and exclusion according to the eligibility criteria, extracted data, and made the risk of bias judgements.
ML, MB, and CG analysed and interpreted the data and results.
ML drafted the manuscript and performed the meta-analyses.
JD and CG were involved in critical revision of the manuscript for important intellectual content.
All authors approved the review for publication.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

Mieke 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.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
 

Internal sources

  • Radboud University Medical Center Nijmegen, Netherlands.

 

External sources

  • The Cochrane Hepato-Biliary Group (CHBG), Denmark.
    The first author, Mieke H Lamers, worked on the review for three months at the CHBG Editorial Team offices.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review

We conducted sensitivity analysis on only the statistical significant findings with only 'best-worse' case scenario and 'worst-best' case scenario (instead of these two with poor outcome analysis and good outcome analysis in both intervention groups) in order to check the robustness of our analysis.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Abbas 2012 {published data only}
  • Abbas Z, Raza S, Hamid S, Jafri W. Randomized controlled trial of interferon gamma versus amantadine in combination with interferon alpha and ribavirin for hepatitis C genotype 3 non-responders and relapsers. Journal of the Pakistan Medical Association 2012;62:338-43.
Bacosi 2002 {published data only}
  • Bacosi M, Russo F, Dínnocenzo S, Santolamazza M, Miglioresi L, Ursitti A, et al. Amantadine and interferon in the combined treatment of hepatitis C virus in elderly patients. Hepatology Research 2002;22(3):231-9.
Herrine 2005 {published data only}
  • Herrine SK, Brown RS Jr, Bernstein DE, Ondovik MS, Lentz E, Te H. Peginterferon alpha-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral breakthrough on therapy with standard interferon alpha-2b plus ribavirin: a pilot study of efficacy and safety. Digestive Diseases and Sciences 2005;50(4):719-26.
Khalili 2000 {published data only}
  • Khalili M, Denham C, Perrillo R. A comparison of combination therapy with interferon and ribavirin vs interferon and amantadine in interferon non-responders with chronic hepatitis C. Hepatology 1999;28(4):169A.
  • Khalili M, Denham C, Perrillo R. Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C. American Journal of Gastroenterology 2000;95(5):1284-9. [PUBMED: 10811340]
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Salmeron 2007 {published data only}
Younossi 2001 {published data only}
  • Younossi ZM, Mullen KD, Zakko W, Brandt E, Hodnick S, Barnes D, et al. Interferon alpha2B-ribavirin vs. interferon alpha2B-amantadine combination in chronic hepatitis C; analyses of a randomized, double-blind trial. Hepatology 1999;30(4):372A.
  • Younossi ZM, Mullen KD, Zakko W, Brandt E, Hodnick S, Easley K, et al. Interferon alpha2b and ribavirin vs interferon alpha2b and amantadine for chronic hepatitis C (non-responder): a multi-center, randomized, double-blind trial. Hepatology 1998;28(4):284A.
  • Younossi ZM, Mullen KD, Zakko W, Hodnick S, Brand E, Barnes DS, et al. A randomized, double-blind controlled trial of interferon alpha-2b and ribavirin vs. interferon alpha-2b and amantadine for treatment of chronic hepatitis C non-responder to interferon monotherapy. Journal of Hepatology 2001;34(1):128-33. [PUBMED: 11211889]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Bellobuono 2002 {published data only}
  • Bellobuono A, Del Poggio P, Jamoletti C, Finazzi R, Covini G, Milazzo L, et al. Combination therapy in naive patients with chronic hepatitis C related to genotype 1: comparison between IFN + ribavirin and IFN + amantadine and between amantadine and ribavirin addition after 3 months in still viremic patients. Hepatology 2002;36:573A.
  • Bellobuono A, Finazzi R, Covini G, Milazzo L, Magni C, Milella AM, et al. Comparison between IFNalpha 2a + ribavirin and IFNalpha 2a + amantadine combination therapy in naive patients with chronic hepatitis C-genotype 1, and between amantadine and ribavirin addition in non responders after 3 months. Journal of Hepatology 2002;36(S1):98.
Di Bisceglie 2001 {published data only}
  • Di 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(1):143.
Gerardi 1998 {published data only}
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Torre 1999 {published data only}
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References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Ideo 2003 {published data only}
  • Ideo G, Antonucci G, Attili AF, Babudieri S, Chirianni A, Craxi A, et al. Peg-IFN alfa-2a (40KD) (Pegasys®) plus amantadine (AMA) or ribavirin (RBV) in naive patients with chronic hepatitis C (CHC). Hepatology 2003;38(4):728A.
  • Ideo G, Attili A, Chirianni A, Craxi A, Di Perri G, Picciotto A, et al. Peg-IFN alfa-2a (40KD) (Pegasys) plus amantadine (AMA) or ribavirin (RBV) in naive patients with chronic hepatitis C (CHC). Hepatology 2002;36(4):570A.
  • Ideo G, Attili, A, Ruggiero G, Craxi A, Di Perri G, Mangia A, et al. Peg-IFN alfa-2a (40KD) (Pegasys) plus amantadine (AMA) or ribavirin (RBV) in naive patients with chronic hepatitis C (CHC). Journal of Hepatology 2003;38(S2):146.
Montaser 2003 {published data only}
  • Montaser MF. Dimethyl dimethoxy biphenyl dicarboxylate and amantadine hydrochloride combination in treatment of chronic hepatitis C: a pilot study in Egypt. Journal of Hepatology 2003;38(S2):158.
Picciotto 1999 {published data only}
  • Picciotto A, Torre F, Brizzolara R, Campo N, Giusto R, Sinelli N, et al. Chronic hepatitis C. New therapeutic strategies. Minerva Gastroenterologica e Dietologica 1999;45(3):169-72. [PUBMED: 16498326]
Pimstone 1997 {published data only}
  • Pimstone NR, Yu AS, Akhondi MM, Lumbra LA. End-of-treatment virologic response of chronic hepatitis C with either amantadine or rimantadine. Hepatology 1997;26(4):217A.

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
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