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Evaluation of amantadine in chronic hepatitis C: a meta-analysis
Journal of Hepatology, Volume 41, Issue 3, (September 2004)
Pierre Deltenreab, Jean Henrionb, Val�rie Canvaa, Sebastien Dharancyac, Fr�d�ric Texiera, Alexandre Louvetac, Stephane De Maeghtb, Jean-Claude Parisa, Philippe Mathurinac
a Services d'H�pato-Gastroent�rologie, H�pital Huriez, CHRU Lille, France. b Services d'H�pato-Gastroent�rologie, H�pital de Jolimont, Haine-Saint-Paul, Belgium. c Services d'H�pato-Gastroent�rologie, Equipe Inserm EPI 0114, France
In western countries, an estimated 0.8 to 1% of the population is infected with hepatitis C virus (HCV) leading to cirrhosis in 15-20% of cases. At present, HCV cirrhosis is the most frequent indication for liver transplantation.
Ten years ago, interferon (IFN) therapy provided a sustained virological response (SR) in 15% of patients with CHC. Combining ribavirin with IFN improved the SR to 40% 2. The most recent therapeutic regimen combining ribavirin with pegylated IFN was associated with a SR rate of 56% in HCV naive patients. Rates of SR vary drastically depending on several factors. In naive HCV patients with genotype 1, the SR is approximately 40-50%, whereas a SR is observed in 80% of patients with genotype 2 or 3. Among patients previously treated, non-responders patients are highly resistant to IFN, whereas relapsers are more sensitive to IFN. In non-responders to IFN, combination therapy with IFN and ribavirin induces a SR in only 13% of cases. Preliminary data on combination therapy with pegylated IFN and ribavirin showed a SR rate around 15% in non-responders. Therefore, alternative therapeutic regimens are required, particularly in patients with a poor probability of SR.
Identification of new drugs constitutes a crucial challenge. Amantadine (1-adamantanamine) is an antiviral agent active against the influenza A virus. Amantadine exerts antiviral activity against other viruses, including flaviridae to which HCV belongs. Amantadine appears to be able to block the function of the HCV p7 protein and dose-dependently reduces the HCV RNA content in cultured peripheral blood mononuclear cells from HCV-infected patients.
In HCV patients, amantadine given as monotherapy improved liver biochemistry to some degree, but did not influence viral load, except in one study. However, the usefulness of combination therapy with amantadine and IFN (double therapy) or combination therapy with amantadine, ribavirin and IFN (triple therapy) remains controversial.
In the present study, we sought to assess the effect of combination therapy with amantadine. For this purpose, we used an evidence-based approach consisting of meta-analysis of randomized controlled trials (RCT). As it is well known that antiviral efficiency drastically differs in untreated patients, relapsers or non-responders, meta-analyses were carried out according to the type of included patients (naive, relapsers and non-responders). Furthermore, sensitivity analyses were performed to analyze the efficacy of combinative therapy using amantadine either in double therapy or triple therapy.
The benefit of amantadine combination therapy, either with interferon (IFN) alone (double therapy) or with ribavirin and IFN (triple therapy) is unknown.
We analyzed the effect of amantadine on the end-of-treatment virological response and the sustained response using meta-analysis of 31 randomized controlled trials.
Overall analysis revealed a significant effect of amantadine. Triple therapy was the best regimen for improving the sustained response (mean difference: 8.4%, 95% CI: 2.4-13.8%, P=0.002). In subgroup analysis, amantadine did not have a significant effect upon naive patients or relapsers. In non-responders, combination therapy with amantadine was associated with a significant effect on the sustained response (mean difference: 8.3%, 95% CI: 1.9-14.6%, P=0.01). In sensitivity analysis, double therapy did not improve virological responses. Conversely, triple therapy tended to improve the end-of-treatment virological response and was associated with a significant effect upon the sustained response (mean difference: 12.7%, 95% CI: 3.8-21.6%, P=0.005).
Combination therapy with amantadine is of no effect upon naive patients or relapsers. In non-responders, triple therapy with amantadine improved the sustained response. New randomized controlled trials are required to confirm this meta-analysis.
The addition of amantadine to IFN alone, or to ribavirin and IFN, has shown promising results in some studies, while others do not confirm these results. The absence of a consensus concerning the effect of combination therapy with amantadine in CHC justified the present overview using a literature-based meta-analysis. Thirty-one RCTs were included which evaluated combination therapy in 3 types of patients: naive patients, relapsers and non-responders. In addition, the effect of amantadine was evaluated in 2 types of regimens: double therapy combining amantadine and IFN, and triple therapy combining amantadine, ribavirin and IFN (standard or pegylated). We observed that triple therapy with amantadine seemed to improve SR on overall analysis of all studies regardless of the type of patients (naive, relapsers and non-responders). In subgroup analysis, we showed that this effect seemed to be restricted to non-responders.
Meta-analysis often searches for a moderate treatment effect not detected by several trials. We agree that our meta-analysis had several methodological limitations. It was not possible to perform a meta-analysis according to the genotype, since heterogeneity in the distribution of genotypes between studies might affect the rates of ETR and SR. Secondly, we observed substantial heterogeneity between studies according to dose, duration and type of IFN (standard or pegylated). For non-responders, some studies included non-responders to IFN alone, whereas others included non-responders to combination therapy with ribavirin and IFN. Another weakness of our study was that we considered meta-analysis as the gold standard of evidence-based medicine. However, the validity of meta-analysis method has recently been called into question. The most accurate approach would be to combine individual data from previous RCTs instead of classical meta-analysis. A recent study using individual data
suggests, like the present study, that amantadine may be an attractive drug in HCV patients. However, that study faced the classical difficulty of obtaining an exhaustive collection of individual data from all studies. Indeed, Mangia et al. compared double therapy to interferon alone using individual data of only 6 studies, whereas we included 17 studies evaluating double and triple therapy as well. Even when considering only double therapy, 13 studies were analyzed in our meta-analysis. At present, combination IFN plus ribavirin is the 'gold standard' of treatment, and the current question is whether amantadine improves the antiviral effect of combination therapy with IFN and ribavirin.
According to our results, amantadine in naive patients and relapsers did not have a significant effect on SR. Regardless of the type of patient (naive or relapser), sensitivity analyses did not show any difference in the rate of SR either in double or triple therapy. In naive patients, it would be useful to analyze the amantadine effect according to genotype, since the need to improve antiviral efficacy concerns mainly patients with non 2-3 genotypes. Unfortunately, we were not able to perform such an analysis because of the absence of descriptive data. Indeed, the recent study of Mangia observed that amantadine was most beneficial in patients infected with genotypes 1 or 4 or with high basal viremia. In relapsers, despite the fact that only 2 studies were analyzed, amantadine did not seem to have a significant effect either on ETR or SR. In these patients, repetitive therapy constitutes an attractive approach, since they are still highly sensitive to conventional therapy with
ribavirin and pegylated IFN. In summary, despite the limitations of the present meta-analysis, our data strongly preclude the future evaluation of amantadine in relapsers. In naive patients, further studies should evaluate the effect of amantadine only in the difficult-to-treat groups of patients (non 2-3 genotypes or high viremia).
In non-responders, combination therapy with amantadine significantly improved SR. In sensitivity analysis, the efficient regimen was triple therapy that significantly improved SR, with a mean difference of around 13% and a trend toward significance in the ETR (19.8%, P=0.07). Taking into account the fact that only triple therapy was effective, a synergetic effect of amantadine and ribavirin could be postulated. Unfortunately, we were unable to identify a subgroup of patients who benefited most from amantadine combination therapy because of the absence of descriptive data. For future evaluation of triple therapy, since 8 patients would need to be treated in order to obtain one additional SR, only RCTs which include a large number of patients could demonstrate such an effect.
In conclusion, the present meta-analysis indicates that, in HCV patients, combination therapy with amantadine is of no benefit in na�ve patients or relapsers. Conversely, in non-responders, triple therapy with amantadine appears to be useful in this highly difficult-to-treat group of patients. However, a firm conclusion regarding the benefit of triple therapy with amantadine in non-responders, drawn from our results, is hampered by the limitations of the studies included in this meta-analysis. In the future, large, well-designed RCTs evaluating triple therapy with amantadine, ribavirin and pegylated IFN should be conducted in difficult-to-treat groups of patients.
Among 107 references identified, 76 studies were excluded for the following reasons: 23 studies were non-randomized; 12 studies did not mention ETR or SR; 20 studies did not compare treatment with and without amantadine but other combinations of treatments including amantadine; 2 studies concerned HIV-HCV co-infected patients; 2 studies were performed in transplanted patients; 1 study did not specify whether patients had received previous therapy or not 80; 2 did not specify the exact number of patients randomized; 14 preliminary studies were excluded as the latest publication of the trial was available.
Amantadine effect on overall patients
Thirty-one studies involving 4831 patients were included. The rates of ETR and SR were mentioned in 3664 and 4099 patients, respectively. In overall analysis of all studies, there was a significant effect of amantadine on ETR with a mean difference of 6% (95% CI: 0.8-11%, P=0.02), and on SR with a mean difference of 3.7% (95% CI: 0.3-7%, P=0.03). We performed a sensitivity analysis according to pre-established criteria to assess the specific effect of double therapy and triple therapy. There was no significant effect of double therapy on ETR, with a mean difference of 3.1% (95% CI: -1 to 7.3%, P=0.1), and on SR with a mean difference of 4% (95% CI: -3.3 to 4.3%, P=0.8). Triple therapy had a significant effect on ETR with a mean difference of 12% and on SR with a mean difference of 8.4%. All the significant results with Der Simonian method were still significant using the Peto method (data not shown).
Subgroup analysis of amantadine effect in naive patients
Seventeen RCTs evaluating the amantadine effect in 3257 naive patients were included. Thirteen studies compared double therapy to IFN alone. Four studies compared triple therapy to ribavirin and IFN. One study 115 compared more than 2 groups of patients. In that study, only groups enabling a comparison between regimens with and without amantadine were taken into account.
There was no significant effect of amantadine on ETR with a mean difference of 3.61% (95% CI: -1.6 to 8%, P=0.17), or on SR with a mean difference of 1.5%. We performed a sensitivity analysis to assess the specific effect of double therapy and triple therapy. There was a significant effect of double therapy on ETR, with a mean difference of 7% (95% CI: 1.5-12.5%, P=0.01), but not on SR with a mean difference of 0.6% (95% CI: -4.9 to 6%, P=0.84). Triple therapy did not have any significant effect either on ETR with a mean difference of -0.6% (95% CI: -10.3 to 9%, P=0.33) or on SR with a mean difference of 3.5% (95% CI: -3.3 to 10.3%, P=0.31).
Subgroup analysis of amantadine effect in relapsers
Three RCTs evaluating the amantadine effect in 304 relapsers were included. Three studies compared triple therapy to ribavirin and IFN. We excluded one study 121 which combined data from relapsers and non-responders and had mistakes in the number of patients in the table of results. One study 122 compared more than 2 groups of patients. In that study, only the groups enabling a comparison between regimens with and without amantadine were taken into account.
There was no significant effect of amantadine on ETR with a mean difference of -2.9% (95% CI: -27 to 21.2%, P=0.8) or on SR with a mean difference of 6.4%.
Subgroup analysis of amantadine effect in non-responders
Twelve studies evaluating the amantadine effect in 1376 non-responders were included. The definition of previous non-response was not homogeneous between studies. Four RCTs compared double therapy to IFN alone. Nine studies compared triple therapy to ribavirin and IFN. We excluded one study 121 which combined data from relapsers and non-responders and which included mistakes for the number of patients in the table of results. Four studies compared more than 2 groups of patients. In those studies, only groups enabling a comparison between regimens with and without amantadine were taken into account.
There was no significant effect of amantadine on ETR with a mean difference of 9.9% (95% CI: -4.3 to 24.3%, P=0.17), but a significant effect on SR was found, with a mean difference of 8%, meaning that 13 patients would need to be treated with amantadine combination therapy in order to obtain one additional SR over the rate expected in the comparison group. The SR rate was 22.9% in patients treated with combination therapy including amantadine and 14.9% in patients without amantadine. In sensitivity analyses, double therapy did not have any effect either on ETR, with a mean difference of -1.1% (95% CI: -7 to 4.8%, P=0.71), or on SR with a mean difference of 2.2% (95% CI: -3.6 to 8%, P=0.46). Triple therapy tended toward an improvement in ETR, with a mean difference of 19.8% (95% CI: -1.5 to 41.1%, P=0.07), and was associated with a significant effect on SR, with a mean difference of 12.7%, meaning that 8 patients would need to be treated with amantadine combination therapy in order
to obtain one additional SR over the rate expected in the comparison group.
Medline, Cancerlit, Embase and manual searches by two observers (PD and PM) were combined 19. Searching terms were: hepatitis C, treatment, amantadine, randomized trial. General reviews and references from published RCTs were used. The two observers extensively screened all abstracts presented at liver and gastroenterology congresses between 2001 and 2003 in English or French.
Criteria for inclusion and exclusion of studies
To be included, a study had to fulfill the following criteria: (a) study design of RCT; (b) comparison of an antiviral regimen including amantadine to the same antiviral regimen without amantadine; (c) publication as a full length paper or as an abstract presented at an international congress using English (AASLD, EASL, DDW) or French (Journ�es Francophones de Pathologie Digestive, AFEF) between 2001 and 2003; (d) use of end-of-treatment virological response (ETR) or SR (undetectable HCV RNA 6 months after the end of treatment) as clinical endpoints. For publications concerning the same study, only the last published study was included.
We excluded: (a) non-RCTs; (b) studies without information concerning ETR or SR; (c) studies using amantadine with a design that did not allow the real assessment of the effect of amantadine; (d) studies in HIV and HCV co-infected patients; (e) studies in liver transplanted patients; (f) studies including patients without information about previous treatment; (g) studies without clear information on the number of randomized patients; (h) publications concerning the same study.
Criteria for combinability
In a first step, we performed an overall meta-analysis of RCTs regardless of the type of patients (naive, relapsers and non-responders) from the core group. The core analysis group was defined as the group of studies that evaluated the amantadine effect either in double or triple therapy consisting of a comparison of an antiviral regimen including amantadine to the same antiviral regimen without amantadine. In a second step, we sought to differentiate the specific effect of double therapy combining amantadine and IFN from the effect of triple therapy combining amantadine, ribavirin and IFN (standard or pegylated). For this purpose, the following sensitivity analyses were performed: (1) in the sensitivity analysis restricted to double therapy we excluded RCTs evaluating triple therapy; (2) in the sensitivity analysis restricted to triple therapy we excluded RCTs evaluating double therapy. Therefore, sensitivity analysis of double therapy compared combination therapy with amantadine
and IFN to IFN alone, whereas sensitivity analysis of triple therapy compared combination therapy with amantadine, ribavirin and IFN to ribavirin and IFN.
In a second step we performed a subgroup analysis using a meta-analysis according to the type of patients: the first part involved naive patients, the second part relapsers and the third part non-responders. In RCTs, the amantadine effect was evaluated in 2 types of regimens: double therapy and triple therapy. The wide heterogeneity between the protocols for each modality led us to combine studies with different schemes of treatment (doses or duration) as long as they evaluated the same combination regimen.
2.4. Statistical methods
The intention to treat method was used. When ETR or SR was given in percentage, the number of patients with ETR or SR was extrapolated from the number of patients. For each meta-analysis, the Peto et al. 20 and Der Simonian and Laird methods 21 were used.
In the Der Simonian and Laird method, studies are considered as a random sample from a population of studies. The random effect model incorporates the heterogeneity of the studies. The overall treatment effect is estimated by a weighted average of the individual effects with weights inversely proportional to the variance of the observed effects. The estimate is expressed by the difference in percentages (risk of treated-risk of controls). A significant level of 5% was taken as the alpha risk. Comparison of the percentages between states was performed using their 95% confidence interval. We tested our assumption of heterogeneity for each planned analysis using the method of Der Simonian and Laird based on work first presented by Cochran 22. Detailed results were given only for Der Simonian and Laird analyses.
All results of the amantadine effect present the mean difference as being the effect (proportion with positive outcome) in patients treated with amantadine combination therapy minus the effect (proportion with positive outcome) in the control.
For relative risks demonstrating a clear benefit for one treatment, the 'number needed to treat' (NTT) was calculated. Arithmetically, the NTT is the inverse of the absolute difference in risk between treatment groups for a particular outcome. For this analysis, the NTT is the number of persons who must undergo combination therapy with amantadine for one patient to obtain one additional SR over the rate expected in the comparison group.
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