Amantadine May Lower the Efficacy of Pegylated Interferon Plus Ribavirin In

Home , Boceprevir, Telaprevir

International Journal of Infectious Diseases 16 (2012) e748–e752

Contents lists available at SciVerse ScienceDirect

International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Meta-analysis: amantadine may lower the efﬁcacy of pegylated interferon plus

ribavirin in treatment-naive hepatitis C genotype 1 patients

1 1

Jian Chen , Jian Shi , Wei-Fen Xie, Xin Zeng *, Yong Lin *

Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

A R T I C L E I N F O S U M M A R Y

Article history: Objective: The current standard therapy for hepatitis C virus genotype 1 (HCV-1) infection is still

Received 16 January 2012

suboptimal. Whether adding amantadine (AMA) to pegylated interferon (PEG-IFN) plus ribavirin (RBV)

Received in revised form 24 May 2012

improves the virological response in treatment-naive HCV-1 patients remains unclear.

Accepted 11 June 2012

Methods: Searches of the electronic databases including Embase, Medline, Cochrane Controlled Trials

Corresponding Editor: Mark Holodniy,

California, USA

carried out. A meta-analysis of randomized clinical trials (RCT) comparing triple therapy (PEG-

IFN + RBV + AMA) and double therapy (PEG-IFN + RBV) was performed.

Keywords: Results: Five RCTs including 1425 patients were assessed. The meta-analysis based on the intention-to-

Hepatitis C

treat analysis indicated that the sustained virological response (SVR) rate was signiﬁcantly lower in the

Amantadine

triple therapy group than in the double therapy group (44.2% vs. 49.2%, risk ratio (RR) 0.90, 95%

Interferon

conﬁdence interval (CI) 0.80–1.00, p = 0.05). The frequency of discontinuing therapy because of adverse

Ribavirin

events was similar in the two groups (RR 1.26, 95% CI 0.90–1.78, p = 0.18). The sensitivity analysis

including the four studies involving Caucasian populations revealed signiﬁcantly lower SVR rates in the

triple therapy group. The other sensitivity analyses also showed similar trends, but did not reach

statistical signiﬁcance.

Conclusions: This meta-analysis suggests no beneﬁcial effect of adding AMA to PEG-IFN + RBV in

treatment-naive HCV-1 patients and even a trend towards a lower virological response rate in the triple

therapy group. This study shows that the administration of AMA should be avoided in the management

of treatment-naive HCV-1 patients.

document the need for a more effective therapeutic regimen for

1. Introduction

the HCV-1-infected population. Currently, two protease inhibitors

(telaprevir and boceprevir) have been approved for HCV genotype

With an estimated prevalence of 2% worldwide, or approxi-

1 and have increased the response rate.

mately 123 million infected individuals, the public health burden

Amantadine (AMA), an antiviral drug against the inﬂuenza A

of hepatitis C virus (HCV) is substantial. The current standard

virus, has a broad antiviral spectrum via its action on the target

treatment is the combination of pegylated interferon (PEG-IFN) 6

protein. The inhibition of the HCV p7 protein (a viral ion channel) by

and ribavirin (RBV), as recommended in the American Association 7

AMA has been observed in vitro. Brillanti et al. showed that the

for the Study of Liver Diseases (AASLD) practical guidelines.

addition of AMA to IFN + RBV combination increased SVR rates from

Although the virological outcome has improved greatly with

40% to 64% in patients with interferon-nonresponsive HCV

interferon-based therapy in HCV genotype 2/3 infections, the 8

infections. In the interferon-nonresponsive patients, about 45%

current therapy is still considered suboptimal due to a failure of

were infected with an HCV genotype other than 1, and most patients

primary target sustained virological response (SVR) rate of about 8

(72%) had previously received interferon alfa treatment. As an

3,4

50% in the ‘difﬁcult to treat’ patients (genotype 1/4). HCV

initial treatment, the addition of AMA to interferon monotherapy

genotype 1 (HCV-1) is the most common type, accounting for 9,10

has been shown to increase response rates. Berg et al. random-

about 60% of global infections. Hence these studies clearly

ized 400 treatment-naive patients to AMA or placebo, in combina-

tion with IFN + RBV. The on-treatment viral response rates at week

24 were signiﬁcantly higher (70% vs. 59%) and SVR rates tended to be

* Corresponding authors.

higher (53% vs. 43%) in the AMA group. Furthermore, favorable

E-mail addresses: [email protected] (X. Zeng),

trends of triple therapy have been described, especially for patients [email protected] (Y. Lin).

1 11,12

Both contributed equally to this study. with an HCV genotype 1 infection and/or a high viral load.

J. Chen et al. / International Journal of Infectious Diseases 16 (2012) e748–e752 e749

A previous meta-analysis reported no beneﬁt of additional 2.2. Criteria for inclusion and exclusion of studies

AMA on SVR rates in treatment-naive HCV-infected patients.

However the study did not refer to the heterogeneity of Criteria for inclusion were: (1) RCT study design; (2) a

genotypes between groups and the different therapeutic regi- comparison of two arms: triple therapy (PEG-IFN, RBV, and

mens, which might have affected SVR rates. The conclusions of AMA) versus double therapy (PEG-IFN and RBV); (3) data provided

that meta-analysis were mainly based on regimens that for treatment-naive patients with HCV genotype 1 infection; and

included only conventional IFN, which is not currently (4) SVR used as the primary endpoint.

recommended, and on a comparison between double therapy Criteria for exclusion were: (1) non-RCT design; (2) data of

and IFN monotherapy. Thus, the conclusions of the meta- patients with HCV genotype 1 not detailed; (3) studies that

analysis cannot be used as a reference by hepatologists currently included patients who had received previous interferon therapy;

treating treatment-naive HCV-infected patients. Since that (4) studies in organ transplantation patients; (5) studies in patients

meta-analysis, several trials comparing the triple regimen with HIV co-infection; and (6) publications concerning the same

PEG-IFN + RBV + AMA and the double regimen PEG-IFN + RBV study (duplicates).

have been published, especially in HCV genotype 1.

The aim of this study was to carry out a meta-analysis on the 2.3. Quality of methodology

randomized clinical trial (RCTs) comparing the efﬁcacy of triple

therapy (PEG-IFN + RBV + AMA) versus standard therapy (PEG- The quality of included trials was scored with the Jadad

IFN + RBV) in the treatment of treatment-naive HCV genotype-1 composite scale, which assesses descriptions of randomization,

14,15

patients. double-blinding, withdrawal, and dropout. The Jadad scale

ranges from 0 to 5 points, with a low-quality study having a score

2. Methods of 2 and a high-quality study having a score of 3. The

methodological quality assessment was performed independently

2.1. Literature search by two of the authors.

A search for RCTs was conducted by two observers using 2.4. Statistical methods

Medline (1966 to September 2011), Embase (1980 to September

2011), the Cochrane Controlled Trials Register (Cochrane Library The meta-analysis was performed using the meta-analysis

Issue 3, 2011), and PubMed (updated to September 2011). A full software, Review Manager (RevMan 5.0, Cochrane Collaboration,

manual search of the bibliographies of each peer-reviewed paper Oxford, UK). We used the SVR rate to estimate the effect. We

selected and the abstracts from the American Digestive Disease determined the signiﬁcance of the pooled risk ratio (RR) using the

Week, the United European Gastroenterology Week, AASLD Annual Z-test, and p < 0.05 was considered to show statistical signiﬁ-

Meeting, and European Association for the Study of the Liver (EASL) cance. RRs were presented with 95% conﬁdence intervals (CI) for

Annual Meeting from 2000 to 2011 was also carried out. The search each included clinical trial. Heterogeneity was assessed using the

strategy was performed using medical subject headings (MeSH) Cochrane Chi-square test (using a 10% signiﬁcance level) and the I

and keywords ‘hepatitis C’, ‘amantadine’, ‘interferon’, ‘ribavirin’, statistic (percentage of variation due to heterogeneity, with higher

‘genotype 1’. The type of article was restricted to RCT. values indicating a greater degree of heterogeneity). Publication

Figure 1. Flowchart of the literature search and selection process.

e750 J. Chen et al. / International Journal of Infectious Diseases 16 (2012) e748–e752

Table 1

Characteristics of the included studies

Reference Regimen Duration Number of SVR rate (%) Discontinuation

(weeks) patients for adverse events (%)

Ferenci et al. 2006 Arm 1:PEG-IFN alfa-2a 180 mg/week, RBV 48 114 46.5 10.5

1000–1200 mg/day, and AMA 200 mg/day

for 48 weeks

Arm 2: PEG-IFN alfa-2a 180 mg/week, RBV 48 95 51.6 6.3

1000–1200 mg/day, and placebo 200 mg/

day for 48 weeks

Calay et al. 2006 Arm 1: PEG-IFN alfa-2b 1.5 mg/kg/week, 48 128 35.4 NA

RBV 800–1200 mg/day, and AMA 200 mg/

day for 48 weeks

Arm 2: PEG-IFN alfa-2b 1.5 mg/kg/week 48 125 45.2 NA

and RBV 800–1200 mg/day for 48 weeks

von Wagner et al. 2008 Arm 1: PEG-IFN alfa-2a 180 mg/week, RBV 48 352 48.6 8.5

1000–1200 mg/day, and AMA from 200

mg/day to 400 mg/day within 2 weeks,

followed by AMA 400 mg/day for 46 weeks

Arm 2: PEG-IFN alfa-2a 180 mg/week and 48 352 52.8 4.8

RBV 1000–1200 mg/day for 48 weeks

Mendez-Navarro et al. 2010 Arm 1: PEG-IFN alfa-2a 180 mg/week, RBV 48 61 42.6 8.2

1000–1200 mg/day, and AMA 200 mg/day

for 48 weeks

Arm 2: PEG-IFN alfa-2a 180 mg/week and 48 63 39.7 9.5

RBV 1000–1200 mg/day for 48 weeks

van Soest et al. 2010 Arm 1: IFN alfa-2b 10 MIU/day for 6 days, 52 65 35.4 13.9

followed by 5 MIU/day for 6 days, followed

by PEG-IFN alfa-2b 1.5 mg/kg/week for 24

weeks, followed by 1.0 mg/kg/week for 26

weeks, RBV 1000–1200 mg/day, and AMA

200 mg/day for 52 weeks

Arm 2: IFN alfa-2b 10 MIU/day for 6 days, 5 52 70 44.3 15.7

MIU/day for 6 days, PEG-IFN alfa-2b

1.5 mg/kg/week for 24 weeks, followed by

1.0 mg/kg/week for 26 weeks and RBV

1000–1200 mg/day for 52 weeks

SVR, sustained virological response; PEG-IFN, pegylated interferon; RBV, ribavirin; AMA, amantadine; NA, not available.

bias was evaluated by funnel plot analysis, and an asymmetric plot 3.2. Meta-analysis

suggested a possible publication bias.

First, we made a primary meta-analysis of trials on the SVR

rates. There was no statistical heterogeneity among the studies,

3. Results and the ﬁxed-effect model was used (Chi-square = 1.84, p = 0.76;

I = 0%). The meta-analysis based on the intention-to-treat analysis

3.1. Description of the selected studies indicated that the SVR rate was signiﬁcantly lower in the triple

therapy group than in the double therapy group (44.2% vs. 49.2%,

The search strategy found 40 studies. From these, we identiﬁed RR 0.90, 95% CI 0.80–1.00, p = 0.05) (Figure 2). The funnel plot of

ﬁve RCTs comparing triple therapy containing AMA and double trials for SVR is given in Figure 3. The slight asymmetry suggests

17–21

therapy for the treatment of HCV-1 infection (Figure 1). Four the possibility of publication bias.

studies were published as peer-reviewed articles and one study In the meta-analysis of the rate of discontinuing therapy

was published as an abstract. The characteristics of the ﬁve trials because of adverse events, there was no statistical heterogeneity

are listed in Table 1. among the studies (Chi-square = 3.68, p = 0.30; I = 18%). The

The meta-analysis involved 1425 patients: 720 patients were meta-analysis showed no signiﬁcant difference in the rate of

randomized to the triple therapy group (PEG-IFN + RBV + AMA) and discontinuing therapy because of adverse events between the two

705 patients to the double therapy group (PEG-IFN + RBV). Three groups (RR 1.26, 95% CI 0.90–1.78, p = 0.18).

studies enrolled only treatment-naive genotype 1 HCV-infected

patients. The other two studies included all HCV genotypes. The 3.3. Sensitivity analysis

duration of treatment ranged from 48 to 52 weeks. The daily dose of

amantadine ranged from 200 mg to 400 mg. The methodological Four RCTs assessed the efﬁcacy of standard dosing regimens of

quality scores of the trials ranged from 2 to 5 (Table 2). PEG-IFN + RBV combination, and one RCT was designed with the

high-dose induction therapy and decreased dose of PEG-IFN. A

Table 2 sensitivity analysis was performed including only those trials

Jadad score for grading the quality of the trials included in the meta-analysis

administering standard dose regimens. The analysis showed that

Study Randomization Blinding Withdrawal Total the SVR rate was lower in the additional AMA group, but the

or Dropout difference did not reach statistical signiﬁcance (45.0% vs. 49.8%, RR

17 0.90, 95% CI 0.81–1.01, p = 0.09) (Table 3).

Ferenci et al. 2006 2 2 1 5

Calay et al. 2006 1 1 0 2 Four RCTs assessed the efﬁcacy of standard dosing regimens of

von Wagner et al. 2008 1 1 1 3 AMA combination therapy (200 mg). A sensitivity analysis was

Mendez-Navarro et al. 2010 1 0 1 2

19 carried out including these four studies; one study with a high

van Soest et al. 2010 2 2 1 5

AMA dose of 400 mg was not included. The SVR rate in the triple

J. Chen et al. / International Journal of Infectious Diseases 16 (2012) e748–e752 e751

Figure 2. Meta-analysis on SVR rates based on intention-to-treat analysis.

therapy group was lower than that in the double therapy group rates in treatment-naive HCV-infected patients, in which 13 of

(39.9% vs. 45.6%), but there was no statistically signiﬁcant the 17 trials compared IFN + AMA double therapy with IFN

difference between the two groups (RR 0.87, 95% CI 0.73–1.03, monotherapy. Three of the other four trials compared IFN + RB-

p = 0.10). V + AMA triple therapy with IFN + RBV double therapy. Only one

Four RCTs were performed in Caucasian populations and one trial compared PEG-IFN + RBV + AMA triple therapy with PEG-

RCT in a Latino population. Thus, we conducted a sensitivity IFN + RBV double therapy, but this trial did not report SVR rates.

analysis including only the four studies involving Caucasian Following this, adding AMA to IFN + RBV became a point of

populations. The analysis showed that the SVR rate in the triple contention, and favorable trends with triple therapy were

therapy group was signiﬁcantly lower than that in the double described especially for patients with an HCV genotype 1 infection

11,12

therapy group (44.3% vs. 50.6%, RR 0.88, 95% CI 0.79–0.99, p = 0.03). and/or a high viral load. Since the introduction of PEG-IFN,

A ﬁnal sensitivity analysis was conducted including only the several new RCTs have been reported. Most trials have not shown

three studies of high quality. The SVR rate in the triple therapy beneﬁts of adding AMA to PEG-IFN and RBV, and even lower SVR

group was lower than that in the double therapy group (46.6% vs. rates in the AMA group. AMA is not recommended for the

25,26

51.5%), but the difference did not reach statistical signiﬁcance (RR management of HCV infection in the most recent guildelines.

0.90, 95% CI 0.80–1.02, p = 0.10). The current optimal therapy for a genotype 1 chronic HCV infection

is the use of boceprevir or telaprevir in combination with

25,26

4. Discussion peginterferon alfa and ribavirin.

In our meta-analysis, we included ﬁve recent RCTs comparing

Currently, one of the major challenges with regard to the the efﬁcacy of PEG-IFN + RBV + AMA triple therapy versus PEG-

treatment of treatment-naive HCV patients is the need for new IFN + RBV double therapy for untreated patients with HCV-1

approaches to increase the SVR rate in genotype 1. Chronic infection. The meta-analysis based on the intention-to-treat

hepatitis C patients with genotype 1 are considered to be ‘difﬁcult analysis showed that the pooled SVR rate was signiﬁcantly lower

to treat’. HCV genotype 1 is one of the most consistently deﬁned in the triple therapy group than in the standard therapy group

virus-related factors associated with a poor response to interferon. (44.2% vs. 49.2%). In the largest trial with 53.1% weight

Many treatment-naive genotype 1 HCV patients fail to achieve SVR contributing to this meta-analysis, a trend towards a lower

with conventional combination therapy and remain at high risk for virological response rate was observed in the group of patients

22,23

cirrhosis, hepatocellular carcinoma, and liver-related death. receiving AMA. The lower rate of virological response in the AMA

Since the 1990s, many studies have explored AMA-containing group might be explained by the higher dropout rate in the AMA

combination therapies in HCV-infected patients. Early studies group compared with the standard therapy group (32% vs. 23%).

explored IFN + AMA versus IFN alone in treatment-naive Concerning the high dropout rate, we performed a further meta-

10 24

patients, then IFN + AMA versus IFN + RBV. The results were analysis of discontinuation for adverse events, which showed no

controversial, with a few studies showing a beneﬁt with AMA. A signiﬁcant difference between the two groups. However in the

meta-analysis demonstrated no beneﬁt of additional AMA on SVR largest trial, only adverse events unknown to PEG-IFN, RBV, and

AMA, or serious adverse events or adverse events leading to dose

modiﬁcation were reported. Thus, the high dropout rate in the

triple therapy group might be ascribed to the increased side effects

after adding high-dose AMA.

Racial differences in the response to antiviral therapy have been

attributed not only to diverse factors such as weight, insulin

27,28

resistance, and socio-cultural factors, but also to host factors.

Table 3

Sensitivity analysis on SVR rates

Number RR (95% CI) p-Value

Standard dosing regimens 4 0.90 (0.81–1.01) 0.09

of PEG-IFN + RBV

Standard AMA dose 4 0.87 (0.73–1.03) 0.10

Caucasian population 4 0.88 (0.79–0.99) 0.03

High-quality studies 3 0.90 (0.80–1.02) 0.10

SVR, sustained virological response; RR, risk ratio; CI, conﬁdence interval; PEG-IFN,

Figure 3. Funnel plot of trials for SVR. pegylated interferon; RBV, ribavirin; AMA, amantadine.

e752 J. Chen et al. / International Journal of Infectious Diseases 16 (2012) e748–e752

11. Berg T, Kronenberger B, Hinrichsen H, Gerlach T, Buggisch P, Herrmann E, et al.

The combination of PEG-IFN + RBV with or without AMA gave an

Triple therapy with amantadine in treatment-naive patients with chronic

SVR of 39–42% in the Latino population, which is lower than that in

hepatitis C: a placebo-controlled trial. Hepatology 2003;37:1359–67.

29,30

non-Latino white patients of between 45% and 55%, but better 12. Mangia A, Ricci GL, Persico M, Minerva N, Carretta V, Bacca D, et al. A

randomized controlled trial of pegylated interferon alpha-2a (40 KD) or inter-

than that in African Americans of 28–30%. A sensitivity analysis

feron alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and

was conducted only enrolling Caucasian patients, conﬁrming the

ribavirin in treatment-naive patients with chronic hepatitis C. J Viral Hepat

negative effect of adding AMA in HCV genotype 1. Also, the other 2005;12:292–9.

13. Deltenre P, Henrion J, Canva V, Dharancy S, Texier F, Louvet A, et al. Evaluation

sensitivity analyses of standard AMA, PEG-IFN, and RBV dose and

of amantadine in chronic hepatitis C: a meta-analysis. J Hepatol 2004;41:462–

high-quality studies showed a trend towards poor SVR rates in the

73.

triple therapy group. 14. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay

There are some limitations in this meta-analysis. First, four of HJ. Assessing the quality of reports of randomized clinical trials: is blinding

necessary? Control Clin Trials 1996;17:1–12.

the included RCTs did not provide detailed baseline data, in

15. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and dis-

particular the percentage of patients with advanced ﬁbrosis or

crepancies between large and small randomized trials in meta-analyses. Ann

cirrhosis and the baseline viral load of HCV-1 patients. The Intern Med 2001;135:982–9.

16. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected

potential impact of these factors on the outcomes remains unclear.

by a simple, graphical test. BMJ 1997;315:629–34.

Second, this study was limited by a relatively small number of

17. Ferenci P, Formann E, Laferl H, Gschwantler M, Hackl F, Brunner H, et al.

trials. Third, some studies were underpowered and this might limit Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a

(40KD) plus ribavirin with or without amantadine in treatment-naive patients

the informativeness of the study. Nevertheless, this meta-analysis

with chronic hepatitis C genotype 1 infection. J Hepatol 2006;44:275–82.

is the ﬁrst to evaluate the efﬁcacy of initial treatment with PEG-

18. Me´ndez-Navarro J, Chirino RA, Corey KE, Gorospe EC, Zheng H, Mora´n S, et al. A

IFN, RBV, and AMA in HCV-1 patients, and provides clinicians with randomized controlled trial of double versus triple therapy with amantadine

for genotype 1 chronic hepatitis C in Latino patients. Dig Dis Sci 2010;55:

important evidence for the treatment strategy.

2629–35.

In conclusion, according to the evidence evaluated in our meta-

19. van Soest H, van der Schaar PJ, Koek GH, de Vries RA, van Ooteghem NA, van

analysis, there is no beneﬁcial effect of adding AMA to PEG- Hoek B, et al. No beneﬁcial effects of amantadine in treatment of chronic

hepatitis C patients. Dig Liver Dis 2010;42:496–502.

IFN + RBV in treatment-naive HCV-1 patients; in fact a trend

20. von Wagner M, Hofmann WP, Teuber G, Berg T, Goeser T, Spengler U, et al.

towards a lower virological response rate in the group of patients

Placebo-controlled trial of 400 mg amantadine combined with peginterferon

receiving AMA was observed. alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection.

Conﬂict of interest: No conﬂict of interest to declare. Hepatology 2008;48:1404–11.

21. Calay V, Hachemane S, Pageaux GP, Canva M, Bourliere M, Portal I, et al. A

Funding: This study was supported by the National Natural

multicentric, randomized, controlled, double-blind study (TRIPEG): PEGINF a-

Science Foundation of China (Nos. 81070347, 30971346 and

2b, ribavirin and amantadine or PEGINF a-2b, placebo, in 269 naive patients

81000167). with chronic hepatitis C. J Hepatol 2006;44:S220.

22. Raimondi S, Bruno S, Mondelli MU, Maisonneuve P. Hepatitis C virus genotype

1b as a risk factor for hepatocellular carcinoma development: a meta-analysis. J References

Hepatol 2009;50:1142–54.

23. Grant WC, Jhaveri RR, McHutchison JG, Schulman KA, Kauf TL. Trends in health

1. Mallet V, Vallet-Pichard A, Pol S. New trends in hepatitis C management. Presse care resource use for hepatitis C virus infection in the United States. Hepatology

Med 2010;39:446–51. 2005;42:1406–13.

2. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and 24. Younossi ZM, Mullen KD, Zakko W, Hodnick S, Brand E, Barnes DS, et al. A

treatment of hepatitis C: an update. Hepatology 2009;49:1335–74. randomized, double-blind controlled trial of interferon alpha-2b and ribavirin

3. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales Jr FL, et al. vs. interferon alpha-2b and amantadine for treatment of chronic hepatitis C

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl non-responder to interferon monotherapy. J Hepatol 2001;34:128–33.

J Med 2002;347:975–82. 25. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment

4. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the

et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus American Association for the Study of Liver Diseases. Hepatology

ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2011;54:1433–44.

2001;358:958–65. 26. European Association for the Study of the Liver. EASL Clinical Practice Guide-

5. Global surveillance and control of hepatitis C. Report of a WHO Consultation lines: management of hepatitis C virus infection. J Hepatol 2011;55:245–64.

organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, 27. Hoofnagle JH, Wahed AS, Brown Jr RS, Howell CD, Belle SH. Early changes in

Belgium. J Viral Hepat 1999;6:35–47. hepatitis C virus (HCV) levels in response to peginterferon and ribavirin

6. McHutchison JG, Patel K. Future therapy of hepatitis C. Hepatology treatment in patients with chronic HCV genotype 1 infection. J Infect Dis

2002;36:S245–52. 2009;199:1112–20.

7. Grifﬁn S, Stgelais C, Owsianka AM, Patel AH, Rowlands D, Harris M. Genotype- 28. Rodriguez-Torres M. Latinos and chronic hepatitis C: a singular population. Clin

dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel. Gastroenterol Hepatol 2008;6:484–90.

Hepatology 2008;48:1779–90. 29. Rodriguez-Torres M, Jeffers LJ, Sheikh MY, Rossaro L, Ankoma-Sey V, Hamzeh

8. Brillanti S, Levantesi F, Masi L, Foli M, Bolondi L. Triple antiviral therapy as a new FM, et al. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites

option for patients with interferon nonresponsive chronic hepatitis C. Hepatol- with hepatitis C. N Engl J Med 2009;360:257–67.

ogy 2000;32:630–4. 30. Hadziyannis SJ, Sette Jr H, Morgan TR, Balan V, Diago M, Marcellin P, et al.

9. Mangia A, Minerva N, Annese M, Leandro G, Villani MR, Santoro R, et al. A Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis

randomized trial of amantadine and interferon versus interferon alone as initial C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med

treatment for chronic hepatitis C. Hepatology 2001;33:989–93. 2004;140:346–55.

10. Mangia A, Leandro G, Helbling B, Renner EL, Tabone M, Sidoli L, et al. Combina- 31. Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N,

tion therapy with amantadine and interferon in naive patients with chronic et al. Peginterferon and ribavirin treatment in African American and Caucasian

hepatitis C: meta-analysis of individual patient data from six clinical trials. J American patients with hepatitis C genotype 1. Gastroenterology

Hepatol 2004;40:478–83. 2006;131:470–7.