Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing...

Meta-analysis: re-treatment of genotype I hepatitis Cnonresponders and relapsers after failing interferon andribavirin combination therapyA. G. Singal*, A. K. Waljee*, M. Shiffman�, B. R. Bacon� & P. S. Schoenfeld*,§

*Division of Gastroenterology,University of Michigan MedicalCenter, Ann Arbor, MI, USA.�Division of Gastroenterology-Hepatology Section, VirginiaCommonwealth University MedicalCenter, Richmond, VA, USA.�Division of Gastroenterology andHepatology, Saint Louis UniversitySchool of Medicine, St Louis, MO,USA.§VA Center of Excellence for HealthServices Research, Ann Arbor, MI,USA.

Correspondence to:Prof. P. S. Schoenfeld, VAMC 111-D,2215 Fuller Road, Ann Arbor, MI48105, USA.E-mail: pschoenf@umich.edu

Publication dataSubmitted 6 May 2010First decision 27 May 2010Resubmitted 10 July 2010Accepted 17 July 2010EV Pub Online 15 August 2010

SUMMARY

BackgroundThe efficacy of re-treating genotype I hepatitis C virus (HCV) patients whofailed combination therapy with interferon ⁄ pegylated interferon (PEG-IFN)and ribavirin remains unclear.

AimsTo quantify sustained virological response (SVR) rates with differentre-treatment regimens through meta-analysis of randomized controlledtrials (RCTs).

MethodsRandomized controlled trials of genotype I HCV treatment failure patientsthat compared currently available re-treatment regimens were selected. Twoinvestigators independently extracted data on patient population, methodsand results. The pooled relative risk of SVR for treatment regimens wascomputed using a random effects model.

ResultsEighteen RCTs were included. In nonresponders to standard inter-feron ⁄ ribavirin, re-treatment with high-dose PEG-IFN combination therapyimproved SVR compared with standard PEG-IFN combination therapy(RR = 1.49; 95% CI: 1.09–2.04), but SVR rates did not exceed 18% in moststudies. In relapsers to standard interferon ⁄ ribavirin, re-treatment withhigh-dose PEG-IFN or prolonged CIFN improved SVR (RR = 1.57; 95%CI: 1.16–2.14) and achieved SVR rates of 43–69%.

ConclusionsIn genotype I HCV treatment failure patients who received combinationtherapy, re-treatment with high-dose PEG-IFN combination therapy issuperior to re-treatment with standard combination therapy, although SVRrates are variable for nonresponders (£18%) and relapsers (43–69%).Re-treatment may be appropriate for select patients, especially relapsers andindividuals with bridging fibrosis or compensated cirrhosis.

Aliment Pharmacol Ther 2010; 32: 969–983

ª 2010 Blackwell Publishing Ltd 969

doi:10.1111/j.1365-2036.2010.04427.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONHepatitis C virus (HCV) infection currently affects over 3million people in the United States1, 2 and is the leadingcause of decompensated cirrhosis (e.g. ascites, hepaticencephalopathy, bleeding oesophageal varices), hepatocel-lular carcinoma (HCC) and liver-related mortality in theUnited States3, 4. Furthermore, the morbidity and mortal-ity associated with HCV infection are projected to increasesteadily over the next decade.2 Although sustained viralresponse (SVR) rates of 54–56% have been achieved withinterferon ⁄ pegylated interferon (PEG-IFN) and RBV com-bination therapy,5–8 individuals with genotype I HCVachieve SVR rates of approximately 40% or less9 and thesepatients account for approximately 75% of HCV patientsin the US. Therefore, a substantial proportion of treat-ment-naı̈ve HCV patients fail to achieve SVR with combi-nation therapy and remain at high risk for decompensatedcirrhosis, HCC and liver-related mortality.10

When HCV-infected patients achieve SVR beforedeveloping cirrhosis, their liver-related mortality is simi-lar to age-matched controls.11 If HCV-infected patientswith cirrhosis achieve SVR, their rates of decompensatedcirrhosis [relative risk = 0.16; 95% CI: 0.04–0.59], HCC[relative risk = 0.21, 95% CI 0.16–0.27] and liver-relatedmortality [relative risk = 0.23; 95% CI: 0.10–0.52] are sig-nificantly lower than similar patients who fail to achieveSVR.12 In fact, treatment failure patients with advancedfibrosis or cirrhosis develop decompensated cirrhosis at arate of 2.9% ⁄ year, develop HCC at a rate of 3.2% ⁄ year,and suffer from liver-related mortality at a rate ofapproximately 2.7% ⁄ year.12 Given the morbidity andmortality associated with treatment failure, effective andsafe re-treatment regimens are needed. Treatment failuresinclude nonresponders (individuals who never clear HCVfrom their serum) and relapsers (individuals who tempo-rarily clear HCV from their serum, but do not sustainviral clearance until 24 weeks after conclusion of ther-apy). Among nonresponders to IFN monotherapy, twometa-analyses demonstrated that re-treatment with IFNand RBV combination therapy was significantly betterthan re-treatment with IFN alone, but SVR was onlyachieved in 13–14% of patients with combination ther-apy.13, 14 Among relapsers after prior IFN monotherapy,combination therapy with IFN and RBV produced SVRrates of 47–56% of patients and was superior to re-treat-ment with IFN alone.15, 16 However, the efficacy andsafety of re-treating nonresponders or relapsers after fail-ing combination therapy remains unclear.

Treatment of HCV-infected individuals will probablyevolve to Specifically Targeted Anti-viral Therapy for

hepatitis C (STAT-C) with the introduction of proteaseinhibitors to HCV therapy.17, 18 However, these proteaseinhibitors may not be widely available in the US until2012. Therefore, selected treatment failure patients whoare at risk for developing decompensated cirrhosis, HCCand liver-related mortality may be appropriate candidatesfor re-treatment before STAT-C therapies become avail-able. This approach is supported by the most recentAmerican Association for Study of Liver Disease (AASLD)and American College of Gastroenterology (ACG) treat-ment guidelines.19 Although multiple randomizedcontrolled trials (RCTs) have assessed the efficacy of high-dose or prolonged combination therapy vs. conventionalPEG-IFN combination therapy in treatment failures, theoptimal re-treatment regimen has not been establishedand SVR rates have not been quantified precisely.

No previous systematic review has quantitativelyreviewed the study design and results of published RCTson this topic. The objective of our meta-analysis is toassess the efficacy and safety of high-dose or prolongedPEG-IFN combination therapies for the re-treatment ofHCV in patients who failed prior pegylated and non-pegylated combination therapy. These data will alsoprovide a comprehensive assessment of SVR rates thatcan be attained with high-dose or prolonged combina-tion therapy and these data can be used for comparisonwith SVR rates achieved with STAT-C based regimens.As genotype I accounts for the vast majority of HCVnonresponders and relapsers in the United States, ourmeta-analysis focuses on this patient population.

METHODS

Literature searchA computer-assisted search was conducted to identifypotentially relevant publications in the OVID MEDLINEdatabase on 1 September 2008. The search ‘1997 to Sep-tember 2008’ was performed using the followingexploded (exp) medical subject heading (MeSH) andtextwords: exp Hepatitis C ⁄ dt [Drug Therapy] AND expretreatment OR recurrence OR treatment failure.mp.[mp=title, original title, abstract, name of substanceword, subject heading word] AND random allocation orrandom$.mp or RCT.mp. This was then limited tohumans, and a search filter designed to retrieve con-trolled clinical trials, systematic reviews, meta-analyses orRCTs was applied. A similar search was also performedin EMBASE from 1997 to 2008. Additional electronicsearches of Digestive Diseases Week (DDW) abstracts,American Association for Study of Liver Diseases

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970 Aliment Pharmacol Ther 2010; 32: 969–983

ª 2010 Blackwell Publishing Ltd

(AASLD) meeting abstracts, American College of Gastro-enterology (ACG) meeting abstracts and European Asso-ciation for the Study of the Liver (EASL) meetingabstracts from 2006 to 2008 were performed with combi-nations of the search terms ‘hepatitis C’ AND ‘retreat-ment’ or ‘treatment failure’ or ‘recurrence’ AND‘controlled trial’ or ‘RCT’ or ‘randomization’. A manualsearch of abstracts from these years was also performed.Manual recursive searches of references from review arti-cles and published RCTs that met inclusion criteria werealso performed. Finally, consultation with expert hepatol-ogists was also performed to identify any additionalabstracts or unpublished data.

Study selection criteriaStudy inclusion criteria were (i) patient population-majority of study patients were genotype I HCV patientswho failed to achieve SVR with combination therapy(note: studies were still included if a minority of studypatients were nongenotype I); (ii) intervention: compari-son of two-drug regimens using currently available treat-ments; (iii) outcome: SVR rates; and (iv) trial design:RCT. One investigator (A.S.) reviewed the titles andabstracts of all citations identified by the literaturesearch. Potentially relevant studies were retrieved. Twoinvestigators (A.S., A.W.) then retrieved full texts ofpotentially relevant studies and applied the selection cri-teria. Agreement between investigators for selection ofstudies for the meta-analysis was >95%, and disagree-ments were resolved by consensus. Studies publishedonly as abstracts were included if they had sufficientinformation on study design, characteristics of partici-pants, interventions and outcomes and ⁄ or if an author ofan abstract could provide this information. Data pub-lished in both abstract and full manuscript forms werederived from the full manuscript.

Data extractionEligible articles were reviewed in a duplicate, indepen-dent manner by two investigators (A.S., A.W.). For eachstudy, the investigators recorded the study design, theinclusion and exclusion criteria, initial treatment regimenthat study patients failed, percentage of patients with cir-rhosis, percentage of patients with genotype 1 HCV,number of relapsers vs. nonresponders, re-treatment reg-imens including dose and duration of study medications,number of patients in each treatment arm, mean age ofstudy patients, percentage of patients achieving the pri-mary endpoint (SVR) and the percentage of patientswho discontinued therapy because of adverse events.

Authors were contacted as necessary for any missinginformation.

Data regarding nonresponders and relapsers were anal-ysed and reported separately. If studies reported SVR ratesseparately for genotype I patients, then these data wereused for meta-analysis instead of using data for the entirepatient population. Furthermore, data from trials thatevaluated patients who initially failed IFN and RBV com-bination therapy are reported separately from trials withpatients who initially failed PEG-IFN and RBV combina-tion therapy. The primary outcome of interest, SVR, wasdefined as an undetectable serum HCV RNA level24 weeks after discontinuation of therapy. Two indepen-dent reviewers (A.S. and A.W.) assessed the quality ofindividual RCTs based on the Jadad scoring system,20 withdiscrepancies resolved by a third reviewer (P.S.).

Statistical analysisThe primary aim of our study was to determine the effi-cacy of different re-treatment regimens for nonrespond-ers and relapsers to prior combination therapy. Thepooled response rate for an individual treatment regimenwas calculated as the total number of responders dividedby the total number of patients who were randomized toreceive the treatment. All outcomes were analysed on anintention-to-treat basis. The pooled relative risk of SVRbetween different treatment regimens was computedusing STATA 10 (StataCorp, College Station, TX, USA).Estimates of effect were pooled using the DerSimonianLaird method for a random effects model.

Heterogeneity was initially evaluated graphically byexamination of forest plots and L’Abbe plots. We furtherevaluated the possibility of statistical heterogeneity by thechi-square test of heterogeneity and the inconsistencyindex (I2). A chi-square P-value <0.05 or I2 values >50%are consistent with the possibility of substantial heteroge-neity.21, 22 Sensitivity analysis, in which one study isremoved at a time from the model, was performed todetermine if there was possible undue influence of a sin-gle study.23 Publication bias was initially evaluatedgraphically by funnel plot analysis and then statisticallyusing Begg’s test.24 A symmetric funnel plot would helprule out the possibility of small studies that were notpublished because of unfavourable results.

RESULTS

Literature searchThe MEDLINE and EMBASE search yielded 148 articles.All citations were downloaded into Reference Manager

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Aliment Pharmacol Ther 2010; 32: 969–983 971

and then EndNote. After review of the titles andabstracts of these articles, 24 studies underwent full-textreview to determine their eligibility for the meta-analysisand 14 were excluded. The remaining 10 studies (eightfull text articles and two abstracts) were selected aftermeeting all applicable inclusion criteria (Figure 1,Table 1). Additional searches of abstracts from theannual meetings of American Association for Study ofLiver Diseases (AASLD), American College of Gastro-enterology (ACG), European Association for the Study ofthe Liver (EASL), and Digestive Disease Week (DDW)from 2006 to 2008 yielded 55 potentially relevantabstracts. After review of the titles and abstracts, 49abstracts were excluded, and the remaining six abstractsmet all inclusion criteria. Finally, recursive literaturesearches identified two additional full text articles thatmet all inclusion criteria, producing a total of 18 studiesfor inclusion in this meta-analysis. Two notable re-treat-ment trials were excluded: EPIC25 was not included as itwas not a RCT, and HALT-C10 was not included becauseit assessed maintenance therapy with the intent of halt-ing disease progression instead of inducing SVR. Therewas excellent agreement between the two reviewers(kappa = 1.0). Based on symmetrical funnel plots andstatistical analysis using Begg’s test (P = 0.51), no evi-dence of publication bias was ascertained.

On quality assessment, the majority of the full manu-scripts (7 ⁄ 11) were adequately randomized, but not dou-ble-blinded (Table S1). The other four full manuscripts

were randomized, but did not describe the method ofrandomization in detail and received Jadad scores of 2.The seven abstracts were possibly of similar quality, butonly received Jadad scores of 1 given insufficient detailregarding randomization and withdrawals. Althoughnone of the 18 trials was double-blinded, this findingmay not be as important given the objectivity of SVR,the primary outcome of interest.

Re-treatment of nonresponders to PEG-interferon andribavirin therapyTwo RCTs26, 27 have assessed the efficacy of re-treatmentin nonresponders to PEG-IFN plus RBV combinationtherapy (Table 1). Neither trial included relapsers. TheREPEAT study (n = 942 patients, 91% genotype 1) was afour-arm RCT that evaluated the impact of high-doseinduction therapy with PEG-IFN alpha 2a (360 lg ⁄ weekvs. 180 lg ⁄ week for 12 weeks) as well as longer treat-ment duration (72 weeks vs. 48 weeks).27 All four armsalso received RBV 1000–1200 mg ⁄ day. If patients didnot achieve undetectable levels of HCV RNA after24 weeks of therapy, then discontinuation of treatmentwas allowed. The DIRECT study (n = 487 patients, 95%genotype 1) compared two different doses of Interferonalfacon-1 (‘consensus interferon’ or CIFN) therapy: CIFN15 lg ⁄ day plus RBV vs. CIFN 9 lg ⁄ day plus RBV.26

Both arms also received RBV 1000–1200 mg ⁄ day. In theDIRECT trial, 80% of the patients were null respondersto their prior course of treatment, whereas it remains

148 Citations Identified by Medline and EMBASE

8 Full Text Articles and 2 Abstracts Included from Search2 Additional Full Text Articles and 6 Abstracts Identified by Recursive Literature Searches

24 Articles underwent Full-Text Review

61 Articles with monotherapy failures11 Articles not assessing SVR43 Articles not RCT4 Articles not Hepatitis C2 Articles not Retreatment3 Articles not commercially available medications

6 Articles with monotherapy failures6 Articles retreated with IFN, not PEG-IFN1 Article not RCT1 Article with repeat data

10 Full Text Articles and 8 AbstractsIncluded in Meta-Analysis

Figure 1 | Map of the literaturesearch and selection process.

Table1|C

haracteristic

iesevalua

tingre-treatmen

nonrespo

ndersor

relapsersto

priorinterferon

basedcombina

tiontherap

Interven

Meanage

(years)

)Advan

fibrosis(%

⁄N)]

Discontinua

oftherap

respon

gylatedinterferon

andribavirincombinatio

ntherapy

48weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

V1000–120

⁄day

*8.1(38

⁄469

72weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

V1000–120

⁄day

⁄473

48weeks

⁄day

V1000–120

⁄day

226.0(14

⁄232

48weeks

⁄day

V1000–120

⁄day

287.7(18

⁄233

respon

tostandard

interferon

ntherapy

48weeks

PEG-IFN

alfa2b

⁄week+RB

0–1400mg

⁄day

⁄352

48weeks

PEG-IFN

alfa2b

⁄week+RB

0–1400mg

⁄day

⁄352

SpanishHigh-do

seIndu

ctionStud

48weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

V1000–120

⁄day

(5⁄28)

12weeks

PEG-IFN

alfa2a

lg⁄w

36weeks

PEG-IFN

alfa2a

⁄week+

1000–120

⁄day

⁄20)

12weeks

PEG-IFN

alfa2a

⁄week,

36weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

V1000–120

⁄day

(9⁄24)

PEG-IFN

alfa2b

Retreatm

entStud

48weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day

49.2�

⁄114)

48weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

49.8�

⁄105)

sensus

Interferon

48weeks

PEG-IFN

alfa2b

⁄week+RB

V>10.6

⁄day

⁄22)

6weeks

⁄day,the

n42weeks

⁄day

V>10.6

⁄day

⁄18)

Table1|(Con

Interven

Meanage

(years)

)Advan

fibrosis(%

⁄N)]

Discontinua

oftherap

BergmannStud

12weeks

PEG-IFN

alfa2b

lg⁄kg

⁄week,

12weeks

PEG-IFN

alfa2b

lg⁄kg

⁄week,

48weeks

PEG-IFN

alfa2b

⁄week+RB

0–120

⁄day

*44(10

⁄23)

48weeks

⁄week+RB

0–120

⁄day

(11⁄30

Scotto

etal.S

48weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

⁄day

7145.8

(8⁄45)

48weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

.318.1

(6⁄47)

�11.1

AlamoStud

yGroup

12weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day,

36weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

8(11⁄143)

�Not

provided

48weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

⁄139

)�Not

provided

Relapsersto

standard

interferon

⁄PEG

interferon

ntherapy

Bernar-1Stud

48weeks

PEG-IFN

alfa2a

lg⁄w

eek+RB

V1000–120

⁄day

16�–

provided

12weeks

alfa2a

thrice

⁄week,

36weeks

alfa2a

thrice

⁄week+

1000–120

⁄day

16�–

provided

AlamoStud

yGroup

12weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day,

36weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

⁄22)

�Not

provided

48weeks

lg⁄kg

⁄week+RB

⁄day

⁄25)

�Not

provided

KaiserCIFN

72weeks

⁄day

+weigh

tbasedRB

(41⁄72

72weeks

PEG-IFN

alfa2a

lg⁄w

tbasedRB

1742(25

⁄60)

PEG-IFN

alfa2b

Retreatm

entStud

48weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day

2549.2�

⁄25)

48weeks

PEG-IFN

alfa2b

⁄week+RB

⁄day

3049.8�

⁄30)

Table1|(Con

Interven

Meanage

(years)

)Advan

fibrosis(%

⁄N)]

Discontinua

oftherap

respon

tointerferon

ntherapytriple

ttreatm

entwith

amantadine

TY42,43

48weeks

PEG-IFN

alfa2a

⁄week+RB

V1000–120

⁄day

⁄71)

�Not

provided

48weeks

alfa2a

qod+RB

V1000–

1200mg

⁄day

(8⁄75)

�Not

provided

Amantadine

48weeks

PEG-IFN

alfa2a

⁄week+RB

V1000–120

⁄day

818.6*

⁄69)§

48weeks

PEG-IFN

alfa2a

⁄week+RB

V1000–120

⁄day

8413.7*

⁄75)§

Herrine

48weeks

PEG-IFN

alfa2b

lg⁄w

eek+RB

0–1000mg

⁄day

(7⁄25)

48weeks

PEG-IFN

alfa2b

lg⁄w

eek+RB

0–1000mg

⁄day

⁄25)

erStud

48weeks

PEG-IFN

alfa2b

lg⁄w

eek+RB

V1000–120

⁄day

⁄51)

provided

48weeks

PEG-IFN

alfa2b

lg⁄w

eek+RB

V1000–120

⁄day

⁄53)

provided

chMultic

enterTrial44

48weeks

PEG-IFN

alfa2a

lg⁄kg

⁄week+RB

0–120

⁄day

17.1(14

⁄82)

48weeks

PEG-IFN

alfa2a

lg⁄kg

⁄week+RB

0–120

⁄day

+placeb

⁄82)

48weeks

PEG-IFN

alfa2a

lg⁄kg

⁄week+RB

V1000–120

⁄day

⁄42)

provided

48weeks

PEG-IFN

alfa2a

lg⁄kg

⁄week+RB

V1000–120

⁄day

+placeb

⁄21)

provided

FargionAmantadine

48weeks

PEG-IFN

alfa2a

⁄week+

0–1000mg

⁄day

26(21⁄82

)�9.4

4weeks

alfa2a

⁄day

+AMA,the

alfa2a

⁄day

24weeks

alfa2a

thrice

⁄week+AMA

0–1000mg

⁄day

8249.1

17(11⁄65

)�20

unknown how many patients were null responders vs.partial responders in the REPEAT trial.

In the REPEAT study, high-dose induction therapyhad no impact on SVR rates. However, patients whowere randomized to 72 weeks of PEG-IFN and RBVwere more likely to achieve SVR than patients receiving48 weeks of treatment [16% (74 ⁄ 473) vs. 8% (38 ⁄ 469),P < 0.001; RR = 1.93; 95% CI: 1.33–2.79]. In multiplelogistic regression analysis, genotype 1 patients were sig-nificantly less likely to achieve SVR than nongenotype Ipatients (P < 0.01). In the DIRECT study, patients withgenotype I had SVR rates of 6.9% (32 ⁄ 464) comparedwith 47.8% (11 ⁄ 23) for nongenotype I. Patients withgenotype I randomized to CIFN 15 lg ⁄ day did not dem-onstrate significantly higher SVR rates than patients whoreceived CIFN 9 lg ⁄ day [7.7% (18 ⁄ 233) vs. 6.0%(14 ⁄ 232), P = 0.47; RR = 1.28; 95% CI: 0.65–2.51].DIRECT trial data also demonstrated that ‘partial’responders who achieved at least a 2-log drop during ini-tial therapy had the ‘best likelihood of responding[achieving SVR] to re-treatment with CIFN’ combinationtherapy compared with ‘null’ responders. Meta-analysisof these two trials was not performed given the substan-tial clinical heterogeneity between the two trials.

High-dose CIFN and prolonged duration PEG-IFNarms were also more likely to lead to treatment discon-tinuation because of adverse events. In the REPEATstudy, more patients receiving 72 weeks of PEG-IFN plusRBV discontinued therapy because of adverse eventscompared with patients receiving 48 weeks of therapy[12% (55 ⁄ 473) vs. 6% (27 ⁄ 469); P = 0.001]. In theDIRECT study, patients treated with high dose of CIFN15 lg ⁄ day trended towards higher rates of discontinua-tion because of adverse events compared with patientswho received CIFN 9 lg ⁄ day [14.3% (35 ⁄ 245) vs. 21.1%(51 ⁄ 242); P = 0.09].

Re-treatment of nonresponders to standard interferonand ribavirin therapySeven RCTs have assessed the efficacy of re-treatment innonresponders to prior standard IFN and RBV ther-apy.28–34 Details regarding the design of these studies areprovided in Table 1. In each of the studies, over 80% ofstudy patients had genotype 1 HCV with the exceptionof the studies by Bergmann et al.28 and Scotto et al.34

where approximately 50–65% of patients had genotype 1disease. However, specific data on SVR rates for geno-type 1 HCV patients were not available for most studies.

Meta-analysis of these trials suggests that SVR ratesfor the re-treatment regimens may be dose-dependent.

Table1|(Con

Interven

Meanage

(years)

)Advan

fibrosis(%

⁄N)]

Discontinua

oftherap

Relapsersto

interferon

ntherapytriple

ttreatm

erStud

48weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day

*42.9(15

⁄35)

provided

48weeks

PEG-IFN

alfa2b

⁄week+RB

V1000–120

⁄day

⁄34)

provided

egylated

inteferon;

CIFN,c

onsensus

interferon

,ribavirin;A

mantadine

ported

percen

ofpatie

ntswith

cirrho

�Dataareforpo

pulatio

nonrespo

ndersandrelapsersin

combinatio

�Dataforgeno

1patie

§Dataforgeno

1and4patie

–Characteristic

sareforwho

pulatio

forrelapsers.

**Totalo

relapsersen

rolledin

trial,bu

notrepo

inabstract.

Re-treatment with higher doses of PEG-IFN is morelikely to produce SVR than combination therapy regi-mens with conventional doses of PEG-IFN: RR = 1.49;95% CI: 1.09–2.04 (Q = 1.24, P = 0.98, I2 = 0.0%)(Figure 2). Assessment of individual trial results suggeststhat SVR rates are not significantly higher in non-responders who failed initial therapy with standard IFNplus RBV compared with nonresponders who failed ini-tial therapy with PEG-IFN plus RBV (Table 1). Amongthe four RCTs that randomized at least 100 patients,31–34

SVR rates were only 10–17% with high-dose PEG-IFNand RBV combination therapy.

Although most studies compared different dosing regi-mens of PEG-IFN, the Consensus Interferon study30

compared CIFN with PEG-IFN combination therapy. Nodifference was observed between patients randomized toCIFN vs. PEG-IFN alpha 2b [22.2% (4 ⁄ 18) vs. 22.7%(5 ⁄ 22), P = 0.97; RR = 0.98; 95% CI: 0.31–3.11]. More-over, no significant difference was observed when Scottoand colleagues assessed equivalent dosing regimens oftwo different forms of PEG-IFN.34 In a sensitivity analy-sis, we removed both the Consensus Interferon studyand the Scotto study from the meta-analysis, but this didnot produce a significant change in the pooled relativerisk of SVR (RR = 1.52; 95% CI: 1.09–2.14).

Discontinuation rates because of adverse events (11–13%) were similar for the treatment arms in most trials

(Table 1). However, in the Consensus Interferon study,discontinuation because of adverse events was signifi-cantly higher with CIFN than PEG-IFN [33% (6 ⁄ 18) vs.4.5% (1 ⁄ 22), P = 0.02].

Re-treatment of relapsers to combination therapyFour RCTs32, 33, 35, 36 studied re-treatment in relapsersafter prior treatment with combination therapy (Table 1).In meta-analysis, SVR rates were increased with higherdose PEG-IFN combination therapy or prolonged(72 weeks) treatment with CIFN-based combinationtherapy: RR 1.57; 95% CI: 1.16–2.14 (Q = 1.19, P = 0.76,I2 = 0.0%) (Figure 3). Several points from these studiesdeserve further emphasis. First, the largest RCT36 com-pared re-treatment with PEG-IFN combination therapyvs. standard IFN combination therapy and demonstratedthat the PEG-IFN combination therapy was superior:43% vs. 26%; P < 0.001; RR = 1.93; 95% CI: 1.15–3.27).Second, another RCT32 showed a trend for higher SVRrates with higher dose PEG-IFN alpha 2b compared withstandard dose PEG-IFN alpha 2b: 50% (15 ⁄ 30) vs. 32.0%(8 ⁄ 25), P = 0.18; RR = 1.56; 95% CI: 0.80–3.07. Finally,the highest SVR (69%) was achieved with a 72-weekcourse of CIFN plus RBV.35 Discontinuation because ofadverse events was not reported for three studies33, 35, 36

and was only reported in combination with a nonre-sponder population in the fourth study.32

Overall (I 2 = 0.0%, P = 0.975)

Bergmann Study

Consensus Interferon Study

Spanish High Dose Induction Study

PEG Interferon alfa2b Retreatment Study

Scotto Study

Alamo Study Group

1.49 (1.09, 2.04)

1.19 (0.61, 2.30)

RR (95% CI)

0.98 (0.31, 3.11)

1.68 (0.59, 4.75)

1.55 (0.61, 3.93)

1.43 (0.99, 2.06)

1.39 (0.52, 3.70)

1.78 (0.68, 4.69)

100.00

Weight (%)

10.211 4.75

Figure 2 | Re-treatment of genotype I hepatitis C nonresponders to standard interferon and ribavirin therapy.

Re-treatment of nonresponders and relapsers to priorstandard interferon and ribavirin therapy withamantadineSeven RCTs37–44 evaluated the possible benefit of addingamantadine to PEG-IFN and RBV during re-treatment(Table 1). Notably, amantadine was added to both treat-ment arms in two studies39, 42, 43 that compared differentdosing regimens of PEG-IFN. With the exception of onestudy,44 at least 67% of the study patients had genotype Idisease.

Amantadine does not appear to be beneficial basedon these studies. Meta-analysis of studies that comparedamantadine plus combination therapy vs. placebo (orno additional treatment) plus combination ther-apy37, 38, 40, 41, 44 demonstrated that amantadine did notimprove SVR rates compared with placebo: RR = 1.07;95% CI: 0.70–1.64 (Q = 3.15, P = 0.53, I2 = 0.0%).Moreover, in meta-analysis of all trials using amanta-dine, SVR rates were not improved for regimens thatincluded amantadine: RR = 1.24; 95% CI: 0.90–1.72(Q = 5.58, P = 0.472, I2 = 0.0%) (Figure 4). Only onestudy provided data regarding the possible benefit ofadding amantadine to PEG-IFN based combinationtherapy in relapser patients.37 There was no significantdifference in SVR rates among relapsers with the addi-tion of amantadine to combination therapy vs. relapserswho received more standard combination therapy:41.2% (14 ⁄ 34) vs. 42.9% (15 ⁄ 35) (P = 0.89). Discontinu-ation because of adverse events was not described for

most of the trials, but was similar among the two treat-ment arms when reported.38, 41, 44

DISCUSSIONMost treatment-naı̈ve genotype I HCV patients fail toachieve SVR with combination therapy and remain at highrisk for decompensated cirrhosis, HCC and liver-relatedmortality.3, 4 Given the morbidity and mortality associatedwith treatment failure, effective and safe re-treatment regi-mens are needed,12 but re-treatment of these patients withconventional PEG-IFN combination therapy usually has apoor outcome. Optimal re-treatment regimens for thesepatients, including high-dose or prolonged re-treatmentregimens, have not been defined. Our meta-analysis is thefirst to quantify the efficacy and safety of re-treatingpatients who fail combination therapy with high-dose orprolonged PEG-IFN and RBV vs. conventional PEG-IFNcombination therapy. It demonstrates that high-dosePEG-IFN and RBV is superior to conventional PEG-IFNcombination therapy for re-treatment of nonresponders tostandard interferon and RBV treatment regimens(RR = 1.49; 95% CI: 1.09–2.04). Furthermore, our meta-analysis demonstrates that relapsers to initial HCV therapycan attain SVR rates of 43–69% during re-treatment andthis may be particularly useful to relapsers who alreadyhave bridging fibrosis or cirrhosis and are at risk forquickly developing sequelae of cirrhosis.

Although treatment of HCV-infected individuals willprobably advance to direct-acting antiviral (DAA) agents,

Overall (I 2 = 0.0%, P = 0.754)

Kaiser Study

BERNAR

Alamo Study Group

PEG Interferon alfa2b Retreatment Study

1.57 (1.16, 2.14)

1.37 (0.95, 1.96)

1.93 (1.15, 3.27)

1.52 (0.38, 6.04)

1.56 (0.80, 3.07)

RR (95% CI)

100.00

Weight (%)

0.166 1 6.04

Figure 3 | Re-treatment of genotype I hepatitis C relapsers to combination therapy.

also known as Specifically Targeted Anti-viral Therapyfor hepatitis C (STAT-C), with protease inhibitors,17, 18

these agents may not be widely available in the US until2012 and may not be available in other countries untilyears later. Therefore, treatment failure patients who areat risk for developing decompensated cirrhosis, HCC andliver-related mortality may be appropriate candidates forre-treatment before DAA therapies become available,especially if they already have bridging fibrosis or com-pensated cirrhosis. Furthermore, the SVR data in ourstudy will provide a comprehensive assessment of SVRrates that can be attained with high-dose or prolongedPEG-IFN combination therapy and these data can beused for comparison with SVR rates achieved with DAAbased regimens.

As 2009 AASLD ⁄ ACG guidelines suggest that deci-sions about re-treatment should be individualized,19 cli-nicians need to identify treatment failure patients whoare most in-need of re-treatment and those who aremost likely to benefit.45 Clearly, relapsers with bridgingfibrosis or compensated cirrhosis appear to be appropri-ate candidates for re-treatment as long as these individu-als have a good understanding of the potential risks andbenefits of re-treatment and express motivation toundergo prolonged or high-dose therapy. SVR ratesbetween 43% and 69% are possible in these patients with

prolonged or high-dose therapy. Nonresponders fail toachieve similar SVR rates with re-treatment, and clini-cians may want to identify additional factors which areassociated with successful re-treatment when makingindividualized decisions for patients. The EPIC trial,25 alarge prospective multi-centre open-label trial assessingre-treatment of 2333 patients who failed combinationtherapy identified other factors associated with SVR dur-ing re-treatment, including genotype 2 ⁄ 3 disease, lowbaseline fibrosis score, low baseline viral load and priorstandard IFN based treatment. EPIC did not assess theimpact of African-American race or high body massindex (BMI), although these factors have been associatedwith decreased likelihood of achieving SVR in trials oftreatment-naı̈ve patients.

Other factors may also contribute to whether or notpatients respond to re-treatment. Based on limiteddata,26 null responders (did not achieve a 2log10 drop inHCV RNA levels during the first 12 weeks of treatmentand had treatment discontinued) are less likely to achieveSVR with re-treatment compared with partial responders(individuals who achieved a 2log10 drop in HCV RNAlevels during the first 12 weeks of treatment). However,the studies in our meta-analysis did not consistentlyreport adequate data regarding whether patients were par-tial responders or null responders to initial combination

Overall (I 2 = 0.0%, P = 0.472)

Hasan Study

Fargion Amantadine Study

French Multicenter Study

Herrine Study

PRETTY

Amantadine Study

Cheinquer Study

1.24 (0.90, 1.72)

1.50 (0.17, 13.56)

1.51 (0.79, 2.91)

RR (95% CI)

1.34 (0.63, 2.87)

1.43 (0.65, 3.15)

1.72 (0.76, 3.89)

0.80 (0.41, 1.55)

0.72 (0.38, 1.37)

100.00

Weight (%)

10.0737 13.6

Figure 4 | Re-treatment of genotype I hepatitis C nonresponders and relapsers to standard interferon and ribavirintherapy with amantadine.

therapy. Future re-treatment studies should continue toreport SVR rates separately for these sub-groups. Finally,HCV patients may be nonresponders because of a lackof compliance with the initial treatment regimen, inap-propriate treatment holidays, or pre-mature discontinua-tion or inappropriate RBV dose reductions. If HCV-RNA titers had decreased appropriately with initial ther-apy prior to this interruption, then these patients may beparticularly likely to respond to re-treatment if theyremain compliant and avoid RBV dose reductions ortreatment holidays. Although it may be difficult forfuture trials to accurately identify patients who meetthese criteria, practitioners may wish to consider re-treat-ment in these patients.

Based on the data in our meta-analysis, cliniciansshould consider the following suggestions for re-treat-ment regimens. For patients who are nonresponders toprior PEG-IFN and RBV combination therapy, pro-longed therapy with PEG-IFN and RBV (72 weeks PEG-IFN alfa2a 180 lg ⁄ week + 1000–1200 mg ⁄ day RBV)results in the highest SVR rates. Similarly, high-dosePEG-IFN combination therapy regimens (48 weeks PEG-IFN alfa2b 3.0 lg ⁄ kg ⁄ week + 1000–1200 mg ⁄ day RBV)can be used to optimize the chance of SVR with re-treat-ment of nonresponders to standard IFN and RBV

therapy. Re-treatment of relapsers to PEG-IFN and RBVcombination therapy appears to achieve the highest SVRrates amongst the three groups, and SVR rates of 69%35

have been achieved with 72 weeks CIFN 9 lg ⁄ day +1000–1200 mg ⁄ day RBV (Figure 5).

When re-treating these treatment failure patients,complete viral suppression at week 12 appears to be cru-cial.27 In REPEAT, patients with undetectable HCV RNAat week 12 had a 35% chance of SVR with 48 weeks oftherapy and a 57% chance of SVR with 72 weeks of ther-apy. In contrast, those with detectable HCV RNA atweek 12 had less than a 5% chance of SVR regardless oftreatment duration. This suggests that complete viralsuppression during the first 12 weeks of re-treatmentmay be critical for success. Patients with unfavourablecharacteristics who have a lower chance of responding tore-treatment should probably wait for DAA therapy withprotease inhibitors especially if these patients only haveminimal fibrosis. DAA therapy with protease inhibitorsmay become available in 2012, and these agents are likelyto produce higher SVR rates than can be achieved withcombination therapy.

Our study is strengthened by the lack of heterogeneityin our sub-group analysis. This statistical analysis providesreassurance that each individual study in sub-group

Patients whofail prior HCV

therapy

* Non- response defined as failure to clear HCV RNA from serum during therapy. Relapse defined as patients who were able to clear HCV RNA atend of therapy but did not have sustained viral response at 24 weeks after therapy was compleated.# Treatment candidacy determined by multiple factors such as prior viral kinetics, prior treatment asherence, and patient motivation forretreatment.

Considertreatment with

PEG-IFN + RBVfor 48-72 weeks

Relapse to priortherapy*

Non-responseto prior

therapy*

Evidence of advanced

fibrosis

Await newtherapies

Evidence of minimal fibrosis

Consider PEG/CIFN + RBV ifgood treatment

candidate #

Do not treat ifpoor treatment

candidate #

Figure 5 | Algorithm for re-treatment of genotype I hepatitis C nonresponders and relapsers prior to hepatitis C virus(HCV) therapy.

analyses had similar study populations, treatment regi-mens and outcomes, making it acceptable to combine datainto a single meta-analysis. However, our meta-analysis islimited by several other factors. First, seven studies in thismeta-analysis are only published in abstract form. There-fore, we cannot report detailed data about frequency ofadverse events, frequency of dose reductions because ofadverse events, specific data on genotype I HCV patients,percentage of patients with advanced fibrosis or cirrhosis,etc. for some of the included studies. The potential impactof this on our results remains unclear. The relative lack ofsafety and tolerability data is particularly problematicbecause of these drug regimens can be associated withclinically important toxicities. Nevertheless, our meta-analysis provides a detailed summary of study design andresults on this topic. Second, some RCTs publishedrecently in abstract form46, 47 did not provide adequatedata to be included in this meta-analysis. Furthermore, themajority of RCTs published in abstract form did not pro-vide sufficient data regarding SVR rates for genotype 1patients. In these cases, data from the entire patient popu-lation were used, which could lead to an overestimation ofresponse rates. Finally, these studies are inadequate todetermine if different dosing regimens of RBV wouldimpact SVR.

In conclusion, our meta-analysis demonstrates thathigh-dose PEG-IFN and RBV is superior to conventionalPEG-IFN combination therapy for re-treatment of non-responders to standard interferon and RBV treatmentregimens (RR = 1.49; 95% CI: 1.09–2.04) and relapserscan attain SVR rates of 43–69% with different regimens.If these patients have bridging fibrosis or cirrhosis andother favourable prognostic factors, then re-treatmentmay be appropriate while awaiting the introduction ofDAA therapy.

ACKNOWLEDGEMENTSDeclaration of personal interests: All the listed authorshave made substantial contributions to the conceptionand design of the study, acquisition of data, or analysis

and interpretation of the data as well as the draft andfinal approval of the version to be submitted. Dr Shiff-man has served on advisory boards for Anadys, Biolex,BristolMyers Squibb, Conatus, GlaxoSmith Kline, Globe-immune, Human Genome Sciences, Novartis, Roche,Romark, Schering-Plough, Valeant, Vertex and Zymo-genetics. He has grant support from Biolex, Conatus,Human Genome Sciences, Idinex, Johnson ⁄ John-son ⁄ Tibotec, Roche, Romark, Schering-Plough, Valeant,Vertex, Wyeth and Zymogenetics. He is a speaker forRoche and Schering-Plough and is a consultant for Pfizerand Roche. He is a Data Safety and Monitoring Boardmember for Anadys and Abbott. Dr Bacon receivesresearch support for Schering Plough, Roche, Gilead,Bristol_Meyers Squibb, Glaxo Smith Kline, Three RiversPharmaceuticals, Valeant, Vertex, Human Genome Sci-ences, Wyeth, Echosense, Romark Labs and Intarcia. Hehas served on advisory boards for Schering Plough,Gilead, Glaxo Smith Kline, Three Rivers Pharmaceuticals,Vertex, Human Genome Sciences. He is a consultant forValeant and Schering Plough, and he is a speaker forSchering Plough, Gilead, and Three Rivers Pharmaceuti-cals. He is a Data Safety Management Board member forMerck, Novartis, and ISIS. Dr Singal has served as a con-sultant for Vertex pharmaceuticals and MD-Evidence. DrWaljee served as a consultant for Vertex pharmaceuticalsand MD-Evidence. Dr Schoenfeld has worked as consul-tant for Vertex Pharmaceuticals and is a partner in MD-Evidence. Declaration of funding interests: This researchwas funded by Vertex Pharmaceuticals.

SUPPORTING INFORMATIONAdditional Supporting Information may be found in theonline version of this article:

Table S1. Jadad quality assessment of trials.Please note: Wiley-Blackwell are not responsible for

the content or functionality of any supporting materialssupplied by authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.

REFERENCES1. Armstrong GL, Wasley A, Simard EP,

McQuillan GM, Kuhnert WL, Alter MJ.The prevalence of hepatitis C virusinfection in the United States, 1999through 2002. Ann Intern Med 2006;144: 705–14.

2. Rustgi VK. The epidemiology of hepati-tis C infection in the United States.J Gastroenterol 2007; 42: 513–21.

3. Grant WC, Jhaveri RR, McHutchisonJG, Schulman KA, Kauf TL. Trends inhealth care resource use for hepatitis C

virus infection in the United States.Hepatology 2005; 42: 1406–13.

4. Kim WR, Brown RS Jr, Terrault NA,El-Serag H. Burden of liver disease inthe United States: summary of a work-shop. Hepatology 2002; 36: 227–42.

5. Bruno S, Stroffolini T, Colombo M,et al. Sustained virological response tointerferon-alpha is associated withimproved outcome in HCV-related cir-rhosis: a retrospective study. Hepatology2007; 45: 579–87.

6. Fried MW, Shiffman ML, Reddy KR,et al. Peginterferon alfa-2a plus ribavirinfor chronic hepatitis C virus infection. NEngl J Med 2002; 347: 975–82.

7. Manns MP, McHutchison JG, GordonSC, et al. Peginterferon alfa-2b plus riba-virin compared with interferon alfa-2bplus ribavirin for initial treatment ofchronic hepatitis C: a randomised trial.Lancet 2001; 358: 958–65.

8. Simin M, Brok J, Stimac D, Gluud C,Gluud LL. Cochrane systematic review:pegylated interferon plus ribavirin vs.interferon plus ribavirin for chronic hep-atitis C. Aliment Pharmacol Ther 2007;25: 1153–62.

9. Hoofnagle JH, Seeff LB. Peginterferonand ribavirin for chronic hepatitis C. NEngl J Med 2006; 355: 2444–51.

10. Di Bisceglie AM, Shiffman ML, EversonGT, et al. Prolonged therapy ofadvanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359: 2429–41.

11. Yoshida H, Arakawa Y, Sata M, et al.Interferon therapy prolonged life expec-tancy among chronic hepatitis Cpatients. Gastroenterology 2002; 123:483–91.

12. Singal AG, Volk ML, Jensen D, DiBisceglie AM, Schoenfeld PS. A sus-tained viral response is associated withreduced liver-related morbidity and mor-tality in patients with hepatitis C virus.Clin Gastroenterol Hepatol 2010; 8:280–8.

13. Cheng SJ, Bonis PA, Lau J, Pham NQ,Wong JB. Interferon and ribavirin forpatients with chronic hepatitis C whodid not respond to previous interferontherapy: a meta-analysis of controlledand uncontrolled trials. Hepatology 2001;33: 231–40.

14. Cummings KJ, Lee SM, West ES, et al.Interferon and ribavirin vs interferonalone in the re-treatment of chronichepatitis C previously nonresponsiveto interferon: a meta-analysis of ran-domized trials. JAMA 2001; 285: 193–9.

15. Davis GL. Combination therapy withinterferon alfa and ribavirin as retreat-ment of interferon relapse in chronichepatitis C. Semin Liver Dis 1999;19(Suppl. 1): 49–55.

16. Shiffman ML, Hofmann CM, SterlingRK, Luketic VA, Contos MJ, Sanyal AJ.A randomized, controlled trial to deter-mine whether continued ribavirin mono-therapy in hepatitis C virus-infectedpatients who responded to interferon-ribavirin combination therapy will

enhance sustained virologic response.J Infect Dis 2001; 184: 405–9.

17. Kwo P, Lawitz EJ, McCone J. HighSustained Virologic Response (SVR) inGenotype 1 (GI) Null Responders toPEG-Interferon alfa-2B (P) plusRibavirin (R) when treated withBoceprevir (BOC) combination therapy.Hepatology 2009; 4: 331A.

18. McHutchison JG, Everson GT, GordonSC, et al. Telaprevir with peginterferonand ribavirin for chronic HCV genotype1 infection. N Engl J Med 2009; 360:1827–38.

19. Ghany MG, Strader DB, Thomas DL,Seeff LB. Diagnosis, management, andtreatment of hepatitis C: an update.Hepatology 2009; 49: 1335–74.

20. Jadad AR, Moore RA, Carroll D, et al.Assessing the quality of reports of ran-domized clinical trials: is blinding neces-sary? Control Clin Trials 1996; 17: 1–12.

21. Higgins J, Thompson SG. Quantifyingheterogeneity in a meta-analysis. StatMed 2002; 21: 1539–58.

22. Higgins JP, Thompson SG, Deeks JJ,Altman DG. Measuring inconsistency inmeta-analyses. BMJ 2003; 327: 557–60.

23. Copas JB, Shi JQ. A sensitivity analysisfor publication bias in systematicreviews. Stat Methods Med Res 2001; 10:251–65.

24. Macaskill P, Walter SD, Irwig L. A com-parison of methods to detect publicationbias in meta-analysis. Stat Med 2001; 20:641–54.

25. Poynard T, Colombo M, Bruix J, et al.Peginterferon alfa-2b and ribavirin:effective in patients with hepatitis C whofailed interferon alfa ⁄ ribavirin therapy.Gastroenterology 2009; 136: 1618–28.

26. Bacon BR, Shiffman ML, Mendes F,et al. Retreating chronic hepatitis C withdaily interferon alfacon-1 ⁄ ribavirin afternonresponse to pegylated inter-feron ⁄ ribavirin: DIRECT results. Hepa-tology 2009; 49: 1838–46.

27. Jensen DM, Marcellin P, Freilich B, et al.Re-treatment of patients with chronichepatitis C who do not respond to pe-ginterferon-alpha2b: a randomized trial.Ann Intern Med 2009; 150: 528–40.

28. Bergmann JF, Vrolijk JM, Van derSchaar P, Vroom B, van Hoek B.Gamma-glutamyltransferase and rapidvirologic response as predictors of suc-cessful treatment with experimental orstandard peginterferon-alpha-2b inchronic hepatitis C non-responders.Liver Int 2007; 27: 1217–25.

29. Diago M, Crespo J, Olveira A, et al.Clinical trial: pharmacodynamics andpharmacokinetics of re-treatment withfixed-dose induction of peginterferonalpha-2a in hepatitis C virus genotype 1true non-responder patients. AlimentPharmacol Ther 2007; 26: 1131–8.

30. Dollinger MM, Dridi Y, Lesske J, Behl S,Fleig WE. Efficacy of daily consensusinterferon and ribavirin compared toPEG-interferon alfa-2b and ribavirin innon-responders with chronic hepatitis C.Hepatology 2005; 42: 691A.

31. Gross J, Johnson S, Kwo P, Afdhal N,Flamm S, Therneau T. Double dose pe-ginterferon alfa-2b with weight-basedribavirin improves response for inter-feron ⁄ ribavirin non-responders withhepatitis C: final results of ‘‘RENEW’’.Hepatology 2005; 42: 219A.

32. Jacobson IM, Gonzalez SA, Ahmed F,et al. A randomized trial of pegylatedinterferon alpha-2b plus ribavirin in theretreatment of chronic hepatitis C. Am JGastroenterol 2005; 100: 2453–62.

33. Lawitz EJ, Bala NS, Becker S, Brown G,Davis M, Dhar R. Pegylated interferonalfa 2b and ribavirin for hepatitis Cpatients who were nonresponders to pre-vious therapy. Gastroenterology 2003;124: 783A.

34. Scotto G, Fazio V, Fornabaio C, et al.Peg-interferon alpha-2a versus Peg-inter-feron alpha-2b in nonresponders withHCV active chronic hepatitis: a pilotstudy. J Interferon Cytokine Res 2008; 28:623–9.

35. Kaiser S, Lutze B, Sauter B, Bissinger L,Werner C. Retreatment of HCV geno-type 1 relapse patients to peginterfer-on ⁄ ribavirin therapy with an extendedtreatment regimen of 72 weeks with con-sensus interferon ⁄ ribavirin versuspeginterferon alpha ⁄ ribavirin. Hepatology2007; 46: 819A.

36. Nevens F, van Vlierberghe H, D’heygereF, Delwaide J, Adler M, Henrion J.Peginterferon alfa-2a (40kDa) plus riba-virin is as effective in patients relapsingafter conventional interferon based ther-apy as in naive patients: results from theBERNAR-1 trial. J Hepatol 2005; 42:214.

37. Cheinquer H, Pessoa M, Almeida P,Silva G, Patelli M. Prospective random-ized study of peginterferon alpha-2a,ribavirin and amantadine vs peginterfer-on alpha-2a plus ribavirin, in hepatitis Cpatients now responders or relapsers tointerferon-alpha and ribavirin. J Hepatol2006; 44: S209.

38. Ciancio A, Picciotto A, Giordanino C,et al. A randomized trial of pegylated-interferon-alpha2a plus ribavirin with orwithout amantadine in the re-treatmentof patients with chronic hepatitis C notresponding to standard interferon andribavirin. Aliment Pharmacol Ther 2006;24: 1079–86.

39. Fargion S, Borzio M, Maraschi A, Carg-nel A. Triple antiviral therapy in HCVpositive patients who failed prior combi-nation therapy. World J Gastroenterol2006; 12: 5293–300.

40. Hasan F, Al-Khaldi J, Asker H, et al.Peginterferon alpha-2b plus ribavirinwith or without amantadine [correctionof amantidine] for the treatment ofnon-responders to standard interferonand ribavirin. Antivir Ther 2004; 9:499–503.

41. Herrine SK, Brown RS Jr, Bernstein DE,Ondovik MS, Lentz E, Te H. Peginterfer-on alpha-2a combination therapies inchronic hepatitis C patients whorelapsed after or had a viral break-through on therapy with standard inter-feron alpha-2b plus ribavirin: a pilotstudy of efficacy and safety. Dig Dis Sci2005; 50: 719–26.

42. Mangia A, Cimino L, Persico M,Demelia L, Rumi M, Spinzi G. Enhancedresponse to peginteferon alfa2a-based

triple therapy in previously non-responsive chronic hepatitis C: finalresults of PRETTY study. J Hepatol2005; 42: 200–1.

43. Mangia A, Ricci GL, Persico M, et al. Arandomized controlled trial of pegylatedinterferon alpha-2a (40 KD) or inter-feron alpha-2a plus ribavirin and aman-tadine vs interferon alpha-2a andribavirin in treatment-naive patientswith chronic hepatitis C. J Viral Hepat2005; 12: 292–9.

44. Maynard M, Pradat P, Bailly F, et al.Amantadine triple therapy for non-responder hepatitis C patients. Clues forcontroversies (ANRS HC 03 BITRI).J Hepatol 2006; 44: 484–90.

45. Jensen D, Marcellin P. Reply to Treat-ment of Nonresponder Patients with

Chronic Hepatitis C: To Repeat or Notto Repeat? That is the Question. Gastro-enterology 2009; 137: 1524.

46. Hezode C, Foucher J, Bronowicki J,Leroy V, Tran A. Efficacy and Safety ofan intensified regimen of pegylated inter-feron alfa-2a plus ribavirin in HCVgenotype 1-infected patients who did notrespond to a prior standard regimen ofpegylated interferon alfa-2a plus ribavi-rin: an interim analysis of the multicen-tric, randomized, controlled SYREN trial.Hepatology 2008; 48: 1148A.

47. Kaiser S, Lutze B, Hass HG. Treatmentof peginterferon ⁄ ribavirin nonresponderswith daily dosingof consensus interferonand ribavirin: results from the germanconsensus interferon multicenter study.Hepatology 2008; 48: 1143A.

Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing...

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