Intervention Review

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Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C

  1. Goran Hauser1,2,*,
  2. Tahany Awad2,
  3. Jesper Brok3,
  4. Kristian Thorlund4,
  5. Davor Štimac1,
  6. Mahasen Mabrouk5,
  7. Christian Gluud2,
  8. Lise Lotte Gluud6

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 28 FEB 2014

Assessed as up-to-date: 13 FEB 2014

DOI: 10.1002/14651858.CD005441.pub3


How to Cite

Hauser G, Awad T, Brok J, Thorlund K, Štimac D, Mabrouk M, Gluud C, Gluud LL. Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD005441. DOI: 10.1002/14651858.CD005441.pub3.

Author Information

  1. 1

    Clinical Hospital Centre Rijeka, Department of Gastroenterology, Rijeka, Croatia

  2. 2

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

  3. 3

    Rigshospitalet, Paediatric Department 4072, Copenhagen, Denmark

  4. 4

    McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada

  5. 5

    Faculty of Medicine, Cairo University, Endemic Medicine and Liver Department, Cairo, Egypt

  6. 6

    Copenhagen University Hospital Hvidovre, Gastro Unit, Medical Division, Hvidovre, Denmark

*Goran Hauser, ghauser@medri.hr.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2014

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Characteristics of included studies [ordered by study ID]
Al-Faleh 2004

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: performed, 48 participants estimated for each group.

Intention-to-treat analysis: used. Participants who discontinued treatment or were lost to follow-up were classified as non-responders.


ParticipantsCountry: Saudi Arabia.

Number of participants randomly assigned: 96; 54 men and 42 women.

All participants were treatment-naive.

Genotype: four.

Inclusion criteria.

  • Persistently raised ALT for at least six months.
  • Serum antibodies to HCV.
  • HCV RNA found by PCR.
  • Diagnosis of chronic hepatitis on liver biopsy sample taken in the preceding 12 months.


Exclusion criteria.

  • Age younger than 18 or older than 70 years.
  • Previous treatment with interferon or ribavirin.
  • Neutropenia (fewer than 1500 neutrophils/mm3).
  • Thrombocytopenia (fewer than 90,000 platelets/mm3).
  • Anaemia (less than 12 g of haemoglobin/dL in women and less than 13 g of haemoglobin/dL in men).
  • Serum creatinine greater than 1.5 times above the upper limit of normal.
  • Serum alpha-fetoproteins concentration above 25 ng/mL.
  • History of alcohol or haemolytic disease.
  • Decompensated cirrhosis.
  • Autoimmune hepatitis.
  • Hepatitis B infection.
  • HIV infection.
  • Current intravenous drug use; severe depressive illness; severe comorbid disease.
  • Organ transplant.
  • Pregnancy.
  • Unwillingness to practice contraception.
  • Hepatocellular cancer.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2b 100 µg plus ribavirin 800 mg for 48 weeks (n = 48).
  • Group 2: interferon alpha-2b 3 MU plus ribavirin 800 mg for 48 weeks (n = 48).


Participants were followed up for 24 weeks after the end of treatment.


OutcomesPrimary outcomes were biochemical and virological responses at the end of treatment and at the end of follow-up.

Other outcomes reported are adverse events.

Limit for hepatitis C virus RNA detection was 3200 copies/mL.


NotesAuthor contacted for additional information, but no reply received.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: randomly generated numbers by a computer program.

Allocation concealment (selection bias)Low riskQuote: performed in a central unit and were distributed in opaque sealed envelopes to individual centres.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the pathologists were blinded to the treatment allocation of the participant.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIt is clearly stated that treatment was discontinued in three and eight participants in peginterferon plus ribavirin and interferon plus ribavirin groups. Intention-to-treat analysis was used when participants who discontinued treatment or were lost to follow-up were classified as non-responders.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskConflict of interest bias might be present. The study was supported in part by a grant from Schering-Plough, Saudi Arabia.

Bruno 2004

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: performed, 151 participants estimated for each group.

Intention-to-treat analysis: not used, although stated.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 323; 194 men and 117 women, and 12 excluded from analyses.

All participants were treatment-naive.

All participants were infected with HCV genotype one.

Inclusion criteria.

  • Previously untreated HCV RNA positive patients between 18 and 65 years of age with ALT values above 1.5 times the upper normal limit.
  • Liver biopsy performed within six months before enrolment and a diagnosis of chronic hepatitis with any degree of fibrosis.
  • Haemoglobin equal to 13 g/dL for males, equal to 12 g/dL for females, WBC count greater than 3000/mm3, granulocyte count greater than 1500/mm3, platelet count greater than 80,000/mm3, bilirubin, albumin and serum creatinine levels within normal limits.


Exclusion criteria.

  • Advanced cirrhosis, that is, large oesophageal varices (F2 or more), history of gastrointestinal bleeding, ascites or encephalopathy.
  • Hepatocellular carcinoma.
  • Anti-HIV or HBsAg positivity.
  • Alcohol abuse (equal to 80 mg/d).
  • Parenteral drug addiction if not abstaining for at least two years; and any other contraindications to interferon or ribavirin.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2b 100 µg for weight 65 kg or greater and 80 µg for weight below 65 kg, for the first eight weeks, followed by a fixed dose of 50 µg for the next 40 weeks plus ribavirin for 48 weeks (n = 163).
  • Group 2: non-pegylated interferon alpha-2b 6 MU plus ribavirin for 48 weeks (n = 148).


For both groups, ribavirin was given at a dose of 1000 mg for participants weighting 75 kg or less and 1200 mg for those weighing more than 75 kg.

Participants were withdrawn from treatment if they did not achieve a virological response that was defined as undetectable serum HCV RNA by PCR 24 weeks after starting treatment.


OutcomesPrimary outcome was sustained virological response, defined as the absence of detectable HCV RNA by PCR 24 weeks after the end of treatment.

Other outcomes reported are end of treatment biochemical and virological response, sustained biochemical response, and frequency of discontinuations and dose reductions with causes.

Limit for hepatitis C virus RNA detection was 50 IU/mL.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: computer-generated scheme. Patients were stratified according to centre and randomised in blocks of four to the peginterferon plus ribavirin or interferon plus ribavirin group.

Allocation concealment (selection bias)Low riskComment: central randomisation centre.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the slides of liver biopsy specimens were coded and read by a single pathologist, who was unaware of clinical data.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The number of participants lost to follow-up is mentioned. Treatment was discontinued in 31 and 46 participants in peginterferon plus ribavirin and interferon plus ribavirin groups.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: Conflict of interest bias might be present. Schering-Plough Italy supplied peginterferon alpha-2b, and the other drugs were provided by the National Health System.

Cariti 2002

MethodsStudy design: randomised clinical trial.

Inclusion criteria: biopsy proven chronic hepatitis C, persistently elevated ALT, HCV RNA positive.


ParticipantsCountry: Italy.

Total number (sample size): 117.

Age: 46.7 group A; 43.7 group B.

Sex (male): group A 73%, group B 76%.

Genotype: one.

Previous HCV treatment: naive.


InterventionsGroup A.

  • Drug: peginterferon alpha-2a.
    • Dosage: 180 µg/wk.
    • Duration: 48 weeks.
  • Ribavirin
    • Dose: 800 to 1000 mg weight-based.
    • Duration: 48 weeks.


Group B.

  • Drug: Interferon alpha-2a.
    • Dosage: 6 MU thrice weekly.
    • Duration: 48 weeks.
  • Ribavirin
    • Dose: 800 mg to 1000 mg weight-based.
    • Duration: 48 weeks.


OutcomesSustained virological response.


NotesAbstract form, study authors were contacted, but we received no reply. It is not clear whether Intention-to-treat analysis was used when participants discontinued treatment or were lost to follow-up. The trial included 150 participants, but data from only 117 are available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "patients where randomised".

Comments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComment: Method of allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the pathologists were blinded to the treatment allocation of the participant.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: It is not clear whether Intention-to-treat analysis was used when participants discontinued treatment or were lost to follow-up. The trial included 150 participants, but the data from only 117 are available.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Derbala 2005

MethodsStudy design: randomised clinical trial.


ParticipantsCountry: Egypt.

Total number (sample size): 70.

Age, years: 42.6 group A; 38.7 group B.

Sex (male): group A 27, group B 26.

Genotype: four.

Previous HCV treatment: naive.

Inclusion criteria: biopsy proven chronic hepatitis C, persistently elevated ALT, HCV RNA positive.


InterventionsGroup A: 35 participants

  • Drug: peginterferon alpha-2b.


    • Dosage: 1.5 µg/kg.
    • Duration: 48 weeks.


Group B: 35 participants.

  • Drug: interferon alpha-2b.


    • Dosage: 6 MU thrice weekly.
    • Duration: 48 weeks.


Ribavirin was given to both groups at a weight-based dose ranging from 800 mg to 1000 mg.

  • 1200 mg (more than 75 kg).
  • 1000 mg (less than 75 kg but more than 65 kg).
  • 800 (less than 65 kg).


OutcomesSustained virological response.

Adverse events.


NotesAbstract only, no data about inclusion and exclusion criteria are provided.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComment: Method of allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is not mentioned whether outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The number and reasons for participant dropout were clearly specified. Intention-to-treat analysis did not change the estimates for sustained virological response.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Derbala 2006

MethodsStudy design: randomised clinical trial.


ParticipantsCountry: Egypt.

Total number: 73 (seven participants did not continue the treatment).

Age, years: 45.5.

Sex (male): 31% to 33%.

Comorbidity: bilharziasis.

Genotype: four.

Previous HCV treatment: naïve.

Inclusion criteria: chronic active hepatitis C as evidenced by the following.

  • Positive serological test for HCV-Ab.
  • Detectable serum HCV-RNA.
  • Elevated serum alanine transaminases.
  • Histopathological criteria of chronic active hepatitis.


Exclusion criteria.

  • Patient with hepatocellular carcinoma.
  • Positive serum pregnancy test and breast feeders.
  • Coinfected patients with HBV, HIV.
  • Patient with other chronic liver disease.


InterventionsGroup A (n = 38).

  • Drug: peginterferon alpha-2a.
  • Dosage: 180 µg.
  • Ribavirin dose: 1200 mg daily.


Group B (n = 35).

  • Drug: INF 2a.
  • Dosage: 3 MU three times.
  • Ribavirin dose: 1200 mg daily.


OutcomesPrimary outcomes: end of treatment response, sustained virological response, adverse events.


NotesPublished article.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Dollinger 2005

MethodsStudy design: randomised multicentre trial.

ITT analysis: performed.

Sample size calculation: not mentioned.


ParticipantsCountry: Germany.

Total number (sample size): 40.

Age: not mentioned.

Sex (male): not mentioned.

Comorbidity: not mentioned.

Genotype: one-b.

Previous HCV treatment: non-responders to previous combination treatment with IFN and RBV.

Inclusion criteria: chronic hepatitis C diagnosed by the following.

  • Histologically proven chronic hepatitis.
  • Hepatitis C, positive HCV-RNA.
  • Elevated transaminases.


InterventionsGroup A (n = 22).

  • Drug: peginterferon alpha-2b.
    • 1.5 µg/kg body weight.
    • Once weekly.


Group B (n = 18).

  • Drug: consensus interferon (CIFN)
    • 18 mcg/d CIFN for six weeks followed by 9 µg/d CIFN for 42 weeks.
  • Ribavirin
    • Dose: > 10.6 mg/kg body weight daily.


OutcomesEarly response rate (24 weeks of treatment); end-of-treatment response rate (52 weeks of treatment); sustained response rate (six months after treatment); adverse events.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method of sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskQuote: "The study was supported by a grant of Yamanouchi and Essexpharma, Germany".

Comments: The study may contain conflict of interest risk of bias.

Esmat 2003

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: used.


ParticipantsCountry: Egypt.

Number of participants randomly assigned: 200; 158 men and 42 women.

All participants were treatment-naive.

Mean inflammatory histological activity index score was 7/18 ± 2 and fibrosis stage 2.7/6 ± 1.3 in both arms.

90% of participants were infected with HCV genotype four.

Inclusion and exclusion criteria: none stated.


InterventionsParticipants were randomly assigned to two groups:

  • Group 1: peginterferon alpha-2b 100 µg with weight-based ribavirin 800 mg or 1000 mg for 48 weeks (n = 100).
  • Group 2: interferon alpha-2b 3 MU with weight-based ribavirin 800 mg or 1000 mg for 48 weeks (n = 100).


If HCV RNA was detectable at week 24, the treatment was stopped. Participants were followed-up for an additional 24 weeks after the end of treatment.


OutcomesPrimary outcome was HCV RNA status at week 72 (end of follow-up).

Other outcomes reported were end of treatment virological response and adverse events.

Limit for hepatitis C virus RNA detection was 50 copies/mL.


NotesThe report is abstract. Abstract only, no data about inclusion and exclusion criteria are provided.

Additional data were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: A computer programme randomly allocated participants to one of the two treatment groups in blocks of 10.

Allocation concealment (selection bias)Low riskComment: The group assignment was concealed in opaque sealed envelopes that were not opened until all study entry criteria were met.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: Participants were not blinded; however, it is mentioned whether outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The number of participants lost to follow-up is stated. 67 participants discontinued treatment in peginterferon plus ribavirin group and 69 in interferon plus ribavirin group. Intention-to-treat analysis was employed.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComments: The trial seem to be free of other sources of bias.

Fargion 2004

MethodsRandomised clinical trial with two parallel-group design.

Samlpe size calculation: not described.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 185.

All participants were non-responders to previous interferon plus ribavirin treatment.

Inclusion and exclusion criteria: none stated.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2a 180 µg plus ribavirin 800 mg to 1000 mg plus amantadine hydrochloride 200 mg for 48 weeks.
  • Group 2: interferon alpha 2a 6 MU daily for four weeks, then 3 MU daily for additional 20 weeks, and then 3 MU thrice weekly for additional 24 weeks plus ribavirin 800 mg to 1000 mg plus amantadine hydrochloride 200 mg for 48 weeks.


Participants with detectable HCV RNA after 24 weeks of treatment were considered non-responders and therapy discontinued. Participants were followed-up for 24 weeks after the end of treatment.


OutcomesPrimary outcome was sustained virological response, defined as undetectable HCV RNA 24 weeks after the end of treatment.

Other outcome reported was end of treatment virological response.


NotesThe report is abstract; because the study has not been published yet, no data about inclusion and exclusion criteria are provided.

Data were extracted from the primary reference and the previous abstract: Fargion S et al. End of treatment and sustained response to peginterferon alfa-2a (40 kD) (Pegasys) plus ribavirin (RBV) (Copegus) and amantadine (AMA), and to induction therapy with interferon (IFN) alfa-2A (Roferon-A) plus RBV and AMA in INF/RBV non-responders with chronic hepatitis C (CHC) [AASLD abstract]. Hepatology 2003;38(4, Suppl 1):733A.

Number of participants in each group is not reported, so we provisionally divided the total number of participants by two.

Study author contacted for additional information, but no data were obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method of sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: No post randomisation dropouts were reported.

Selective reporting (reporting bias)Unclear riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComments: The trial seem to be free of other sources of bias.

Fried 2002

MethodsRandomised clinical trial with three-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: not used, although stated (28 participants who were randomly assigned and did not receive allocated intervention were excluded from analyses). All participants who received at least one dose of study medication were included in all efficacy analyses, and if they had undergone at least one safety assessment after baseline, they were included in the safety analysis. All participants with follow-up of less than 20 weeks were considered to have had no response to treatment.


ParticipantsCountry: 81 centres worldwide.

Number of participants randomly assigned: 1149; 800 men and 321 women, and 28 excluded from analyses.

All participants were treatment-naive.

Genotype: one.

Inclusion criteria.

  • Adult patients who had never received interferon and who had at least 2000 copies of HCV RNA per millilitre of serum according to a PCR assay.
  • Serum ALT activity above the upper limit of normal within six months before entry into the study;
  • Liver biopsy result consistent with the diagnosis of chronic hepatitis C.


Exclusion criteria.

  • Neutropenia (fewer than 1500 neutrophils per cubic millimetre).
  • Thrombocytopenia (fewer than 90,000 platelets per cubic millimetre).
  • Anaemia (less than 12 g of haemoglobin per decilitre in women and less than 13 g of haemoglobin per decilitre in men).
  • HIV infection.
  • Decompensated liver disease.
  • Serum creatinine level greater than 1.5 times the upper limit of normal.
  • Poorly controlled psychiatric disease.
  • Alcohol or drug dependence within one year before entry into the study.
  • Substantial coexisting medical conditions.


InterventionsParticipants were randomly assigned to three groups.

  • Group 1: peginterferon alpha-2a 180 µg plus ribavirin for 48 weeks (n = 453).
  • Group 2: interferon alpha-2b 3 MU plus ribavirin for 48 weeks (n = 444).
  • Group 3: peginterferon alpha-2a 180 µg plus placebo for 48 weeks (n = 224).


For two arms, ribavirin was given at a dose of 1000 mg for participants weighing 75 kg or less and 1200 mg for those weighing more than 75 kg.

Participants were withdrawn from treatment if they continued to have viraemia at week 24, if they missed four consecutive doses, or at the discretion of the investigator. Participants were followed for 24 weeks after the end of treatment.


OutcomesPrimary outcome was sustained virological response, defined as the absence of detectable HCV RNA at the end of follow-up according to a PCR assay.

Other outcomes reported are end of treatment virological response, incidence of treatment discontinuation, dose modification, and adverse events.

Limit for hepatitis C virus RNA detection was 50 IU/mL (100 copies/mL).


NotesThe study was designed by the sponsor in collaboration with expert hepatologists. Data were collected by the Pegasys International Study Group. Data analysis was performed by the sponsor and the authors of the report; the authors had full access to the data, and the decision to publish was not limited by the sponsor.

Data were extracted from the primary reference and Hassanein T, et al. The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C. Journal of Hepatology 2004;40:675-81.

Study author contacted for additional information, but no reply obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Sequence generation was performed by a computer programme.

Allocation concealment (selection bias)Low riskComments: Central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments:Method of blinding was not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: No postrandomisation dropouts were reported.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskThe trial was sponsored by Roche. Designed by the sponsor in collaboration with expert hepatologists. Data were collected by the Pegasys International Study Group. Data analysis was performed by the sponsor and the authors of the report; the authors had full access to the data, and the decision to publish was not limited by the sponsor. This trial may contain conflict of interest bias.

Hinrichsen 2002

MethodsRandomised clinical trial with two-group design.

Samlpe size calculation: unclear, not described.

Intention-to-treat analysis: used.


ParticipantsCountry: Germany.

Number of participants randomly assigned: 72; 41 men and 31 women.

All participants were treatment-naive.

All participants were infected with HCV genotype two and three.

Inclusion and exclusion criteria: none stated.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2b 100 µg with ribavirin 800 mg for 24 weeks (n = 36).
  • Group 2: interferon alpha-2b 3 MU with ribavirin 1000 mg to 1200 mg for 24 weeks (n = 36).


OutcomesPrimary outcomes were sustained and end of treatment virological responses.

Other outcome reported is quality of life.

Limit for hepatitis C virus RNA detection was 50 IU/mL.


NotesThe report is abstract; because the study has not been published yet, no data about inclusion and exclusion criteria are provided.

Study author contacted for additional information, but no data obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Low riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The trial seems to have addressed incomplete outcome data adequately.

Selective reporting (reporting bias)Unclear riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Horsmans 2008

MethodsStudy design: multi-centre, controlled randomised trial comparing three groups.

ITT analysis: performed.


ParticipantsCountry: Belgium.

Total number (sample size): 258 (initially 336, but 78 had not commenced treatment).

Age, years (STD) : 45, 46, and 45.

Sex (male, number): 63, 62, and 36.

Genotype: one, two, and three.

Previous HCV treatment: naive.

Inclusion criteria: chronic hepatitis C diagnosed by the following.

  • Elevated alanine aminotransferase (ALT) activity.
  • Presence of HCV RNA in serum.


Exclusion criteria.

  • Patients with decompensated liver cirrhosis.
  • Patients with other chronic liver disease (e.g., HBV).
  • Patients coinfected with HIV.
  • Active alcohol abuse and intravenous drug abuse.
  • Patients with contraindication to RBV.


InterventionsGroup 1 (n = 101).

  • Drug: interferon alpha-2b (daily) 4 MIU sc for participants > 65 kg or 0.06 MIU/kg ≤ 65 kg.


Group 2 (n = 98).

  • Drug:  peginterferon alpha-2b 100 µg/wk for participants > 65 kg or 1.5 µg/kg/d for participants ≤ 65 kg.


Group 3 (n = 59).

  • Drug: IFN-2b.


    • Dosage: 3 MIU three times a week.


  • Ribavirin.


    • Dose: 1000 mg/d for participants weighing less than 75 kg or 1200 mg/d for participants weighing more than 75 kg.


OutcomesEnd of treatment response; sustained virological response; adverse events.


NotesInconsistency in the figures across the study report is evident: total number (sample size): 258 (initially 336, but 78 had not commenced treatment).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method of sequence generation is not mentioned. Randomisation process is not well described.

Allocation concealment (selection bias)Unclear riskComments: The allocation concealment process is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskComents: open-label trial.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: 78 participants had not commenced treatment; it is not clear whether the trial adhered to the intention-to-treat analysis.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskAll medication was provided by Schering-Plough.

Izumi 2004

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: unclear, not described.


ParticipantsCountry: Japan.

Number of participants randomly assigned: 49; 23 men and 26 women.

63% of participants were treatment-naive and 37% were retreated.

None of the participants had cirrhosis.

All participants were infected with HCV genotype one. Limit for hepatitis C virus RNA detection was 10 copies/mL.

Mean HCV RNA levels (kIU/mL) were 720 in peginterferon plus ribavirin group and 640 in interferon plus ribavirin group.

Inclusion criteria.

  • Biopsy-proven chronic hepatitis C.
  • Genotype one-b infection.
  • HCV RNA greater than 100 kIU/mL by Amplicore Monitor assay; Roche Molecular Diagnostics Co., Tokyo, Japan.


Exclusion criteria.

  • Cirrhosis.
  • Autoimmune hepatitis.
  • Alcoholic liver injury.
  • HBsAg or HIV antibody in serum.
  • Immunomodulatory therapy before enrolment in the study.
  • History of excessive alcohol drinking (more than 80 g/d).


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2b 1.5 µg/kg for 48 weeks (n = 23).
  • Group 2: interferon alpha-2b 6 MU intramuscularly, daily for the first two weeks and then thrice weekly for additional 46 weeks (n = 26).


Both arms received ribavirin 600 mg for participants who weighed less than 60 kg, 800 mg for participants who weighed between 60 and 80 kg, and 1000 mg for participants who weighed more than 80 kg.


OutcomesPrimary outcome was HCV RNA dynamics.

No other outcomes were reported.


NotesData were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComments: The trial seems to be free of other sources of bias.

Lee 2005

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: performed, 70 participants estimated for each group.

Intention-to-treat analysis: used (14 and five participants discontinued treatment in peginterferon plus ribavirin and interferon plus ribavirin groups).


ParticipantsCountry: Taiwan.

Number of participants randomly assigned: 153; 105 men and 48 women.

All participants were treatment-naive.

Genotype: one, two, three, four.

Inclusion criteria.

  • HCV RNA detectable in serum by PCR assay.
  • Had undergone a liver biopsy within one year before entry that was consistent with chronic hepatitis.
  • Elevated serum ALT defined as two (upper limit of normal) for at least two measurements within six months preceding trial entry.


Exclusion criteria.

  • Positive HBsAg.
  • Previous liver transplantation.
  • Neutropenia (fewer than 1500/mm3).
  • Thrombocytopenia (fewer than 100,000/mm3).
  • Anaemia (less than 13 g/dL for men and less than 12 g/dL for women).
  • HIV infection.
  • Decompensated liver disease.
  • Other causes of liver disease.
  • Abnormal serum creatinine or alpha-fetoprotein level.
  • Abnormal thyroid function test.
  • Preexisting psychiatric disorders.
  • Haemoglobinopathies.
  • Autoimmune-type disease.
  • Poorly controlled coexisting medical conditions.
  • Unable to use contraception.


InterventionsParticipants were randomly assigned to two arms.

  • Group 1: peginterferon alpha-2b 1.5 µg/kg plus ribavirin 1000 mg to 1200 mg (n = 76).
  • Group 2: interferon alpha-2b 3 MU plus ribavirin 1000 mg to 1200 mg (n = 77).


The dose of ribavirin was based on body weight (1000 mg for weight 75 kg, and 1200 mg for weight greater than 75 kg). Participants were treated for 24 weeks and were followed for another 24 weeks after the end of treatment.


OutcomesPrimary outcomes were biochemical response, virological response, which was defined as the persistent disappearance of serum HCV RNA, and degree of histological improvement.

Other outcomes reported are adverse events.

Limit for hepatitis C virus RNA detection was 50 IU/mL.


NotesThe trial was supported by research grants from Schering-Plough Limited, Taiwan.

Additional data were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Sequence generation was performed by a computer programme.

Allocation concealment (selection bias)Low riskComments: Central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the liver histology was analysed by a single pathologist, who was unaware of the participant's identity, treatment regimen, response or timing of the biopsy relative to treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: The trial was supported by research grants from Schering-Plough Limited, Taiwan. The study may have conflict of interest bias.

Mangia 2005

MethodsRandomised clinical trial with three parallel-group design.

Sample size calculation: performed, 118 participants estimated for each group.

Intention-to-treat analysis: used. Participants who discontinued treatment or were lost during follow-up were considered to be virological non-responders (i.e., no sustained virological response). 39 participants discontinued treatment in peginterferon plus ribavirin plus amantadine group, 46 in interferon plus ribavirin plus amantadine group, and 54 in interferon plus ribavirin group.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 362; 215 men and 147 women.

All participants were treatment-naive.

Genotype: one, two, three.

Mean HCV RNA levels (UI/mL × 1000) were 2817 ± 4318. 618 in peginterferon plus ribavirin plus amantadine group and 1998 ± 2255. 631 in interferon plus ribavirin plus amantadine group.

Inclusion criteria.

  • Previously untreated patients
  • Aged 18 to 70 years.
  • Histologically proven chronic hepatitis C.
  • Positive for anti-HCV and HCV RNA by PCR.
  • At least a 1.5-fold increase in ALT levels for at least six months before the start of the study.
  • Haemoglobin levels at least 13 g/dL in men and 12 g/dL in women.
  • Leukocyte counts at least 3000/mm3.
  • Platelet counts higher than 70,000/mm3.


Exclusion criteria.

  • Contraindications to interferon, ribavirin, and amantadine.
  • Immune suppression.
  • Concomitant liver disease; attributable to a cause other than HCV infection.
  • Severe systemic diseases.
  • Intravenous drug use.
  • Alcohol abuse.


InterventionsParticipants were randomly assigned to three groups.

  • Group 1: peginterferon alpha-2a 180 µg and amantadine hydrochloride 200 mg for 48 weeks (n = 121).
  • Group 2: interferon alpha-2a 3 MU and amantadine hydrochloride 200 mg for 48 weeks (n = 120).
  • Group 3: interferon alpha-2a 3 MU for 48 weeks (n = 121).


All participants received ribavirin 1000 mg (body weight less than 75 kg) or 1200 mg (body weight greater than 75 kg).

Participaants were evaluated for virological response at 24 weeks of treatment. Therapy was continued only in participants with undetectable HCV RNA at this time.


OutcomesPrimary outcome was sustained virological response, defined as undetectable HCV RNA 24 weeks after the end of treatment (study week 72).

Other outcomes reported included end of treatment virological response, sustained and end of treatment biochemical responses, and adverse events.
Limit for hepatitis C virus RNA detection was 50 copies/mL.


NotesThe study was conducted by the Al-liver Study Group.

Data were extracted from the primary reference, and additional data were obtained through personal communication with the study author.

Dose reductions are reported only if they were greater than 20% of the prescribed drugs and for longer than 20% of the prescribed duration.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Sequence generation was performed by a computer programme.

Allocation concealment (selection bias)Low riskComments: Central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the liver histology was analysed by a single pathologist, who was unaware of the participant's identity, treatment regimen, response, or timing of the biopsy relative to treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: No conflict of interest statement was provided.

Manns 2001

MethodsRandomised clinical trial with three parallel-group design.

Sample size calculation: performed. This study was designed to include 525 participants per group.

Intention-to-treat analysis: used. As prospectively specified in the protocol, all safety and efficacy analyses, except for changes from baseline in the histological scores, were based on all participants who received at least one dose of study medication. Participants who were missing HCV RNA values during follow-up were classified as non-responders. Analyses of changes from baseline in histological scores were based on participants who had both a pretreatment and a post-treatment biopsy sample. 72 participants discontinued treatment in higher-dose peginterferon plus ribavirin group, 67 in lower-dose peginterferon plus ribavirin group, and 66 in interferon plus ribavirin group.


ParticipantsCountry: 62 centres in Europe, Canada, Argentina, and the USA.

Number of participants randomly assigned: 1530; 1003 men and 527 women.

All participants were treatment-naive.

Genotype: one, two, three.

Geometric mean HCV RNA levels (copies/mL × 1,000,000) were 2.7 in both peginterferon plus ribavirin arms, and 2.8 in interferon plus ribavirin group. Limit for hepatitis C virus RNA detection was 100 copies/mL.

Inclusion criteria.

  • Previously untreated adults.
  • HCV RNA detectable in serum by PCR.
  • Liver biopsy within one year before entry that was consistent with chronic hepatitis.
  • High serum values of ALT (above the upper limit of normal more than 43 IU/L for men, more than 34 IU/L for women).
  • Minimum haematological and biochemical values of: haemoglobin 120 g/L for women and 130 g/L for men; WBC count 3000 × 1,000,000/L; neutrophil count 1.5 × 1,000,000/L; platelet count 100 × 1,000,000/L.
  • Bilirubin, albumin, and creatinine within normal limits.


Exclusion criteria.

  • Decompensated cirrhosis.
  • Serum alpha-fetoprotein concentration greater than 50 µg/L.
  • HIV infection.
  • Previous organ transplantation.
  • Other causes of liver disease.
  • Preexisting psychiatric disease.
  • Seizure disorders.
  • Cardiovascular disease.
  • Haemoglobinopathies.
  • Haemophilia.
  • Poorly controlled diabetes.
  • Autoimmune-type disease.
  • Inability to use contraception.


InterventionsParticipants were randomly assigned to three groups.

  • Group 1: peginterferon alpha-2b 1.5 µg/kg plus ribavirin 800 mg for 48 weeks (n = 511).
  • Group 2: peginterferon alpha-2b 1.5 µg/kg for the first four weeks, followed by 0.5 µg/kg for the next 44 weeks plus ribavirin 1000 mg to 1200 mg for 48 weeks (n = 514).
  • Group 3: interferon alpha-2b 3 MU plus ribavirin 1000 mg to 1200 mg for 48 weeks (n = 505).


In the two arms receiving 1000 mg to 1200 mg of ribavirin, the dose was adjusted according to body weight (1000 mg for weight below 75 kg and 1200 mg for weight 75 kg or more).

Both drugs were started and stopped at the same time.

Participants were followed-up for 24 weeks after the end of treatment.


OutcomesPrimary outcome was sustained virological response, defined as undetectable HCV RNA in serum at the end of follow-up.

Other outcomes reported included end of treatment virological response, sustained and end of treatment biochemical responses, histological response, and rates of discontinuation of treatment, dose reductions, and adverse events.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: computer generated. Eligible participants were randomly assigned the three study treatments in equal proportions, stratified by HCV genotype (one versus others) and the presence or absence of cirrhosis. The randomisation schedule, balanced within each country participating in the study, used a block size of three for each stratum and was generated by the study sponsor (Schering Plough Research Institute).

Allocation concealment (selection bias)Low riskComment: Randomisation of participants to treatment was done by an independent central randomisation centre (Information Management Systems, Silver Springs, MD, USA). When a participant was found to be eligible for participation in the study, the study site sent a fax to the randomisation centre documenting the participant's eligibility; the centre sent a return fax with the participant's treatment assignment and identification number for the study.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: It is mentioned only that the liver histology was analysed by a single pathologist, who was unaware of the participant's identity, treatment regimen, response, or timing of the biopsy relative to treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: As prospectively specified in the protocol, all safety and efficacy analyses, except for changes from baseline in histological scores, were based on all participants who received at least one dose of study medication. Participants who were missing HCV RNA values during follow-up were classified as non-responders. Analyses of changes from baseline in histological scores were based on participants who had both a pretreatment and a post-treatment biopsy sample.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: The study may contain conflict of interest bias. The study was supported by research grants from Schering Plough Research Institute, Kenilworth, NJ, and by clinical research centre grants from Massachusetts General Hospital, Scripps Clinic, and University of Florida. Study authors received grants from Schering Corp as part of their participation in current clinical trials. The study was conducted by International Hepatitis Interventional Therapy Group.

Napoli 2005

MethodsRandomised clinical trial with two-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: used.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 64; 45 men and 19 women.

All participants were treatment-naive.

Inclusion criteria.

  • Positive for HCV RNA by PCR.
  • Serum levels of ALT above the upper limit of normal values for at least six months before treatment.
  • Histopathological confirmation of chronic hepatitis.


Exclusion criteria.

  • Decompensated liver cirrhosis.
  • Haematological abnormalities (haemoglobin level less than 12 g/dL in women and less than 13 g/dL in men; neutrophil count fewer than 1.5 × 1000 cells/mL; platelet count fewer than 90 × 1.000 cells/mL).
  • Preexisting severe psychiatric conditions.
  • Severe cardiac disease.
  • Haemoglobinopathies.
  • Haemophilia.
  • Autoimmune diseases.
  • HIV coinfection.
  • Previous liver transplantation.
  • Other causes of liver disease.
  • Women unable or unwilling to practice contraception.


InterventionsParticipants were randomly assigned to two arms:

  • Group 1: peginterferon alpha-2b 1.5 µg/kg plus ribavirin 800 mg to 1200 mg (n = 32).
  • Group 2: non-pegylated leucocyte interferon alpha 6 MU plus ribavirin 800 mg to 1200 mg (n = 32).


Dose of ribavirin depended on pretreatment body weight: 800 mg for weight less than 60 kg; 1000 mg for weight greater than and equal to 60 kg and less than 75 kg; 1200 mg for weight greater than and equal to 75 kg.

Duration of treatment was 48 weeks for participants infected with HCV genotype one and 24 weeks for participants infected with genotypes two and three.


OutcomesPrimary outcomes were end of treatment and sustained virological responses, defined as the absence of detectable HCV-RNA in the serum at the end of treatment and at week 24 of post-treatment follow-up.

Other outcomes reported are adverse events and dose reductions.

Limit for hepatitis C virus RNA detection was 3200 copies/mL.


NotesThe study was supported by grants from Ministero dell Universita e della Ricerca Scientifica e Tecnologica, Rome, Italy.

Additional data were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Sequence generation was performed by a computer programme.

Allocation concealment (selection bias)Low riskComments: central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

Nevens 2010

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: used. All participants who received at least one dose of study medication were included in the analysis (ITT/e = exposed). Participants without measurements at the end of the 24-week untreated follow-up period were considered as non-responders.


ParticipantsCountry: Belgium.

Number of participants randomly assigned: 443; 241 men and 202 women.

78% of participants were treatment-naive and 22% were relapsers.

Inclusion criteria.

  • Patients 18 years of age or older.
  • Serologically proven chronic hepatitis C.
  • Quantifiable HCV RNA (more than 1000 IU/mL).
  • Compensated liver disease (Child-Pugh Grade A).
  • Naive to any therapy or had a relapse after previous interferon-based treatment.


Exclusion criteria: none stated.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2a 180 µg plus ribavirin 1000 mg to 1200 mg for 48 weeks (n = 230).
  • Group 2: interferon alpha-2a 6 MU for eight weeks, and then 3 MU for additional 40 weeks plus ribavirin 1000 mg to 1200 mg for 48 weeks (n = 213).


Participants were followed-up for 24 weeks after the end of treatment.


OutcomesPrimary outcome was sustained virological response, defined as undetectable HCV RNA at the end of follow-up.

Other outcomes reported are sustained biochemical response and adverse events.

Limit for hepatitis C virus RNA detection was 50 IU/mL.


NotesFollow-up: 71 and 119 participants discontinued treatment in peginterferon plus ribavirin and interferon plus ribavirin groups. Additional data were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuote: “Randomisation was stratified according to pre-treatment status (treatment naïve versus relapse) and presence of cirrhosis”.

Allocation concealment (selection bias)Low riskComment: no data about allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: open-label study.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

PRETTY 2005

MethodsRandomised clinical trial with two-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: unclear, not described.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 178; 119 men and 59 women.

Genotype: one, two, three.

All participants were non-responders to previous interferon plus ribavirin treatment.

Inclusion and exclusion criteria: none stated.


InterventionsParticipants were randomly assigned to two arms:

  • Group 1: peginterferon alpha-2a 180 µg plus ribavirin 1000 mg to 1200 mg and amantadine hydrochloride 200 mg for 48 weeks.
  • Group 2: interferon alpha-2a 6 MU plus ribavirin 1000 mg to 1200 mg and amantadine hydrochloride 200 mg for 48 weeks.


OutcomesPrimary outcomes were biochemical and virological responses.

Other outcome reported was dose reduction.


NotesThe report is abstract; because the study has not been published yet, no data about inclusion and exclusion criteria were provided.

We calculated sustained virological response based on reported proportions of participants because no absolute numbers of participants with sustained virological response were reported.

Number of participants in each group is not reported, so we provisionally divided the total number of participants by two.

Study author contacted for additional informations, but no reply obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Unclear riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: It was not possible to assess whether the trial was free of other sources of bias.

Rahman 2007a

MethodsStudy design: randomised controlled trial.

ITT analysis: yes.

Sample size calculation: not mentioned.


ParticipantsCountry: not known.

Total number (sample size): 310.

Genotype: one.

Previous HCV treatment: naive.

Inclusion criteria: chronic hepatitis C infection.

Exclusion criteria: not mentioned.


InterventionsGroup 1: peginterferon alpha-2b induction plus ribavirin.

  • Dosage: induction two weeks interferon alpha-2b 10 -> 5 MU qd followed by 36 weeks peginterferon alpha-2b 1.5 µg/kg,weekly.


Group 2: peginterferon alpha-2b  standard plus ribavirin.

  • Dosage: 1.5 µg/kg weekly.


Group 3: CIFN induction plus ribavirin.

  • Dosage: 12 weeks CIFN 27 -18 µg qd followed by 36 weeks CIFN 9 µg qd.


Group 4: CIFN plus ribavirin.

  • Dosage: 9 µg qd.


OutcomesSustained virological response.

Adverse events.


NotesOnly published abstract; no data about inclusion and exclusion criteria were provided.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Unclear riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Rahman 2007b

MethodsStudy design: randomised clinical trial.

ITT analysis: yes.

Sample size calculation: not mentioned.


ParticipantsCountry: not known.

Total number (sample size): 262.

Genotype: two, three.

Previous HCV treatment: naive.

Inclusion criteria: chronic hepatitis C infection.

Exclusion criteria: not mentioned.


InterventionsGroup 1: peginterferon alpha-2b  plus ribavirin.

  • Dosage: 1.5 µg/kg weekly.


Group 2: consensus interferon plus ribavirin.

  • Dosage: 9 µg qd.


OutcomesSustained virological response.

Adverse events.


NotesOnly published abstract; no data about inclusion and exclusion criteria provided.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method used to perform sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to outcome assessors is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Unclear riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Roffi 2008

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: yes.

Intention-to-treat analysis: yes.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 91; 64 men and 27 women.

Participant status regarding previous antiviral therapy not described.

Genotype: one, two, three

All participants had bridging fibrosis or cirrhosis.

Inclusion criteria.

  • Participants with chronic hepatitis C.
  • Liver biopsy performed within 12 months before entry to the protocol.
  • Pathology report confirming a histological diagnosis of advanced disease: stage greater than four sec. Ishak; stage greater than three sec. Knodell.
  • Compensated liver disease.
  • Minimum biochemical criteria: haemoglobin 13 g/dL for men, 12 g/dL for women, WBC greater than 3000/mm3, granulocyte greater than 1500/mm3, platelets greater than 80,000/mm3, bilirubin within normal limits.


Exclusion criteria.

  • Decompensated.
  • Child-Pugh class B or C cirrhosis.
  • Medium-sized or large varices.
  • Coinfection with hepatitis B or HIV.


InterventionsParticipants were randomly assigned to two groups (n = 93):

  • Group 1: peginterferon alpha-2b 1.0 µg for four weeks, then 50 µg for up to 24 weeks plus ribavirin for 24 weeks (n = 57).
  • Group 2: interferon alpha-2b 3 MU plus ribavirin for 24 weeks (n = 36).


Ribavirin

  • Dose: 800 mg/d for participants weighing less than 65 kg, 1000 mg/d for participants weighing between 65 kg and 75 kg, or 1200 mg/d for participants weighing more than 75 kg.


Participants were followed-up for 48 weeks after the end of treatment.


OutcomesPrimary outcomes were end of treatment and sustained virological responses.

Other outcome reported is treatment discontinuation.


NotesFollow-up: Six and five participants discontinued treatment in peginterferon plus ribavirin and interferon plus ribavirin groups.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComments: Sequence generation was performed by a computer programme.

Allocation concealment (selection bias)Low riskComments: central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: It is mentioned only that the pathologists reviewed the biopsy specimens in a blinded manner.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

Scotto 2005

MethodsRandomised clinical trial with three parallel-group design.

Sample size calculation: not described.

Intention-to-treat analysis: used.


ParticipantsCountry: Italy.

Number of participants randomly assigned: 78; 36 men and 42 women.

All participants were treatment-naive.

All participants were infected with HCV genotype one-b.

Mean histological activity index score was 13.7 ± 2.9 in peginterferon plus ribavirin group, 13.7 ± 3.8 in lower-dose interferon plus ribavirin group, and 13.9 ± 3.2 in higher-dose interferon plus ribavirin group.

Inclusion criteria.

  • Serum ALT levels at least twice the upper normal limit for at least six months before treatment.
  • Presence of anti-HCV antibodies determined by means of a third-generation enzyme-linked immunosorbent assay (HCV ELISA, Ortho Diagnostic System, Raritan, NJ, USA) and confirmed by additional third-generation recombinant immunoblot assay (RIBA, Ortho Diagnostic System, Raritan, NJ, USA).
  • Presence of measurable serum HCV RNA (Cobas Amplicor HCV Monitor test, Roche Molecular System, Basel, Suisse).
  • HCV genotype one-b (Inno-Lipa HCV II Kits, Innogenetics, Zwijmaarden, Belgium).
  • Leukocyte counts greater than 3000/mm3.
  • Platelet counts greater than 75,000/mm3.
  • Haemoglobin concentration greater than 13 g/dL for men and greater than 12 g/dL for women.
  • Liver biopsy performed within one year of the start of treatment with histological diagnosis of chronic hepatitis based on the histological activity index score as described by Knodell et al. and modified by Ishak et al.


Exclusion criteria.

  • Previous episodes of decompensated liver disease (i.e., ascites, bleeding from oesophageal varicose veins, encephalopathy).
  • HIV coinfection.
  • Active intravenous drug use.
  • Potential cause of liver disease other than HCV.


InterventionsParticipants were randomly assigned to three groups.:

  • Group 1: peginterferon alpha-2b 1.5 µg/kg for 52 weeks (n = 26).
  • Group 2: interferon alpha-2b 6 MU for 52 weeks (n = 26).
  • Group 3: interferon alpha-2b 3 MU daily for 52 weeks (n = 26).


All participants also received ribavirin at 800 to 1000 to 1200 mg according to body weight (less than 65 kg, 65 to 85 kg, and more than 85 kg).

Participants were followed up for 24 weeks after the end of treatment.


OutcomesPrimary outcomes were early, end of treatment, and sustained biochemical and virological responses.

Other outcomes reported are histological changes, adverse events, and treatment discontinuations.


NotesFollow-up: Three participants discontinued treatment in peginterferon plus ribavirin group, four in lower-dose interferon plus ribavirin group, and eight in higher-dose interferon plus ribavirin group. Study author contacted for additional information, but no reply obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: Randomisation was performed using a matrix of casual numbers, which generated the random allocation sequence table.

Allocation concealment (selection bias)Low riskComments: central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

Shobokshi 2003

MethodsRandomised clinical trial with three parallel-group design.

Sample size calculation: unclear, not described.

Intention-to-treat analysis: unclear, not described.


ParticipantsCountry: Saudi Arabia.

Number of participants randomly assigned: 180; 119 men and 61 women.

Participant status regarding previous antiviral therapy not described.

Histological activity index (22) mean was 6.9 in peginterferon plus ribavirin group and 8.1 in interferon plus ribavirin group.

All participants were infected with HCV genotype four.

Mean HCV RNA levels (UI/mL) were 459,590 in peginterferon plus ribavirin group and 411,028 in interferon plus ribavirin group.

Inclusion and exclusion criteria: none stated.


InterventionsParticipants were randomly assigned in three groups to receive the following.

  • Group 1: peginterferon alpha-2a 180 µg plus ribavirin 800 mg for 48 weeks (n = 60).
  • Group 2: peginterferon alpha-2a 180 µg (n = 60).
  • Group 3: interferon alpha 2a 4.5 MU plus ribavirin 800 mg for 48 weeks (n = 60).


Participants were followed up for 24 weeks after the end of treatment.


OutcomesPrimary outcomes were sustained and end of treatment virological responses.

Other outcomes reported are sustained and end of treatment biochemical responses.


NotesThe report is abstract because the study has not been published yet.

The study was conducted by MOH PEG-IFN Clinical Trial Group.

Data were extracted from the primary reference and abstracts: Shobokshi, et al. Peginterferon alfa-2a (40KDA) as a monotherapy or in combination with ribavirin significantly improves end of treatment response rate in hepatitis C virus genotype 4 chronic active hepatitis patients. Saudi Medical Journal 2003;24(Suppl 2):S92-3; and Shobokshi et al. Early virological response at week 12 has positive predictive value for end of treatment response for hepatitis C virus genotype 4 chronic active hepatitis cases treated with combination therapy of peginterferon plus ribavirin. Saudi Medical Journal 2003;24(Suppl 2):S92-3.

Follow-up: Seven participants discontinued treatment in peginterferon plus ribavirin group, four in peginterferon group, and one in interferon plus ribavirin group.

Study author contacted for additional information, but no reply obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: Method of sequence generation was not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasUnclear riskComment: The trial may have conflict of interest bias.

Sjögren 2007

MethodsRandomised clinical trial with two parallel-group design.

Intention-to-treat analysis: used.


ParticipantsCountry: USA.

Number of participants randomly assigned: 59.

All participants are treatment-naive.

All participants are infected with HCV genotype one.

Inclusion criteria: HCV RNA positive patients with liver biopsy compatible with chronic HCV infection

Exclusion criteria: minimum haemoglobin 12g/L for women and 13g/L for men, WBC < 3x103/mm3, Neutrophil count < 1,5x103/mm3, platelet count < 75x103/mm3, prothrombin time > 2 sec above the upper limit of normal, severe psychiatric conditions, other causes of liver disease than HCV infection


InterventionsParticipants are randomly assigned to two groups.

  • Group 1: peginterferon 1.5 µg/kg and ribavirin 1000 mg or 1200 mg (n = 29).
  • Group 2: non-pegylated consensus interferon 15 µg and ribavirin 1000 mg or 1200 mg (n = 30).


Treatment is planned for 48 weeks if serum HCV RNA is undetectable at week 24; otherwise, drugs are to be discontinued.


OutcomesPrimary outcome is sustained virological response, which will be determined at week 72.

Other outcomes reported include end of treatment virological response and adverse events.


NotesAn ongoing study with interim results. No new publications regarding this data.

Study author contacted for additional information, but no reply obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomised using a computerized system".

Allocation concealment (selection bias)Low riskComments: central allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "HCV RNA and HCV genotype were tested at a central laboratory". However, it is not clear whether adverse event outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The trial seems to be free of other sources of bias.

Thakeb 2003

MethodsStudy design: randomised clinical trial.

ITT analysis: performed.


ParticipantsCountry: not known.

Total number (sample size): 100.

Genotype: four.

Previous HCV treatment.


InterventionsGroup A (n = 51).

  • Drug: peginterferon alpha-2a.
  • Dosage: 180 µg.


Group B (n = 49).

  • Drug: IFN-2a.
  • Dosage: 3 MU.


Ribavirin.

  • 1000 or 1200 mg depending on body weight.


OutcomesSustained virological response.

Adverse events.


NotesPublished abstract only; no data about inclusion and exclusion criteria were provided.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method of sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Method of allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: It is not mentioned whether outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Unclear riskComment: It is unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

Tsubota 2005

MethodsRandomised clinical trial with two parallel-group design.

Sample size calculation: not described.

Intention-to-treat analysis: used.


ParticipantsCountry: Japan.

Number of participants randomly assigned: 48; 31 men and 17 women.

All participants were treatment-naive.

None of the participants had cirrhosis.

All participants were infected with HCV genotype one.

Mean HCV RNA levels (kIU/mL) were 540 (120 to 2100) in peginterferon plus ribavirin group and 700 (250 to 2800) in interferon plus ribavirin group.

Inclusion criteria.

  • HCV genotype one-b confirmed by PCR.
  • Serum HCV RNA levels greater than 100,000 IU/mL on quantitative PCR assay (defined as ‘‘high’’ viral load, Amplicor HCV Monitor Version 2.0, Roche Diagnostics, Tokyo, Japan).
  • Serum ALT concentrations above the upper limit of normal (greater than 45 IU/L).
  • Diagnosis of chronic hepatitis on a liver biopsy specimen obtained within the preceding year, using the ranking system for grading of necrotic inflammation activity and staging of fibrosis.
  • Haemoglobin concentration 12.0 g/dL.
  • Neutrophil count 1500/mL.
  • Platelet count greater than 100,000/mL.
  • Creatinine clearance greater than 51 mL/min.
  • Body weight between 40 and 100 kg.
  • Older than 20 years of age.


Exclusion criteria.

  • Liver cancer or severe liver failure.
  • Other forms of liver disease.
  • Coexisting serious psychiatric or medical illness, including seizure disorders, diabetes mellitus, cardiovascular or lung disease, and autoimmune-type disease.
  • Previous organ transplantation.
  • Treatment with any other antiviral or immunomodulatory agent administered within the previous 180 days.
  • History of interferon monotherapy or combination therapy with ribavirin.
  • Positive test for HBsAg.
  • Hypersensitivity to interferon, peginterferon, or ribavirin.
  • Pregnancy or lactation, including patients’ partners.
  • Inability to use contraception.


InterventionsParticipants were randomly assigned to two groups.

  • Group 1: peginterferon alpha-2b 1.5 µg/kg plus ribavirin for 48 weeks (n = 28).
  • Group 2: interferon alpha-2b 6 MU intramuscularly, daily with ribavirin for the initial two weeks, followed thrice weekly for 46 weeks (n = 20).


For both treatment groups, ribavirin at the total dose of 600 mg to 1000 mg was administered for 48 weeks; the dose was adjusted according to body weight (600 mg for weight 60 kg or less, 800 mg for weight 60 kg to 80 kg, and 1000 mg for weight 80 kg to 100 kg).

Both non-pegylated peginterferon and ribavirin were concurrently initiated.

Treatment was provided for 48 weeks, with a subsequent 24-weeks follow-up period.


OutcomesPrimary outcome was viral kinetics.

Other outcomes reported include biochemical and virological responses.

Limit for hepatitis C virus RNA detection was 50 IU/mL.


NotesAdditional data were obtained through personal communication with the study author.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: Randomisation was achieved through computer-generated random numbers.

Allocation concealment (selection bias)Low riskComment: Randomisation of eligible participants to treatment was carried out by an independent randomisation centre.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: It is not mentioned whether outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComments: Incomplete outcome data were addressed adequately.

Selective reporting (reporting bias)Unclear riskComment: It is unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

Wakil 2006

MethodsStudy design: randomised trial.

ITT analysis: not mentioned.


ParticipantsCounty: Egypt.

Total number (sample size): 50.

Age, years: 38.24 ± 8.56.

Sex (male): not stated.

Genotype: four.

Previous HCV treatment: naive.

Inclusion criteria: treatment-naive chronic hepatitis C patients.

Exclusion criteria: not mentioned.


InterventionsGroup 1 (n = 18).

  • Drug: peginterferon alpha-2b.
  • Dosage: 1.5 µg/kg weekly.


Group 2 (n = 17).

  • Drug: IFN alpha-2b.
  • Dosage: 3 MU thrice weekly.


Group 3 (n = 15).

  • Drug: IFN alpha-2b.
  • Dosage: 5 MU thrice weekly.


All three groups were given weight-based ribavirin (1000 mg to 1200 mg).


OutcomesSustanied virological response.

Adverse events.


NotesPublished abstract only; no data about inclusion and exclusion criteria were provided.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComments: Method of sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComments: Method of allocation concealment is not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComments: It is not mentioned whether outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Information was insufficient to permit assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

Selective reporting (reporting bias)Unclear riskComment: It is unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported.

Other biasLow riskComment: The study seems to be free of other sources of bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

ACTG 2005Randomised clinical trial in HIV co-infected participants.

Ali 2010Not a randomised clinical trial.

APRICOT 2004Randomised clinical trial in HIV co-infected participants.

Asahina 2004Not reported whether the trial was randomised.
First study author contacted for additional information, but no reply obtained.

Gromova 2004Pilot study.

Laguno 2004Randomised clinical trial in HIV co-infected participants.

RIBAVIC 2004Randomised clinical trial in HIV co-infected participants.

 
Comparison 1. Peginterferon plus ribavirin versus non-pegylated interferon plus ribavirin

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

 1 Liver-related morbidity plus all-cause mortality51789Odds Ratio (M-H, Fixed, 95% CI)1.14 [0.38, 3.42]

 2 Adverse events leading to treatment discontinuation174868Risk Ratio (M-H, Random, 95% CI)0.86 [0.66, 1.12]

 3 Sustained virological response276104Risk Ratio (M-H, Random, 95% CI)1.39 [1.25, 1.56]

 
Comparison 2. Adverse events

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

 1 Haematological effects13Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Anaemia
133854Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.98, 1.27]

    1.2 Neutropenia
133855Risk Ratio (M-H, Fixed, 95% CI)2.15 [1.76, 2.61]

    1.3 Thrombocytopenia
102195Risk Ratio (M-H, Fixed, 95% CI)2.63 [1.68, 4.11]

 2 Fatigue and flu-like symptoms13Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 General fatigue
113608Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.96, 1.07]

    2.2 Headache
63146Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.93, 1.07]

    2.3 Rigours
42641Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.88, 1.08]

    2.4 Arthralgia
42934Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.05, 1.35]

    2.5 Myalgia
53087Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.90, 1.06]

    2.6 Pyrexia
63180Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.99, 1.18]

    2.7 Weight loss
62524Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.98, 1.39]

    2.8 Asthenia
32126Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.88, 1.25]

 3 Psychiatric symptoms12Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Depression
123743Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.82, 1.02]

    3.2 Insomnia
53087Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.91, 1.10]

    3.3 Irritability
32491Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.86, 1.09]

 4 Dermatological symptoms8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Alopecia
53087Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.88, 1.09]

    4.2 Pruritus
53027Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.25]

    4.3 Skin rash
52740Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.25]

    4.4 Injection site reaction
41817Risk Ratio (M-H, Fixed, 95% CI)1.71 [1.50, 1.93]

 5 Thyroid malfunction81222Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.73, 2.00]

 6 Gastrointestinal symptoms6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Decreased appetite
63136Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.93, 1.19]

    6.2 Nausea
43023Risk Ratio (M-H, Fixed, 95% CI)1.13 [1.01, 1.26]

    6.3 Diarrhoea
32126Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.93, 1.41]

 
Comparison 3. Subgroup and sensitivity analysis

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

 1 Sustanied virological response according to trial methodological quality27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Lower risk of bias trials
144285Risk Ratio (M-H, Random, 95% CI)1.33 [1.17, 1.51]

    1.2 High risk of bias trials
131819Risk Ratio (M-H, Random, 95% CI)1.55 [1.23, 1.95]

 2 Sustanied virological response according to baseline treatment history26Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Naive participants
225223Risk Ratio (M-H, Random, 95% CI)1.42 [1.25, 1.62]

    2.2 Non-responders and relapsers
4389Risk Ratio (M-H, Random, 95% CI)1.24 [0.96, 1.61]

    2.3 Unknown
149Risk Ratio (M-H, Random, 95% CI)1.41 [0.67, 2.97]

 3 Sustained virological response according to genotype27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Genotype one
163548Risk Ratio (M-H, Random, 95% CI)1.47 [1.27, 1.70]

    3.2 Genotypes two and three
91659Risk Ratio (M-H, Random, 95% CI)1.10 [1.03, 1.19]

    3.3 Genotype four
9721Risk Ratio (M-H, Random, 95% CI)1.76 [1.30, 2.39]

 4 Sustained virological response according to baseline viral load27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 High viral load
51777Risk Ratio (M-H, Random, 95% CI)1.33 [1.01, 1.75]

    4.2 Low viral Load
51027Risk Ratio (M-H, Random, 95% CI)1.29 [1.05, 1.58]

    4.3 Predominantly high viral load (more than 65% of total participants)
196Risk Ratio (M-H, Random, 95% CI)1.5 [0.87, 2.59]

    4.4 Predominantly low viral load (more than 65% of total participants)
6920Risk Ratio (M-H, Random, 95% CI)1.58 [1.22, 2.06]

    4.5 Similar proportions of high and low baseline viral loads
4607Risk Ratio (M-H, Random, 95% CI)1.31 [1.01, 1.70]

    4.6 Unknown baseline viral load
111690Risk Ratio (M-H, Random, 95% CI)1.38 [1.11, 1.71]

 5 Sustained virological response according to the type of peginterferon27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Peginterferon alpha-2a
92361Risk Ratio (M-H, Random, 95% CI)1.85 [1.46, 2.35]

    5.2 Peginterferon alpha-2b
183534Risk Ratio (M-H, Random, 95% CI)1.14 [1.06, 1.22]

 6 Sustained virological response according to the type of peginterferon and the type of interferon27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Peginterferon alpha-2a versus interferon alpha-2a
81464Risk Ratio (M-H, Random, 95% CI)1.98 [1.63, 2.40]

    6.2 Peginterferon alpha-2a versus interferon alpha-2b
1897Risk Ratio (M-H, Random, 95% CI)1.27 [1.11, 1.45]

    6.3 Peginterferon alpha-2b versus interferon alpha-2b
132799Risk Ratio (M-H, Random, 95% CI)1.15 [1.06, 1.25]

    6.4 Peginterferon alpha-2b versus consensus interferon
4671Risk Ratio (M-H, Random, 95% CI)1.07 [0.92, 1.23]

    6.5 Peginterferon alpha-2b versus leucocyte interferon
164Risk Ratio (M-H, Random, 95% CI)1.75 [1.05, 2.92]

 7 Sustained virological response in trials with or without amantadine27Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Trial without amantadine
245500Risk Ratio (M-H, Random, 95% CI)1.37 [1.22, 1.53]

    7.2 Trial with amantadine
3604Risk Ratio (M-H, Random, 95% CI)1.68 [1.26, 2.23]

 
Summary of findings for the main comparison. Peginterferon plus ribavirin versus non-pegylated interferon plus ribavirin for chronic hepatitis C

Peginterferon plus ribavirin versus non-pegylated interferon plus ribavirin for chronic hepatitis C

Patient or population: patients with chronic hepatitis C.
Settings: mainly outpatients.
Intervention: peginterferon.
Comparison: non-pegylated.

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

Assumed riskCorresponding risk

Non-pegylatedPeginterferon

Liver-related morbidity plus all-cause mortalityFive per 1000Six per 1000
(two to 17)
OR 1.14
(0.38 to 3.42)
1789
(five studies)
⊕⊕⊝⊝
low1

Adverse events leading to treatment discontinuation207 per 1000178 per 1000
(141 to 226)
RR 0.86
(0.68 to 1.09)
4571
(15 studies)
⊕⊕⊝⊝
low2,3

Sustained virological response386 per 1000537 per 1000
(482 to 602)
RR 1.39
(1.25 to 1.56)
6104
(27 studies)
⊕⊝⊝⊝4,5
very low
All trials had high risks of bias.

Only an unvalidated surrogate outcome.

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio.

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

 1Low due to imprecision and indirectness wide confidence interval. The meta-analysis included only nine events.
2Low due to imprecision and indirectness.The proportions of observed adverse events differ substantially across trials, and the direction of effect is heterogeneous. However, because the event rate is still relatively low across trials, all of the included trials may be subject to considerable random error, thus explaining the apparent heterogeneity in the direction of estimates.
3The observed treatment effects differ in both direction and magnitude, but most confidence intervals have considerable overlap. Low due to indirectness.
4Sustained virological response does not seem to be a valid surrogate marker for assessing hepatitis C virus treatment efficacy of interferon treatment. Very low due to high risk of bias in all trials and imprecision and indirectness due to surrogate
5Only randomised clinical trials were included.