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Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

  1. Goran Hauser1,2,*,
  2. Tahany Awad2,
  3. Kristian Thorlund3,
  4. Davor Štimac1,
  5. Mahasen Mabrouk4,
  6. Christian Gluud2

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 28 FEB 2014

Assessed as up-to-date: 30 MAY 2012

DOI: 10.1002/14651858.CD005642.pub3


How to Cite

Hauser G, Awad T, Thorlund K, Štimac D, Mabrouk M, Gluud C. Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD005642. DOI: 10.1002/14651858.CD005642.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

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

  4. 4

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

*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]
Ascione 2010

MethodsStudy design: randomised clinical trial.

Inclusion criteria: Detectable serum HCV RNA level, have an ALT level > 1.5 times the upper limit of normal for > 6 months, have a liver biopsy performed within 12 months of starting treatment graded according to Scheuer’s criteria (unless not indicated or refused), have a negative pregnancy test result, use contraceptive methods during therapy and for 6 months after the end of treatment, and have abstained from alcohol use for at least 6 months.

Exclusion criteria: patients were excluded if they had a haemoglobin level < 120 g/L; had a neutrophil count < 1.5 x 109/L or a platelet count < 70 x 109/L; had an abnormal serum creatinine level; were hepatitis B surface antigen positive or human immunodeficiency virus positive; had any other cause of liver disease; had a history of liver decompensation; had clinically relevant depression or any other psychiatric disease; had cancer; had severe cardiac, pulmonary, or renal disease; or had uncontrolled diabetes or severe hypertension with vascular complications, including retinopathy.

ITT analysis: yes, the trial used the worst-case scenario for intention-to-treat analysis 'Patients who withdrew from the study for any reason were considered to be nonresponders in the efficacy assessment'.

Sample size calculation: yes (160 participants for each group).


ParticipantsStudy location: Italy.

Total number (sample size): 320.

Mean (SD) age: 50.2 (10.9).

Sex (male sex (n (%)): n = 175 (54.7%).

Comorbidity: liver cirrhosis.

Genotype: 1 to 4.

Previous HCV treatment: naive patients.

Viral load (median HCV RNA (IU/mL x 103)): 600 (0.20 to 10,800).

Histology at biopsy: only for cirrhotic patients (230 patients). Fibrosis grade was 2.13 (± 1.03).


InterventionsGroup A: n = 160.

Drug: peginterferon alpha-2a: 180 μg/week.

Drug: ribavirin 1000 mg/d (< 75 kg) or 1200 mg/d (75 kg).

Group B: n = 160.

Drug: peginterferon alpha-2b (PEG-Intron): 1.5 μg/kg/week.

Drug: ribavirin 1000 mg/d (< 75 kg) or 1200 mg/d (75 kg).

Patients affected by genotypes 1/4 received 48 weeks of treatment, while those affected by genotypes 2/3 were treated for 24 weeks.


OutcomesSustained virological response.

Adverse events.


NotesPublished data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: randomisation was computer generated.

Allocation concealment (selection bias)Low riskQuote: "Patients who accepted the treatment were assigned to one of the 2 treatment arms on the basis of a computer-generated randomisation list that was not available to the treating physician. The physician received the communication on the allocation of each patient from an independent researcher who did not know the patient or his or her characteristics".

Blinding (performance bias and detection bias)
svr
Unclear riskQuote: "The phase of the analysis of data, the person who did it received the results under code: treatment A and treatment B without any information on the type of drug used".

Comment: open label study.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The trial reports the reasons for all patients (in according to the treatment groups) who interrupt the therapy or needed dose modification.

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.

Berak 2005

MethodsStudy design: randomised trial.

Inclusion criteria: patients with chronic hepatitis C.

Exclusion criteria: not mentioned.

ITT: yes, however it is not clear which intention-to-treat analysis scenario was used.

Sample size calculation: not mentioned.


ParticipantsStudy location: Poland.

Total number (sample size): 237; at follow-up 208.

Age: not mentioned.

Sex (male sex (n (%)): not mentioned.

Co-morbidity: not mentioned.

Genotype: all other except for 2 and 3.

Previous HCV treatment: not mentioned.

Viral load (mean HCV RNA (log10 IU/ml)): not mentioned.

Histology at biopsy: analysed according to Knodell´s and Scheuer´s score.


InterventionsGroup A: n = 116.

Drug: peginterferon alpha-2a (Pegasys, 40 KD).

Drug: ribavirin.

Group B: n = 121.

Drug: peginterferon alpha-2b (PegIntron, 12KD).

Drug: ribavirin.


OutcomesAdverse events and early virological response.


NotesOnly the abstract was available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised.....".

Comment: The method of sequence generation is not mentioned.

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

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding of the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were six patients lost to follow-up, however, intention-to-treat analysis was adopted. It is not clear which intention-to-treat analysis scenario was used.Sample size is 237, finally analysed 208 and authors explained only 6 dropouts.

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

Other biasLow riskComment: Authors have indicated they have no relationships to disclose.

Bruno 2004

MethodsStudy design: randomised trial.

Inclusion criteria: interferon-naive, HCV RNA levels greater or equal to 2000 copies per mL of serum by PCR assay, serum alanine aminotransferase (ALT) above the upper limit of normal within six months before entry into the trial, and a liver biopsy result consistent with the diagnosis of CHC performed within six months of trial entry.

Exclusion criteria: absolute neutrophil count of < 1500 cells/mm3, a platelet count of < 90 000/mm3, a haemoglobin concentration of < 12 g/dL (women) or < 13 g/dL (men), or a serum creatinine level of > 1.5 times the upper limit of normal. Coinfection with the human immunodeficiency virus, decompensated liver disease, poorly controlled psychiatric disease, alcohol or drug dependence within one year before entry into the trial, and substantial coexisting medical conditions were additional exclusion criteria.

Duration: 12 weeks.

ITT analysis: yes.

Sample size calculation: not mentioned.


ParticipantsStudy location: Italy.

Total number (sample size): (n = 22).

Age: peginterferon alpha-2a: 47 ± 8 years, peginterferon alpha-2b: 40 ± 10 years.

Sex (male sex (n (%))): peginterferon alpha-2a: 70%, peginterferon alpha-2b: 75%.

Comorbidity: not mentioned.

Genotype: 13 patients with HCV genotype 1; 9 patients with genotype 2/3; peginterferon alpha-2a: genotype 1 was 70% (7/10), peginterferon alpha-2b: genotype 1 was 50% (6/12).

Previous HCV treatment: naive patients.

Viral load (mean HCV RNA (log10 IU/ml)): peginterferon alpha-2a: 5.75 ± 0.38, peginterferon alpha-2b: 5.65 ± 0.50.

Histology at biopsy: cirrhosis; peginterferon alpha-2a: 20%, peginterferon alpha-2b: 16%.


InterventionsGroup A: n = 10.

Drug: peginterferon alpha-2a: 180 μg/week.

Drug: ribavirin 1000 mg/d (≲ 75 kg) or 1200 mg/d (≥ 75 kg).

Group B: n = 12.

Drug: peginterferon alpha-2b (PEG-Intron): 1.0 μg/kg/week.

Drug: ribavirin 1000 mg/d (≲ 75 kg) or 1200 mg/d (≥ 75 kg).


OutcomesPharmacokinetics and viral kinetics.


NotesPublished and unpublished data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomisation was done by a computer".

Allocation concealment (selection bias)Unclear riskQuote: "the investigators allocated the intervention based on patients agreement to take part in the study".

Blinding (performance bias and detection bias)
svr
Unclear riskComment: It is not clear if the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: There was not patients lost to follow-up.

Selective reporting (reporting bias)Unclear riskComment: The protocol is not available and the study does not report on SVR .

Other biasUnclear riskComment: The trial was not stopped early for benefit, but there might be a conflict of interest bias. Hoffman-LaRoche provided the drug peginterferon alpha-2a.

Di Bisceglie 2007

MethodsStudy design: randomised, active control, parallel assignment, pharmacodynamics trial.

Inclusion criteria: adult patients at least 18 years of age, chronic hepatitis C infection, genotype 1, use of two forms of contraception during the trial in both men and women.

Exclusion criteria: previous systemic therapy with anti-viral, anti-neoplastic, or immunomodulatory agents; medical condition associated with chronic liver disease (eg, haemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposure); decompensated liver disease; women who are pregnant or breastfeeding.

ITT: yes. However it is not clear which intention-to-treat analysis scenario was used.

Sample size calculation: yes (sample size of 172 for each group).


ParticipantsStudy location: Italy.

Total number: pre-randomisation: 385, post-randomisation: 380.

Age: peginterferon alpha-2a: 48.4 ± 0.56 years (age > 40 years 157 (83.1%)), peginterferon alpha-2b: 40 ± 10 years (age > 40 years 70 (89.0%)).

Sex (male sex (n (%))): peginterferon alpha-2a: 121 (64%), peginterferon alpha-2b: 136 (71%).

Comorbidity: cirrhotic: peginterferon alpha-2a: 28(14.8%), peginterferon alpha-2b: 29 (15.2%).

Genotype: 1.

Previous HCV treatment: naive patients.

Viral load (log10 IU/ml, mean ± SE): peginterferon alpha-2a: 6.5 ± 0.03; peginterferon alpha-2b: 6.5 ± 0.03.

Histology at biopsy: not mentioned.


InterventionsExperimental: n = 189.

Drug: peginterferon alpha-2a 180 µg weekly.

Drug: ribavirin 1000 mg/d to 1200 mg/day.

Active comparator: n = 191.

Drug: peginterferon alpha 2b1.5 µg/kg weekly.

Drug: ribarivin1000 mg/d to 1200 mg/day.


OutcomesAdverse events, EVR, and RVR.


NotesPublished and unpublished data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The study randomisation was done by a central randomisation centre (a professional third party). The computer-generated schedule of randomisation was only known to the randomisation centre." "The randomisation schedule was generated in block size of two in 1:1 ratio balanced for the whole study regardless of centre. A sequential number in the chronological order of randomisation for the entire study was recorded. A separate four-digit patient number, which identified the centre and was sequential within each centre, was also assigned at randomisation. This patient number was used to identify the patient throughout the trial".

Allocation concealment (selection bias)Low riskQuote: "The study randomisation was done by a central randomisation centre (a professional third party). The computer generated schedule of randomisation was only known to the randomisation centre. The site had no control over the treatment assignment. The site, after verifying the eligibility of the patient, would call the randomisation centre to provide the patient information and the centre would fax the treatment assignment to the site."

Blinding (performance bias and detection bias)
svr
Unclear riskComment: It is not clear if the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Five patients did not receive any medication and were not included in the ITT analysis (n = 380). There was 45 patients lost to follow-up but the trial adhered to the intention-to-treat analysis. However it is not clear which intention-to-treat analysis scenario was used.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported. There were no differences between the protocol and the trial report, and all the outcomes were defined prior to the beginning of the trial. The study was located on clinicaltrials.gov Identifier: NCT 00087607.

Other biasUnclear riskComment: There might be conflict of interest bias. The trial was supported by Roche Laboratories.

Kamal 2011

MethodsProspective, randomised, open label, parallel-group clinical trial.

Inclusion criteria: chronic hepatitis C patients IFN naive with proven chronic HCV-4; elevated serum ALTat least two times above the upper limit of normal (ULN: 40 U/l) during the preceding 6 months, detectable anti-HCV, detectable HCV RNA by PCR.

Exclusion criteria: previously an IFN-a-based regimen, evidence of other liver diseases, including hepatitis A, hepatitis B, autoimmune hepatitis, alcoholic liver disease, drug-induced hepatitis and decompensated liver disease, coinfection with schistosomiasis or HIV, leucocyte count < 3000/mm3, neutropenia (< 1500 cells/mm3), haemoglobin level < 12 g/dl for women and <13 g/dl for men, thrombocytopenia (< 90 000 cells/mm3), creatinine concentration 1.5 times above ULN, organ transplantation, malignant conditions, severe cardiac or pulmonary disease, unstable thyroid dysfunction, severe depression or psychiatric disorder, active substance abuse, current pregnancy or breast feeding, body mass index (BMI) > 30 kg/m2 or known sensitivity to the drugs tested or therapy with immunomodulatory agents within the last 6 months.

Sample size calculation: yes.

ITT analysis: yes.


ParticipantsStudy location: Egypt.

Total number (sample size): 226 screened, 9 have been excluded 217 eligible for randomisation.

Age: the mean age of the entire cohort was 41.4 years for females and 41.0 for males.

Sex (male sex (n (%)): n = 107 (49.31%).

Comorbidity: no.

Genotype: 4.

Previous HCV treatment: naive patients.

Viral load (mean HCV RNA (log10 IU/ml)): 765.61 kIU (Group A) and 762.065 kIU (Group B).

Histology at biopsy:

Grading scores 5.0 for both groups.

Fibrosis score 1.0 for both groups.


InterventionsGroup A 109 patients:

Drug: peginterferon alpha-2a injections: 180 μg once per week plus ribavirin.Dose ranged between 1000 and 1200 mg/day according to body weight. ≥75 kg, 1200 mg/day and < 75 kg 1000 mg/day respectively.

Group B 108 patients:

Drug: peginterferon alpha-2b:1.5 mg/kg one per week plus ribavirin.Dose ranged between 1000 and 1200 mg/day according to body weight (≥75 kg, 1200 mg/day and <75 kg 1000 mg/day respectively.


OutcomesPrimary outcome measures:

SVR, defined as undetectable serum hepatitis C virus RNA (< 5 IU/ml).

[Time frame: 24 weeks after discontinuation of treatment] [Designated as safety issue: yes]

Secondary outcome measures:

  • Normalisation of ALT at the end of follow-up period.Histological response defined as an improvement of greater than 2 points from pretreatment baseline necro-inflammatory scores.
  • improvement in the HRQOL scores after completion of therapy.


NotesContacted author due to serious adverse events and all cause mortality.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Eligible patients were randomised in blocks of four..."

Allocation concealment (selection bias)Low riskQuote: "...the randomisation process, which was concealed from both the investigators and patients".

Blinding (performance bias and detection bias)
svr
Low riskQuote: An independent coordinator (A. A.) blinded to the patients’ demographics or clinical characteristics used computer-generated lists for the randomisation process, which was concealed from both the investigators and patients.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote. "The primary efficacy analysis was an intention to-treat analysis (ITT) that included all participants allocated to a given regimen whether they completed it or not".

Selective reporting (reporting bias)Low riskAll clinically relevant and reasonably expected outcomes were reported. Protocol has been registered www.clinicaltrials.gov (NCT00502099).

Other biasUnclear riskAuthors provided no conflict of interest statement (positive or negative), no data about study funding.

Kolakowska 2008

MethodsRandomised open label clinical trial.

Inclusion criteria: chronic hepatitis C patients.

Exclusion criteria: not mentioned.

Sample size calculation: not mentioned.

ITT analysis: not clear.


ParticipantsStudy location: Poland.

Total number: 67.

Group A: peginterferon alfa-2a: 33.

Group B: peginterferon alfa-2b: 34.

Genotype: genotype 3.

Previous HCV treatment: naive.


InterventionsGroup A: n = 33.

Drug: PEG 2a plus weight-based ribavirin.

Group B: n = 34.

Drug: PEG 2b plus weight-based ribavirin.


OutcomesSustanied virological response.


NotesOnly the abstract was available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomised study.....".

Comment: The method of sequence generation is not mentioned.

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

Blinding (performance bias and detection bias)
svr
Unclear riskComment: It is not clear if the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: There seems to be no patients lost to follow-up, but it is not clear if the trial adhered to the intention-to-treat analysis.

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

Other biasUnclear riskComment: The study was not stopped for early stopping, but it is not clear if the study is free of other sources of bias.

Laguno 2009

MethodsStudy design: randomised, multi-centre clinical trial.

Inclusion criteria: untreated chronic hepatitis C, HIV (CD4+ cell count above 250 cells/mm3 and viral load lower than 50.000 copies/mL).

Exclusion criteria: known contraindication for PEG INF or RBV; decompensated liver disease; pregnancy.

ITT: yes, however it is not clear which intention-to-treat analysis scenario was used.

Sample size calculation: yes (total sample size of 182).


ParticipantsStudy location: Spain.

Total number: 182.

Age: peginterferon alpha-2a: 40.6 years, peginterferon alpha-2b: 40.7.

Sex (male sex (n (%))): peginterferon alpha-2a: 64 (66.7%), peginterferon alpha-2b: 68 (79.1%).

Comorbidity: HIV.
Genotype: 1 to 4.

Previous HCV treatment: naive patients.

Histological findings: 68% had fibrosis index ≥ 2.

Viral load: 600,000 IU in 59% of patients and ≤ 400,000 in 24% of patients.


InterventionsGroup A: n = 96.

Drug: peginterferon alpha-2a 180 μg.

Drug: ribavirin 1000 mg/d to 1200 mg/day.

Group B: n = 86.

Drug: peginterferon alpha-2b 80 to 150 μg.

Drug: ribavirin 1000 mg/d to1200 mg/day.


OutcomesSustained virological response.

Adverse events.


NotesContacted author due to serious adverse events and all-cause mortality. Answer: no patients died.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned to one of the two study treatments in equal proportions by means of a computer-generated table of random numbers".

Allocation concealment (selection bias)Low riskComment: Allocation was performed centrally.

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 34 patients were lost to follow-up, but intention-to-treat analysis was adopted.

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.

Mach 2011

MethodsStudy design: Randomised, prospective, open-label study, single centre in Poland.

Inclusion criteria: antiHCV and HCV-RNA in serum and elevated alanine aminotransferase (ALT) levels at least 6 months before the inclusion, chronic hepatitis confirmed by histological examination, body mass index (BMI) below 30 kg/m2.

Exclusion criteria: decompensated liver cirrhosis, autoimmune liver disease, alcohol abuse, liver cancer, hepatitis B virus or HIV coinfection, any severe chronic disease, diabetes, dyslipidaemia, metabolic syndrome, haemochromatosis, and immunosuppressive therapy.

ITT: No.

Sample size calculation: No.


ParticipantsStudy location: Poland.

Total number: 260.

Age: peginterferon alpha-2a: 45.2 ± 10.5 years, peginterferon alpha-2b: 44.2 ± 13.6.

Sex (male sex (n (%))): peginterferon alpha-2a: 80 (50.8%), peginterferon alpha-2b: 73 (59.9%).

Comorbidity: not mentioned.
Genotype: 1a.

Previous HCV treatment: not mentioned.

Histological findings Batts-Ludwig score: F0-2 64 (78.1%), F 3-4 18 (21.9%).

Viral load x106 IU/ml: peginterferon alpha-2a: 4.01 ± 2.17, peginterferon alpha-2b: 3.45 ± 0.92.


InterventionsGroup A: peginterferon alfa-2a 180 μg subcutaneously once a week and oral ribavirin 1.0–1.2 g daily.

Group B: peginterferon alfa-2b 1.5 mg/kg of body weight once a week and oral ribavirin 1–1.2 g daily.


OutcomesEarly virological response; end of treatment response; sustained virological response.


NotesCorrespondace with the contact author: naive patients were treated and they used sealed envelopes in randomisation process.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "They were randomly assigned to 1 of the 2 treatment groups".

Comment: see notes.

Allocation concealment (selection bias)High riskComment: Open label study. Authors did not mention allocation process.

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: No patients were lost to follow-up.

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

Other biasLow riskQuote: "The study was supported by the Polish National Health Fund and conducted according to the relevant recommendations."

Marcellin 2011

MethodsStudy design: randomised clinical trial.

Inclusion criteria: treatment-naive patients aged 18 to 65 years with chronic HCV genotype 1 infection. Additional inclusion criteria were serum HCV RNA level 10,000 IU/mL, absolute neutrophil count 1500 mm3, and platelet count 100,000 mm3. Liver fibrosis status had to have been documented within 18 months (no or minimal fibrosis, portal fibrosis, bridging fibrosis, or cirrhosis) with a liver biopsy or transient elastography.

Exclusion criteria: co-infection with human immunodeficiency virus or hepatitis B, any other cause of liver disease, poorly controlled diabetes mellitus (glycated haemoglobin value >8.5%), morbid obesity (weight >125 kg), severe depression or a severe psychiatric disorder, or active substance abuse.

Sample size calculation: yes.

ITT: yes.


ParticipantsStudy location: Europe - Austria, Belgium, France, Germany, Italy, Spain, The Netherlands.

Total number of patients: 161.

Age: Group A 47.5, Group B 47.5 Group C 40.0, Group D 49.0.

Sex male n (%): Group A 20 (50.0%), Group B 20 (47.6%), Group C 21 (52.5%), Group D 19 (48.7%).

Comorbidity: N/A.

Previous HCV treatment: naive.

Genotype: 1.

Histological findings n (%):

Cirrhosis: Group A 1 (2.5), Group B 1 (2.4), Group C 0, Group D 2 (5.1).

Bridging fibrosis: Group A 8 (20.0%), Group B 10 (23.8%), Group C 7 (17.5%), Group D 12 (30.8%).

Portal fibrosis: Group A 16 (40.0%), Group B 16 (38.1%), Group C 11 (27.5%), Group D 13 (33.3%).

No or minimal fibrosis: Group A 15 (37.5%), Group B 15 (35.7%), Group C 22 (55.0%), Group D 11 (28.2%).

Virological load:

< 800.000: Group A 10 (25.0%), Group B 8 (19.0%), Group C 7 (17.5%), Group D 5 (12.8%).

> 800.000: Group A 30 (75.0%), Group B 34 (81.0%), Group C 33 (82.5%), Group D 34 (87.2%).


InterventionsGroup A telaprevir 750 mg q8h plus peginterferon alfa-2a/ribavirin (q8h alfa-2a).

Group B telaprevir 750 mg q8h plus peginterferon alfa-2b/ribavirin (q8h alfa-2b).

Group C telaprevir 1125 mg q12h plus peginterferon alfa-2a/ribavirin (q12h alfa-2a).

Group D telaprevir 1125 mg q12h plus peginterferon alfa-2b/ribavirin (q12h alfa-2b).

Peginterferon alfa-2a was administered at 180 μg/wk with ribavirin at 1000 to 1200 mg/day; peginterferon alfa-2b was administered at 1.5 μg/kg/wk1 with ribavirin at 800 to 1200 mg/day.


OutcomesSustained virological response.

Adverse events.

Pharmacokinetics.


NotesIn the published article safety data has been presented only for the whole cohort (161 patients). It is not possible extract data regarding different treatment groups. Corresponding author has been contacted for further information regarding adverse events but no answer obtained.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: "The randomisation lists were generated by means of permuted blocks before the start of the trial, under the supervision of the sponsor".

Allocation concealment (selection bias)Low riskComment: Central allocation before the star of the trial under supervision of the sponsor.

Blinding (performance bias and detection bias)
svr
High riskComment: "Because this was an open label trial, blinding procedures were not applicable".

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 79.5% of patients completed the treatment, but intention-to-treat analysis, worst-case scenario, was adopted and all patients have been included in final analysis.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported. Study protocol registered in ClinicalTrials.gov (NCT00528528).

Other biasHigh riskQuote: "This clinical trial was funded by Janssen Pharmaceuticals, and by Vertex Pharmaceuticals Inc. The study sponsor was involved in the trial design and conduct, data collection, and data analysis. Several authors are employees of the sponsor".

McHutchison 2009

MethodsStudy design: randomised clinical trial.

Inclusion criteria: HCV genotype 1 infection and a detectable plasma HCV RNA level, and had not been previously treated for hepatitis C infection. The patients had an absolute neutrophil count of 1500/mm3, a platelet count of 80,000 or more/mm3, and haemoglobin level of 12 g (for women) or 13 g (for men) or more per dL.

Exclusion criteria: co-infection with human immunodeficiency virus or hepatitis B, any other cause of liver disease, poorly controlled diabetes mellitus (glycated haemoglobin value >8.5%), morbid obesity (weight > 125 kg), severe depression or a severe psychiatric disorder, or active substance abuse.

Sample size calculation: yes.

ITT: yes. However it is not clear which intention-to-treat analysis scenario was used.


ParticipantsStudy Location: USA.

Total number of patients: 3070.

Age: Group A 47.6 ± 8.2, Group B 47.5 ± 7.8, Group C 47.5 ± 8.1.

Sex male n (%): Group A 613 (59.2%) Group B 613 (60.2%), Group C 607 (59.7%).

Comorbidity: steatosis.

Previous HCV treatment: naive.

Genotype: 1.

Histological findings: METAVIR Group A 102 (10.6%), Group B 111 (10.9%), Group C 107 (10.5%).

Virological load: > 600.000: Group A 852 (82.3%), Group B 836 (82.0%), Group C 830 (81.7%).


InterventionsGroup A: n = 1035.

Drug: peginterferon alpha-2a: 180 μg/week.

Drug: ribavirin 1000 mg/d to 1200 mg/d.

Group B: n = 1016.

Drug: peginterferon alpha-2b (PEG-Intron): 1.5 μg/kg/week.

Drug: ribavirin 1000 mg/d to 1200 mg/d.

Group C: n = 1019.

Drug: peginterferon alpha-2b (PEG-Intron): 1.0 μg/kg/week.

Drug: ribavirin 1000 mg/d to 1200 mg/d.


OutcomesFailure of sustained virological response.

Adverse events.

Failure of end of treatment response.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: The randomisation was done centrally so we assumed it was conducted with low risk of bias.

Allocation concealment (selection bias)Low riskComment: Centralised telephone-based IVRS was used.

Blinding (performance bias and detection bias)
svr
Unclear riskQuote: "The study was double-blinded with regard to the dose of peginterferon alfa-2b".

Comment: It is not mentioned if the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: There were 653 patients lost to follow-up, but the trial adopted intention-to-treat analysis.

Selective reporting (reporting bias)Low riskComment: All clinically relevant and reasonably expected outcomes were reported.The study protocol was published in ClinicalTrial.gov (NCT00081770)

Other biasUnclear riskQuote: "The principal investigators had unrestricted access to the data, wrote the manuscript, and vouch for the accuracy and integrity of the data and analyses".

Comment: The study was not stopped early for benefit, but there might be conflict of interest bias, as the trial is sponsored by Schering-Plough.

Miyase 2012

MethodsStudy design: prospective, randomised, open label, single centre.

Inclusion criteria: antiHCV and HCV-RNA in serum and elevated alanine aminotransferase (ALT) levels at least 6 months before the inclusion, chronic hepatitis confirmed by histological examination, body mass index (BMI) below 30 kg/m2.

Exclusion criteria: decompensated liver cirrhosis, autoimmune liver disease, alcohol abuse, liver cancer, hepatitis B virus or HIV coinfection, any severe chronic disease, diabetes, dyslipidaemia, metabolic syndrome, haemochromatosis, and immunosuppressive therapy.

ITT: yes.

Sample size calculation: yes.


ParticipantsStudy location: Japan.

Total number: 206 randomised, but 201 were eligible to receive at least one dose of treatment.

Age: peginterferon alpha-2a: 59.2 ± 9.1 years, peginterferon alpha-2b: 58.9.2 ± 10.8.

Sex (male sex (n (%))): peginterferon alpha-2a: 39 (38.6%), peginterferon alpha-2b: 40 (40.0%).

Comorbidity: not mentioned.
Genotype: 1.

Previous HCV treatment: naive.

Histological findings METAVIR score: peginterferon alpha-2a fibrosis 81 (80.2%), peginterferon alpha-2b 83 (83.0%).

Viral load log IU/ml: peginterferon alpha-2a: 6.3 ± 0.6, peginterferon alpha-2b: 6.2 ± 0.7.


InterventionsGroup A: peginterferon alpha-2a at a dosage of 180 µg once weekly.

Group B: peginterferon alpha-2b once weekly at a dosage of 60 to 150 µg/kg of body.
Weight (35 to 45 kg, 60 µg; 46 to 60 kg, 80 µg; 61to 75 kg 100 µg; 76 to 90 kg, 120 µg; 91 to 120 kg, 150 µg).

The ribavirin dosage was determined by body weight in both regimens (600 mg/day in patients ≤ 60 kg; 800 mg/day in patients 60–80 kg; 1000 mg/day in patients > 80 kg.


OutcomesSustained virological response and adverse events.


NotesPublished and unpublished data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The patients who accepted the treatment were randomly assigned to 1 of 2 treatment arms"

Comment: authors did not explain randomisation method they used.

Allocation concealment (selection bias)Unclear riskComment: Authors did not explain stated allocation process.

Blinding (performance bias and detection bias)
svr
Low riskQuote: "The patients who accepted the treatment were randomly assigned to 1 of 2 treatment arms, to which the treating physician was blinded."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 43 patients were excluded, but intention-to-treat analysis, worst-case scenario, was adopted and all patients have been included in final analysis.

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

Other biasLow riskQuote: "The authors declare that they have no conflict of interest."

Rumi 2010

MethodsStudy design: randomised clinical trial.

Inclusion criteria: treatment-naive patients infected with chronic hepatitis C, serum HCV-RNA, higher than normal alanine aminotransferase (ALT) activity, and a diagnostic liver biopsy done in the previous 24 months.
Exclusion criteria: patients with persistently normal ALT; haemoglobin 12 g/dL for women and 13 g/dL for men; white blood cell count 2.5 x 103/mm3; neutrophil count 1.5 x 103/mm3; platelet count 75 x 103/mm3; serum creatinine level 1.5 times the upper limit of normal; any other liver disease; human immunodeficiency virus coinfection; autoimmune diseases; and general contraindications to the IFN and RBV.

Sample size calculation: yes (n = 210 for each group).

ITT: yes, the trial used the worst-case scenario for intention-to-treat analysis 'By intention-to-treat analysis, patients for whom HCVRNA levels had not been measured by the end of the follow-up period as well as those who discontinued treatment for any reason were categorized as nonresponders'.


ParticipantsStudy location: Italy.

Total number: eligible number was 431 after of initial assessment of 473 patients.

Previous HCV treatment: treatment naive.

Median age: peginterferon alpha 2a: 54 years versus peginterferon alpha 2b: 56 years.

Sex: peginterferon alpha 2a: 60% males versus peginterferon alpha 2b:55% males.

Body mass index: peginterferon alpha 2a: 25.5 kg/m2 versus peginterferon alpha 2b: 24.8 kg/m2.

Comorbidity: cirrhosis: peginterferon alpha 2a: 20% versus peginterferon alpha 2b:18%.

Genotype distribution 1 to 4: peginterferon alpha 2a: 51% versus peginterferon alpha 2b: 52%.

Viral load > 800,000 IU: peginterferon alpha 2a: 102 (48.1%) versus peginterferon alpha 2b: 103 (47.0%).

Histological findings: Ishak score S5,6 peginterferon alpha 2a: 43 (20.3%) versus peginterferon alpha 2b: 39 (17.8%).


InterventionsGroup A: n = 212.

Drug: peginterferon alpha-2a: 180 μg/week.

Drug: ribavirin 800 mg/d to 1200 mg/d.

Group B: n = 219.

Drug: peginterferon alpha-2b (PEG-Intron): 1.5 μg/kg/week.

Drug: ribavirin 800 mg/d to 1400 mg/d.

Ribavirin was weight-dosed in patients receiving peginterferon alpha-2a but patients with genotype 2 and 3 on peginterferon alpha-2a received a fixed dose of 800 mg/day ribavirin.


OutcomesSustained virological response.

Adverse events.


NotesContacted author due to serious adverse events and all-cause mortality.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: Patients were randomised using a computer-generated list.

Allocation concealment (selection bias)Low riskComment: The allocation was telephone-based (central).

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding of the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 119 patients were lost to follow-up but the trial adhered to the intention-to-treat analysis. The trial used the worst case scenario for intention-to-treat analysis 'By intention-to-treat analysis, patients for whom HCV RNA levels had not been measured by the end of the follow-up period as well as those who discontinued treatment for any reason were categorized as nonresponders'.

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

Other biasUnclear riskQuote: one author disclosed grants and research support from different pharma companies.

Scotto 2008

MethodsStudy design: randomised, single centre.

Inclusion criteria: HCV patients with positive HCV-RNA detectable in plasma by means of real time PCR in plasma (sensitivity < 100IU/mL), ALT levels greater than two-fold than upper limit of normal for at least three times during the six months before screening, liver biopsy performed within one year before trial enrolment with histological diagnosis of chronic hepatitis according to Knodell’s histological activity classification, no ongoing antiviral and or immunosuppressive treatment during the six months before the trial enrolment.

Exclusion criteria: presence of other causes of chronic liver disease (HBV infection, Wilson’s disease, alpha-1-antitrypsin deficiency, haemochromatosis, and autoimmune hepatitis), HIV positive patients, active drug abusers, patients with pre-existing and or social contraindications, patients with prior cirrhotic decompensation, pregnancy, and breastfeeding women.

ITT analysis: yes. However, it is not clear which intention-to-treat analysis scenario was used.

Sample size calculation: not mentioned.


ParticipantsStudy location: Italy.

Total number (sample size): 143.

Age: peginterferon alpha-2a: 45.86 years, peginterferon alpha-2b: 47.82 years.

Sex (male sex): peginterferon alpha-2a : 42, peginterferon alpha-2b: 40.

Comorbidity: not declared.

Genotype

  • genotype 1: Group A 45 (63%) Group B 47 (65%)
  • genotype 2: Group A 6 (8%) Group B 5 (7%)
  • genotype 3: Group A 8 (11%) Group B 9 (12%)
  • genotype 4: Group A 12 (16%) Group B 11 (15%).


Previous HCV treatment: non-responders to standard interferon.

Viral load IU/ml: Group A mean 2.4 ± 5 x 106, Group B mean 2.1 ± 3 x 106.

Histological assessment Knodell histological activity: Group A mean score 10 ± 4, Group B mean score 9 ± 1.


InterventionsGroup A: n = 71.

Drug: peginterferon alpha 2a.

Dosage: 180 μg weekly plus RBV 15 mg/kg daily.

Duration: 48 weeks.

Group B: n = 72.

Drug: peginterferon alpha 2b.

Dosage: 1.5 μg/kg weekly plus RBV 15mg/kg daily.

Duration: 48 weeks.


OutcomesSustained virological response.

Adverese events.


NotesPublished and unpublished data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were enrolled by a pre-established numerical randomisation method determined by the Clinic’s medical staff" "Computer generated random numbers".

Allocation concealment (selection bias)Low riskQuote: "While allocation concealment was sequentially numbered, and we used sealed opaque envelopes".

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding to the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 18 patients were lost to follow-up. The trial adopted intention-to-treat analysis. However it is not clear which intention-to-treat analysis scenario was used.

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

Other biasLow riskQuote: "We disclose any potential conflict of interest. The authors do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript."

Comment: The trial seems to be free of other sources of bias.

Silva 2006

MethodsStudy design: Double-blinded, randomised, multi centre, parallel-group trial.

Inclusion criteria: patients between the ages of 18 and 65 years who were infected with HCV genotype 1a or 1b, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels less-than-or-equals, slant 10 times the upper limit of normal (ULN), normal haemoglobin.

Exclusion criteria: liver disease due to causes other than chronic HCV infection, HIV positivity, haemoglobinopathy, haemophilia, severe pre-existing psychiatric disease, poorly controlled diabetes mellitus, significant Ischaemic heart disease, chronic obstructive lung disease, or active autoimmune disease.

ITT: no.

Sample size calculation: yes (18 for each group).


ParticipantsStudy location: Argentina, Mexico, and Germany.

Total number: 36.

Age: peginterferon alpha-2a plus ribavirin: 45.6 (± 11.8), peginterferon alpha-2b plus ribavirin: 48.3 (± 9.7).

Sex (male sex (n (%))): peginterferon alpha-2a plus ribavirin: 9, peginterferon alpha-2b plus ribavirin: 10.

Comorbidity: not mentioned.

Genotype: 1.

Previous HCV treatment: naive patients.

Viral load (mean HCV RNA (log 10 IU/ml)): peginterferon alpha-2a plus ribavirin 1.8 ( ± 0.1), peginterferon alpha-2b plus ribavirin 1.8 (± 0.2).

Histology at biopsy: not mentioned.


InterventionsGroup A: n = 18.

Drug: peginterferon alpha-2a 180 μg/week.

Group B: n = 18.

Drug: peginterferon alpha-2b 1.5 μg/kg/week.

After the fourth week of treatment, oral ribavirin therapy was added to the regimen at a dose of 13 mg/kg, in a divided twice a day dose.


OutcomesAdverse events.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The investigator requested randomisation by faxing the central randomisation service. Only the site pharmacist responsible for medication preparation received confirmation of both the assigned treatment and the subject number. The investigator received the subject number only".

Allocation concealment (selection bias)Low riskQuote: "The investigator requested randomisation by faxing the central randomisation service. Only the site pharmacist responsible for medication preparation received confirmation of both the assigned treatment and the subject number. The investigator received the subject number only".

Blinding (performance bias and detection bias)
svr
Low riskQuote: "Study drug was prepared by a site pharmacist and administered by a qualified, independent third party who was blinded to protocol assignments".

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: Six patients dropped out, and the trial did not adhere to the intention-to-treat analysis.

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

Other biasUnclear riskComment: There might be conflict of interest bias. Some of the authors are employees of Schering-Plough and own company stock.

Sinha 2004

MethodsStudy design: randomised trial.

Inclusion criteria: chronic hepatitis C patients.

Exclusion criteria: not mentioned.

Sample size: not mentioned.

Intention-to-treat analysis: yes, however it is not clear which intention-to-treat analysis scenario was used.


ParticipantsStudy location: USA.

Total number (sample size): 42.

Age: Group A: peginterferon alfa-2a: 24; Group B: peginterferon alfa-2b: 18.

Genotype: all: mixed, 13/42 (30%) had genotype other than genotype 1.

Previous HCV treatment: naive.


InterventionsGroup A: n =24.

Drug: PEG 2a plus weight-based ribavirin (1000 mg to 1200 mg).

Group B: n =18.

Drug: PEG 2b plus weight-based ribavirin (1000 mg to 1200 mg).


OutcomesSustanied virological response.

Adverse events.


NotesAbstract publication.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: The sequence generation was computer-generated.

Allocation concealment (selection bias)Low riskComment: Allocation concealment was performed by the mean of sealed envelopes.

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding of the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 1 patient was lost to follow-up but 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 biasLow riskComment: The trial was not stopped early for benefit, and the study seems to be free of other sources of bias.

Sporea 2006

MethodsStudy design: randomised open label trial.

Inclusion criteria: presence of chronic C viral hepatitis (proven by liver biopsy performed maximum 6 months before the treatment) and the quantification of the viral load (by PCR) before treatment and after 12 weeks of treatment.

Exclusion criteria: not mentioned.

ITT: not mentioned.

Sample size calculation: not mentioned.


ParticipantsStudy location: Romania.

Total number: 116

Age: peginterferon alfa-2a: 49.3 years; peginterferon alfa-2b: 50.9 years.

Sex (male sex (n (%))): peginterferon alfa-2a: 21 (36%); peginterferon alfa-2b: 14 (24%).

Co-morbidity: not mentioned.

Genotype: all genotypes.

Previous HCV treatment.

Peginterferon alfa-2a: 48 patients were naïve (N1), 7 were relapsers after previous treatment (RL1) and 3 non-responders to previous treatment (NR1).
Peginterferon alfa-2b: 33 patients were naïve (N2), 18 relapsers (RL2) and 7 non-responders (NR2)

Viral load (mean HCV RNA (log10 IU/mL)): peginterferon alfa-2a: 1.20 ± 0.43 (MIU/mL). peginterferon alfa-2b: 1.38 ± 1.85 (MIU/mL).

Histology at biopsy (total Knodell score): peginterferon alfa-2a: 10 ± 2.4 peginterferon alfa-2b: 10.7 ± 2.8.


InterventionsGroup A: n = 58.

Drug: peginterferon alfa-2a: 180mg/week.

Drug: ribavirin 800-1200 mg/day.

Group B: n = 58.

Drug: peginterferon alfa-2b :1.5 mg/kg/week.

Drug: ribavirin 800 to 1200 mg/day.


OutcomesFailure of early virological response.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The patients were randomised in chronological order to be treated with either one of the two products".

Comment: quasi-randomisation.

Allocation concealment (selection bias)Unclear riskComment: No statement about allocation concealment.

Blinding (performance bias and detection bias)
svr
Unclear riskComment: Blinding of the outcome assessor is not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: The trial did not mention any dropouts or missing data.

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

Other biasLow riskQuote: "This study was not financed by any of the pharmaceutical companies producing the Peg-IFNs."

Comment: The study seems to be free of other sources of bias.

Yenice 2006

MethodsStudy design: randomised clinical trial.

Inclusion criteria: positive antiHCV; normal and/or elevated serum transaminase levels; positive HCV RNA by quantitative polymerase chain reaction (PCR); and at least stage 1 fibrosis according to Knodell Scoring System on liver biopsy. Biochemical criteria: haemoglobin 12 g/dl for women and 13 g/dl for men; leukocyte 3 x 103/mm3; neutrophils 1.5 x 103/mm3; and platelets 100 x 103/mm3; and bilirubin, albumin, and creatinine levels had to be within the normal range.

Exclusion criteria: patients with abdominal ascites; history of bleeding from oesophageal varicosities; HCC or other malignant disorders; positive test results for hepatitis B virus (HBV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV) antibodies or antigens; use of antidepressants or tranquillising agents for more than three months; a history of depression, psychosis or suicide attempt; and significant cardiac or pulmonary problems were excluded.

ITT: no, only per protocol analysis.

Sample size calculation: not mentioned.


ParticipantsStudy location: Turkey.

Total number: 80.

Age - mean: peginterferon alpha 2a: M/F 48.2/50.9, peginterferon alpha 2b: M/F 50.8/50.85.

Sex (male sex (n (%))): peginterferon alpha 2a: 13 (35%), peginterferon alpha 2b: 10 (27%).

Comorbidity: none of the patients had positive test results for hepatitis B virus (HBV), hepatitis D virus (HDV), or human immunodeficiency virus (HIV) antibodies or antigens.

Genotype: 1.

Previous HCV treatment: naive.

Viral load (mean HCV RNA (log10 IU/ml)): not mentioned.

Histology at biopsy: all patients had least stage 1 fibrosis according to Knodell scoring system on liver biopsy.


InterventionsGroup A: allocated 40 patients but finally analysed n = 37.

Drug: peginterferon alpha-2a: 180 μg/week.

Drug: ribavirin (40 to 64 kg: 800 mg; 65 to 85 kg: 1000 mg; > 85 kg: 1200 mg).

Group B: allocated 40 patients but finally analysed n = 37.

Drug: peginterferon alpha-2b (PEG-Intron): 1.5 μg/kg/week.

Drug: ribavirin (40 to 64 kg: 800 mg; 65 to 85 kg: 1000 mg; > 85 kg: 1200 mg).


OutcomesSustained virological response.

Adverse events.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients who met the selection criteria were randomly assigned into two treatment groups".

Comment: the method used for sequence generation is not mentioned.

Allocation concealment (selection bias)Unclear riskComment: The method used for allocation concealment was not mentioned.

Blinding (performance bias and detection bias)
svr
Unclear riskComment: It is not mentioned if the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "The assessments were limited to patients who received the full dose of pegylated interferon for 48 weeks".

Comment: Six patients were excluded due to adverse events , so they were not included in the analysis.

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.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Andrade 2006Retrospective study of a randomised trial to assess the vascular ophthalmalgic side effects associated with antiviral therapy for chronic hepatitis C.

Barros 2010aCost effectiveness analysis, not a randomised clinical trial.

Barros 2010bCost effectiveness analysis, not a randomised clinical trial.

Bruchfeld 2006Non-randomised clinical study.

Cozzolongo 2006Retrospective study.

Craxi 2008Non-randomised clinical study.

El Raziky 2013Retrospective study.

Escudero 2008Non-randomised clinical study.

Espinosa 2007Retrospective study to assess anaemia associated with antiviral therapy for chronic hepatitis C.

Hofmann 2006Retrospective study.

Lee 2010Retrospective, non-randomised study.

Rumi 2012Review article.

Villa 2012Non-randomised clinical study.

Witthoeft 2008Retrospective study.

 
Comparison 1. Peginterferon alpha-2a versus peginterferon alpha-2b

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

 1 All-cause mortality13070Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.64, 6.08]

 2 Liver-related morbidity136Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.70, 12.93]

 3 Serious adverse events43900Risk Ratio (M-H, Random, 95% CI)1.12 [0.95, 1.30]

 4 Adverse events leading to treatment discontinuation125340Risk Ratio (IV, Random, 95% CI)0.84 [0.57, 1.22]

 5 All other (non serious) adverse events94981Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 6 Sustained virological response125174Risk Ratio (M-H, Random, 95% CI)1.12 [1.06, 1.18]

 
Comparison 2. Subgroup analysis

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

 1 Sustained virological response according to genotype11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Genotype 1 or 4
104621Risk Ratio (M-H, Random, 95% CI)1.15 [1.06, 1.26]

    1.2 Genotype 2 or 3
5503Risk Ratio (M-H, Random, 95% CI)1.11 [1.02, 1.22]

 2 Sustanied virological response according to treatment history12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Naive patients
115031Risk Ratio (M-H, Random, 95% CI)1.12 [1.06, 1.18]

    2.2 Non-responders
2360Risk Ratio (M-H, Random, 95% CI)0.77 [0.47, 1.26]

 3 Sustained virological response according to risk of bias from randomisation125174Risk Ratio (M-H, Random, 95% CI)1.12 [1.06, 1.18]

    3.1 Trials with low risk of bias from randomisation
84566Risk Ratio (M-H, Random, 95% CI)1.12 [1.05, 1.20]

    3.2 Trials with high risk of bias from randomisation
4608Risk Ratio (M-H, Random, 95% CI)1.16 [1.02, 1.33]

 4 Sustained virological response according to risk of bias from blinding12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Trials with blinding protecting against detection bias
2418Risk Ratio (M-H, Random, 95% CI)1.29 [1.10, 1.51]

    4.2 Trials without blinding
104756Risk Ratio (M-H, Random, 95% CI)1.10 [1.04, 1.16]

 5 Sustained virological response in patients without HIV co-infection114992Risk Ratio (M-H, Random, 95% CI)1.12 [1.06, 1.18]

 
Summary of findings for the main comparison. Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

Patient or population: patients with chronic hepatitis C.
Settings: mainly out-patients in tertiary and teaching hospitals.
Intervention: peginterferon alpha-2a versus peginterferon alpha-2b.

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

Assumed riskCorresponding risk

Peginterferon alpha-2bPeginterferon alpha-2a

All-cause mortality
Deaths during and after the treatment
Follow-up: 48 to 72 weeks
Study populationRR 1.97
(0.64 to 6.08)
3070
(1 study)
⊕⊝⊝⊝
very low1,2

3 per 10006 per 1000
(2 to 18)

Moderate

3 per 10006 per 1000
(2 to 18)

Liver-related morbidity
Number of events
Follow-up: 8 weeks
Study populationRR 3
(0.7 to 12.93)
36
(1 study)
⊕⊝⊝⊝
very low2

111 per 1000333 per 1000
(78 to 1000)

Moderate

111 per 1000333 per 1000
(78 to 1000)

Serious adverse events
Number of events
Follow-up: 48 to 72 weeks
Study populationRR 1.12
(0.95 to 1.3)
3900
(4 studies)
⊕⊕⊝⊝
low3,4

114 per 1000127 per 1000
(108 to 148)

Moderate

70 per 100078 per 1000
(66 to 91)

Adverse events leading to treatment discontinuation
Number of events
Follow-up: 48-72 weeks
Study populationRR 0.84
(0.57 to 1.22)
5340
(12 studies)
⊕⊕⊝⊝
low1,4,5,6

99 per 100083 per 1000
(56 to 120)

Moderate

80 per 100067 per 1000
(46 to 98)

All other (non-serious) adverse events
Follow-up: 48 to 72 weeks
See commentSee commentNot estimable4981
(9 studies)
⊕⊝⊝⊝
very low4,5,6

Quality of life
SF 36 and CLDQ
Follow-up: 48 to 71 weeks
See commentSee comment434
(1 study)
⊕⊝⊝⊝
very low7,8

Sustained virological response
Absence of viraemia 24 weeks after the treatment
Follow-up: 48 to 72 weeks
Study populationRR 1.12
(1.06 to 1.18)
5013
(12 studies)
⊕⊕⊕⊝9,10
moderate

421 per 1000480 per 1000
(451 to 510)

Moderate

510 per 1000581 per 1000
(546 to 617)

*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.

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

 1 The trial is at low risk of bias due to the allocation sequence generation and allocation concealment.
2Data from only one trial, wide confidence interval. Incomplete outcome data. Very low due to imprecision.
3Post hoc required information size calculation based on a 10% risk of adverse events in the peginterferon alpha-2b group, a minimally important difference of 10%, a 5% type I error, and a 80% power, suggests that a minimum of 27,000 patients need to be randomised for a conclusive meta-analysis on adverse events. The current number of patients is only approximately 5000.
4Wide confidence interval. Low due to imprecision.
5Trials yield widely differing estimates of effect. Low due to imprecision.
6 Reporting of all other adverse events was poor and inconsistent across all included trials. The proportions of observed adverse events differ substantially across the trials, and the direction of effect is heterogeneous. Because the event proportion is relatively low across all trials, all of the included trials may be subject to considerable random errors, thus explaining the apparent heterogeneity in direction of estimates.
7 Data from only one trial. Low due to imprecision
8 Investigators fail to report the details necessary for calculating the effect estimate of the quality of life assessment. Very low due to imprecision.
9Sustained virological response does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. Moderate quality of evidence due to indirectness due to surrogate and risk of bias.
10All trials are with high risk of bias. Sensitivity analyses did not show any important change in the intervention effects when we focused on trials with lower risk of bias.