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Meta-Analysis
. 2014 Feb 28;2014(2):CD005441.
doi: 10.1002/14651858.CD005441.pub3.

Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C

Goran Hauser, Tahany Awad, Jesper Brok, Kristian Thorlund, Davor Štimac, Mahasen Mabrouk, Christian Gluud, Lise Lotte Gluud
Meta-Analysis

Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C

Goran Hauser et al. Cochrane Database Syst Rev. .

Abstract

Background: Pegylated interferon (peginterferon) plus ribavirin is the recommended treatment for patients with chronic hepatitis C, but systematic assessment of the effect of this treatment compared with interferon plus ribavirin is needed.

Objectives: To systematically evaluate the benefits and harms of peginterferon plus ribavirin versus interferon plus ribavirin for patients with chronic hepatitis C.

Search methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index-Expanded, and LILACS. We also searched conference abstracts, journals, and grey literature. The last searches were conducted in September 2013.

Selection criteria: We included randomised clinical trials comparing peginterferon plus ribavirin versus interferon plus ribavirin with or without co-intervention(s) (e.g., other antiviral drugs) for chronic hepatitis C. Quasi-randomised and observational studies retrieved through the searches for randomised clinical trials were also considered for reports of harms. Our primary outcomes were liver-related morbidity, all-cause mortality, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. Our secondary outcome was sustained virological response in serum, that is, undetectable hepatitis C virus RNA in serum by sensitive tests six months after the end of treatment.

Data collection and analysis: Two review authors independently used a standardised data collection form. We meta-analysed data with both fixed-effect and random-effects models. For each outcome, we calculated the odds ratio (OR) (for liver-related morbidity or all-cause mortality) or the risk ratio (RR) along with 95% confidence interval (CI) based on intention-to-treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risk of random errors (play of chance).For each outcome, we calculated the RR with 95% CI based on intention-to-treat analysis. Effects of interventions on outcomes were assessed according to GRADE.

Main results: We included 27 randomised trials with 5938 participants. All trials had high risk of bias. We considered that the risk of bias did not impact on the quality of evidence for liver-related mortality and adverse event outcomes, but it did for virological response. All trials compared peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin versus interferon plus ribavirin for participants with chronic hepatitis C. Three trials administered co-interventions (amantadine hydrochloride 200 mg daily to both intervention groups), and 24 trials were conducted without co-interventions. The effect observed between the two intervention groups regarding liver-related morbidity plus all-cause mortality (5/907 (0.55%) versus 4/882 (0.45%) was imprecise: OR 1.14 ( 95% CI 0.38 to 3.42; five trials; low quality of evidence), as was the risk of adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.68 to 1.09; 15 trials; low quality of evidence) or regarding adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.66 to 1.12; 17 trials; low quality of evidence). However, peginterferon plus ribavirin versus interferon plus ribavirin significantly increased the risk of neutropenia (332/2202 (15.1%) versus 117/1653 (7.1%); RR 2.15, 95% CI 1.76 to 2.61; 13 trials), thrombocytopenia (65/1113 (5.8%) versus 23/1082 (2.1%); RR 2.63, 95% CI 1.68 to 4.11; 10 trials), arthralgia (517/1740 (29.7%) versus 282/1194 (23.6%); RR 1.19, 95% CI 1.05 to 1.35; four trials), injection site reaction (627/1168 (53.7%) versus 186/649 (28.7%); RR 1.71, 95% CI 1.50 to 1.93; four trials), and nausea (606/1784 (34.0%) versus 354/1239 (28.6%); RR 1.13, 95% CI 1.01 to 1.26; four trials). The most frequent adverse event was fatigue, which occurred in 57% of participants (2024/3608). No significant difference was noted between peginterferon plus ribavirin versus interferon plus ribavirin in terms of fatigue (1177/2062 (57.1%) versus 847/1546 (54.8%); RR 1.01, 95% CI 0.96 to 1.07; 12 trials). No significant differences were reported between the two treatment groups regarding anaemia, headache, rigours, myalgia, pyrexia, weight loss, asthenia, depression, insomnia, irritability, alopecia, pruritus, skin rash, thyroid malfunction, decreased appetite, or diarrhoea. We were unable to identify any data on quality of life. Peginterferon plus ribavirin versus interferon plus ribavirin seemed to significantly increase the number of participants achieving sustained virological response (1673/3300 participants (50.7%) versus 1081/2804 patients (36.7%); RR 1.39, 95% CI 1.25 to 1.56; I2 = 64%; 27 trials; very low quality of evidence). However, the risk of bias in the 13/27 (48.1%) trials reporting on this outcome was high and was considered only 'lower' in the remainder. Because the conventional meta-analysis did not reach its required information size (n = 14,486 participants), we used trial sequential analysis to control for risks of random errors. Again, in this analysis, the estimated effect was statistically significant in favour of peginterferon. Subgroup analyses according to risk of bias, viral genotype, baseline viral load, past treatment history, and type of intervention yielded similarly significant results favouring peginterferon over interferon on the outcome of sustained virological response.

Authors' conclusions: Peginterferon plus ribavirin versus interferon plus ribavirin seems to significantly increase the proportion of patients with sustained virological response, as well as the risk of certain adverse events. However, we have insufficient evidence to recommend or reject peginterferon plus ribavirin for liver-related morbidity plus all-cause mortality compared with interferon plus ribavirin. The clinical consequences of achieved sustained virological response are unknown, as sustained virological response is still an unvalidated surrogate outcome. We found no evidence of the potential benefits on quality of life in patients with achieved sustained virological response. Further high-quality research is likely to have an important impact on our confidence in the estimate of patient-relevant outcomes and is likely to change our estimates.There is very low quality evidence that peginterferon plus ribavirin increases the proportion of patients with sustained virological response in comparison with interferon plus ribavirin. There is evidence that it also increases the risk of certain adverse events.

PubMed Disclaimer

Conflict of interest statement

Tahany Awad acted as an invited speaker for Roche and is now employed by AbbVie.

Figures

1
1
Methodological quality graph: review authors' judgements about all methodological quality items presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Funnel plot of comparison: peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, outcome: 1.2 Adverse events leading to treatment discontinuation.
4
4
Forest plot of comparison: pegylated interferon plus ribavirin versus interferon plus ribavirin, outcome: 1.1 Sustained virological response.
5
5
Funnel plot of comparison: pegylated interferon plus ribavirin versus interferon plus ribavirin, outcome: 1.1 Sustained virological response.
6
6
Trial sequential analysis (TSA): pegylated interferon plus ribavirin versus interferon plus ribavirin ‐ sustained virological response.
 
 Lan‐DeMets statistical monitoring boundaries for assessing statistical significance regarding sustained virological response to pegylated interferon plus ribavirin versus interferon plus ribavirin. The diversity‐adjusted required information size of n = 14,486 was calculated based on an event proportion of 50.6% of participants in the interferon‐treated group (Pc) with a risk ratio (RR) reduction of 10% in pegylated interferon group; an alpha (a, type I error) of 5%, a beta (b, type II error) of 10%, and the observed diversity D = 72%.
 
 The solid blue curve presents the cumulative meta‐analysis test Z‐score and the inward sloping red curves present the adjusted threshold for statistical significance according to the two‐sided Lan‐DeMets trial sequential boundaries. The cumulative Z‐score crosses the boundaries for superiority, and this corresponds with superiority of pegylated interferon.
7
7
Trial sequential analysis (TSA): pegylated interferon plus ribavirin versus interferon plus ribavirin ‐ sustained virological response.
 
 Lan‐DeMets statistical monitoring boundaries for assessing statistical significance regarding sustained virological response to pegylated interferon plus ribavirin versus interferon plus ribavirin. The diversity‐adjusted required information size of n = 20,513 was calculated based on an event proportion of 50.6% of participants in the interferon‐treated group (Pc) with a risk ratio (RR) reduction of 10% in the pegylated interferon group; an alpha (a, type I error) of 1%, a beta (b, type II error) of 10%, and the observed diversity D = 72%.
 
 The solid blue curve presents the cumulative meta‐analysis test Z‐score and the inward sloping red curves present the adjusted threshold for statistical significance according to the two‐sided Lan‐DeMets trial sequential monitoring boundaries. The cumulative Z‐score crosses the boundaries for superiority, and this corresponds with the superiority of pegylated interferon.
1.1
1.1. Analysis
Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 1 Liver‐related morbidity plus all‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 2 Adverse events leading to treatment discontinuation.
1.3
1.3. Analysis
Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 3 Sustained virological response.
2.1
2.1. Analysis
Comparison 2 Adverse events, Outcome 1 Haematological effects.
2.2
2.2. Analysis
Comparison 2 Adverse events, Outcome 2 Fatigue and flu‐like symptoms.
2.3
2.3. Analysis
Comparison 2 Adverse events, Outcome 3 Psychiatric symptoms.
2.4
2.4. Analysis
Comparison 2 Adverse events, Outcome 4 Dermatological symptoms.
2.5
2.5. Analysis
Comparison 2 Adverse events, Outcome 5 Thyroid malfunction.
2.6
2.6. Analysis
Comparison 2 Adverse events, Outcome 6 Gastrointestinal symptoms.
3.1
3.1. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 1 Sustanied virological response according to trial methodological quality.
3.2
3.2. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 2 Sustanied virological response according to baseline treatment history.
3.3
3.3. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 3 Sustained virological response according to genotype.
3.4
3.4. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 4 Sustained virological response according to baseline viral load.
3.5
3.5. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 5 Sustained virological response according to the type of peginterferon.
3.6
3.6. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 6 Sustained virological response according to the type of peginterferon and the type of interferon.
3.7
3.7. Analysis
Comparison 3 Subgroup and sensitivity analysis, Outcome 7 Sustained virological response in trials with or without amantadine.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD005441.pub2

References

References to studies included in this review

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Hinrichsen 2002 {published data only}
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Horsmans 2008 {published data only}
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Izumi 2004 {published data only}
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Lee 2005 {published data only}
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Mangia 2005 {published data only}
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Manns 2001 {published data only}
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Napoli 2005 {published data only}
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Rahman 2007a {published data only}
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Sjögren 2007 {published data only}
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Wakil 2006 {published data only}
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References to studies excluded from this review

ACTG 2005 {published data only}
    1. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al. Peginterferon alfa‐2a plus ribavirin versus interferon alfa‐2a plus ribavirin for chronic hepatitis C in HIV‐coinfected persons. New England Journal of Medicine 2004;351(5):451‐9. - PMC - PubMed
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