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

doi:10.1002/14651858.CD005441.pub3

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Figure 1

Methodological quality graph: review authors' judgements about all methodological quality items presented as percentages across all included studies.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 3

Funnel plot of comparison: peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, outcome: 1.2 Adverse events leading to treatment discontinuation.

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Figure 4

Forest plot of comparison: pegylated interferon plus ribavirin versus interferon plus ribavirin, outcome: 1.1 Sustained virological response.

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Figure 5

Funnel plot of comparison: pegylated interferon plus ribavirin versus interferon plus ribavirin, outcome: 1.1 Sustained virological response.

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Figure 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.

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Figure 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.

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Analysis 1.1

Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 1 Liver‐related morbidity plus all‐cause mortality.

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Analysis 1.2

Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 2 Adverse events leading to treatment discontinuation.

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Analysis 1.3

Comparison 1 Peginterferon plus ribavirin versus non‐pegylated interferon plus ribavirin, Outcome 3 Sustained virological response.

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Analysis 2.1

Comparison 2 Adverse events, Outcome 1 Haematological effects.

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Analysis 2.2

Comparison 2 Adverse events, Outcome 2 Fatigue and flu‐like symptoms.

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Analysis 2.3

Comparison 2 Adverse events, Outcome 3 Psychiatric symptoms.

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Analysis 2.4

Comparison 2 Adverse events, Outcome 4 Dermatological symptoms.

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Analysis 2.5

Comparison 2 Adverse events, Outcome 5 Thyroid malfunction.

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Analysis 2.6

Comparison 2 Adverse events, Outcome 6 Gastrointestinal symptoms.

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Analysis 3.1

Comparison 3 Subgroup and sensitivity analysis, Outcome 1 Sustanied virological response according to trial methodological quality.

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Analysis 3.2

Comparison 3 Subgroup and sensitivity analysis, Outcome 2 Sustanied virological response according to baseline treatment history.

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Analysis 3.3

Comparison 3 Subgroup and sensitivity analysis, Outcome 3 Sustained virological response according to genotype.

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Analysis 3.4

Comparison 3 Subgroup and sensitivity analysis, Outcome 4 Sustained virological response according to baseline viral load.

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Analysis 3.5

Comparison 3 Subgroup and sensitivity analysis, Outcome 5 Sustained virological response according to the type of peginterferon.

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Analysis 3.6

Comparison 3 Subgroup and sensitivity analysis, Outcome 6 Sustained virological response according to the type of peginterferon and the type of interferon.

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Analysis 3.7

Comparison 3 Subgroup and sensitivity analysis, Outcome 7 Sustained virological response in trials with or without amantadine.

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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.
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Non‐pegylated	Peginterferon
Liver‐related morbidity plus all‐cause mortality	Five per 1000	Six per 1000 (two to 17)	OR 1.14 (0.38 to 3.42)	1789 (five studies)	⊕⊕⊝⊝ low¹
Adverse events leading to treatment discontinuation	207 per 1000	178 per 1000 (141 to 226)	RR 0.86 (0.68 to 1.09)	4571 (15 studies)	⊕⊕⊝⊝ low^2,3
Sustained virological response	386 per 1000	537 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.

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Liver‐related morbidity plus all‐cause mortality Show forest plot	5	1789	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.38, 3.42]

2 Adverse events leading to treatment discontinuation Show forest plot	17	4868	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.66, 1.12]

3 Sustained virological response Show forest plot	27	6104	Risk Ratio (M‐H, Random, 95% CI)	1.39 [1.25, 1.56]

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

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Comparison 2. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Haematological effects Show forest plot	13		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Anaemia	13	3854	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.98, 1.27]
1.2 Neutropenia	13	3855	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [1.76, 2.61]
1.3 Thrombocytopenia	10	2195	Risk Ratio (M‐H, Fixed, 95% CI)	2.63 [1.68, 4.11]
2 Fatigue and flu‐like symptoms Show forest plot	13		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 General fatigue	11	3608	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.96, 1.07]
2.2 Headache	6	3146	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.93, 1.07]
2.3 Rigours	4	2641	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.08]
2.4 Arthralgia	4	2934	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.05, 1.35]
2.5 Myalgia	5	3087	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.90, 1.06]
2.6 Pyrexia	6	3180	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.99, 1.18]
2.7 Weight loss	6	2524	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.98, 1.39]
2.8 Asthenia	3	2126	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.88, 1.25]
3 Psychiatric symptoms Show forest plot	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Depression	12	3743	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.82, 1.02]
3.2 Insomnia	5	3087	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.91, 1.10]
3.3 Irritability	3	2491	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.86, 1.09]
4 Dermatological symptoms Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Alopecia	5	3087	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]
4.2 Pruritus	5	3027	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.96, 1.25]
4.3 Skin rash	5	2740	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.93, 1.25]
4.4 Injection site reaction	4	1817	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [1.50, 1.93]
5 Thyroid malfunction Show forest plot	8	1222	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.73, 2.00]

6 Gastrointestinal symptoms Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Decreased appetite	6	3136	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.93, 1.19]
6.2 Nausea	4	3023	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [1.01, 1.26]
6.3 Diarrhoea	3	2126	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.93, 1.41]

Comparison 2. Adverse events

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Comparison 3. Subgroup and sensitivity analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Sustanied virological response according to trial methodological quality Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Lower risk of bias trials	14	4285	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.17, 1.51]
1.2 High risk of bias trials	13	1819	Risk Ratio (M‐H, Random, 95% CI)	1.55 [1.23, 1.95]
2 Sustanied virological response according to baseline treatment history Show forest plot	26		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Naive participants	22	5223	Risk Ratio (M‐H, Random, 95% CI)	1.42 [1.25, 1.62]
2.2 Non‐responders and relapsers	4	389	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.96, 1.61]
2.3 Unknown	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.67, 2.97]
3 Sustained virological response according to genotype Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Genotype one	16	3548	Risk Ratio (M‐H, Random, 95% CI)	1.47 [1.27, 1.70]
3.2 Genotypes two and three	9	1659	Risk Ratio (M‐H, Random, 95% CI)	1.10 [1.03, 1.19]
3.3 Genotype four	9	721	Risk Ratio (M‐H, Random, 95% CI)	1.76 [1.30, 2.39]
4 Sustained virological response according to baseline viral load Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 High viral load	5	1777	Risk Ratio (M‐H, Random, 95% CI)	1.33 [1.01, 1.75]
4.2 Low viral Load	5	1027	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.05, 1.58]
4.3 Predominantly high viral load (more than 65% of total participants)	1	96	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.87, 2.59]
4.4 Predominantly low viral load (more than 65% of total participants)	6	920	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.22, 2.06]
4.5 Similar proportions of high and low baseline viral loads	4	607	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.01, 1.70]
4.6 Unknown baseline viral load	11	1690	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.11, 1.71]
5 Sustained virological response according to the type of peginterferon Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Peginterferon alpha‐2a	9	2361	Risk Ratio (M‐H, Random, 95% CI)	1.85 [1.46, 2.35]
5.2 Peginterferon alpha‐2b	18	3534	Risk 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 interferon Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Peginterferon alpha‐2a versus interferon alpha‐2a	8	1464	Risk Ratio (M‐H, Random, 95% CI)	1.98 [1.63, 2.40]
6.2 Peginterferon alpha‐2a versus interferon alpha‐2b	1	897	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.11, 1.45]
6.3 Peginterferon alpha‐2b versus interferon alpha‐2b	13	2799	Risk Ratio (M‐H, Random, 95% CI)	1.15 [1.06, 1.25]
6.4 Peginterferon alpha‐2b versus consensus interferon	4	671	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.92, 1.23]
6.5 Peginterferon alpha‐2b versus leucocyte interferon	1	64	Risk Ratio (M‐H, Random, 95% CI)	1.75 [1.05, 2.92]
7 Sustained virological response in trials with or without amantadine Show forest plot	27		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Trial without amantadine	24	5500	Risk Ratio (M‐H, Random, 95% CI)	1.37 [1.22, 1.53]
7.2 Trial with amantadine	3	604	Risk Ratio (M‐H, Random, 95% CI)	1.68 [1.26, 2.23]

Comparison 3. Subgroup and sensitivity analysis

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