Ribavirin monotherapy for chronic hepatitis C

Jesper Brok; Lise Lotte Gluud; Christian Gluud

doi:10.1002/14651858.CD005527.pub2

Monoterapia con ribavirina para la hepatitis C crónica

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Bodenheimer 1997

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases for more than six months. Histologic evidence of chronic hepatitis. Exclusion criteria: Hepatitis B. Human immune deficiency virus. Gilberts syndrome. Chronic or haemolytic anaemia. Excessive alcohol consume. Significant concurrent systemic illness. Haemoglobin less than 10.5 mg/dl. Hematocrit less than 32%. Immunosuppressive therapy within 6 months before study entry. Characteristics of included patients: Mean age: 45 years. Males: 70%. Cirrhotics: 17%. Genotype 1: 89%. ‐ 19% were treatment naive.
Interventions	Ribavirin 1200 mg daily for 36 weeks versus placebo.
Outcomes	Outcomes assessed 16 weeks after the end of treatment.
Notes	The trial included naive, relapsers, and non‐responders. Quality of life was assessed by self‐developed symptom questionnaires.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Low risk	"Allocation concealed at independent pharmacy."
Blinding? All outcomes	Low risk	Patients were randomised "in equal numbers to receive 200 mg ribavirin capsules or three identically appearing placebo capsules twice daily. The placebo was composed of capsules whose primary ingredients were lactose and cellulose."
Incomplete outcome data addressed? All outcomes	Unclear risk	Report that "two patients refused follow‐up biopsy."
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported virological response at end of treatment only, but they reported on clinical outcomes and adverse reactions.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	There was no baseline imbalance in important characteristics.
Free of source of funding bias?	High risk	Grant from Valeant Pharmaceuticals International.

Buti 1991

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Chronic non‐A and non‐B hepatitis. Exclusion criteria: Not reported. Characteristics of included patients: Mean age and proportion of males, cirrhotics and genotypes not reported.
Interventions	Ribavirin 1200 mg daily for eight weeks versus placebo.
Outcomes	Outcomes assessed at end of treatment.
Notes	Previous antiviral treatment unclear.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	Low risk	placebo‐controlled trial.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported in the abstract only end of treatment biochemical response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Unclear risk	Not described.
Free of source of funding bias?	Unclear risk	Not described.

Chemello 1995

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases for more than six months. Histologic evidence of chronic hepatitis. Exclusion criteria: Cirrhosis. Other potential cause of liver disease. Characteristics of included patients: Mean age: 41 years. Males: 100%. Cirrhotics: 0%. Genotype 1: 40%.
Interventions	Ribavirin 15 mg/kg daily versus interferon 3 million units thrice a week for 26 weeks.
Outcomes	Outcomes assessed 52 weeks after end of treatment.
Notes	This trial also includes a treatment group receiving ribavirin plus interferon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"Table of random numbers."
Allocation concealment?	Low risk	"Allocation concealed by sealed envelopes."
Blinding? All outcomes	High risk	No blinding.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. Reported on the primary outcomes in the review.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No relevant significant difference.
Free of source of funding bias?	Unclear risk	Not described.

Di Bisceglie 1995b

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases. Histologic evidence of chronic hepatitis. Exclusion criteria: Therapy with other agents within six months. Decompensated liver diseases. Pregnancy. Anaemia. Hepatitis B or D. Human immune deficiency virus. Alcohol abuse. Characteristics of included patients: Mean age: 44 years. Men: 67%. Cirrhosis: not described. Genotype 1: 78%. 71% were treatment naive.
Interventions	Ribavirin 1200 mg daily for 12 months versus placebo.
Outcomes	Outcomes assessed 26 weeks after end of treatment.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Table of random numbers.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	Low risk	Use of placebo identical in appearance and given in the same manner as ribavirin.
Incomplete outcome data addressed? All outcomes	Low risk	"All patients were followed for the full 48 weeks and all had liver biopsy."
Free of selective reporting?	Unclear risk	Protocol is not available. Reported on the primary outcomes in the review.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Support from Valeant Pharmaceuticals International.

Dusheiko 1996

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases. Histological evidence of chronic hepatitis. Exclusion criteria: No interferon or immunosuppressive therapy within six months. Alcohol abuse. Hepatitis B. Human immune deficiency virus. Intravenous drug abuse. Haemoglobin less than 10 g/dl. Haemolytic anaemia. Gout or other significant systemic illness. Other forms of liver disease. Autoantibodies. Characteristics of included patients: Mean age: 44 years. Males: 86%. Cirrhotics: not reported. Genotype 1: 55%.
Interventions	Ribavirin 1000 to 1200 mg daily versus placebo for 24 weeks.
Outcomes	Outcomes assessed 24 weeks after end of treatment.
Notes	The trial included naive, relapsers, and non‐responders.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Table of random numbers.
Allocation concealment?	Low risk	Allocation concealed by sealed envelopes.
Blinding? All outcomes	Low risk	"Use identical placebo capsules."
Incomplete outcome data addressed? All outcomes	Low risk	Analysed with intention to treat: "93 had HCV‐RNA measured and 77 had liver biopsy at end of follow‐up."
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported on the primary outcomes in the review.
Early stopping?	Low risk	Sample size estimation of 120 patients; 118 patients were randomised.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Grant from Valeant Pharmaceuticals International.

Felipe 2000

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases for at least six months. Liver biopsy proven chronic hepatitis. Treatment naive. Exclusion criteria: Hepatitis B antigen or anti‐HCV positive. Pregnancy. Decompensated cirrhosis. Hepatocellular carcinoma or other significant concurrent diseases. Characteristics of included patients: Mean age: 45 years. Males: 82%. Cirrhotics: not reported. Genotype 1: not reported.
Interventions	Ribavirin 600 mg daily for 8 weeks, then 1000 mg daily for 8 weeks, then 1200 mg daily for 8 weeks versus placebo.
Outcomes	Outcomes assessed 12 weeks after end of treatment.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	Low risk	Use of placebo.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported only on the end of treatment virological response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Support from ICI‐Frama Ind. Farmac. Ltda. Grants from CNPq and FAPESP

Gonzalez‐Peralt 1997

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated transaminases for at least six months. Liver biopsy proven chronic hepatitis. Exclusion criteria: Hepatitis B or human immune deficiency virus. Characteristics of included patients: Median age: 42 years. Males: 64%. Cirrhotics: not reported. Genotype 1: 86%.
Interventions	Ribavirin 1200 mg daily versus placebo for 36 weeks.
Outcomes	Outcomes assessed 24 weeks after end of treatment.
Notes	Previous antiviral treatment unclear. A comparison group with 15 patients were receiving interferon, but they were not randomised.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	Low risk	Placebo‐controlled trial.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported only on the end of treatment virological response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	Low risk	Grant from Children's Miracle Network Reasearch Fund.

Hoofnagle 2003

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus RNA positive. Elevated amino transferase. Liver biopsy proven chronic hepatitis. Non‐responders after 24 weeks combination therapy with ribavirin and interferon. Exclusion criteria: Symptomatic coronary or cerebrovascular diseases. Autoimmune diseases. Renal insufficiency. Haemolysis or anaemia. Age younger than 18 years. Hepatitis B or human immune deficiency virus. Characteristics of included patients: Median age: 47 years. Males: 74%. Cirrhotics: 15%. Genotype 1: 97%.
Interventions	Ribavirin 1000 to 1200 mg daily versus placebo for 48 weeks.
Outcomes	Outcomes assessed 24 weeks after end of treatment.
Notes	All patients were treated with interferon plus ribavirin for 24 weeks. Those who did not clear hepatitis C virus were subsequently randomised to ribavirin versus placebo.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	Low risk	"Identical appearing placebo tablets."
Incomplete outcome data addressed? All outcomes	Low risk	"All had HCV‐RNA measured and all but two had liver biopsy."
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported on adverse events and clinical outcomes but not on sustained virological response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Support from Schering‐Ploigh research Institute (placebo tablets).

Kakumu 1993b

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Liver biopsy proven chronic hepatitis. Exclusion criteria: Hepatitis B. Characteristics of included patients: Median age: 50 years. Males: 69%. Cirrhotics: not reported. Genotype 1: not reported.
Interventions	Ribavirin 800 to 1000 mg daily versus no intervention versus interferon beta 3 million units thrice a week for 24 weeks versus no intervention.
Outcomes	Outcomes assessed 24 weeks after end of treatment.
Notes	Previous antiviral treatment unclear. This trial also includes a treatment group receiving ribavirin plus interferon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described
Blinding? All outcomes	High risk	No blinding.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported on the primary outcomes in the review.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	Unclear risk	Not described.

Khakoo 1998

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus RNA positive. Histologic evidence of chronic hepatitis. Treatment naive or relapsers to previous interferon therapy. Exclusion criteria: Hepatitis B. Human immune deficiency virus. Interferon neutralising antibodies. Significant other medical or psychiatric illness. Substance abuse. Other causes of liver disease or advanced liver disease. Characteristics of included patients: Mean age: 38 years. Males: 63%. Cirrhotics: not reported. Genotypes: not reported.
Interventions	Ribavirin 1200 mg daily versus interferon alfa‐2b 3 million units thrice weekly with or without ribavirin 1200 mg daily for six weeks
Outcomes	Outcomes assessed four weeks after end of treatment.
Notes	Patients who completed the full 10 weeks were offered ribavirin plus interferon for 24 weeks.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Sequence generation by computer.
Allocation concealment?	Low risk	Allocation concealed by sealed envelopes.
Blinding? All outcomes	High risk	No blinding.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. The authors did not report on virological response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Unclear risk	Not described.
Free of source of funding bias?	Unclear risk	Not described.

Pawlotsky 2004

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus 1b RNA positive. treatment naive. Exclusion criteria: Not reported. Characteristics of included patients: Mean age: 46 years. Males: 67%. Cirrhotics: not reported. Genotypes. All were genotype 1b.
Interventions	Ribavirin 1000 to 1200 mg daily versus interferon alfa‐2b 3 million units daily versus interferon 3 million units thrice weekly versus no intervention for 12 weeks.
Outcomes	Outcomes assessed at end of treatment.
Notes	This study also includes a treatment group receiving ribavirin plus interferon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Unclear risk	Not described
Blinding? All outcomes	High risk	No blinding.
Incomplete outcome data addressed? All outcomes	Unclear risk	Not described.
Free of selective reporting?	Unclear risk	Protocol is not available. DId not report on sustained virological response.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Unclear risk	Not described.
Free of source of funding bias?	Unclear risk	Not described.

Sostegni 1998

Methods	Study design: randomised clinical trial.
Participants	‐ Non‐responders to previous interferon treatment. ‐ Mean age 48 years. ‐ Men 82%. ‐ Cirrhosis 22%. ‐ Genotype 1: 68%. ‐ HCV‐RNA limit 50 copies/ml.
Interventions	Leukocyte interferon 3 million units thrice a week or ribavirin 1000 mg daily for 26 weeks.
Outcomes	Outcomes assessed at the end of treatment.
Notes	The trial also includes a third group receiving ribavirin plus interferon. Furthermore, the ribavirin group received interferon after ribavirin. Thus, only data at end of ribavirin treatment are included.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Use of computer.
Allocation concealment?	Unclear risk	Not described.
Blinding? All outcomes	High risk	No double blinding.
Incomplete outcome data addressed? All outcomes	Low risk	Report on patients dropping out from study.
Free of selective reporting?	Unclear risk	Protocol is not available.
Early stopping?	Unclear risk	Not described.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	Unclear risk	Not described.

Stanimirovic 2002

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated aminotransferase for at least six months. Liver biopsy proven chronic hepatitis. Treatment naive. Exclusion criteria: Pregnancy. Hepatitis B. Human immune deficiency virus. Ascites, hepatic encephalopathy or oesophageal varices. Significant systemic illness. Excessive alcohol intake. Gilbert diseases. Renal impairment. Evidence of other forms of liver disease. Characteristics of included patients: Mean age: 41 years. Males: 64%. Cirrhotics: 8% Genotypes not reported.
Interventions	Ribavirin 1200 mg daily for 48 weeks or placebo.
Outcomes	Outcomes assessed 16 weeks after end of treatment.
Notes	Treatment naive. Sustained virological and biochemical response were assessed 16 weeks after the end of treatment. A decrease in ALT of more than 50% were considered as normalisation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Low risk	Allocation concealed at independent medical department.
Blinding? All outcomes	Low risk	Use of placebo. Furthermore, monitor and nursing staff were blinded.
Incomplete outcome data addressed? All outcomes	Low risk	Number and reasons for drop‐outs clearly described in 'Final report' page 38 to 40.
Free of selective reporting?	Low risk	Protocol available and reported on relevant and pre‐specified outcomes.
Early stopping?	Low risk	Sample size estimation fulfilled.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Grant from Valeant Pharmaceuticals International.

Veldt 2003

Methods	Study design: randomised clinical trial.
Participants	Inclusion criteria: Hepatitis C virus antibody and RNA positive. Elevated aminotransferase. Liver biopsy proven chronic hepatitis. Non‐responders to previous antiviral therapy. Exclusion criteria: Pregnancy. Infection with other types of hepatitis. Metabolic liver diseases. Liver diseases related to other factors. Significant medical illness. Treatment with steroids. Low levels of haemoglobin, platelet count, or white blood cells. Hepatocellular carcinoma. Drug or alcohol addiction. Characteristics of included patients: Mean age: 47 years. Males: 77%. Cirrhotics: 35%. Genotype 1: 65%.
Interventions	Ribavirin 1000 to 1200 mg daily versus ribavirin placebo versus interferon 3 million units thrice weekly for 24 weeks.
Outcomes	Outcomes assessed 24 weeks after end of treatment.
Notes	This trial also includes a treatment group receiving ribavirin plus interferon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described.
Allocation concealment?	Low risk	Allocation concealment: sealed envelopes.
Blinding? All outcomes	Low risk	"Use of matched placebo".
Incomplete outcome data addressed? All outcomes	Low risk	Number and reasons for drop‐outs described (Figure 1).
Free of selective reporting?	Unclear risk	Protocol is not available. The authors reported on the primary outcomes in the review.
Early stopping?	Low risk	Sample size estimation fulfilled.
Baseline characteristics	Low risk	No significant difference.
Free of source of funding bias?	High risk	Financial support form Valeant Pharmaceuticals International and Schering Plough.

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Abergel 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Adinolfi 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Andreone 1999a	Randomised trial comparing ribavirin plus interferon versus interferon.
Andreone 1999b	Randomised trial comparing ribavirin plus interferon versus interferon.
Andreone 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Antignano 1999	Randomised trial comparing different ribavirin plus interferon regimens.
Ascione 1998	Randomised trial comparing ribavirin plus interferon versus interferon.
Bacon 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Bailey 1997	Observational study.
Baracetti 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Barbaro 1998a	Randomised trial comparing ribavirin plus interferon versus interferon.
Barbaro 1998b	Randomised trial comparing ribavirin plus interferon versus interferon.
Barbaro 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Barbaro 2000a	Randomised trial comparing ribavirin plus interferon versus interferon.
Bekkering 2000	Observational study.
Bell 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Belli 2001	Randomised trial including patients who had undergone liver transplantation
Bellobouno 1997	Randomised trial comparing ribavirin plus interferon versus interferon.
Bellobouno 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Bellobouno 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Bellobuono 1995	Observational study.
Bellobuono 2000a	Randomised trial comparing ribavirin plus interferon versus interferon.
Bellobuono 2000b	Observational study.
Bellobuono 2000c	Observational study.
Benetti 2001	Randomised trial comparing ribavirin plus interferon versus interferon.
Benhamou 2007	Randomised trial comparing ribavirin vs viramidine.
Berg 2000a	Randomised trial comparing ribavirin plus interferon versus interferon.
Berg 2000b	Randomised trial comparing ribavirin plus interferon versus interferon.
Bernatik 2000	Observational study.
Bernstein 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Bjøro 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Bresci 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Brillanti 1995	Randomised trial comparing ribavirin plus interferon versus interferon.
Brillanti 1999	Randomised trial comparing ribavirin plus interferon with ribavirin plus interferon plus amantadine.
Brouwer 2001	Randomised trial comparing ribavirin plus interferon versus interferon.
Bugliescu 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Calanca 2007	Randomised trial comparing ribavirin versus amantadine versus historical control group without antiviral treatment.
Camps 1993	Observational study.
Caremani 1996	Randomised trial comparing ribavirin plus interferon versus interferon.
Cattral 1999	Observational study.
Cavaletto 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Chapman 2001	Randomised trial comparing ribavirin plus interferon versus interferon.
Cheinquer 1998	Observational study.
Colantoni 2000	Observational study.
Davis 1998	Randomised trial comparing ribavirin plus interferon versus interferon.
De Bac 1998	Possibly randomised trial comparing different ribavirin plus interferon regimens.
De Franceschi 2000	Observational study.
Dettmer 2002	Randomised trial comparing ribavirin plus interferon versus interferon.
Di Bisceglie 1992	Observational study.
Di Bisceglie 1995	Randomised trial comparing ribavirin plus interferon versus interferon.
Di Marco 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Ehardt 2000	Observational study.
el‐Zayadi 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Ersöz 2000	Observational study.
Feher 2000	Observational study.
Ferenci 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Ferenci 2001	Randomised trial comparing ribavirin plus interferon versus interferon.
Fraquelli 2000	Observational study.
Gallego 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Gane 1998	Randomised trial concerning recurrent HCV infection in liver transplant recipients.
Garnier 1997	Observational study.
Gerotto 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Gish 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Gish 2007	Randomised trial comparing ribavirin vs viramidine.
Glue 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Gross 1999a	Randomised trial comparing ribavirin plus interferon versus interferon.
Gross 1999b	Randomised trial comparing ribavirin plus interferon versus interferon.
Götz 1998	Observational study.
Harris 2000	Observational study.
Herrine 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Junqing 1996	Observational study.
Juszezyk 2000	Observational study.
Kallinowski 1999	Randomised trial comparing different ribavirin plus interferon regimens.
Katsarou 2000	Observational study.
Koshy 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Lai 1996	Randomised trial comparing ribavirin plus interferon versus interferon.
Lee 1998	Observational study.
Lin 2004	Randomised trial comparing ribavirin vs viramidine.
Lédinghen 2002a	Randomised trial comparing ribavirin plus interferon versus interferon.
Lédinghen 2002b	Randomised trial comparing ribavirin plus interferon versus interferon.
Malik 2002	Randomised trial comparing ribavirin plus interferon versus interferon.
Mangia 2001	Randomised trial comparing ribavirin plus interferon versus interferon.
Marcellin 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Marco 2000	Randomised trial comparing different ribavirin plus interferon regimens.
Marco 2002	Randomised trial comparing ribavirin plus interferon versus interferon.
Mazzaferro 1997	Observational study.
McHutchison 1998	Randomised trial comparing ribavirin plus interferon versus interferon.
Menzel 2000	Randomised trial comparing different regimens of interferon plus amantadine plus ribavirin.
Milella 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Nagayama 2005	Randomised patients that responded (cleared HCV‐RNA) to combination therapy to ribavirin versus placebo.
Nunes 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Perasso 1999	Observational study.
Pol 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Pol 2000a	Randomised trial comparing ribavirin plus interferon versus interferon.
Poordad 2008	Randomised trial comparing ribavirin vs viramidine.
Portal 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Poynard 1998a	Randomised trial comparing ribavirin plus interferon versus interferon.
Quadri 2000	Observational study.
Reichard 1998	Randomised trial comparing ribavirin plus interferon versus interferon.
Ricchiuti 1996	Randomised trial comparing ribavirin plus interferon versus interferon.
Ricchiuti 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Rosen 1999	Randomised trial comparing different ribavirin plus interferon regimens.
Rothstein 1998	Randomised trial comparing different ribavirin plus interferon regimens.
Salmeron 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Sarin 1999	Randomised trial comparing ribavirin plus interferon versus interferon.
Scotto 1996	Randomised trial comparing ribavirin plus interferon versus interferon.
Shakil 1999	Randomised trial in liver transplant recipients.
Sherif 1996	Observational study.
Shiffman 2000	Randomised trial comparing ribavirin plus interferon versus interferon.
Shiffman 2001	Randomised patients that responded (cleared HCV‐RNA) to combination therapy to ribavirin versus placebo.
Stalke 2000	Observational study.
Tassopoulos 1999	Randomised trial comparing different ribavirin plus interferon regimens.
Teuber 2000	Observational study.
Toccaceli 1997	Randomised trial comparing ribavirin plus interferon versus interferon.
Tripi 1998	Randomised trial comparing ribavirin plus interferon versus ribavirin.
Verbaan 2002	Randomised trial comparing ribavirin plus interferon versus interferon.
Vogel 2002	Randomised trial comparing ribavirin plus interferon versus interferon.
Wiese 2000a	Observational study.
Wood 1998	Randomised trial comparing ribavirin plus interferon versus interferon.

Data and analyses

Open in table viewer

Comparison 1. Ribavirin versus placebo or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA) Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA).
1.1 Sustained virological response	5	353	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.03]
1.2 End of treatment virological response	10	513	Risk Difference (M‐H, Fixed, 95% CI)	‐ [‐0.03, 0.03]
2 Liver‐related morbidity and all‐cause mortality Show forest plot	11	521	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.03]
Open in figure viewer Analysis 1.2 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 2 Liver‐related morbidity and all‐cause mortality.
3 Adverse events Show forest plot	7		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 3 Adverse events.
3.1 Depression	1	59	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.01, 0.33]
3.2 Anaemia	7	444	Risk Difference (M‐H, Fixed, 95% CI)	0.16 [0.11, 0.22]
3.3 Fatique (weakness)	3	172	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.01, 0.11]
3.4 Irritability	2	138	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.03, 0.08]
3.5 Anxiety	1	58	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.06, 0.12]
3.6 Pruritus (itching)	3	172	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.00, 0.12]
3.7 Infections	1	58	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.03, 0.32]
3.8 Cough	1	59	Risk Difference (M‐H, Fixed, 95% CI)	0.21 [0.04, 0.38]
3.9 Chest pain	2	139	Risk Difference (M‐H, Fixed, 95% CI)	0.07 [0.00, 0.14]
3.10 Skin disorders (non‐specific)	1	116	Risk Difference (M‐H, Fixed, 95% CI)	0.14 [0.06, 0.23]
3.11 Nervous system disorders (Non‐specific)	1	116	Risk Difference (M‐H, Fixed, 95% CI)	0.14 [0.06, 0.23]
3.12 Gastrointestinal pain	1	80	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.04, 0.09]
3.13 Headache	1	80	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.04, 0.09]
3.14 Vasculitis	1	79	Risk Difference (M‐H, Fixed, 95% CI)	0.02 [‐0.04, 0.09]
3.15 Dose reductions	6	387	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [0.06, 0.16]
3.16 Treatment discontinuations	6	428	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.10]
4 Failure of biochemical response (number of patients with elevated transaminase) Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 4 Failure of biochemical response (number of patients with elevated transaminase).
4.1 Sustained biochemical response	5	294	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.05, 0.06]
4.2 End of treatment biochemical response	10	509	Risk Difference (M‐H, Fixed, 95% CI)	‐0.23 [‐0.29, ‐0.17]
5 Failure of histologic response (number of patients without improvement in liver histology) Show forest plot	3		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 5 Failure of histologic response (number of patients without improvement in liver histology).
5.1 Combined necro‐inflammatory and fibrosis score (Intention to treat)	3	211	Risk Difference (M‐H, Fixed, 95% CI)	‐0.14 [‐0.25, ‐0.02]
5.2 Combined necro‐inflammatory and fibrosis score (Per protocol)	3	156	Risk Difference (M‐H, Fixed, 95% CI)	‐0.20 [‐0.35, ‐0.06]
6 Quality of life Show forest plot	1		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 Ribavirin versus placebo or no intervention, Outcome 6 Quality of life.
6.1 Improvement of fatigue at end of treatment	1	59	Risk Difference (M‐H, Fixed, 95% CI)	‐0.11 [‐0.27, 0.06]

Open in table viewer

Comparison 2. Ribavirin versus interferon

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA) Show forest plot	5		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 Ribavirin versus interferon, Outcome 1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA).
1.1 Sustained virological response	2	48	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.04, 0.29]
1.2 End of treatment virological response	5	151	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.07, 0.27]
2 Liver‐related and all‐cause morbidity and mortality Show forest plot	5	151	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.06, 0.06]
Open in figure viewer Analysis 2.2 Comparison 2 Ribavirin versus interferon, Outcome 2 Liver‐related and all‐cause morbidity and mortality.
3 Failure of biochemical response (number of patients with elevated alanine aminotransferase) Show forest plot	4		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.3 Comparison 2 Ribavirin versus interferon, Outcome 3 Failure of biochemical response (number of patients with elevated alanine aminotransferase).
3.1 Sustained biochemical response	2	48	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [‐0.01, 0.35]
3.2 End of treatment biochemical response	4	135	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.05, 0.29]
4 Adverse events Show forest plot	4		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.4 Comparison 2 Ribavirin versus interferon, Outcome 4 Adverse events.
4.1 Flu‐like syndrome (non‐specific)	1	30	Risk Difference (M‐H, Fixed, 95% CI)	‐0.2 [‐0.42, 0.02]
4.2 Weight loss	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.18, 0.18]
4.3 Fatique/Weakness	2	54	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.31]
4.4 Irritability	2	93	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.12, 0.11]
4.5 Abdominal pain	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [0.03, 0.23]
4.6 Diarrhea	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.06, 0.33]
4.7 Pruritus	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.03, 0.15]
4.8 Herpes labialis	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.11, 0.37]
4.9 Anaemia	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.09 [‐0.01, 0.18]
4.10 Headache	1	24	Risk Difference (M‐H, Fixed, 95% CI)	‐0.17 [‐0.51, 0.17]
4.11 Pharyngitis	1	24	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.12, 0.29]
4.12 Viral infections	1	24	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.12, 0.29]
4.13 Myalgia	1	24	Risk Difference (M‐H, Fixed, 95% CI)	‐0.08 [‐0.29, 0.12]
4.14 Dose reductions	3	72	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.04, 0.21]
4.15 Treatment discontinuations	3	117	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.09, 0.11]

Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included trials.

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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

Trial sequential analysis illustrating that the cumulative Z‐curve (blue) has not crossed the monitoring boundary (red) but have surpassed the information size (n = 232) needed to detect of reject an effect size corresponding to a number needed to treat of 10 patient (or fewer) for ribavirin. Thus we can rule out a number needed to treat of 10 patients (or fewer) for ribavirin regarding sustained virological response.

Trial sequential analysis was performed with a type I error of 5% and type II error of 20% (80% power). We assumed a baseline event rate of 97% without sustained virological response in the placebo/no intervention group. We used an event rate of 87% (number needed to treat = 10 patients) without sustained virological response in the ribavirin group.

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Figure 4

Trial sequential analysis illustrating that the cumulative Z‐curve (blue) has not crossed the monitoring boundary (red) nor reached the information size (n = 3014) needed to detect of reject an effect size corresponding to a number needed to treat of 50 (or fewer) for ribavirin. Thus we can not rule out a number needed to treat of 50 (or fewer) for ribavirin regarding sustained virological response. Additionally 2661 (3014 ‐ 353) patients are needed to detect or reject this effect size.

Trial sequential analysis was performed with a type I error of 5% and type II error of 20% (80% power). We assumed a baseline event rate of 97% for sustained virological response in the placebo/no intervention group. We used an event rate of 95% (number needed to treat = 50) without sustained virological response in the ribavirin group.

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Analysis 1.1

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA).

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Analysis 1.2

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 2 Liver‐related morbidity and all‐cause mortality.

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Analysis 1.3

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 3 Adverse events.

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Analysis 1.4

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 4 Failure of biochemical response (number of patients with elevated transaminase).

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Analysis 1.5

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 5 Failure of histologic response (number of patients without improvement in liver histology).

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Analysis 1.6

Comparison 1 Ribavirin versus placebo or no intervention, Outcome 6 Quality of life.

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Analysis 2.1

Comparison 2 Ribavirin versus interferon, Outcome 1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA).

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Analysis 2.2

Comparison 2 Ribavirin versus interferon, Outcome 2 Liver‐related and all‐cause morbidity and mortality.

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Analysis 2.3

Comparison 2 Ribavirin versus interferon, Outcome 3 Failure of biochemical response (number of patients with elevated alanine aminotransferase).

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Analysis 2.4

Comparison 2 Ribavirin versus interferon, Outcome 4 Adverse events.

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Comparison 1. Ribavirin versus placebo or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA) Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Sustained virological response	5	353	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.03]
1.2 End of treatment virological response	10	513	Risk Difference (M‐H, Fixed, 95% CI)	‐ [‐0.03, 0.03]
2 Liver‐related morbidity and all‐cause mortality Show forest plot	11	521	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.03]

3 Adverse events Show forest plot	7		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Depression	1	59	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.01, 0.33]
3.2 Anaemia	7	444	Risk Difference (M‐H, Fixed, 95% CI)	0.16 [0.11, 0.22]
3.3 Fatique (weakness)	3	172	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [‐0.01, 0.11]
3.4 Irritability	2	138	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.03, 0.08]
3.5 Anxiety	1	58	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.06, 0.12]
3.6 Pruritus (itching)	3	172	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.00, 0.12]
3.7 Infections	1	58	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.03, 0.32]
3.8 Cough	1	59	Risk Difference (M‐H, Fixed, 95% CI)	0.21 [0.04, 0.38]
3.9 Chest pain	2	139	Risk Difference (M‐H, Fixed, 95% CI)	0.07 [0.00, 0.14]
3.10 Skin disorders (non‐specific)	1	116	Risk Difference (M‐H, Fixed, 95% CI)	0.14 [0.06, 0.23]
3.11 Nervous system disorders (Non‐specific)	1	116	Risk Difference (M‐H, Fixed, 95% CI)	0.14 [0.06, 0.23]
3.12 Gastrointestinal pain	1	80	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.04, 0.09]
3.13 Headache	1	80	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.04, 0.09]
3.14 Vasculitis	1	79	Risk Difference (M‐H, Fixed, 95% CI)	0.02 [‐0.04, 0.09]
3.15 Dose reductions	6	387	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [0.06, 0.16]
3.16 Treatment discontinuations	6	428	Risk Difference (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.10]
4 Failure of biochemical response (number of patients with elevated transaminase) Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Sustained biochemical response	5	294	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.05, 0.06]
4.2 End of treatment biochemical response	10	509	Risk Difference (M‐H, Fixed, 95% CI)	‐0.23 [‐0.29, ‐0.17]
5 Failure of histologic response (number of patients without improvement in liver histology) Show forest plot	3		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Combined necro‐inflammatory and fibrosis score (Intention to treat)	3	211	Risk Difference (M‐H, Fixed, 95% CI)	‐0.14 [‐0.25, ‐0.02]
5.2 Combined necro‐inflammatory and fibrosis score (Per protocol)	3	156	Risk Difference (M‐H, Fixed, 95% CI)	‐0.20 [‐0.35, ‐0.06]
6 Quality of life Show forest plot	1		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Improvement of fatigue at end of treatment	1	59	Risk Difference (M‐H, Fixed, 95% CI)	‐0.11 [‐0.27, 0.06]

Comparison 1. Ribavirin versus placebo or no intervention

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Comparison 2. Ribavirin versus interferon

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure of serum virological response (number of patients with detectable hepatitis C virus RNA) Show forest plot	5		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Sustained virological response	2	48	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.04, 0.29]
1.2 End of treatment virological response	5	151	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.07, 0.27]
2 Liver‐related and all‐cause morbidity and mortality Show forest plot	5	151	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.06, 0.06]

3 Failure of biochemical response (number of patients with elevated alanine aminotransferase) Show forest plot	4		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Sustained biochemical response	2	48	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [‐0.01, 0.35]
3.2 End of treatment biochemical response	4	135	Risk Difference (M‐H, Fixed, 95% CI)	0.17 [0.05, 0.29]
4 Adverse events Show forest plot	4		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Flu‐like syndrome (non‐specific)	1	30	Risk Difference (M‐H, Fixed, 95% CI)	‐0.2 [‐0.42, 0.02]
4.2 Weight loss	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.18, 0.18]
4.3 Fatique/Weakness	2	54	Risk Difference (M‐H, Fixed, 95% CI)	0.11 [‐0.09, 0.31]
4.4 Irritability	2	93	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.12, 0.11]
4.5 Abdominal pain	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [0.03, 0.23]
4.6 Diarrhea	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.06, 0.33]
4.7 Pruritus	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.06 [‐0.03, 0.15]
4.8 Herpes labialis	1	30	Risk Difference (M‐H, Fixed, 95% CI)	0.13 [‐0.11, 0.37]
4.9 Anaemia	2	93	Risk Difference (M‐H, Fixed, 95% CI)	0.09 [‐0.01, 0.18]
4.10 Headache	1	24	Risk Difference (M‐H, Fixed, 95% CI)	‐0.17 [‐0.51, 0.17]
4.11 Pharyngitis	1	24	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.12, 0.29]
4.12 Viral infections	1	24	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.12, 0.29]
4.13 Myalgia	1	24	Risk Difference (M‐H, Fixed, 95% CI)	‐0.08 [‐0.29, 0.12]
4.14 Dose reductions	3	72	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [‐0.04, 0.21]
4.15 Treatment discontinuations	3	117	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.09, 0.11]

Comparison 2. Ribavirin versus interferon

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Referencias

Referencias de los estudios incluidos en esta revisión

Bodenheimer 1997 {published data only}

Buti 1991 {published data only}

Chemello 1995 {published data only}

Di Bisceglie 1995b {published data only}

Dusheiko 1996 {published data only}

Felipe 2000 {published data only}

Gonzalez‐Peralt 1997 {published data only}

Hoofnagle 2003 {published data only}

Kakumu 1993b {published data only}

Khakoo 1998 {published data only}

Pawlotsky 2004 {published data only}

Sostegni 1998 {published data only}

Stanimirovic 2002 {published data only}

Veldt 2003 {published data only}

Referencias de los estudios excluidos de esta revisión

Abergel 1999 {published data only}

Adinolfi 2000 {published data only}

Andreone 1999a {published data only}

Andreone 1999b {published data only}

Andreone 2000 {published data only}

Antignano 1999 {published data only}

Ascione 1998 {published data only}

Bacon 1998 {published data only}

Bailey 1997 {published data only}

Baracetti 2000 {published data only}

Barbaro 1998a {published data only}

Barbaro 1998b {published data only}

Barbaro 1999 {published data only}

Barbaro 2000a {published data only}

Bekkering 2000 {published data only}

Bell 1999 {published data only}

Belli 2001 {published data only}

Bellobouno 1997 {published data only}

Bellobouno 1998 {published data only}

Bellobouno 1999 {published data only}

Bellobuono 1995 {published data only}

Bellobuono 2000a {published data only}

Bellobuono 2000b {published data only}

Bellobuono 2000c {published data only}

Benetti 2001 {published data only}

Benhamou 2007 {published data only}

Berg 2000a {published data only}

Berg 2000b {published data only}

Bernatik 2000 {published data only}

Bernstein 1998 {published data only}

Bjøro 2000 {published data only}

Bresci 2000 {published data only}

Brillanti 1995 {published data only}

Brillanti 1999 {published data only}

Brouwer 2001 {published data only}

Bugliescu 2000 {published data only}

Calanca 2007 {published data only}

Camps 1993 {published data only}

Caremani 1996 {published data only}

Cattral 1999 {published data only}

Cavaletto 2000 {published data only}

Chapman 2001 {published data only}

Cheinquer 1998 {published data only}

Colantoni 2000 {published data only}

Davis 1998 {published data only}

De Bac 1998 {published data only}

De Franceschi 2000 {published data only}

Dettmer 2002 {published data only}

Di Bisceglie 1992 {published data only}

Di Bisceglie 1995 {published data only}

Di Marco 2000 {published data only}

Ehardt 2000 {published data only}

el‐Zayadi 1999 {published data only}

Ersöz 2000 {published data only}

Feher 2000 {published data only}

Ferenci 2000 {published data only}

Ferenci 2001 {published data only}

Fraquelli 2000 {published data only}

Gallego 2000 {published data only}

Gane 1998 {published data only}

Garnier 1997 {published data only}