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Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review

World J Hepatol. 2013 March 27; 5(3): 120-126.
Published online 2013 March 27. doi: 10.4254/wjh.v5.i3.120.

Copyright©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Simona Bota, Ioan Sporea, Roxana Şirli, Alina Popescu, Adriana Maria Neghină, Mirela Dănilă and Mihnea Străin.
Simona Bota, Ioan Sporea, Roxana Şirli, Alina Popescu, Mirela Dănilă, Mihnea Străin, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, 300736 Timişoara, Romania
Adriana Maria Neghină, Department of Biochemistry and Pharmacology, University of Medicine and Pharmacy, 300736 Timişoara, Romania
Author contributions: Bota S, Sporea I and Şirli R designed the manuscript; Bota S wrote the manuscript; Bota S, Şirli R, Popescu A and Neghină AM acquired the data; Bota S and Neghină AM performed the statistical analysis; Bota S, Sporea I, Şirli R, Popescu A, Dănilă M and Strain M interpreted the data; Sporea I, Şirli R, Popescu A, Neghina AM, Dănilă M and Străin M revised the manuscript draft; Bota S, Sporea I, Şirli R, Popescu A, Neghină AM, Dănilă M and Străin M approved the final version of the article.
Correspondence to: Simona Bota, MD, Department of Gastroenterology, University of Medicine and Pharmacy, 300736 Timişoara, Romania.
bota_simona1982@yahoo.com
Telephone: +40-721-656147 Fax: +40-256-488003
Received June 18, 2012; Revised November 26, 2012; Accepted January 17, 2013;


Abstract
AIM: To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients.
METHODS: We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk.
 
RESULTS: We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001).
 
CONCLUSION: Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.
 
Keywords: Liver cirrhosis, Hepatitis C virus, Adverse events, Sustained virological response
 
INTRODUCTION
Chronic hepatitis C virus (HCV) infection is a worldwide public health concern, affecting approximately 170 million people[1]. This condition is responsible for 25%-30% of global cases of cirrhosis and is the most common cause for liver transplantation[2]. Cirrhotic patients infected with HCV develop hepatic decompensation at a rate of 30% over 10 years and hepatocellular carcinoma at annual rates ranging from 3% to 8%[3,4].
 
In the last 10 years, pegylated interferon (PegIFN) and ribavirin became the standard of care (SOC) treatment in chronic HCV infection. The sustained virological response (SVR) rates range from 42% to 46% in patients with genotype 1 or 4 infection and from 76% to 82% in patients with genotype 2 or 3 infection[5-7]. In patients with liver cirrhosis, the SVR rate is even lower, at approximately 20% in genotype 1 or 4 infection and 55% in patients with genotype 2 or 3 infection[8]. Also, cirrhotic patients have a reduced tolerance to therapy[9,10] but the risk of further complications is smaller in patients who achieve SVR[11].
 
This systematic review aims to identify and analyze the severe adverse events (SAE) that lead to treatment discontinuation during treatment with PegIFN and ribavirin in cirrhotic patients infected with HCV.
 
MATERIALS AND METHODS
Eligibility criteria
 
This review included all the studies published in English prior to December 2011 that evaluated SAEs in cirrhotic patients infected with HCV and treated with SOC therapy: PegIFN alpha 2a (dosage: 135-180 μg/wk) or PegIFN alpha 2b (dosage: 1 or 1.5 μg/kg per week) and ribavirin (dosage range: 800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk. The diagnosis of cirrhosis was made either by liver biopsy or by clinical, ultrasonographic, endoscopic or laparoscopic signs of cirrhosis. Studies that included liver-transplanted patients or cases co-infected with hepatitis B virus or human immunodeficiency virus were excluded from the analysis.
 
Outcomes
The pre-specified primary outcome was the rate of SAEs (leading to treatment discontinuation) that occurred during treatment with PegIFN and ribavirin in cirrhotic patients infected with HCV.
The secondary outcomes were: description of SAEs; the possible relationships between SAE rates in cirrhotic patients and the following factors: decompensation of the disease (class Child-Pugh B or C), type of PegIFN (alpha 2a and alpha 2b) used in SOC therapy and HCV genotype; the proportion of patients in whom the medication dosage was reduced; and the SVR rate in cirrhotic patients, according to HCV genotype.
SVR was defined as undetectable HCV RNA in serum by real-time polymerase chain reaction 6 mo after discontinuation of therapy.
 
Data sources and searches
Relevant studies published prior to December 2011 were searched in PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases using the following keywords: liver cirrhosis, chronic hepatitis C, HCV, adverse events, sustained virological response, SVR.
Study selection and data collection
 
Two authors independently screened titles and abstracts for potential eligibility and the full texts for final eligibility. The following data were extracted: country of origin, year of publication, number of patients, age and weight of the patients, HCV genotype, the Child-Pugh class, the baseline treatment history (naive or previously treated), the treatment administered, the rate and description of SAEs that lead to treatment discontinuation, the proportion of patients in whom the doses of PegIFN and/or ribavirin were reduced, and the SVR rate according to HCV genotype.
Statistical analysis
 
Statistical analysis were carried out with the software package SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL). Descriptive statistics (percentage, 95%CI) were calculated for each variable as appropriate. Standard binomial tests for differences in proportions were used to compare patient subgroups (“n” designates the total number of patients included in a particular subgroup). A P value of less than 0.05 was regarded as statistically significant.
 
RESULTS
Of 8793 titles identified during the initial search, 8764 were excluded based on one of the following reasons: data published only in abstract, duplicated titles, data on cirrhotic patients not presented, the treatment regimen did not include PegIFN in combination with ribavirin or the same author had several similar articles, but with a different number of patients (we selected the article with the higher number of patients if we did not receive the information regarding the number of patients included in two or more studies from the author). Twelve articles which presented data on cirrhotic patients were excluded for the following reasons: the dosage or treatment duration with PegIFN and ribavirin were not standard; liver-transplanted patients were included; and the study presented the follow-up of patients after SOC therapy, but not the SAE leading to the therapy discontinuation. Finally, seventeen papers with 1133 patients with HCV liver cirrhosis were retrieved for analysis[12-28] (Figure 1). The main characteristics of the studies included in this systematic review are presented in Table 1.
 
Table 1
Characteristics of the studies included in the systematic analysis
 
Ref.Study designNo. of patientsAge (yr)WeightHCV genotypeBaseline treatment historyChild-Pugh classTreatment
Syed et al[12]Retrospective cohort study10452 ± 7.682 ± 15 kg (mean weight)1, 2, 3Naive and previously treatedAPegylated interferon alpha 2a (180 μg/wk) or alpha 2b (1-1.5 μg/kg per week)
Ribavirin (800-1200 mg/d)
Butt et al[13]Prospective cohort study6646.2 ± 10.122.3 ± 3.1 kg/m² (mean BMI)3Naive and previously treatedA, BPegylated interferon alpha 2a (180 μg/wk) or alpha 2b (1 μg/kg per week)
Ribavirin (10-12 mg/kg per day)
Giannini et al[14]Retrospective cohort study8556 ± 9Not specified1, 2, 3, 4Naive and previously treatedA, BPegylated interferon alpha 2a (180 μg/wk) or alpha 2b (1.5 μg/kg per week)
Ribavirin (800-1200 mg/ d)
Helbling et al[15]Randomized controlled trial (standard doses vs low doses)6447 (median age)74 kg (median weight)1, 2, 3, 4NaiveAPegylated interferon alpha 2a (180 μg/wk)
Ribavirin (1000-1200 mg/ d)
Iacobellis et al[16]Prospective cohort study94Not specifiedNot specified1, 2, 3, 4NaiveBPegylated interferon alpha 2b (1.5 μg/kg per week)
Ribavirin (800-1200 mg/d)
Roffi et al[17]Randomized controlled trial (pegylated interferon vs IFN standard)5756 (median age)75 kg (median weight)1, 2, 3NaiveAPegylated interferon alpha 2b (1 μg/kg per week)
Ribavirin (800-1200 mg/d)
Sood et al[18]Retrospective cohort study2848.3 ± 773.9 ± 11.2 kg (mean weight)3 (25/28 patients) and not specified for the other patientsNaiveA, BPegylated interferon alpha 2b (1 μg/kg per week)
Ribavirin (10-12 mg/kg per day)
Tekin et al[19]Cohort study2054.2 ± 5.9Not specified1Not specifiedA, BPegylated interferon alpha 2a (135 μg/wk)
Ribavirin (1000-1200 mg/d)
Moreno Planas et al[20]Cohort study1252 ± 8Not specified1, 3Naive and previously treatedA, BPegylated interferon alpha 2b (1.5 μg/kg per week)
Ribavirin (10.6 mg/kg per day)
Di Marco et al[21]Randomized controlled trial (pegylated interferon alpha 2B + ribavirin vs pegylated interferon alpha 2b)5257 ± 6.671 ± 10.1 kg (mean weight)1, 2, 3, 4Naive and previously treatedA, BPegylated interferon alpha 2b (1 μg/kg per week)
Ribavirin (800 mg/d)
Höroldt et al[22]Retrospective cohort study61Not specifiedNot specified1, 2, 3NaiveA, BPegylated interferon alpha 2a or alpha 2b + ribavirin
Bruno et al[23]Randomized study106Not specifiedNot specified1, 2, 3, 4NaiveAPegylated interferon alpha 2a (180 μg/wk)
Ribavirin (1000-1200 mg/d)
Floreani et al[24]Prospective cohort study8755.7 ± 9.125.3 ± 3.1 kg/m² (mean BMI)1, 2, 3NaiveAPegylated interferon alpha 2b (80-100 μg/wk)
Ribavirin (1000-1200 mg/d)
Annicchiarico et al[25]Prospective cohort study1551.5Not specified1, 2, 3Naive and previously treatedB, CPegylated interferon alpha 2b (1.5 μg/kg per week)
Ribavirin (800-1200 mg/d)
Aghemo et al[26]Prospective cohort study10657 ± 9.372.5 ± 11.8 kg (mean weight)1, 2, 3, 4NaiveAPegylated interferon alpha 2b (1.5 μg/kg per week)
Ribavirin (≥ 10.6 mg/kg per day)
Kim et al[27]Cohort study8656.4 ± 9.6Not specified1 and non-1Not specifiedAPegylated interferon alpha 2b (1.5 μg/kg per week)
or Pegylated interferon alpha 2a (180 μg/wk)
Ribavirin (1000-1200 mg/d)
Reiberger et al[28]Prospective cohort study9051 ± 826.6 ± 5 kg/m² (mean BMI)1, 2, 3, 4Not specifiedAPegylated interferon alpha 2b (1.5 μg/kg per week)
or pegylated interferon alpha 2a (180 μg/wk)
Ribavirin (1000-1200 mg/d)
HCV: Hepatitis C virus; BMI: Body mass index; IFN: Interferon.
 
 
 
Figure 1
Flowchart of the selection of the studies. SOC: Standard of care; SAE: Severe adverse event.
 
 
Table 2
Description of severe adverse event leading to premature discontinuation of antiviral treatment in hepatitis C virus cirrhotic patients (%)
 
Name of severe adverse eventNo. of patient discontinuities
Severe thrombocytopenia and/or neutropenia27 (23.2)
Psychiatric disorders (depression, psychosis, confusion, lethargy)18 (15.5)
Decompensation of liver cirrhosis (ascites with or without spontaneous bacterial peritonitis; jaundice; hepatic encephalopathy)14 (12.1)
Severe anemia13 (11.2)
Occurrence of malignancies6 (5.1) - 4 cases of hepatocellular carcinoma, 1 case of tongue carcinoma and 1 case of Non-Hodgkin’s lymphoma recurrence
Allergic reactions to medication5 (4.3)
Severe infections5 (4.3)
Severe fatigue5 (4.3) - in 2 cases accompanied also by “flu-like” syndrome
Neurological disorders (stroke, polyneuropathy, hemiparesthesia)5 (4.3)
Heart disease (heart failure or acute coronary syndrome)3 (2.5)
Endocrinology disorders3 (2.5)
Diabetes decompensation2 (1.7)
Persistent fever2 (1.7)
Severe denutrition2 (1.7)
Aminotransferases flare1 (0.8)
Severe decrease of vision1 (0.8)
Upper gastrointestinal bleeding1 (0.8) - the cause of bleeding was not specified
Acute pancreatitis1 (0.8)
Severe flare of psoriasis1 (0.8)

World J Hepatol. 2013 March 27; 5(3): 120–126.
Published online 2013 March 27. doi: 10.4254/wjh.v5.i3.120.

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