ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2018.6255 ETM-0-0-6255 Articles Psychiatric side effects of pegylated interferon-α and ribavirin therapy in Iranian patients with chronic hepatitis C: A meta-analysis DavoodiLotfollah 1 MasoumBabak 2 MoosazadehMahmood 3 JafarpourHamed 4 HaghshenasMohammad Reza 5 MousaviTahoora 6 Department of Infectious Diseases, Mazandaran University of Medical Sciences, Sari 48147-88458, Iran Psychiatry and Behavioral Sciences Research Center, Department of Psychiatry, Mazandaran University of Medical Sciences and Health Service, Sari 48147-88458, Iran Health Science Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari 48147-88458, Iran Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48147-88458, Iran Department of Microbiology, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48147-88458, Iran Student Research Committee, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 48147-88458, Iran Correspondence to: Dr Tahoora Mousavi, Student Research Committee, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Farah Abad Road, Sari 48147-88458, Iran, E-mail: stm.jmums@gmail.com 08 2018 06 06 2018 16 2 971 978 03112017 08022018 Copyright © 2018, Spandidos Publications 2018

An estimated 185 million people worldwide are infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon-α (peg IFN) and ribavirin is the first line of treatment against the psychiatric side effects, including mood disorders, anxiety and irritability. In the present study, all of the studies electronically published between 2000 and 2016 were retrieved using databases including Scopus, PubMed, Institute for Scientific Information, Science Direct and Google Scholar. All of the articles were independently evaluated by two reviewers and the results were compared, followed by removal of duplicate, irrelevant and re-published studies after reviewing. The studies were assessed based on the heterogeneity of their results using the Cochrane test and I2 analysis. All groups included neuropsychiatric side effects, fatigue was reported at the highest rate in 60.41% [95% confidence interval (CI)=39.18–81.64%] and insomnia was reported at a lower rate in 16.28% of cases (95% CI=6.59–25.98%). In conclusion, the present meta-analysis indicated that treatment with peg IFN + ribavirin or interferon only is associated with a wide range of neuropsychiatric side effects, including fatigue, mood disorders, anxiety, irritability, emotional ability and agitation.

 psychiatric side effects pegylated interferon-α ribavirin Iran chronic hepatitis C meta-analysis Introduction

An estimated 185 million individuals worldwide are infected with Hepatitis C virus (1,2). Most of the mortalities associated with hepatitis C virus infection are due to cirrhosis and liver cancer (3). Combination therapy with pegylated interferon-α (peg IFN) and ribavirin is the first line of treatment (4). On average, 55% of patients consistently used these drugs (5). peg IFN in combination with ribavirin is the currently recommended treatment for 70–80% of genotype 2 or 3 and is also used for 40–50% of genotype 1 patients with HCV infection, and conventional interferon were used for other patients (6,7). peg IFN and ribavirin are successful antiviral treatment for numerous adverse effects, including fatigue, mood disorders, anxiety, irritability, emotional lability, agitation, apathy, anhedonia, anorexia, retardation, sleep disturbance, sexual dysfunction and cognitive deficits have been reported during and after the treatment of hepatitis C (8–10). Various studies have reported psychiatric side effects in ~84.5% of patients during treatment with peg IFN and in 42.6% of patients at 6 months after completion of treatment (7,11). In terms of psychiatric side effects, a relatively large body of literature documents high rates of psychiatric symptoms, the definition of which varies between studies, but all of them indicated that IFN induced psychiatric side effects ranging from 30–70% for depression, 39–80% for fatigue, 18–45% for sleep disturbances, 16–50% for irritability, 11–45% for anxiety, 0.0–3.2% for mania, 0.0–0.6% for psychosis, 3.5–10% for suicidal ideation and 0.0–0.2% for suicidal attempts Previous studies have demonstrated that non-specific symptoms occur early and that certain psychiatric side effects may occur following the onset of therapy; most of these events occur after 3 weeks (12,13). These side effects were evaluated in patients treated with peg IFN and ribavirin in order to determine whether it is reasonable to reduce these effects by replacing those drugs. The present meta-analysis study assessed the psychiatric side effects of peg IFN and ribavirin in Iranian patients with chronic hepatitis C infection.

 Materials and methods <sec> <title>Data source

In the present study, all of the studies published in electronic format from January 2000 up to December 2016 were included. Articles were searched using various international and Persian databases, including Scopus, PubMed, Institute for Scientific Information, Science Direct, Google Scholar, Magiran and SID (sid.ir). The search strategy was performed using the following major key words: ‘Prevalence’, ‘HCV’, ‘Iran’, ‘psychiatry’, ‘ribavirin’ and ‘interferon’. ‘AND’/‘OR’ operators were used to identify the articles, e.g. (interferon alpha OR pegylated interferon) AND (HCV OR Hepatitis C virus OR hepatitis C) AND (Iran OR Islamic Republic of Iran). In addition, all of the studies with a different aim to the present study were removed using the ‘NOT’ operator. For increasing the sensitivity of the present study, the references of retrieved articles were also considered. Two reviewers performed random searches in order to retrieve all of the relevant studies.

 Study selection Retrieval of articles

During the advanced search, all articles retrieved were collected, and duplicates and irrelevant articles were removed after reviewing the titles and abstracts. In addition, re-publication bias was prevented via excluding the any studies containing duplicated data. The articles were evaluated by two reviewers (T.M. and M.M.) independently and their results were compared with each other. Any disagreements were resolved by consultation with another researcher.

 Quality assessment

In the present study, the quality of the selected articles was assessed with a STROBE checklist. This checklist comprised 22 questions based on the Strengthening the Reporting of Observational Studies in Epidemiology statement (14). These questions contain all of the aspects of the methodology, including data collection methods and tools, type of the study, definition of the variables, statistical analysis tests, study objectives, sample size estimation selection and study population. Each question was assigned to score one point. In this checklist, the minimum and maximum scores are 0 and 44, respectively. Based on the results of the quality assessment, studies were divided into three categories: Low (<15.5), average (15.5–29.5) and high quality (>30) and studies with low-quality scores were excluded from the final meta-analysis.

 Inclusion criteria

All of the articles in English and Persian language with sufficient quality scores were included in meta-analysis if they met the following inclusion criteria: i) HCV patients using interferon or ribavirin or a combination of these two drugs during treatment; ii) the studies reported on psychiatric side effects among patients receiving IFN or ribavirin or their combination; iii) cross-sectional (descriptive-analytic) studies or cohort studies.

 Exclusion criteria

The exclusion criteria applied in the present study were as follows: i) Case reports, author replies, animal studies, case series, reviews, commentaries, studies presented at conferences, studies that did not achieve the desired scores or that were unpublished; ii) duplicated studies and iii) studies reporting on psychiatric side effects among HCV patients that received other drugs.

 Data extraction

The following information was extracted from the selected the articles: Title, author names, publication date, study location, population group, population size, age, study language, drug use and factors of psychiatric side effects. The information was recorded in an excel spreadsheet.

 Statistical analysis

The standard error for primary studies was calculated with a binomial distribution formula: (Se=P.(1-P)n). The degree of heterogeneity among the results was estimated by Cochrane's test (Q) and I2 indexes. For detection of heterogeneity, a forest plot was used to indicate the mean frequency of occurrence and estimates with 95% confidence intervals (CIs; horizontal lines). Furthermore, publication biases were evaluated with Egger's test (with a significance level of <0.01). All statistical analyses were performed using the Stata SE, v.11 software (StataCorp LP, College Station, TX, USA).

 Results <sec> <title>Study selection

In the initial search, 2,483 articles in the field of interest were identified. After the first limitation, 1,674 articles were preliminarily selected according to the search strategy. Subsequently, 387 duplicated articles on the same study were excluded and thereafter, 406 articles were removed due to having an irrelevant title and/or abstract. Finally, 16 eligible studies were retained (15–30), which were included in the meta-analysis (Fig. 1; Table I).

 Quality evaluation

Among the selected studies, the prevalence of fatigue was reported in 5 articles comprising 802 patients and ranged from 21.6–74.0% (Table I). As there was heterogeneity between the results for fatigue, the random-effects model was used for assessment. By combining the results of these 5 studies, the frequency of fatigue was determined to be 60.41% (95% CI; 39.18–81.64%; Fig. 2; Table II).

In the present study, the prevalence of depression was reported in 6 articles comprising 706 patients and ranged between 5.8 and 39% (Table I). Combination of these 6 studies in the same manner as for fatigue, using the random effect model revealed that the frequency of depression was 17.46% (95% CI; 9.03–25.88%; Fig. 3).

A total of 6 articles including 646 patients reported on the prevalence of headache, which ranged from 10.3–71.40% (Table I). Due to the heterogeneity in the results of the primary studies (Table II), the random-effects model used for assessment. By combining these 6 articles, it was revealed that headache had a prevalence of 29.71% (95% CI; 16. 55–42.87%; Fig. 4).

The prevalence of mood disorders was reported in 6 articles comprising 275 patients and ranged from 27.5–48% respectively (Table I). Based on the heterogeneity between the results of the primary studies (Table II), the random-effects model was used for assessment. By combining of these 6 articles, mood disorders were determined to have a prevalence of 32.97% (95% CI; 27.45–38.49; Fig. 5).

The prevalence of insomnia was assessed in 7 articles including 897 patients and the rate of insomnia varied between 4.9 and 32.8% (Table I) (21,28). Based on the heterogeneity between the results of the primary studies (Table II), the random-effects model was used for assessment, revealing a frequency of insomnia in 16.28% (95% CI; 6.59–25.98%) of patients among the 7 studies (Fig. 6).

The prevalence of anorexia was assessed in 4 articles comprising 494 patients and was reported to range from 0–66.2% (Table I). Due to the heterogeneity in the results of the primary studies (Table II), the random-effects model was employed. Combined analysis of these 4 articles revealed that anorexia occurred in 31.35% of patients (95% CI; 6.10–56.59%; Fig. 7).

In the present meta-analysis, adverse events of nervousness, dizziness, lethargy and irritability as well as morning headache were reported to be 34.7, 20, 21, 24 and 3.4%, respectively. Two studies reported on the prevalence of somnolence, which was 22.5 and 13.7%, respectively. Anxiety and excitability rates were reported as 41 and 16.1%, respectively. Weakness was reported in 3 studies with a prevalence of 0.5, 32.2 and 17.2%, respectively.

Egger's test was performed to assess the publication bias and the results are presented in Tables II. This test indicated that publication bias was not statistically significant (except for the outcome of anorexia). In addition, the age of the patients, duration of drug use and publication year were considered as variables associated with heterogeneity in the Meta regression (Table III). The publication year had a significant role regarding the heterogeneity in the results for fatigue, depression and headache among the initial studies. Due to the small amount of data, subgroup analysis was not performed. Furthermore, due to the insufficient amount of evidence, it was not possible to consider the factors determining the heterogeneity regarding the outcome of anorexia.

The present study demonstrated that the majority of the psychiatric side effects, including weakness, anorexia, mood change, irritability, headache, fatigue, depression, nervousness, insomnia, anxiety, lethargy and dizziness were detected in patients who received ribavirin and interferon. Conversely, somnolence, morning headache and excitability were demonstrated in patients who ribavirin treatment. These results suggest that taking ribavirin alone is the most effective for treatment of patients with HCV, particularly in individuals suffering from mental illness.

 Discussion

The present meta-analysis study assessed the neuropsychiatric side effects among Iranian patients with hepatitis C that received peg IFN and ribavirin treatments for the first time, to the best of our knowledge. In all groups, the neuropsychiatric side effects with the highest and lowest frequency were fatigue 60.41% (95% CI; 39.18–81.64%) and insomnia 16.28% (95% CI; 6.59, 25.98%).

In the present study, fatigue was the most common neuropsychiatric symptom during IFN plus ribavirin or IFN therapy 60.41% (95% CI, 39.18–81.64%). It has been indicated that fatigue is associated with decreased adherence to treatment and reduced viral response (17,18,22). Certain patients receiving IFN plus ribavirin or IFN only develop fatigue without necessarily suffering from any somatic symptoms of depression or depressive emotional complaints, including sadness, hopelessness, guilt or anhedonia. Although patients receiving IFN-based therapy may have fatigue without fulfilling the criteria for clinical depression, fatigue may be considered to be an important symptom of depression (15,18,20–22).

For the above reasons, patients receiving IFN-ribavirin therapy who present with fatigue as well as sleep and/or appetite disturbance should be evaluated for clinical depression. In certain studies, headache is reported as one of the most frequent neuropsychiatric side effects of IFN-based treatment (occurrence rate, 29.6%) (20–25), which was similar to the results reported in the meta-analysis in the present study 29.61% (95% CI; 16.44–42.77%).

An important neuropsychiatric side effect, which is most frequently associated with IFN plus ribavirin or IFN monotreatment, is depression (16,17). In this context, depression occurs in a spectrum from minor to clinical depression in the range of 5.80% (95% CI, 1.20–15.90%) and 39% (95% CI, 29.44–48.56%). Certain studies have diagnosed depression based on certain symptoms (16,26,29), while others have defined depression as a syndrome characterized by a defined set of emotional and physical symptoms (15,17,20).

The prevalence of depression was determined to be 17.46% (95% CI, 9.03–25.88%) in the present meta-analysis. Although this is not a very high rate, it is important, as depression occurring during the treatment of hepatitis C may be associated with a reduced quality of life and also interfere with the patient pursuing to receive health care (20). Of note, as certain adverse effects, including fatigue as well as sleep and appetite disturbances may overlap with depression, patients should be evaluated for major depression.

Numerous patients treated with IFN plus ribavirin or IFN only for hepatitis C experienced mood disorders. Of note, in the present meta-analysis the prevalence of mood disorders was determined to be 32.97% (95% CI, 27.45–38.49%). Irritability in patients receiving IFN plus ribavirin was reported by one study (17) and excitability was reported by one study on IFN (24). Certain patients have been suffered from sleep disturbances as a side effect of hepatitis treatment (26). In the present meta-analysis, the rate of insomnia was determined to be 16.28% (95% CI, 6.59–25.98%). Only two studies reported on the prevalence of somnolence, providing rates of 22.5 and 13.7% (24,25). Appetite disturbances were more frequent and anorexia was determined in 31.35% (95% CI, 6.10–56.59%) of patients according to the present meta-analysis. Nervousness (34%) (15), dizziness (20%) (17), lethargy (21%) (17) and anxiety (41%) (17) were reported in only one study for each. In the present meta-analysis, immune suppression and the length of treatment with peg IFN and ribavirin in chronic patients were not taken into account, which is a limitation of the present study.

In conclusion, the present meta-analysis indicated that treatment with IFN plus ribavirin or IFN only is associated with a wide range of neuropsychiatric side effects. Fatigue is the most common single neuropsychiatric symptom during IFN-based therapy. Other common neuropsychiatric side effects were mood disorders and depression, headache, anorexia and sleep disturbances. Certain patients who were treated with IFN plus ribavirin or IFN only experienced nervousness, dizziness, lethargy, irritability and anxiety. Finally, based on the results of the present meta-analysis, it is recommended that psychiatrists are increasingly involved in the care of such patients.

 Acknowledgements

Not applicable.

 Funding

No funding was received.

 Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

 Authors' contributions

LD, TM and BM conceived and designed the study and wrote the manuscript. MRH and HJ performed the literature search and collected the data. MM performed the statistical analysis, and all authors read and approved the final version of the manuscript.

 Ethical approval and consent to participate

Not applicable.

 Consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing of interests.

 References ShepardCWFinelliLAlterMJGlobal epidemiology of hepatitis C virus infectionLancet Infect Dis5558567200510.1016/S1473-3099(05)70216-416122679 WuJYShadboltBTeohNBlunnAToCRodriguez-MoralesIChitturiSKayeGRodrigoKFarrellGInfluence of psychiatric diagnosis on treatment uptake and interferon side effects in patients with hepatitis CJ Gastroenterol Hepatol2912581264201410.1111/jgh.1251524955454 TeohNCFarrellGCChanHLIndividualisation of antiviral therapy for chronic hepatitis CJ Gastroenterol Hepatol2512061216201010.1111/j.1440-1746.2010.06392.x20594246 SpennatiAParianteCMWithdrawing interferon-α from psychiatric patients: clinical care or unjustifiable stigma?Psychol Med4311271132201310.1017/S003329171200180822975198 HauserPMorascoBJLinkeABjornsonDRuimySMatthewsARifaiAIndestDWLoftisJMAntiviral completion rates and sustained viral response in hepatitis C patients with and without preexisting major depressive disorderPsychosomatics50500505200910.1016/S0033-3182(09)70843-619855036 FriedMWShiffmanMLReddyKRSmithCMarinosGGonçalesFLJrHäussingerDDiagoMCarosiGDhumeauxDPeginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infectionN Engl J Med347975982200210.1056/NEJMoa02004712324553 MannsMPMcHutchisonJGGordonSCRustgiVKShiffmanMReindollarRGoodmanZDKouryKLingMAlbrechtJKPeginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trialLancet358958965200110.1016/S0140-6736(01)06102-511583749 LoftisJMHauserPThe phenomenology and treatment of interferon-induced depressionJ Affect Disord82175190200410.1016/j.jad.2004.04.00215488246 AsnisGMde La GarzaRIIMillerAHRaisonCLRibavirin may be an important factor in IFN-induced neuropsychiatric effectsJ Clin Psychiatry65581582200410.4088/JCP.v65n0420b15119925 AsnisGMde La GarzaRRegoSAHendersonMAReinusJFInterferon for hepatitis C patients with psychiatric disordersAm J Psychiatry16123322334200410.1176/appi.ajp.161.12.2332-a15569920 HuckansMFullerBWheatonVJaehnertSEllisCKolessarMKrizDAndersonJRBerggrenKOlavarriaHA longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis CJ Psychosom Res78184192201510.1016/j.jpsychores.2014.07.02025219976 MasipMTuneuLPagèsNTorrasXGallegoAGuardiolaJMFausMJManguesMAPrevalence and detection of neuropsychiatric adverse effects during hepatitis C treatmentInt J Clin Pharm3711431151201510.1007/s11096-015-0177-126267215 ComanHGHERŢADCNemeşBPsychiatric adverse effects of interferon therapyClujul Med86318320201326527969 Von ElmEAltmanDGEggerMPocockSJGøtzschePCVandenbrouckeJPIniciativa STROBE: The strengthening the reporting of observational studies in epidemiology [STROBE] statement: Guidelines for reporting observational studiesGac Sanit221441502008(In Spanish)10.1157/1311932518420014 AlavianSMKabirAHajarizadehBNayebpourMDorodiTBaralleFEPreliminary report of interferon α2b in combination with ribavirin for 48 weeks for treatment of iranian patients with chronic hepatitis C: A quasi-experimental studyShiraz E Med J7182006 AlavianSMHajarizadehBHajibeigiBDoroudiTHamadanizadehAKAbarKEfficacy and safety of pegylated interferon alfa-2a plus ribavirin for treatment of chronic hepatitis C and cirrhosis in IranianHepat Mon453582004 AlavianSMTabatabaeiSVKeshvariMBehnavaBMiriSMElizeePKLankaraniKBPeginterferon alpha-2a and ribavirin treatment of patients with haemophilia and hepatitis C virus infection: A single-centre study of 367 casesLiver Int3011731180201010.1111/j.1478-3231.2010.02296.x20629950 AlavianSMAbolghasemiHMiriSMKeshvariMKarimi ElizeePBehnavaBTabatabaeiSVHajibeigiBLankaraniKBSafety and Efficacy of Pegylated Interferon Alfa-2a for the Treatment of Hepatitis C in Patients with Major ThalassemiaIranian J Biood Cancer11291372009 AlavianSMAhmadzadMKeshvariMBehnavaBHajibeigiBEfficacy and safety of Interferon-alpha (Dferon B®and Ribavirin combination therapy in patients with chronic hepatitis C in IranHep Mon611182006 BafandehYSaberiFMBAGHERILKEvaluation of combination therapy with interferon and ribavirin in patients with chronic hepatitis CA genotype based study2007 ForootanHSharifiAMirmomenSHDaryaniNEGhofraniHFarahvashMNasiriMTalebiMGhavidelAVosoghiniaHA multicenter study to evaluate the safety and efficacy of heber on (interferon alfa-2b) in combination with ribavirin for the treatment of chronic hepatitis C in iranMed J Islam Repub Iran197122005 JabbariHBayatianASharifiAHZaer-RezaeeHFakharzadehEAsadiRZaminiHShahzamaniKMeratSNassiri-ToosiMSafety and efficacy of locally manufactured pegylated interferon in hepatitis C patientsArch Iran Med13306312201020597564 MeratSSohrabpourAAKhaleghiSSohrabiMRSamimi-RadKRadmardARMalekzadehRPeginterferon alfa-2a and ribavirin in patients with chronic hepatitis C and inherited bleeding disordersHepat Mon459642004 MirmomenSEbrahimi DaryaniNMalekzadehRZaliMRHaghpanahBPoursamimiPHashemiSAlavianSMThe efficacy and safety of peginterferon alpha-2a (PEGASYS) monotherapy in the treatment of chronic hepatitis C infected subjects with transfusion dependent thalassemiaHepat Mon465702004 MirmomenSGhofraniHForootan PishbuaryHEbrahimi DaryaniNJafar FarahvashMSharifianRAzmodehFMalekzadehRSafety and efficacy of interferon alfa for the treatment of chronic hepatitis C infected subjects with transfusion dependent thalassemia in IranMed J Islam Repub Iran1787952003 NamazeeNSaliSAsadiSShafieiMBehnavaBAlavianSMReal response to therapy in chronic hepatitis C virus patients: A study from iranHepat Mon12e6151201210.5812/hepatmon.615123087759 Nasser EbrahimiDBabakHAliRezaSAli AsadHMohammadBParisaPNikbinMThe efficacy and side effects of therapy with peginterferon alpha-2 a (PEGASYS) combined with ribavirin in chronic hepatitis C patients: An open label clinical trialHepat Mon200471742004 PouresmaeeliMAlavianSMKeshvariMSalimiSMehrnoushLEfficacy and tolerability of peginterferon alpha-2a and peginterferon alpha-2b in Iranian patients with chronic hepatitis CHepat Mon15e30780201510.5812/hepatmon.3078026504470 SandoughdaranSAlavianSMSharafiHBehnavaBSalimiSMehrnoushLKarimi ElizeePKeshvariMEfficacy of prolonged treatment with pegylated interferon (Peg-IFN) and ribavirin in thalassemic patients with hepatitis C who relapsed after previous peg-IFN-based therapyHepat Mon15e23564201510.5812/hepatmon.2356425741371 ZaliMRShalmaniHMNorouziniaMAlizadehAHNowrooziABerouzNPeginterferon Alfa-2a (Pegasys) and Ribavirin in the treatment of chronic hepatitis CHepat Mon475782004

Flow diagram of the selection of studies included in the present meta-analysis.

Forest plot of fatigue in primary studies. ES, effect size; CI, confidence interval.

Forest plot of depression in primary studies. ES, effect size; CI, confidence interval.

Forest plot of headache in primary studies. ES, effect size; CI, confidence interval.

Forest plot of mood disorders in primary studies. ES, effect size; CI, confidence interval.

Forest plot of insomnia in primary studies. ES, effect size; CI, confidence interval.

Forest plot of anorexia in primary studies. ES, effect size; CI, confidence interval.

Characteristics of primary studies.

First author, year Sample size age, years Drug treatment Duration (months) Nerv. Fat. Dep. Morning Ha. Ha. Dizzi. Lethargy Somn. Anxiety Exc. Mood changes Weak. Irrit. Ins. An. Scorea (Refs.)
Namazee, 2012 100 42.0 Interferon+ribavirin 48 74 39 38 7 18 (26)
Alavian, 2006 176 38.9 Interferon+ribavirin 48 34.7 21.6 0.5 19 (19)
Mirmomen, 2004 32 24.1 Interferon 48 16.3 22.5 16.1 29 32.2 17 (24)
Alavian, 2004 52 38.5 Interferon+ribavirin 48 5.8 18 (16)
Alavian, 2010 367 30.0 Interferon+ribavirin 48 60 19 36 20 21 41 24 26 18 (17)
Alavian, 2009 51 25.0 Interferon 48 74 20   (18)
Bafandeh, 2007 118 37.47 Interferon+ribavirin 24 15 16 (20)
Forootan, 2005 97 35.1 Interferon+ribavirin 12 13.6 36 4.9 34 18 (21)
Jabbari, 2010 108 39.0 Interferon 24 73.5 66.2 17 (22)
Mirmomen, 2003 29 25.24 Interferon 12 3.4 10.3 13.7 27.5 17.2 17 (25)
Merat, 2004 37 30.1 Interferon+ribavirin 48 31.4 16 (23)
Zali, 2004 57 41 Interferon+ribavirin 48 29.4 17 (30)
Sandoughdaran, 2015 21 29.7 Interferon+ribavirin 72 23.8 71.4 9 16 (29)
Pouresmaeeli, 2015 247 39.2 Interferon-2a+ribavirin 32.8 25.9 17 (28)
Pouresmaeeli, 2015 42 37.7 Interferon-2b+ribavirin 9.5 0 17 (28)
Nasser Ebrahimi, 2004 23 45.43 Interferon+ribavirin 48 48 26 15 (27)
Alavian, 2006 48 39.8 Interferon+ribavirin 6.25 19 (15)

Strobe checklist was used to score. Nerv., nervousness; Fat., fatique; Dep., depression; Ha., headache; Diz., dizziness; Somn., Somnolence; Exc., excitability; Weak., weakness; Irrit., Irritability; Ins., insomnia; An., anorexia.

Results of meta-analysis and publication bias (Egger's test).

Frequency Heterogeneity Publication bias (Egger's test)
Complication type Number of studies Sample size % CI 95% I-squared Q P-value β P-value
Fatigue 5 802 60.41 39.18–81.62   97.6% 166.9 <0.001 8.9 0.460
Depression 6 706 17.31   8.88–25.75 91.5   42.8 <0.001 1.2 0.743
Headache 6 646 29.61 16.44–42.77 92.2   63.9 <0.001 0.1 0.979
Mood disorders 6 275 32.97 27.45–38.49 0   3.54 0.617 0.3 0.849
Insomnia 7 897 16.21   6.61–25.80 93.6   93.2 <0.001 0.7 0.877
Anorexia 4 494 31.29   3.65–58.94 99.1 347.7 <0.001 10.4 0.043

CI, confidence interval.

Factors associated with heterogeneity between primary studies in the Meta regression analysis.

Age Duration of drug use Publication year
Adverse event β P-value β P-value β P-value
Fatigue −0.7 0.735 −0.7 0.598 8.9 0.058
Depression   0.06 0.963   0.2 0.690 2.9 0.033
Headache   0.8 0.661   0.8 0.032 3.9 0.002
Insomnia   0.2 0.832 0.1 0.639 0.2 0.875