more than 170 million persons worldwide are infected with the hepatitis c virus ( hcv ) , and the number of deaths caused by hcv - related liver diseases is more than 35 thousand per year.1 in addition , hcv infection is associated with an increased incidence of hepatocellular carcinoma.2 to reduce the risk of developing hepatocellular carcinoma and hcv - related liver diseases , a treatment based on interferon ( ifn ) is commonly used for patients with chronic hepatitis c.3 two types of pegylated interferon ( peg - ifns ) ( alfa-2a and alfa-2b ) are used , which are pegylated to improve their pharmacokinetic effects and pharmacodynamic actions , and which have a higher rate of sustained virologic response ( svr ) and lower frequency of incidence of adverse reactions than ifn.4 thus far , the general recommendation for the treatment of patients with chronic hepatitis c involves combination therapy with peg - ifn ( alfa-2a or alfa-2b ) and ribavirin ( rbv).3 however , previous studies that have compared the effectiveness and safety of treatment with peg - ifn alfa-2a and alfa-2b for patients with chronic hepatitis c have yielded conflicting results.58 the largest randomized controlled trial ( rct ) to date was a comparison in 2009 of svr and safety in the treatment of 3,070 patients with chronic hcv genotype 1 among three groups ( low - dose peg - ifn alfa-2b plus rbv ; standard - dose peg - ifn alfa-2b plus rbv ; and peg - ifn alfa-2a plus rbv).9 that study excluded patients with hepatitis b virus ( hbv ) or human immunodeficiency virus ( hiv ) infection , as well as other liver diseases , and found that the rates of svr and adverse event profiles among the three groups were similar . on the other hand , some meta - analyses of rcts comparing peg - ifn alfa-2a and alfa-2b suggested a higher svr rate in the alfa-2a group than in the alfa-2b group.5,6 however , several limitations involving the study quality were pointed out , including a small sample size as well as inadequate blinding and randomization.5 a large retrospective cohort study was conducted to compare the svr rate obtained with peg - ifn alfa-2a and alfa-2b for the treatment of patients with chronic hepatitis c in germany.10 a total of 3,414 patients were identified as a study cohort from the database . this study allowed the inclusion of patients who had a comorbid hbv or hiv infection and any hcv genotype , and used matched pair analysis , using the baseline patient characteristics to compare the rates of svr with peg - ifn alfa-2a and alfa-2b . although a higher svr rate was found for alfa-2a than for alfa-2b , the possibility of residual uncontrolled confounding was acknowledged , such as details of the therapeutic profiles , for eg , the duration of therapy in the two groups were different , even after subject matching.10 thus far , a definitive conclusion has yet to be reached regarding the superiority of one peg - ifn over the other . in this study , we aimed to compare the rates of svr with peg - ifn alfa-2a and alfa-2b in combination with rbv for chronic hepatitis c , using a large database of hepatitis cases to improve the generalizability of these results . because hepatitis is becoming one of the most prevalent major infectious diseases , the basic act on measures against hepatitis in japan was established to conquer hepatitis , by providing high quality medical care for patients with a hepatitis viral infection.11 as part of this measure , the japanese interferon database , which is comprised of more than 16,000 patient records regarding ifn treatment for chronic hepatitis and/or cirrhosis , collected retrospectively from throughout japan , was developed . this database contains diagnosis , ifn treatment data ( type of ifn , with or without rbv ) , results of laboratory tests ( date of test , hcv rna , type of hcv genotype , aspartate aminotransferase , alanine aminotransferase [ alt ] , and platelet count ) , adverse drug reactions , and outcomes ( svr , and completed or discontinued treatment ) , which have been recorded in a standardized report form by practitioners . serum hcv rna levels were quantitated by cobas amplicor hcv monitor v2.0 ( roche molecular systems , pleasanton , ca , usa ) or cobas taqman hcv test ( roche molecular systems ) . this study was approved by the institutional review board of the national center for global health and medicine . we identified all of the patients with chronic hepatitis c from the japanese interferon database who had received a combination treatment of peg - ifn ( alfa-2a or alfa-2b ) and rbv between december 2009 and april 2013 . patients meeting any of the following criteria were excluded from this study : comorbid cirrhosis or hbv infection ; without rbv use ; dual therapy with peg - ifn alfa-2a and alfa-2b ; any missing data items ( sex , age , diagnosis , and/or comorbid condition , ie , liver diseases ) ; and age under 16 years . descriptive statistics were calculated as absolute numbers , percentages , and means (  standard deviation [ sd ] ) for each group . patient baseline characteristics were compared between peg - ifn alfa-2a and alfa-2b , using a t - test for age , the wilcoxon rank - sum test for duration of therapy , the mantel haenszel chi - square statistic for genotype , and the chi - square test for the other categorical variables . we also compared adverse events in the patients withdrawn from study , according to hcv genotype , using the fisher s exact test . to explore the association of patient svr with chronic hepatitis c , we used multivariate logistic regression to calculate the adjusted odds ratio ( or ) and the associated 95% confidence intervals ( cis ) . we included covariates to adjust for age , sex , platelet counts , alt level , hcv viral load , genotype , and frequency of treatment . interaction analyses were performed with the logistic regression model , to test for interactions between peg - ifn and level of treatment experience or hcv genotype . the results indicated that there were no significant interactions ( between type of peg - ifn and treatment experience [ p=0.229 ] or between type of peg - ifn and hcv genotype [ p=0.069 ] ) . because hepatitis is becoming one of the most prevalent major infectious diseases , the basic act on measures against hepatitis in japan was established to conquer hepatitis , by providing high quality medical care for patients with a hepatitis viral infection.11 as part of this measure , the japanese interferon database , which is comprised of more than 16,000 patient records regarding ifn treatment for chronic hepatitis and/or cirrhosis , collected retrospectively from throughout japan , was developed . this database contains diagnosis , ifn treatment data ( type of ifn , with or without rbv ) , results of laboratory tests ( date of test , hcv rna , type of hcv genotype , aspartate aminotransferase , alanine aminotransferase [ alt ] , and platelet count ) , adverse drug reactions , and outcomes ( svr , and completed or discontinued treatment ) , which have been recorded in a standardized report form by practitioners . serum hcv rna levels were quantitated by cobas amplicor hcv monitor v2.0 ( roche molecular systems , pleasanton , ca , usa ) or cobas taqman hcv test ( roche molecular systems ) . this study was approved by the institutional review board of the national center for global health and medicine . we identified all of the patients with chronic hepatitis c from the japanese interferon database who had received a combination treatment of peg - ifn ( alfa-2a or alfa-2b ) and rbv between december 2009 and april 2013 . patients meeting any of the following criteria were excluded from this study : comorbid cirrhosis or hbv infection ; without rbv use ; dual therapy with peg - ifn alfa-2a and alfa-2b ; any missing data items ( sex , age , diagnosis , and/or comorbid condition , ie , liver diseases ) ; and age under 16 years . descriptive statistics were calculated as absolute numbers , percentages , and means (  standard deviation [ sd ] ) for each group . patient baseline characteristics were compared between peg - ifn alfa-2a and alfa-2b , using a t - test for age , the wilcoxon rank - sum test for duration of therapy , the mantel haenszel chi - square statistic for genotype , and the chi - square test for the other categorical variables . we also compared adverse events in the patients withdrawn from study , according to hcv genotype , using the fisher s exact test . to explore the association of patient svr with chronic hepatitis c , we used multivariate logistic regression to calculate the adjusted odds ratio ( or ) and the associated 95% confidence intervals ( cis ) . we included covariates to adjust for age , sex , platelet counts , alt level , hcv viral load , genotype , and frequency of treatment . interaction analyses were performed with the logistic regression model , to test for interactions between peg - ifn and level of treatment experience or hcv genotype . the results indicated that there were no significant interactions ( between type of peg - ifn and treatment experience [ p=0.229 ] or between type of peg - ifn and hcv genotype [ p=0.069 ] ) . between december 2009 and april 2013 , a total of 16,349 patients were recorded in the japanese interferon database . of these , 3,643 subjects were excluded for the following reasons : comorbid condition of cirrhosis in 569 subjects and hbv infection in 300 subjects ; without rbv use in 2,414 subjects ; dual therapy of peg - ifn alfa-2a and alfa-2b in 225 subjects ; missing data ( any of sex , age , diagnose , and/or comorbid condition [ liver diseases ] ) in 261 subjects ; and under 16 years of age in three subjects ( figure 1 ) . , 3,578 subjects ( 1,710 [ 48% ] males ; 1,868 [ 52% ] females ) were taking peg - ifn alfa-2a , with a mean age ( sd ) of 59.1 ( 10.0 ) years ; and 9,128 subjects ( 4,652 [ 51% ] males ; 4,476 [ 49% ] females ) were taking peg - ifn alfa-2b , with a mean age (  standard deviation ) of 57.2 ( 10.9 ) years ( table 1 ) . several differences were found between the two groups , as follows : the mean age was higher in the alfa-2a group than in the alfa-2b group ; the proportion of male patients was higher in the alfa-2b group ; the proportion of patients with an hcv genotype1 infection in the peg - ifn alfa-2a group ( 2,874 [ 83% ] ) was higher than in alfa-2b group ( 5,564 [ 62% ] ) ; and , a higher proportion of initial treatment patients was obtained in the alfa-2b group ( 2,181 [ 62% ] ) than in the alfa-2a ( 7,086 [ 79% ] ) . the svr rate in patients receiving peg - ifn alfa-2b was higher than that in patients receiving alfa-2a ( crude or=1.31 ; 95% ci : 1.23 to 1.44 ) . after adjustment for potential confounders ( including age , sex , platelet count , alanine aminotransferase [ alt ] level , hcv viral load , genotype , and treatment experience ) , no significant difference was found in svr rates between the peg - ifn alfa-2a group and the peg - ifn alfa-2b group ( adjusted or=0.96 ; 95% ci : 0.88 to 1.05 ) ( table 2 ) . no significant differences were found between the peg - ifn alfa-2b and alfa-2a groups , in terms of adjusted svr rate , in patients receiving their initial treatment ( crude or=1.27 ; 95% ci : 1.14 to 1.40 ; adjusted or=0.90 ; 95% ci : 0.80 to 1.01 ) , patients receiving retreatment ( crude or=1.15 ; 95% ci : 1.00 to 1.33 ; adjusted or=1.09 ; 95% ci : 0.93 to 1.27 ) , and patients with hcv genotype 1 infections ( crude or=1.00 ; 95% ci : 0.91 to 1.09 ; adjusted or=0.95 ; 95% ci : 0.86 to 1.05 ) . the adjusted svr rate for peg - ifn alfa-2b in patients with hcv genotype 2 or 3 was superior to that of peg - ifn alfa-2a ( crude or=1.36 ; 95% ci : 1.10 to 1.69 ; adjusted or=1.35 ; 95% ci , 1.08 to 1.69 ) ( figure 2 ) . during the study , significant differences between the two treatments were observed in patients with hcv genotype 1 . ninety - six patients withdrew from treatment due to throm - bocytopenia ( 46 [ 1.6% ] in the peg - ifn alfa-2a group and 50 [ 0.9% ] in the alfa-2b group [ p=0.005 ] ) , and 57 patients withdrew due to retinopathy ( 13 [ 0.5% ] in the alfa-2a group and 44 [ 0.8% ] in alfa-2b group [ p=0.091 ] ) ( table 3 ) . in contrast were the patients with genotype 2 or 3 , who displayed anemia ( ten [ 1.6% ] in the alfa-2a group and 25 [ 0.7% ] in the alfa-2b group [ p=0.034 ] ) , thrombocytopenia ( eight [ 1.3% ] in the alfa-2a group and 14 [ 0.4% ] in alfa-2b group [ p=0.012 ] ) , and retinopathy ( five [ 0.8% ] in the alfa-2a group and five [ 0.1% ] in the alfa-2b group [ p=0.010 ] ) ( table 4 ) . between december 2009 and april 2013 , a total of 16,349 patients were recorded in the japanese interferon database . of these , 3,643 subjects were excluded for the following reasons : comorbid condition of cirrhosis in 569 subjects and hbv infection in 300 subjects ; without rbv use in 2,414 subjects ; dual therapy of peg - ifn alfa-2a and alfa-2b in 225 subjects ; missing data ( any of sex , age , diagnose , and/or comorbid condition [ liver diseases ] ) in 261 subjects ; and under 16 years of age in three subjects ( figure 1 ) . , 3,578 subjects ( 1,710 [ 48% ] males ; 1,868 [ 52% ] females ) were taking peg - ifn alfa-2a , with a mean age ( sd ) of 59.1 ( 10.0 ) years ; and 9,128 subjects ( 4,652 [ 51% ] males ; 4,476 [ 49% ] females ) were taking peg - ifn alfa-2b , with a mean age (  standard deviation ) of 57.2 ( 10.9 ) years ( table 1 ) . several differences were found between the two groups , as follows : the mean age was higher in the alfa-2a group than in the alfa-2b group ; the proportion of male patients was higher in the alfa-2b group ; the proportion of patients with an hcv genotype1 infection in the peg - ifn alfa-2a group ( 2,874 [ 83% ] ) was higher than in alfa-2b group ( 5,564 [ 62% ] ) ; and , a higher proportion of initial treatment patients was obtained in the alfa-2b group ( 2,181 [ 62% ] ) than in the alfa-2a ( 7,086 [ 79% ] ) . the svr rate in patients receiving peg - ifn alfa-2b was higher than that in patients receiving alfa-2a ( crude or=1.31 ; 95% ci : 1.23 to 1.44 ) . after adjustment for potential confounders ( including age , sex , platelet count , alanine aminotransferase [ alt ] level , hcv viral load , genotype , and treatment experience ) , no significant difference was found in svr rates between the peg - ifn alfa-2a group and the peg - ifn alfa-2b group ( adjusted or=0.96 ; 95% ci : 0.88 to 1.05 ) ( table 2 ) . we also performed subgroup analyses , according to treatment experience and genotype . no significant differences were found between the peg - ifn alfa-2b and alfa-2a groups , in terms of adjusted svr rate , in patients receiving their initial treatment ( crude or=1.27 ; 95% ci : 1.14 to 1.40 ; adjusted or=0.90 ; 95% ci : 0.80 to 1.01 ) , patients receiving retreatment ( crude or=1.15 ; 95% ci : 1.00 to 1.33 ; adjusted or=1.09 ; 95% ci : 0.93 to 1.27 ) , and patients with hcv genotype 1 infections ( crude or=1.00 ; 95% ci : 0.91 to 1.09 ; adjusted or=0.95 ; 95% ci : 0.86 to 1.05 ) . the adjusted svr rate for peg - ifn alfa-2b in patients with hcv genotype 2 or 3 was superior to that of peg - ifn alfa-2a ( crude or=1.36 ; 95% ci : 1.10 to 1.69 ; adjusted or=1.35 ; 95% ci , 1.08 to 1.69 ) ( figure 2 ) . during the study , significant differences between the two treatments were observed in patients with hcv genotype 1 . ninety - six patients withdrew from treatment due to throm - bocytopenia ( 46 [ 1.6% ] in the peg - ifn alfa-2a group and 50 [ 0.9% ] in the alfa-2b group [ p=0.005 ] ) , and 57 patients withdrew due to retinopathy ( 13 [ 0.5% ] in the alfa-2a group and 44 [ 0.8% ] in alfa-2b group [ p=0.091 ] ) ( table 3 ) . in contrast were the patients with genotype 2 or 3 , who displayed anemia ( ten [ 1.6% ] in the alfa-2a group and 25 [ 0.7% ] in the alfa-2b group [ p=0.034 ] ) , thrombocytopenia ( eight [ 1.3% ] in the alfa-2a group and 14 [ 0.4% ] in alfa-2b group [ p=0.012 ] ) , and retinopathy ( five [ 0.8% ] in the alfa-2a group and five [ 0.1% ] in the alfa-2b group [ p=0.010 ] ) ( table 4 ) . we conducted a retrospective cohort study to compare the svr rate in patients with chronic hepatitis c treated with peg - ifn alfa-2a and alfa-2b in combination with rbv , using data from the large japanese interferon database to improve the generalizability of the results . we employed multivariate logistic regression analysis to adjust for potential confounders , as the demographic characteristics at baseline differed between the two groups . we found similar svr rates in patients with chronic hepatitis c who received either peg - ifn alfa-2a or alfa-2b in combination with rbv . our findings were consistent with previous results from the largest reported rct , which involved 3,070 patients.9,12,13 on the other hand , some other previous studies,10,14 including the largest retrospective cohort study , which involved 3,414 subjects , presented results that conflicted with our findings . as mentioned above , several limitations of these previous studies have been pointed out ( eg , small sample size , inadequate blinding or randomization , difference in treatment regimen , and different study populations).5,15 to enhance generalizability , we conducted a study with a larger sample size ( 12,706 subjects ) than used in previous studies.57,9,10 we found no difference in the adjusted svr rate between the two treatment groups , even though the sample size was large enough to detect such a difference . in addition , our results were obtained from a realistic medical setting , using data recorded according to the actual treatments applied to patients with hepatitis , by practitioners . previously , few studies had been performed that reflected a realistic medical setting for treatment of patients with chronic hepatitis c because most of the previous studies were rcts.57 we also performed two subgroup analyses , according to treatment experience and genotype , because the largest reported rct9 had included only patients receiving their initial treatment and patients with hcv genotype 1 . similar to our other results , we also found no difference in the adjusted svr rate between treatment with peg - ifn alfa-2a and alfa-2b from the subgroup analyses , except for the subgroup of genotypes 2 and 3 . in this subgroup , alfa-2b had higher a svr rate , although the interaction was not significant . while the present study suggests that peg - ifn alfa-2b may be the preferable treatment for patients with hcv genotypes 2 and 3 , the results of several rcts9,16,17 showed no difference between treatment with peg - ifn alfa-2a or alfa-2b in patients with genotype 1 or with genotypes 14 . in a study comparing the pharmacokinetics and pharmacodynamics of the two drugs,18 peg - ifn alfa-2b displayed a greater effect of biological activity by reducing hcv - rna and upregulating ifn - related response genes . however , the duration of this effect may be affected by the time period between dosing because the volume of distribution of peg - ifn alfa-2b is large , and it is metabolized faster than peg - ifn alfa-2a.8 due to its higher molecular weight and branched pegylation , the extravascular volume of distribution of peg - ifn alfa-2a is smaller . thus , its duration in the body is longer than that of peg - ifn alfa-2b . in general , the amount of a drug in the body tends to decrease as body weight increases ; however , in this study , the amount of peg - ifn alfa-2b in the body was constant regardless of body weight because the dosage was adjusted for body weight.18 in the present study , peg - ifn alfa-2b was more effective than peg - ifn alfa-2a for the treatment of patients with genotypes 2 and 3 . this may be because the patients treated with peg - ifn alfa-2b received a dosage based on body weight , whereas patients treated with peg - ifn alfa-2a were treated with a fixed dosing regimen , without accounting for weight . however , information regarding the patients body weight and dosage of peg - ifn was not included in this database . we found that proportions of adverse events , such as thrombocytopenia , retinopathy , and anemia , were higher in patients treated with peg - ifn alfa-2a . in a previous study comparing pharmacokinetics and pharmacodynamics,18 both leukocytes and neutrophils were significantly decreased in patients receiving peg - ifn alfa-2a versus those receiving peg - ifn alfa-2b . additionally , the incidences of hematological abnormalities tend to be higher in peg - ifn alfa-2a  treated patients.18 in contrast , rcts comparing peg - ifn alfa-2a and alfa-2b , including a japanese study19 and the largest study ever conducted,9 showed no difference in hematological abnormalities following termination of treatment . in the rcts , the subjects may have been selected from patients in good condition or from those who were expected to adhere to the study treatment . our data suggests that hematological abnormalities , such as thrombocytopenia , may develop in actual medical care situations , because we used data obtained from the database of medical records from patients receiving ifn treatment . the strengths of our study include the large sample size , the use of data collected from actual medical settings , and the inclusion of patients with all types of hcv genotype infections and patients with or without previous treatment experience . first , there were residual confounders , which could persist due to unmeasured or imprecisely measured potential confounding factors . secondly , there was a reporting bias because the data were recorded by practitioners using a standardized report form . additional studies are needed to validate the data , using an alternative existing database source ( eg , electronic medical records database or claims database ) . thirdly , the viral load levels might have been misclassified because the measurement methods for hcv rna in this database differed depending on the time of therapy . finally , further studies are required to assess the rate of svr between the two medications in combination with simeprevir , a new agent for the treatment of chronic hepatitis c , because the current standard therapy for chronic hepatitis c is triple therapy with peg - ifn ( alfa-2a or alfa-2b ) , rbv , and simeprevir.20,21 there was no significant difference in the svr rates and safety profile between chronic hepatitis c patients treated with the peg - ifn alfa-2a and alfa-2b .
purposewe aimed to compare the rates of sustained virologic response ( svr ) achieved with peginterferon ( peg - ifn ) alfa-2a and alfa-2b in combination with ribavinin ( rbv ) for chronic hepatitis c , using a large database of hepatitis cases to improve the generalizability of these results.methodswe identified patients with chronic hepatitis c who were treated with peg - ifn alfa-2a or alfa-2b and rbv , from the japanese interferon database , between december 2009 and april 2013 . 
 this database contains the medical records of ifn treatment collected from 36 prefectures in japan . 
 multivariable logistic regression analysis was used to compare svr rates obtained with peg - ifn alfa-2a and alfa-2b , in combination with rbv.resultsa total of 16,349 patients were recorded in the japanese interferon database . 
 after application of the exclusion criteria , 12,706 patients ( 3,578 [ 1,710 males , 1,868 females ] on peg - ifn alfa-2a ; and 9,128 [ 4,652 males , 4,476 females ] on peg - ifn alfa-2b ) were included in this analysis . 
 the svr rate in the peg - ifn alfa-2b group was 62.0% , as compared with a rate of 55.1% in the peg - ifn alfa-2a group ( crude odds ratio = 1.31 ; 95% confidence interval [ ci ] : 1.23 to 1.44 ) . 
 there was no significant difference in the adjusted svr rates between the two groups ( adjusted odds ratio = 0.96 ; 95% ci : 0.88 to 1.05 ) . 
 similar proportions of adverse events were observed in the two groups , with the exception of thrombocytopenia , retinopathy , and anemia.conclusionthere was no significant difference in the svr rates and safety profile between chronic hepatitis c patients treated with the peg - ifn alfa-2a and alfa-2b .