antitumor necrosis factor - alpha ( tnf- ) agents are widely used for effective treatment of autoimmune rheumatic and dermatological diseases such as rheumatoid arthritis ( ra ) , ankylosing spondylitis ( sa ) , psoriasis ( ps ) , or psoriatic arthritis ( psa ) .
nevertheless , anti - tnf- agents have been associated with growing number of adverse events , particularly infections [ 1 , 2 ] of which some can be life threatening .
tnf- is an important proinflammatory cytokine in the host defense mechanism against many intracellular pathogens .
it suppresses hepatitis b virus ( hbv ) replication and promotes hbv eradication by stimulating hbv - specific cytotoxic t - cell response [ 35 ] .
it has been reported that reactivation of hbv infection may occur directly due to lack of tnf- or indirectly via diminishing t - cell activation [ 6 , 7 ] .
tnf- inhibitors are therefore likely to induce hbv replication and reactivation in cases when chronic infection is present .
hbv is regarded as a leading cause of acute hepatitis , cirrhosis , and hepatocellular carcinoma , being responsible for about 600000 deaths every year .
chronic hbv infection is defined as an overt when hepatitis b surface antigen ( hbsag ) is detectable in the serum .
patients who present antibodies to hepatitis b core antigen ( anti - hbc ) with concurrent hbsag negativity do not have chronic hepatitis but only experienced hbv infection and were able to clear it .
nevertheless , some of these patients may be occult carriers , harboring intrahepatic hbv replication , and therefore can be susceptible to hbv reactivation .
hepatitis b virus ( hbv ) reactivation in patients treated with anti - tnf- agents has been frequently reported in the last decade , with inconsistent results .
considering the high socioeconomic burden of hbv infection related conditions , as well as increasing role of anti - tnf- agents in treatment of autoimmune rheumatic and dermatological diseases , it is highly important to estimate the impact of anti - tnf- agents to hbv reactivation in these patients .
we have conducted a systematic review and meta - analysis in order to assess the prevalence of hbv reactivation among patients treated with anti - tnf- agents because of ra , sa , ps , and psa .
we conducted comprehensive literature search of medline , scopus , and isi web of knowledge databases using the following search : ( [ infliximab ] or [ rituximab ] or [ etanercept ] or [ adalimumab ] or [ abatacept ] or [  anti - tnf  ] ) and [  hbv reactivation  ] .
the search was limited to human subjects with language restriction to english studies until 1st september 2013 .
the snowball strategy , including manual search of the references listed by studies retrieved from the online databases and from previously published systematic reviews , was also performed to identify potential additional studies .
the eligibility criteria for inclusion in the review implied that ( i ) patients should be affected by at least one of the following diseases : rheumatoid arthritis ( ra ) , ankylosing spondylitis ( sa ) , psoriasis ( ps ) , or psoriatic arthritis ( psa ) ; ( ii ) study must refer to treatment with one or more of the following biologic agents : infliximab , rituximab , etanercept , adalimumab , and abatacept ; ( iii ) the hbv serological status of patients prior to the pharmacological treatment and the prevalence of hbv reactivation after the treatment should be reported .
studies were excluded if it included only hepatitis c virus ( hcv ) infected patients ( other than those also coinfected with hbv ) .
data from the included studies were independently extracted by two investigators ( np and el ) and entered into an excel 2010 ( microsoft corp . ,
any discrepancies regarding individual study inclusion , data extraction , and interpretation were resolved by consulting a third investigator ( sb ) .
we extracted the following data : first author name , year of publication , number of patients , mean age , and gender of patients .
further we extracted data on the hbv serological status of patients , medical conditions for which patients were treated , the biologic agent used , the presence of other disease modifying antirheumatic drugs ( dmards ) , and antiviral prophylaxis .
the main outcome used in the meta - analysis was the prevalence of hbv reactivation reported as prevalence proportion . the studies with sample size less than 15 were not included in meta - analysis .
additionally , when available , we collected individual - level data on hbv reactivation , namely , age , gender , condition treated for , anti - tnf agent used , and , if any , antiviral prophylaxis . based on this data we performed additional meta - analyses according to diseases and biologic agents when possible .
based on the serological status , we stratified results of the meta - analysis according to two main subgroups of patients expected to have different prevalence hbv reactivation : patients presenting with overt chronic hbv infection ( being hbsag positive ) and patients presenting with occult hbv infection ( being hbsag negative and anti - hbc positive ) .
based on information reported in the article full text and tables , it was always possible to obtain the data on the subgroups . to determine pooled proportions , the variances of the raw proportions ( r / n ) were stabilized using a freeman - tukey - type arcsine square root transformation : y = arcsine[(r/(n + 1 ) ) ] + arcsine[(r + 1)/(n + 1 ) ] , with a variance of 1/(n + 1 ) , where n is the denominator for population size .
pooled proportions from all studies were calculated as the back transform of the weighted mean of the transformed proportions , using a random - effects model .
we assessed heterogeneity among studies using the cochran q test and quantified inconsistencies across studies and their impact on the analysis by using the i statistic [ 24 , 25 ] .
as we anticipated large heterogeneity considering the very different clinical presentation of patients , we considered statistically significant heterogeneity when pheterogeneity < 0.1 . the robustness of pooled proportions was explored by conducting sensitivity and subgroup analyses .
the results of the literature search are reported in a flow chart ( figure 1 ) . after searching 3 databases we identified 632 relevant articles .
additionally , 4 more relevant papers were identified through reference search of relevant systematic reviews . after removing duplicates ,
226 remaining abstracts were examined , and further 161 were excluded because of being unrelated to the subject , 34 were excluded because they referred to medical conditions other than those named in inclusion criteria , and 5 were systematic reviews or meta - analyses .
finally when we retrieved full text of the remaining 26 papers , 5 were excluded as they were case reports .
the characteristics of the 21 studies included in the systematic review are reported in table 1 [ 1120 , 2636 ] .
six studies included patients with overt chronic hbv infection and 9 included patients with occult hbv infection , while 6 studies addressed both groups of patients .
fourteen studies included patients treated with biologic agents because of rheumatoid arthritis ( 66.7% ) , 6 ( 28.6% ) patients treated because of ankylosing spondylitis , 5 ( 23.8% ) because of psoriasis , and 4 ( 19.0% ) because of psoriatic arthritis . in 18 ( 85.7% ) studies patients were treated with etanercept , in 16 ( 76.2% ) with infliximab , in 17 ( 81.0% ) with adalimumab , and in 3 ( 14.3% ) with rituximab . in eleven ( 52.4% ) studies antiviral prophylaxis
eleven studies ( 57.1% ) out of 21 were excluded because of the small sample size ( < 15 subjects ) , so the analysis was restricted to 10 studies .
the result of the meta - analysis is reported in table 2 , with a pooled estimate of hbv reactivation being 4.2% ( 95% ci : 1.48.2% , i : 74.7% ) , with significant heterogeneity among studies .
in the subgroup analyses , the pooled prevalence of hbv reactivation among patients with occult infection was 3.0% ( 95% ci : 0.67.2 ,
i : 77.1% ) and the pooled prevalence of hbv reactivation among patients with overt hbv infection was 15.4% ( 95% ci : 1.241.2% , i : 79.9% ) .
in both subgroups , high heterogeneity was present ( table 2 ) . by restricting the meta - analysis to patients with rheumatoid arthritis the pooled prevalence of hbv reactivation was 3.3% ( 95% ci : 0.77.5% , i : 62.6% ) , with significant heterogeneity among studies ( table 3 ) . when these results were stratified according to occult or overt infection ,
results show that the hbv reactivation for patients with occult infection was 2.6% ( 95% ci : 0.46.6% , i : 59.2% ) , compared with 10.7% ( 95% ci : 1.450.2% ,
we also addressed the prevalence of hbv reactivation in relation to the anti - tnf agent used .
the pooled prevalence of hbv reactivation among patients treated with etanercept was 3.9% ( 95% ci : 1.18.4% , i : 51.1% ) and 3.0% ( 95% ci : 0.57.6% , i : 49.6% ) for those with occult hbv infection ( table 4 ) .
patients treated with adalimumab showed a pooled prevalence of hbv reactivation of 4.6% ( 95% ci : 0.512.5% , i : 28.7% ) ( table 5 ) .
no case of hbv reactivation was recorded in studies eligible for meta - analysis among 81 patients treated with infliximab ( 80 occult carriers and 1 overt ) .
finally we pooled data on hbv reactivation rate in relation to usage of antiviral prophylaxis .
pooled hbv reactivation rate was 4.0% ( 95% ci : 1.28.3% , i : 75.6% ) for patients without any antiviral prophylaxis ( table 6 ) .
analysis on patients submitted to antiviral prophylaxis as well as stratification on occult and overt carriers was not possible because small numbers of cases were included .
based on meta - analysis we conducted , we report relatively low pooled prevalence of hbv reactivation in patients treated with anti - tnf- agents for rheumatic and dermatological conditions . the pooled reactivation rate for all patients included , as well as for those with ra , was several times higher in chronic overt hbv carriers compared to occult carriers .
the pooled reactivations rates for those treated with etanercept and adalimumab were similar and also similar to overall pooled reactivation rate .
the pooled reactivation rate for patients with no antiviral prophylaxis did not differ from overall pooled reactivation rate .
several studies addressed the issue whether anti - tnf- agent induced hbv reactivation , with inconsistent results .
we report considerably low overall pooled hbv reactivation rate of 4.2% compared to some authors before , who included both overt and occult patients with reported reactivation rate up to 6.8% . having this in mind
, it could be said that some of previous studies overestimated the risk of hbv reactivation in patients treated for rheumatic and dermatological conditions .
this is especially true for the patients with occult infection as kim et al .   and urata et al .  
previously reported hbv reactivation rate among occult carriers of 15.6% and 9.6% , respectively , while pooled rate for occult carriers from our analysis is only 3.0% . however , when interpreting these results , substantial heterogeneity among the studies should be taken into account .
for example , study by kim et al .   used a 2-fold or greater increase in liver function test as the criteria for reactivation , while most of the others tried to detect hbv dna .
furthermore regional differences in hbv infection prevalence could also influence the observed reactivation rates because of small samples size .
it is possible that presence of certain comorbidities , such as diabetes mellitus or obesity , or some other clinical parameters mediate the risk for hbv reactivation .
however no study reported these data so we hope that studies to come will be more informative .
we observed a higher prevalence of hbv reactivation among patients with chronic infection compared to those with the occult one .
this is reasonable and expected , as patients positive with anti hbc antibodies and negative with hbsag do not necessary harbor undetected intracellular hbv replication .
however , the high pooled reactivation rate among overt carriers should be having implication on clinical guidelines , as we consider patients with detectable hbsag to be eligible for antiviral prophylaxis in order to prevent anti - tnf- induced hbv reactivation . unfortunately , we were not able to confirm this in our meta - analysis as numbers of patients included were too few to distinguish between the overt carriers subjected and not subjected to antiviral prophylaxis
. instead we were able to calculate only the pooled reactivation rate for all patients nontaking antiviral prophylaxis , irrespective to their hbv infection status .
this rate did not differ significantly from the overall pooled one , but the vast majority of cases included were the occult carriers .
the future studies including considerable numbers are needed in order to clearly define the criteria for antiviral prophylaxis in patients treated with anti - tnf- agents at risk for hbv reactivation .
we also tried to estimate whether hbv reactivation rate is dependent on anti - tnf- agents used , as well as on underlying condition .
however it was possible only to conduct subanalysis on patients treated with etanercept and adalimumab , as on those treated for ra .
as observed pooled reactivation rates did not show considerable difference among the subgroups ; we did not find any of these to determine patients ' susceptibility towards hbv reactivation .
still , if such an association exists it needs to be confirmed in studies to come .
we have included only patients treated with anti - tnf- agents for rheumatic and dermatological conditions .
this limits external validity of our findings , as anti - tnf- agents are also used for treatment of other autoimmune conditions , such as inflammatory bowel diseases , and are part of chemotherapeutic protocols in treatment of b - cell lymphomas .
however , with limiting the analysis on specific subgroup of patients we aimed to decrease heterogeneity and therefore make the results more reliable .
further , we believe that certain comorbidities , such as diabetes and obesity , could mediate a risk for hbv reactivation among patients treated with anti - tnf- agents . unfortunately none of the studies reported them , so we were not able to include them in the analysis .
we were also unable to conduct subanalysis on patients treated with infliximab and rituximab and to distinguish the pooled reactivation rates among overt and occult carriers treated with antiviral prophylaxis .
finally , there is a question of heterogeneity among studies in relation to criteria defining hbv reactivation , which could lead to differences in interpretation of the collected data .
nevertheless , we find our results valuable to the clinicians encountering patients in risk for hbv reactivation being in need for anti - tnf- agents in everyday practice . in conclusion , although hbv reactivation rate appears to be relatively low in patients treated with anti - tnf- agents for rheumatic and dermatological conditions , the antiviral prophylaxis is recommended in patients with overt chronic hbv infection .
more informative studies including large number of cases are needed in order to identify if any patient or treatment related factor mediates the reactivation risk .
the individual approach and close monitoring of each patient could be an answer in balancing the need for therapy with hazard associated with hbv reactivation .
 
 introduction . 
 antitumor necrosis factor - alpha ( tnf- ) agents are widely used for treatment of rheumatic and dermatological diseases . 
 we conducted the systematic review and meta - analysis to assess the prevalence of hbv reactivation among patients treated with anti - tnf-. methods and findings . 
 a comprehensive literature search of medline , scopus , and isi web of knowledge databases was conducted . from 21 studies included in the systematic review , 9 included patients with occult chronic hbv infection and 6 included patients with overt infection while 6 addressed both groups . based on 10 studies eligible for meta - analysis 
 we report pooled estimate of hbv reactivation of 4.2% ( 95% ci : 1.48.2% , i2 : 74.7% ) . 
 the pooled prevalence of reactivation was 3.0% ( 95% ci : 0.67.2 , i2 : 77.1% ) for patients with occult infection , and 15.4% ( 95% ci : 1.241.2% , i2 : 79.9% ) for overt infection . 
 the prevalence of reactivation was 3.9% ( 95% ci : 1.18.4% , i2 : 51.1% ) for treatment with etanercept and 4.6% ( 95% ci : 0.512.5% , i2 : 28.7% ) for adalimumab . 
 for subgroup of patients without any antiviral prophylaxis the pooled reactivation was 4.0% ( 95% ci : 1.28.3% , i2 : 75.6% ) . conclusion . 
 although hbv reactivation rate is relatively low in patients treated with anti - tnf- for rheumatic and dermatological conditions , the antiviral prophylaxis would be recommended in patients with overt chronic hbv infection . 
1. Introduction
2. Methods
3. Results
4. Discussion