Does infection by the hepatitis C virus decrease the response of immunization against the hepatitis B virus in individuals undergoing dialysis ?

DOI: 10.5935/0101-2800.20170020 Introduction: Vaccination is the most effective tool in preventing transmission of Hepatitis B Virus (HBV). The patient with chronic kidney disease (CKD) on dialysis appear to be at greater risk of becoming infected with this virus and does not show the same vaccine response when compared to patients without uremia. Objectives: To evaluate the results related to the HBV vaccine and identify factors associated with the response in patients with CKD on hemodialysis. Methods: Individuals with HBsAG and negative anti-HBC, under hemodialysis were assessed in two units of São Luis, Maranhão and were undergone full vaccination schedule for HBV. They were divided in groups: anti-HBs10 mUI/ mL and compared as to age, gender, presence of diabetes mellitus (DM), time on dialysis and anti-HCV status. Logistic regression analysis was performed to identify factors independently associated with the vaccine response. p10mUI/ Ml (or = 5.239 IC: 1.279-21.459, p = 0.021). Conclusion: The rate of vaccine response to HBV in patients with CKD on dialysis was 70% and the lack of anti-HCV infection was associated with seroconversion of anti-HBs suggesting that infection by the hepatitis C virus may be a factor that decreases the response of the HBV vaccine in dialysis CKD patients. AbstRAct


Resumo
Palavras-chave: hepatite C; insuficiência renal crônica; vacinação; vacinas contra hepatite B; vírus da hepatite B. in human health, as 786,000 deaths per year are connected to the disease's acute and chronic manifestations. 2ccording to a recent review, the global prevalence of infection by the hepatitis B virus (HBV) among individuals on dialysis ranges from 1.2% to 6%. 3 Individuals with chronic kidney disease (CKD) are at risk of contracting HBV infection mainly when dialysis units fail to comply with the standards for the prevention of transmission of bloodborne pathogens. 4Immunization against the virus stands as one of the main means to prevent infection by HBV. 5,6eroconversion rates after vaccination against HBV in individuals with CKD range between 50% and 80%. 7The impaired response to immunization seen in patients treated for CKD vis-à-vis individuals with normal renal function has been attributed to disordered immune function in areas such as antigen processing, antibody formation, and cell-mediated immunity associated with renal impairment and uremia. 6[10][11][12] The Brazilian Reference Center for Special Immunobiologicals (Centro de Referência para Imunobiológicos Especiais -CRIE) recommends that individuals with CKD be immunized with four doses (time zero then on months one, two, and six) of the HBV vaccine, using twice the dosage recommended for the patient's age. 13his study aimed to assess the response of patients with CKD undergoing hemodialysis in two renal replacement therapy (RRT) centers in São Luís, Brazil, to immunization against HBV and identify associated factors.

methods
This analytical cross-sectional study used the database from study "Occult hepatitis B virus infection in patients with chronic kidney disease undergoing hemodialysis," approved by the institution's Ethics Committee and granted permit no.004913/2009-40 (Annex 1), whose results were published recently. 14he aforementioned study was carried out from 2010 to 2013 in the two largest dialysis centers in São Luís, the capital of the State of Maranhão, Brazil.The two units combined responded for more than two thirds of the patients on dialysis in São Luís.
All HBsAg-negative patients on hemodialysis for at least six months seen in the two RRT centers were interviewed.Three hundred and two of the 342 individuals meeting the enrollment criteria provided written consent to join the study.
The selected patients had blood samples taken and tested for HBsAg, total anti-HBc, anti-HBs, and anti-HCV.The enrolled patients were immunized against HBV infection as per the recommendations of the CRIE. 13The following data were taken from the patients' charts: age, gender, marital status, etiology of renal disease, and time on RRT.
Confirmatory tests were run to validate the HBsAg-negative status of every patient.The study included anti-HBc-negative individuals grouped based on anti-HBs levels: < 10 mIU/mL or ≥ 10 mIU/m.The differences between groups were analyzed in terms of age, time on dialysis, gender, diagnosis of diabetes mellitus (DM) and positive anti-HCV tests.
Software package IBM SPSS Statistics version 22.0 was used in data analysis.Numerical variables were presented in the form of mean values ± standard deviation (SD); frequencies were presented in the form of percent values.The differences between numerical variables were calculated using Student's t-test, while nominal variables had their differences analyzed through the chi-square or Fisher's exact test, when appropriate.
Multivariate logistic regression analysis was performed to identify the factors independently associated with anti-HBs levels ≥ 10 mIU/m.Statistical significance was attributed to differences with p values ≤ 0.05.

Results
The study sample included 188 patients (HBsAgand anti-HBc-negative).Most (54.8%) were males, and their mean age was 46.1 years (11 to 83 years of age).The mean time on dialysis was 40.9 months.Fifty patients (26.6%) were diagnosed with DM and ten (5.3%) were anti-HCV-positive.See Table 1 for a summary of patient information.
One hundred and thirty-two patients (70.2%) had anti-HBs ≥ 10 IU/mL and 56 (29.8%) had anti-HBs < 10 IU/mL.The mean age (45 ± 15.6 and 48.7 ± 14.4) and time on dialysis in months (40.4 ± 30.1 and 41.9 ± 32.7) of the individuals in the two groups were similar (p = 0.13 and p = 0.76, respectively).The groups were not statistically different in terms of gender or diagnosis of DM.Only anti-HCV-positive test results were statistically associated with low anti-HBs titers (p = 0.008) (Table 2).Logistic regression analysis, including all variables from univariate analysis, revealed that only anti-HCV-negative test results were independently associated with anti-HBs levels ≥ 10 mIU/mL (OR = 5.239 CI:1.279-21.459,p = 0.021) (Table 3).

dIscussIon
Dialysis patients with CKD are more susceptible to parenterally transmitted diseases such as HBV infection.Compliance to universal pathogen transmission prevention measures in dialysis units has decreased the global prevalence of HBV infection. 15e of the main preventive measures is immunization against HBV. 16his study found that 70% of the immunized individuals susceptible to HBV had levels above 10 mIU/ ml and were deemed protected against infection.This finding has also been reported in other studies, with seroconversion rates ranging between 50% and 80% 3,[6][7][8][9][10] .
The pathogenesis of this trait was recently reviewed by Sit et al. 17  Of the factors analyzed in this study through multivariate analysis, only positive anti-HCV test results were negatively related to anti-HBs seroconversion.Anti-HCV-negative individuals had a five-fold chance of having protective anti-HBs levels than HCV-positive patients.
The association between infection by HCV and impaired response to immunization in the population on dialysis is controversial.A recently published metaanalysis including eight studies (and 520 patients altogether) was unable to show a negative effect of infection by HCV on anti-HBs seroconversion. 18owever, the authors recognized that the quality of the included studies and the number of patients may have biased and potentially reduced the accuracy of the reported results.
One of the studies included in this meta-analysis was a randomized trial carried out in the Brazilian State of Rio Grande do Sul, in which infection by HCV (OR = 8.69 CI:1.26-58.8p = 0.028) and old age (OR = 1.2 CI:1.02-1.30p = 0.022) were reported as the only independent factors associated with nonseroconversion of anti-HBs. 9nother possible explanation for the lack of response to vaccination against HBV is the presence of occult hepatitis B virus infection (chronic infection by HBV with negative HBsAg), since HCV may inhibit HBV replication and produce non-positive HBsAg test results, while infection is present. 19,20Occult hepatitis B virus infection (OBI) has been frequently observed in CKD patients with HCV infection. 21,22In fact, our study involved 302 HBsAg-negative individuals (188 of whom were studied) and identified infection by HCV as the only factor associated with OBI. 14 Another possible explanation for the nonseroconversion of anti-HBs in these individuals is the presence of liver disease, since changes in liver function may cause significant immune impairment, thus limiting the response to vaccination. 23,24Unfortunately, this fact could not be confirmed since the study was based on a database in which there was no information on the level of liver involvement of the patients infected by HCV.

conclusIon
This study found that the response rate to HBV immunization was within the range expected for patients with CKD on dialysis, and that anti-HCVnegative individuals had higher chances of responding to vaccination.Studies with a greater number of patients, including the assessment of their levels of liver involvement, may shed light on whether infection by HCV hinders the response to HBV immunization in individuals on hemodialysis.

TITLE: OccuLT hEpaTITIs b vIrus InfEcTIOn In paTIEnTs wITh chrOnIc kIdnEy dIsEasE undErOgOIng hEmOdIaLysIs
Dear Patient, This study will look into the status of occult hepatitis B virus infection affecting individuals with chronic kidney disease (CKD) undergoing hemodialysis in the city of São Luís.This important will provide you with important information on serology parameters.Blood samples will be taken -the same way it is done every month in the clinic you go to.We would like to invite you to join our study.In the first part of the study you will be invited to answer a questionnaire on facts such as your age, marital status, level of education, and social status.Then, a series of questions concerning your disease will be asked and a sample of your blood will be taken.This study is entirely separated from your treatment.Your refusal to join the study will not affect your condition as a patient at all.Nonetheless, you might benefit from joining the study, as you will be required to reflect on your health and have some time to discuss whatever questions you may have.If you agree to join the study, the information gathered in the study may be passed on to your health care team and help them understand your case.The researchers responsible for this study will treat the information you give them with the utmost confidentiality.
Your data will be grouped and presented together with the answers given by other participants without identifying anyone involved.
and has been attributed to a series of variables such as genetic characteristics, nutritional factors, vaccine dosages and route of administration, stage of CKD, diagnosis of diabetes mellitus, time on dialysis, dialysis adequacy, co-infection by HIV or HCV, and others.