Developed Hepatitis B Virus Reactivation Research Articles

Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection

Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is found in HBV or HCV endemic areas, and in specific populations exhibiting a high risk of parenteral viral transmission. Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients. The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations. Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections. Strikingly, approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV. The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined. Furthermore, approximately 30% of dually infected patients lost hepatitis B surface antigen (HBsAg) within 5 years after the start of peginterferon-based therapy, and 40% of them harbored occult HBV infection. The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations. Moreover, the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future, which warrants further clinical trials.

Treatment of patients with dual hepatitis C virus and hepatitis B virus infection: Resolved and unresolved issues

Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission. In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. In the past decade, the following issues have been resolved. In dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin was effective, the treatment outcomes being similar to patients with HCV monoinfection. During long-term follow-up, the HCV response was sustained in around 97% of patients; and the long-term outcomes including the development of hepatocellular carcinoma and liver-related mortality were improved. However, several clinical issues remain to be resolved. First, host and viral factors influencing the long-term outcomes and treatment options in patients with dual HCV/HBV infection await further studies. Second, about 60% of dually infected patients with baseline undetectable serum HBV DNA levels develop HBV reactivation after the start of treatment. How to prevent and treat HBV reactivation should be clarified. Third, about 30% of dually infected patients lose hepatitis B surface antigen at 5 years after the end of combination therapy; the mechanisms need further investigations. Fourth, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis should be explored in future clinical trials. Finally, the role of new direct-acting antiviral-based therapy for the treatment of patients with dual HCV/HBV infection also remains to be evaluated.

Abstract P5-13-12: Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/ hepatitis B core antibody positive and/or hepatitis B surface antibody positive breast cancer patients who receive chemotherapy

Abstract Background: Recently, chemotherapy-induced reactivation of hepatitis B virus (HBV) has been reported not only in patients positive for hepatitis B surface antigen (HBsAg), but also in patients negative for it. Although HBV reactivation is associated with substantial morbidity and mortality in patients undergoing cancer chemotherapy, the exact frequency and risk for HBV reactivation in HBsAg-negative breast cancer patients who receive chemotherapy remains unclear. In this study, we examined the frequency and risk for HBV reactivation in Japanese breast cancer patients who have received chemotherapy. Methods: A total of 562 HBsAg-negative breast cancer patients received chemotherapy from June 2008 to May 2009 at the Cancer Institute Hospital of JFCR in Japan. Antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs) were screened for before chemotherapy in all patients. In patients who were positive for anti-HBc and/or anti-HBs, serum HBV-DNA levels were measured and monitored during and after chemotherapy. Results: 93 (17.4%) HBsAg-negative breast cancer patients were found to have resolved hepatitis B (HBsAg-negative, anti-HBc-positive and/or anti-HBs-positive). One patient was found to be positive for HBV DNA before the initiation of chemotherapy and received adjuvant chemotherapy with Entecavir prophylaxis. 65 patients received chemotherapy in adjuvant or neoadjuvant setting, 28 patients received it for metastatic disease. In our monitoring period (median 15.3 months), no HBsAg-negative/ anti-HBc-positive and/or anti-HBs-positive breast cancer patients developed HBV reactivation during and after their chemotherapy. Conclusions: A number of HBsAg-negative breast cancer patients have received chemotherapy with a risk for HBV reactivation; however, it has been determined that conventional chemotherapy regimens for breast cancer are unlikely to increase the risk of developing HBV reactivation in these patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-12.

Hepatitis B Related Serological Events In Hematopoietic Stem Cell Transplant Patients and Efficacy Of Lamivudine Prophylaxis Against Reactivation

IntroductionRemote Hepatitis B Infection (RHBI) is an immunological stage in the life cycle of Hepatitis B virus (HBV). It is characterized by the persistence of HBV DNA at low level within the liver or blood of people infected in past. As a result HBsAg, HBeAg and HBV DNA in serum are negative while Anti-HBs and/or Anti-HBc IgG are positive with normal liver enzymes. In Hematopoietic stem cell transplant (HSCT) patients, reactivation of RHBI leads to increased HBV replication and increased HBV DNA titres in blood and/or HBsAg or HBeAg positivity. There may be loss or gain of Anti-HBs and/or Anti-HBc IgG. The importance of recognizing this stage with a potential for reactivation is highlighted by the fact that: 1) HBV reactivation can lead to fulminant hepatitis & 2) Anti-HBV therapy such as lamivudine can prevent HBV reactivation. In this study we have aimed to determine the incidence of RHBI and HBV reactivation in our patients, the role of lamivudine in preventing HBV reactivation and the pattern of change in serological markers after reactivation. MethodsAll patients undergoing HSCT from March 2010 to May 2013 were included. Pre transplant, all patients were tested by ELISA for HBsAg, Anti-HBs, Anti-HBc IgM and Anti-HBc IgG. Post transplant, at the time of deranged liver function, all patients were tested for HBsAg, Anti-HBs, Anti-HBc IgM, Anti-HBc IgG, Anti-HCV, Anti-HEV and Anti-HAV. HBV DNA and HCV RNA were tested by polymerase chain reaction. RHBI was defined as positive Anti-HBc IgG and/or Anti-HBs (without history of HBV vaccination) with negative HBsAg and Anti-HBc IgM and normal liver function. HBV reactivation was defined as increase in transaminases to more than 3 times the upper limit of normal with HBV DNA and/or Anti-HBs and/or Anti-HBc IgG positivity (HBsAg and Anti-Hbc IgM being negative) at the time of deranged liver function. Lamivudine at a dose of 100 mg/d or 3 mg/kg/d (children <12 years) was given to all but one patient with Anti-HBc IgG positivity pre transplant irrespective of Anti-HBs positivity (Prophylaxis Group). Patients who had only Anti-HBs positivity did not receive prophylaxis (No Prophylaxis Group). Data was analyzed to explore the role of prophylactic lamivudine in preventing HBV reactivation and to determine the pattern of change of HBV serological markers at the time of reactivation. The time to respond to lamivudine was calculated as the interval from start of prophylaxis to normalization of liver enzymes. ResultsTwo hundred five patients underwent HSCT (autologous - 103 and allogeneic - 102) from March 2010 to May 2013. Twenty-eight (14%) patients were diagnosed to have RHBI (autologous-9, allogeneic-19). Thirteen patients did not receive prophylactic lamivudine (No-Prophylaxis Group) while 15 patients received prophylactic lamivudine (Prophylaxis Group). Twelve (92%) patients in No-Prophylaxis Group developed HBV reactivation while none (0%) in the Prophylaxis Group (P<0.001). The incidence of HBV reactivation was 10% (21 of 205 patients) which included 11 (52%) with only Anti-HBs positive, 1 with only Anti-HBc IgG positive and nine (43%) with all HBV serological markers negative (i.e. no evidence of RHBI) pre transplant. Six of these 9 patients sero-converted (5 - Anti-HBc IgG and 1 - Anti-HBs positive) at the time of reactivation. Seven (33%) developed HBV viremia at the time of HBV reactivation, of which 6 were Anti-HBs negative pre transplant. In contrast, of the patients with undetectable HBV DNA at the time of reactivation (14 patients), only 4(29%) were Anti-HBs negative pre transplant (P=0.0237). Seven (33%) patients were on steroids and 9(43%) were on cyclosporine at the time of reactivation. All patients responded to lamivudine within a median time of 17 days. ConclusionsIncidence of RHBI in patients undergoing HSCT is high in our setting.Lamivudine prophylaxis protects against HBV reactivation post transplant. We would recommend lamivudine prophylaxis in patients with RHBI with isolated Anti-HBs positivity in addition to those with Anti-HBc IgG positivity given the high rate of HBV reactivation in these patients.All serological markers for Hepatitis B being negative pre transplant does not preclude HBV reactivation post transplant. Therefore, all serological markers for HBV should be repeated at the time of deranged liver functions post transplant.Anti-HBs positivity pre transplant decreases the risk of HBV viremia at the time of reactivation. Disclosures:No relevant conflicts of interest to declare.

Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation in Patients With Lymphoma and Resolved Hepatitis B

The role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation before rituximab-based chemotherapy in patients with lymphoma and resolved hepatitis B is unclear. Eighty patients with CD20(+) lymphoma and resolved hepatitis B were randomly assigned to receive either prophylactic entecavir (ETV) before chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n = 41) or to receive therapeutic ETV at the time of HBV reactivation and hepatitis B surface antigen (HBsAg) reverse seroconversion since chemotherapy (control group, n = 39). Fifty-eight patients (72.5%) were positive for hepatitis B surface antibody, and HBV DNA was undetectable in 50 patients (62.5%). During a mean 18-month follow-up period, one patient (2.4%) in the ETV prophylactic group and seven patients (17.9%) in the control group developed HBV reactivation (P = .027). The cumulative HBV reactivation rates at months 6, 12, and 18 after chemotherapy were 8%, 11.2%, and 25.9%, respectively, in the control group, and 0%, 0%, and 4.3% in the ETV prophylactic group (P = .019). Four patients (50%) in the control group had HBsAg reverse seroconversion after HBV reactivation. The cumulative HBsAg reverse seroconversion rates at months 6, 12, and 18 since chemotherapy were 0%, 6.4%, and 16.3% in the control group, respectively, which were significantly higher than those in the ETV prophylactic group (P = .032). Patients with detectable or undetectable viral load could develop HBV reactivation and HBsAg reverse seroconversion. Undetectable HBV viral load before chemotherapy did not confer reactivation-free status. Antiviral prophylaxis can potentially prevent rituximab-associated HBV reactivation in patients with lymphoma and resolved hepatitis B.

Hepatitis B virus reactivation risk varies with different chemotherapy regimens commonly used in solid tumours

Background:Hepatitis B virus (HBV) reactivation may occur with chemotherapy and has significant morbidity and mortality. The United States Centre for Disease Control and Prevention recommends pre-chemotherapy hepatitis B screening for all cancer patients, while the American Society of Clinical Oncology finds that there is insufficient evidence currently to support such a recommendation. Apart from anthracyclines, HBV reactivation rates from other commonly used chemotherapy regimens in solid tumours are not well described.Methods:We compared HBV reactivation risk in patients receiving several commonly used chemotherapy regimens for solid tumours associated with different immunosuppression risk at a tertiary cancer centre in an HBV endemic region.Results:A total of 1149 patients were identified, including 434, 196, 245 and 274, respectively, who received doxorubicin-based, oxaliplatin- or irinotecan-based, carboplatin/gemcitabine, and capecitabine chemotherapy. HBV screening rate was 39% overall. Thirty out of 448 (7%) screened patients were HBsAg positive and 28 out of 30 received prophylactic antiviral therapy with no reactivation. Three out of 1149 patients overall (0.3%) developed HBV reactivation, all from the unscreened doxorubicin group (3 out of 214, 1.4%). No unscreened patients (0 out of 487) in the other three treatment groups developed reactivation (P<0.001).Conclusion:Not all chemotherapy regimens result in HBV reactivation. Routine hepatitis B screening for low- or moderate-risk regimens may not be warranted.

Hepatitis B virus reactivation in hepatitis B virus surface antigen negative patients receiving immunosuppression: A hidden threat

To present the characteristics and the course of a series of anti-hepatitis B virus core antibody (HBc) antibody positive patients, who experienced hepatitis B virus (HBV) reactivation after immunosuppression. We retrospectively evaluated in our tertiary centers the medical records of hepatitis B virus surface antigen (HBsAg) negative patients who suffered from HBV reactivation after chemotherapy or immunosuppression during a 3-year period (2009-2011). Accordingly, the clinical, laboratory and virological characteristics of 10 anti-HBc (+) anti-HBs (-)/HBsAg (-) and 4 anti-HBc (+)/antiHBs (+)/HBsAg (-) patients, who developed HBV reactivation after the initiation of chemotherapy or immunosuppressive treatment were analyzed. Quantitative determination of HBV DNA during reactivation was performed in all cases by a quantitative real time polymerase chain reaction kit (COBAS Taqman HBV Test; cut-off of detection: 6 IU/mL). Twelve out of 14 patients were males; median age 74.5 years. In 71.4% of them the primary diagnosis was hematologic malignancy; 78.6% had received rituximab (R) as part of the immunosuppressive regimen. The median time from last chemotherapy schedule till HBV reactivation for 10 out of 11 patients who received R was 3 (range 2-17) mo. Three patients (21.4%) deteriorated, manifesting ascites and hepatic encephalopathy and 2 (14.3%) of them died due to liver failure. HBsAg-negative anti-HBc antibody positive patients can develop HBV reactivation even 2 years after stopping immunosuppression, whereas prompt antiviral treatment on diagnosis of reactivation can be lifesaving.

An optimized antiviral modification strategy for prevention of hepatitis B reactivation in patients undergoing prophylactic lamivudine and chemotherapy: a pilot study

In patients receiving prophylactic lamivudine (LAM) and chemotherapy, hepatitis B virus (HBV) reactivation cannot be eliminated without knowing the latent causes and optimal management. In our previous study, virus breakthrough and relapse were highly suspected as potential virologic causes for HBV reactivation. Therefore, we reviewed 24 previous studies and 447 patients who underwent chemotherapy and prophylactic LAM, with an incidence of 7.2 % HBV reactivation. Virus breakthrough and relapse were seldom investigated in these studies. In addition, 72 patients that underwent prophylactic LAM and chemotherapy at our centers were also analyzed. Among them, eight patients developed virus breakthrough, with another nine developing virus relapse after discontinuation of LAM. Eight patients received antiviral modification, which included administration of adefovir for patients with virus breakthrough or resumption of LAM for patients with virus relapse and none of them developed HBV reactivation. In contrast, of the nine patients who did not receive antiviral modification, six developed HBV reactivation and two died. In conclusion, this study demonstrated that virus breakthrough and relapse were the critical causative factors of HBV reactivation in patients receiving chemotherapy and prophylactic LAM. An optimized antiviral modification strategy could effectively prevent HBV reactivation in patients with virus breakthrough or relapse.

Hepatitis B Virus Reactivation in Chronic Myeloid Leukemia Treated with Various Tyrosine Kinase Inhibitors: Multicenter, Retrospective Study

AbstractAbstract 3738 BackgroundBCR/ABL tyrosine kinase inhibitors (TKI) is now a standard initial treatment for chronic myeloid leukemia (CML). Several cases reported that hepatitis B virus (HBV) reactivation were related to imatinib therapy. However, it is still unclear whether imatinib or other TKIs induce HBV reactivation in hepatitis B surface antigen (HBsAg)-positive patients. The aim of this study is to investigate the incidence of HBV reactivation and analyze risk factors associated with HBV reactivation in CML patients who are treated with various TKIs. MethodsWe retrospectively reviewed the medical records from 8 centers in South Korea. HBsAg-positive CML patients under imatinib or other TKIs treatment were analyzed. Results702 patients were diagnosed CML from participating centers. HBsAg-positive rate was 6.1% (43/702) at diagnosis. In the 43 HBsAg-positive patients, nine patients received prophylactic therapy and HBV reactivation rate was 34.9% (15/43) (95% CI: 21.0–50.9%). Patients who received prophylaxis did not develop HBV reactivation. The median age and the male to female ratio of the HBV reactivated patients were 47.0 years (range; 22–63) and 4:1, respectively. HBV reactivation according to each TKI treatments were: 12 cases under imatinib, 2 cases under dasatinib, and 1 case under nilotinib. Median time to HBV reactivation was 9.3 months (range; 2.3–68.8 months) (95% CI: 5.9 – 28.5 months). None of the patients died due to HBV reactivation, but one patient received liver transplantation due to hepatic failure. Prophylactic therapy and HBV DNA level at diagnosis were the factors associated with HBV reactivation (P=0.011 and P=0.036, respectively). ConclusionThis is first report that has analyzed HBV reactivation in HBsAg-positive CML patients during TKIs treatment. Prophylaxis should be considered to prevent HBV reactivation during TKI treatment. Also, we recommend that HBsAg-positive patients with CML receiving TKI treatment be closely monitored. Disclosures:No relevant conflicts of interest to declare.

Effect of Antiviral Prophylaxis Strategy for Chemotherapy-Associated Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients with Hepatitis B Virus Infection: A Retrospective Cohort Study.

Recent data indicates that nucleoside/nucleotide analogue (NUC) is effective in preventing and controlling hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the ideal antiviral agent and optimal application protocol still needs to be determined. Meanwhile, it is uncertain whether those with past HBV infection require antiviral prophylaxis during chemotherapy. This report retrospectively analyzed non-Hodgkin's lymphoma (NHL) patients seen from January, 2004 to June, 2009 in West China Hospital. We found that the prevalence of chronic HBV infection in our NHL patients was 20.7% while that of past HBV infection was 21.05%. Compared with the high rate (25.6%) of HBV reactivation in patients with chronic HBV infection, none of those with past HBV infection in fact had occult HBV infection thus none experienced reactivation. Of the 82 patients with chronic HBV infection who received chemotherapy, antiviral prophylaxis could significantly reduce the incidence of HBV reactivation (5.0 vs. 45.2% in the control group) and the incidence of liver function damage (32.5 vs. 73.8% in the control group). The results of the current study confirmed previous reports that prophylactic NUCs administration can effectively prevent HBV reactivation and significantly reduce the incidence of HBV reactivation especially for patients receiving rituximab-containing regimens. Due to the fact that none of individuals who had past HBV infection developed HBV reactivation reported in our study, antiviral prophylaxis may not be required for patients with past HBV infection. Close observation of alanine aminotransferase and HBV-DNA contributes to early diagnosis and timely treatment of HBV reactivation.

Hepatitis B reactivation risk in patients with solid tumors receiving single-agent capecitabine versus doxorubicin-based chemotherapy.

1575 Background: Reactivation of hepatitis B virus (HBV) in cancer patients on chemotherapy is a challenge especially in Asia where HBV infection is endemic. Risk of HBV reactivation differs according to cancer type, chemotherapy regimen, and concomitant use of steroids. The United States Centre for Disease Control and Prevention recommends universal screening for chronic HBV infection for all patients before chemotherapy although screening for low-risk chemotherapy regimens may not be cost effective. Methods: We sought to assess and compare HBV reactivation risk and effectiveness of prophylactic anti-viral therapy in preventing HBV reactivation in patients receiving a ‘high-risk’ (doxorubicin-based) chemotherapy regimen for which prophylactic anti-viral therapy for hepatitis B carriers is generally accepted versus a ‘low-risk’ (single agent capecitabine) chemotherapy regimen for solid tumours at a tertiary cancer centre. The electronic medical records of eligible patients were reviewed between January 2007 and December 2010. Results: A total of 708 patients were identified, including 434 and 274 who received doxorubicin-based chemotherapy and single agent capecitabine respectively. HBV screening rate was 42.6% (51% for doxorubicin-based chemotherapy, 30% for single agent capecitabine, p&lt;0.0001). 15/302 (5%) screened patients were found to be hepatitis B carriers (6 on doxorubicin, 9 on capecitabine). Overall, 3/708 patients (0.4%) developed HBV reactivation (all from the unscreened doxorubicin group, 3/214 (1.4%) compared to 0/192 (0%) unscreened patients in the capecitabine group, p&lt;0.0001). All 15 identified hepatitis B carriers received prophylactic anti-viral therapy (14 received lamuvidine, 1 had entacavir) and none had HBV reactivation. Conclusions: Not all chemotherapy regimens are associated with risk of HBV reactivation. Routine hepatitis B screening and prophylaxis for low-risk chemotherapy regimens such as single agent capecitabine may add morbidity and may not be cost effective.

Hepatitis B virus reactivation in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization therapy

The effect of transcatheter arterial chemoembolization (TACE) therapy on hepatitis B virus (HBV) reactivation in hepatocellular carcinoma (HCC) patients with prior resolved hepatitis B is not fully understood. From January 2006 to December 2010, 43 hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core antigen (HBc) positive patients with newly diagnosed unresectable HCC were enrolled in the study. All underwent TACE therapy. Four patients (9.3%) developed HBV reactivation with mild/moderate hepatitis. The median number of TACE cycles received was 3.5 (range 3-4 cycles). The median time interval between the occurrence of HBV reactivation and the completion of TACE therapy was 3 months (range 1-5 months) and their median HBV DNA level was 1.58 × 10(4) IU/mL (range, 1.65 × 10(3) -6.42 × 10(4) IU/mL). After the introduction of lamivudine at the occurrence of HBV reactivation, all had resolution of hepatitis. An exploratory analysis indicated that significant predictors of HBV reactivation included increased serum total bilirubin coexisting with cirrhosis and the total number of cycles of TACE received. The administration of TACE therapy may increase the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients diagnosed with unresectable HCC. Further studies are warranted to explore the optimal management of HBV reactivation in patients with prior resolved hepatitis B.

Use of biological disease‐modifying anti‐rheumatic drugs in patients with concurrent rheumatic disease and hepatitis B

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the management of inflammatory arthritides. Reactivation of hepatitis B virus (HBV) is a potential adverse outcome in patients treated with bDMARDs. There is currently no consensus on the approach to identifying and treating these patients with underlying HBV infection. The aims of this study were to assess the risk of HBV reactivation in patients treated with bDMARDs, and to determine whether HBV screening should be carried out in all patients prior to commencing bDMARDs. A literature search was undertaken to identify all reports of patients with inflammatory arthritides and concurrent HBV infection being treated with bDMARDs. Forty-three patients with HBV infection were identified, of whom eight patients developed HBV reactivation after exposure to bDMARDs. Of the patients who experienced reactivation, two had unknown infection that surfaced during bDMARD therapy. Patients who experienced reactivation were promptly treated with antiviral therapy and saw clinical improvement. There are no long-term data on these patients. HBV reactivation may result in serious consequences, including death. Tuberculosis screening prior to bDMARD treatment is already standard practice, as is HBV screening for patients undergoing cancer chemotherapy. Implementing HBV screening for all patients prior to bDMARD treatment can identify patients with chronic HBV who may require antiviral therapy.

Prospective study of HBV reactivation risk in rheumatoid arthritis patients who received conventional disease-modifying antirheumatic drugs

Studies that reported hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients have caused attention of disease-modifying antirheumatic drug (DMARD)-related HBV reactivation. Most of the studies were focused on HBV reactivation risk of biologic DMARDs; insufficient data are available to identify the exact risk of conventional DMARD (c-DMARD)-related HBV reactivation. This prospective study aimed to investigate the risk of HBV reactivation in HBV-infected RA patients who received c-DMARDs. A total of 476 RA patients were screened in this prospective non-randomized, non-controlled study. HBV-infected patients characterized by hepatitis B surface antigen (HBsAg) positive or HBsAg negative/anti-hepatitis B core antigen (anti-HBc) positive were analyzed for HBV DNA, followed with HBV DNA monitoring scheduled every 3 months, serum alanine aminotransferase test at 2-month intervals, or more frequently. Prevalence of HBsAg positive and HBsAg negative/anti-HBc positive was 6.51 and 51.1 %, respectively, among the 476 RA patients. Among 211 patients (23 patients were HBsAg positive and 188 patients were HBsAg negative/anti-HBc positive) who received c-DMARDs without antiviral prophylactic treatment, 4 patients developed HBV reactivation. Both HBsAg positive and HBsAg negative/anti-HBc positive patients have the possibility of developing HBV reactivation. There was no correlation between HBV reactivation and any specific c-DMARD. Glucocorticoid coadministration and negative anti-hepatitis B surface antigen (anti-HBs) at baseline showed correlation with reactivation. In conclusion, it would be rational to initiate antiviral prophylaxis according to risk stratification rather than universal prophylaxis for HBV-infected RA patients. Conventional DMARDs are relatively safe to HBV-infected patients with low reactivation risk (low HBV DNA level, no GCs administration, and anti-HB positive).

Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma

Reactivation of hepatitis B virus (HBV) replication happens in patients who receive transarterial chemoembolization or systemic chemotherapy for hepatocellular carcinoma (HCC). The incidence and risk factors of HBV reactivation during the perioperative period in HCC patients receiving hepatic resection is unknown. Between May 2009 and November 2010, 164 consecutive patients with HBV-related HCC who underwent hepatic resection were prospectively enrolled in the study. Among these, 126 patients received antiviral treatment before the operation (the antiviral group) and 38 patients did not receive any antiviral treatment (the non-antiviral group). Ten patients (6.1%) developed HBV reactivation perioperatively (within 1 month after hepatectomy). The incidence of HBV reactivation in the antiviral group and non-antiviral group were 1.6% (2/126) and 21.1% (8/38), respectively (P < 0.001). On univariate analysis, preoperative HBV DNA < 1.0 × 10(3) copies/mL and non-antiviral therapy were significantly correlated with the occurrence of HBV reactivation (P = 0.044 and P < 0.001, respectively). Only non-antiviral therapy remained as a predictive factor on multivariate analysis (odds ratio, 15.46; 95% confidence interval, 2.80-85.46, P = 0.002). The recovery of liver function (defined as a decrease of alanine aminotransferase back to normal) was achieved in 86.8% (132/152) patients without HBV reactivation and in 37.5% (3/8) patients with HBV reactivation when evaluated on day 30 after hepatectomy (P < 0.001). Hepatectomy could reactivate HBV replication during the perioperative period, especially in patients who did not receive any antiviral therapy. A close monitoring of HBV DNA during the perioperative period was necessary irrespective of the preoperative HBV DNA level. Once HBV was reactivated, antiviral therapy should be given.

Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy

ObjectiveTo investigate the kinetics of hepatitis B virus (HBV) viral loads and HBV reactivation in rheumatoid arthritis (RA) patients undergoing therapy with tumour necrosis factor alpha (TNFα) inhibitors.MethodsThe authors investigated...

Prospective Analysis of Hepatitis B Virus Reactivation In Patients with Diffuse Large B Cell Lymphoma After Rituximab Combination Chemotherapy

AbstractAbstract 3950Reactivation of hepatitis B virus (HBV) was reported in patients who were being treated with rituximab-combination chemotherapy (R-chemotherapy). HBV reactivation was a well-known complication in lymphoma patients who were positive for hepatitis B surface antigen (HBsAg) in the pre-rituximab era. Recently, it was reported that HBV reactivation can occur in HBsAg-negative patients with past infection of HBV, upon administering R-chemotherapy for B-cell lymphoma. The association between rituximab and HBV reactivation is still unknown. There have been cases of HBV reactivation in patients with past HBV infection during the course of chemotherapy and/or immunotherapy, sometimes proving fatal. Nevertheless, it remains uncertain whether diffuse large B-cell lymphoma (DLBCL) patients with past HBV infection are at substantial risk for reactivation of latent HBV.We prospectively studied the frequency of and risk factors for HBV reactivation in DLBCL patients who received R-chemotherapy. A total of 356 HBsAg-negative patients with DLBCL were treated with R-chemotherapy. Anti-HBs and anti-HBc tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. The serum HBV-DNA load was determined by quantitative RT-PCR [COBAS® AmpliPrep/COBAS® TaqMan® HBV-Test, Roche Diagnostics K.K. Tokyo, Japan].A total of 356 HBsAg-negative patients with DLBCL were enrolled in this study. Among the 51 (16.2%) HBV carriers, 6 patients developed HBV reactivation and 45 patients did not develop HBV reactivation during the study period. Exploratory analysis was conducted on potential factors associated with the development of HBV reactivation. Male gender and having a low anti-HBs titer before R-chemotherapy were significantly associated with HBV reactivation. Age, clinical stage, B symptoms, lactate dehydrogenase (LDH), performance status, international prognostic index, and chemotherapy regimen were not associated with HBV reactivation. Among the 51 HBV carriers, 8 patients (15.7%) were positive for only anti-HBs, 27 (53%) were positive for both anti-HBs and anti-HBc, and 16 (31.3%) were positive for only anti-HBc. HBV reactivation occurred during or after R-chemotherapy in the 6 patients (12%); two patients developed reactivation after three or seven cycles of R-CHOP, respectively, whereas four patients developed reactivation after completion of R-CHOP therapy at a median interval of 90 days (range, 20 to 143 days). All 6 patients who developed HBV reactivation were positive for anti-HBc, and 3 of them were also positive for anti-HBs. The pretreatment anti-HBs titer of the 6 patients was low (range, <2.0 to 40.2 mIU/ml). When HBV-DNA became detectable in the serum, entecavir administration was started and the serum HBV-DNA became negative within 13 weeks. Elevation of ALT and AST was not observed in any of the 6 patients. The serum HBV-DNA level did not increase after entecavir administration was started in any patient. When HBV reactivation occurred, the liver function did not become elevated and HBsAg remained negative in all six patients. After serum HBV-DNA became undetectable, R-chemotherapy was resumed. None of the 6 patients developed hepatitis B. In the 6 patients who developed HBV reactivation, the anti-HBs titer before R-chemotherapy and the anti-HBs titer at the time of HBV reactivation did not significantly differ. In the 45 patients who did not develop HBV reactivation, the anti-HBs titer before R-chemotherapy ranged from 11.6 to <1,000 mIU/ml. After the end of R-chemotherapy, the anti-HBs titer was lower in 42 of the 45 patients. The posttreatment anti-HBs titer of the 42 patients was 10.2–542 mIU/ml. The anti-HBs titer returned to the value before the start of R-chemotherapy 6–18 months after the end of R-chemotherapy.HBV reactivation occurred in some patients who had been anti-HBs-negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of R-chemotherapy, but R-chemotherapy could be resumed after entecavir administration reduced the serum HBV-DNA level. Entecavir prophylaxis was not performed when R-chemotherapy was started, and it was thought that entecavir could be started when the serum HBV-DNA increased. Disclosures:No relevant conflicts of interest to declare.

Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy

Recently, there have been reports of hepatitis B virus (HBV) reactivation after rituximab combination chemotherapy in hepatitis B surface antigen (HBsAg) -negative patients with B-cell lymphoma. In this prospective study, the frequency of and risk factors for HBV reactivation in patients who were receiving rituximab chemotherapy were examined. A total of 314 HBsAg-negative patients with diffuse large B-cell lymphoma were treated with rituximab chemotherapy. Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. Of the 314 patients, 51 (16.2%) were HBV carriers. HBV reactivation occurred during or after rituximab chemotherapy in six patients (12%). All six patients who developed HBV reactivation were anti-HBc positive, and three of them were also anti-HBs positive. In these six patients, the pretreatment anti-HBs titer was low. Entecavir administration was started when serum HBV DNA became positive, and serum HBV-DNA became negative within 1 to 3 weeks. Rituximab chemotherapy was then continued. Risk factors for HBV reactivation were being male and having a low anti-HBs titer. HBV reactivation occurred in some patients who had been anti-HBs negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of rituximab chemotherapy, but rituximab chemotherapy could be continued after entecavir administration reduced the serum HBV-DNA level. Entecavir (BMS 200495) prophylaxis was not performed when rituximab chemotherapy was started, and it was thought that entecavir could be started when serum HBV-DNA increased.

Reactivation of hepatitis B virus after rituximab‐containing treatment in patients with CD20‐positive B‐cell lymphoma

Reactivation of hepatitis B virus (HBV) after rituximab-containing chemotherapy in patients with B-cell lymphoma has been recognized as a potentially serious complication in HBV immune patients. To determine the HBV reactivation in patients treated with rituximab, a retrospective study of HBV-related markers was performed before and after rituximab-containing treatment in 261 consecutive patients with CD20-positive B-cell lymphoma. Of the 261 patients, 230 patients were tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) before treatment. Fifty-six (24.3%) of 230 patients were anti-HBc positive, and the remaining 174 (75.6%) patients were anti-HBc negative. Among the 56 anti-HBc-positive patients, 5 (8.9%) became HBsAg positive (HBV reactivation), whereas none of the 174 anti-HBc-negative patients became HBsAg positive with a median follow-up of 24 months (P = .001). Among the 5 patients with HBV reactivation, 4 were negative for antibody to HBsAg (anti-HBs), and 1 patient was positive for anti-HBs. All 5 of these patients were treated successfully with entecavir on detection of HBsAg, although 4 of the 5 patients exhibited mild to moderate elevation of alanine aminotransferase. Among 56 anti-HBc-positive patients, those negative for anti-HBs had a higher probability of developing HBV reactivation compared with those positive for anti-HBs (4 of 19; 21.1% vs 1 of 37; 2.7%, P = .014). Patients with isolated anti-HBc are at high risk of HBV reactivation and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, and transaminase levels during and after rituximab-containing treatment. Although preemptive use of entecavir enabled successful management of HBV reactivation, mild to moderate hepatic flare was still observed. These approaches should be further evaluated in a prospective study with regard to clinical usefulness, safety, and cost-effectiveness.

Acute hepatitis B despite a previous high titer of anti-HBs

Loss of HBsAg and development of surface and core antibodies represent clinical cure. However, recent evidence suggests that hepatitis B virus (HBV) persists in a latent state even in those with mounted protective antibodies. After significant immunosuppression, anti-HBs may decrease and HBsAg may reappear (reverse seroconversion). Reverse seroconversion of HBV has been observed in association with hematopoietic stem cell transplantation, renal transplantation, intensive chemotherapy, human immunodeficiency infection, or rituximab usage. We present here a case study of a patient with a previous high titer of anti-HBs who later developed HBV reactivation following intensive chemotherapy for leukemia. We conclude that in immunosuppressed patients with a history of HBV infection may carry a risk for reverse seroconversion and monitoring anti-HBs levels may help recognising this risk.