Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B‐cell lymphoma patients who are HBsAg‐negative/ HBcAb‐positive: a multicenter retrospective study

Background: Reactivation of hepatitis B virus (HBV) is less common in lymphoma patients with prior resolved HBV infection [characterized by hepatitis B surface antigen (HBsAg)‐negative/hepatitis B core antibody (HBcAb)‐positive status] compared with chronic HBV infection (HBsAg positive) when receiving chemotherapy alone. The use of rituximab in chemotherapy regimen might increase the risk of HBV reactivation in patients with prior resolved HBV infection. However, the incidence of HBV reactivation is uncertain, and prophylactic antiviral treatment for this group of patients during rituximab‐containing chemotherapy is controversial. The objective of this study was to determine the incidence of HBV reactivation in HBsAg‐negative/HBcAb‐positive patients diagnosed of diffuse large B‐cell lymphoma (DLBCL) and treated with CHOP‐like or RCHOP‐like regimen. In addition, this study also aims to explore the relationship of HBV reactivation and HBV serology. Methods: Patients were identified using data from six university hospitals collected between January 1998 and November 2008. Four hundred and thirty‐seven patients with complete data were selected based on the diagnosis of CD20+ DLBCL, availability of HBV serum markers prior to initiation of chemotherapy and during the development of hepatitis, completion of at least four cycles of chemotherapy using CHOP‐like or RCHOP‐like regimen, and follow‐up for at least 6 months after completion of treatment. The characteristics of the HBsAg‐negative/HBcAb‐positive patients treated with CHOP‐like regimen were compared to those treated with RCHOP‐like regimen. Results: Eighty‐eight patients of the total 437 patients had pretreatment serology of prior resolved hepatitis B, with a prevalence of 20.1%. Among them, 45 patients received CHOP‐like regimen while 43 patients received RCHOP‐like regimen. Five patients developed hepatitis during treatment, two from CHOP group and three from RCHOP group. Only one patient treated with RCHOP had hepatitis associated with HBV reactivation, while the other four patients did not have evidence of HBV reactivation. Those four patients also demonstrated positive HBsAb at baseline, while the only patient who suffered from HBV reactivation had negative HBsAb status. This patient was successfully treated with antiviral medications. There were no statistically significant risk factors predictive of HBV reactivation. Conclusions: The present study revealed a low HBV reactivation rate of 2.3% in prior resolved hepatitis B among DLBCL patients undergoing RCHOP‐like therapy.     

A snapshot of virological presentation and outcome of immunosuppression‐driven HBV reactivation from real clinical practice: Evidence of a relevant risk of death and evolution from silent to chronic infection

The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression‐driven HBV reactivation. Seventy patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti‐HBV treatment for a median (IQR) follow‐up of 31(13‐47) months. At baseline‐screening, 72.9% of patients were HBsAg‐negative and 27.1% HBsAg‐positive. About 71.4% had a diagnosis of biochemical reactivation [median (IQR) HBV DNA and ALT: 6.9 (5.4‐7.8) log IU/mL and 359 (102‐775) U/L]. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg‐positive and HBsAg‐negative patients at baseline‐screening (median [IQR] prophylaxis duration: 24[15‐33] and 25[17‐36] months, respectively). Notably, HBV reactivation occurred 2‐24 months after completing the recommended course of anti‐HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline‐screening, only 27% returned to HBsAg‐negative status during prolonged follow‐up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline‐screening, converting a silent into a chronic infection, requiring long‐term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti‐HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.     

Eighteen‐month lamivudine prophylaxis on preventing occult hepatitis B virus infection reactivation in patients with haematological malignancies receiving immunosuppression therapy

This study evaluated the long‐term efficacy and safety of an 18‐month lamivudine prophylaxis in 68 HBsAg‐negative/anti–HBc‐positive patients with oncohaematological disease. All 68 consecutive HBsAg‐negative/anti–HBc‐positive patients with an oncohaematological disease and naïve for chemotherapy observed from April 2008 to December 2012 at 2 Hematology Units in Naples were treated with lamivudine for 18 months after stopping chemotherapy and monitored for HBsAg at months 1 and 3 during chemotherapy and then every 3 months after its discontinuation. During follow‐up, 13 (19.1%) of the 68 patients died of complications related to their oncohaematological disease, and 3 (4%) showed a virological HBV reactivation (retroconversion to HBsAg positivity) 1‐7 months after the discontinuation of lamivudine prophylaxis (2 treated for chronic lymphocytic leukaemia and one for Waldenstrom's disease); of these, 2 showed a biochemical reactivation. Comparing the demographic and clinical characteristics of the 3 patients with a virological HBV reactivation to the 65 without, the former were older (median age and range: 67 years [75‐78] vs. 61 [24‐88]; P = .05) and were less frequently treated for B‐cell non‐Hodgkin lymphoma (B‐NHL) (0 vs. 70.7%, P = .03). In conclusion, a 18 months of lamivudine prophylaxis was effective in preventing HBV reactivation in HBsAg‐negative/anti–HBc‐positive patients treated for B‐NHL. However, in patients with chronic and severe immunodepression, such as those with chronic lymphocytic leukaemia and Waldenstrom's disease, prophylaxis should be continued for an indefinite period.     

Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin's lymphoma

We used regimens containing rituximab in the treatment of five hepatitis B virus surface antibody (HBsAb)-positive patients with non-Hodgkin's lymphoma (NHL). Serum levels of HBsAb were obtained and analyzed in four of these patients. Two patients were HBs antigen (HBsAg) positive. One of these HBsAg-positive patients was treated with lamivudine because the patient developed fulminant hepatitis from hepatitis B virus (HBV) infection prior to chemotherapy. However, none of the other patients were administered lamivudine. An HBsAg-positive patient who did not receive lamivudine treatment later developed fulminant hepatitis. Another HBsAg-positive patient receiving lamivudine prophylaxis did not develop severe hepatitis arising from HBV. In the three patients not receiving lamivudine treatment, serum HBsAb titers decreased soon after the administration of rituximab. These results suggest that rituximab reduced the antibody titer for HBV, thus inducing an immunological environment leading to easy reactivation of HBV. Lamivudine prophylaxis was effective, at least when rituximab was given to an HBsAg-positive patient with non-Hodgkin's lymphoma.     

Antiviral prophylaxis for hepatitis B carriers improves the prognosis of diffuse large B‐cell lymphoma in Taiwan – a population‐based study

The prevention of hepatitis B virus (HBV) reactivation during rituximab treatment for diffuse large B‐cell lymphoma (DLBCL) is important in the HBV‐endemic area. This population‐based study examines the impact of antiviral prophylaxis for DLBCL patients with HBV infections. We identified 3702 adult patients with newly diagnosed DLBCL between 2011 and 2015 receiving R‐CHOP, R‐CVP, CHOP or CVP from the Taiwan Cancer Registry. We further stratified them into three groups: HBsAg‐negative patients (HBV‐negative, N = 2921), HBV carriers who received antiviral prophylaxis (HBV + Px, N = 711), and HBV carriers who did not receive antiviral prophylaxis (HBV + No Px, N = 70). HBV + Px patients were the youngest, and 69·4% received entecavir for antiviral prophylaxis. The median overall survival (mOS) of HBV‐negative and HBV + Px patients was similar (74·23 months and not reached, respectively). However, the mOS of HBV + No Px patients was only 35·61 months (P = 0·0028 compared with HBV + Px patients), indicating that antiviral prophylaxis improves OS in HBsAg‐positive DLBCL patients. The multivariate analysis showed that the HBV status and antiviral prophylaxis was an independent prognostic factor. In conclusion, our population‐based study illustrates the importance of antiviral prophylaxis in HBsAg‐positive DLBCL patients. Under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV‐negative patients.     

Re‐appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection

Background and aim: De novo hepatitis B virus (HBV)‐related hepatitis is a well‐known fatal complication following chemo‐immunosuppressive therapy in patients with past HBV infection (HB surface antigen and serum HBV DNA negative, but HB core antibody and/or HB surface antibody positive). This research was conducted to evaluate the incidence of and clinical features associated with re‐appearance of serum HBV DNA following chemo‐immunosuppressive therapy in Japanese patients with past HBV infection. Methods: This is a retrospective review. Forty‐five patients with past HBV infection who had received chemo‐immunosuppressive therapy for haematological disease were followed up for >6 months, to determine whether the serum test for HBV changed from negative to positive (i.e. re‐appearance of serum HBV DNA following chemo‐immunosuppressive therapy). Results: Re‐appearance of serum HBV DNA was confirmed in five (20.8%) of the 24 patients who had received treatment regimens containing rituximab, but in none of the 21 patients who had not received treatment regimens containing rituximab (P=0.035). The HBV genotype could be determined in four of the five aforementioned patients, and in all four, HBV genotype C, which is the most prevalent genotype in Japan, was identified. Conclusion: This research showed that re‐appearance of serum HBV DNA is not rare in Japanese patients treated with chemotherapy regimens containing rituximab, and no other factors related to such re‐appearance of serum HBV DNA could be identified. Well‐designed clinical studies, including immunological and genetic analyses of the host and of the HBV, are required for further elucidation.     

Hepatitis B virus reactivation in breast cancer patients undergoing chemotherapy: A review and meta‐analysis of prophylaxis management

Hepatitis B virus (HBV) reactivation during or after chemotherapy in patients with breast cancer has become a remarkable clinical problem. Prophylactic nucleos(t)ide analogues (NAs) are recommended for patients with breast cancer who are hepatitis B surface antigen (HBsAg) positive before chemotherapy. We performed an up‐to‐date meta‐analysis to compare the efficacy of prophylactic lamivudine use with nonprophylaxis in HBsAg‐positive breast cancer patients undergoing chemotherapy. PubMed, the Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were searched for relevant articles until June 2016. Eligible articles comparing the efficacy of prophylactic lamivudine use with nonprophylaxis in HBsAg‐positive breast cancer patients undergoing chemotherapy were identified. Eight studies which had enrolled 709 HBsAg‐positive breast cancer patients undergoing chemotherapy were analysed. Lamivudine prophylaxis significantly reduced the rates of chemotherapy‐associated hepatitis B flares in chronic hepatitis B in breast cancer compared with patients with nonprophylaxis (odds ratio [OR]=0.15, 95% confidence interval [CI]: 0.07‐0.35, P<.00001). Chemotherapy disruption rates attributed to HBV reactivation in the prophylaxis groups were significantly lower than the nonprophylaxis groups (OR=0.17, 95% CI: 0.07‐0.43, P=.0002). Patients with lamivudine prophylaxis had a higher risk for tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif mutations than patients with nonprophylaxis (OR=6.33, 95% CI: 1.01‐39.60, P=.05). Prophylactic antiviral therapy management is necessary for HBsAg‐positive breast cancer patients undergoing chemotherapy, in spite of high correlation with lamivudine‐resistant HBV variants with YMDD motif mutations.     

Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis

The use of rituximab has been associated with increased risk of hepatitis B virus (HBV) reactivation in patients who are hepatitis B surface antigen (HBsAg) negative and antihepatitis B core antibody (anti-HBc) positive. We aim to determine the rate of HBV reactivation in this group of patients who received rituximab-containing combination chemotherapy without concomitant antiviral prophylaxis and to identify potential risk factors for reactivation. Sixty-two HBsAg negative/anti-HBc positive patients with B-cell lymphoma treated with rituximab-based immunochemotherapy from 2006 to 2009 were included. None of the patients received concomitant antiviral prophylaxis. In this cohort, 48 (77%) patients received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), eight (13%) received rituximab with cyclophosphamide, vincristine and prednisolone, and six (10%) received other chemotherapy regimens. Two patients suffered HBV reactivation; both were above 70 years of age, received R-CHOP chemotherapy and were negative for antihepatitis B surface antibody (anti-HBs) at baseline. One of the two patients reactivated shortly after completion of R-CHOP chemotherapy while the other reactivated during rituximab maintenance treatment. Thus, the overall reactivation rate in this cohort of patients is 3% (2/62), 4% (2/48), and 25% (1/4) in patients who received R-CHOP chemotherapy and who received rituximab maintenance, respectively. The rate of HBV reactivation is low in patients who are HBsAg negative/anti-HBc positive receiving rituximab-based combination chemotherapy without concomitant antiviral prophylaxis. However, elderly patients, particularly those without anti-HBs, seemed particularly at risk.     

High risk of hepatitis B‐virus reactivation after hematopoietic cell transplantation in hepatitis B core antibody‐positive patients

We investigated the serological changes in hepatitis B virus (HBV)‐related markers in 55 and 26 hepatitis B surface antigen (HBsAg)‐negative patients undergoing allogeneic and autologous stem cell transplantation, respectively, over the past 4 yr. Five of the 17 allogeneic and one of the five autologous patients with pretransplant anti‐hepatitis B core antigen antibodies (anti‐HBc) were HBsAg‐positive after transplantation, whereas none of the patients negative for anti‐HBc were HBsAg‐positive in both groups. All patients who became HBsAg‐positive received steroid‐containing immunosuppressive therapy for chronic graft versus host disease (GVHD) or myeloma. Four of the six patients developed flare of HBV hepatitis, and two patients did not. One patient developed fulminant hepatitis treated with lamivudine and plasma exchange. Other five patients received entecavir from the detection of HBsAg. Although HBV‐DNA levels became below the limit of detection in all patients, HBsAg positivity remained in three patients after 6 months of treatment. We concluded that anti‐HBc positivity is a risk factor for reactivation of HBV after both autologous and allogeneic transplantation, and HBV‐related markers should be monitored regularly in these patients. We also stress the efficacy of pre‐emptive use of antiviral agents in controlling HBV replication and limiting hepatic injury due to reactivation of HBV in these patients.     

Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases

Hepatitis B virus reactivation (HBVr) can be a serious complication of cancer chemotherapy. However, underutilization of HBV screening and secondary underutilization of antiviral prophylaxis have been frequently reported. The authors electronically distributed a 30‐point questionnaire to members of the American Association for the Study of Liver Diseases to capture experiences with HBVr during cancer chemotherapy. The questionnaire specified diagnostic criteria and collected information on HBV screening, antiviral prophylaxis and clinical outcomes. Ninety‐nine respondents reported 188 patients who met the criteria for HBV reactivation. Forty‐one practised outside the United States, and most were hepatologists (n = 71) or gastroenterologists (n = 12). One hundred and twenty‐six patients had haematologic malignancies, of which 88 (70%) had lymphoma. Seventy‐five patients (40%) had screening for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti‐HBc), and an additional 24 patients (13%) had HBsAg screening alone. Prophylactic antiviral therapy was reported in only 18 patients (10%). Chemotherapy was interrupted in 52 patients (41%) with haematologic malignancies and 26 of 41 patients (63%) with solid tumours (P = 0.01). Rituximab‐treated patients (n = 66) required hospitalization more frequently (P = 0.04), but their overall survival did not differ from individuals not treated with rituximab. Death due to liver failure was reported in 43 patients overall (23%). Underutilization of prophylactic antiviral therapy occured in a substantial number of patients who were found to be HBV infected prior to the initiation of cancer chemotherapy. The reasons for this need further exploration because reactivation results in serious yet preventable outcomes.     

Hepatitis B reactivation after kidney transplantation in hepatitis B surface antigen‐negative,core antibody‐positive recipients

Nowadays, intensive immunosuppressive therapy including rituximab is commonly used prior to kidney transplantation (KT), raising concerns over hepatitis B virus (HBV) reactivation among hepatitis B surface antigen (HBsAg)‐negative and anti‐hepatitis B core (HBc)‐positive KT recipients. Recent practice guidelines suggested watchful monitoring or antiviral prophylaxis for the first 6‐12 months, the period of maximal immunosuppression. However, the actual risk for HBV reactivation, and whether short‐term antiviral therapy in the early period is necessary, remains unclear. A total of 449 HBsAg‐negative and anti‐HBc‐positive KT recipients were analysed for HBV reactivation. During a median follow‐up of 6.7 (interquartile range: 4.2‐9.4) years, HBV reactivation was observed in 9 patients (2.0%). The median time of HBV reactivation from KT was 2.8 years (range: 1.4‐11.5 years), with cumulative incidence rates of 0%, 1% and 2% for 1, 3 and 5 years, respectively. There were no severe adverse outcomes, including liver transplantation or mortality related to HBV reactivation. The risk of HBV reactivation was not high, even in anti‐HBs‐negative patients (n = 60, 4% at 5 years), ABO mismatch (n = 92, 4% at 5 years), use of rituximab (n = 66, 3% at 5 years) or plasmapheresis (n = 17, 7% at 5 years), and acute rejection (n = 169, 3% at 5 years). In conclusion, the HBV reactivation risk was not high and the time of detection was not clustered in the early post‐KT period. Our findings favour continued watchful monitoring over antiviral prophylaxis in the early period.     

Hepatitis B reactivation in HBsAg‐negative/HBcAb‐positive patients receiving rituximab for lymphoma: a meta‐analysis

Patients with chronic hepatitis B (HBsAg‐positive) are at risk of viral reactivation if rituximab is administered without antiviral treatment, a potentially fatal complication of treatment. Patients with so‐called ‘resolved hepatitis B virus infection’ (HBsAg‐negative/cAb‐positive) may also be at risk. We performed a systematic review of the English and Chinese language literature to estimate the risk of hepatitis B virus (HBV) reactivation in HBsAg‐negative/cAb‐positive patients receiving rituximab for lymphoma. A pooled risk estimate was calculated for HBV reactivation. The impact of HBsAb status and study design on reactivation rates was explored. Data from 578 patients in 15 studies were included. ‘Clinical HBV reactivation’, (ALT >3 × normal and either an increase in HBV DNA from baseline or HBsAg seroreversion), was estimated at 6.3% (I² = 63%, P = 0.006). Significant heterogeneity was detected. Reactivation rates were higher in prospective vs retrospective studies (14.2% vs 3.8%; OR = 4.39, 95% CI 0.83–23.28). Exploratory analyses found no effect of HBsAb status on reactivation risk (OR = 0.083; P = 0.151). Our meta‐analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients exposed to rituximab. However, heterogeneity in the existing literature limits the generalizability of our findings. Large, prospective studies, with uniform definitions of HBV reactivation, are needed to clarify the risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients.     

利妥昔单抗联合化疗治疗非霍奇金淋巴瘤致肝功能衰竭报道并文献复习

目的：探讨利妥昔单抗联合 CHOP 方案（R-CHOP）治疗非霍奇金淋巴瘤合并非活动性 HBsAg 携带者的治疗方法。方法报道1例行 R-CHOP 方案治疗非霍奇金淋巴瘤合并非活动性 HBsAg 携带者患者,未行抗病毒治疗的疾病进程,并复习近年来国内外发表的相关文献。结果本例患者应用 R-CHOP 方案化疗前未行抗病毒治疗,引起HBV 再激活,致肝功能衰竭。结论应明确抗病毒治疗对防止非霍奇金淋巴瘤患者化疗过程中 HBV 再激活的重要性。     

Tolerability and efficacy of anti‐HBV nucleos(t)ide analogues in HBV‐DNA‐positive cirrhotic patients with HBV/HCV dual infection

Summary. We evaluated tolerability and virological and clinical impact of anti‐Hepatitis B Virus (HBV) nucleos(t)ide analogues in cirrhotic patients with HBV/Hepatitis C Virus (HCV) coinfection. The virological and clinical course of 24 consecutive HBsAg/HBV‐DNA/anti‐HCV‐positive patients with cirrhosis was compared with that of 24 HBsAg/HBV‐DNA‐positive, anti‐HCV‐negative cirrhotic patients, pair‐matched for age (±5 years), sex, HBeAg/anti‐HBe status and Child‐Pugh class. Patients in both groups were previously untreated with oral antiviral agents at enrolment and were treated for at least 24 months (range 24–54). At the 12th and 18th month of treatment, HBV‐DNA was negative in 21 (87.5%) and 23 (95.8%) patients with hepatitis B and C and in 20 (83.3%) and 22 (91.6%) in patients with isolated HBV; all patients in both groups were HBV‐DNA‐negative at month 24 and at subsequent observations. Treatment was well tolerated by all patients in both groups. At the last observation (for co‐infected patients, median 44 months and range 24–54; for mono‐infected patients, median 40 months and range 24–54), a deterioration in Child class was observed in eight (47%) of 17 patients in patients with both HBV and HCV who were HCV‐RNA‐positive at baseline, but in none of seven HCV‐RNA‐negative patients in the same group, and in one patient (4.2%) in the mono‐infected patients. Reactivation of HCV infection was relatively infrequent (12.5% of cases) and never associated with a clinical deterioration. Treatment with nucleotides in HBsAg/HBV‐DNA/anti‐HCV‐positive patients with cirrhosis showed a favourable virological effect in all cases, but a favourable clinical result only in the HCV‐RNA‐negative at baseline.     

Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation‐related mortality in chemotherapy patients: a meta‐analysis

Background: Hepatitis B viral (HBV) reactivation in patients undergoing chemotherapy is associated with significant morbidity and mortality. Lamivudine has been suggested to be useful as a prophylaxis for HBV reactivation; however, its impact on overall survival and HBV reactivation‐related liver disease survival is unclear. Objective: To determine the effect of lamivudine prophylaxis on the rate of HBV reactivation, overall survival and HBV reactivation‐related survival in patients with HBV undergoing chemotherapy. Methods: A comprehensive search of MEDLINE, Cochrane Collaboration Database, reference lists and abstracts from national meetings. Statistical analysis was performed using revman . Results: Eleven studies met the defined inclusion criteria and were included in the analysis. Two‐hundred and twenty patients received lamivudine prophylaxis and 400 did not receive prophylaxis. Patients given lamivudine prophylaxis had an 87% decrease in HBV reactivation [risk ratio (RR) 0.13, 95% confidence interval (CI), 0.07–0.24] than patients not given prophylaxis [absolute risk reduction (ARR) ?0.46, 95% CI, ?0.61 to ?0.31]. The number needed to treat to prevent one reactivation was 3. The Lamivudine prophylaxis group was also associated with a 70% reduction in reactivation‐related mortality (RR 0.30, 95% CI, 0.1–0.94) compared with controls (ARR ?0.03, 95% CI, 0.07–0.00). There was a reduction in treatment delays and premature termination of chemotherapy in the lamivudine prophylaxis arm (RR 0.41, 95% CI, 0.27–0.63; ARR ?0.33, 95% CI, ?0.33 to ?0.15). There was no significant heterogeneity in the comparisons. Conclusion: Lamivudine prophylaxis during chemotherapy is effective in reducing the rate of HBV reactivation, and reactivation‐related liver mortality. Patients with lamivudine prophylaxis had less chemotherapy treatment delays and premature termination of their chemotherapy. Few patients need to be treated to prevent reactivation. Patients with HBV undergoing chemotherapy should be started on lamivudine prophylaxis.     

Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non-Hodgkin's lymphoma

Chemotherapy for non-Hodgkin's lymphoma (NHL) patients with chronic hepatitis B virus (HBV) infection may be accompanied by severe hepatitis. Of 86 consecutive NHL patients, 11 (12.8%) exhibited a positive serum HBsAg. Six of these patients (54.5%) developed acute exacerbation of chronic HBV infection following chemotherapy and received lamivudine. Five of the six patients demonstrated a clinical improvement, one patient died from fulminant hepatic failure owing to delayed lamivudine therapy and poor compliance. These data suggest that HBsAg screening is necessary before commencing chemotherapy for NHL patients in a hyperendemic area and that lamivudine is effective in treating hepatitis B reactivation during chemotherapy.     

HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct‐acting antivirals

Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct‐acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV‐RNA and HBV‐DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow‐up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV‐DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti‐HBc positive, 12 anti‐HBc/anti‐HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty‐seven patients (64.4%) were HCV‐RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg‐positive patients treated with NUCs remained HBV‐DNA negative, but three of four untreated patients showed an increase in HBV‐DNA of 2‐3 log without a biochemical flare and achieved HBV‐DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV‐DNA remained not detectable in all 37 anti‐HBc‐positive patients but in three of them (8.1%) HBV‐DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV‐coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre‐emptive therapy with NUCs should be considered in this setting. Anti‐HBc‐positive patients rarely reactivate HBV without clinical or virological outcomes.     

Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies

The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti‐viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy‐induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti‐HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre‐emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre‐emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre‐treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.     

Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg‐negative and anti‐HBc antibodies‐positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer

Summary. We studied clinical outcome and clinico‐virological factors associated with hepatitis B virus reactivation (HBV‐R) following cancer treatment in hepatitis B virus surface antigen (HBsAg)‐negative/anti‐hepatitis B core antibodies (anti‐HBcAb)‐positive patients. Between 11/2003 and 12/2005, HBV‐R occurred in 7/84 HBsAg‐negative/anti‐HBcAb‐positive patients treated for haematological or solid cancer. Virological factors including HBV genotype, core promoter, precore, and HBsAg genotypic and amino acid (aa) patterns were studied. Patients presenting with reactivation were men, had an hepatitis B virus surface antibody (HBsAb) titre <100 IU/L and underwent >1 line of chemotherapy (CT) significantly more frequently than controls. All were treated for haematological cancer, 3/7 received haematopoietic stem cell transplantation (HSCT), and 4/7 received rituximab. Using multivariate analysis, receiving >1 line of CT was an independent risk factor for HBV‐R. Fatal outcome occurred in 3/7 patients (despite lamivudine therapy in two), whereas 2/4 survivors had an HBsAg seroconversion. HBV‐R involved non‐A HBV genotypes and core promoter and/or precore HBV mutants in all cases. Mutations known to impair HBsAg antigenicity were detected in HBV DNA from all seven patients. HBV DNA could be retrospectively detected in two patients prior cancer treatment and despite HBsAg negativity. HBV‐R is a concern in HBsAg‐negative/anti‐HBcAb‐positive patients undergoing cancer therapy, especially in males presenting with haematological cancer, a low anti‐HBsAb titre and more than one chemotherapeutic agent. HBV DNA testing is mandatory to improve diagnosis and management of HBV‐R in these patients. The role of specific therapies such as rituximab or HSCT as well as of HBV aa variability deserves further studies.     

Risk stratification for hepatitis B virus related hepatocellular carcinoma

Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia–Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐HBV (REVEAL‐HBV) study from Taiwan illustrated the strong association between HBV‐DNA level at study entry and risk of HCC over time. In this community‐based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV‐DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital‐based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL‐HBV. The risk of HCC started to increase when HBV‐DNA level was higher than 2000 IU/mL. Both HBV‐DNA and HBsAg levels were shown to be associated with HCC development. While HBV‐DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV‐DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL‐HBV, a risk calculation for predicting HCC in non‐cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV‐DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk.