Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP

Preemptive lamivudine in lymphoma patients undergoing intensive chemotherapy can effectively prevent chemotherapy-related HBV reactivation. Nevertheless, the safety profile after withdrawal of lamivudine and the impact of rituximab-containing chemotherapy on HBV reactivation has not been defined. To illustrate the necessity of prolonged surveillance after cessation of preemptive lamivudine in lymphoma patients treated with rituximab and chemotherapy, four patients with B-cell NHL carrying HBV received rituximab plus CHOP. Preemptive lamivudine therapy was administered 1 week before chemotherapy until 4 weeks after completion of chemotherapy. Serial serum alanine aminotransferase (ALT), total bilirubin, and HBV-DNA levels were prospectively monitored in three patients. The fourth patient was closely monitored for ALT. The HBV DNA was checked after development of clinical overt hepatitis. The peripheral blood CD20⁺ B-lymphocyte counts were analyzed periodically in two patients. All of the three patients studied prospectively had virological relapses with surgence of HBV DNA 6–8 months after completion of rituximab-plus-CHOP (R+CHOP) therapy. Two of the three patients had biochemical relapses and one of them developed severe hepatitis. Sequencing for HBV polymerase gene in these patients failed to show evident emergence of lamivudine-resistant mutations. The fourth patient developed a hepatitis flare-up 6 months after completion of chemotherapy. The CD20⁺ lymphocytes were totally depleted when HBV DNA started to increase. Delayed HBV reactivation can occur in lymphoma patients receiving R+CHOP after withdrawal of preemptive lamivudine. More protracted lamivudine therapy may be an alternative to close monitoring following chemotherapy, and further studies are needed to define optimal duration of lamivudine therapy.     

Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients

Hepatitis B virus (HBV) reactivation is a well-known complication of lymphoma treatment in the pre-rituximab era. This complication has not been as well studied, however, since monoclonal anti-CD20 antibody became the standard regimen for B cell lymphoma. In this retrospective study, 115 B cell lymphoma patients who received rituximab-containing therapy were analyzed. Of 15 hepatitis B surface antigen (HBsAg)-positive patients, five received lamivudine prophylaxis and did not develop HBV-related hepatitis during lymphoma treatment. Eight of ten HBV carriers without lamivudine prophylaxis experienced HBV-related hepatitis, including one fatal hepatic failure. Four (4.2%) of 95 HBsAg-negative patients developed de novo HBV-related hepatitis and two died of fulminant hepatitis. In conclusion, rituximab-based therapy may cause serious HBV-related complications and even death in both HBsAg-positive and HBsAg-negative patients.     

A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial

Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non-Hodgkin's lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5-fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% versus 56%, P = 0.001), HBV-related hepatitis (7.7% versus 48%, P = 0.001), or severe hepatitis (ALT more than 10-fold ULN) (0 versus 36%, P < 0.001). No hepatitis-related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two patients, both in group P, died of HBV reactivation-related hepatitis, 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine-na?ve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV-related hepatitis nor changed the patterns of HBV reactivation. CONCLUSION: Prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy-related HBV reactivation in NHL patients.     

Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies

Summary.  Although hepatitis B virus (HBV) reactivation in HBV carriers undergoing immunosuppressive therapy is clearly documented, the role of antiviral prophylaxis in such individuals is still controversial. The aim of this study was to determine the efficacy of lamivudine prophylaxis in HBV carriers with haemato/oncological malignancies, who receive chemotherapy. Eighteen HBV carriers with malignancy, who were candidates for chemotherapy, were enrolled. Eight subjects (three with leukaemia, four with lymphoma and one with multiple myeloma) were enrolled for prophylactic lamivudine therapy. The remaining 10 patients (six with leukaemia, three with lymphoma and one with breast cancer) were not treated with lamivudine and were used as a control. Lamivudine was administered beginning on the same day as the chemotherapy and was maintained for a year after chemotherapy was discontinued. No HBV-related mortality was observed in either group. In the lamivudine-treated group, none of the subjects had clinical, biochemical or serological evidence of HBV reactivation during the time they were receiving chemotherapy and after their chemotherapy was discontinued. In contrast, five of the 10 HBV carriers not receiving lamivudine therapy experienced a reactivation of HBV infection. This reactivation of HBV was observed during the chemotherapy in four with one individual experiencing a HBV activation 12 months after chemotherapy was discontinued. No lamivudine-related major adverse effects were observed. Hence prophylactic lamivudine treatment in HBV carriers with haemato/oncological malignancy receiving chemotherapy prevents chemotherapy-induced HBV reactivation.     

Fatal Fulminant Hepatitis B after Withdrawal of Prophylactic Lamivudine in Hematopoietic Stem Cell Transplantation Patients

Hepatitis B virus (HBV) reactivation can give rise to acute hepatitis and even fatal fulminant hepatitis in patients receiving immunosuppressive or cytostatic treatment. Recently, the prophylactic use of lamivudine for HBV reactivation in HBV surface antigen-positive chronic-disease patients undergoing hematopoietic stem cell transplantation (HSCT) has been reported. However, the appropriate duration for this prophylactic therapy is unclear. Here, we report 2 cases of fatal fulminant hepatitis B reactivation in HSCT patients after lamivudine withdrawal. One patient with non-Hodgkin's lymphoma completed 6 courses of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) and autologous peripheral blood SCT (PBSCT). Lamivudine was discontinued 3 months after transplantation. The second patient had acute myeloid leukemia. He received induction chemotherapy and postremission allogeneic PBSCT as late intensified consolidation therapy. Lamivudine treatment was discontinued 10 months after transplantation. In both patients, HBV reactivation 2 to 3 months following lamivudine cessation led to fatal fulminant hepatitis. We suggest that the duration of prophylactic use of lamivudine in chronic HBV carriers receiving HSCT be prolonged until the patient's immune system has been reconstituted.     

Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers

Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.     

Hepatitis B virus reactivation in a patient undergoing steroid-free chemotherapy

A 62-year-old Japanese man who was positive for hepatitis B surface antigen (HBsAg) and anti-HBe antibody, underwent chemotherapy for non-Hodgkin‘s lymphoma (NHL). Mutations were detected in the precore region (nt1896) of HBV. Because steroid-containing regimen may cause reactivation of hepatitis B virus (HBV) and hepatitis may progress to be fulminant afcer its withdrawal, we administered CHO (CPA, DOX and VCR) therapy and the patient obtained complete response. However, he developed acute exacerbation of hepatitis due to HBV reactivation. Recovery was achieved with lamivudine (100 mg/d) and plasma exchange. The present case suggests that acute exacerbation of hepatitis can occur with steroid-free regimen. Because the efficacy of the prophylactic use of lamivudine has been reported and the steroid enhances curability of malignant lymphoma,the steroid containing regimen with prophylaxis of lamivudine should be evaluated further.     

Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy

Reactivation of hepatitis B virus (HBV) infection is a frequent complication of cytotoxic chemotherapy that includes steroids. International studies have shown that lamivudine reduces the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy to treat malignancies. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations. Here, we studied the role of entecavir in preventing morbidity and mortality associated with HBV reactivation. Three patients with both solid malignancies and hepatitis B surface antigen-positive hepatitis B underwent cytotoxic chemotherapy with steroids. They were followed up for at least 6 months after the completion of chemotherapy. The chemotherapeutic regimens comprised carboplatin and paclitaxel for non-small-cell lung cancer, and docetaxel monotherapy or cyclophosphamide plus epirubicin for breast cancer, respectively. All patients completed chemotherapy with steroids without developing severe hepatitis that could be attributable to HBV reactivation. Entecavir prevented the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Although further studies are required to evaluate whether entecavir can prevent the increased risk of YMDD mutation and decrease the rates of disrupted chemotherapy due to severe hepatitis more effectively than lamivudine, entecavir should be considered before lamivudine for such patients.     

Role of lamivudine in the reactivation of hepatitis B virus infection in immunodepressed patients.

INTRODUCTION: hepatitis B virus (HBV) reactivation in immunocompromised states is a well-known event that may be a serious problem in endemic areas of infection. Presently, the investigation of hepatitis B status has been recommended prior to receiving cytotoxic treatment. Lamivudine has been used in the reactivation of HBV in immunocompromised states. We report our corresponding data for lamivudine in the treatment of HBV reactivation after intensive chemotherapy in patients with lymphoma and after kidney transplantation. CLINICAL OBSERVATION: we present two cases of HBV reactivation after chemotherapy for lymphoma and two cases after cadaveric renal transplantation treated with lamivudine (100-150 mg/day). RESULTS: we observed a prompt clinical improvement in all patients after lamivudine treatment. Furthermore, laboratory data showed a rapid biochemical and antiviral response. However, the response in lymphoma patients was quicker than in patients who had post-transplantation reactivation of HBV. Therapy was well tolerated and no relevant side effects appeared during follow-up (twenty four months). The HBV remained negative in three cases. CONCLUSION: lamivudine is effective and safe in the treatment of HBV reactivation in immunodepressed patients. Lamivudine therapy should be considered for the treatment of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication.     

拉米夫定在预防乙型肝炎携带的淋巴瘤患者化疗后肝炎发生中作用

探讨慢性HBV携带的淋巴瘤患者化疗前预防应用拉米夫定在减少化疗后肝炎发生率以及严重程度方面的作用。40例患者化疗前及整个化疗期间口服拉米夫定,并持续用至化疗结束后至少8周以上;另外历史对照组116例患者未接受预防性拉米夫定口服。对二组患者肝炎发生率、严重性以及不良临床后果进行比较,对肝炎发生的危险因素进行分析。结果显示预防应用拉米夫定能够明显减少肝炎的发生率及明显改善患者接受化疗后出现的不良临床后果;并显示激素的应用是肝炎发生的高危因素。对HBV携带的淋巴瘤患者化疗前应预防使用拉米夫定,尤其对于接受含激素的化疗方案的患者。     

原发性肝癌局部化疗后肝炎及乙型肝炎抗病毒治疗的临床研究

目的分析肝癌化疗后肝炎发生的病因,探讨核苷类似物抗病毒治疗对化疗后乙肝病毒再激活肝炎疗效。方法收集明确诊断乙型肝炎后肝细胞癌患者120例,男108例,女12例,年龄28~85岁,平均（53.88±12.16）岁。肝癌患者均接受1次经导管肝动脉化疗栓塞（TACE）治疗;并分为抗病毒治疗组35例;未行抗病毒治疗组85例。抗病毒组中TACE前2周23例服拉米夫定;12例服阿德福韦酯,维持抗病毒治疗TACE后4周为观察终点。随访4周后,监测2组患者TACE前后肝功能及HBV载量水平变化和肝炎发生情况,观察核苷类似物抗病毒治疗HBV再激活肝炎的疗效。结果肝细胞癌患者化疗后HBV再激活33例,化疗后未再激活87例,HBV再激活发生率为27.50%。HBV再激活肝炎23例,发生率为69.70%;化疗药物性肝炎11例,发生率为12.64%,2种肝炎的发生之间差异有统计学意义（P=0.00）。抗病毒治疗组与未抗病毒组之间HBV再激活肝炎的发生差异有统计学意义（2χ=5.78,P〈0.05）,2组间药物性肝炎的发生差异无统计学意义。结论肝细胞癌化疗后发生HBV再激活肝炎和化疗药物性肝炎;HBV再激活肝炎的发生较化疗药物性肝炎多。核苷类似物（拉米夫定/阿德福韦酯）抗病毒治疗可明显降低肝细胞癌患者化疗后HBV再激活肝炎的发生。     

A possible role for lamivudine as prophylaxis against hepatitis B reactivation in carriers of hepatitis B who undergo chemotherapy and autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

Hepatitis B virus (HBV) reactivation, a well-known complication in immunosuppressed patients, can give rise to acute hepatitis and even fatal fulminant hepatitis. Three Japanese males with non-Hodgkin's lymphoma (NHL) who were carriers of HBV received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). To prevent HBV reactivation, all received oral lamivudine (150 mg/day), a nucleoside analogue, at the start of chemotherapy. All were treated at full-dose intensity, including corticosteroids, without modification of treatment regimens. All three patients completed the total course of chemotherapy and PBSCT, with no signs of HBV reactivation. Peripheral blood stem cell (PBSC) harvests and hematological recoveries after transplantation were not affected by lamivudine, which was continued for at least 16 weeks after transplantation. HBV-DNA and DNA polymerase levels remained negative/normal after discontinuation of lamivudine. Lamivudine effectively inhibits HBV replication and has few serious adverse effects, particularly those related to hematopoiesis. Thus, prophylactic use of lamivudine from initiation of chemotherapy deserves consideration in the treatment of HBV carriers who require immunosuppressive chemotherapy, and may prevent HBV reactivation.     

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.     

Fatal postlymphoma chemotherapy hepatitis B reactivation secondary to the emergence of a YMDD mutant strain with lamivudine resistance in a noncirrhotic patient

Hepatitis B reactivation is a well-known complication during or after chemotherapy in chronic hepatitis B (HBV) carriers. The current practice guidelines in Canada and the United States recommends patients receive antiviral prophylaxis prior to the onset of chemotherapy in chronic HBV carriers with lamivudine. We report a case of a 57-year-old man with follicular lymphoma on lamivudine prophylaxis and no clinical evidence of cirrhosis, and developed fatal HBV reactivation after the emergence of a YMDD mutant strain of HBV that confers lamivudine resistance. Fatal reactivation secondary to the development of lamivudine resistance has not, to date, been well- reported. Our experience indicates the need to carefully monitor patients for suspected drug- resistant HBV mutants with the addition of anti-viral agents effective against the YMDD mutational strain, when lamivudine resistance emerges.     

Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients treated with anti-TNFα agents: A retrospective analysis of 49 cases

Clinical guidelines regarding anti-viral prophylaxis for HBV surface antigen (HBsAg) carriers starting anti-TNFα agents are not yet fully established, even in endemic regions of HBV infection. We retrospectively collected the clinical data of 52 HBsAg carriers with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) that had been administered anti-TNFα treatment at seven medical centers in South Korea. Periodic data of liver function tests and serum HBV DNA were both utilized to assess HBV reactivation. The YMDD motif mutation of HBV DNA polymerase was tested in lamivudine-treated patients with elevated HBV DNA. Three of the 52 patients were excluded from the analysis. Of the 49 analyzed patients, 20 patients received anti-viral prophylaxis (15 lamivudine, five entecavir) with anti-TNFα treatment. The remaining 29 patients were treated with anti-viral agents if needed at the discretion of the clinician and did not receive prophylaxis. Of the 29 patients who did not receive primary prophylaxis, two (6.9%) developed viral reactivation within a year of anti-TNFα treatment. In the prophylaxis group, one patient developed viral reactivation at week 64 of anti-TNFα therapy attributed to YMDD mutation caused by lamivudine. Patients with HBV reactivation all responded well to anti-viral therapy. In summary, anti-viral prophylaxis helped preventing HBV reactivation in HBsAg carriers with RA or AS starting anti-TNFα, yet mutation in the YMDD motif of HBV DNA polymerase could be detrimental to some patients under long-term 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.     

肿瘤患者化疗后乙型肝炎病毒再激活病例临床分析

目的观察肿瘤合并慢性HBV携带者化疗后HBV再激活抗病毒治疗的效果及化疗前预防性抗病毒用药对HBV再激活的预防作用。方法采用回顾性分析将13例肿瘤合并慢性HBV携带者分成两组：治疗性用药组8例，为化疗后HBV再激活致肝功能异常者，均停用原有化疗药物，给予拉米夫定100mg／d及保肝药治疗。预防性用药组5例，化疗前即予以拉米夫定100mg／d治疗，待血清HBV DNA水平降至〈10^3拷贝／ml之后再行化疗。随访两组患者的肝功能、HBV DNA水平及预后。结果8例化疗后HBV再激活者，出现肝功能异常后才给予拉米夫定抗病毒治疗，5例因肝功能衰竭而死亡，3例经抗病毒治疗后肝功能恢复，但推迟甚至终止了化疗。5例在化疗前接受预防性抗病毒治疗的患者中未观察到HBV再激活现象，无死亡病例。结论对于需要化疗的HBV携带者，预防比治疗更有意义。     

Antiviral prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) carriers are at considerable risk of reactivation of HBV infection when undergoing chemotherapy or immunosuppressive therapy. Complications of HBV reactivation, including asymptomatic elevation of HBV DNA levels, acute hepatitis, acute liver failure, and delays or dose reductions in chemotherapy, are avoidable with appropriate prophylactic oral antiviral therapy. This article reviews evidence for and presents a grade A recommendation supporting primary prophylaxis among HBV carriers with lamivudine. The dose and duration of prophylaxis, risk of lamivudine resistance, and future directions of prophylactic therapy for HBV reactivation during chemotherapy are discussed. Recommendations are suggested based on expert opinion for prophylaxis with the combination of lamivudine plus adefovir or with entecavir as alternative antiviral strategies that substantially reduce or avoid the risk of HBV antiviral drug resistance.     

Hepatic Failure Caused by Reactivation of YMDD Mutants Occurring during Preemptive Lamivudine Therapy

Reactivation of hepatitis B virus (HBV) replication is a frequent phenomenon in patients receiving immunosuppressants or chemotherapy. It was recently reported that regional therapy, such as transarterial chemotherapy (TAC) or radiotherapy, can also induce HBV reactivation in patients with hepatocellular carcinoma (HCC), and this can be prevented by preemptive lamivudine treatment. We report an unusual case of fatal hepatitis caused by reactivation of the tyrosine-methionine-aspartate-aspartate (YMDD) lamivudine-resistant strain in a 51-year-old male patient with HCC who was receiving preemptive lamivudine therapy. This patient received combined helical tomotherapy and TAC for the treatment of HCC with pulmonary metastasis. HBV reactivation and hepatitis exacerbation occurred after 2 months of therapy, but preemptive antiviral therapy was continued. Laboratory tests showed that the serum HBV DNA level had increased by more than 10,000-fold and a severe elevation of the aminotransferase level to 1,060 U/L. Although adefovir was added to lamivudine immediately after detecting the YMDD mutants, the patient eventually died of hepatic failure. Our experience suggests that for preemptive therapy, the use of potent antiviral drugs with a low risk of drug resistance as well as close viral monitoring are important for chronic HBV carriers undergoing intensive anticancer therapy.     

Frequency of hepatitis B virus mutant in asymptomatic hepatitis B virus carriers receiving prophylactic lamivudine during chemotherapy for hematologic malignancies

Hepatitis B virus (HBV) reactivation is a potentially fatal complication of chemotherapy in asymptomatic HBV carriers. Prophylactic lamivudine has proven effective for its prevention, but the potential emergence of lamivudine-resistant HBV YMMD mutants, as shown in patients treated for chronic hepatitis, may limit its use. To evaluate the frequency of HBV YMMD mutant and its clinical significance, we have analysed 32 courses of primary lamivudine prophylaxis given to HBV carriers with haematologic malignancies, from the start until 1-5 months after the end of chemotherapy. Lamivudine was used for a median of 6 months (range 2-24+) and median follow-up was 19.5 months (range 5-40). Four episodes of HBV reactivation with mild hepatitis and no evidence of mutant strain occurred after chemotherapy completion and after lamivudine withdrawal. At follow-up YMMD mutant was detected in one patient with normal transaminase levels, who had been on continuous lamivudine for 20 months. In conclusion, among HBV carriers treated with chemotherapy for haematologic malignancies, the emergence of HBV YMMD mutant occurred in 3.1% of prophylactic lamivudine courses and was of little clinical relevance.