因血液系统肿瘤疾病而行免疫抑制治疗的患者乙肝病毒重新激活并伴有很高几率的肝衰竭的报道非常多见。推荐乙肝表面抗原阳性的患者常规应用拉米夫定进行抗病毒治疗，但是对于乙肝表面抗原阴性、乙肝核心抗体阳性的患者的治疗，尚没有统一的意见。在第64届美国肝病研究学会（AASLD）年会上公布的一项研究评估了包含或不包含拉米夫定的细胞毒性药物治疗乙肝表面抗原阴性、乙肝核心抗体阳性的霍奇金淋巴瘤(HL)或非霍奇金淋巴瘤(NHL)患者对乙肝病毒感染的影响。
研究设计
这是一项回顾-前瞻性观察试验，将2007年-2013年间参与那不勒斯大学附属意大利第三中心医院Federico II计划的所有霍奇金淋巴瘤和非霍奇金淋巴瘤患者纳入研究。共有123位患者被纳入研究，21位患者为非霍奇金淋巴瘤，其中11位患者接受R-CHOP方案（利妥昔单抗联合CHOP方案）化疗，10位患者接受CHOP方案（环磷酰胺＋多柔比星＋长春新碱＋泼尼松）化疗，102位霍奇金淋巴瘤患者全部接受ABVD方案(阿霉素+博来霉素+长春花碱+氮烯唑胺)化疗。我们系统评估了乙肝病毒血清标志物和肝功能试验。乙肝病毒重新激活的定义为毒性药物治疗期间及之后的6个月中，乙肝表面抗原和乙肝病毒DNA的阳性，无论伴或不伴谷丙转氨酶（ALT）的升高。
研究结果
经观察，总共46位乙肝表面抗原和乙肝病毒DNA阴性的患者中（男女比例为24/22，年龄从24-74岁不等，中位数为49岁），治疗后有33位患者单独乙肝核心抗体阳性，13位患者乙肝核心抗体和乙肝表面抗体阳性。46位患者中有6位接受包含利妥昔单抗的细胞毒性药物治疗方案，其中5位患者应用拉米夫定成功地预防乙肝病毒重新激活(3位患者单独乙肝核心抗体阳性，2位患者乙肝核心抗体及乙肝表面抗体阳性)。只观察到一位应用R-CHOP方案且没有应用拉米夫定预防的患者（治疗前乙肝核心抗体及乙肝表面抗体阳性)在化疗结束后的一个月乙肝病毒重新激活。该患者治疗后乙肝表面抗原阳性，ALT升高(200/35 UI/ml)，乙肝病毒DNA阳性(x 2 log)。该患者应用拉米夫定治疗后，转氨酶马上变为正常，乙肝病毒DNA也转为阴性。其他40位接受不包含利妥昔单抗的细胞毒药物治疗(ABVD/CHOP: 32/8) 且未进行预防的患者，无一发生乙肝病毒重新激活。
结论
接受包含利妥昔单抗化疗的表面抗原阴性，乙肝核心抗体阳性的患者（也就是乙肝病毒潜伏感染）如不进行抗病毒预防措施，乙肝病毒重新激活的风险很大。相反，接受不含利妥昔单抗方案的患者（特别是ABVD和CHOP方案）似乎不存在乙肝病毒重新激活的风险。这一初步研究报告显示，乙肝病毒重新激活与免疫抑制治疗的类型有关，需根据具体情况选择抗病毒预防措施。
原文摘要
Hepatitis B reactivation has been widely reported in patients undergoing immunosuppressive therapy for oncohaematological diseases, with a high frequency of hepatic failure. Routine antiviral prophylaxis with Lamivudine is recommended for HBsAg+ subjects, while for patients showing HBsAg-/HBcAb+ virological pattern a definite consensus was not reached. We conducted a study to evaluate the effects on HBV infection of cytotoxic chemotherapy containing or not Rituximab in patients HBsAg negative/HBcAb positive with Hodgkin Lymphoma (HL) and Non Hodgkin Lymphoma (NHL).
This is a retrospective-prospective observational study, including all consecutive patients with HL and NHL who attended an Italian tertiary referral hospital at University of Naples “Federico II”, from 2007 to 2013. A total of 123 patients were enrolled: 21 with NHL , of which 11 treated with R-CHOP and 10 with CHOP, and 102 with HL treated with ABVD. We systematically evaluated serum HBV markers and liver function test. HBV reactivation was defined as occurrence of HBsAg and HBV-DNA, with or without ALT elevation, during cytotoxic therapy and since to 6 months after.
A total of 46 (37%) HBsAg and HBV-DNA negative patients (M/F 24/22, median age 49 yrs, range 21-74 yrs), 33 with isolated anti-HBc and 13 with anti-HBc/anti-HBs positivity, were observed. Six/46 were treated with therapeutic cytotoxic schedule containing Rituximab. Of them, 5/6 received successfully prophylaxis with Lamivudine (3 with isolated anti-HBc+ and 2 with positivity for anti-HBc/anti-HBs). HBV reactivation was observed in the only patient (anti-HBc+/anti-HBs+) treated with R-CHOP without Lamivudine prophylaxis one month after the end of chemotherapy; he showed HBsAg positivity, increase of ALT (200/35 UI/ml) and HBV-DNA (x 2 log). Immediately he started Lamivudine therapy with rapid normalization of aminotransferase and negativization of HBV-DNA. No one of the other 40 patients treated with cytotoxic chemotherapy without Rituximab (ABVD/CHOP: 32/8) and without receiving prophylaxis, showed HBV reactivation.
HBsAg negative/HBcAb positive patients (i.e., with a potential occult HBV infection) receiving chemotherapy containing Rituximab without antiviral prophylaxis are at risk of HBV reactivation. On the contrary, in patients undergoing Rituximab-free schedule, especially ABVD and CHOP regimens, the risk of reactivation seems to be absent. This preliminary report underlines the concept that HBV reactivation is strongly related to the type of immunosuppressive therapy administered and that antiviral prophylaxis needs to be tailored.
