Does suppression of HBV replication by antiviral therapy confer the same benefit as host immune control of HBV?
Does suppression of HBV replication by antiviral therapy confer the same benefit as host immune control of HBV?
复制标题
通过抗病毒治疗抑制 HBV 复制是否与 HBV 宿主免疫控制具有相同的益处？
DOI：
10.1136/gutjnl-2014-306935
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发表时间：
2014
期刊：
影响因子：
24.5
通讯作者：
Lok,AnnaS
中科院分区：
文献类型：
--
作者：
Yapali,Suna;Lok,AnnaS
全球约50%的肝细胞癌是由慢性乙肝病毒感染引起的。1《基于人群的病毒载量升高和相关肝病/癌症--乙肝病毒暴露风险评估》的数据显示，高水平的血清HBVDNA与肝硬变、肝细胞癌和肝脏相关死亡的风险增加有关。2在登记时HBVdna水平高的乙肝表面抗原阳性者中，随访期间HBVdna水平下降的人与HBVdna持续高水平的人相比，患肝癌的风险较低。这些数据表明，抗病毒治疗可能通过抑制乙肝病毒复制来降低肝细胞癌的风险。只有一项核糖核酸类似物(NUC)治疗慢性乙型肝炎(CHB)患者的随机对照试验，其中肝细胞癌是预先确定的结果之一。3这项比较拉米夫定和安慰剂的研究在中位时间32.4个月(范围1-42个月)后终止，因为两组之间的疾病进展综合结果(包括肝细胞癌)有显著差异。在研究结束时，拉米夫定治疗组和安慰剂组的肝细胞癌发生率分别为3.9%和7.4%，HR为0.49%，95%可信区间为0.25%至0.99(p=0.047)；然而，当排除第一年诊断的5例肝细胞癌后，这种差异不再显著(p=0.052)。一项系统回顾和荟萃分析发现，接受NUC治疗的CHB患者与未接受治疗的CHB患者相比，肝细胞癌的发生率较低。4 5在肝硬变、病毒学应答和HBe抗原(HBeAg)阳性的患者中，治疗组与未治疗组之间的差异更大。在几个单独的研究中也观察到了类似的结果，这些研究比较了接受NUC治疗的CHB患者和未经治疗的CHB患者患肝癌的风险。3 6-8然而，这些研究有一个或多个局限性：(1)纳入不同阶段的乙肝病毒感染患者，其中肝硬变患者和肝癌患者太少，无法进行有意义的分析；(2)对照与治疗患者不太匹配；(3)随访时间太短，无法观察NUC治疗的益处；或(4)没有足够的数据来检验NUC治疗的病毒学应答效果和肝癌风险。一项针对818名HBeAg阴性的希腊患者的研究发现，即使在病毒学缓解的患者中，长期的NUC治疗也不能降低肝癌的风险；然而，当排除前24个月诊断的肝癌病例时，病毒学缓解的患者患肝癌的几率略低于没有缓解的患者(p=0.062)。9这些数据表明，需要足够的病毒学缓解期来改善临床结果。事实上，对替诺福韦3期试验患者的长期结果的分析发现，观察到的肝癌发病率与直到第3年的预测风险相似，但显著低于最后一次随访时的预测(中位数为5.5年)。10同样，研究NUC治疗对肝纤维化的影响的研究没有显示出NUC治疗1年后的肝活检的改善，但在NUC治疗3-5年后的肝活检中观察到纤维化的显著减少，甚至肝硬变的逆转。CHO等人的研究是独一无二的，因为通过比较接受NUC治疗的1378名慢性乙型肝炎患者(621HBeAg阴性)和1014名非活动携带者的肝癌发病率来确定…
Approximately 50% of hepatocellular carcinoma (HCC) worldwide is attributed to chronic HBV infection. 1 Data from the population-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV REVEAL-HBV study showed that high levels of serum HBV DNA are associated with increased risk of cirrhosis, HCC and liver-related mortality. 2 The REVEAL-HBV study also demonstrated that among hepatitis B surface antigen positive persons with high levels of HBV DNA at enrolment, the risk of HCC was lower in those who had decline in HBV DNA levels during follow-up compared with those with persistently high levels of HBV DNA. These data suggest that antiviral therapy may decrease the risk of HCC through suppression of HBV replication. There has been only one randomised controlled trial of nucleos (t) ide analogue (NUC) treatment in patients with chronic hepatitis B (CHB) with HCC as one of the predefined outcomes. 3 This study comparing lamivudine versus placebo was terminated after a median of 32.4 months (range 1–42 months) because a significant difference in the composite outcome of disease progression which included HCC was observed between the two groups. At the time of study termination, HCC had occurred in 3.9% of the lamivudinetreated group and 7.4% of the placebo group with a HR of 0.49, and 95% CI 0.25 to 0.99 (p= 0.047); however, this difference was no longer significant when the five cases of HCC diagnosed during the 1st year were excluded (p= 0.052). A systematic review and a meta-analysis found that patients with CHB who received NUC had a lower incidence of HCC compared with untreated patients with CHB. 4 5 The difference between treated patients and untreated controls was greater in patients with cirrhosis, those with virological response and those who were hepatitis B e antigen (HBeAg)-positive. Similar results were observed in several individual studies that compared the risk of HCC between patients with CHB receiving NUC and untreated patients with CHB. 3 6–8 However, these studies had one or more limitations:(1) inclusion of patients in various stages of HBV infection with small number of patients with cirrhosis and too few patients with HCC for meaningful analysis,(2) controls not well matched to treated patients,(3) duration of follow-up too short to observe a benefit of NUC therapy if any, or (4) inadequate data to examine effect of virological response to NUC therapy and HCC risk. One study of 818 HBeAgnegative Greek patients found that longterm NUC therapy did not reduce the risk of HCC even among those with virological remission; however, when the HCC cases diagnosed in the first 24months were excluded, patients with virological remission had a marginally lower incidence of HCC than those without (p= 0.062). 9 These data suggest that an adequate period of virological remission is needed to improve clinical outcome. Indeed, analysis of the long-term outcomes of patients in the phase 3 trial of tenofovir found that the observed incidence of HCC was similar to the predicted risk up to year 3 but significantly lower than predicted at the last follow-up (median 5.5 years). 10 Similarly, studies examining the effect of NUC therapy on liver fibrosis failed to show an improvement in liver biopsies obtained after 1year of NUC therapy but a significant decrease in fibrosis and even reversal of cirrhosis was observed in liver biopsies obtained after 3–5 years of NUC therapy. 11–13 The study by Cho et al14 is unique in that the incidence of HCC in 1378 patients with CHB (621 HBeAg-negative) treated with NUC was compared with 1014 inactive carriers to determine …