Chronic hepatitis B virus (HBV) infection is a global public health issue. Although the disease cannot be cured effectively, disease management has been improved over the past decade. The introduction of potent nucleos(t)ide analogues (NAs) to suppress viral replication represented a giant leap in the control of this disease. It has been shown that tenofovir treatment, a potent NA, complements current immunoprophylaxis to diminish mother-to-infant transmission in pregnant women with a high viral load. For patients with chronic HBV infection, quantitative hepatitis B surface antigen is a useful tool to define inactive carriers and to guide antiviral therapy. Quantification of HBV mutants is also useful in predicting long-term outcomes more precisely than ever. The next challenge is how to achieve an HBV cure; although immunotherapy is a promising strategy, the current results from two clinical trials using therapeutic vaccines to induce HBV-specific immune response in patients with chronic HBV infection are disappointing. In the coming years, we are expecting to see a combination of therapeutic agents with various modes of action to complete the mission of HBV elimination.
Keywords
HBV Chronic hepatitis B HBsAg Immunotherapy 作者: StephenW 时间: 2017-4-21 18:26
消除乙型肝炎：这是一个可能的使命吗？
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The possible mission of functional cure for HBV
HBsAg loss is regarded as a functional cure for HBV and serves as an ideal treatment endpoint. Nevertheless, it is rare to achieve the ultimate goal using current treatment modalities. There are several novel strategies to clear HBsAg, including killing of HBV-infected hepatocytes via cytotoxic T cell (CTL)-induced immunotherapy as the most promising one. Although HBV-specific CTL response is vigorous and multi-specific during acute HBV infection, it is usually weak or even undetectable during the CHB stage [26]. An ideal immune-therapeutic strategy should combine profound suppression of viral replication to prevent uninfected hepatocytes from HBV infection and restoration of HBV-specific CTL response to clear the infected hepatocytes. The former goal can be achieved by existing NA treatment and the later one could be partially enhanced by therapeutic vaccines [27]. To date, two clinical trials have been performed using different therapeutic vaccines to treat CHB patients with a similar strategy, yet the results of both have been disappointing [28, 29]; neither of the two therapeutic vaccines could clear HBsAg more effectively compared to the control group. There are two issues that must be considered. Firstly, HBV-specific CTL function has been shown to be preserved in children and young adults, but not in older patients [30]. Since both studies enrolled older patients, HBV-specific CTL response may fail to be triggered by therapeutic vaccinations. Second, the immune tolerant effects of the liver microenvironment must be considered. HBV-specific CTL response can be induced in peripheral blood, but is rapidly exhausted after the initiation of cytotoxic effects against HBV-infected hepatocytes (Fig. 1a,b). Either of the above issues may have led to the failure of the two clinical trials. If the failure was caused by the engagement of PD-1 on T cells and PD-L1 on hepatocytes, which leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion, an immune checkpoint inhibitor, such as anti-PD1, could be considered as an addition to the therapeutic vaccine for the amplification of these effects (Fig. 1c). Indeed, the success of this combination strategy has been demonstrated in a woodchuck model [31]. Although the current results of immunotherapy in CHB treatment are unsatisfactory, it remains the most attractive method to clear the virus as long as the appropriate patient population can be selected and optimal study designs can be implemented.
Fig. 1
a Patients with chronic hepatitis B are characterized by a high viral load and antigenaemia, as well as a small number of dysfunctional HBV-specific T-cells. b Failure of combining therapeutic vaccine and nucleos(t)ide analogue treatment could be attributed to T cell exhaustion induced by PD1 and PD-L1 engagement. c Combining anti-PD1, an immune checkpoint inhibitor, with strategy b may be a solution to cure chronic HBV infection
Perspectives作者: StephenW 时间: 2017-4-21 18:27
Potent NA treatment has improved the management of CHB infection over the past decade [32]. Prolonged NA treatment has halted disease progression and halved the HCC incidence in CHB patients who have already developed liver cirrhosis [33, 34, 35]. The next challenge is to achieve functional HBV cure and the development of new agents with various modes of action is urgently awaited. In the clinical practice, additional unmet needs should also be addressed. The first is to identify patients who require HCC surveillance. Previous studies have indicated that approximately 25–40% of patients with CHB infection will develop HCC in their lifetime, and therefore HCC surveillance is indicated [36]. Although prediction of HCC is difficult, it is possible to identify true inactive HBV carriers who are at the lowest risk of HCC development by combining multiple host, viral, and liver fibrosis markers. The current criteria to define inactive carriers include normal ALT level, negative HBeAg, HBV DNA < 2000 IU/mL, and HBsAg < 1000 IU/mL; their HCC risk is comparable to that of the normal population [6]. The possibility of further reduction of HCC risks by including biomarkers, such as a liver biomarker indicating early liver fibrosis stage, along with the current criteria should be explored.
The second issue to be addressed is whether HCC development could be prevented by earlier initiation of NA treatment in CHB patients. Most of the evidence of HCC risk reduction comes from prolonged NA treatment in patients with HBV-related liver cirrhosis [33, 34, 35]. However, all studies show that HCC still develops during long-term NA therapy. This fact may suggest HCC development is inevitable once advanced liver fibrosis has occurred. Further evidence has been provided by the recent finding that the integration of the HBV genome into the host chromosome, which is considered as an oncogenic event, could be detected at the early stage of chronic infection [37]. Collectively, it is conceivable to achieve an HCC-free era through early initiation of NA therapy before emergence of significant fibrosis or massive viral genome integration. This may be implemented into practice by widening the therapeutic target of HBV carriers and earlier identification using more comprehensive screening. This strategy may provide an alternative method to eliminate HCC risk before curing HBV. However, this concept needs to be proved by clinical studies.作者: StephenW 时间: 2017-4-21 18:28
透视
过去十年来，有效的NA治疗改善了CHB感染的治疗[32]。长期的NA治疗已经停止疾病进展，并将已经发展为肝硬化的CHB患者的HCC发病率减半[33,34,35]。下一个挑战是实现功能性乙肝治疗，并迫切期待开发具有各种作用方式的新药物。在临床实践中，还应该解决未满足的需求。首先是确定需要HCC监测的患者。以前的研究表明，约25-40％的CHB感染患者在其一生中会发展为HCC，因此HCC监测被指示[36]。虽然HCC的预测是困难的，但可以通过组合多个宿主，病毒和肝纤维化标记鉴定处于HCC发展风险最低的真正的无活性HBV携带者。目前用于定义无活性载体的标准包括正常ALT水平，阴性HBeAg，HBV DNA <2000 IU / mL和HBsAg <1000 IU / mL;他们的HCC风险与正常人群的风险相当[6]。应该探讨通过包括生物标志物（如指示早期肝纤维化分期的肝脏生物标志物）以及目前的标准来进一步降低HCC风险的可能性。