Letter to the Editor
Nucleos(t)ide analogue interruption: Alternative approach to intrahepatic set point for spontaneous control of HBV replication?Author links open overlay panelYiqiYu123†JingWang1†GuojunLi4ChuanShen5ShaolongChen1JunHuang1XinyuWang1CaiyanZhao5YuxianHuang1BinWang3XuanyiWang23JimingZhang13ChaoQiu123WenhongZhang1231Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China2Institutes of Biomedical Sciences, Fudan University, Shanghai, China3Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China4Department of Hepatology, the Second Hospital of Yinzhou of Ningbo, Ningbo, China5Department of Infectious Diseases, the Third Hospital of Hebei Medical University, Shijiazhuang, China
Available online 6 October 2017.
https://doi.org/10.1016/j.jhep.2017.09.026Get rights and content
Refers toThomas Berg, Karl-Georg Simon, Stefan Mauss, Eckart Schott, Renate Heyne, Dietmar M. Klass, Christoph Eisenbach, Tania Mara Welzel, Reinhart Zachoval, Gisela Felten, Julian Schulze-zur-Wiesch, Markus Cornberg, Marjoleine L. Op den Brouw, Belinda Jump, Hans Reiser, Lothar Gallo, Tobias Warger, Jörg Petersen
Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE studyJournal of Hepatology, Volume 67, Issue 5, November 2017, Pages 918-924
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Referred to byThomas Berg, Jörg Petersen
Reply to: “Nucleos(t)ide analogue interruption: Alternative approach to intrahepatic set point for spontaneous control of HBV replication?”Journal of Hepatology, Volume 68, Issue 3, March 2018, Pages 611-612
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To the Editor:
With great interest, we read the manuscript by Berg et al. in the Journal of Hepatology.1 Although prolonged antiviral treatment reduced the levels of intrahepatic viral replicative forms,2 during the initial course of tenofovir disoproxil fumarate (TDF) off-therapy, viral rebound developed in all patients who had achieved suppression of serum HBV DNA to an undetectable level for at least 3.5 years. This finding raises an unresolved question regarding the optimal virological set point for the spontaneous control of HBV replication. Herein, we evaluated whether such a set point could be accomplished through long-term nucleos(t)ide analogue (NA) therapy. Durable viral suppression was observed in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) and low or undetectable serum HBV DNA and normal aminotransferase levels, which was previously referred to as the “inactive carrier” phase.3 Recapitulation of the inactive carrier state is considered an acceptable endpoint for cessation of therapy. Therefore, we compared the levels of the viral replicative forms of HBV in serum and liver samples between HBeAg-negative patients who had been successfully treated with entecavir (ETV) for >1 year and inactive carriers. Treatment-naive HBeAg-negative chronic patients experiencing active hepatitis were also included for comparison. As shown in Fig. 1A, significantly lower levels of serum HBV RNA were observed in ETV-treated HBeAg-negative patients (2.57 log10 copies/ml, range = 2.00–3.73 log10 copies/ml) than in treatment-naive patients (4.74 log10 copies/ml, range = 2.76–5.75 log10 copies/ml; p <0.0001). In line with recent studies,4 serum HBV RNA (<200 copies/ml) was undetectable in 6/22 (27.3%) ETV-treated patients. However, cases with undetectable serum HBV RNA were more frequent (12/16, 75%) among inactive carriers (Fig. 1A, p = 0.0076).  Fig. 1. Levels of viral replicative forms and spontaneous control of HBV replication. (A) Levels of serum HBV-RNA, (B) intrahepatic HBV-RNA, (C) intrahepatic total HBV DNA, (D) and cccDNA under ETV treatment in comparison to those of IA and IC patients. Level of cccDNA in one ETV-treated case, one IC case and one IA case were below the lower detectable limit. ETV, HBeAg-negative patients receiving ETV treatment; IA, HBeAg-negative patients in the immune-active phase who were naive to treatment, also known as HBeAg-negative chronic hepatitis B; IC, inactive carrier, also known as HBeAg-negative HBV infection (Mann–Whitney test, *p <0.05; **p <0.01; ***p <0.001). cccDNA, covalently closed circular DNA; ETV, entecavir; HBeAg, hepatits B e-antigen; HBV, hepatitis B virus.
In liver biopsies, intrahepatic HBV RNA was detectable for all patients. The intrahepatic HBV RNA levels of patients treated with ETV (2.76 log10 copies/ml, range = 0.30–4.40 log10 copies/ml) were not significantly lower (p = 0.2786) than those of treatment-naive patients (2.06 log10 copies/ml, range = 1.09–3.10 log10 copies/ml), and remained higher than those of inactive carriers (1.21 log10 copies/ml, range = 0–1.87 log10 copies/ml; p = 0.0019) (Fig. 1B). In comparison to treatment-naive patients, levels of intrahepatic total HBV DNA (Fig. 1C) and covalently closed circular DNA (cccDNA) (Fig. 1D) were significantly decreased in ETV-treated patients and inactive carriers, but no differences were observed between the latter two groups. Therefore, our data suggested that although NA therapy induced the remission of liver disease and reduced the size of the cccDNA pool, the levels of intrahepatic HBV RNA could not be reduced to the comparably low levels of inactive carriers. This finding explains why patients under prolonged treatment remained at higher risk of HBV reactivation than patients with spontaneous HBeAg seroconversion.5 Lower levels of intrahepatic HBV RNA approaching those of inactive carriers, might also be considered a useful virological endpoint for cessation of NA therapy. Berg et al.’s study also disclosed some encouraging discoveries, inspiring further investigations. During the 144-week follow-up period, four patients who discontinued NA therapy experienced hepatitis B surface antigen (HBsAg) loss and three of them achieved HBsAg seroconversion, whereas no such change in HBsAg was detected in the patients that continued therapy. In the context of CHB, the T cell response to HBV is generally weak and dysfunctional, and could be partially restored by long-term NA therapy.6 Moreover, most HBV-specific T cells are sequestered in the liver and do not circulate through the peripheral tissues.7 Thus, HBV rebound after withdrawal of long-term NA therapy might directly activate liver-resident HBV-specific T cells,8 which would more effectively restrict viral replication than the immune responses elicited by traditional HBV therapeutic vaccines inoculated peripherally.7 We propose that “NA interruption” might serve as a novel therapeutic approach for directly boosting liver-resident immune responses against HBV and further suppressing viral activity toward an intrahepatic set point for achieving spontaneous control. However, further studies are needed to define the mechanisms of NA interruption required for realizing spontaneous control of HBV replication and to identify patients prone to clinical relapse after NA interruption using HBsAg quantification or other predicators.9,10 Lastly, NA interruption as a therapeutic approach is associated with several limitations. Firstly, the durability of viral control that might be achieved by this approach is currently uncertain. Secondly, viral replication in the presence of a low drug concentration could potentially lead to the development of viral variants with drug resistance. Therefore, NA agents with a high genetic barrier are highly recommended for this approach. Thirdly, NA interruption as a therapeutic approach should not be recommended for patients with cirrhosis, because of the risk of liver failure due to viral reactivation. Close follow-up would be required to prevent uncontrolled conditions such as recurrent viremia, alanine transaminase flares, and clinical decompensation. In conclusion, levels of intrahepatic HBV RNA might be a potential indicator and virological set point for withdrawal of NA therapy. Financial supportThis work was supported by the National Natural Science Foundation of China Grant (81373064, 81571981, 81670560), National Grand Program on Key Infectious Disease Control (2017ZX10302201-004-004), and Specialized Project on Scientific Research Within the Health Care Industry of China (201302010). |
发表于 2018-2-17 15:21