Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B

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• 作者：Ching-Lung Lai¹ ; ² ; ^&dagger ; ; ^{hrmelcl@hku.hk} ; Danny Wong¹ ; ² ; ^&dagger ; ; ^{dannykhwong@gmail.com} ; Philip Ip³ ; Malgorzata Kopaniszen¹ ; Wai-Kay Seto¹ ; ² ; James Fung¹ ; ² ; Fung-Yu Huang¹ ; Brian Lee⁴ ; Giuseppe Cullaro⁵ ; Chun Kong Chong¹ ; Ringo Wu¹ ; Charles Cheng¹ ; John Yuen¹ ; Vincent Ngai¹ ; Man-Fung Yuen¹ ; ²
• 关键词：Hepatitis B virus ; Liver biopsy ; Antiviral therapy ; Virus replication ; Circular DNA
• 刊名：Journal of Hepatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：66
• 期：2
• 页码：275-281
• 全文大小：677 K
• 卷排序：66

文摘

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA.MethodsAmong 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145 months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined.ResultsAt the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88 log IU/ml, 0.03 copies/cell, and 0.01 copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54 log (71.46%), ihHBV DNA levels by 2.81 log (99.84%), and cccDNA levels by 2.94 log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021 copies/cell, with 40% of patients having undetectable pgRNA.ConclusionsLong-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study.Lay summaryIt is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126 months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.