Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy

Rokuhara, Akinori; Matsumoto, Akihiro; Tanaka, Eiji; Umemura, Takeji; Yoshizawa, Kaname; Kimura, Tetsunori; Maki, Norio; Kiyosawa, Kendo

doi:10.1007/s00535-006-1856-4

Cited by 70 publications

(87 citation statements)

References 24 publications

(26 reference statements)

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“…The results enabled us to evaluate the clinical significance of HBV RNA levels with confidence. Previous studies reported that serum HBV RNA is transcribed from intrahepatic HBV cccDNA and thus that it may be a potential alternative marker for intrahepatic cccDNA levels (8,11,15). Here, we confirmed that serum HBV RNA is a valid marker but that it is nevertheless inferior to serum HBV DNA with respect to reflecting the level of intrahepatic cccDNA before treatment.…”

Section: Discussionsupporting

confidence: 71%

“…The presence of HBV RNA in serum of HBV-infected patients was identified as early as 1996, and it might serve as a new viral marker for CHB patients during nucleos(t)ide analogue (NUC) therapy (8)(9)(10). However, the nature and origin of serum HBV RNA were still unclear until a recent study confirmed that serum HBV RNA is pgRNA and that it presents in virus-like particles (11).…”

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confidence: 99%

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Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?

Gao

Meng

et al. 2017

J Clin Microbiol

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The study was designed to investigate whether serum hepatitis B virus (HBV) RNA is a strong surrogate marker for intrahepatic HBV covalently closed circular DNA (cccDNA) compared with serum HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) in HBeAg-positive chronic hepatitis B (CHB) patients. Serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA were quantitatively detected at baseline (n ϭ 82) and 96 weeks (n ϭ 62) after treatment with nucleos(t)ide analogue (NUC) in HBeAg-positive CHB patients. The correlations among serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA levels were then statistically analyzed. The results showed that pretreatment intrahepatic cccDNA levels correlated better with serum HBV DNA levels (r ϭ 0.36, P Ͻ 0.01) than with serum HBV RNA levels (r ϭ 0.25, P ϭ 0.02), whereas no correlations were found between pretreatment intrahepatic cccDNA levels and HBsAg (r ϭ 0.15, P ϭ 0.17) or HBeAg (r ϭ 0.07, P ϭ 0.56) levels. At 96 weeks after NUC treatment, intrahepatic cccDNA levels correlated well with HBsAg levels (r ϭ 0.39, P Ͻ 0.01) but not with serum HBV RNA, HBV DNA, and HBeAg levels (all P Ͼ 0.05). Besides, the decline in the intrahepatic cccDNA level from baseline to week 96 correlated better with the reduction in the serum HBsAg levels than with the decreases in the levels of the other markers (for the HBsAg decline, r ϭ 0.38, P Ͻ 0.01; for the HBV DNA decline, r ϭ 0.35, P ϭ 0.01; for the HBV RNA decline, r ϭ 0.28, P Ͻ 0.05; for the HBeAg decline, r ϭ 0.18, P ϭ 0.19). In conclusion, the baseline serum HBV RNA level or its decline after 96 weeks of NUC therapy correlated with the corresponding intrahepatic cccDNA level, while it was less than that seen with serum HBV DNA at baseline and HBsAg (or its decline) at 96 weeks after treatment, respectively. KEYWORDS chronic hepatitis B, covalently closed circular DNA, HBV DNA, HBV RNA, hepatitis B surface antigen, nucleos(t)ide analogue H epatitis B virus (HBV) infection is a global health problem; an estimated 240 million persons are chronically infected, and about 650,000 people die annually due to chronic hepatitis B (CHB) worldwide (1). Though the currently available antiviral drugs can effectively reduce HBV DNA levels in serum of CHB patients, HBV may not be eliminated due to the persistence of HBV covalently closed circular DNA (cccDNA) in the infected hepatocytes, which represents the key HBV replicative intermediate (2). The fundamental role of intrahepatic cccDNA is as a template for transcription of all viral RNAs, including pregenomic RNA (pgRNA), which further produces the offspring virion

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Section: Discussionsupporting

confidence: 71%

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confidence: 99%

Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?

Gao

Meng

et al. 2017

J Clin Microbiol

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“…HBV RNA was quantified by the method reported by Rokuhara et al [2006]. DNA was extracted from liver biopsy specimens using the QIAamp DNA mini kit (Qiagen, Hilder, Germany) according to the manufacturer's instructions.…”

Section: Quantitation Of Hbv Rna and Intrahepatic Cccdnamentioning

confidence: 99%

Impact of peginterferon alpha‐2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B

Hagiwara

Kudo

Osaki

et al. 2013

Journal of Medical Virology

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The ideal approach to treat chronic hepatitis B remains controversial. This pilot study aimed to evaluate the effectiveness of peginterferon (PEG-IFN) α-2b and entecavir hydrate (ETV) as a combination therapy for patients with chronic hepatitis B, particularly in the context of virological response and the reduction of intrahepatic covalently closed circular DNA (cccDNA). A total of 17 patients with hepatitis B virus (HBV) genotype C were enrolled in this study. All subjects were treated with this combination therapy for 48 weeks and observed for an additional 24 weeks. All patients underwent liver biopsy before and after the therapy period. Changes in cccDNA levels and liver histology were monitored between biopsies. Among the 11 patients who exhibited pre-therapy hepatitis B e antigen (HBeAg), 8 (73%) showed evidence of HBeAg seroconversion by the end of the follow-up period. Serum HBV DNA levels decreased by 5.2 and 3.3 log copies/ml (mean) by the end of the therapy and follow-up periods, respectively. In addition, intrahepatic cccDNA decreased significantly to 1.4 log copies/µg (mean) by the end of the therapy period. Among the 11 patients who did not experience viral relapse, only 2 (18%) exhibited high levels of cccDNA (>4.5 log copies/µg) by the end of the treatment period. In contrast, all relapsed subjects exhibited significantly higher levels of cccDNA than subjects who did not relapse (P = 0.027). The combination regimen is a promising approach to treat chronic hepatitis B and may achieve significant reduction in serum HBV DNA and intrahepatic cccDNA. Wiley Periodicals, Inc.

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“…Additionally, the amount of cccDNA in serum is reported to be higher in patients who develop YMDD mutants than in patients who do not [Yuen et al, 2005]. Recently, it was established that HBV RNA is detectable in serum and the elevation of HBV RNA is a predictor of early occurrence of viral mutation during lamivudine therapy [Rokuhara et al, 2006;Hatakeyama et al, 2007]. However, these HBV DNA, HBV RNA, or cccDNA detection assay methods remain complicated and difficult to perform.…”

Section: Introductionmentioning

confidence: 99%

Correlation between serum hepatitis B virus core‐related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients

Suzuki

Miyakoshi

Kobayashi

et al. 2008

Journal of Medical Virology

166

187

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Nucleos(t)ide analogues are utilized for the treatment of chronic HBV infection, and HBe seroconversion and HBV DNA levels are commonly used as markers of viral status and as primary treatment endpoints. Recently, a new assay was prepared for the detection of serum HBV corerelated antigen (HBcrAg), consisting of HBcAg, HBeAg, and p22cr, which is a precore protein from amino acid À28 to at least amino acid 150, by coding the precore/core region. In this study, we examined the correlation between serum HBcrAg concentration and viral status by the analysis of serum HBeAg, HBsAg, peripheral HBV DNA, and intrahepatic covalently closed circular DNA (cccDNA) in 57 chronic hepatitis B patients. Intrahepatic cccDNA was detected in all 57 patients, 42 patients were HBcrAg-positive, and serum HBcrAg concentration level was closely correlated with cccDNA. Additionally, positive HBcrAg concentration level results were observed in 6 out of 13 HBsAg seroclearance patients and 20 out of 31 HBV DNA-negative patients. Moreover, the correlation between HBcrAg and cccDNA in these 31 HBV DNAnegative patients was statistically significant (r ¼ 0.482, P ¼ 0.006). These data suggest that serum HBcrAg concentration is well correlated with intrahepatic cccDNA level, and that the measurement of serum HBcrAg may be clinically useful for monitoring intrahepatic HBV viral status, especially in patients under treatment with nucleos(t)ide analogues.

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Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy

Cited by 70 publications

References 24 publications

Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?

Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?

Impact of peginterferon alpha‐2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B

Correlation between serum hepatitis B virus core‐related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients

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