Comparison of Serum Hepatitis B Virus RNA Levels and Quasispecies Evolution Patterns between Entecavir and Pegylated-Interferon Mono-treatment in Chronic Hepatitis B Patients

Yu, Xiaoqi; Wang, Mingjie; Yu, Demin; Chen, Peizhan; Zhu, Mingyu; Huang, Wei; Han, Yue; Gong, Qiming; Zhang, Xinxin

doi:10.1128/jcm.00075-20

Cited by 7 publications

(14 citation statements)

References 34 publications

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“…Similarly to our results, no significant difference was found between HBV RNA and HBV DNA quasispecies complexity at baseline quasispecies. While the results were similar, we analyzed a different region of the HBV genome (the region of the HBX between nt 1255 to 1611) than the study by Yu et al [ 6 ] (a sequence stretch within the region encoding for the terminal protein domain of the viral polymerase), and our group of patients is more heterogeneous, especially in terms of viral genotype composition. Thus, results from the 2 studies are not directly comparable, and further studies in larger groups of patients are required to confirm the tendency of HBV DNA quasispecies toward higher quasispecies complexity, as shown by mean RHL values.…”

Section: Discussionmentioning

confidence: 96%

“…In addition, the slower decline of serum HBV RNA levels may also make it possible to study circulating viral quasispecies, even when serum HBV-DNA levels are too low to do so. However, few studies to date have analyzed circulating HBV-RNA quasispecies[ 4 , 6 ] and little data is therefore available on their similarities and differences. Indeed, it is reasonable to think that both quasispecies may display significant differences between them, as they are subjected to different sources of genetic variability, due to the error-prone viral polymerase, contributing to an estimated error rate of approximately 1 per 10 4 -10 5 bp for minus-strand DNA synthesis and approximately 1 per 3.6-15 × 10 4 bp for second-strand DNA synthesis[ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, these differences were not statistically significant, either when including all patients or when separating them according to their degree of fibrosis (nonsignificant fibrosis and significant fibrosis or cirrhosis). The RHL shows high correlation with Shannon entropy, an abundance diversity index[ 17 ], which was used in a recent study by Yu et al [ 6 ] to compare HBV-DNA and RNA quasispecies in sequential serum samples in a group of HBeAg+ve patients receiving entecavir or pegylated interferon. Similarly to our results, no significant difference was found between HBV RNA and HBV DNA quasispecies complexity at baseline quasispecies.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, both quasispecies may be different in terms of nucleic acid variability/conservation and genetic variant complexity. Few studies to date have analyzed circulating HBV-RNA quasispecies[ 4 , 6 ] and similarities and differences with DNA quasispecies should therefore be assessed in more detail. In addition, serum HBV-RNA has been reported to be genetically homogenous to intrahepatic HBV-RNA[ 4 ], the main target for targeted gene therapy, which may favor achieving functional cure of HBV infection, the ideal end point of therapy based on sustained hepatitis B virus surface antigen (HBsAg) loss[ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: Different quasispecies?

Garcia-Garcia¹,

Cortese²,

Tabernero³

et al. 2021

WJG

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BACKGROUND Different forms of pregenomic and other hepatitis B virus (HBV) RNA have been detected in patients’ sera. These circulating HBV-RNAs may be useful for monitoring covalently closed circular DNA activity, and predicting hepatitis B e-antigen seroconversion or viral rebound after nucleos(t)ide analog cessation. Data on serum HBV-RNA quasispecies, however, is scarce. It is therefore important to develop methodologies to thoroughly analyze this quasispecies, ensuring the elimination of any residual HBV-DNA. Studying circulating HBV-RNA quasispecies may facilitate achieving functional cure of HBV infection. AIM To establish a next-generation sequencing (NGS) methodology for analyzing serum HBV-RNA and comparing it with DNA quasispecies. METHODS Thirteen untreated chronic hepatitis B patients, showing different HBV-genotypes and degrees of severity of liver disease were enrolled in the study and a serum sample with HBV-DNA > 5 Log 10 IU/mL and HBV-RNA > 4 Log 10 copies/mL was taken from each patient. HBV-RNA was treated with DNAse I to remove any residual DNA, and the region between nucleotides (nt) 1255-1611 was amplified using a 3-nested polymerase chain reaction protocol, and analyzed with NGS. Variability/conservation and complexity was compared between HBV-DNA and RNA quasispecies. RESULTS No HBV-DNA contamination was detected in cDNA samples from HBV-RNA quasispecies. HBV quasispecies complexity showed heterogeneous behavior among patients. The Rare Haplotype Load at 1% was greater in DNA than in RNA quasispecies, with no statistically significant differences ( P = 0.1641). Regarding conservation, information content was equal in RNA and DNA quasispecies in most nt positions [218/357 (61.06%)]. In 102 of the remaining 139 (73.38%), HBV-RNA showed slightly higher variability. Sliding window analysis identified 4 hyper-conserved sequence fragments in each quasispecies, 3 of them coincided between the 2 quasispecies: nts 1258-1286, 1545-1573 and 1575-1604. The 2 hyper-variable sequence fragments also coincided: nts 1311-1344 and 1461-1485. Sequences between nts 1519-1543 and 1559-1587 were only hyper-conserved in HBV-DNA and RNA, respectively. CONCLUSION Our methodology allowed analyzing HBV-RNA quasispecies complexity and conservation without interference from HBV-DNA. Thanks to this, we have been able to compare both quasispecies in the present study.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: Different quasispecies?

Garcia-Garcia¹,

Cortese²,

Tabernero³

et al. 2021

WJG

View full text Add to dashboard Cite

show abstract

“…After 5 years of NA treatment, HBV RNA was detected in 14% of the HBV DNA negative patients ( 9 ). Among 122 CHB patients treated with ETV, HBV DNA could not be detected in 90% of patients at week 48, and only 18% of the patients had HBV RNA below the detection limit ( 17 ). Our data showed that compared to the baseline, HBV DNA and HBV RNA both showed a downward trend at week 24, week 48, week 96, year 5, and year 10 after ETV treatment.…”

Section: Discussionmentioning

confidence: 99%

The decline of HBV RNA associated with HBeAg seroconversion and double-negative HBV DNA and RNA in chronic hepatitis B patients who received entecavir therapy: a 10-year retrospective cohort study

Ye¹,

Zhao²,

Yang³

et al. 2022

Ann Transl Med

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Background Whether the decline of hepatitis B virus (HBV) RNA was associated with antiviral efficacy in chronic hepatitis B (CHB) patients receiving long-term nucleos(t)ide analogues (NAs) therapy remains unclear. We observed the levels of serum HBV RNA in CHB patients treated with entecavir (ETV) for 10 years and explored the clinical significance of HBV RNA during long-term antiviral treatment. Methods A total of 33 hepatitis B surface antigen (HBsAg)-positive CHB patients treated with ETV for up to 10 years were recruited for this study. Liver function, HBsAg, hepatitis B envelope antigen (HBeAg), HBV DNA, and HBV RNA were measured at the baseline and each follow-up points. Antiviral efficacy was defined as negative HBV DNA (<20 IU/mL) and HBV RNA (<300 Copies/mL). Results (I) Serum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years (P<0.001). (II) There were positive correlations between serum HBV DNA and HBV RNA at each follow-up point (r=0.62 and P<0.001 at baseline, r=0.77 and P<0.001 at week 24, r=0.71 and P<0.001 at week 48, r=0.81 and P<0.001 at week 96, r=0.60 and P<0.01 at year 5 and r=0.77 and P<0.001 at year 10). (III) HBeAg and HBsAg levels at baseline and 10th year after ETV treatment have significant difference (P<0.05 and P<0.01). (IV) The decline of HBV RNA after ETV treatment was associated with HBeAg seroconversion, the area under the ROC curves (AUROCs) of the declines of HBV RNA were 0.25 at the baseline, 0.62 at week 24, 0.78 at week 48 and 0.86 at week 96, respectively. (V) The decline of HBV RNA after ETV treatment was associated with antiviral efficacy, the AUROCs of the declines of HBV RNA were 0.33 at the baseline, 0.74 at week 24, 0.83 at week 48 and 0.86 at week 96, respectively. Conclusions Serum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years. The decline of HBV RNA was associated with HBeAg seroconversion and antiviral efficacy in CHB patients receiving long-term ETV therapy, and the earliest prediction point was week 24.

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Circulating HBV RNA: From biology to clinical applications

et al. 2022

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Chronic HBV infection can hardly be cured due to the persistence of an intrahepatic pool of viral covalently closed circular DNA (cccDNA) transcription template, which is refractory to current antivirals. The direct analyses of cccDNA quantity and transcriptional activity require an invasive biopsy. Recently, circulating HBV RNA has been identified as a promising noninvasive surrogate marker of cccDNA and can be used for monitoring disease progression and predicting prognosis of patients with chronic HBV infection. To better understand this surrogate biomarker of cccDNA, we reviewed the current knowledge about the molecular characteristics and potential clinical applications of circulating HBV RNA. Specifically, we summarized the reported species and existing forms of circulating HBV RNA and discussed their biogenesis and the capacity of de novo infection by RNA virions. Moreover, we described the potential applications of circulating HBV RNA in different clinical scenarios, such as classifying the phases of chronic HBV infection, analyzing sustained on‐treatment and off‐treatment outcomes of treated patients, as well as predicting HCC development. Perspectives on future research of circulating HBV RNA were also proposed in this review.

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Comparison of Serum Hepatitis B Virus RNA Levels and Quasispecies Evolution Patterns between Entecavir and Pegylated-Interferon Mono-treatment in Chronic Hepatitis B Patients

Cited by 7 publications

References 34 publications

Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: Different quasispecies?

Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: Different quasispecies?

The decline of HBV RNA associated with HBeAg seroconversion and double-negative HBV DNA and RNA in chronic hepatitis B patients who received entecavir therapy: a 10-year retrospective cohort study

Circulating HBV RNA: From biology to clinical applications

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