New therapeutic perspectives in <scp>HBV</scp>: when to stop <scp>NA</scp>s

Pérez-Cameo, Cristina; Pons, Mónica; Esteban, Rafael

doi:10.1111/liv.12398

Cited by 23 publications

(18 citation statements)

References 44 publications

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“…Antiviral therapies with nucleos(t)ide analog inhibitors of HBV reverse transcriptase dramatically reduce the viral load, significantly improve the liver function and lower the incidence of liver failure and hepatocellular carcinoma, but fail to cure the viral infection [3, 4], due to the persistence of covalently closed circular (ccc) DNA in the nuclei of infected hepatocytes [5–8]. Hence, better understanding the molecular mechanisms underlying the formation and maintenance of cccDNA is critical for development of novel therapeutics to cure chronic HBV infection.…”

Section: Introductionmentioning

confidence: 99%

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus

et al. 2016

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Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined. Here we conducted targeted genetic screening in combination with chemical inhibition to identify the cellular DNA polymerase(s) responsible for cccDNA formation, and exploited recombinant HBV with capsid coding deficiency which infects HepG2-NTCP cells with similar efficiency of wild-type HBV to assure cccDNA synthesis is exclusively from de novo HBV infection. We found that DNA polymerase κ (POLK), a Y-family DNA polymerase with maximum activity in non-dividing cells, substantially contributes to cccDNA formation during de novo HBV infection. Depleting gene expression of POLK in HepG2-NTCP cells by either siRNA knockdown or CRISPR/Cas9 knockout inhibited the conversion of rcDNA into cccDNA, while the diminished cccDNA formation in, and hence the viral infection of, the knockout cells could be effectively rescued by ectopic expression of POLK. These studies revealed that POLK is a crucial host factor required for cccDNA formation during a de novo HBV infection and suggest that POLK may be a potential target for developing antivirals against HBV.

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Section: Introductionmentioning

confidence: 99%

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus

et al. 2016

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“…Sustained suppression or elimination of HBV replication is the ultimate goals of HBV treatment [22,23]. Nucleotide analogues are currently regarded as standard treatment for patients with chronic hepatitis B over 10 years by effectively inhibiting HBV virus replication to prevent development of hepatic complications, as well as cirrhosis, hepatic decompensation, and HCC.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Telbivudine and Entecavir Therapy on Nephritic Function and Drug Resistance in Patients with Hepatitis B Virus-Related Compensated Cirrhosis

Shen

Ding

Wang

et al. 2016

Cell Physiol Biochem

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Background: To compare the impact of telbivudine (LDT) and entecavir (ETV) administration on nephritic function. Method: One hundred thirty patients diagnosed with hepatitis B virus (HBV)-related compensated cirrhosis were randomly divided into LDT (600 mg/d) or ETV (0.5 mg/d) groups. Results: The drug resistance rate was higher following LDT treatment compared to ETV treatment (16.9% vs. 1.5%, P=0.0006). The mean creatinine level decreased compared to baseline in the LDT group (0.81 vs. 0.94 mg/dl, P=0.000). The change in median glomerular filtration rate (eGFR) compared to baseline in the LTD and ETV groups was 22.3 and -3.3, respectively, at 2 years (P=0.000). In patients with mild nephritic injury (eGFR< 90 ml/min/1.73m²), the median eGFR increased by 28.0 ml/min/1.73m² in the LDT group and decreased by 4.3 ml/min/1.73m² in the ETV group (p=0.000). The eGFR in 88.5% of patients (23/26) from the LDT group increased > 90 ml/min/1.73m². The percentage of patients with an eGFR > 90 ml/min/1.73m² increased from 60.0% to 92.3% in the LDT group and from 64.6% to 69.2% in the ETV group. Conclusion: In patients with HBV-related compensated cirrhosis, LDT treatment was more effective in protecting nephritic function and was associated with a higher drug resistance rate, but did not contribute to a better outcome compared with ETV treatment.

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“…HBV‐related morbidities and hepatocellular carcinoma (HCC) are responsible for 0.5‐1.0 million deaths yearly, representing a major global health concern. A complete cure of chronic hepatitis B (CHB) is accomplished by the complete eradication of covalently closed circular DNA (cccDNA), which serves as the transcriptional template of HBV and a reservoir for future replication cycles . However, cccDNA is particularly stable and persistent.…”

Section: Introductionmentioning

confidence: 99%

“…However, cccDNA is particularly stable and persistent. Thus, clearance of hepatitis B surface antigen (HBsAg), a replication product that reflects the transcriptional activity of cccDNA, is considered to be the closest event to a cure for CHB, with sustained off‐therapy HBsAg loss recognized as the ideal endpoint of therapy …”

Section: Introductionmentioning

confidence: 99%

The role of peginterferon in nucleos(t)ide‐analogue‐treated chronic hepatitis B patients: A review of published literature

Zhang

Xie

Ning

et al. 2017

Journal of Viral Hepatitis

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Chronic hepatitis B infection (CHB) causes up to 1.0 million deaths annually. Currently, more than 90% of CHB patients worldwide are receiving indefinite nucleos(t)ide analogue (NA) therapy. New strategies for optimizing hepatitis B surface antigen (HBsAg) loss are required for NA-treated patients as the majority are unable to achieve HBsAg loss and may require lifelong therapy. In hepatitis B e antigen (HBeAg)-positive patients, switching from NAs to finite peginterferon (PegIFN) therapy can double HBeAg seroconversion rates. One in five patients who switch to PegIFN can achieve HBsAg loss, whereas patients who continue NA therapy typically do not. In HBeAg-negative NA-treated patients, add-on PegIFN therapy achieves higher, albeit modest, HBsAg loss rates compared with continued NA monotherapy and offers the opportunity for NA-treated patients to achieve the inactive carrier state. In the absence of curative therapies, PegIFN represents a valuable, finite option for NA-treated patients who would otherwise require potentially lifelong therapy.

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New therapeutic perspectives in HBV: when to stop NAs

Cited by 23 publications

References 44 publications

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus

DNA Polymerase κ Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus

Comparison of Telbivudine and Entecavir Therapy on Nephritic Function and Drug Resistance in Patients with Hepatitis B Virus-Related Compensated Cirrhosis

The role of peginterferon in nucleos(t)ide‐analogue‐treated chronic hepatitis B patients: A review of published literature

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