Large‐scale survey of naturally occurring HBV polymerase mutations associated with anti‐HBV drug resistance in untreated patients with chronic hepatitis B

Mirandola, Silvia; Campagnolo, Davide; Bortoletto, Gladis; Franceschini, L; Marcolongo, M.; Alberti, Alfredo

doi:10.1111/j.1365-2893.2011.01435.x

Cited by 44 publications

(50 citation statements)

References 41 publications

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“…Therefore, rtV191I mutation may be the new resistance site to LAM. Since rt224I/V has never been reported before [13,[22][23][24][25][26], further observation of these patients might address the question whether these mutations are associated with other nucleoside analogue resistance or affect the outcome of the disease.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Wang

Han

Duan

et al. 2017

J Infect Dev Ctries

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Introduction: Previous studies have indicated that the drug-resistant mutations of hepatitis B virus (HBV) are a major obstacle to antiviral therapy. However, it is still unclear whether there are pre-existent resistance mutations in patients with HBV infection and the relationship between drug-resistant mutation, genotypes, and progression of hepatitis B disease. Methodology: A total of 357 treatment-naïve patients with HBV infection were involved in this retrospective study. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. Results: Lamivudine (LAM) resistance was detected in 8 patients (3.7%) with chronic hepatitis B (CHB), 13 (11.7%) patients with liver cirrhosis (LC), and 6 (21.4%) patients with hepatocellular carcinoma (HCC). Adefovir(ADV)-resistant mutations were detected in 10 (4.6%) patients with CHB, 15 (13.5%) patients with LC and 4 (14.5%) patients with HCC. Both LAM and ADV resistant mutations were detected in 2 patients (0.9%) with CHB, 1 patient (0.9%) with LC and 1 patient (3.6%) with HCC. Significant differences (p <0.01) were observed in the drug-resistance rates among patients with CHB, LC and HCC. Meanwhile, all the drug-resistant mutations were found in patients with HBV genotype C. Conclusions: This study demonstrated higher risk of pre-existing drug-resistant mutations in patients with HBV genotype C comparing to patients with HBV genotype B. Likewise, increasing prevalence of pre-existing drug-resistant mutations was shown, alongside with the progression of the disease.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Wang

Han

Duan

et al. 2017

J Infect Dev Ctries

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“…Rates of primary NAs resistance in newly diagnosed HBV patients have been 4 (6.15%) L180/rtA181T 3 (4.62%) rtL80V+rtL180M/A181+rtM204V+rtM204I 3 (4.62%) rtL180/rtA181T+rtM204I 2 (3.08%) rtL80V 2 (3.08%) rtL80V+rtM204I 2 (3.08%) rtL80V+rtV/G173L+rtL180M/A181+rtM204I 1 (1.54%) rtL80V+L180/A181 1 (1.54%) rtL80V+rtL180M/A181+rtM204V 1 (1.54%) rtL80V+rtL180M/rtA181T 1 (1.54%) rtL80V+rtM204V+rtM204I 1 (1.54%) rtL80V+rtL80I+rtL180M/rtA181T 1 (1.54%) rtL80I+rtM204I 1 (1.54%) rtL80I+rtL180M/A181+rtM204V 1 (1.54%) rtV/G173L+rtM204I 1 (1.54%) rtV/G173L+rtL180M/A181+rtM204V+rtN236T 1 (1.54%) rtV/G173L+rtL180M/A181+rtM204V 1 (1.54%) L180/A181+rtM204V 1 (1.54%) rtL80V+rtL180M/rtA181T+rtM204V+rtM204I 1 (1.54%) rtM204V+rtM204I 1 (1.54%) rtL80V+rtL80I+rtL180M/A181+rtM204V 1 (1.54%) reported only occasionally (Mirandola, 2011;Cuestas, 2010). Naturally occurring HBV variants with primary antiviral resistance were rarely observed.…”

Section: Discussionmentioning

confidence: 99%

“…Naturally occurring HBV variants with primary antiviral resistance were rarely observed. In a group of Argentine and Italian patients, the frequency of primary antiviral resistance did not exceed 5% (Mirandola, 2011;Cuestas, 2010). Naturally occurring HBV variants were also tested in HIV/HBV-coinfected patients in Spain.…”

Section: Discussionmentioning

confidence: 99%

Mutations in Pol gene of hepatitis B virus in patients with chronic hepatitis B before and after therapy with nucleoside/nucleotide analogues

Januszkiewicz‐Lewandowska¹,

A²,

Kowala‐Piaskowska³

et al. 2014

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Summary. -Chronic hepatitis B (CHB) is one of the most common infections worldwide. Currently approved treatments of CHB include nucleoside/nucleotide analogues (NAs). However, long-term NA therapy is associated with accumulation of resistant mutations within the hepatitis B virus (HBV) polymerase gene. The incidence of naturally occurring HBV mutations leading to primary antiviral resistance has not been fully elucidated yet. The objective of present study was to detect the frequency of mutations within the HBV polymerase gene in 263 patients naïve to nucleoside/nucleotide analogues. Prevalence of HBV Pol gene mutations secondary to NA treatment in patients without pre-existing antiviral resistance mutations was also examined. Retrospective analysis showed that HBV Pol gene mutations were present in 7 out of 263 patients prior to the treatment. Mutations observed in NA-naïve CHB patients were associated only with resistance to lamivudine and adefovir. Compensatory mutations were observed as well. In the course of antiviral treatment, HBV Pol gene mutations were identified in 65 out of the remaining 256 CHB patients (25.39%), while no mutations of any type were detected in 160 patients (62.5%). The profiles of detected mutations were comparable to those observed in other studies that focused on the analysis of clinically relevant NA-resistant mutations. In conclusion, we found out that antiviral resistance mutations may pre-exist in the overall viral population present in untreated patients, although the incidence of HBV Pol gene mutations in NA-naïve CHB patients was low and reached only up to 2.66%. However, possible circulation and transmission of NAs-resistant HBV mutants in human population should be taken into account.

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“…Such variability is likely to occur due to the differences in the methods applied to determine the mutation in the HBV pol gene, overall study design, and study population (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). However, Sayan et al, mentioned that the direct sequencing approach could limit the detection of primary resistance mutations (11).…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Molecular Characterization of Drug Resistance in Hepatitis B Viruses Isolated from Patients with Chronical Infection in Turkey

et al. 2018

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Background: Hepatitis B virus (HBV) has a high mutation rate due to its unusual replication strategy leading to the production of a large number of virions with single and double mutations. The mutations, in turn, are associated with the development of drug resistance to nucleos(t)ide analogs (NUCs) in patients before and during NUCs therapy. Objectives: The current study aimed at investigating the molecular characterization of HBV in Turkish patients with chronic hepatitis B (CHB) infection. Methods: Polymerase chain reaction (PCR) amplification and direct sequencing procedures were used to analyze mutations. The detected drug resistance mutations were divided into the nucleos(t)ide analogs primary, partial, and compensatory resistance groups. The amino acid substitutions of hepatitis B surface antigen (HBsAg) were categorized into antiviral drug -associated potential vaccine -escape mutations (ADAPVEMs) and typical HBsAg amino acid substitutions, which included hepatitis B hyperimmunoglobulin (HBIg) -selected escape mutation, vaccine escape mutation, hepatitis B misdiagnosis, and immune -selected amino acid substitutions. Results: The number of patients included in the study was 528 out of which 271 (51.3%) were treatment -naive and 351 (66.3%) were hepatitis B e antigen (HBeAg) -negative. Moreover, 325 (61.6%) were males with a mean age of 38 years (range: 18 -69). Primary, partial, and compensatory resistance to NUCs was reported in 174 (32.9%) patients. Six different ADAPVEM motifs were determined in both treatment -naive and treatment -experienced patients, namely, sF161L/rtI169X, sE164D/rtV173L, sL172L/rtA181T, sL173F/rtA181V, sS195M/rtM204V, and sS196L/rtM204I. The prevalence of ADAPVEMs and typical HBsAg escape mutations was 5.3% (n = 28) and 34.8% (n = 184), respectively. Conclusions:The analysis of drug resistance should constitute a fundamental part of the follow -up period of patients with CHB undergone treatment with NUCs. The surveillance of development of drug resistance mutations, while receiving treatment for hepatitis B is of paramount importance to monitor and control the emerging resistance.

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Large‐scale survey of naturally occurring HBV polymerase mutations associated with anti‐HBV drug resistance in untreated patients with chronic hepatitis B

Cited by 44 publications

References 41 publications

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Mutations in Pol gene of hepatitis B virus in patients with chronic hepatitis B before and after therapy with nucleoside/nucleotide analogues

Molecular Characterization of Drug Resistance in Hepatitis B Viruses Isolated from Patients with Chronical Infection in Turkey

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