The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen–positive and hepatitis B e antigen–negative hepatitis B virus strains #

Amini-Bavil-Olyaee, Samad; Herbers, Ulf; Sheldon, Julie; Luedde, Tom; Trautwein, Christian; Tacke, Frank

doi:10.1002/hep.22790

Cited by 124 publications

(118 citation statements)

References 40 publications

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“…We did not find the mutation rtA194T which was proposed to be associated with tenofovir resistance by Amini-Bavil-Olyaee et al [16] The result of another large study from China [17] also supports our findings in this regard as they did not find this mutation. Our data is also consistent with another recent study by Chen et al [18] who found the mutations rtA181T and rtN236T from lemivudine and adefovir resistant patients, although we did not find rtN236T and rtA181T from our samples.…”

Section: Discussionsupporting

confidence: 85%

Analysis of resistant mutations in reverse transcriptase domain of hepatitis B virus from patients from Islamabad, Pakistan

Mahmood¹,

Anwar²

2017

JUMD

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Aim:To explore nucleoside/nucleotide analogues resistance mutations in hepatitis B virus (HBV) reverse transcriptase (RT) domain from non-responder Pakistani patients. Methods: Blood samples were taken from 20 chronic HBV patients who were non-responders to different nucleoside/nucleotide analogues. HBV DNA was extracted and a fragment of genome including RT domain was sequenced. The sequence was aligned with wild type HBV sequences and compared with resistant mutations in the RT domain. Results: Resistant mutations were detected in samples of 13 (65%) patients who were non-responders to more than one drug. The mutations were found at amino acid positions rt80, rt135, rt169, rt173, rt180, rt181, rt184 and rt204 and rt248. Mutations rtY135S and rtN248H were detected from 13 (65%) and 12 (60%) samples respectively. Mutations rtL180M and rtA181V were present in 6 (30%) samples, rtM204V and rtV173L in 5 (25%) samples while rtI169P, rtL80G and rtT184Y were identified from 3 (15%), 2 (10%) and 1 (5%) sample respectively. Conclusion: Nucleoside /Nucleotide analogues resistant mutations rt135, rtL180M, rtA181V, rtM204V, rtV173L and rtN248H are frequent in HBV strains isolated from non-responder Pakistani patients while mutations rtI169P, rtL80G and rtT184Y are also present in low proportion. Key words:Hepatitis B virus, resistant mutations, reverse transcriptase, nucleos(t)ide analogues, Pakistan ABSTRACTArticle history:

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Section: Discussionsupporting

confidence: 85%

Analysis of resistant mutations in reverse transcriptase domain of hepatitis B virus from patients from Islamabad, Pakistan

Mahmood¹,

Anwar²

2017

JUMD

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“…All constructs were confirmed by digestion analysis and direct sequencing (Applied Biosystems, Foster City, CA) (24). To generate HBeAg-negative vectors, the 1.28-fold HBV replication-competent plasmids harboring G1896A/C1858T PC and A1762T/ G1764A BCP mutations were used (2,24). The fragment containing the LAMresistant/immune escape mutant was excised by EcoRI and NcoI restriction enzymes (New England Biolabs, Ipswich, MA) and ligated into the same region within the PC and BCP plasmids.…”

Section: Methodsmentioning

confidence: 99%

Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Amini-Bavil-Olyaee

Vucur

Luedde

et al. 2010

J Virol

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Immune escape variants of the hepatitis B virus (HBV) represent an emerging clinical challenge, because they can be associated with vaccine escape, HBV reactivation, and failure of diagnostic tests. Recent data suggest a preferential selection of immune escape mutants in distinct peripheral blood leukocyte compartments of infected individuals. We therefore systematically analyzed the functional impact of the most prevalent immune escape variants, the sG145R and sP120T mutants, on the viral replication efficacy and antiviral drug susceptibility of common treatment-associated mutants with resistance to lamivudine (LAM) and/or HBeAg negativity. Replication-competent HBV strains with sG145R or sP120T and LAM resistance (rtM204I or rtL180M/rtM204V) were generated on an HBeAg-positive and an HBeAg-negative background with precore (PC) and basal core promoter (BCP) mutants. The sG145R mutation strongly reduced HBsAg levels and was able to fully restore the impaired replication of LAM-resistant HBV mutants to the levels of wild-type HBV, and PC or BCP mutations further enhanced viral replication. Although the sP120T substitution also impaired HBsAg secretion, it did not enhance the replication of LAM-resistant clones. However, the concomitant occurrence of HBeAg negativity (PC/BCP), sP120T, and LAM resistance resulted in the restoration of replication to levels of wild-type HBV. In all clones with combined immune escape and LAM resistance mutations, the nucleotide analogues adefovir and tenofovir remained effective in suppressing viral replication in vitro. These findings reveal the differential impact of immune escape variants on the replication and drug susceptibility of complex HBV mutants, supporting the need of close surveillance and treatment adjustment in response to the selection of distinct mutational patterns.

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“…Considering the noncross-resistance between ETV and TDF, the use of ETV should be effective in these cases, either as mono-or combination therapy ( Table 2). In vitro data indeed demonstrated that ETV is effective against TDF-resistant strains (24,26). The situation might be more complex in patients with multiple drug-resistant mutations due to an extended treatment history.…”

Section: Tdf Resistance and Multi-drug Resistancementioning

confidence: 96%

“…In vitro, this rtA194T polymerase mutation is associated with a partial drug resistance against TDF. On the other hand, the rtA194T mutation impairs replication competence of HBV constructs in vitro, possibly explaining the low occurrence of this mutant in clinical practice (24).…”

Section: Tdfmentioning

confidence: 99%

Treatment for hepatitis B in patients with drug resistance

Tacke¹,

Kroy²

2016

Ann. Transl. Med.

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Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication. Importantly, these drugs have different barriers to resistance, explaining the higher incidence of treatment failure in the past due to drug resistant viral strains for the older compounds LMV, LdT and ADV. On

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The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen–positive and hepatitis B e antigen–negative hepatitis B virus strains #

Cited by 124 publications

References 40 publications

Analysis of resistant mutations in reverse transcriptase domain of hepatitis B virus from patients from Islamabad, Pakistan

Analysis of resistant mutations in reverse transcriptase domain of hepatitis B virus from patients from Islamabad, Pakistan

Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Treatment for hepatitis B in patients with drug resistance

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