Evaluation of drug resistance mutations in patients with chronic hepatitis B

Alaçam, Sema; Karabulut, Nuran; Yolcu, Ayfer; Önel, Mustafa; Atasoy, Alp; Kaymakoğlu, Sabahattin; Ağaçfidan, Ali

doi:10.1007/s12223-018-0650-z

Cited by 8 publications

(13 citation statements)

References 23 publications

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“…However, findings from in vitro phenotyping data yielded conflicting results 18,19 . Recently, a retrospective study reported a high prevalence of rtA194T in CHB patients in Turkey 20 . In this study, 10 out of 318 (3%) patients with CHB harboured rtA194T alone or in combination with known ADV, LAM or ETV mutations, although the authors did not specifically associate the mutation with clinical resistance.…”

Section: Introductionsmentioning

confidence: 69%

Characterization of Hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance

Liu

Chang

Martin

et al. 2020

Journal of Viral Hepatitis

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Both the A194T and a quadruple mutation CYEI (S106C, H126Y, D134E and L269I) in hepatitis B virus (HBV) polymerase reverse transcriptase domain (pol/RT) are suggested to be associated with treatment failure with tenofovir disoproxil fumarate (TDF). To further evaluate this assertion, the prevalence of these mutations at baseline as well as their development and/or loss during TDF and tenofovir alafenamide (TAF) treatment was analysed in 3886 patients enrolled in Gilead HBV clinical studies. In total, six out of 3886 (0.2%) patients carried the rtA194T mutation, while only 1 patient carried a triple CYE and 2 patients carried a quadruple CYEI mutation at baseline. All the patients harbouring rtA194T or CYE/CYEI at baseline achieved viral suppression by week 96 after TDF or TAF treatment. No patients developed an rtA194T mutation or > 1 substitution of CYEI, and the number of patients losing any substitutions of CYEI (n = 17) was similar to the number who developed a single substitution of CYEI (n = 32) during treatment. Phenotypic evaluation of the site‐directed mutant (SDM) panel containing these mutations with or without other resistance mutations did not demonstrate a significant shift in TFV and TAF potency in vitro. No evidence of rtA194T and CYEI conferring resistance to TDF or TAF was observed based on the treatment responses to TDF or TAF in patients with mutations at baseline, the lack of selection of mutations after starting TDF or TAF treatment and no change in susceptibility to TFV or TAF in vitro.

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Section: Introductionsmentioning

confidence: 69%

Characterization of Hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance

Liu

Chang

Martin

et al. 2020

Journal of Viral Hepatitis

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“…Because ETV has minimal antiviral effects in patients with ETV resistance, TDF monotherapy is more likely to have comparable antiviral effects compared with TDF plus ETV combination therapy. However, one major concern is that TDF genetic resistance occurred in LMV-experienced patients [17], and an rtL180M/T184L/A200V/M204V mutation with resistance to TDF was found in ETV-resistant patients receiving TDF monotherapy [18]. Whether primary resistant mutations to ETV resistance could increase the rate of mutations resistant to TDF in long-term TDF monotherapy is unknown.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Different Nucleoside Analog Rescue Therapies for Entecavir-Resistant Chronic Hepatitis B Patients

Shang

Zhou

Liu

et al. 2020

Preprint

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Background: Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. Methods: Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups.Results: The rate of ETV resistance increased form 6.04% in 2011 to 15.02% in 2017. Regarding the rates of negative HBV DNA at 48 weeks, no significant differences occurred in the TDF monotherapy and TDF combination groups (74.07% vs 70.00%), while the ETV and ADV group showed the worst virologic response (28.00%). TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function between the three groups. Conclusions: TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

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“…The mutations rtM204V/I represent one of the most common primary resistance mutations in hepatitis B patients, which directly decrease the susceptibility to NAs, especially to LAM and LdT. [11][12][13][14][15] LAM is the most widely used and longest-serving antiviral drug, but it also has the highest resistance rate. Recent studies have indicated that the percentage of LAMassociated resistance mutations that appear after 1 year may vary from 7% to 30%.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of Hepatitis B Virus M204V Mutation Quantitatively via Real-time PCR

Liang¹,

Liang²,

Ma³

et al. 2021

Journal of Clinical and Translational Hepatology

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Background and Aims: Drug-resistant DNA mutations of the hepatitis B virus (HBV) affect treatment response in chronic hepatitis B patients. We have established a new, sensitive, specific, accurate and convenient real-time PCR method to detect HBV mutations quantitatively. Methods: Blood samples were collected from patients showing viral breakthrough, primary nonresponse, or poor response during treatment, and mutations were detected via direct sequencing to assess our method. A plasmid containing the M204V mutation was synthesized and standard curves plotted. Results: The determination coefficient for linear correlation between Ct and log plasmid copy numbers was 0.996, where Ct value was −3.723log (DNA concentration) +48.647. Coefficients of variation indicated good reproducibility. Correctness was within tolerable bias. Limit of detection was 10 3 copies/ mL. Specificity, accuracy, positive predictive value and negative predictive value were 92.86%, 100%, 96.88%, 100% and 94.74%, respectively. Conclusions: These results show that our method can be used to detect HBV M204V mutations with the advantages of sensitivity, specificity and efficiency, providing a new choice for monitoring drug resistance.

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Evaluation of drug resistance mutations in patients with chronic hepatitis B

Cited by 8 publications

References 23 publications

Characterization of Hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance

Characterization of Hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance

Efficacy of Different Nucleoside Analog Rescue Therapies for Entecavir-Resistant Chronic Hepatitis B Patients

Detection of Hepatitis B Virus M204V Mutation Quantitatively via Real-time PCR

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