Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure

Villet, Stéphanie; Pichoud, Christian; Billioud, Gaëtan; Barraud, Luc; Durantel, Sandra; Trépo, Christian; Zoulim, Fabien

doi:10.1016/j.jhep.2008.01.027

Cited by 174 publications

(163 citation statements)

References 31 publications

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“…A181 substitutions are associated with both LVD-resistance and ADV-resistance, as well as resistance to LVD and ADV combination therapy. 25,30 Fifteen patients in the long-term resistance cohort had A181 substitutions at some time during ETV therapy, two from study ETV-022, 12 from ETV-026, and one from ETV-015. These include changes of A181 to C, G, S, T, or V. Seven of the 15 patients had baseline A181 substitutions.…”

Section: Resultsmentioning

confidence: 99%

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Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

et al. 2009

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Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ؎ L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (>300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (>1 log 10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. ( A pproximately 400 million people worldwide have chronic hepatitis B virus (HBV) infections, with a risk for chronic, life-threatening liver disease. 1 Antiviral therapy for HBV can provide suppression of viral replication and halt disease progression. 2,3 However, therapeutic benefits are diminished with the emergence of drug-resistant virus, which occurs most often with prolonged therapy and incomplete viral suppression. 4 Resistance to nucleoside/nucleotide antivirals arises through substitutions in the HBV polymerase reverse transcriptase domain (RT), that arise spontaneously through low-fidelity replication and are enriched through drug-selective pressure. 2,3 Antiviral therapies are characterized by their barrier to resistance, which includes three components: (1) the potency of the antiviral in suppressing viral replication, (2) a "genetic barrier", i.e., the number of genetic changes required to effectively reduce drug susceptibility that results in virologic breakthrough, and (3) the replication fitness of the resistant virus. These factors act together to determine the levels of resis...

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Section: Resultsmentioning

confidence: 99%

“…[22][23][24] Recently, evidence for cross-resistance of ADV and tenofovir with LVDr HBV with A181V or T substitutions was reported. 25 LVDr also reduces the barrier to resistance with ETV. ETV exhibits ϳ8-fold reduced potency against LVDr HBV.…”

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confidence: 98%

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

et al. 2009

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“…rtA181T mutation‐associated ADV resistance has been reported 28, 32, 33, 34. This mutation is often associated with a stop codon at the overlapping surface gene, and the sW172stop mutation impairs HBsAg secretion by generating a truncated protein and also causes the susceptibility to ADV to deteriorate.…”

Section: Discussionmentioning

confidence: 99%

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Yamada

Sugiyama

Nitta

et al. 2017

Hepatology Communications

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The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti‐HBV reagents; it has a very low resistance rate and is used as the first‐line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV‐refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare‐up) and assessed ETV resistance using replication‐competent 1.38‐fold HBV genome‐length molecular clones. The full genome sequences of infected HBVs in ETV‐refractory patients were determined. The HBV molecular clones were generated with the patient‐derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core‐particle‐associated HBV DNA using Southern blotting and real‐time polymerase chain reaction. Among these cases, ETV‐resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV‐resistant mutation was detected in the other cases. The identified ETV‐resistant mutations did not confer resistance to tenofovir disoproxil fumarate. Conclusion: The HBV replication model with patient‐derived sequences is useful for assessing replication efficiency, susceptibility to anti‐HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment‐failure cases of chronic hepatitis B. (Hepatology Communications 2017;1:110‐121)

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“…This point mutation was recently reported in CHB patients with viral breakthrough after LMV or ADV treatment (5)(6)(7)(8)(9). Recent studies have indicated that the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential through its transactivation activity (4,(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 79%

Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis

Zheng

Jiang

2016

Jpn J Infect Dis

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SUMMARY:We investigated the biological effect of hepatitis B virus (HBV) rtA181T/sW172* point mutation on HBsAg secretion and the potential mechanisms involved in hepatocarcinogenesis. Fulllength HBV wild type (wt) and HBV rtA181T/sW172 * expression plasmids were transfected into HepG2 cell lines or were injected into C57BL/6 mice. The extracellular and intracellular expression levels of HBsAg and HBeAg proteins, in mouse serum and liver tissues were detected by ELISA. The localization of the truncated protein was characterized in vitro. The mRNA expression of endoplasmic reticulum (ER) stress gene GRP78 was determined. HBsAg levels were significantly higher in both supernatant of cells transfected with HBV wt and serum of mice injected with HBV wt, compared with that of HBV rtA181T/sW172* mutant. The reversed trend was observed in intracellular cells and intrahepatic liver cells. Wild type S protein alone could rescue this dysfunction. HBV rtA181T/sW172 * truncated surface proteins showed a more aggregated cytoplasmic pattern which were also localized to the ER in comparison with HBV wt. Furthermore, GRP78 mRNA expression was increased 72 h post-transfection in HBV rtA181T/sW172 * cells relative to HBV wt cells (P ＝ 0.0154). The HBV sW172 * truncation variant has a defect on HBsAg secretion which can lead to surface protein retention in the ER, where it may contribute to hepatocarcinogenesis through activating the ER stress signaling pathway.

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Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure

Cited by 174 publications

References 31 publications

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis

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