Molecular epidemiology of hepatitis B virus mutants associated with vaccine escape, drug resistance and diagnosis failure

Lello, Federico A. Di; Ridruejo, Ezequiel; Martínez, Alfredo P.; Pérez, Paula Soledad; Campos, Rodolfo Héctor; Flichman, Diego Martín

doi:10.1111/jvh.13052

Cited by 18 publications

(16 citation statements)

References 71 publications

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“…Overall, immune escape mutations were detected in 10.7% HBV genomes. Similar rates have been determined in cohorts from Argentina (7.5-10.7%) (Di Lello et al, 2019), China (9.01%) (Yan et al, 2017), Spain (6.6-12.5%) (Avellon and Echevarria, 2006), and Turkey (8.3%) (Sayan et al, 2010). Only 4 of the 25 escape mutations had total frequencies of ≥1% (I/T126S, 1.8%; G145R, 1.2%; M133T, 1.2%; and Q129R, 1.0%), consistent with a previous large-scale analysis showing frequencies of no less than 1% for most escape mutations (Ma and Wang, 2012).…”

Section: Discussionsupporting

confidence: 83%

Comprehensive Analysis of Clinically Significant Hepatitis B Virus Mutations in Relation to Genotype, Subgenotype and Geographic Region

2020

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Hepatitis B virus (HBV) is a highly variable DNA virus due to its unique life cycle, which involves an error-prone reverse transcriptase. The high substitution rate drives the evolution of HBV by generating genetic variants upon which selection operates. HBV mutants with clinical implications have been documented worldwide, indicating the potential for spreading and developing their own epidemiology. However, the prevalence of such mutants among the different HBV genotypes and subgenotypes has not been systematically analyzed. In the current study, we performed large-scale analysis of 6,479 full-length HBV genome sequences from genotypes A-H, with the aim of gaining comprehensive insights into the relationships of relevant mutations associated with immune escape, antiviral resistance and hepatocellular carcinoma (HCC) development with HBV (sub)genotypes and geographic regions. Immune escape mutations were detected in 10.7% of the sequences, the most common being I/T126S (1.8%), G145R (1.2%), M133T (1.2%), and Q129R (1.0%). HBV genotype B showed the highest rate of escape mutations (14.7%) while genotype H had no mutations (P < 0.001). HCC-associated mutations were detected in 33.7% of the sequences, with significantly higher frequency of C1653T, T1753V and A1762T/G1764A in genotype G than C (P < 0.001). The overall frequencies of lamivudine-, telbivudine-, adefovir-, and entecavir-resistant mutants were 7.3, 7.2, 0.5, and 0.2%, respectively, while only 0.05% showed reduced susceptibility to tenofovir. In particular, the highest frequency of lamivudine-resistant mutations was observed in genotype G and the lowest frequency in genotype E (32.5 and 0.3%; P < 0.001). The prevalence of HBV mutants was also biased by geographic location, with North America identified as one of the regions with the highest rates of immune escape, antiviral resistance, and HCC-associated mutants. The collective findings were discussed in light of natural selection and the known characteristics of HBV (sub)genotypes. Our data provide relevant information on the prevalence of clinically relevant HBV mutations, which may contribute to further improvement of diagnostic procedures, immunization programs, therapeutic protocols, and disease prognosis.

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Section: Discussionsupporting

confidence: 83%

Comprehensive Analysis of Clinically Significant Hepatitis B Virus Mutations in Relation to Genotype, Subgenotype and Geographic Region

2020

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“…A study performed in Argentina that analyzed HBsAg and HBVPol sequences from 530 samples of HBV-infected individuals found that diagnostic failure mutants (DFM) and vaccine escape mutants (VEM) were detected in 10.7% and 7.5%, respectively. The most frequent DFM was Y100C in subgenotype A1 and was frequently detected in HBsAg negative samples [ 172 ]. Despite that, even if this mutation has been frequently identified in the lack of HBsAg detection in serum samples, in vitro assays suggested that this substitution alone is not enough to evade HBsAg detection by commercial ELISA assay [ 173 ].…”

Section: Viral Epitopesmentioning

confidence: 99%

Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability

Campos-Valdez

Monroy-Ramírez

Armendáriz‐Borunda

et al. 2021

Viruses

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The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.

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“…A recent study showed that HBV mutants associated with vaccine escape, diagnosis failure, and drug resistance could be genotypic and sub-genotypic specific. 44 Further studies should be done to assess the impact of anti-HBV therapies on the incidence and spread of HBV escape mutants.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Antigen Escape Mutations in Chronic HBV-Infected Patients in Upper Egypt

El‐Mokhtar¹,

Hetta²,

Mekky³

et al. 2021

IDR

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Background Mutations within the “a” determinant region (position 124–147) that is present in the major hydrophilic region (MHR, position 99–160) of the hepatitis B surface antigen (HBsAg) are associated with vaccine-escape, lack of diagnosis, and failure to hepatitis B immunoglobulin (HBIG) therapy. Data regarding the amino acid changes of “a” determinant region of HBsAg are limited in Egypt. The prevalence and mutations in this region among chronic HBV (CHB)-infected patients in Upper Egypt are not known. Material and Methods Blood samples were collected from HBsAg-positive CHB-infected patients (n=123) admitted to Assiut University Hospitals. Serum samples were screened for HBsAg, HBeAg, anti-HBs and anti-HBe antibodies using commercially available ELISA kits. Viral load was determined by qPCR. In addition, mutational analysis was carried out targeting the HBV surface gene to determine the HBV genotype and vaccine escape mutations. Results Sequencing analysis of HBV DNA revealed that genotype D is the major circulating type (81.3%), followed by genotype E (18.7%). Analysis of the HBV genome revealed that 103/123 (83.7%) patients showed wild-type sequences and 20/123 (16.3%) showed mutations in the HBsAg gene. Mutation in seventeen patients (17/20, 85%) showed only one mutation, and three patients showed two mutations (3/20, 15%) in the “a” determinant region. The observed mutations were T115S (3/20, 15%), P120T/S (3/20, 15%), T126S (1/20, 5%), Q129R (2/20, 10%), M133T (2/20, 10%), S143L (5/20, 25%), D144E/A (3/20, 15%), and G145R/A (4/20, 20%). Mutations in the “a” determinant region were detected in genotype D isolates only. Conclusion We described for the first time the prevalence and characterization of vaccine escape mutants in CHB patients in Upper Egypt. Mutational analysis of the “a” determinant region revealed the presence of a wide spectrum of mutants in the circulating HBV isolates that could be a potential threat to HBV diagnosis, therapy success, and HBV vaccination program in Upper Egypt.

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Molecular epidemiology of hepatitis B virus mutants associated with vaccine escape, drug resistance and diagnosis failure

Cited by 18 publications

References 71 publications

Comprehensive Analysis of Clinically Significant Hepatitis B Virus Mutations in Relation to Genotype, Subgenotype and Geographic Region

Comprehensive Analysis of Clinically Significant Hepatitis B Virus Mutations in Relation to Genotype, Subgenotype and Geographic Region

Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability

Characterization of Antigen Escape Mutations in Chronic HBV-Infected Patients in Upper Egypt

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