A Case of S-Variant Hepatitis B Virus: An Immune System Escape Artist

Genomic variants of the hepatitis B virus (HBV) preS/S protein are well-known to occur. Typically, immunity is gained through recovered HBV infection or by immunization. Very rarely, there are certain mutations that may enable HBV escape from the immune detection. PreS/S mutants may present with unpredictable pathobiologic, clinical, and transmittable implications. Standard laboratory testing for genomic HBV variants is not routinely performed by reference guidelines. s-variant HBV management remains challenging. Herein is a case of s-variant chronic HBV infection in a 55-year-old man. Diagnosis and treatment are described.

Global Occurrence of Clinically Relevant Hepatitis B Virus Variants as Found by Analysis of Publicly Available Sequencing Data

Several viral factors impact the natural course of hepatitis B virus (HBV) infection, the sensitivity of diagnostic tests, or treatment response to interferon-α and nucleos(t)ide analogues. These factors include the viral genotype and serotype but also mutations affecting the HBV surface antigen, basal core promoter/pre-core region, or reverse transcriptase. However, a comprehensive overview of the distribution of HBV variants between HBV genotypes or different geographical locations is lacking. To address this, we performed an in silico analysis of publicly available HBV full-length genome sequences. We found that not only the serotype frequency but also the majority of clinically relevant mutations are primarily associated with specific genotypes. Distinct mutations enriched in certain world regions are not explained by the local genotype distribution. Two HBV variants previously identified to confer resistance to the nucleotide analogue tenofovir in vitro were not identified, questioning their translational relevance. In summary, our work elucidates the differences in the clinical manifestation of HBV infection observed between genotypes and geographical locations and furthermore helps identify suitable diagnostic tests and therapies.

Complex genetic encoding of the hepatitis B virus on-drug persistence

Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.

Analysis of Hepatitis B virus (HBV) mutations in patients from Western Saudi Arabia with chronic disease

Introduction: Extensive research has provided a link between HBV variants and the clinical complications of liver diseases. This study was performed to further investigate the relationship between HBV variants in preS, S and BCP/PC regions and disease progression in chronic hepatitis B (CHB) cases in Jeddah, Saudi Arabia. Methodology: 182 CHB patients were recruited for this study. HBV DNA was amplified by PCR in the PreS, S, and BCP/PC regions. Sequences were generated from 31 and 26 treated cases in PreS and S regions respectively and from 72 cases in the BCP/PC region. Results: The majority of cases (86.7%) were genotype D. Mutations at preS1-A2922C, X-A1624C and PC-G1887A were detected only in cases with either a high fibrosis score or hepatocellular carcinoma (HCC), while mutations at positions PC-C1982A, PC-G1951T, X-C1628T and X-A1630G were detected more frequently in HCC cases, without reaching statistical significance. Seven deletions were detected in the PreS-region. No deletions were detected in the CCAAT box. The accumulation of mutations per sample in the preS1-2 and S regions were associated with elevated ALT (p < 0.001, 0.001 and 0.001; respectively) and increased fibrosis (p = 0.018, 0.02 and 0.013; respectively). The accumulation of mutations per sample in the BCP/PC region is associated with high viral load. Occult hepatitis B infection (OBI) was identified in 5 samples. Conclusion: Our results add to the knowledge about HBV genotype-D variants. The accumulation of mutations per sample and OBI seem to play a role in the progression of HBV infection. G1896A was associated with the HBeAg negativity. The preS deletions did not play a role in liver disease progression.