article · Viruses
Deep sequencing of near-full-length Hepatitis B virus sequences from 104 people living with HIV revealed critical low-frequency viral variants present at frequencies between 5 and 50 percent. Traditional sequencing approaches routinely miss variants falling below a 20 percent detection threshold. Utilising a specialised bioinformatics pipeline, the study identified immune escape mutations in nearly eight percent of samples and drug resistance mutations in almost twenty-nine percent, alongside notable truncation mutations. Furthermore, variants linked to hepatocellular carcinoma were detected in nearly eight percent of the sequences. More than one thousand unique uncharacterised variants were also catalogued across open reading frames, with the viral RNaseH domain carrying the highest mutational burden. These outcomes indicate that standard sequencing can underreport critical mutations in co-infected populations, establishing the clinical importance of high-resolution sequencing.
Standard testing can fail to detect low-frequency viral mutations that cause drug resistance or increase liver cancer risk. By identifying these hidden variants in people living with HIV, medical professionals can better understand treatment failure risks and disease progression. This detailed genetic insight supports more precise clinical decision-making and long-term care management for co-infected patients.
The work highlights the utility of next-generation sequencing and custom bioinformatics workflows for sensitive viral monitoring. These insights could interest clinical diagnostics providers and software developers creating viral resistance surveillance tools. At present, this represents early-stage observational research, as the abstract does not indicate a validated commercial product, regulatory pipeline, or immediate clinical deployment strategy.
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(1) Background: The Hepatitis B virus (HBV) is characterized by extensive genetic diversity, including low-frequency variants that contribute to disease progression. We aimed to characterize low-frequency variants and evaluate their potential clinical impact. (2) Methods: We utilized 104 HBV near-full-length sequences generated using next-generation sequencing (NGS) from people living with HIV (PLHIV). We used an in-house bioinformatics suite (HBVgenomeR v5.9.7) to filter for low-frequency variants (5–50%), which were compared to escape and drug resistance mutations (DRMs) and hepatocellular carcinoma (HCC)-associated mutations reported at the consensus level. Unclassified variants were characterized by HBV open reading frames (ORFs) to determine mutation frequency per genomic region. (3) Results: A total of six escape mutations were detected in 8/104 (7.7%) sequences, with surfaceN131T being the most prevalent (5/8). We also observed six DRMs in 30/104 (28.8%), with rtV173L being the most prevalent (21/30). Truncation mutations were also observed with rtA181T/sW172* and rtM204I/sW196L being the most prevalent. A total of 8/104 (7.7%) sequences had four variants associated with HCC. The xP46S was the highest observed HCC-associated mutation at 5/8. We report 1152 unique uncharacterized variants across all ORFs, and these were found in 94/104 (90.4%) sequences. The RNaseH domain had the highest burden (330/1152, 28.6%). (4) Conclusions: Deep sequencing results identified clinically significant mutations, including those below the 20% detection limit of traditional sequencing, that would go unreported. This highlights the possible underreporting of mutational burden in people living with HBV/HIV, indicating the importance of deep sequencing to aid in HBV/HIV understanding and management.
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DOI: 10.3390/v18080904
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