乙型肝炎病毒遗传多样性预测实现功能性治愈的潜力

StephenW

乙型肝炎病毒遗传多样性预测实现功能性治愈的潜力

如果有一种方法可以预测哪些患者更有可能实现慢性乙型肝炎病毒感染的功能性治愈呢？

Doherty Institute 的科学家们已经做到了这一点，他们发现乙型肝炎病毒 (HBV) 的多样性较低的人更有可能通过治疗实现功能性治愈。

据估计，全世界有 2.96 亿人感染 CHB。 CHB 可导致肝硬化、肝功能衰竭和肝癌，据估计 2015 年有 887,000 人直接死于 CHB 相关疾病。

“慢性乙型肝炎无法治愈，但在极少数情况下，目前的抗病毒治疗可以实现我们所说的‘功能性治愈’——即乙型肝炎表面抗原 (HBsAg) 的消失，这是一种指示血液中病毒的生物标志物，”皇家墨尔本医院的 Peter Revill 教授解释说，他是 Doherty 研究所维多利亚传染病参比实验室 (VIDRL) 的高级医学科学家。

“我们想知道 CHB 患者在抗病毒治疗期间达到功能性治愈的可能性有多大。”

HBV 是一种 DNA 病毒，具有 RNA 阶段，这对病毒复制至关重要。当 RNA 被复制到 DNA 时，没有错误的纠正，并且产生了 HBV 基因组的许多不同版本（变体）。单倍型数 (HN) 是这种多样性的量度——数字越低，病毒基因组的多样性就越低。

该团队使用深度测序研究了乙型肝炎病毒感染者的乙型肝炎病毒变体，以确定疾病结果和治疗反应的预测因子。

在这项发表在《消化药理学与治疗学》医学杂志上的世界首创研究中，研究人员发现患者的单倍型数量较低 (≤2) 与抗病毒治疗实现功能性治愈的几率较高有关。

皇家墨尔本医院的多尔蒂研究所 VIDRL 生物信息学家兼主要作者约瑟夫瓦格纳博士说：“这是第一项表明基线单倍型数量可以预测哪些患者可能会或可能不会通过当前的抗病毒治疗实现功能性治愈的研究。”的纸。

“目前我们的研究结果仅限于乙型肝炎病毒基因型 A 和 D，还需要对其他 HBV 基因型进行进一步研究。”

皇家墨尔本医院的 Doherty 研究所 VIDRL 高级医学科学家 Margaret Littlejohn 博士说，这是为临床医生提供工具以更有效地治疗患者的重要一步。

“SARS-CoV-2 大流行已经规范了下一代（深度）测序的使用，以前所未有的规模快速分析病毒分离物，包括单倍型研究，”Littlejohn 博士解释说。

“对于患有慢性乙型肝炎的患者，我们现在可以快速有效地从血清样本中建立 HBV 单倍型群体，预测哪些患者在某些情况下可能会或可能不会通过治疗实现功能性治愈，从而为临床医生提供治疗反应的有效生物标志物。”

该团队感谢美国吉利德科学公司的支持。

资助：美国吉利德科学
DOI：10.1111/apt.17299

StephenW

Hepatitis B virus genetic diversity predicts potential to achieve functional cure

What if there was a way to predict which patients are more likely to achieve functional cure of chronic hepatitis B virus infection? 

Doherty Institute scientists have done just that by uncovering that people living with hepatitis B virus (HBV) that is less diverse are more likely to achieve functional cure on treatment.  

It is estimated that 296 million people live with CHB infection around the world. CHB can lead to cirrhosis, liver failure and liver cancer, and 887,000 people were estimated to have died in 2015 directly from CHB-related conditions.  

“There is no cure for CHB but, on rare occasions, current antiviral treatment can achieve what we call ‘functional cure’ - that is the loss of hepatitis B surface antigen (HBsAg), a biomarker indicative of the virus in the blood,” explained the Royal Melbourne Hospital’s Professor Peter Revill, Senior Medical Scientist in the Victorian Infectious Diseases Reference Laboratory (VIDRL) at the Doherty Institute. 

“We wanted to know how likely a person with CHB is to reach functional cure during their antiviral therapy.” 

HBV is a DNA virus that has an RNA phase, which is critical for viral replication. When the RNA is copied to DNA, there is no correction of errors, and many different versions (variants) of the HBV genome are produced. A haplotype number (HN) is a measure of this diversity – the lower the number, the less diverse the viral genome. 

Using deep sequencing, the team studied hepatitis B virus variants in people living with HBV to identify predictors of disease outcome and treatment response. 

In this world-first study published in the Alimentary Pharmacology & Therapeutics medical journal, the researchers found that a lower haplotype number (≤2) in a patient was associated with a higher chance to achieve functional cure on antiviral therapy. 

“This is the first study to show that haplotype number at baseline predicts which patients may, or may not, achieve functional cure on current antiviral therapy,” said the Royal Melbourne Hospital’s Dr Josef Wagner, Bioinformatician in VIDRL in the Doherty Institute and lead author of the paper. 

“At present our findings are limited to hepatitis B virus genotypes A and D, and further studies are required with additional HBV genotypes.” 

The Royal Melbourne Hospital’s Dr Margaret Littlejohn, Senior Medical Scientist in VIDRL at the Doherty Institute said that this is a great step in providing tools for clinicians to treat their patients more efficiently. 

“The SARS-CoV-2 pandemic has normalised the use of next-generation (deep) sequencing for rapid analysis of viral isolates on an unprecedented scale, including haplotype studies,” Dr Littlejohn explained. 

“For patients living with chronic hepatitis B, we can now establish the HBV haplotype population from a blood serum sample in a fast and efficient manner, predicting which patients may or may not achieve functional cure on treatment in some settings, thereby providing clinicians with an effective biomarker of treatment response.” 

The team acknowledges the support from Gilead Sciences, USA.

Funding: Gilead Sciences, USA 
DOI: 10.1111/apt.17299