免疫檢查點抑製劑和乙型肝炎病毒動力學-全地區隊列研究

StephenW

Immune checkpoint inhibitors and hepatitis B viral kinetics--a territory-wide cohort study   

HBV Reactivation Rare in HBV Patients Who Used Immune Checkpoint Inhibitors

EASL 2020, Digital International Liver Congress, August 27-29, 2020

Mark Mascolini

In a territory-wide Hong Kong study, people with chronic or past HBV infection who took immune checkpoint inhibitors rarely had HBV reactivation [1]. No hepatitis B surface antigen (HBsAg)-positive people attained HBsAg seroclearance after immunotherapy.

Monoclonal antibody immune checkpoint inhibitors have improved survival of people with diverse advanced or metastatic malignancies. These agents exert their effect by disrupting immune tolerance, but the relationship between toxicity and response remains incompletely understood.

Recent work suggests that new checkpoint inhibitors—programmed death receptor 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors—may have a role in treating chronic HBV infection. HBV-specific T cells in the liver express PD-1, and chronic HBV infection drives PD-L1 expression in hepatocytes. Researchers at the Chinese University of Hong Kong and collaborators who conducted this study in people with HBV note that hepatic adverse events are common with immune checkpoint inhibitors and are linked to worse overall survival.

To learn more about the potential impact of these agents in people with chronic hepatitis B or past HBV infection, the Chinese University team mounted a retrospective observational cohort study across the territory of Hong Kong. Using the Clinical Data Analysis and Reporting System (CDARS), they identified consecutive adult Chinese patients who took at least one dose of a checkpoint inhibitor from July 2014 through October 2018. Participants had (1) chronic HBV infection, defined as being HBsAg-positive for at least 6 months or (2) past HBV infection, defined as being HBsAg-negative but positive for antibody to hepatitis B core antigen (anti-HBc-positive). The analysis excluded people with hepatitis C or D virus or HIV coinfection as well as people missing HBsAg, anti-HBc, or alanine aminotransferase (ALT) results.

The analysis included 395 HBV patients—237 who were HBsAg-positive (current infection) and 158 who were HBsAg-negative but positive for anti-HBc (past infection). Participants with chronic HBV were younger than those with past HBV (average 57.9 vs 62.9 years), more likely to be men (84.4% vs 69.6%), and had higher ALT (average 0.8 vs 0.6 at the upper limit of normal [ULN]). HBV DNA averaged 1.9 log10 IU/mL in the chronic HBV group and 0.06 log10 IU/mL in the past HBV group.

Almost everyone in the chronic HBV group (97%) took some nucleos(t)ide analog, compared with 28% in the past HBV group. Treatment usually included entecavir (89% and 27%).

People with chronic HBV had marginally more biochemical and virologic flares than the past-HBV group. When the researchers defined HBV reactivation as ALT more than 2 times ULN, 31.0% of the HBsAg-positive group and 22.3% of the anti-HBc-positive group had a flare (P = 0.282). Smaller proportions had reactivation defined as ALT more than 5 times the upper limit of normal (12.7% vs 11.6%, P = 0.665). When the research team defined reactivation virologically as HBV DNA above 2000 IU/mL, only 2 HBsAg-positive people (1.7%) and no anti-HBC-positive people had a flare (P = 0.506). When they defined reactivation as more than a 10-fold jump in HBV DNA IU/mL, only 6 HBsAg-positive people (4.1%) and no anti-HBC-positive people had a flare (P = 0.085).

The investigators found that no HBsAg-positive people cleared HBsAg (seroconversion) and no anti-HBc-positive person had HBsAg seroreversion during follow-up.

The Hong Kong team concluded that HBV reactivation is rare in people who received immunotherapy for chronic or past HBV infection. They stressed that none of 237 HBsAg-positive people had HBsAg seroclearance after immunotherapy.

Reference
1. Wong GLH, Yip TCF, Wong VWS, et al. Immune checkpoint inhibitors and hepatitis B viral kinetics--a territory-wide cohort study. EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract AS092.

StephenW

免疫檢查點抑製劑和乙型肝炎病毒動力學-全地區隊列研究

使用免疫檢查點抑製劑的HBV患者中HBV激活很少

EASL 2020，數字國際肝臟大會，2020年8月27日至29日

馬克·馬斯科利尼

在香港範圍內的一項研究中，服用了免疫檢查點抑製劑的慢性或過去HBV感染者很少再激活HBV [1]。免疫治療後，沒有乙型肝炎表面抗原（HBsAg）陽性的人達到HBsAg血清清除率。

單克隆抗體免疫檢查點抑製劑可改善患有各種晚期或轉移性惡性腫瘤的人的生存率。這些藥物通過破壞免疫耐受發揮其作用，但毒性和反應之間的關係仍未完全了解。

最近的工作表明，新的檢查點抑製劑-程序性死亡受體1（PD-1）抑製劑和程序性細胞死亡配體1（PD-L1）抑製劑-可能在治療慢性HBV感染中起作用。肝臟中的HBV特異性T細胞表達PD-1，而慢性HBV感染則驅動肝細胞中PD-L1的表達。香港中文大學的研究人員和在HBV患者中進行過這項研究的合作夥伴指出，肝臟不良事件在免疫檢查點抑製劑中很常見，並且與整體生存率降低有關。

為了進一步了解這些藥物對慢性乙型肝炎或以前的HBV感染者的潛在影響，中國大學團隊在香港範圍內進行了一項回顧性觀察隊列研究。他們使用臨床數據分析和報告系統（CDARS），確定了從2014年7月至2018年10月連續服用至少一劑檢查點抑製劑的中國成年患者。參與者患有（1）慢性HBV感染，定義為HBsAg陽性持續至少6個月或（2）HBV感染後，定義為HBsAg陰性，但對乙型肝炎核心抗原的抗體呈陽性（抗HBc陽性）。該分析排除了患有丙型或丁型肝炎病毒或HIV合併感染的人，以及缺少HBsAg，抗HBc或丙氨酸轉氨酶（ALT）結果的人。

分析包括395例HBV患者-237例HBsAg陽性（當前感染）和158例HBsAg陰性但抗HBc陽性（過去感染）。慢性HBV的參與者比過去HBV的參與者年輕（平均57.9 vs 62.9歲），男性更有可能（84.4％vs 69.6％），並且ALT更高（正常上限[ULN]分別為0.8 vs 0.6） ）。慢性HBV組的HBV DNA平均為1.9 log10 IU / mL，過去的HBV組為0.06 log10 IU / mL。

慢性HBV組中幾乎所有人（97％）都服用了一些核苷酸類似物，而過去的HBV組中這一比例為28％。治療通常包括恩替卡韋（89％和27％）。

與過去的HBV組相比，慢性HBV患者的生化和病毒學耀斑略多。當研究人員將HBV復活定義為ALT大於ULN的2倍時，HBsAg陽性組的31.0％和抗HBc陽性組的22.3％出現了耀斑（P = 0.282）。較小比例的再激活被定義為ALT超過正常上限的5倍以上（12.7％對11.6％，P = 0.665）。當研究小組從病毒學角度將復活定義為高於2000 IU / mL的HBV DNA時，只有2個HBsAg陽性的人（1.7％），沒有抗HBC陽性的人出現耀斑（P = 0.506）。當他們將再激活定義為HBV DNA IU / mL跳升超過10倍時，只有6名HBsAg陽性的人（4.1％），沒有抗HBC陽性的人出現耀斑（P = 0.085）。

研究者發現，在隨訪期間，沒有HBsAg陽性的人清除HBsAg（血清轉化），也沒有抗HBc陽性的人發生HBsAg血清逆轉。

香港研究小組得出結論，在接受針對慢性或過去的HBV感染的免疫治療的人群中，HBV激活很少。他們強調，接受免疫治療後，沒有HBsAg陽性的237名HBsAg陽性患者。

參考
1. Wong GLH，Yip TCF，Wong VWS等。免疫檢查點抑製劑和乙型肝炎病毒動力學-一項全港範圍的隊列研究。 EASL 2020，數字國際肝臟大會，2020年8月27日至29日。摘要AS092。