HBV 治疗可降低 HBV 不确定期的 HCC 风险

StephenW

HBV 治疗可降低 HBV 不确定期的 HCC 风险

AASLD—肝脏会议，2022 年 11 月 4 日至 8 日，华盛顿特区

马克·马斯科里尼

通过 15 年的随访 [1]，未定期慢性乙型肝炎病毒 (HBV) 感染的抗病毒治疗可将 HCC 风险降低 70%。新加坡国立大学的研究人员和世界各地的 REAL-B 联盟同事认为，他们的发现可能支持扩大慢性 HBV 治疗标准。

与丙型肝炎、酒精或非酒精性脂肪性肝炎 (NASH) 相比，慢性 HBV 感染导致的 HCC 病例更多 [2,3]。多达 40% 的慢性 HBV 患者处于不确定期，其中包括未被分类为免疫耐受、免疫活跃或非活跃的任何人。先前的研究表明，不确定期的 HCC 发病率明显高于非活动期 [4]。

新的多中心研究旨在探索抗HBV治疗与HBV不确定期HCC风险之间的潜在关联。这项对慢性 HBV 感染者的回顾性分析在美国、欧洲和亚洲的 14 个地点进行。参与者必须年满 18 岁，并且未接受过抗 HBV 治疗。研究人员通过两组连续的丙氨酸氨基转移酶 (ALT) 和 HBV DNA 评估以及 HBeAg 测试证实了他们的不确定阶段状态，HBeAg 是一种指示 HBV 复制的 HBV 蛋白。

一长串患者特征和肝脏指标可能会将一个人排除在分析之外：不到 1 年的随访，在索引日期后 6 个月内发展为 HCC，同时感染 HCV 或 HIV，移植，FIB-4 高于 3.25，瞬时弹性成像高于 12.5 kPA，通过磁共振弹性成像检测的肝脏硬度高于 4.63 kPA，或肝活检表明 3 或 4 期纤维化。研究人员依据世界卫生组织 HBV 预防和治疗指南 [5] 将慢性 HBV 分类为免疫耐受、免疫活跃、非活跃或不确定。

研究人员通过年龄、性别、ALT、天冬氨酸氨基转移酶 (AST)、HBV DNA、HBeAg、血小板计数、糖尿病的存在和随访时间的治疗加权逆概率平衡了抗病毒治疗组和未治疗组之间的基线特征。单变量和多变量 Cox 比例风险回归估计与 HCC 发展相关的因素的风险比。

在对 REAL-B 联盟 [6] 中的 29,400 名慢性 HBV 患者应用纳入和排除标准后，研究人员最终对 855 人进行了当前分析，其中 405 人接受了 HBV 治疗，450 人未接受治疗。

在治疗加权逆概率之前，治疗组与未治疗组在年龄（平均 47.4 对 45.6，P = 0.05）、男性比例（65.7% 对 52.9%，P < 0.001）、HBeAg 阳性比例（28.4 % vs 13.1%, P < 0.001), HBV DNA log10 IU/mL (5.2 vs 3.8, P < 0.0001), ALT (中位数 43 vs 33, P < 0.0001), FIB-4 低于 1.45 (62.0% vs 72.2) %，P = 0.001），与 FIB-4 的比例为 1.45 至 3.25（38% 对 27.8%，P = 0.001），以及 ALT 测量之间的时间间隔（5.5 对 7.5，P < 0.0001）。治疗加权的逆概率消除了所有这些差异，创建了由 394 名接受治疗的人和 425 名未接受治疗的人组成的平衡组。

在 15 年内，抗病毒治疗组的 HBV 不确定期 HCC 发生率显着降低（9.4% 对 19.1%，P = 0.02）。每1000人年的发病率在治疗组为5.2，在未治疗组为11.6。在治疗加权队列的逆概率中，治疗降低 HCC 的机会 70%（调整后的风险比 [aHR] 0.30，95% 置信区间 [CI] 0.10 至 0.60，P = 0.001）。 HCC 的所有其他独立预测因素均增加了风险：年龄超过 45 岁（aHR 4.6，95% CI 2.1 至 10.1，P < 0.001），男性（aHR 32.5，95% CI 3.5 至 304.5，P = 0.002），ALT 高于低于正常上限（aHR 2.4, 95% CI 1.0 至 5.6, P = 0.05）和 HBeAg 阳性（aHR 3.7, 95% CI 1.8 至 7.7, P < 0.001）。

对于 45 岁以上的亚组，治疗对降低 HCC 发病率的影响在 15 年内仍然显着，但对于较年轻的亚组则不然。无论 ALT 是高于还是低于正常上限，抗病毒治疗都显着降低了 15 年的 HCC 发病率。当 HBV DNA 高于但不低于 1000 IU/mL 时，治疗可显着降低 15 年的 HCC 发病率。

尽管研究小组是多民族的，但大多数人是亚洲人，因此研究人员警告说，研究结果可能不适用于其他种族群体。

由于结果可能有利于扩大慢性 HBV 治疗标准，因此研究人员认为有必要研究更广泛治疗建议的成本效益。
参考
1. Huang DQ, Tran A, Yeh M-L, et al.抗病毒治疗可降低处于不确定期的 HBV 患者的肝细胞癌风险。 AASLD—肝脏会议，2022 年 11 月 4 日至 8 日，华盛顿特区。摘要 36。
2. Sung H、Ferlay J、Siegel RL 等人。 2020 年全球癌症统计数据：GLOBOCAN 估计全球 185 个国家 36 种癌症的发病率和死亡率。 CA 癌症 J 临床。 2021；71:209-249。 doi: 10.3322/caac.21660。 https://acsjournals.onlinelibrar ... /10.3322/caac.21660
3. Huang DQ, Singal AG, Kono Y, et al. 2010年至2019年全球肝癌流行病学变化：NASH是肝癌增长最快的原因。细胞代谢物。 2022 5；34:969-977.e2。 doi: 10.1016/j.cmet.2022.05.003。 https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00185-1
4. 黄大清，李新，乐MH，等。未经治疗的未定期慢性乙型肝炎患者的自然史和肝细胞癌风险。临床胃肠肝素。 2022;20:1803-1812.e5。 doi: 10.1016/j.cgh.2021.01.019。 https://pubmed.ncbi.nlm.nih.gov/33465482/
5. 世界卫生组织。慢性乙型肝炎感染者预防、护理和治疗指南。 2015 年 3 月 1 日。https://www.who.int/publications/i/item/9789241549059
6. Yang H-I, Yeh M-L, Wong G, et al.科克伦图书馆。用于预测接受口服抗病毒治疗的慢性乙型肝炎患者肝细胞癌的 REAL-B（来自亚太地区肝病协会的 HBV 真实世界有效性）风险评分。 https://www.cochranelibrary.com/ ... al/CN-01989952/full

StephenW

HBV Therapy Slices HCC Risk in HBV’s Indeterminate Phase

AASLD—The Liver Meeting, November 4-8, 2022, Washington, DC

Mark Mascolini

Antiviral therapy for chronic hepatitis B virus (HBV) infection in the indeterminate phase sliced HCC risk by 70% through 15 years of follow-up [1]. Researchers from the National University of Singapore and REAL-B Consortium colleagues across the world believe their findings may support expansion of chronic HBV treatment criteria.

Chronic HBV infection accounts for more cases of HCC than hepatitis C, alcohol, or nonalcoholic steatohepatitis (NASH) [2,3]. As many as 40% of chronic HBV patients fit into the indeterminate phase, which includes anyone not classified as immune tolerant, immune active, or inactive. Prior research showed that HCC incidence stands significantly higher in the indeterminate phase than in the inactive phase [4].

The new multicenter study aimed to explore potential associations between anti-HBV therapy and HCC risk in HBV’s indeterminate phase. This retrospective analysis of people with chronic HBV took place at 14 sites in the United States, Europe, and Asia. Participants had to be at least 18 years old and naive to anti-HBV therapy. Researchers confirmed their indeterminate phase status by two consecutive sets of alanine aminotransferase (ALT) and HBV DNA assessments, plus a test for HBeAg, the HBV protein indicating ongoing HBV replication.

A long list of patient characteristics and liver measures could exclude a person from the analysis: less than 1 year of follow-up, HCC developing within 6 months of the index date, coinfection with HCV or HIV, transplantation, FIB-4 above 3.25, transient elastography above 12.5 kPA, liver stiffness by magnetic resonance elastography above 4.63 kPA, or liver biopsy indicating stage 3 or 4 fibrosis. The investigators relied on World Health Organization HBV prevention and treatment guidelines [5] to categorize chronic HBV as immune tolerant, immune active, inactive, or indeterminate.

The researchers balanced baseline characteristics between the antiviral treated and untreated groups by inverse probability of treatment weighting for age, sex, ALT, aspartate aminotransferase (AST), HBV DNA, HBeAg, platelet count, presence of diabetes, and follow-up time. Univariable and multivariable Cox proportional hazards regression estimated hazard ratios for factors associated with HCC development.

After applying inclusion and exclusion criteria to 29,400 people with chronic HBV in the REAL-B consortium [6], the researchers ended up with 855 people for the current analysis, 405 of them treated for HBV and 450 untreated.

Before inverse probability of treatment weighting, the treated group differed significantly from the untreated group in age (average 47.4 vs 45.6, P = 0.05), proportion of men (65.7% vs 52.9%, P < 0.001), proportion HBeAg-positive (28.4% vs 13.1%, P < 0.001), HBV DNA log10 IU/mL (5.2 vs 3.8, P < 0.0001), ALT (median 43 vs 33, P < 0.0001), proportion with FIB-4 below 1.45 (62.0% vs 72.2%, P = 0.001), proportion with FIB-4 1.45 to 3.25 (38% vs 27.8%, P = 0.001), and time between ALT measurement in months (5.5 vs 7.5, P < 0.0001). Inverse probability of treatment weighting erased all these differences, creating balanced groups of 394 treated people and 425 untreated people.

HCC incidence in HBV’s indeterminate phase proved significantly lower in the antiviral-treated group through 15 years (9.4% vs 19.1%, P = 0.02). Incidence per 1000 person-years stood at 5.2 in the treated group and 11.6 in the untreated group. In the inverse probability of treatment weighting cohort, treatment cut chances of HCC 70% (adjusted hazard ratio [aHR] 0.30, 95% confidence interval [CI] 0.10 to 0.60, P = 0.001). All other independent predictors of HCC raised the risk: age over 45 years (aHR 4.6, 95% CI 2.1 to 10.1, P < 0.001), male sex (aHR 32.5, 95% CI 3.5 to 304.5, P = 0.002), ALT above versus below the upper limit of normal (aHR 2.4, 95% CI 1.0 to 5.6, P = 0.05), and HBeAg-positive (aHR 3.7, 95% CI 1.8 to 7.7, P < 0.001).

The impact of treatment in lowering HCC incidence remained significant through 15 years for the subgroup older than 45 but not for the younger subgroup. Antiviral treatment significantly lowered HCC incidence through 15 years regardless of whether ALT was above or below the upper limit of normal. Treatment significantly cut HCC incidence through 15 years when HBV DNA stood above but not below 1000 IU/mL.

Although the study group was multinational, most people were Asian, so the researchers cautioned that findings may not apply to other ethnic groups.

Because results may favor expansion of chronic HBV treatment criteria, the investigators see a need to study the cost-effectiveness of wider treatment recommendations.

References
1. Huang DQ, Tran A, Yeh M-L, et al. Antiviral therapy reduces hepatocellular carcinoma risk among HBV patients in the indeterminate phase. AASLD—The Liver Meeting, November 4-8, 2022, Washington, DC. Abstract 36.
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-249. doi: 10.3322/caac.21660. https://acsjournals.onlinelibrar ... /10.3322/caac.21660
3. Huang DQ, Singal AG, Kono Y, et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022 5;34:969-977.e2. doi: 10.1016/j.cmet.2022.05.003. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00185-1
4. Huang DQ, Li X, Le  MH, et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase. Clin Gastroenterol Hepatol. 2022;20:1803-1812.e5. doi: 10.1016/j.cgh.2021.01.019. https://pubmed.ncbi.nlm.nih.gov/33465482/
5. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 1 March 2015. https://www.who.int/publications/i/item/9789241549059
6. Yang H‐I, Yeh M‐L, Wong G, et al. Cochrane Library. REAL-B (Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV) risk score for the prediction of hepatocellular carcinoma in chronic hepatitis B patients treated with oral antiviral therapy. https://www.cochranelibrary.com/ ... al/CN-01989952/full