HCV 治愈后的 HCC 危险因素不同 有与没有肝硬化和随着时间的

StephenW

HCV 治愈后的 HCC 危险因素不同
有与没有肝硬化和随着时间的推移

AASLD，肝脏会议，2021 年 11 月 12-15 日

马克·马斯科利尼

根据一项 98,612 人的美国退伍军人分析，使用直接作用抗病毒药物 (DAA) 进行病毒学 HCV 治愈后发生肝细胞癌 (HCC) 的危险因素在最初患有肝硬化的人和未患有肝硬化的人之间存在差异[1]。由于风险因素可能会在 HCV 治愈后 12 至 24 个月内发生变化，分析美国退伍军人事务部数据的团队认为，可以通过在 HCV 治愈后 2 年重复评估来改进风险估计。

休斯顿 Michael E. DeBakey VA 医疗中心的研究人员和其他中心的合作者指出，在用 DAA 病毒学治愈 HCV 感染后，HCC 风险仍然存在，但很少有研究检查自 HCV 治愈后风险因素如何随时间变化或是否存在 HCC 风险有或没有基线肝硬化的人之间存在差异。

为了解决这些问题，研究人员利用了国家退伍军人管理局企业数据仓库和中央癌症登记处的数据。该研究包括在 2014 年 1 月至 2018 年 12 月期间通过 DAA 获得持续病毒学应答 (SVR) 的 HCV 患者。参与者必须年满 18 岁，并且可以在美国 130 个 VA 设施中的任何一个接受治疗。研究人员通过中央癌症登记处或通过发现两个或多个表明 HCC 的 ICD-9 或 ICD-10 代码来确定 HCC。他们在基线和 SVR 后 1 年和 2 年记录了感兴趣的变量。

分析的重点是 98,612 名 HCV 病毒学治愈的人，其中 2298 人在平均 3.1 年的随访期间治愈后被诊断出 HCC。虽然 31,543 人患有肝硬化，但 67,069 人没有。

有或没有肝硬化的人在年龄（总体平均 61.6 岁）或男性（总体 96.4%）、白人（51.2%）、黑人（38.5%）或西班牙裔（3.5%）比例方面没有显着差异。肝硬化患者的胆红素和白蛋白较高，但肌酐和血红蛋白相似。肝硬化组的糖尿病患病率较高（44.1% 和 33.8%），但高血压（87.1% 和 81.8%）、血脂异常（52.1% 和 51.1%）和当前吸烟率（45.0% 和 50.5%）相似。

在没有肝硬化的人群中，HCV 治愈后 1 年的年 HCC 发病率为 0.21%，治愈后 2 年为 0.27%。肝硬化患者的年 HCC 发病率高出 7 倍以上——HCV 治愈后 1 年为 1.6%，治愈后 2 年为 1.9%。

在病毒学治愈 HCV 感染和肝硬化的人群中，HCC 的危险因素包括人口统计学变量（如性别和种族）、病毒危险因素（如 HCV 基因型 3）以及肝硬化相关因素（如更长的肝硬化持续时间、静脉曲张、较高的胆红素和较低的白蛋白），如以下风险比 (HR)（和 95% 置信区间）所示：

肝硬化
女性的 HCC 风险低于男性：
— 基线时女性与男性的对比：HR 0.55 (0.38-0.79, P = 0.0013)
— 12 个月时：HR 0.60（0.40-0.90，P = 0.0139）
— 24 个月时：HR 0.45（0.23-0.82，P = 0.095）

黑人的 HCC 风险低于白人
— 基线时黑人与白人：HR 0.80 (0.71-0.90, P = 0.0002)
— 12 个月时：HR 0.86（0.74-0.99，P= 0.0322）
— 第 24 个月：不显着

HCV 基因型 3 与 1a 相比，HCC 风险更高
— 基线时 HCV 基因型 3 与 1a：HR 1.45 (1.22-1.73, P < 0.0001)
— 12 个月时：HR 1.47（1.19-1.81，P = 0.0004）
— 24 个月时：不显着

静脉曲张的 HCC 风险较高
— 基线时有或无静脉曲张：HR 1.62 (1.45-1.81, P < 0.0001)
— 12 个月时：HR 1.58（1.38-1.80，P < 0.0001）
— 24 个月时：HR 1.75（1.48-2.06，P < 0.0001）

对于没有肝硬化的病毒学治愈 HCV 感染的人，关键预测因素是代谢状况，如糖尿病和高血压，以及 FIB-4 增加表明纤维化恶化，如以下 HR（和 95% 置信区间）所示：

无肝硬化
糖尿病患者 HCC 风险更高
— 基线时有与无糖尿病的比较：HR 1.42 (1.19-1.70, P = 0.0001)
— 12 个月时：HR 1.42（1.16-1.75，P = 0.0008）
— 24 个月时：HR 1.42（1.09-1.84，P = 0.0085）

高血压患者 HCC 风险更高
— 基线时有与无高血压：HR 2.06 (1.52-2.79, P < 0.0001)
— 12 个月时：HR 2.13（1.47-3.07，P < 0.0001）
— 24 个月时：HR 1.81（1.13-2.91，P = 0.0143）

从基线到 12 或 24 个月，FIB-4 的 HCC 风险从低到高增加
— 12 个月时：HR 2.36（1.46-3.79，P = 0.0005）
— 24 个月时：HR 2.04（1.01 至 4.10，P = 0.0455）

在基线肝硬化组中，在基线 (HR 0.79, 95% CI 0.67-0.93, P = 0.005) 和 HCV 治愈后 12 个月 (HR 0.77, 95% CI 0.65- 0.92，P = 0.0038）但不是在 HCV 治愈后 24 个月。在没有基线肝硬化的人群中，与当前吸烟者相比，非吸烟者在基线、治愈后 12 个月或治愈后 24 个月时的 HCC 风险并未显着降低。
总而言之，研究人员强调，在病毒学治愈 HCV 感染的人群中，HCC 风险因素在基线肝硬化和非基线肝硬化之间存在差异。 对于肝硬化患者，HCC 危险因素主要涉及疾病严重程度，而在非肝硬化患者中，代谢特征作为主要危险因素占主导地位。

由于风险可能在治愈后 12 个月至 24 个月内发生变化，因此研究人员认为“基于 2 年重复测量的风险评估是实用的，并且可以改善病毒学治愈的 HCV 患者的风险分层，无论其基线时的肝硬化状态如何。”

参考
1. Kramer JR, Cao Y, Li L, et al. 丙型肝炎病毒感染和病毒学治愈患者的危险因素与随后发生肝细胞癌的风险之间的纵向

StephenW

HCC Risk Factors After HCV Cure Differ
With vs Without Cirrhosis and Over Time

AASLD, The Liver Meeting, November 12-15, 2021

Mark Mascolini

Risk factors for development of hepatocellular carcinoma (HCC) after virologic HCV cure with direct-acting antivirals (DAAs) differed between people who initially had cirrhosis and those who did not, according to a 98,612-person US veteran analysis [1]. Because risk factors could change from 12 to 24 months after HCV cure, a team parsing US Veterans Affairs data believes risk estimates can be improved by repeating assessments 2 years after HCV cure.

Researchers at the Michael E. DeBakey VA Medical Center in Houston and collaborators at other centers noted that HCC risk persists after virologic cure of HCV infection with DAAs, but little research has examined how risk factors may change with time since HCV cure or whether HCC risk differs between people with or without baseline cirrhosis.

To address these questions, the investigators tapped data in the National Veterans Administration Corporate Data Warehouse and the Central Cancer Registry. The study included people with HCV who attained sustained virologic response (SVR) with DAAs between January 2014 and December 2018. Participants had to be at least 18 years old and could be in care at any of the 130 VA facilities across the United States. The researchers identified incident HCC through the Central Cancer Registry or by finding two or more ICD-9 or ICD-10 codes indicating HCC. They recorded variables of interest at baseline and 1 and 2 years after SVR.

The analysis focused on 98,612 people with a virologic HCV cure, 2298 of whom got an HCC diagnosis after that cure during an average 3.1 years of follow-up. While 31,543 people had cirrhosis, 67,069 did not.

People with or without cirrhosis did not differ substantially in age (average 61.6 years overall) or proportions of men (96.4% overall), whites (51.2%), blacks (38.5%), or Hispanics (3.5%). People with cirrhosis had higher bilirubin and higher albumin, but similar creatinine and hemoglobin. The cirrhosis group had a higher diabetes prevalence (44.1% vs 33.8%) but similar rates of hypertension (87.1% and 81.8%), abnormal lipids (52.1% and 51.1%), and current smoking (45.0% and 50.5%).

In people without cirrhosis, annual HCC incidence measured 0.21% 1 year after HCV cure and 0.27% 2 years after cure. Annual HCC incidence was more than 7-fold higher in people with cirrhosis—1.6% 1 year after HCV cure and 1.9% 2 years after cure.

In people virologically cured of HCV infection and with cirrhosis, risk factors for HCC included demographic variables like sex and race, viral risk factors like HCV genotype 3, and cirrhosis-related factors like longer cirrhosis duration, varices, higher bilirubin, and lower albumin, as indicated by the following hazard ratios (HR) (and 95% confidence intervals):

WITH CIRRHOSIS
Lower HCC risk in women than men:
— Women vs men at baseline: HR 0.55 (0.38-0.79, P = 0.0013)
— At 12 months: HR 0.60 (0.40-0.90, P = 0.0139)
— At 24 months: HR 0.45 (0.23-0.82, P = 0.095)

Lower HCC risk in blacks than whites
— Blacks vs whites at baseline: HR 0.80 (0.71-0.90, P = 0.0002)
— At 12 months: HR 0.86 (0.74-0.99, P= 0.0322)
— At 24 months: not significant

Higher HCC risk with HCV genotype 3 vs 1a
— HCV genotype 3 vs 1a at baseline: HR 1.45 (1.22-1.73, P < 0.0001)
— At 12 months: HR 1.47 (1.19-1.81, P = 0.0004)
— At 24 months: Not significant

Higher HCC risk with varices
— With vs without varices at baseline: HR 1.62 (1.45-1.81, P < 0.0001)
— At 12 months: HR 1.58 (1.38-1.80, P < 0.0001)
— At 24 months: HR 1.75 (1.48-2.06, P < 0.0001)

For people with virologically cured HCV infection without cirrhosis, key predictors were metabolic conditions like diabetes and hypertension and increasing FIB-4 indicating worsening fibrosis, as indicated by the following HR (and 95% confidence intervals):

WITHOUT CIRRHOSIS
Higher HCC risk with diabetes
— With vs without diabetes at baseline: HR 1.42 (1.19-1.70, P = 0.0001)
— At 12 months: HR 1.42 (1.16-1.75, P = 0.0008)
— At 24 months: HR 1.42 (1.09-1.84, P = 0.0085)

Higher HCC risk with hypertension
— With vs without hypertension at baseline: HR 2.06 (1.52-2.79, P < 0.0001)
— At 12 months: HR 2.13 (1.47-3.07, P < 0.0001)
— At 24 months: HR 1.81 (1.13-2.91, P = 0.0143)

Higher HCC risk with FIB-4 increase from low to high from baseline to 12 or 24 months
— At 12 months: HR 2.36 (1.46-3.79, P = 0.0005)
— At 24 months: HR 2.04 (1.01 to 4.10, P = 0.0455)

In the group with baseline cirrhosis, nonsmokers had a significantly lower risk of HCC than current smokers at baseline (HR 0.79, 95% CI 0.67-0.93, P = 0.005) and 12 months after HCV cure (HR 0.77, 95% CI 0.65-0.92, P = 0.0038) but not 24 months after HCV cure. Among people without baseline cirrhosis, nonsmokers did not have a significantly lower risk of HCC at baseline, 12 months after cure, or 24 months after cure when compared with current smokers.

Summing up, the researchers stressed that in people with virologically cured HCV infection, HCC risk factors differed between people with and without baseline cirrhosis. For those with cirrhosis, HCC risk factors mainly involved disease severity, while in people without cirrhosis, metabolic traits held sway as dominant risk factors.

Because risk could change from 12 months to 24 months after cure, the investigators argued that “risk assessment based on repeat measurements at 2 years is practical and can improve risk stratification in patients with virologically cured HCV, regardless of their cirrhosis status at baseline.”

Reference
1. Kramer JR, Cao Y, Li L, et al. Longitudinal associations between risk factors and subsequent risk of hepatocellular cancer in patients with hepatitis C virus infection and virological cure. AASLD, The Liver Meeting, November 12-15, 2021. Abstract 903.