研究目的

在近三十年里，全球肝癌疾病负担持续下降，但是不同国家/地区间疾病负担的时间趋势存在明显差异。本论文第一部分进一步探索了其区域异质性及其潜在的驱动因素，预测了未来肝癌的疾病负担。随后，本论文第二部分针对全球最主要的肝癌致癌因素——感染性因素，以中国为例，基于经过校准的模型，量化既往干预措施的影响，并研究进一步加强肝癌防控措施对未来负担的影响。最后采用卫生经济学分析，评价其成本-效果及成本-效用。

材料与方法

1. 全球肝癌疾病负担的流行趋势及预测研究。基于2019年全球疾病负担研究数据库，提取204个国家或地区1990-2019年肝癌疾病负担数据。采用增长混合模型（growth mixture models, GMMs）分析不同国家近三十年来肝癌负担时间趋势的异质性。并基于识别出来的趋势亚组，探讨五个主要的肝癌危险因素在肝癌负担变化中所起的作用及不同亚组间的社会经济水平差距。随后采用贝叶斯年龄-时期-队列模型进一步预测了未来2035年的肝癌负担。

2. 中国肝癌预防策略研究。基于第一部分的结果，针对感染性因素这一最主要的肝癌危险因素，本论文以中国这一肝癌负担最为沉重的国家（占全球总负担的40%左右）为研究地区，系统综合现有最新研究证据，分别构建乙肝（hepatitis B virus, HBV）和丙肝（hepatitis C virus, HCV）确定性、动态、年龄分层数学模型。模型根据HBV/HCV相关的健康状态及年龄将人群分为上千个健康状态，并在每个年龄别的健康状态中均模拟了HBV/HCV感染的传播、进展和治疗以及相关终末期肝病的发生发展。模型选用年龄别的HBsAg阳性率、HCV RNA阳性率及肝癌死亡率作为校准目标，采用杂交算法系统搜索参数空间，以寻找最佳拟合值集。随后，基于经过校准的模型，以1950年至2100年中国全部人群为研究对象，模拟病毒性肝炎的传染过程，预测病毒性肝炎相关疾病负担的未来趋势，评估中国近期干预措施改善（HBV抗病毒治疗适应症的扩大及DAAs的引入）带来的影响；其次通过设置不同的干预情景，评价进一步扩大干预覆盖率的效果。最后，本研究采用卫生经济学分析，从医疗卫生体系视角进行成本效果和成本效用分析。

研究结果

1.不同国家/地区间肝癌疾病负担趋势差距显著。全球肝癌年龄标化发病率/死亡率总体呈现下降趋势，而全球发病/死亡人数呈现先上升后下降再上升的趋势。根据GMMs结果，不同国家/地区间肝癌的年龄标化发病率/死亡率时间趋势差异显著，可分为三个亚组，即上升组、稳定组和下降组。大多数国家和地区其肝癌年龄标化发病率及死亡率均被归类为稳定组，而近一半的美洲国家被归入下降组，上升组则在欧洲地区最为常见。

2. 不同趋势亚组间的主要危险因素及社会经济水平存在差异。在下降组中，HBV慢性感染率降低是疾病负担下降的主要驱动因素，HBV相关肝癌发病/死亡率的下降幅度占总的肝癌发病/死亡率下降幅度的63.4%和60.4%。在上升组中，饮酒、HCV慢性感染和HBV慢性感染对其上升趋势的贡献最大。在社会经济水平方面，相较于下降及稳定组，处于上升组的国家和地区其社会人口指数（Socio-demographic Index, SDI）、人均国内生产总值（Gross Domestic Product, GDP）、人均卫生支出和全民健康覆盖服务覆盖指数均远高于另外两组（P值均小于0.05）。

3. 全球肝癌负担的不平等性在未来仍会持续存在。预测结果显示，至2035年上升组发病/死亡率的上升趋势将会得到遏止，但下降组的下降趋势将会消失，在2035年前下降组的发病率及死亡率一直保持三组中的最高。而发病及死亡人数则在所有亚组中均会持续攀升。就国家层面来看，中国（归为下降组）在2019-2035年间仍将是全球肝癌发病及死亡人数最多的国家，感染性因素是其主要的肝癌危险因素。

4. 中国慢性肝炎相关疾病负担虽迅速下降，但仍处于较高水平。如果维持现在的肝炎防治现状不变，中国慢性肝炎感染人数将从2023年的8094万下降至2046年的3926万，23年间下降一半以上。慢性肝炎相关肝癌年龄标化发病率、年龄标化死亡率也随之下降。近期HBV抗病毒治疗适应症的扩大及DAAs的引进将挽救151.3万人的肝炎相关死亡（其中包括96.5万的肝癌相关死亡）。但是，以慢性肝炎相关肝癌为代表的终末期肝病未来仍将是威胁中国人民健康的重要因素，中国将在2040年迎来慢性肝炎相关肝癌死亡的高峰期（29.1万）。截止至2100年，肝炎感染将导致2263.3万死亡（其中包括1330.9万的肝癌死亡）。

5.加强抗病毒治疗能进一步降低疾病负担，助力消除慢性肝炎及其相关肝癌。在2030年前对40%的病例进行抗病毒治疗（后续达到80%），可以挽救795.0万死亡（其中包括396.4万肝癌死亡），如果在2030年就实现80%的抗病毒治疗覆盖率，则将进一步挽救166.6万死亡（其中包括79.0万肝癌死亡），但由于中国慢性HBV感染人群庞大，即使在该情景下，HBV感染死亡率也只能在2081年才能下降至WHO设定的目标（4/10万），而HCV感染死亡率将于2046年达到WHO设定的目标（2/10万），感染相关肝癌年龄标化发病率将于2046年下降至4/10万以下，且于2056年下降至2.5/10万以下。

6. HBV、HCV抗病毒治疗具有良好的成本效用。卫生经济学分析结果显示，扩大HBV、HCV抗病毒治疗覆盖率均具有良好的卫生经济学效益，而于2030年达到WHO设定的目标覆盖率（80%）能进一步降低挽救一个质量调整生命年（quality-adjusted life-year，QALY）所需的成本。如果能在2030年实现80%的慢性肝炎抗病毒治疗覆盖率，HBV、HCV抗病毒治疗的增量成本效果比（incremental cost-effectiveness ratio，ICER）分别为7648美元/QALY和721美元/QALY。

研究结论

在过去三十年中，全球不同国家/地区间肝癌负担的时间趋势存在明显差异。下降组的肝癌负担虽然经历了大幅度的下降，但仍高于其他两组。且在2035年前，这种巨大的差距仍将持续存在。此外，下降组其社会经济水平及卫生资源情况远逊于上升组，如何在这种资源有限的地区进行肝癌防控是如今亟待解决的现实问题。中国是下降组中一个典型的国家，慢性病毒性肝炎感染是其最主要的致癌因素。因此对慢性肝炎感染人群进行积极的治疗和筛查是我国目前主要的肝癌防控策略。近些年来，中国在慢性肝炎治疗领域取得了重大进步，但以肝癌为代表的终末期肝病死亡负担仍将持续增加至2036年。通过更广泛的病例发现和抗病毒治疗，能够扭转死亡负担的上升趋势，且具有良好的成本效益。值得注意的是，随着未来慢性病毒性肝炎感染率的进一步下降，非感染性危险因素在肝癌防控领域的重要性也将愈加凸显，在此社会经济转型之际，对其进行积极控制也必不可少。

Objectives

The global burden of liver cancer disease has decline over the last three decades, but large disparities exist in liver cancer burden trends across countries. In the first part of this study, we aimed to explore the heterogeneity in the liver cancer burden trend, identify its potential drivers and predict the future liver cancer burden through 2035. Subsequently, the second part of this study focused on the world's most important liver cancer carcinogens (infectious factors), taking China as an example, quantifying the impact of previous intervention measures, and studying the impact of further strengthening liver cancer prevention and control measures on the future burden. Moreover, we used health economic evaluation to access its cost-effectiveness and cost-utility.

Materials and Methods

1. Study on the epidemiological trend of liver cancer burden: Data on the liver cancer burden in 204 countries and territories from 1990 to 2019 were extracted from the Global

Burden of Disease Study. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) trajectories were defined using growth mixture models. Based on the identified trajectories, we explored the contributions of the five main liver cancer risk factors in the changing burden of liver cancer and the disparity in socio-economic levels between the different trajectories A Bayesian age–period–cohort model was used to predict future trends through 2035.

2. Study on prevention strategy for liver cancer in China: Through the results of the first part, chronic viral hepatitis was the most important risk factor for liver cancer in the world and China (the country with the heaviest burden of liver cancer). We developed deterministic, dynamic, age-structured mathematical models for HBV and HCV, respectively. The models categorized the population into thousands of health states based on HBV/HCV-related health status and age, and simulated the transmission, progression, and treatment of chronic HBV/HCV infections and the development of end-stage liver disease in each age-specific health state. Age-specific HBsAg prevalence, HCV RNA prevalence, and liver cancer mortality were selected as calibration targets for the model, and the parameter space was systematically searched using a hybridization algorithm to find the best-fit set of values. Subsequently, based on the calibrated model, we simulated the transmission process of chronic viral hepatitis from 1950 to 2100 in the Chinese population, predicted the future viral hepatitis burden and assessed the impact of previous interventions (expansion of HBV antiviral treatment indications and introduction of DAAs) and the effect of further expansion of treatment interventions by setting up different intervention scenarios. Further, we conducted health economic evaluation to evaluate its cost-effectiveness and cost-utility from a healthcare perspective.

Results

1. Large disparities existed in the burden trend of liver cancer between different countries/regions. The global ASIR and ASDR of liver cancer showed a downward trend, while the number of new cases and deaths displayed an upward trend in the initial period, followed by a rapid decreasing and then an increasing trend. According to the results of GMMs, global disparities were observed in liver cancer burden trajectories, which can be classified into three subgroups, i.e., the increasing group, the stable group and the decreasing group. Most countries and territories followed stable ASIR and ASMR trajectories. Almost half of the American countries were classified in the decreasing group, and the increasing group was the most common in the European region.

2. Differences in major risk factors and socio-economic levels were found between the different trajectories. In the decreasing group, the decrease of liver cancer due to hepatitis B contributed 63.4% and 60.4% of the total decreases in ASIR and ASMR, respectively. The increase of liver cancer due to alcohol use, hepatitis C, and hepatitis B contributed the most to the increase in the increasing group. The increasing group was associated with a higher sociodemographic index, gross domestic product per capita, health expenditure per capita, and universal health coverage (all P <0.05).

3. The inequality of the burden of global liver cancer will continue into the future. According to the projected results, by 2035, increasing trends in this group were expected to ease in the next decade. Unfortunately, the ASIR and ASMR of the decreasing group were predicted to remain at their current elevated levels. Before 2035, the incidence and mortality rates of the decreasing group will consistently exhibit the highest levels among the three groups. The absolute number of new cases and deaths would continue to increase in all subgroups. At the national level, China (both incidence and mortality rates are classified as declining group) would still be the country with the largest number of liver cancer new cases and deaths in the world from 2019 to 2035, and infectious factors are its main liver cancer risk factors.

4. The burden of chronic hepatitis-related disease in China, although declining rapidly, is still at a high level. If the coverage of all interventions remained at their current levels, the number of chronic hepatitis infections in China would decrease from 80.94 million in 2023 to 39.26 million in 2046, a reduction of more than half in 23 years. ASIR and ASDR of chronic hepatitis-associated liver cancer would decrease as well. The recent expansion of indications for initiating HBV antiviral therapy and the introduction of interferon-free direct-acting antivirals (DAAs) would avert 1.51 million hepatitis-related deaths (including 965,000 liver cancer-related deaths). However, end-stage liver disease, represented by chronic hepatitis-related liver cancer, would remain a nonnegligible threat to the health of the Chinese people in the future, and the peak of chronic hepatitis-related liver cancer deaths would be observed in 2040 (291,000). By 2100, hepatitis infection would cause 22.63 million deaths (including 13.31 million liver cancer deaths).

5. Strengthening antiviral therapy can further reduce the disease burden and contribute to the elimination of chronic hepatitis and its associated liver cancer. Initiating antiviral treatment for 40% of chronic hepatitis infection patients before 2030 (80% in the follow-up) could save 7.95 million deaths (including 3.96 million liver cancer deaths), and if 80% antiviral treatment coverage was achieved in 2030, a further 1.67 million deaths (including 790,000 liver cancer deaths) would be saved. However, due to the large number of people with chronic HBV infection in China, even in this scenario, the mortality rate associated with HBV infection cannot be reduced to WHO’s target set (4/100,000) until 2081, while the mortality rate of HCV infection would reach the WHO’s target (2 per 100,000) in 2046. Age-standardized incidence rate for infection-associated liver cancer would fall to less than 4 per 100,000 in 2046 and to less than 2.5 per 100,000 in 2056.

6. Antiviral treatment for HBV and HCV is cost-effective. Results of health economic evaluation showed that expanding the coverage of HBV and HCV antiviral treatment had good health economic benefits, and reaching the coverage target set by the WHO as early as possible can further reduce the cost of saving one quality-adjusted life-year (QALY). If 80% antiviral treatment coverage for chronic hepatitis can be achieved in 2030, the incremental cost-effectiveness ratio (ICER) of antiviral treatment for HBV and HCV would be US$ 7648/QALY and US$ 721/QALY respectively.

Conclusions

Over the past three decades, there have been marked disparities in the temporal trends of liver cancer burden among different countries / regions. The burden of liver cancer in the decreasing group, although it has experienced a substantial decrease in the last three decades, is still highest among three groups. And this large gap will continue to exist until 2035. In addition, the socio-economic level and health resources of the decreasing group are much lower than those of the increasing group, so how to prevent and control liver cancer in this resource-limited setting is a crucial problem. China is a typical country in the decreasing group, where chronic viral infections are the most important hepatocellular carcinogenic factors. In recent years, China has made significant progress in the field of chronic hepatitis control, but the death burden from end-stage liver disease will continue to increase until 2036. The rising trend of the death burden can be reversed through active case finding and antiviral therapy, which is cost-effective. It is worth noting that as the prevalence of chronic viral hepatitis infections declines further, the importance of non-infectious risk factors in the field of liver cancer control will rise, and active control of these factors is essential in this period of rapid socioeconomic transition.