目的

我国有8600万HBV感染者和980万HCV感染者，是乙肝和丙肝高负担国。虽然目前临床上已经具备效果良好的抗病毒治疗手段，但根据估计，我国乙肝和丙肝抗病毒治疗率低，距离实现2030年消除病毒性肝炎公共卫生危害的目标仍有很大差距。现阶段，我国缺少全国层面和省级层面乙肝和丙肝抗病毒治疗监测体系，不能准确、及时了解抗病毒治疗情况，存在感染者主动筛查和转介就诊机制尚不成熟，整合的医疗服务体系不完善，尚未形成闭环管理，公众对疾病认识不足等问题。本研究拟借助已有的全国31（30）个省的药物利用数据库，推算乙肝和丙肝标准化抗病毒治疗人数，可填补现阶段国家及省级层面乙肝和丙肝抗病毒治疗情况监测数据的空白。根据不同时期标准化治疗人数的变化，对旨在促进乙肝和丙肝抗病毒治疗的药物政策进行效果评价，探索药物政策外医疗卫生体系相关影响因素，为有针对性地促进抗病毒治疗循证决策提供依据。此外，通过政策文件和文献学习其他国家消除病毒性肝炎公共卫生危害的先进经验。

方法

借助艾昆纬（IQVIA）中国医院药品审计报告（China Hospital Pharmacy Purchase Audit, CHPA）系统，得到全国31个省份乙肝（2013-2021年）和30个省份丙肝（2017-2021年）抗病毒治疗药物利用数据。根据药品说明书以及乙肝和丙肝防治指南，将药品消耗量数据转化为乙肝和丙肝标准化抗病毒治疗人数，并分别建立面板数据库。基于以上数据库开展以下研究：

①全国及省级层面标准化抗病毒治疗人数时间趋势描述性分析和抗病毒治疗药品使用情况描述性分析；②采用普通最小二乘回归，发现标准化治疗人数变化显著年份，识别促进抗病毒治疗效果显著的政策；③采用多时点双重差分法，评估国家组织药品集中采购和使用试点及其扩围区域范围（4+7试点及扩围）政策实施对乙肝标准化抗病毒治疗人数的平均影响效应，结合事件研究法评估其动态效应；④采用间断时间序列分析法，评估2020年1月首批三种丙肝直接抗病毒治疗药品纳入国家谈判药品目录和2021年3月首批自主研发丙肝抗病毒治疗药品纳入国家谈判药品目录先后实施对丙肝标准化抗病毒治疗人数影响效应；⑤采用间断时间序列分析法，分析2016年首批国家药品谈判和2019年4+7试点及扩围政策先后实施在省级层面对乙肝标准化抗病毒治疗人数影响效应；⑥采用工具变量法评估居民健康素养对乙肝抗病毒治疗的影响效应；⑦基于潜类别轨迹模型，探讨丙肝标准化抗病毒治疗人数增长模式及其影响因素。

结果

①乙肝和丙肝标准化抗病毒治疗人数逐年增加，乙肝治疗人数从2013年103.22万人增加到2021年的321.55万人，丙肝治疗人数在2020年前处于较低水平，2020年及之后迅速上升，2021年度累积标准化治疗49592人。②从2018年开始后，乙肝标准化抗病毒治疗人数显著增加，相比于2018年前，2018年后乙肝标准化抗病毒治疗人数增加14.74%（0.1474=e^0.1375-1，P=0.004），2019年后治疗人数增加34.35%（0.3435=e^0.2953-1，P<0.001），2020年后增加29.87%（0.2987=e^0.2614-1，P=0.006），但2021年乙肝治疗人数增加并不显著。③4+7试点及扩围后，乙肝标准化治疗人数平均增加42.35%（0.4235=e^0.3531-1，P<0.001），动态效应在33.22%（0.3322=e^0.2868-1，P<0.001）到53.65%（0.5365=e^0.4295-1，P<0.001）间波动。⑤首批3个DAAs组合纳入国家医保当月，丙肝标准化抗病毒治疗人数增加3668人；该政策实施后，标准化治疗人数增长速率增加551人/月，政策对丙肝标准化治疗人数存在瞬时和长期影响，但暂未发现2021年3月国产DAAs纳入国家医保后对治疗人数存在瞬时效应或长期趋势影响。⑥各省份居民健康素养随时间每增加1%，乙肝标准化治疗人数增加7.15%（0.0715=e^0.0691-1，P<0.001）。⑦潜类别轨迹模型将30省丙肝标准化治疗人数增长趋势分为高、中、低治疗水平三类，可能与各省经济发展水平、疾病负担相关。

结论

近年来在我国一系列医药卫生政策推动下，乙肝和丙肝抗病毒治疗人数持续增加，2019年和2020年尤为显著，但仍远低于应治患者80%的目标。4+7试点及扩围和通过国家谈判将抗病毒治疗药物纳入医保目录政策使药品降价明显，显著增加抗病毒治疗人数。乙肝NAs已经降至国际最低水平，国产丙肝DAAs尚未形成与进口产品的有力竞争，对经济困难群体的安全网制度有待进一步筑牢。在当前药品价格较低的背景下，提升基层医疗机构诊疗水平，发挥其在消除病毒性肝炎公共卫生危害中的作用，完善筛查、诊断、治疗、随访和监测系统，形成整合的医疗服务体系是下一步应该努力的方向。此外，提升居民健康素养水平，做好宣传教育工作在消除病毒性肝炎中起到重要作用。

Objective

China has 86 million HBV-infected and 9.8 million HCV-infected individuals, making it a high burden country for viral hepatitis B and C. Although effective antiviral treatments are available, it is estimated that the treatment rate for both diseases is low in China, and there is a large gap to achieve the goal of eliminating viral hepatitis as a public health threat by 2030. Currently, China lacks a national and provincial-level monitoring system for antiviral treatment of hepatitis B and C, which makes it difficult to accurately and timely understand the situation of antiviral treatment, and there is an immature mechanism for voluntary screening and referral of infected individuals, an incomplete integrated healthcare system without a closed-loop management, and insufficient public awareness of these diseases. This study aims to use existing medicines utilization databases from all 31(30) provinces to estimate the number of patients receiving antiviral treatment for hepatitis B and C, and to fill the data void on treatment monitoring at national and provincial levels. Furthermore, this study evaluates the effectiveness of medicines policies aimed at promoting antiviral treatment for hepatitis B and C based on changes in standardized treatment numbers over different periods of time, and explores other factors in the healthcare system that may affect antiviral treatment numbers in order to provide evidence-based policy recommendations for promoting targeted antiviral treatment. Additionally, lessons can be learned from policy documents and literature on how other countries have eliminated the public health hazards of viral hepatitis.

Methods

Using the China Hospital Pharmacy Purchase Audit (CHPA) system from IQVIA, we obtained data on the consumption of nucleoside/nucleotide analogues (NAs) for HBV (2013-2021) and direct acting antivirals (DAAs) for HCV (2017-2021) in 31 and 30 provinces, respectively. Based on the drug instructions and HBV and HCV prevention and treatment guidelines, medication consumption data were converted into standardized antiviral treatment numbers for HBV and HCV and panel database were created. Based on the above databases,

1) descriptive analysis of the time trends of antiviral medicines usage and standardized antiviral treatment numbers at the national and provincial levels;

2) using ordinary least squares regression (OLS) to identify significant years of change in standardized treatment numbers to identify effective policies;

3) evaluating the average impact of the implementation of nationwide adoption of the ‘4 + 7’ pilot-pooled procurement prices on standardized antiviral treatment numbers for HBV using multi-time-point double-difference, combined with event research to evaluate their dynamic effects;

4) using interrupted time series (ITS) analysis to evaluate the effects of the implementation of the first batch of three DAAs for HCV in the national insurance list in January 2020 and the first batch of self-developed HCV DAAs f in the national insurance list in March 2021 on standardized antiviral treatment numbers for HCV;

5) using ITS analysis to evaluate the effects of the implementation of the first national medicines negotiation policy in 2015 and the 4+7 pilot-pooled procurement policy in 2019 on standardized antiviral treatment numbers for HBV at the provincial level;

6) using instrumental variable analysis to evaluate the impact of residents' health literacy on HBV antiviral treatment;

7) using latent class trajectory models to explore the growth patterns of HCV antiviral treatment numbers and their influencing factors.

Results

(1). The number of standardized antiviral treatment for both hepatitis B and C has increased year by year. The antiviral treatment numbers of hepatitis B has increased from 1.03 million in 2013 to 3.22 million in 2021. The antiviral treatment numbers of hepatitis B was low before 2020 but has rapidly increased since then, with 49,592 receiving standardized treatment in 2021.

(2). The number of standardized antiviral treatments for hepatitis B significantly increased after 2018, with a 14.74% (0.1474=e^0.1375-1, P=0.004) increase in treatment numbers after 2018 compared to before, a 34.35% (0.3435=e^0.2953-1, P<0.001) increase after 2019, and a 29.87% (0.2987=e^0.2614-1, P=0.006) increase after 2020. However, the increase in treatment numbers in 2021 was not significant.

(3). After the 4+7 pilot-pooled procurement, the average increase in number of hepatitis B treatment was 42.35% (0.4235=e^0.3531-1, P<0.001), and the dynamic effect fluctuated from 33.22% (0.3322=e^0.2868-1, P<0.001) to 53.65% (0.5365=e^0.4295-1, P<0.001).

(4). The inclusion of the first three DAAs combinations in the national medical insurance increased the number of standardized treatments for hepatitis C by 3,668 people. The policy had an immediate and long-term positive impact on the number of antiviral treatment for hepatitis C, but no significant effect was observed after the inclusion of domestically produced DAAs in March 2021.

(5). For every 1% increase in health literacy among residents in each province, the number of hepatitis B patients receiving treatment increased by 7.15% (0.0715=e^0.0691-1, P<0.001).

(6). The latent class trajectory model divided the growth trend of number of standardized treatment for hepatitis C in 30 provinces into three classes: high-, medium-, and low-level of treatment, which may be related to the economic development level and disease burden of each province.

Conclusion

In recent years, under a series of healthcare policies in China, the number of standardized antiviral treatment for hepatitis B and C has continued to increase, with significant increases in 2019 and 2020. However, the treatment rate is still far below the goal that 80% of patients who should be treated. The 4+7 pilot-pooled procurement and the inclusion of antiviral medicines in the national medical insurance policy have significantly increased the number of antiviral treatment. The price of NAs has nearly reached lowest level all of world, but domestically produced DAAs have not formed strong competition with imported products and need to strengthen safety net systems for economically disadvantaged groups. In the current context of low price of medicines, improving the diagnosis and treatment level of primary medical institutions, and forming an integrated medical service system to eliminate the public health risks of viral hepatitis through screening, diagnosis, treatment, follow-up, and monitoring are the next steps to be taken. In addition, improving the level of health literacy among residents and doing a good job of publicity and education play an important role in eliminating viral hepatitis.