研究目的

1. 立足中国宫颈癌防控现状与世界卫生组织（WHO）“90-70-90”战略目标的差距，评估中国按不同时间或速度开展全国性人乳头瘤病毒（HPV）疫苗接种和宫颈筛查项目的成本效果，量化延迟实施疫苗接种和宫颈筛查项目的健康和经济影响。

2. 面对九价HPV疫苗供应受限的现实条件，在考虑九价HPV疫苗产量满足全国接种需求的时间、可能的混合疫苗接种程序的情况下，评估中国女性从接种二价HPV疫苗转为接种九价HPV疫苗的成本效果，探索最优的疫苗转换策略。

研究方法

本研究采用HPV动态传播-宫颈癌自然史模型模拟在不同宫颈癌防控策略下中国女性的终生宫颈癌发病和死亡数、卫生效果、经济支出以及宫颈癌消除时间，从全社会视角评价各宫颈癌防控策略的成本效果。卫生效果用质量调整寿命年（QALY）表示，计算增量成本效果比（ICER）判断成本效果最优的策略。两部分研究纳入评估的策略分别如下：

1. 延迟实施全国性HPV疫苗接种和宫颈筛查项目的健康和经济影响：共纳入70种备选宫颈癌防控策略，即10种不同年份启动的全国性HPV疫苗接种策略与7种不同筛查方法、不同覆盖率增长速度的筛查策略的联合策略。疫苗策略包括从2022年开始接种、延迟1-8年接种（即分别从2023-2030年开始接种，8种策略）、以及维持现状的不接种策略。筛查策略包括分别以快、中、慢速推广的以HPV检测为基础、或以液基细胞学（LBC）为基础的筛查，以及维持现状的筛查策略。

2. 中国HPV疫苗从二价转向九价的卫生经济学研究：假设九价疫苗的产量将在2030-2050年满足全国接种需求，之后可以全国性接种九价疫苗。在不同的九价疫苗产量满足全国接种需求的年份（2030、2035、2040、2045、2050年）及不同的筛查背景（维持现状筛查、覆盖率提升的HPV筛查）下，评价5种单一疫苗接种策略和2种混合疫苗接种策略：1）不接种疫苗；2）立即接种二价疫苗；3）二价转九价疫苗；4）等待接种九价疫苗；5）等待接种九价疫苗并补接种；6）不限制接种间隔的二价和九价疫苗混合接种转九价疫苗；7）限制接种间隔为5年的二价和九价疫苗混合接种转九价疫苗。

研究结果

1. 延迟实施全国性HPV疫苗接种和宫颈筛查项目的健康和经济影响：无论接种何种类型的HPV疫苗，2022年立即开展全国性HPV疫苗接种项目，并快速推广以HPV为基础的宫颈筛查（即在2030年实现70%的筛查覆盖率）的不延迟策略，是成本最低且效果最优的策略。与当前防控策略相比，这一策略可以在中国2022-2100年期间生活的女性一生中避免1,480万-1,580万宫颈癌新发病例和575万-611万宫颈癌死亡病例，节省217亿-277亿美元的经济支出，而且可以让中国在2059-2063年消除宫颈癌。全国性HPV疫苗接种项目的延迟实施、筛查方法未转变为高质量的HPV检测、筛查覆盖率目标的延迟实现，均将导致较大的宫颈癌疾病负担和经济损失。与不延迟策略相比，筛查不延迟、疫苗接种延迟8年预计将增加43.4万-54.3万宫颈癌新发病例和13.8万-17.8万宫颈癌死亡病例，增加28.6亿-44.4亿美元的经济支出，并使宫颈癌消除时间推迟9-10年。与不延迟策略相比，即使在2022年立即实施全国性疫苗接种，但如果筛查方法不转变为HPV筛查并将筛查覆盖率推迟至2070年达到70%，这将在我国增加253万-306万宫颈癌新发病例和90.9万-104万宫颈癌死亡病例，增加50.98亿-57.14亿美元的经济支出，而且在接种较低价次的国产二价疫苗或进口四价疫苗的情况下，这一策略无法在本世纪末消除宫颈癌（2100年的年龄标准化发病率为4.09-4.21/10万女性）。

2. 中国HPV疫苗从二价转向九价的卫生经济学研究：无论何种筛查背景、九价疫苗何时开始接种，与维持接种二价HPV疫苗相比，转为接种九价HPV疫苗都将降低本世纪末宫颈癌发病率并节省成本（维持现状筛查：发病率降低50.57%-64.26%，节省25.89亿-52.11亿美元；覆盖率提升的HPV筛查：发病率降低52.81%-63.59%，节省18.52亿-37.89亿美元）。当仅考虑单一疫苗接种策略时，如果九价疫苗能够在2030年开始全国接种，最优策略为从该年开始常规接种九价疫苗并补接种至18岁，其健康效果和经济效益略高于二价转九价疫苗策略，明显高于等待接种九价疫苗策略；如果九价疫苗在2035年及之后才能开始接种，等待接种九价疫苗并补接种策略的健康效果和经济效益明显下降，最优策略变为立即接种二价疫苗随后转为九价疫苗。与维持接种二价疫苗相比，上述最优策略将在生活在2023-2100年的女性一生中额外避免79.1万-374万宫颈癌新发病例和28.0万-148万宫颈癌死亡病例，节省18.52亿-54.60亿美元的经济支出，并挽救23.7万-176万个QALY。当混合接种两种不同疫苗可被接受时，不论九价疫苗何时开始接种，最优接种策略均为不限制接种间隔的二价和九价疫苗混合接种转九价疫苗策略。与上述单一疫苗接种策略中的最优策略相比，这种混合疫苗接种策略将进一步避免5.9万-106万宫颈癌新发病例和1.9万-43.9万宫颈癌死亡病例，节省13.36亿-42.80亿美元的经济支出，并挽救8.7万-83.3万个QALY。

研究结论

在不同时间和速度开展的宫颈癌防控策略中，不延迟策略，即2022年立即开展全国性HPV疫苗接种，并快速推广HPV筛查且在2030年实现70%的筛查覆盖率，是成本最低且效果最优的策略，该策略预计能让中国在2059-2063年消除宫颈癌。延迟开展HPV疫苗接种、筛查方法未转变为高质量的HPV检测、筛查覆盖率提升延迟均会在宫颈癌发病、死亡、消除时间、经济成本方面造成较大的损失，这强调了尽早启动和扩大全国性HPV疫苗接种和以HPV检测为基础的宫颈筛查项目的紧迫性。对于各种疫苗接种策略，在九价HPV疫苗尚不满足全国接种需求的阶段，与等待接种九价疫苗相比，立即接种二价疫苗更具有成本效果，提示我国应当优先保障适龄女孩二价疫苗的供应和接种；在此阶段如果可接受HPV疫苗混合接种，最优接种策略为常规年龄接种1剂次二价疫苗并延迟接种1剂次九价疫苗。当九价HPV疫苗满足全国接种需求时，立即转为接种九价疫苗比维持接种二价疫苗能够节省成本。

Objectives

1. Based on the gap between current status of cervical cancer prevention in China and the “90-70-90” strategic targets of World Health Organization (WHO), to assess the cost-effectiveness of implementing national human papillomavirus (HPV) vaccination and cervical screening programs in China at different initiation time and scale-up pace, then to quantify the health and economic impacts of delaying HPV vaccination and screening implementation.

2. In the face of the limited availability of the nonavalent HPV vaccine, to assess the cost-effectiveness of switching from a bivalent to a nonavalent HPV vaccination program in China and to explore the optimal vaccination strategy during the transition time, taking into account the year when nonavalent HPV vaccine is available in sufficient quantities for national vaccination, and the potential inclusion of mixed vaccination schedules.

Methods

A transmission dynamic model was used to project the lifetime cervical cancer cases and deaths, effectiveness, costs, and timeline for cervical cancer elimination of alternative cervical cancer prevention strategies among Chinese women. The cost-effectiveness analysis of alternative strategies was evaluated from a societal perspective. The effectiveness was evaluated using quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER) was calculated to identify the optimal strategy. The strategies included in the two sections were as follows:

1. Health and economic impacts of delaying a national HPV vaccination and screening program: 70 alternative cervical cancer prevention strategies were included, consisting of the combination of 10 vaccination initiation strategies with 7 screening strategies differing in screening modalities and coverage. Vaccination strategies included vaccination initiated in 2022, vaccination delayed by 1-8 years (i.e., vaccination initiated in 2023-2030, respectively), as well as vaccination never initiated. Screening strategies included rapid, moderate, and gradual scale-up of screening using HPV testing or liquid-based cytology (LBC), as well as status quo screening.

2. Cost-effectiveness analysis of switching from a bivalent to a nonavalent HPV vaccination program in China: Sufficient quantities of nonavalent HPV vaccine were assumed to be available for national vaccination between 2030 and 2050, after which national nonavalent HPV vaccination can be initiated. Under different years when nonavalent HPV vaccine is available (2030, 2035, 2040, 2045, and 2050) and screening scenarios (maintaining status quo screening, and improved HPV-based screening), we evaluated five mono-vaccine strategies and two mixed-vaccine strategies: (1) no vaccination; (2) maintaining bivalent HPV vaccination; (3) switching from bivalent to nonavalent HPV vaccination; (4) waiting for nonavalent HPV vaccination; (5) waiting for nonavalent HPV vaccination with a catch-up; (6) a mixed schedule of bivalent and nonavalent HPV vaccination without restriction on the interval between two doses, with a switch to nonavalent HPV vaccination; (7) a mixed schedule of bivalent and nonavalent HPV vaccination with restriction of a 5-year maximum interval between two doses, with a switch to nonavalent HPV vaccination.

Results

1. Health and economic impacts of delaying a national HPV vaccination and screening program: Regardless of vaccine type, immediate national HPV vaccination initiated in 2022 and rapid scale-up of HPV-based screening to achieve 70% coverage in 2030 (no-delay strategy) would be the least costly and most effective strategy. Compared with the status quo strategy, the no-delay strategy would avert 14.8-15.8 million cervical cancer cases and 5.75-6.11 million deaths, and save $21,700-27,700 million net costs over the lifetime of Chinese women who lived in 2022-2100. This no-delay strategy would also allow China to eliminate cervical cancer by 2059-2063. Any of the three scenarios respectively involving delays in the initiation of national HPV vaccination, no switch of screening to high-performance HPV testing, and slower increases in screening coverage would result in increased disease burden and net costs. Compared with the no-delay strategy, delaying vaccination by 8 years would result in 434,000-543,000 additional cervical cancer cases, 138,000-178,000 deaths, and $2,863-4,437 million costs, and delay elimination by 9-10 years. Even with immediate vaccination initiated in 2022, the gradual scale-up of LBC-based screening to 70% coverage in 2070 would result in 2.53-3.06 million additional cervical cancer cases, 0.909-1.04 million deaths, and $5,098-5,714 million costs compared with no delay strategy, and could not achieve elimination if domestic bivalent or imported quadrivalent HPV vaccines are used (4.09-4.21 cases per 100,000 woman in 2100).

2. Cost-effectiveness analysis of switching from a bivalent to a nonavalent HPV vaccination program in China: Regardless of the nonavalent HPV initiation years and the screening scenarios, compared with maintaining bivalent HPV vaccination, switching to nonavalent HPV vaccination would always reduce cervical cancer incidence in 2100 and be cost-saving (maintaining status quo screening: 50.57%-64.26% reduction in incidence, net cost saving $2,589-5,211 million; improved HPV-based screening: 52.81%-63.59% reduction in incidence, net cost saving $1,852-3,789 million). In the mono-vaccine strategies, if the nonavalent HPV vaccination was initiated in 2030, the optimal strategy was waiting for nonavalent HPV vaccination with a catch-up to age 18. This strategy would result in slightly higher health and economic benefits than switching from bivalent to nonavalent vaccination, and substantially higher benefits than waiting for nonavalent vaccination without a catch-up. If the nonavalent HPV vaccination was initiated after 2035, nonavalent HPV vaccination with a catch-up would result less health and economic benefits, and the optimal strategy became immediate bivalent HPV vaccination with a switch to nonavalent HPV vaccination. Compared with maintaining bivalent HPV vaccination, the above optimal strategies would avert 0.79-3.74 million additional cervical cancer cases and 0.28-1.48 million deaths, save $1,852-5,460 million net costs, and gain 0.24-1.76 million QALYs over the lifetime of women who lived in 2023-2100. When administering two different HPV vaccines to the same individual is acceptable, regardless of the nonavalent HPV initiation years, the optimal strategy was the mixed-vaccine strategy without restriction on the interval between two doses, with a switch to nonavalent HPV vaccination. Compared with the optimal strategy in the mono-vaccine strategies, this mixed-vaccine strategy would further avert 59,000-1,060,000 cervical cancer cases and 19,000-439,000 deaths, save $1,336-4,280 million net costs, and gain 87,000-833,000 QALYs.

Conclusions

In alternative cervical cancer prevention strategies at different initiation time and scale-up pace, the no-delay strategy, i.e., immediate national HPV vaccination initiated in 2022 and rapid scale-up of HPV-based screening to achieve 70% coverage in 2030 was least costly and most effective, which could allow China to eliminate cervical cancer by 2059-2063. Delays in national HPV vaccination, no switch of screening to high-performance HPV testing, and slower increases in screening coverage have detrimental consequences for cervical cancer morbidity, mortality, expenditure, and timeline for cervical cancer elimination. These findings emphasize the urgency of early implementation and scale-up of national HPV vaccination and HPV-based screening. For various vaccination strategies, when nonavalent HPV vaccine was not available in sufficient quantities for national vaccination, prompt administration of currently available bivalent vaccine is cost-effective compared with waiting for the nonavalent HPV vaccine. This suggests that achieving high bivalent HPV vaccine coverage among young girls should be given priority. If the mixed schedules were acceptable, the optimal strategy was the mixed-vaccine strategy of one-dose bivalent vaccine at routine age and one-dose delayed nonavalent vaccine. When nonavalent HPV vaccine was available in sufficient quantities for national vaccination, immediate switching to nonavalent HPV vaccination was cost-saving compared with maintaining bivalent HPV vaccination.