Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial.
Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial.
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接种二价AS 04佐剂HPV疫苗后，非疫苗可预防的HPV类型引起的宫颈癌前病变：来自随机哥斯达黎加HPV疫苗试验的长期随访研究分析
DOI：
10.1016/s1470-2045(22)00291-1
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发表时间：
2022-07
期刊：
影响因子：
51.1
通讯作者：
Kreimer, Aimee R.
中科院分区：
文献类型：
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作者：
Shing, Jaimie Z.;Hu, Shangying;Herrero, Rolando;Hildesheim, Allan;Porras, Carolina;Sampson, Joshua N.;Schussler, John;Schiller, John T.;Lowy, Douglas R.;Sierra, Monica S.;Carvajal, Loretto;Kreimer, Aimee R.
在接种人乳头瘤病毒（HPV）疫苗的妇女中，宫颈疾病和相关程序的减少导致更多的妇女具有完整的转化区，可能增加由非疫苗可预防类型引起的宫颈病变的风险，这种现象称为“临床暴露”。我们的目的是评估HPV疫苗对宫颈上皮内瘤变2+级（CIN 2+）和宫颈上皮内瘤变3+级（CIN 3+）归因于不可预防的类型，通过接种后11年的长期随访阶段的哥斯达黎加HPV疫苗试验（CVT）的有效性。CVT是一项随机（1：1）、双盲试验，在哥斯达黎加的18-25岁女性中接种Cervarix®、二价AS 04佐剂HPV疫苗（N=3727）或对照甲型肝炎疫苗（N=3739），在0、1和6个月时肌内注射0.5 mL剂量。使用区组随机化方法生成分配序列，排列区组大小为14、16和18。在整个4年的随机试验阶段，疫苗分配保持盲态，之后对照组接受HPV疫苗并退出研究;仅筛选未接种疫苗的对照组（UCG）入组。UCG和HPV疫苗组随后随访7年，在此期间治疗分配不设盲。CVT长期随访阶段预先设定的主要终点之一是与疫苗未预防的HPV类型相关的癌前病变（主要结局1b），我们将其定义为组织学证实的归因于不可预防类型（HPV 16/18/31/33/45除外的任何类型）的CIN 2 +/CIN 3+事件。由于临床解蔽可能发生在侵袭性较低的基因型导致疾病的后期，我们的主要分析期为7-11年，即观察随访期。我们还研究了1-4年以及这两个时期的组合。每个分析阶段的合格标准包括在相应阶段至少有一次随访的所有女性，并排除了既往终点（即，改良的意向治疗队列）。对于每一个结果，女性都被随访，直到达到终点或进行宫颈手术。我们计算了终点的相对和绝对减少值以及95%置信区间（95%CI）。随机、设盲试验阶段已经完成，而HPV疫苗接种组中的一个非设盲妇女亚组仍在积极研究中（Clinicaltrials.gov，NCT 00128661，NCT 00867464）。2004年6月28日至2005年12月21日，7466名妇女参加了CVT（HPV疫苗组=3727;对照组=3739）。2009年3月30日至2012年7月5日，2 836名妇女参加了新的UCG。主要分析队列（7-11年）包括HPV疫苗组的2767名女性和UCG组的2563名女性，用于CIN 2+终点评估，HPV疫苗组的2826名女性和UCG组的2592名女性，用于CIN 3+终点评估。在7-11年期间，HPV疫苗组纳入CIN 2+分析的女性的中位随访时间为52.8个月（四分位距44.0 - 60.7），UCG组为49.8个月（四分位距42.0 - 56.9）。在7-11年期间，观察到临床揭盲，对不可预防类型的CIN 2+的显著阴性VE [−71·2%（95%CI − 164%，−12.5%）]。在11年中，我们观察到每1000名接种疫苗的妇女与未接种疫苗的妇女相比，有9.2（95%CI 0.8，17.8）例额外的CIN 2+事件归因于不可预防的类型;尽管有这种增加，我们观察到每1000名接种疫苗的妇女中，无论类型如何，CIN 2+事件都减少了27.0（95%CI 14.2，39.9）。同样，在7-11岁期间，归因于不可预防类型的CIN 3+的VE为−135%（95%CI − 330%，− 33.5%）。接种疫苗的女性与未接种疫苗的女性相比，由于不可预防的类型而导致的CIN 2 +/CIN 3+率较高，这表明在筛查人群中成功实施HPV疫苗接种计划后，揭盲可能会削弱高级别疾病的长期减少。重要的是，疫苗接种的净效益仍然相当可观，因此，HPV疫苗接种仍应优先作为宫颈癌的一级预防。CVT由国家癌症研究所（N 01-CP-11005）和国家卫生研究院妇女健康研究办公室资助。
In human papillomavirus (HPV)-vaccinated women, reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable types, a phenomenon termed “clinical unmasking”. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grades 2+ (CIN2+) and cervical intraepithelial neoplasia grades 3+ (CIN3+) attributed to non-preventable types, through 11 years post-vaccination in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT). CVT is a randomised (1:1), double-blinded trial which vaccinated women in Costa Rica aged 18-25 years with Cervarix®, the bivalent AS04-adjuvanted HPV vaccine (N=3727), or control hepatitis A vaccine (N=3739), administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. The allocation sequence was generated using a blocked randomisation method, with permuted block sizes of 14, 16, and 18. Blinding of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which controls were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group (UCG) was enrolled. The UCG and HPV-vaccine arm were then followed for seven years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase of CVT was precancers associated with HPV types not prevented by the vaccine (primary outcome 1b), which we defined as histologically-confirmed incident CIN2+/CIN3+ attributed to non-preventable types (any type except HPV16/18/31/33/45). Because clinical unmasking may occur later when less aggressive genotypes cause disease, our primary analytical period was years 7-11, the observational follow-up phase. We also examined years 1-4 and both periods combined. Eligibility criteria for each analytical period included all women with at least one follow-up visit in the respective period and excluded women with a prior endpoint (i.e., modified intention-to-treat cohort). For each outcome, women were followed until the endpoint was reached or a cervical procedure was performed. We computed relative and absolute reductions in endpoints, and 95% confidence intervals (95%CIs). The randomised, blinded trial phase has been completed while an unblinded subset of women in the HPV-vaccinated arm is still under active investigation (Clinicaltrials.gov, NCT00128661, NCT00867464). Between June 28, 2004, and December 21, 2005, 7466 women enrolled in CVT (HPV-vaccine arm=3727; control arm=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new UCG. The primary analytical cohort (years 7-11) included 2767 women in the HPV-vaccine arm and 2563 in the UCG for the CIN2+ endpoint assessment and 2826 women in the HPV-vaccine arm and 2592 in the UCG for the CIN3+ endpoint assessment. Median follow-up time during years 7-11 for women included for the CIN2+ analysis was 52·8 months (interquartile range 44·0-60·7) for the HPV-vaccine arm and 49·8 months (interquartile range 42·0-56·9) for the UCG. During years 7-11, clinical unmasking was observed with a significant negative VE against CIN2+ attributed to non-preventable types [−71·2% (95%CI −164%, −12.5%)]. Through 11 years, we observed 9·2 (95%CI 0.8, 17.8) additional CIN2+ events attributed to non-preventable types per 1000 vaccinated women versus unvaccinated women; despite this increase, we observed 27·0 (95%CI 14·2, 39·9) fewer CIN2+ events irrespective of type per 1000 vaccinated women. Similarly, VE against CIN3+ attributed to non-preventable types during years 7-11 was −135% (95%CI −330%, −33·5%). Higher CIN2+/CIN3+ rates due to non-preventable types in vaccinated versus unvaccinated women suggests unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs in screened populations. Importantly, the net benefit of vaccination remains considerable therefore, HPV vaccination should still be prioritized as primary prevention for cervical cancer. CVT is funded by the National Cancer Institute (N01-CP-11005) and National Institutes of Health Office of Research on Women's Health.