HPV16/18二价疫苗预防宫颈癌前病变的Meta分析

Meta-analysis in human papillomaviruses 16/18 bivalent vaccine against cervical precancer

目的评价人乳头状瘤病毒(human papillomaviruses,HPV)16/18二价疫苗在预防宫颈HPV16/18相关感染和癌前病变的作用,对预防接种人群提出合理化建议。方法通过Web of science搜索引擎搜索MEDLINE、Web of Science核心合集、BIOSIS Previews等数据库,通过Endnote X9 Online Search搜索EBSCO数据库,通过Cochrane Library搜索Cochran Central Register of Controlled Trials(CENTRAL)数据库。另外,通过www.clinicaltrials.gov临床试验平台获取相关文献和数据。搜索的英文主题词或关键词包括HPV16/18、bivalent vaccine、cervical neoplasm和clinical trial。采用Review manager 5.3评估HPV16/18二价疫苗接种的近期和远期疗效、可靠性、危险度和统计偏倚,并根据结果做预防接种管控分析。结果总计纳入了2004-2017年19篇英文文献报告的10个临床随机研究结果,40066例受试者进入Meta分析。在HPV阴性的健康女性受试者中,接种HPV16/18二价疫苗者与对照组相比HPV16/18相关宫颈偶发性感染(incident infection)、6个月和12个月的持续性感染(persistent infection,PI)相对风险(relative risk,RR)分别降低68%~78%、82%~94%和84%~97%;HPV16/18相关宫颈不典型鳞状细胞-意义未明及以上(ASC-US+)、宫颈上皮内瘤变1级及以上(CIN1+)和2级及以上(CIN2+)的患病RR分别降低89%~94%、87%~91%和87%~92%;任何HPV相关ASC-US+、CIN1+、CIN2+、CIN3+和原位癌(AIS)的患病RR,分别降低28%~29%、50%、64%~72%、86%~93%和93%。在健康女性受试者中,不管入组时HPV DNA状态如何,与对照组相比,接种二价疫苗至少降低1次HPV16/18相关ASC-US+、CIN1+、CIN2+、CIN3+和AIS患病RR,分别为57%、50%、45%、34%和70%;任何HPV表型相关CIN1+、CIN2+、CIN3+和AIS的患病RR降低,分别为26%~28%、28%~33%、34%~45%和77%。结论二价疫苗对于基线时没有感染HPV的年轻女性宫颈偶发性和持续性感染以及宫颈癌前病变具有良好的保护作用。即使对于HPV暴露的不同风险人群,二价疫苗对于降低宫颈癌前病变和原位癌的患病风险也有一定的作用。

Objective To evaluate human papillomaviruses(HPV)16/18 bivalent vaccine protection against cervical infection and precancer associated with HPV 16/18,thus providing a reasonable suggestion for vaccination population.Methods Clinical trials and data were retrieved from search engine of Web of science,Endnote X9 online search,Cochran Central Register of Controlled Trials(CENTRAL)and www.clinicaltrials.gov using topic words or key words consisting of HPV 16/18,bivalent vaccine,cervical neoplasm,clinical trial.Meta-analysis was conducted using Review manager 5.3 to assess the efficacy of HPV 16/18 bivalent vaccine against HPV infection and cervical precancer.Relative risks and statistical bias were also analyzed.Results Ten randomized trials(more than 40000 cases)reported in 19 articles from 2004 to 2017 were identified.When young HPV-negative women at enrollment were vaccinated with three doses of(ATP-naive)or at least one dose(total vaccinated cohort-naive,TVC-naive)HPV16/18 bivalent vaccine compared with control women,relative risks of cervical incident infection,6-month persistent infection(PI)and 12-month PI associated with HPV16/18 were reduced by 68%-78%,82%-94%and 84%-97%,respectively;relative risks to develop cervical atypical squamous cell of undetermined significance and above(ASC-US+),cervical intraepithelial neoplasia of grade 1 and above(CIN1+)and CIN2+associated with HPV16/18 infection were reduced by 89%-94%,87%-91%and 87%-92%,respectively.As compared with control women,relative risks of TVC-naive to develop ASC-US+,CIN1+,CIN2+,CIN3+and adenocarcinoma in situ(AIS)irrespective of infection with HPV types were reduced by 28%-29%,50%,64%-72%,86%-93%and 93%,respectively.When young women regardless of HPV and DNA status at enrollment were vaccinated with at least one dose(TVC-E)of HPV16/18 bivalent vaccine compared with control women,relative risks to develop ASC-US+,CIN1+,CIN2+,CIN3+and AIS associated with HPV 16/18 infection were reduced by 57%,50%,45%,34%and 70%,respectively;relative risks to develop ASC-US+,CIN1+,CIN2+,CIN3+and AIS irrespective of infection with HPV types were reduced by 57%,50%,45%,34%and 70%,respectively.Conclusion HPV 16/18 bivalent vaccine provides excellent protection against both cervical HPV incident and persistent infection,as well as cervical precancer in HPV-negative young women.Even in people with different risks of HPV exposure,HPV16/18 bivalent vaccine has certain effect on reducing relative risks of cervical precancer and even carcinoma in situ.