Department of Metabolism, Digestion, and Reproduction and Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
BMJ. 2022 Aug 3;378:e070135. doi: 10.1136/bmj-2022-070135.
To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment.
Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021.
Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals.
22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I=58%, τ=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I=0%, τ=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I=71%, τ=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low.
HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection.
PROSPERO CRD42021237350.
探讨人乳头瘤病毒（HPV）疫苗接种对接受局部手术治疗的个体 HPV 感染风险和 HPV 感染相关疾病复发的疗效。
系统评价和荟萃分析。
从建库到 2021 年 3 月 31 日，PubMed（Medline）、Scopus、Cochrane、Web of Science 和 ClinicalTrials.gov 进行了筛选。
纳入了报道 HPV 感染风险和 HPV 感染相关疾病复发的研究，这些研究的对象是接受局部治疗的有生育能力的女性，在接种疫苗后发生侵袭性生殖器疾病。主要结局测量指标为局部手术后宫颈上皮内瘤变 2 级或以上（CIN2+）的复发风险，随访时间由各研究报告。次要结局测量指标为 HPV 感染或其他与 HPV 感染相关的病变的风险。分别对观察性研究和随机对照试验采用 ROBINS-I 和 RoB-2 工具进行独立和重复的数据提取和质量评估。采用推荐评估、制定和评估（GRADE）对主要结局进行分级。从事后分析的随机对照试验中对观察性研究和随机对照试验进行了单独分析。采用随机效应荟萃分析模型计算风险比和 95%置信区间。使用受限极大似然估计作为异质性的估计器，使用 Hartung-Knapp-Sidik-Jonkman 方法得出置信区间。
22 篇文章符合综述的纳入标准；其中 18 篇还报告了未接种疫苗组的数据，并纳入了荟萃分析（12 篇观察性研究、2 篇随机对照试验和 4 篇事后分析的随机对照试验）。与未接种疫苗的个体相比，接种疫苗的个体的 CIN2+复发风险降低（11 项研究，19909 名参与者；风险比 0.43，95%置信区间 0.30 至 0.60；I=58%，τ=0.14，中位随访时间 36 个月，四分位间距 24-43.5）。当评估与 HPV 亚型 HPV16 或 HPV18 相关的疾病的 CIN2+复发风险时，效应估计值甚至更强（6 项研究，1879 名参与者；风险比 0.26，95%置信区间 0.16 至 0.43；I=0%，τ=0）。通过 GRADE 评估，CIN2+总体和与 HPV16 或 HPV18 相关的 CIN2+的荟萃分析的置信度范围从低到中等，可能是因为发表偏倚和荟萃分析中纳入的研究不一致。疫苗接种也降低了 CIN3 的复发风险，但不确定性很大（3 项研究，17757 名参与者；0.28，0.01 至 6.37；I=71%，τ=1.23）。尽管每个结局的研究和参与者数量较少，但缺乏对阴道、外阴和肛门上皮内瘤变、生殖器疣和持续性及新发 HPV 感染的复发的证据。
HPV 疫苗接种可能降低接受局部切除治疗的女性的 CIN 复发风险，特别是与 HPV16 或 HPV18 相关的 CIN 复发风险。GRADE 评估表明，数据尚无定论。需要开展大规模、高质量的随机对照试验，以确定 HPV 疫苗接种在治疗 HPV 感染相关疾病的女性中的有效性和成本效益。
PROSPERO CRD42021237350。
