https://orcid.org/0000-0003-4324-5473
Figures
Abstract
Background
The prophylactic vaccines available to protect against infections by human papillomavirus (HPV) are well tolerated and highly immunogenic. This systematic review and meta-analysis aimed to explore the efficacy of HPV vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment.
Methods
A literature search was performed using PubMed/MEDLINE, Embase, the Cochrane Library, Scopus, Web of Science, and bioRxiv/medRxiv from inception to July 15, 2024. Randomized controlled trials (RCTs) reporting the effect of HPV vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment vs no HPV vaccination were included. The primary outcome measure was risk of recurrence cervical high-grade squamous intraepithelial lesion (HSIL) after local surgical treatment, with follow-up as reported by individual studies. Included studies were assessed for risk of bias using the Revised Cochrane risk-of-bias (RoB 2.0 tool). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated. No restrictions were applied on language, the date of publication, age, sex, and country. All analyses were carried out using the Review Manager 5 software (version 5.4).
Results
Eight RCTs (n = 3068) met the inclusion criteria. The risk of cervical HSIL recurrence was not reduced in individuals who were vaccinated compared with those who were not vaccinated (RR 0.92, 95% CI: 0.66–1.27; I2 = 40%). However, HPV vaccination reduced the risk of recurrence of cervical HSIL related to the HPV types HPV16/18, but uncertainty was large (RR 0.57, 95% CI: 0.18–1.84; I2 = 29%).
Conclusions
Adjuvant HPV vaccination after surgical excision is not associated with a reduced risk of recurrent HSIL overall or a reduced risk of recurrent lesions caused by the most oncogenic strains (HPV16/18). Therefore, HPV vaccination should not be considered for adjuvant treatment in patients undergoing surgical excision.
Citation: Cao Q, Hou Y, Wang C, Yin J (2024) Effect of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: A systematic review and meta-analysis. PLoS ONE 19(12): e0312128. https://doi.org/10.1371/journal.pone.0312128
Editor: Mehmet Demirci, Kirklareli Universitesi, TÜRKIYE
Received: August 15, 2024; Accepted: October 1, 2024; Published: December 31, 2024
Copyright: © 2024 Cao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This research was funded by grant from Science and Technology Department of Henan Province (Award Number 112102310306). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
With the vaccination of human papillomavirus (HPV) vaccines, cervical cancer prophylaxis has been revolutionized [1]. Cervical cancer could be virtually eliminated by increasing HPV vaccines coverage and efforts to improve cervical cancer screening [2]. HPV vaccines can prevent HPV infection and related diseases in children before puberty, but cannot eliminate existing lesions and are ineffective against already existing lesions caused by HPV [3–7].
Women undergoing local surgery for cervical high-grade squamous intraepithelial lesion (HSIL) have been identified as a target high-risk population, and can benefit from vaccination with adjuvant vaccines to prevent cervical cancer. Cervical HSILs are the precursor condition to cervical cancer [8]. Patients with cervical HSIL on a cervical biopsy followed by a negative conization specimen are particularly susceptible to HPV infection and may be reinfected quickly [8,9]. These women are also at high risk of recurrent cervical HSIL and other malignancies associated with HPV infection [10–12], and repeated conisations may carry an increased risk of adverse reproductive outcomes [13–16].
The VENUS study demonstrates that HPV vaccination elicits a stronger immune response than natural infection [17]. Natural immunity from induced antibodies appears to weaken with the passage of time, while it was reported that vaccines can provide protection against reinfection or reactivation in seropositive individuals with prior clearance of the infection [18–20]. This vaccination may confer beneficial effects against new infections and reinfections from the same HPV type shortly after treatment, although this effect is unlikely to promote the clearance of an established infection in isolation. The potential of the vaccine to enhance the efficacy of local surgical treatment and promote viral clearance remains unknown.
Evidence of the efficacy of vaccination against human papillomavirus after conization is inconsistent. Two randomized controlled trials (RCTs) showed a reduced recurrence rate of cervical HSIL [21,22]. However, other studies reached contrary conclusions and suggested no benefit [23–25].
This meta-analysis aimed to assess the effect of HPV vaccines on the risk of HPV infection and recurrence of preinvasive disease related to HPV infection after local surgical treatment for cervical diseases.
Materials and methods
Protocol and registration
This systematic review was registered with the International prospective register of systematic reviews (PROSPERO, CRD42024512507), and was conducted in strict accordance with the recommendations of the Cochrane Handbook [26] and the updated Preferred Reporting Items for Systematic Reviews of Interventions (PRISMA) guidelines [27].
Eligibility criteria
When the outcomes of the same studies were reported in different publications, the study with the largest sample size was enrolled in this meta-analysis. Inclusion criteria were predetermined and organized in accordance with the PICOS acronym: Participants (P): patients with cervical HSIL who have undergone local surgical treatment; Intervention (I): HPV vaccine; Control (C): no HPV vaccine; Outcomes (O): recurrence of cervical HSIL after local surgery related to HPV; recurrence of cervical LSIL, and cervical HSIL related to HPV16/18 types; and HPV infections after treatment; and Study design (S): included only RCTs. Cohort studies, matched case-control series, reviews, and studies lacking of information on outcomes, were excluded. No restrictions were imposed on language, the date of publication, age, sex, and country.
The study included all RCTs that reported HPV infection rates or recurrence of diseases related to HPV infection after local surgery for genital diseases related to HPV in vaccinated individuals. And only those studies that also reported the results of an unvaccinated cohort as control group were enrolled in this review. No restrictions were imposed on language, region, publication time, participant demographics, or publication status. Studies were enrolled independent of surgical technique, type of vaccine, and timing of vaccination.
Search strategy
A comprehensive literature search was conducted in PubMed/Medline, EMBASE, the Cochrane Library databases, Scopus, Web of Science, and bioRxiv/medRxiv (from inception to July 15, 2024). Two independent reviewers (QXC and JTY) formulated the search strategy and screened the studies. The Cochrane-validated filter for randomized controlled trials was applied [28]. The search strategy was adjusted based on descriptors in each database. In addition, references of all included studies were also manually searched to determine any potentially qualified studies.
Study screening and selection
Two authors (Q.X.C. and C.Y.W.) performed independently the screening and selection of the studies. The inconsistencies were resolved by a third author (J.T.Y.). The first step was to import the research papers from the designated database into EndNote X20 and deleted the duplicate items. After excluding irrelevant studies by evaluating their titles and abstracts, the full texts of the studies were read. If the information of studies located in databases was incomplete, the corresponding author was contacted by data extractors (J.T.Y. and C.Y.W.) via email for relevant information.
Data extraction
If the studies met the eligibility criteria, data were extracted by two independent investigators (Q.X.C. and C.Y.W.) in a prespecified data extraction form. The data extraction form included the following items: the first author’s name, the publication year, the region in which the study was conducted, the mean age of the participants, type of vaccine, Vaccination timing, Follow-up duration, outcomes, recurrence, and associated factors were all included in the data extraction form.
Quality assessment
Risk of bias was evaluated by two investigators independently (QXC and CYW) according to the updated Cochrane risk-of-bias tool (RoB-2.0 tool) for randomized controlled trials [29,30]. Disagreements between investigators were discussed or solved by a third investigator (JTY).
Definitions of outcomes
The primary outcome was recurrence of cervical HSIL after local surgery related to HPV. Secondary outcomes included cervical HSIL related to HPV16/18 types, recurrence of cervical LSIL, and HPV infections after treatment.
Statistical analysis
The data from randomized controlled trials were pooled, which reported the effect of vaccination shortly before, at the time of, or within 12 months after the local surgery. We used crude data for the primary outcome, and sensitivity and subgroup analyses.
We estimated each pooled effect size by using risk ratio (RR) and corresponding 95% confidence interval (CI) with a fixed- or random- effect model based on the Mantel-Haenszel method [31]. Statistical heterogeneity was evaluated using the χ2 test (P<0.10) and was quantified using I2 [32,33].
When more than 10 studies reported a certain outcome, visual inspection of the funnel plot and Egger’s test were used to evaluate the effects of publication bias [34]. The method of “trim and fill” was adopted to assess the effect of publication bias if publication bias was detected.
To identify possible sources of heterogeneity, a leave-one-out sensitivity analysis [31] was conducted for the primary outcome (risk of recurrence of cervical HSIL after local surgery). A series of subgroup analyses were also carried out to identify sources of heterogeneity and differences in pooled estimates for the primary outcome (risk of recurrence of cervical HSIL after local surgery) based on timing of vaccination (up to three months before vs at the time of or up to 12 months after treatment) and vaccine type (Cervarix vs Gardasil vs Gardasil-9). All statistical analyses were carried out with the Review Manager 5 software (version 5.4).
Results
Characteristics of the included studies
There were 11362 studies were identified. All of them were screened for inclusion by title and abstract assessment, and 10 full-text articles were screened for eligibility. No other studies were retrieved from the reference lists of enrolled studies. Of these, 2 were ruled out because of the study design (not RCT) [35,36]. Thus, 8 studies with 3068 participants, all peer-reviewed studies, met the criteria for inclusion and were included into the review (Fig 1; Table 1) [21,22,24,25,37–40]. All of the 8 studies were assessed as low risk of bias according to the revised Cochrane RoB-2.0 tool (Fig 2).
AIN anal intraepithelial neoplasia, CIN cervical intraepithelial neoplasia, CKC cold knife conisation, HPV human papilloma virus, HSIL high-grade squamous intraepithelial neoplasia, ICC invasive cervical cancer, LLETZ large loop excision of the transformation zone, LSIL low-grade squamous intraepithelial neoplasia, MSM men who have sex with men, N/A not applicable, RCT randomised controlled trial, VIN/VaIN vulvar intraepithelial neoplasia/vaginal intraepithelial neoplasia.
Recurrence of cervical HSIL
The analysis for risk of recurrence of cervical HSIL after local surgery showed that no significant difference was observed in RR of cervical HSIL recurrence between vaccinated participants at the time of treatment and unvaccinated participants (6 studies, 1376 participants; RR 0.92, 95% CI: 0.66–1.27, I2 = 40%) (Fig 3). Sensitivity analysis (one-by-one elimination method) showed that all of the six results remained statistically no significant (Table 2).
Subgroup analysis was conducted based on type of vaccine. No significant difference in RR of recurrence of cervical HSIL between the two groups in studies that used the Cervarix vaccine (three studies, 838 participants; RR 1.60, 95% CI: 0.68–3.78, I2 = 38%), the Gardasil vaccine (two studies, 352 participants; RR 0.53, 95% CI: 0.07–4.23, I2 = 58%), or the Gardasil-9 vaccine (one studies, 187 participants; RR 0.67, 95% CI: 0.36–1.24; Fig 4).
Another subgroup analysis was carried out by timing of vaccination. Vaccination before treatment did not reduce the risk of recurrence of cervical HSIL, (2 studies, 685 participants; RR 1.23, 95% CI: 0.15–10.10, I2 = 67%; Fig 5A), nor did vaccination at the time of or after treatment reduce the risk of cervical HSIL recurrence despite the high degree of uncertainty (4 studies, 692 participants; RR 0.81, 95% CI: 0.57–1.15; I2 = 12%; Fig 5B).
A, Before the treatment. B, At the time or after the treatment.
Recurrence of cervical HSIL related to HPV16/18
HPV vaccination did not reduce the risk of cervical HSIL recurrence related to HPV16/18 (4 studies, 1050 participants; RR 0.57, 95% CI: 0.18–1.84, I2 = 29%; Fig 6).
Recurrence of cervical LSIL
No significant difference in RR of cervical LSIL recurrence between participants who were vaccinated at the time of treatment and unvaccinated participants (four studies, 853 participants; RR 1.20, 95% CI: 0.88–1.64, I2 = 18%; Fig 7).
Publication bias
The funnel plot exhibited no asymmetry of studies examining HSIL recurrence for the assessment of publication bias, which indicates that there was no publication bias detected in our study (Fig 8).
Discussion
The findings of this review indicate that adjuvant HPV vaccination at the time of local excision for cervical intraepithelial neoplasia (CIN) cannot reduce the risk of recurrence of cervical HSIL or LSIL. Moreover, HPV vaccination cannot reduce the risk of recurrence of cervical HSIL related to the HPV16/18. In studies that used the vaccine Cervarix, Gardasil, or Gardasil-9 respectively, no significant difference was shown in RR of recurrence of cervical HSIL between the two groups. Vaccination before treatment did not reduce the risk of recurrence of cervical HSIL, nor did vaccination at the time of or after treatment reduce the risk of cervical HSIL recurrence. Therefore, HPV vaccination should not be considered for adjuvant treatment in patients receiving local surgical treatment. The potential reasons for the observed lack of efficacy include differences in the timing of vaccination, the participants studied, or the nature of surgical treatment, which may also be the reason for heterogeneity.
To the best of our knowledge, our study is the first meta-analysis of RCTs to evaluate the effect of adjuvant HPV vaccination on the risk of cervical HSIL recurrence in individuals treated with local surgery. Whilst CIN2/3 is widely accepted as a surrogate marker for cervical cancer vaccine efficacy in studies of prophylactic or therapeutic HPV vaccines [41,42], and is generally be incorporated in HSIL according to the Bethesda System for Reporting Cervical Cytology (TBS), it is a poor predictor of progression [43,44]. After implementation of the new guidelines, conservative management became more frequent, and is now used for more than half of women with CIN2 [44]. Therefore, in this review, we chose recurrence of cervical HSIL rather than CIN2/3 after local surgical treatment as the primary outcome.
Up to now, there have been eight meta-analyses attempting to pool the evidence [45–52]. However, our findings on pooled estimates were in inconsistent with the outcomes of these meta-analyses, and our analysis sparked worries about data quality. All of the eight studies focused primarily on the CIN2/3 recurrence after local surgery, rather than cervical HSIL. Additionally, these studies included case control and cohort studies in addition to randomized controlled trials.
Our meta-analysis comprehensively assessed the effect of adjuvant HPV vaccination after surgical excision for cervical and other non-cervical diseases related to HPV infection, and rigorously assessed the risk of bias and heterogeneity. This analysis only enrolled RCTs in which vaccines were administered at the time of or after local surgery, which made potential inaccurate assessment of effect estimates eliminated and lowered heterogeneity. We examined the quality of the studies enrolled in our meta-analysis using the updated Cochrane RoB 2.0 tool. We also assessed the publication bias in this meta-analysis, and conducted analyses irrespective of HPV type and analyses for HPV16/18. We also performed two subgroup analyses based on timing of vaccination and type of vaccine. The results of which were basically consistent with the overall effect, proving the robustness of the conclusions.
However, the findings of our study should be interpreted with caution, as this study also has several limitations. Firstly, vaccinated participants might be younger than unvaccinated individuals, and the increased risk of disease recurrence may be partly due to older age. Secondly, confounding factors (such as smoking and drinking) that are associated with a higher risk of recurrence were not controlled in some studies. Thirdly, in each study, participants were vaccinated at different time points before or after local treatment for cervical intraepithelial neoplasia. Fourthly, the time period during which the enrolled studies were conducted might lead to bias because the staging system, terms and definitions may change with the passage of time. The enrolled studies were carried out over a long period, and populations can be recruited using the Bethesda or recently evolving ASCCP terminology. Finally, variability in length of follow-up (follow-ups of all the 8 enrolled studies were 24–64 months), diagnostic methods, timing of HPV vaccination, and type of HPV vaccine across studies might affect the accuracy of the effect estimates. The risk of cervical HSIL recurrence was lower with a median follow-up of >24 months, despite large uncertainty. Although the most frequent recurrence occurred within the first 24 months [53], the uneven length of follow-up is inherent defect of this study and similar studies; moreover, future disease episodes may not be associated with the originally, treated disease and confound estimates of (potential) vaccine impact. Therefore, large scale, high quality randomized controlled trials with follow-up ≥24 months are needed to provide more definitive evidence for the effect of HPV vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment.
Conclusions
In conclusion, adjuvant HPV vaccination after local surgical treatment for CIN is not associated with a reduced risk of HSIL recurrence overall or a reduced risk of recurrent lesions due to the most carcinogenic strains (HPV16/18). Therefore, HPV vaccination should not be considered for adjuvant treatment in patients receiving local surgical treatment.
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