Globally, cervical cancer is one of the most common cancers among women. Fifteen high-risk human papillomavirus (HPV) oncogenic types are known to cause cervical cancer.1,2 3 4,5
Human papillomavirus vaccination has been shown to be both cost-effective and successful in preventing persistent HPV infection,6 7 8 9 10
The ASCCP has developed consensus management guidelines for the treatment of cervical dysplasia. For women younger than age 30 years with a histologic diagnosis of cervical intraepithelial neoplasia (CIN) 2 or greater, excision (eg, loop electrosurgical excision, cold knife conization), ablation (eg, cervical cryotherapy, laser ablation), or conservative management are acceptable treatment modalities; for women aged 30 years or older, either excision or ablation are recommended.11 12
Recent studies suggest that adjuvant HPV vaccination may help to prevent recurrence of CIN 2 or greater, vulvar intraepithelial neoplasia (VIN), and genital warts. In a 2012 post hoc analysis of a randomized trial, Joura et al found that adjuvant HPV vaccination was associated with a 64.9% reduced risk of recurrent CIN 2 or greater, and a 46.2% reduction of all HPV-related disease.13 14
DATA SOURCES
With the assistance of a librarian, electronic databases including Cochrane, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov
This meta-analysis was conducted according to the methods described in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for reporting systematic reviews and meta-analyses of randomized controlled trials.15
Details of the review protocol were registered on PROSPERO, an international database of prospectively registered systematic reviews, and can be accessed at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=135870
STUDY SELECTION
We searched for randomized controlled trials and cohort studies on HPV vaccination in the setting of treatment (loop electrosurgical excision procedure [LEEP], conization, and cryosurgery therapy) for CIN 2 or greater. We included studies in which women undergoing surgical treatment received at least one dose of an intradermal, intracervical, or intramuscular HPV-16,18 targeted vaccine, licensed to-date, within 48 months prior-to or after surgical treatment. All included studies had both treatment and control, or placebo groups, comparing the intervention. Exclusion criteria included studies in which participants had invasive disease, immunodeficiency, or autoimmune conditions; were on systemic corticosteroids other than inhaled corticosteroids or prednisone 10 mg or less (or equivalent); or were pregnant or less than 3 months postpartum or breastfeeding. Additionally, studies were excluded whose intervention included experimental vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin within 60 days before study entry.
All published studies that were deemed suitable were retrieved and reviewed using Covidence software. Two reviewers independently screened titles and abstracts. When discrepancies arose between reviewers, a third team member served as a third adjudicator and a final decision. Reviewers used a similar process for data extraction and to evaluate studies' risk of bias. Data were extracted and input into Covidence. In several cases, study authors were contacted to obtain, confirm, and clarify data. Additionally, Refworks was used throughout the review process for reference management.
Determination of whether to perform a meta-analysis was based on qualitative assessment of reasonably comparable study populations and interventions. We presumed that, if studies met our inclusion criteria, the outcome of recurrent cervical disease would be comparable across studies. Clinical, methodologic, and statistical evidence of heterogeneity was assessed and was considered in the assessment to do a meta-analysis. A pairwise meta-analysis was performed comparing adjuvant HPV vaccination compared with surgical excision alone. In deciding whether to present summary relative risk (RR) estimates, clinical and methodologic sources of heterogeneity across studies were considered. The Q statistic, the I 2 and the Tau-squared were used for statistical heterogeneity; for the Q statistic, a critical value of less than 0.1 was used; for the I 2 statistic, I 2 values of 25–50%, 51–75% and 76–100% signified low, moderate and high heterogeneity respectively.16 P value for the Cochrane Q statistic less than 0.1), the random-effects model of Der-Simonian and Laird was used to obtain the pooled RR estimate.
Study quality was evaluated using both the Cochrane Risk of Bias tool to evaluate randomized studies,17 18
The ROBINS-I tool includes seven domains broken into three parts: preintervention, at intervention, and postintervention. In the preintervention domain, bias owing to confounding and participant selection were evaluated. We identified possible preintervention confounding factors to include age, race, ethnicity, comorbidities, immune status, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), tobacco use, HPV strain (ie, 16,18), HPV vaccine type (bivalent, quadrivalent, or nonavalent), and vaccine manufacturer. Bias “at intervention” stems from misclassification of interventions (surgery alone vs surgical therapy plus HPV vaccination). We also identified bias “at intervention” to include the time lapse from surgery to administration of the HPV vaccine, as well as time between vaccinations. Postintervention biases included: deviations from intended interventions, missing data, measurement of outcomes, selection of the reported result, time to follow-up, patients lost to follow-up, and process for monitoring recurrence of disease. In the end, the risk of bias in each category was categorized as low, high, or unclear.
The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) tool was used as a framework to assess quality of evidence presented in our study for each outcome. The quality of evidence was based on five factors: 1) limitations of detailed design and execution (risk of bias criteria), 2) inconsistency or heterogeneity between studies, 3) indirectness (Patient, Problem, or Population; Intervention; Comparison or Control; Outcome [PICO] and applicability),19 20
The primary outcome of interest for this meta-analysis is the proportion of women who have recurrence of CIN 2 or greater within 6–48 months of treatment, irrespective of HPV type. We selected CIN 2 or greater as the primary outcome of interest, because CIN 2 or greater is widely accepted as a surrogate marker for vaccine efficacy in studies of prophylactic HPV vaccines against cervical cancer.21
Although both the ASCCP and the American College of Obstetricians and Gynecologists support the use of the LAST (Lower Anogenital Squamous Terminology) guidelines, the majority of studies included in this analysis used CIN terminology, and this was therefore used for consistency. For the purpose of this meta-analysis, studies reporting high-grade squamous intraepithelial lesions (HSIL) were categorized as CIN 2 or greater. Secondary outcomes included the incidence of low-grade intraepithelial lesion (CIN 1 or greater), incidence of recurrent CIN lesions associated with HPV16,18, clearance of HPV, VIN and vaginal intraepithelial neoplasia, and the development of HPV-related genital warts. Data for CIN 1 or greater included all cases reported to be of severity CIN 1 or greater, thus including low-grade squamous intraepithelial lesions, HSIL, CIN 2, and CIN 3.
RESULTS
Our initial search identified 5,928 bibliographic references stemming from the five electronic databases and Clinical Trails.gov 22,23 ClinicaTrials.gov 24 25 Fig. 1 ).
Fig. 1.: Flow of identification, screening and eligibility, and inclusion. HPV, human papillomavirus.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
The main characteristics of the studies included in the review are summarized in Table 1 . Of the studies included there was: one randomized controlled trial, two prospective case–control trial, one retrospective pooled analysis of two randomized controlled trials, one post hoc analysis of a prospective cohort, and one subgroup analysis of a community-based randomized trial. Studies included were conducted in Italy, Costa Rica, the United States, the Republic of Korea, and one was international, occurring in 14 different countries. All studies had both intervention (HPV vaccination) and comparison (placebo or hepatitis A vaccine) groups. Two studies vaccinated women with the bivalent HPV-16,18 AS04-adjuvanted vaccine (CervarixVR, GSK) Vaccines)13,26 14,27–29
Table 1.: Studies Included in the Meta-analysis and Systematic Review
Table 1-A.: Studies Included in the Meta-analysis and Systematic Review
Six studies reported on the incidence of CIN 2 or greater and CIN 1 or greater, comparing patients who underwent surgical resection with adjuvant HPV vaccination and those who underwent surgical resection plus placebo or hepatitis A vaccination, for a total of the 2,984 women. One randomized trial and one nonrandomized trial recorded events of CIN 3, and four studies specifically evaluated the recurrence of lesions that were positive for HPV 16,18 at the time of recurrence. Human papillomavirus testing for HPV 16,18 was performed in the research setting only to determine clearance of these specific HPV types. Of the four studies that evaluated recurrence of HPV 16,18 lesions, two studies vaccinated women with the quadrivalent vaccine,15,29 28,30 28 13
Only a single study reported on incidence of VIN and genital warts.13
Two studies14,26 14 26 26
Using the Cochrane Risk of Bias tool, the randomized trials were found to have an overall high risk of bias (Fig. 2 ). The studies were determined to have a high risk of selection bias because randomization occurred at entry into the main trial and not at the time of LEEP. Both studies were assessed to have appropriate concealment and blinding of participants and personnel. The studies were determined to have high rates of reporting bias owing to deviations from prespecified outcomes in the protocol. Lastly, other bias was determined based on the design of the study—one was a post hoc analysis and the other a subgroup analysis. We deemed these to have a higher risk of bias owing to the fact that these analyses were not prespecified at the time of the original randomized trial.
Fig. 2.: A . Cochrane risk of bias summary: review authors' judgments about each risk of bias item for each included randomized study. B . Cochrane risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
Using the ROBINS-I tool,18 Fig. 3 ). Regarding the risk for confounding, studies were all noted to have a high risk of bias as confounders were not controlled with randomization. In regard to bias stemming from the measurement of the intervention, all studies had a low risk of bias as all were dichotomous interventions. For studies without a protocol, the bias owing to deviations from intended interventions was unclear.
Fig. 3.: A . Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) risk of bias summary: review authors' judgments about each risk of bias item for each included nonrandomized study. B . ROBINS-I risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
In total, six studies were included in the meta-analysis for a pooled total of 2,984 women. The women included in the studies were between the ages of 15 and 45. Of all women included, 1,360 (45.6%) received adjuvant HPV vaccination and 1,624 (54.4%) received either a placebo hepatitis A vaccine 806 (59.3%), or surgical management alone 554 (40.7%). The summary of evidence for each outcome of interest and the magnitude of effect is summarized in Table 2 .
Table 2.: Summary of Findings: Efficacy of Adjuvant Human Papillomavirus Vaccination vs Placebo or Control for Prevention of Recurrent High-Grade Cervical Intraepithelial Neoplasia After Surgical Excision*
All six studies reported on recurrence of cervical CIN 2 or greater within 6–48 months after treatment. Of the 2,984 women included in the pooled analysis, CIN 2 or greater occurred in 115 women (3.9%) total. In the vaccinated group, CIN 2 or greater recurrence occurred in 26 women (1.9%); in the unvaccinated group, CIN 2 or greater recurrence occurred in 89 women (5.5%) (RR 0.36 95% CI 0.23–0.55)—Figure 4 . Three studies reported a significant risk reduction of CIN 2 or greater, and another two studies reported a nonsignificant risk reduction among women treated with adjuvant vaccination. One study reported a higher risk of recurrence.27
Fig. 4.: Forest plot of the risk of cervical intraepithelial neoplasia 2 or greater recurrence with comparison of human papillomavirus (HPV) vaccination vs control (irrespective of HPV type). I2 statistic represents the interstudy heterogeneity as a proportion of the total heterogeneity. I2 values of 25–50%, 51–75%, and 76–100% signified low, moderate, and high heterogeneity, respectively. Risk of bias for randomized trials: A indicates random sequence generation (selection bias), B indicates allocation concealment (selection bias), C indicates blinding of outcome assessment (performance bias), D indicates blinding of outcome assessment (detection bias), E indicates incomplete outcome data (attrition bias), F indicates selective reporting (reporting bias), and G indicates other bias. Risk of bias for nonrandomized trials: A indicates bias due to confounding, B indicates biases in selection of participants into the study, C indicates bias in classification of interventions, D indicates bias due to deviations from intended interventions, E indicates bias due to missing data, F indicates bias in measurement of the outcome, and G bias in selection of the reported results. M-H, Mantel-Haenszel.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
On examining the incidence of CIN 1 or greater within 6–48 months among women who received adjuvant vaccination compared with those who underwent surgery alone, (plus placebo hepatitis A vaccine), a reduction in recurrent CIN 1 or greater was also noted for those who underwent surgery with adjuvant vaccination. There was a pooled total of 243 events of CIN 1 or greater, with 86 in the patients who received adjuvant vaccination (6.3%) and 157 in the patients who did not receive adjuvant HPV vaccination (9.7%). Overall, adjuvant vaccination was associated with a 33% reduction in the risk of CIN 1 or greater in the vaccinated group (RR 0.67 95% CI 0.52–0.85)—Figure 5 . All six studies reported on the risk of recurrent CIN 1 or greater in HPV vaccinated and unvaccinated patients; three studies reported a significant risk reduction of CIN 1 or greater, and another two studies reported a nonsignificant risk reduction among women treated with adjuvant vaccination. One study reported a higher risk of recurrence.27
Fig. 5.: Forest plot of the risk of cervical intraepithelial neoplasia 1 or greater recurrence with comparison of human papillomavirus (HPV) vaccination vs control (irrespective of HPV type). I2 statistic represents the interstudy heterogeneity as a proportion of the total heterogeneity. I2 values of 25–50%, 51–75%, and 76–100% signified low, moderate, and high heterogeneity, respectively. Risk of bias for randomized trials: A indicates random sequence generation (selection bias), B indicates allocation concealment (selection bias), C indicates blinding of outcome assessment (performance bias), D indicates blinding of outcome assessment (detection bias), E indicates incomplete outcome data (attrition bias), F indicates selective reporting (reporting bias), and G indicates other bias. Risk of bias for nonrandomized trials: A indicates bias due to confounding, B indicates biases in selection of participants into the study, C indicates bias in classification of interventions, D indicates bias due to deviations from intended interventions, E indicates bias due to missing data, F indicates bias in measurement of the outcome, and G bias in selection of the reported results. M-H, Mantel-Haenszel.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
Two studies recorded events of CIN 3 within 6–48 months after surgical treatment. Among the 1,137 women followed in these two studies, 496 women were vaccinated and 641 received a control or placebo. There were 17 total events (1.5%) of subsequent CIN 3 across both studies. There were three events (0.6%) in the vaccinated group, and 14 events (2.2%) in the unvaccinated cohort. Overall, there was a 68% reduction of CIN 3 in the vaccinated group (RR 0.32 95% CI 0.10–1.02)—Figure 6 .
Fig. 6.: Forest plot of the risk of cervical intraepithelial neoplasia 3 recurrence with comparison of human papillomavirus (HPV) vaccination vs control (irrespective of HPV type). I2 statistic represents the interstudy heterogeneity as a proportion of the total heterogeneity. I2 values of 25–50%, 51–75%, and 76–100% signified low, moderate, and high heterogeneity, respectively. Risk of bias for randomized trials: A indicates random sequence generation (selection bias), B indicates allocation concealment (selection bias), C indicates blinding of outcome assessment (performance bias), D indicates blinding of outcome assessment (detection bias), E indicates incomplete outcome data (attrition bias), F indicates selective reporting (reporting bias), and G indicates other bias. Risk of bias for nonrandomized trials: A indicates bias due to confounding, B indicates biases in selection of participants into the study, C indicates bias in classification of interventions, D indicates bias due to deviations from intended interventions, E indicates bias due to missing data, F indicates bias in measurement of the outcome, and G bias in selection of the reported results. M-H, Mantel-Haenszel.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
Four studies specifically evaluated the recurrence of lesions that were positive for HPV 16,18 at the time of recurrence. There was a pooled total of 35 events of HPV 16,18 CIN 2 or greater. Nine occurred in women who received adjuvant vaccination (0.9%) and 26 occurred in those who did not receive the vaccine (2.0%). There was a statistically significantly reduction in recurrence of HPV 16,18 related CIN 2 or greater (RR 0.41 95% CI 0.20–0.85) (Fig. 7 ). There were 49 events of HPV 16,18 related CIN 1 or greater; 11 in those vaccinated (1.1%) 38 in those unvaccinated (3.1%). There was also a statistically significant reduction in recurrence of HPV 16,18 related CIN 1 or greater (RR 0.35 95% CI 0.18–0.67) (Fig. 8 ).
Fig. 7.: Forest plot of the risk of cervical intraepithelial neoplasia 2 or greater recurrence with comparison of human papillomavirus (HPV) vaccination vs control (HPV 16,18). I2 statistic represents the interstudy heterogeneity as a proportion of the total heterogeneity. I2 values of 25–50%, 51–75%, and 76–100% signified low, moderate, and high heterogeneity, respectively. Risk of bias for randomized trials: A indicates random sequence generation (selection bias), B indicates allocation concealment (selection bias), C indicates blinding of outcome assessment (performance bias), D indicates blinding of outcome assessment (detection bias), E indicates incomplete outcome data (attrition bias), F indicates selective reporting (reporting bias), and G indicates other bias. Risk of bias for nonrandomized trials: A indicates bias due to confounding, B indicates biases in selection of participants into the study, C indicates bias in classification of interventions, D indicates bias due to deviations from intended interventions, E indicates bias due to missing data, F indicates bias in measurement of the outcome, and G bias in selection of the reported results. M-H, Mantel-Haenszel.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
Fig. 8.: Forest plot of the risk of cervical intraepithelial neoplasia 1 or greater recurrence with comparison of human papillomavirus (HPV) vaccination vs control (HPV 16,18). I2 statistic represents the interstudy heterogeneity as a proportion of the total heterogeneity. I2 values of 25–50%, 51–75%, and 76–100% signified low, moderate, and high heterogeneity, respectively. Risk of bias for randomized trials: A indicates random sequence generation (selection bias), B indicates allocation concealment (selection bias), C indicates blinding of outcome assessment (performance bias), D indicates blinding of outcome assessment (detection bias), E indicates incomplete outcome data (attrition bias), F indicates selective reporting (reporting bias), and G indicates other bias. Risk of bias for nonrandomized trials: A indicates bias due to confounding, B indicates biases in selection of participants into the study, C indicates bias in classification of interventions, D indicates bias due to deviations from intended interventions, E indicates bias due to missing data, F indicates bias in measurement of the outcome, and G bias in selection of the reported results. M-H, Mantel-Haenszel.Lichter. Human Papillomavirus Vaccine to Reduce Recurrent CIN. Obstet Gynecol 2020.
The I 2 statistic, which showed the inter-study heterogeneity as a proportion of the total heterogeneity, ranged between 0% and 46% which indicates a low level of heterogeneity between the studies in each of the meta-analyses.
DISCUSSION
This meta-analysis summarizes the currently available data on the efficacy of HPV vaccination as an adjuvant treatment to surgery for CIN 2 or greater. Our review of the available data demonstrates that adjuvant HPV vaccination in women ages 15–45 is associated with a significantly reduced risk of recurrence of CIN 2 or greater by 64% as well as CIN 1 or greater by 33% in the first 6–48 months after treatment. Given that CIN 1 and CIN 2 or greater are both caused by HPV and both require close clinical follow-up, which is burdensome to patients, these findings may have significant clinical effects. Furthermore, adjuvant vaccination was also associated with a reduced subsequent CIN 2 or greater recurrence, irrespective of HPV type, as well as lesions that were specifically found to be positive for HPV 16,18. Although the post hoc analysis of a large randomized controlled trial included in this meta-analysis exemplified this significant risk reduction,28
The mechanism explaining the efficacy of HPV vaccination as an adjuvant therapy to reduce recurrence is not well understood, as it was engineered to be a primary preventive vaccine. Current HPV vaccines prevent infection by producing virus-like particles, which elicit production of neutralizing antibodies and memory B-cells to these virus-like particles and block entrance into host cells. However, these vaccines are not effective in eliminating pre-existing infections because the target antigens (L1 capsid proteins) identified by the immune system after vaccination are not expressed in infected basal epithelial cells. Therefore, it is not effective at clearing virus in the large number of individuals who have already acquired HPV.27
Several hypotheses for its efficacy have been proposed.15 30 31–35
A second hypothesis for the efficacy of adjuvant HPV vaccination is that the change in the immune microenvironment induced by surgery may create a new background, similar to the unexposed patient, in which prophylactic vaccine is efficacious. This proposed theory is supported by immunologic trials as well. Excision of primary HPV-related lesions causes a modulation in the inflammatory mucosal environment. Although patients with persistent HPV infection display increased levels of tumor necrosis factor-alpha in tissues,36 15
The strengths of this study include that this meta-analysis comprehensively evaluates all the data from the available evidence to provide a large sample size to investigate the utility of adjuvant HPV vaccination after surgical excision for CIN 2 or greater compared with placebo or surgical procedure alone. Additionally, the strength of the methodology used (Q statistic, the I 2 and the Tau-squared), as well as strict criteria of inclusion, specifically studies that compared adjuvant HPV vaccination after surgical excision for CIN 2 or greater compared with placebo or surgical procedure alone, ultimately allowed us to focus and more definitively answer the proposed question.
There are several limitations of this study. First, a small number of studies were included in the final analysis, and two of the studies accounted for nearly 60% of patients, potentially skewing the data in favor of those studies' findings. Second, because not all studies included were randomized, our results may not be generalized to all patients in this setting. We ultimately decided to include both randomized and nonrandomized studies in the final analysis as published literature on this subject is limited. By pooling the data, we can begin to investigate and make associations of reduced recurrence rates with adjuvant HPV vaccination in this setting. Third, each study vaccinated women at different time points before and after surgery and also there were different periods of follow-up among included studies. Finally, the time span among the included studies might introduce bias because of changes in the staging system, terminology, and definition over time. The included studies were published over a long period, and included populations using both the Bethesda and recent ASCCP terminology that have evolved over time.
The quality of our evidence for the primary outcome of interest, CIN 2 or greater, is moderate. Secondary outcomes of interest ranged from moderate to very low. In several analyses, the summary estimate of effect is statistically significant (P <.01), with narrow CIs suggesting a strong evidence in support of HPV vaccination; however, there was inconsistency between study designs and inconsistent results across studies. This limits the interpretation of our findings. Although the conclusion of almost all studies included in this systematic review and meta-analysis was that adjuvant vaccination was associated with decreased recurrence of cervical dysplasia, the conclusion from Hildesheim et al showed an increased risk of recurrence. The analysis from this article is a subgroup of the cohort that underwent a LEEP, and those patients included were not separately randomized; this study was therefore likely underpowered to detect a difference and may also have introduced bias.30
Our analysis excluded studies that were conducted to test newly developed HPV vaccines that have not been FDA approved. These vaccines include VGX-3100 and pNGVL4a-Sig/E7(detox)/HSP70.37–39
In conclusion, this meta-analysis demonstrates that treatment with adjuvant HPV vaccination in women undergoing primary surgical excision of CIN 2 or greater is associated with a decreased risk of recurrent disease on the order of 66%. Additionally, considering the burden of HPV-related disease over the next few decades will be greatest among women who have not been vaccinated, the development of effective therapies targeting persistent infection remains imperative. These data advocate for further investigation with large randomized controlled trials to continue to prove the utility of the HPV vaccine as adjuvant therapy as well as its critical role in primary prevention.
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