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Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis

BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2022-070135 (Published 03 August 2022) Cite this as: BMJ 2022;378:e070135

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Re: Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis

Dear Editor,

Thank you for bringing those interesting points to our attention.

The effect estimate of our main analysis is in line with previously published reports [1-8]. The difference with the review by Tjalma et al 2022 [9] is not significant and can be explained by: 1) the data synthesis from studies with different designs including post-hoc analyses of randomised controlled trials (RCTs), 2) the inclusion of an additional study by De La Rosa et al [10], and 3) the differences in statistical methodology used to combine the effect estimates across the included studies.

We have considered each individual point below:

1. We agree with Tjalma and colleagues [9] that the inclusion criteria in the study by Karimi-Zarchi et al. [11] could be difficult to interpret. It is our interpretation that the vaccine was administered post-surgery of CIN2+ or persistent CIN1, as stated in the article, and the effect of the vaccine on the rates of residual/recurrent Cervical Intraepithelial Neoplasia (CIN) was compared between the vaccinated and non-vaccinated groups. The aforementioned study has also been included in other systematic reviews and meta-analyses on the topic [6 8]. An exclusion of this study from the analysis does not lead to material change of the main outcome and GRADE assessment (10 studies, 19 667 participants; risk ratio 0.38, 95% confidence interval 0.26 to 0.56, I2= 87%, very low to moderate certainty of evidence).

2. Given the wide variation of vaccination timing across studies, in our analysis we grouped studies that administered the vaccine ‘at or after surgery’ to include all studies that vaccinated up to a maximum of 1 month before treatment, at the time of treatment and up to 12 months after. The second group included those vaccinated ‘before treatment’ that included those vaccinated more than a month before treatment [12 13]. As such, this study [14] was appropriately allocated as per our definitions.

3. We have included grey literature in the main analysis, as per the Cochrane handbook recommendation [15], and performed sensitivity analysis to exclude those studies. The effect estimates remained essentially similar after the exclusion of this publication [12] (10 studies, 19 796 participants; risk ratio 0.41, 95% confidence interval 0.28 to 0.59, I2= 63%, very low certainty of evidence) (Table S5 of main paper). Regarding the vaccination timing for this study [12], our interpretation is that the vaccine was administered 2 months prior to treatment as stated in the methods section of the publication’s abstract [12].

4 & 5. Despite the study by Grześ et al. [16] is correctly described in the Table of Characteristics of our manuscript, it was erroneously included in the wrong subgroup analysis. Similarly, the study by del Pino et al. [17] was allocated to a different subgroup, provided that some women received the nonavalent vaccine. The allocation of the Del Pino to the “unknown” subgroup and Grzes to the “GARDASIL” subgroup, suggested no major differences in the effect estimates and heterogeneity.

Finally, in the supplementary results of our published paper we indicate that six clinical trials appear active in assessing the value of the nonavalent vaccine at the time of treatment on CIN recurrence rates (four studies) and anogenital warts (two studies), and that three are currently recruiting [18-20].

We conclude that prophylactic HPV vaccination at the time of local treatment for CIN might reduce the risk of recurrence of high grade preinvasive cervical lesions, but the current evidence is inconclusive and at moderate to high overall risk of bias, and the overall effect estimate therefore likely inaccurate. Large, adequately powered randomised controlled trials are therefore required to establish the effectiveness and cost-effectiveness of adjuvant HPV vaccination at the time of local surgical treatment of CIN.

References
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2. Jentschke M, Kampers J, Becker J, et al. Prophylactic HPV vaccination after conization: A systematic review and meta-analysis. Vaccine 2020
3. Lichter K, Krause D, Xu J, et al. Adjuvant human papillomavirus vaccine to reduce recurrent cervical dysplasia in unvaccinated women: a systematic review and meta-analysis. Obstet Gynecol 2020;135(5):1070-83.
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Competing interests: No competing interests

24 November 2022
Maria Kyrgiou
Professor in Gynaecological Oncology
Konstantinos Kechagias, Ilkka Kalliala, Maria Paraskevaidi, Areti Angeliki Veroniki
Imperial College London
London SW7 2AZ