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Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study

BMJ 2019; 365 doi: (Published 03 April 2019) Cite this as: BMJ 2019;365:l1161

Linked editorial

The remarkable impact of bivalent HPV vaccine in Scotland

Linked opinion

Bivalent HPV vaccine in Scotland is having a considerable and sustained effect

Rapid Response:

Re: Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study

Response to Rapid responses 7iv2019

As the Corresponding Author for the above paper, I thank John Stone, Peter Selley, Juan Gervas and Christopher Exley for their comments. We have considered their comments, and offer the following response.

John Stone. Cervical screening programmes have reduced the incidence of invasive cervical cancer. The rationale for cervical cancer screening is based on the detection (and management of) of pre-invasive lesions: CIN2 and CIN3, thereby preventing progression to invasive cancer. It is therefore a reasonable expectation that the reduction of CIN2 and CIN3 described in the paper will lead to a reduction in cancer. The paper does not show a reduction in cancer due to the natural history of the disease and the time frame of assessment, given that immunised women are only just reaching the age at which they might be diagnosed with cancer. However cervical screening systems and cancer registries in the UK are set up in a way that will allow us to monitor cancer incidence in immunised cohorts in due course. Scotland is in the process of analysing data on the longer term efficacy of immunisation, including cohorts in which cancers have been diagnosed.
We believe that the recent rise in invasive cancer in England (in a particular age cohort) to which Mr Stone refers reflects changes in screening practice, as indicated by Sasieni and Castenon, and note that it has occurred in a cohort of largely unvaccinated women. The commitment to longitudinal monitoring in Scotland of both pre-invasive and invasive disease stratified by age and immunisation status will be of value in understanding why this increase has been observed. Given the changes in pre-invasive disease observed in 20-year olds, and the natural history of CIN and invasive cancer, HPV immunisation is unlikely to be a relevant factor.

Peter Selley. The reduction in the numbers of terminations of pregnancy in Scotland will have many causes, including the availability of emergency birth control and changes in contraception practice. Arguably data on STI are a better indicator of changes in sexual behaviour than the rates for termination of pregnancy. The data on HPV prevalence in cervical samples (Kavanagh et al, Lancet Infectious Diseases 2017) have shown that other high risk HPV did not decrease while 16/18/31/33/45 did. This suggests that sexual behaviour has not changed and that reduction of aforementioned types is strongly driven by immunisation. Obtaining robust proxies of sexual behaviour is challenging and we could not capture specific information on this aspect within this population based study. While we accept that temporal changes in sexual behaviour may have had an influence on the observations, we would suggest that it would be unlikely solely account for the significant reductions observed.

Juan Gervas. We accept that this is an observational study with associated unavoidable limitations; however we would reject the notion that the results are “clinically irrelevant”. The published evidence of vaccination on both HPV and clinical outcomes in the UK and elsewhere shows that there are already benefits to women and health care systems from reduced referral for colposcopy for high grade disease. The effect of an intervention on the absolute risk of a disease such as cervical cancer, which has a long natural history, will take time to become apparent. The timeframe of the study, and nature of the cohorts involved – those attending for first screen - means that we cannot determine impact over a life time at this stage. However, we are committed to monitoring the longitudinal impact of vaccine in women to address this.

Christopher Exley. The references cited in the introduction to the paper give the global and Scottish background to the significance of cervical cancer as a disease. With regard to the specific questions raised about the attendance for screening and the performance of the Scottish Screening programme, these have been considered in the Discussion. Additionally, national statistics on the performance and uptake of screening, the incidence and mortality from cervical cancer and the incidence of pre-invasive disease are reported and published, and aggregated data are accessible online.
With regard to serious adverse reactions to the vaccine, we have not included a discussion on vaccine safety because the purpose of this particular study is the evaluate vaccine effectiveness. However, in her linked Editorial, Professor Julia Brotherton does address the question of vaccine safety. In Scotland and the UK, as elsewhere, we monitor vaccine safety routinely and have shown no serious adverse effects that can be objectively linked to the administration of the vaccine. (Cameron R et al, Intern Med J. 2016 Apr;46(4):452-7. doi: 10.1111/imj.13005; Skufka J et al, Vaccine 36 (2018) 5926–5933).
Although no reduction on invasive disease has yet been demonstrated, this is a function of the length time since the introduction of the vaccines, the biology of the oncogenesis by HPV, and the characteristics of the screening programme. As noted above in the response to Mr Stone, the very success of cytology-based screening programmes, predicated as they are on the detection and treatment of CIN2 and CIN3, indicates that the reduction in CIN2 and CIN3 incontrovertibly demonstrated in this paper will be followed by a reduction in invasive cancer in the near future.

The wider context within which HPV immunisation should be considered is set out in the accompanying editorial and opinion piece.

Competing interests: No competing interests

07 April 2019
Timothy J Palmer
Senior Lecturer in Pathology, University of Edinburgh and Clinical Lead for Cervical Screening in Scotland
University of Edinburgh.