Effectiveness of quadrivalent…

Elizabeth Crowe. public health physician 1 2 ,

Nirmala Pandeya. biostatistician 1 ,

Julia M L Brotherton. public health physician and medical epidemiologist 3 ,

Annette J Dobson. biostatistician 1 ,

Stephen Kisely. public health physician 4 ,

Stephen B Lambert. public health physician 5 6 ,

David C Whiteman. cancer epidemiologist 1 7

1 The University of Queensland, School of Population Health, Brisbane, Australia

2 NHS Borders, Department of Public Health, Melrose, Scotland, UK

3 Victorian Cytology Service, Melbourne, Victoria, Australia

4 The University of Queensland, Rural and Southern Clinical Schools, Wooloongabba, Australia

5 Queensland Children’s Medical Research Institute, The University of Queensland and Children’s Health Queensland, Brisbane, Australia

6 Queensland Health Immunisation Program, Brisbane, Australia

7 QIMR Berghofer Medical Research Institute, Population Health Department, Brisbane, Australia

Correspondence to: E Crowe NHS Borders, Department of Public Health, Melrose, Scotland, UK e.crowe1 uq.edu.au

Accepted 31 January 2014

Abstract

Objective To measure the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical abnormalities four years after implementation of a nationally funded vaccination programme in Queensland, Australia.

Design Case-control analysis of linked administrative health datasets.

Setting Queensland, Australia.

Participants Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011. High grade cases were women with histologically confirmed high grade cervical abnormalities (n=1062) and “other cases” were women with any other abnormality at cytology or histology (n=10 887). Controls were women with normal cytology (n=96 404).

Main outcome measures Exposure odds ratio (ratio of odds of antecedent vaccination (one, two, or three vaccine doses compared with no doses) among cases compared with controls), vaccine effectiveness ((1−adjusted odds ratio)×100), and number needed to vaccinate to prevent one cervical abnormality at first screening round. We stratified by four age groups adjusted for follow-up time, year of birth, and measures of socioeconomic status and remoteness. The primary analysis concerned women whose first ever smear test defined their status as a case or a control.

Results The adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%.

Conclusion The quadrivalent HPV vaccine conferred statistically significant protection against cervical abnormalities in young women who had not started screening before the implementation of the vaccination programme in Queensland, Australia.

Introduction

Two prophylactic human papillomavirus (HPV) vaccines are currently available worldwide. Phase III studies have shown that both the quadrivalent vaccine, targeted against HPV types 6, 11, 16, and 18, and the bivalent vaccine, targeted against types 16 and 18, prevent cervical lesions associated with the respective HPV types.1 2 3 4 Some cross protection against other HPV types has also been shown.5 6 7 The quadrivalent vaccine also prevents high grade vulval and vaginal lesions and genital warts in women, as well as genital warts and high grade anal disease in men.1 2 Efficacy against cervical abnormalities was greatest in the population of women who tested negative for the relevant vaccine HPV types at enrolment, as the vaccine does not seem to impact on the clinical course of existing infections. Although clinical trials conducted in controlled settings have shown the efficacy of the quadrivalent vaccine, less is known about the vaccine’s effectiveness when delivered to the broader population.

Prophylactic HPV vaccination programmes have been implemented in over 40 countries.8 Australia was the first country to implement a publicly funded national vaccination programme with the quadrivalent HPV vaccine in April 2007. As well as initiating an ongoing programme for 12 and 13 year old girls, an extensive catch-up programme was implemented and ran until December 2009. The school based catch-up programme targeted 12-17 year olds, whereas the community catch-up phase offered vaccination to women aged 18 to 26 years in general practice and community settings. The school based programme achieved vaccination rates of 84%, 79%, and 70% for one, two, and three doses, respectively, while the corresponding rates for the community programme were 64%, 53%, and 33%.9 We estimated the effectiveness of full and partial courses of quadrivalent HPV vaccine against high grade and other cervical abnormalities in the population of Queensland women targeted by both the school and the community based catch-up vaccination programmes in the first four years after their introduction.

Methods

Study overview and population

We performed a case-control analysis using linked, anonymised data obtained from population registers in Queensland, Australia, for a four year period after the introduction of the HPV vaccination programme in April 2007. The study population comprised all female Queensland residents who attended for their first ever cervical smear test between 1 April 2007 and 31 March 2011 and who had been eligible for HPV vaccination during the nationally funded catch-up programme—that is, those born between July 1980 and July 1997.

Our primary objective was to estimate the effectiveness of the quadrivalent vaccine in the population of sexually naïve young women with no previous infection. Information on sexual history was not available from study participants. The Australian national cervical screening programme recommends that cervical screening should start between the ages of 18 and 20 in women who have ever been sexually active, or one or two years after first having sexual intercourse, whichever is later.10 To best realise our objective using the data available, we restricted our study to women who presented for their first smear test.

Sampling frame

We determined case-control status from cytology and histology test results as recorded on the Queensland Health Pap Smear Register. This depository is an “opt off” register, which has stored results since 199911 and is estimated to contain data for 98.5-99.5% of all Queensland women participating in the cervical screening programme.12 Cervical cytology results are coded by reporting laboratories according to the Australian standard modified Bethesda coding schedule and electronically forwarded to the register.

Case-control definitions

We defined two case groups (table 1 ⇓ ) based on the first abnormal test result returned by a woman during the study period. High grade cases were those women who had a high grade cervical abnormality (cervical intraepithelial neoplasia 2 or adenocarcinoma in situ, or worse) confirmed by histology during the study period. We took the index date to be the date of the abnormal cytology test result immediately preceding the histology test result satisfying the high grade case definition, because from that point women entered a phase of diagnostic testing. “Other cases” were those women who did not meet the high grade case definition but had any other abnormality (either a low grade abnormality at histology or an abnormal cytology result that was not confirmed by histology). Thus, other cases included women with high grade cytological abnormalities who did not have subsequent histological testing during the study period, as well as women whose subsequent histology identified only a low grade abnormality or a negative finding. We classified cases with simultaneous squamous and endocervical abnormalities according to the endocervical abnormality. Endocervical abnormalities were judged to be more important because they are rare, always an indication for diagnostic testing, and of particular interest because cervical screening is not sensitive in detecting and preventing adenocarcinoma. The index date for other cases was the date of the first cytological abnormality to occur in the study period.

Frequency of cytological and histological diagnoses for cases, 1 April 2007 to 31 March 2011, primary analysis

We assigned control status to the remaining women. By definition all controls had only negative cytology results during the study period. A negative cytology test result consisted of a negative result for the squamous component and negative or unsatisfactory result for the endocervical component. A woman provided control data only once.

Source of exposure information and exposure definitions

Our exposure of interest was receipt of the HPV vaccine before the index date, as recorded on the Queensland Health Vaccination Information Vaccination Administration System. The register includes several mandatory fields: name, date of birth, address, practitioner and clinic details, date of vaccination, type of vaccine, and dose number. Dose dates are recorded against the relevant dose number, as reported by the healthcare provider. A complete vaccination course consists of three doses over a 4-6 month period. We considered a vaccine dose to be valid if administered in line with national guidelines for minimum intervals, and a woman to be fully vaccinated if no more doses were clinically indicated.13 We also excluded individual doses that were subject to a cold chain breach (that is, the vaccine stored outside of the recommended temperature range) or were duplicate vaccine doses (where the same dose date was recorded more than once per woman). We defined women as unvaccinated (no doses), partially vaccinated (one or two doses), or fully vaccinated (≥3 doses) where receipt of vaccine doses occurred at any point before the index date.

Data linkage

Extracts from the Queensland cervical smear register and Queensland vaccination administration system were sent for linkage to Queensland Health Data Linkage Unit. The unit used the LinkageWiz software package to probabilistically identify potentially matching records for each woman. Weighting scores were assigned to matching variables, including full name, sex, date of birth, and address. The linkage generated a total of 287 224 potential matches (pairs) with weighting scores between 12 and 35. Of these, 249 885 pairs (87.0%) were automatically accepted because of a weighting score of more than 19 or an exact match on full name and address or full name and date of birth. The remaining 37 339 pairs were reviewed; 27 257 (73.0%, 9.5% overall) were accepted as true pairs and 10 082 (27.0%, 3.5% overall) were rejected. We received an anonymised linked dataset.

Ineligibility and exclusions

We excluded women whose first record in the cervical smear register was for a histology test result, and women who had any of the following characteristics: a recorded histology test during the study period that was not preceded by a record of an abnormal cytology test, duplicate records in the vaccination administration system that could not be combined into one record, inconsistent vaccination records (for example, an unreliable sequence of vaccination dose dates), or a postcode that was not possible to assign to a socioeconomic or remoteness category. We excluded cytology and histology tests that were reported as unsatisfactory for clinical reporting purposes. The figure ⇓ and supplementary figure 1 on bmj.com show the numbers of women in each of these exclusion categories.

Eligibility and exclusions, primary analysis. VIVAS=Queensland Health Vaccination Information Vaccination Administration System

Covariates

For measures of remoteness and socioeconomic status, we assigned women to a category according to the 2006 Australian Bureau of Statistics (ABS) Remoteness Area (a measure of the remoteness of a location from the services provided by large towns or cities) and to a 2006 ABS Index of Relative Socioeconomic Disadvantage quintile based on current residential postcode on the Queensland cervical smear register. We calculated the median follow-up time from study start date to index date for the study population overall and assigned women to follow-up time quartiles. We included year of birth as a covariate. No information was available on other potential confounders, such as lifestyle factors, from the administrative datasets.

Statistical analysis

Analyses were conducted for all women and within strata of four age groups (at 2007): 11-14 years, 15-18 years, 19-22 years, and 23-27 years. We restricted our primary analysis to those women who had no cytology tests before their index date (women whose first ever smear test result defined their status as a case or control). This was because the number of previous cytology tests differed between cases and controls. Our secondary analysis comprised cases and controls with one or more cytology tests before their index date. For the secondary analysis, we randomly selected an index date for controls from all negative test results to minimise any opportunity for exposure bias. Such a bias might otherwise have occurred had we used the last test result available, allowing control women to be in the study longer and therefore have more opportunity to become vaccinated than cases.

Our measure of association was the exposure odds ratio—that is, the ratio of exposure odds among cases to the exposure odds among controls. We estimated the exposure odds ratio for each vaccination dose compared with no vaccination using multinomial logistic regression models for each of the two mutually exclusive case categories (high grade cases, other cases) compared with controls. We adjusted for potential confounding by socioeconomic status, remoteness, age, and follow-up time. We estimated vaccine effectiveness and associated 95% confidence intervals using the formula (1−adjusted odds ratio)×100. We calculated approximate point and interval estimates of the number needed to be vaccinated to prevent one cervical abnormality at first screening round using multiple logistic regression with adjustment for confounding variables, according to the method of Bender and Blettner.14 We used SAS statistical software (version 9.4) for all data cleaning and analyses.

Sensitivity analyses

We tested the impact of excluding cases and controls in whom the time interval (latent period) between date of last vaccination and index date was shorter than nominated latent periods. We assumed putative latent periods of 30, 180, and 365 days based on uncertainties about the timing of immune responses to HPV vaccination and the interval between infection and neoplasia.15 16 Because the date of origin of a cervical lesion cannot be known with certainty, it is possible that our decision to define the event date as the cytology test result immediately preceding the abnormal histology result may have introduced bias. We therefore repeated our secondary analyses using the date of the first abnormal cytology test result as the index date for high grade cases.

It was possible for a woman to have no record of a first or second vaccine dose but records for subsequent doses. In our initial analysis, we assigned exposure status using the actual number of doses that had dates recorded against them, ignoring provider assigned dose numbers. We repeated all analyses after reassigning exposure status based on the last dose number for which there was a valid dose date occurring before the index date, analogous to the “third dose assumption” used to estimate coverage of primary course vaccines in children.17

Results

Participants

In total, 108 353 women were eligible for inclusion in the primary analysis: 1062 (1.0%) high grade cases, 10 887 (10.0%) other cases, and 96 404 (89.0%) controls (figure). See supplementary figure 1 on bmj.com for the numbers included in the secondary analysis. The median follow-up time from study start date to index date for women in the primary analysis was 808 days (interquartile range 456-1131 days) for controls, 654 (313-1038) days for other cases, and 766 (381-1087) days for high grade cases. Cases were older, more disadvantaged, and less likely to live in major cities than controls (table 2 ⇓ ). These differences were more pronounced for high grade cases. Supplementary table 1 on bmj.com presents the characteristics for women in the secondary analysis. Table 1 presents the histological and cytological diagnoses for cases (see supplementary table 2 on bmj.com for secondary analysis). For the primary analysis 11.2% of high grade cases (n=119), 18.5% of other cases (n=2013), and 23.8% of controls (n=22 987) were fully vaccinated (≥3 doses) before their index date (figure). Fully vaccinated women were younger at first vaccine dose (median age 17.0 years (interquartile range 16.0-19.4 years) than partially vaccinated women (19.6 (18.0-22.4) years for two doses; 21.0 (19.1-23.7) years for one dose).

Comparison of characteristics of cases and controls, 1 April 2007 to 31 March 2011, primary analysis. Values are numbers (percentages) unless stated otherwise

Notes

Cite this as: BMJ 2014;348:g1458

Footnotes

We thank the following units within Queensland Health for providing the data and conducting the linkage for this study: Communicable Diseases Branch, Cancer Screening Services Branch, Health Statistics Centre. We thank Claire DeBats, Nathan Dunn, Belinda Eagle, and Vicki Bryant for the data extraction. The provision of linked data was made possible through HealthLinQ, the Queensland node of the Population Health Research Network, funded by the Australian Government’s National Collaborative Research Infrastructure Strategy. This project was overseen by a steering group and we thank the following members for their contributions: Christine Selvey, Jennifer Muller, and Leane Christie. We thank Paddy Farrington for discussions on study design and analysis and Tim Patterson for his comments on earlier drafts. EC thanks the South East of Scotland Postgraduate Deanery and NHS Borders for support to undertake this research during postgraduate training.

Contributors: EC, AJD, SK, and DCW designed the study. EC is guarantor. EC and NP analysed the data. EC, JMLB, AJD, SK, SBL, NP, and DCW interpreted the data. EC wrote the first draft. JMLB, AJD, SK, SBL, NP, and DCW made substantial contributions to drafts of the manuscript and critically revised the report. All authors saw and approved the final version of the report.

Funding: No specific project funding was received but EC was supported by a salary from the University of Queensland and NHS Borders. DCW was supported by a Future Fellowship from the Australian Research Council (FT0990987). NP was supported by an early career fellowship from the National Health and Medical Research Council (631691). SK and AJD were supported by salaries from the University of Queensland. JMLB was supported by salary from the Victorian Cytology Service. SBL was supported by an early career fellowship from the National Health and Medical Research Council (GNT1036231) and is a Queensland Children’s Medical Research Institute senior research fellow supported by the Children’s Health Foundation Queensland (50025).

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. SBL has received research grants, travel funds, and payments from Merck, GSK, and BioCSL. JMLB has been a co-investigator on Australian HPV epidemiology grants that have received partial unrestricted funding from BioCSL and Merck. The University of Queensland receives royalties from the sale of Gardasil (Merck). There are no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: This study was approved by the University of Queensland medical research ethics committee (2010001247) and Queensland Health human research ethics committee (HREC/10/QHC/48).

Data sharing: No additional data available.

Transparency: EC affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/ .

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