Measuring vaccine effectiveness against persistent HPV infections: a comparison of different statistical approaches.

BACKGROUND: Persistent high-risk human papillomavirus (HPV) infection is endorsed by the World Health Organization as an intermediate endpoint for evaluating HPV vaccine effectiveness/efficacy. There are different approaches to estimate the vaccine effectiveness/efficacy against persistent HPV infections. METHODS: We performed a systematic literature search in Pubmed to identify statistical approaches that have been used to estimate the vaccine effectiveness/efficacy against persistent HPV infections. We applied these methods to data of a longitudinal observational study to assess their performance and compare the obtained vaccine effectiveness (VE) estimates. RESULTS: Our literature search identified four approaches: the conditional exact test for comparing two independent Poisson rates using a binomial distribution, Generalized Estimating Equations for Poisson regression, Prentice Williams and Peterson total time (PWP-TT) and Cox proportional hazards regression. These approaches differ regarding underlying assumptions and provide different effect measures. However, they provided similar effectiveness estimates against HPV16/18 and HPV31/33/45 persistent infections in a cohort of young women eligible for routine HPV vaccination (range VE 93.7-95.1% and 60.4-67.7%, respectively) and seemed robust to violations of underlying assumptions. CONCLUSIONS: As the rate of subsequent infections increased in our observational cohort, we recommend PWP-TT as the optimal approach to estimate the vaccine effectiveness against persistent HPV infections in young women. Confirmation of our findings should be undertaken by applying these methods after longer follow-up in our study, as well as in different populations.

Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study.

BACKGROUND: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. METHODS: The three arms are: Control arm - liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm - hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm - hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. RESULTS: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. CONCLUSION: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

Self-collection of genital human papillomavirus specimens in heterosexual men.

BACKGROUND: We assessed the accuracy of self-collected human papillomavirus (HPV) specimens in men compared with clinician-collected specimens from men in British Columbia and determined the prevalence of HPV subtypes at different male genital sites. METHODS: Heterosexual men were recruited at the Provincial Sexually Transmitted Infection (STI) Clinic in Vancouver, Canada. Participants were randomly assigned to conduct self-collection or clinician-collected specimens first. Clinicians obtained specimens using emery paper followed by saline-moistened Dacron swab from three genitourinary sites: glans penis/foreskin, penile shaft (ventral and dorsal surfaces) and scrotum. Participants received written instructions and took specimens from one of the three sites using the same technique as clinicians. HPV testing was performed with the Roche Amplicor HPV test and samples found to be reactive were tested with the Roche Linear Array HPV typing assay to establish the HPV genotype(s) in the sample. RESULTS: Overall prevalence of any HPV genotype from any site was 69.8% in clinician-collected specimens and 55.3% in self-collected specimens. Order of collection (clinician vs self-collected) did not impact on the prevalence of HPV in the specimens. The kappa scores for agreement between clinician-collected and self-collected specimens ranged from fair to excellent. Overall, there was better agreement between self-collected and clinician-collected specimens for HPV-18 (range: kappa = 0.88 to 0.92) than for HPV-16 (range: kappa = 036 to 0.62). CONCLUSION: HPV is a prevalent genital tract infection in men. Site-specific agreement for specific HPV genotypes between clinician-collected and self-collected specimens varied broadly and neither clinicians nor patients routinely obtained samples with consistently higher or lower prevalence at specific genital sites, indicating there are continued opportunities to improve techniques for clinician-collected and self-collected male specimens for HPV.

Intention of parents to have male children vaccinated with the human papillomavirus vaccine.

BACKGROUND: Although already approved for use in males in some jurisdictions, there is little information about parental attitudes toward having their sons receive the human papillomavirus (HPV) vaccine. The goal of this study was to ascertain parental intentions to vaccinate their sons with an HPV vaccine and to determine factors that predict this intention. METHODS: Parents of children aged 8-18 years were recruited from across Canada through random digit dialling. Participants were asked to respond to a series of questions in the context of a Grade 6 (age 11/12 years old), publicly funded school-based HPV vaccine programme, including their intention to vaccinate their sons with the HPV vaccine. Parents were also asked about a series of characteristics thought to predict intention to vaccinate as well as demographic characteristics. Backwards logistic regression was conducted to calculate adjusted odds ratios (AOR) to identify the factors that are predictive of parents' intention to vaccinate their son(s) against HPV. RESULTS: Of the 1381 respondents with male children, 67.8% (95% CI 65.3 to 70.3) intend to vaccinate their son(s) against HPV. Parents who had positive attitudes toward vaccines and the HPV vaccine in particular (AOR 41.5, 95% CI 9.5 to 181.7), parents who were influenced by subjective norms (AOR 7.8, 95% CI 5.8 to 10.5), parents who felt that the vaccine had limited influence on sexual behaviour (AOR 2.3, 95% CI 1.6 to 3.3) and parents who were aware of HPV (AOR 1.4, 95% CI 1.1 to 2.0) were significantly more likely to report an intention to vaccinate boys against HPV. In contrast, residence in British Columbia compared to Atlantic Canada (AOR 0.4, 95% CI 0.2 to 0.8) and higher education (AOR 0.7, 95% CI 0.5 to 0.9) were negatively associated with intention to vaccinate. Parents who reported an intention to vaccinate their daughters were also highly likely to report an intention to vaccinate their sons (kappa = 0.9, p<0.001). DISCUSSION: The majority of Canadian parents would intend to have their male children receive the HPV vaccine in the context of a publicly funded school-based immunisation programme. Overall attitudes toward vaccine, recommendations from health professionals and impact of the vaccine on sexual practices are important predictors of intention to have a male child receive the HPV vaccine.

Population-based evaluation of type-specific HPV prevalence among women in British Columbia, Canada.

BACKGROUND: British Columbia (BC) introduced a school-based HPV vaccine program in September 2008. As part of the HPV vaccine program evaluation, we determined the type-specific HPV prevalence in a population-based sample of women presenting for routine cervical cancer screening in the province. METHODS: From June 2010 to February 2011, a total of 1100 physicians from all health regions in BC were invited to return ten sequential cytobrushes used during routine office-based Pap screening to the Provincial Health Services Authority Laboratories for HPV type-specific testing. Client age was the only identifier provided. Specimens were screened by the Digene Hybrid Capture(®) 2 High-Risk (hr) HPV DNA Test (HC2). HC2 positive specimens were then genotyped using the Roche cobas(®) 4800 HPV Test, the Roche Linear Array (LA) HPV Genotyping Test and the Digene(®) HPV Genotyping LQ Test. RESULTS: Overall, 12.2% of the 4330 specimens with valid HC2 results were hrHPV positive. Age range was 15-69 (median 39.0). By age group, the proportion HC2 hrHPV positive was: 15-19, 25.7%; 20-24, 33.2%; 25-29, 21.9%; 30-34, 12.6%; 35-39, 9.5%; 40-44, 8.4%; ≥45, 3.4%. Overall hrHPV prevalence was 10.1% by Roche cobas(®) 4800, 10.5% by Roche LA and 10.3% by Digene LQ. For HPV 16/18, rates by age group by Roche LA were: 15-19, 5.1%/2.8%; 20-24, 9.5%/3.9%; 25-29, 6.2%/1.0%; 30-34, 2.4%/1.7%; 35-39, 1.2%/1.0%; 40-44, 1.6%/0.2%; ≥45, 0.3%/0.2%. Similar HPV 16/18 rates were obtained with the Digene LQ and Roche cobas(®) 4800 methods. Agreement between the three genotyping methods for HPV 16 and 18 was high. CONCLUSIONS: Comparable to other evaluations, hrHPV positivity was highest among younger women and HPV 16 was the most frequent genotype detected. These baseline estimates will be useful for monitoring the effectiveness of the HPV vaccine in BC. Type-specific analyses repeated at regular intervals over time may determine whether the use of HPV vaccine results in hrHPV genotype replacement in the province.

Diagnostic accuracy of self collected vaginal specimens for human papillomavirus compared to clinician collected human papillomavirus specimens: a meta-analysis.

BACKGROUND/OBJECTIVES: Providing summary recommendations regarding self collection of vaginal specimens for human papillomavirus (HPV) testing is difficult owing to the wide range of published estimates for the diagnostic accuracy of this approach. To determine summary estimates from analyses of reported findings of the sensitivity, specificity and summary receiver operating characteristic curves (SROC) for self collected vaginal specimens for HPV testing compared to the reference standard, clinician collected HPV specimens. METHODS: Standard search criteria for a diagnostic systematic review were employed. Eligible studies were combined using a random effects model and summary ROC curves were derived for overall and for specific subgroups. RESULTS: Summary measures were determined from 12 studies. Six studies where patients used Dacron or cotton swabs or cytobrushes to obtain samples were pooled and had an overall sensitivity of 0.74 (95% CI 0.61 to 0.84) and specificity of 0.88 (95% CI 0.83 to 0.92), with diagnostic odds ratio of 22.3 and an area under the curve of 0.91. Self specimens using Dacron or cotton swabs or cytobrushes collected by women enrolled at referral clinics had an overall sensitivity of 0.81 (95% CI 0.65 to 0.91) and specificity of 0.90 (95% CI 0.80 to 0.95). Sensitivity and specificity of tampons ranged from 0.67-0.94 and 0.80-0.85 respectively. CONCLUSIONS: Our findings indicate that the combined sensitivity for HPV-DNA is more than 70% when patients use Dacron swabs, cotton swabs, or cytobrushes to obtain their own vaginal specimens for HPV-DNA evaluation. Self collected HPV-DNA swabs may be an appropriate alternative for low resource settings or in patients reluctant to undergo pelvic examinations.