David Mesher

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

BACKGROUNDnHuman papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations.nnnMETHODSnWe searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure.nnnFINDINGSnWe identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects.nnnINTERPRETATIONnOur results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement.nnnFUNDINGnThe Canadian Institutes of Health Research.

Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England.

Highlights • We monitor HPV infection in sexually active young women in England.• The prevalence of HPV 16/18 has reduced within 3 years of HPV immunisation.• Reductions in HPV 16/18 were greatest at ages with highest immunisation coverage.• The data suggest reductions in HPV 16/18 amongst unvaccinated young women and men.

Declining Genital Warts in Young Women in England Associated With HPV 16/18 Vaccination: An Ecological Study

Background.u2003Diagnoses of genital warts (GW) in genitourinary medicine (GUM) clinics have been increasing in England for many years. In 2008, an HPV immunization program began with a bivalent vaccine (Cervarix). This was expected to markedly reduce infections and disease due to human papillomavirus (HPV) 16/18 but not HPV 6/11 infections or disease. However, from 2009 to 2011 there were decreases in reported diagnoses of GW in young females at GUM clinics. Methods.u2003Using data from GUM clinics and a sample of general practices (GPs) throughout England, we analyzed rates of GW diagnoses by age, year of diagnosis, and estimated immunization coverage. Results.u2003The overall reduction in GW diagnoses at GUM clinics between 2008 and 2011 was 13.3% among 16- to 19-year-old females, with the greatest decline of 20.8% in 17-year-olds. Declines were positively associated with estimated immunization coverage. A similar pattern was seen in GP diagnoses, but not among older women, and for other GUM consultations. Conclusions.u2003Several factors might contribute to declines in GW. However, the size and pattern of the declines strongly suggest that we are observing an unexpected, moderately protective effect of HPV 16/18 vaccination against GW.

Continuing reductions in HPV 16/18 in a population with high coverage of bivalent HPV vaccination in England: an ongoing cross-sectional study.

Objectives The human papillomavirus (HPV) immunisation programme in England was introduced in 2008. Monitoring changes in type-specific HPV prevalence allows assessment of the population impact of this vaccination programme. Methods Residual vulva-vaginal swab specimens were collected from young sexually active women (aged 16–24u2005years) attending for chlamydia screening across England. Specimens were collected between 2010 and 2013 for type-specific HPV-DNA testing. HPV prevalence was compared to a similar survey conducted in 2008 prior to the introduction of HPV vaccination. Results A total of 7321 specimens collected in the postvaccination period, and 2354 specimens from the prevaccination period were included in this analysis. Among the individuals aged 16–18u2005years, with an estimated vaccination coverage of 67%, the prevalence of HPV16/18 infection decreased from 17.6% in 2008 to 6.1% in the postvaccination period. Within the postvaccination period, there was a trend towards lower HPV16/18 prevalence with higher vaccination coverage and increasing time since vaccine introduction from 8.5% in the period 2–3u2005years postvaccination to 4.0% in the period 4–5u2005years postvaccination. The prevalence of HPV31 reduced from 3.7% in the prevaccination period to 0.9% after vaccine introduction, although this no longer reached statistical significance after additional consideration of the uncertainty due to the assay change. Smaller reductions were seen in the individuals aged 19–21u2005years with lower estimated vaccination coverage, but there was no evidence of a reduction in the older unvaccinated women. Some overall increase in non-vaccine types was seen in the youngest age groups (ORs (95% CI); 1.3 (1.0 to 1.7) and 1.5 (1.1 to 2.0) for individuals aged 16–18 and 19–21u2005years, respectively, when adjusted for known population changes and the change in assay) although this should be interpreted with caution given the potential unmasking effect. Conclusions These data demonstrate a reduction in the HPV vaccine types in the age group with the highest HPV vaccination coverage.

Population-Level Effects of Human Papillomavirus Vaccination Programs on Infections with Nonvaccine Genotypes

After introduction of vaccination, some prevalences of nonvaccine types changed, without clear evidence for type replacement.

Coverage of the English National human papillomavirus (HPV) Immunisation Programme among 12 to 17 year-old females by area-level deprivation score, England, 2008 to 2011

The English national human papillomavirus (HPV) immunisation programme has offered vaccination to girls aged 12 years at the start of each school year since September 2008. A catch-up programme has offered vaccination to girls up to 18 years. Delivery is predominantly school-based, with some general practitioner (GP)-based immunisation. The relationship between HPV immunisation coverage and deprivation (index of multiple deprivation, IMD) was assessed by geographical area (N=151) for each school year offered the HPV vaccine between 2008 to 2011 using the Spearman’s rank correlation coefficient, and compared to that for adequate cervical screening of women aged 25 to 49 years. Coverage at age 12 showed no significant association with IMD at the area-level (p=0.12). Within the catch-up years, there was some suggestion of higher deprivation being associated with lower coverage. This was not significant for girls offered immunisation under 16 years (in compulsory education) (p=0.09), but was more marked and statistically significant for older girls (p<0.0001). The proportion of women aged 25 to 49 years with an adequate cervical screen was negatively associated with deprivation (p<0.0001). School-based HPV immunisation delivery appears to be successfully reducing inequalities in cervical cancer control at area-level. However, the catch-up cohorts above the age of compulsory education may face increased inequality. Further investigation is needed into individual-level factors associated with coverage.

Impact and cost-effectiveness of selective human papillomavirus vaccination of men who have sex with men.

Summary Offering human papillomavirus (HPV) vaccination to men who have sex with men up to age 40 years via genitourinary clinics will have a large impact on HPV-related diseases and is likely to be cost-effective.

Type-specific HPV prevalence in invasive cervical cancer in the UK prior to national HPV immunisation programme: baseline for monitoring the effects of immunisation

Aims To establish the human papillomavirus (HPV) type-specific prevalence in cervical cancer and high-grade cervical lesions in the UK prior to the introduction of national HPV vaccination. Methods Specimens of cervical cancer (n=1235) and cervical intraepithelial neoplasia (CIN)3 (n=2268) were tested for HPV genotypes in England, Scotland, Wales and Northern Ireland. Data were pooled and weighted estimates presented. Results Among cervical cancer cases, 95.8% were positive for at least one high-risk (HR) HPV type. Restricting to those with HR HPV, the proportion positive for HPV16 and/or HPV18 was similar across countries (weighted overall prevalence 83.0%). This proportion decreased with increasing age at diagnosis (p=0.0005). HPV31, HPV33, HPV45, HPV52 and/or HPV58 were detected in 16.1% of HR HPV-positive cervical cancers and there was no significant association with age for these types. For HR HPV-positive CIN3 cases, there was a similar age-specific pattern with the highest positivity of HPV16 and/or HPV18 in the youngest age group (77.2%). The proportion of HR HPV CIN3 cases positive for HPV31, HPV33, HPV45, HPV52 and/or HPV58 was 36.3% in those aged <30u2005years at diagnosis. Conclusions The prevalence of HPV 16 and/or 18 was high in all UK countries and highest in those diagnosed at a younger age. The UK is well placed to monitor the impact of HPV vaccination on type-specific HPV prevalence in cervical disease.

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial

Background:Cervical screening identifies many women with low-grade abnormalities. In vitro and in vivo studies have shown that diindolylmethane (DIM) could potentially halt (cervical) carcinogenesis. We report on a randomised controlled trial of the effect of DIM in women with low-grade cervical cytological abnormalities.Methods:We conducted a pragmatic double-blind, randomised controlled trial of 150u2009mg DIM (from BioResponse DIM) or placebo daily for 6 months in women with newly diagnosed, low-grade cytological abnormalities. Randomisation was in the ratio 2 (DIM) to 1 (placebo). All women were invited for colposcopy at 6 months with biopsy of any abnormality.Results:Of the 551 randomised women available for analysis, 9% on DIM and 12% on placebo had cervical intraepithelial neoplasia-2 (CIN2) or worse after 6-month supplementation (risk ratio (RR) 0.7 (95% confidence interval (CI): 0.4–1.2)), whereas 4.6% and 5.1%, respectively, had CIN3 or worse (RR 0.9 (95% CI: 0.4–2.0)). A total of 27.3% of women on DIM and 34.3% on placebo had no sign of disease (negative cytology, colposcopy and human papilloma virus (HPV) tests) at 6 months (RR 0.8 (95% CI: 0.6–1.0)). Of those HPV-positive at baseline, 69% (114 out of 166) of the DIM group were positive at 6 months compared with 61% (43 out of 71) of the placebo group: RR 1.1 (95% CI: 0.9–1.4). Diindolylmethane supplementation was well tolerated.Conclusion:The results suggest that short-term DIM supplementation (150u2009mgu2009day−1) is well tolerated, but is unlikely to have an effect on cytology or HPV infection. Uncertainty remains regarding its effect on CIN2+.

Decline in genital warts diagnoses among young women and young men since the introduction of the bivalent HPV (16/18) vaccination programme in England: an ecological analysis

Background For several decades, diagnoses of genital warts at genitourinary medicine (GUM) clinics in England had been increasing. In 2008, a national human papillomavirus (HPV) vaccination programme was introduced using the bivalent vaccine (types 16 and 18 only). A decrease in genital warts was not anticipated. However, rates of genital warts in GUM clinics have declined significantly since the introduction of the vaccine. Methods Using data from GUM clinics across England, we analysed rates of genital warts by age, gender, sexual orientation and estimated vaccine coverage. Results The reduction in rates of genital warts diagnoses at GUM clinics between 2009 and 2014 was 30.6% among young women aged 15–19u2005years and 25.4% among same age heterosexual young men. Overall there was an association showing higher warts reduction with increasing vaccination coverage with the largest declines in warts diagnoses observed in young women aged 15u2005years (50.9%) with the highest vaccination coverage. No such declines were observed in men who have sex with men (MSM) of the same age. Conclusion The results of these ecological analyses are strongly in keeping with the bivalent HPV vaccine providing modest protection against genital warts.