Effect of the HPV vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia by socioeconomic deprivation in England: population based observational study.

OBJECTIVES: To replicate previous analyses on the effectiveness of the English human papillomavirus (HPV) vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) using 12 additional months of follow-up, and to investigate effectiveness across levels of socioeconomic deprivation. DESIGN: Observational study. SETTING: England, UK. PARTICIPANTS: Women aged 20-64 years resident in England between January 2006 and June 2020 including 29 968 with a diagnosis of cervical cancer and 335 228 with a diagnosis of CIN3. In England, HPV vaccination was introduced nationally in 2008 and was offered routinely to girls aged 12-13 years, with catch-up campaigns during 2008-10 targeting older teenagers aged <19 years. MAIN OUTCOME MEASURES: Incidence of invasive cervical cancer and CIN3. RESULTS: In England, 29 968 women aged 20-64 years received a diagnosis of cervical cancer and 335 228 a diagnosis of CIN3 between 1 January 2006 and 30 June 2020. In the birth cohort of women offered vaccination routinely at age 12-13 years, adjusted age standardised incidence rates of cervical cancer and CIN3 in the additional 12 months of follow-up (1 July 2019 to 30 June 2020) were, respectively, 83.9% (95% confidence interval (CI) 63.8% to 92.8%) and 94.3% (92.6% to 95.7%) lower than in the reference cohort of women who were never offered HPV vaccination. By mid-2020, HPV vaccination had prevented an estimated 687 (95% CI 556 to 819) cervical cancers and 23 192 (22 163 to 24 220) CIN3s. The highest rates remained among women living in the most deprived areas, but the HPV vaccination programme had a large effect in all five levels of deprivation. In women offered catch-up vaccination, CIN3 rates decreased more in those from the least deprived areas than from the most deprived areas (reductions of 40.6% v 29.6% and 72.8% v 67.7% for women offered vaccination at age 16-18 and 14-16, respectively). The strong downward gradient in cervical cancer incidence from high to low deprivation in the reference unvaccinated group was no longer present among those offered the vaccine. CONCLUSIONS: The high effectiveness of the national HPV vaccination programme previously seen in England continued during the additional 12 months of follow-up. HPV vaccination was associated with a substantially reduced incidence of cervical cancer and CIN3 across all five deprivation groups, especially in women offered routine vaccination.

The impact of over ten years of HPV vaccination in England: Surveillance of type-specific HPV in young sexually active females.

INTRODUCTION: The UK national human papillomavirus (HPV) vaccination programme was introduced in 2008 using the bivalent HPV16/18 vaccine, changing to the quadrivalent HPV6/11/16/18 vaccine from 2012. We provide an analysis of type-specific HPV prevalence in young sexually active females in England to end 2020 (when the first routinely HPV vaccinated females were reaching 25 years of age and entering the National Health Service Cervical Screening Programme), showing the impact of over ten years of high coverage HPV vaccination. METHODS: Residual vulvovaginal swabs (VVS) were collected from 16 to 24 year old women attending for chlamydia screening between 2010 and 2020, anonymised and tested for type-specific HPV DNA. Trends in vaccine and non-vaccine HPV type prevalence were compared over time and association with vaccination coverage was evaluated within the post-vaccination period. RESULTS: A total of 21,168 eligible VVS specimens were tested for HPV DNA. The prevalence of HPV16/18 in sexually active 16-18 year old females who were offered vaccination aged 12-13 years was <1% in the most recent years tested, compared to over 15% prior to the vaccination programme in 2008. The magnitude of these decreases also suggests reduced transmission is offering some herd protection to unvaccinated females. HPV31/33/45 prevalence also steadily decreased, providing evidence of cross-protection. HPV6/11 prevalence remained stable during the bivalent vaccine period, with more recent declines, as expected due to the use of the quadrivalent vaccine. There has been no substantive increase in the prevalence of other high-risk (HR) HPV types. DISCUSSION: More than ten years of high coverage HPV vaccination in adolescent females in England has delivered dramatic declines in the prevalence of HPV vaccine-types and closely related HPV types in females in the vaccine eligible age group, and no indication of type replacement. These findings should enable confidence in planning for cervical screening of these females, and in predicting declines in HPV-related cancers.

The impact of catch-up bivalent human papillomavirus vaccination on cervical screening outcomes: an observational study from the English HPV primary screening pilot.

BACKGROUND: In England, bivalent vaccination (Cervarix) against high-risk human papillomavirus (HR-HPV) genotypes 16/18 was offered in a population-based catch-up campaign in 2008-2010 to girls aged 14-17 years. These women are now entering the national cervical screening programme. We determined the impact of catch-up bivalent vaccination on their screening outcomes. METHODS: We studied the overall and genotype-specific screening outcomes in 108,138 women aged 24-25 (offered vaccination) and 26-29 years (not offered vaccination) included in the English HPV screening pilot between 2013 and 2018. RESULTS: At 24-25 years, the detection of high-grade cervical intraepithelial neoplasia (CIN2+) associated with HPV16/18 decreased from 3 to 1% (p < 0.001), with estimated vaccine effectiveness of 87% (95% CI: 82-91%). The detection of any CIN2+ halved from 6 to 3% (p < 0.001), with an estimated vaccine effectiveness of 72% (95% CI: 66-77%). The positive predictive value of a colposcopy for CIN2+ decreased for both low-grade (p < 0.001) and high-grade (p = 0.02) abnormalities on triage cytology. The decreases in screen-detected abnormalities at age 26-29 were of a substantially smaller magnitude. CONCLUSIONS: These data confirm high effectiveness of bivalent HPV vaccination delivered through a population-based catch-up campaign in England. These findings add to the rationale for extending screening intervals for vaccinated cohorts.

The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.

BACKGROUND: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12-13 years with a catch-up programme for females aged 14-18 years in 2008-10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations. METHODS: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20-64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders. FINDINGS: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25-41) for age 16-18 years (school year 12-13), 62% (52-71) for age 14-16 years (school year 10-11), and 87% (72-94) for age 12-13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36-41) for those offered at age 16-18 years, 75% (72-77) for age 14-16 years, and 97% (96-98) for age 12-13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339-556) fewer than expected cervical cancers and 17 235 (15 919-18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England. INTERPRETATION: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12-13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995. FUNDING: Cancer Research UK.

What Do Diagnoses of Pelvic Inflammatory Disease in Specialist Sexual Health Services in England Tell Us About Chlamydia Control?

BACKGROUND: Pelvic inflammatory disease (PID) is an outcome measure for the evaluation of chlamydia screening programs. We explore PID diagnoses in specialist sexual health services (SSHSs) in England to inform the evaluation of the National Chlamydia Screening Programme, which was implemented nationally in 2008. METHODS: We conducted descriptive analyses using data on diagnoses of PID-with and without Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC)-by age and year of birth, in SSHSs between 2009 and 2019 from the GUMCAD STI Surveillance System database. Rates were calculated per 100 000 females residing in England. RESULTS: CT screening activity peaked in 2010. The rates of all PID diagnoses decreased between 2009 and 2019 by 39%. CT-associated PID (CT-PID) declined by 58%, and nonspecific PID declined by 37%. GC-PID increased by 34%. CT-PID decreased across all age groups with the highest observed decline, 71%, in 15- to 19-year-olds. A dose-response relationship was observed between CT-PID rates and screening, with rates lowest in those with the greatest exposure to screening. CONCLUSIONS: There was a marked decline in diagnoses of CT-PID, and nonspecific PID, at SSHSs after the introduction of widespread chlamydia screening, whereas GC-PID diagnoses increased. This ecological trend was broadly consistent with what we would have expected to see if widespread screening reduced the incidence of chlamydia-associated PID (and of nonspecific PID), as has been observed in randomized controlled trials of screening.

Post-vaccination HPV seroprevalence among female sexual health clinic attenders in England.

BACKGROUND: The National HPV Immunisation Programme was introduced in England in September 2008 using the HPV16/18 bivalent vaccine. We conducted serological surveillance to explore vaccination coverage levels. We also conducted a case-control study to investigate a hypothesised cross-protective effect of the HPV16/18 vaccine against genital warts. METHODS: Residual serum specimens from 16 to 20 year-old women attending six specialist sexual health services (SSHS) between 2011 and 2015 in England were tested for antibodies against HPV16 and HPV18 using a virus-like particle (VLP)-based multiplex serology assay. Patients were classified as having vaccine-induced seropositivity if they were seropositive for both HPV types and either had high antibody levels for at least one HPV type, or moderately high levels for both HPV types. Differences in vaccine-induced seropositivity by patient characteristics were investigated using logistic regression. Vaccine-induced seropositivity was then compared for patients with genital warts (cases) and matched patients without (controls). RESULTS: Of 3,973 serum specimens collected, 3,870 (97.4%) had a valid result. The proportion of women with vaccine-induced seropositivity decreased with age (from 78.1% in 16-year-olds to 52.6% in 20-year-olds). Vaccine-induced seropositivity was lower among women born outside the UK, from more deprived areas and with a history of chlamydia diagnosis. A difference in uptake by ethnic group was also seen but this was largely confounded by differences in deprivation and country of birth. Among 537 cases and 1,515 controls, there was little evidence of a protective effect of the bivalent HPV vaccine against genital warts (adjusted odds ratio 0.93; 95% CI: 0.74-1.18). DISCUSSION: Vaccine-induced seropositivity in this high-risk population was in line with vaccination coverage in the general population although was lower in some at-risk sub-groups. This study does not provide evidence to support a cross-protective effect of the HPV16/18 vaccine against genital warts.

HPV16 and HPV18 seropositivity and DNA detection among men who have sex with men: a cross-sectional study conducted in a sexual health clinic in London.

OBJECTIVES: Men who have sex with men (MSM) have an increased risk of human papillomavirus (HPV) infection and related diseases compared with men who have sex exclusively with women. From April 2018, there has been a phased roll-out of HPV vaccination offered to MSM aged up to 45 years old who are attending sexual health clinics and HIV clinics in England. The vaccine is most effective if delivered prior to HPV infection. We estimated the proportion of MSM with no current vaccine-type infection and no serological evidence of prior infection, in a study undertaken prior to vaccine introduction. METHODS: We conducted a cross-sectional study among 484 MSM aged 18-40 years old who attended a sexual health clinic in London between 2010 and 2012. We estimated the prevalence of current and past infection by testing for HPV DNA in anogenital samples and for serum antibodies to HPV16 and HPV18. RESULTS: The median age was 30 years (IQR 25-35). The prevalence of HPV16 and HPV18 DNA was 13.2% and 6.2%, respectively. Seropositivity for HPV16 and HPV18 was 28.5% and 17.1%, respectively, with 11.4% seropositive for both types. Seropositivity for the same HPV type was strongly associated with anogenital DNA detection. 279 MSM (57.6%) tested negative for both HPV16 and HPV18 serology and were DNA negative for these two types; only 5 MSM (1.0%) were seropositive and DNA positive for both HPV types. CONCLUSIONS: This is the first study to determine both the prevalence of HPV DNA in anogenital samples and HPV seroprevalence among MSM attending a sexual health clinic in the UK. Over half of MSM in this study had no evidence of a previous or current infection with either of the high-risk HPV types included in the quadrivalent vaccine, which supports the rationale for opportunistic HPV vaccination of MSM attending sexual health clinics.

Human papillomavirus (HPV) vaccination and oropharyngeal HPV in ethnically diverse, sexually active adolescents: community-based cross-sectional study.

OBJECTIVES: Oropharyngeal squamous cell carcinoma is the most common human papillomavirus (HPV)-associated cancer in the UK, but little is known about the prevalence of oropharyngeal HPV in sexually active teenagers. We investigated reported HPV vaccination coverage (in females) and prevalence of oropharyngeal HPV in sexually active students attending six technical colleges in London, UK. METHODS: In 2017, we obtained mouthwash samples and questionnaires from male and female students taking part in the 'Test n Treat' chlamydia screening trial. Samples were subjected to HPV genotyping. RESULTS: Of 232 participants approached, 202 (87%) provided a mouthwash sample and questionnaire. Participants' median age was 17 years and 47% were male. Most (73%) were from black and minority ethnic groups, 64% gave a history of oral sex, 52% reported having a new sexual partner in the past 6 months, 33% smoked cigarettes, 5.9% had concurrent genitourinary Chlamydia trachomatis infection and 1.5% Neisseria gonorrhoeae and 5.0% were gay or bisexual. Only 47% (50/107) of females reported being vaccinated against HPV 16/18, of whom 74% had received ≥2 injections. HPV genotyping showed three mouthwash samples (1.5%, 95% CI 0.3% to 4.3%) were positive for possible high-risk human papillomavirus (HR-HPV), one (0.5%, 0.0% to 2.7%) for low-risk HPV 6/11, but none (0.0%, 0.0% to 1.8%) for HR-HPV. Four samples (2.0%, 0.5% to 5.0%) were positive for HPV16 using a HPV16 type-specific quantitative PCR, but these were at a very low copy number and considered essentially negative. CONCLUSIONS: Despite the high prevalence of oral sex and genitourinary chlamydia and low prevalence of HPV vaccination, the prevalence of oropharyngeal HR-HPV in these adolescents was negligible.

Performance of human papillomavirus DNA detection in residual specimens taken for Chlamydia trachomatis and Neisseria gonorrhoeae nucleic acid amplification testing in men who have sex with men.

OBJECTIVES: Rectal swab specimens, either alone or pooled with first-void urine (FVU) and pharyngeal swab specimens, are used to test for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection in men who have sex with men (MSM). Following introduction of human papillomavirus (HPV) vaccination for MSM attending UK sexual health services (SHSs), HPV testing of residual CT/NG test specimens has been proposed to monitor HPV prevalence in this population. Performance of HPV detection in such specimens has not been evaluated previously. METHODS: MSM attending a UK SHS provided three specimens: (1) rectal swab for CT/NG, (2) pooled rectal/pharyngeal/FVU specimen for CT/NG and (3) dedicated anal swab for HPV. Specimen 3 and residual material from specimens 1 and 2 were tested for type-specific HPV DNA. HPV detection was by an in-house multiplex PCR and luminex-based genotyping assay. RESULTS: A total of 129 MSM were recruited with a mean age of 38.1 years; 24% were HIV-positive. Of the 129 MSM, 92 (71%) had any type-specific HPV DNA in ≥1 specimen; 80 (62%) had high risk (HR) HPV. Of 123 participants with sufficient residual pooled and dedicated specimens, 70 (56.9%) had detectable HPV on both, and 40 (32.5%) were negative on both; overall concordance was 89% (95% CI 83% to 94%), and kappa statistic was 0.78 (95% CI 0.66 to 0.89). Pooled samples had a 4.1% (95% CI -1.9% to 10.0%) higher test positivity rate than dedicated samples.Of 125 participants with sufficient residual rectal and specimens, 74 (59.2%) had detectable HPV on both, and 36 (28.8%) were negative on both; overall concordance was 88% (95% CI 81% to 93%), and kappa statistic was 0.74 (95% CI 0.61 to 0.86). Residual rectal samples had 5.6% (95%CI -0.6% to 11.8%) higher test positivity than dedicated samples. CONCLUSIONS: We observed high concordance between the dedicated and residual STI test specimens. Our data support the strategy of testing residual specimens for HPV prevalence monitoring in MSM to evaluate the impact of the targeted vaccination programme.

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

HPV vaccination of gay, bisexual and other men who have sex with men in sexual health and HIV clinics in England: vaccination uptake and attendances during the pilot phase.

BACKGROUND: Human papillomavirus (HPV) vaccination for gay, bisexual and other men who have sex with men (GBMSM) aged up to 45 years attending sexual health clinics (SHC) and HIV clinics began in England as a pilot in June 2016, with national roll-out from April 2018. The recommended course is three doses of the quadrivalent HPV vaccine over one to 2 years. We present the methodology and results of monitoring vaccination uptake (initiation and completion), and attendance patterns, during the pilot phase. METHODS: Total numbers of eligible GBMSM receiving HPV vaccine doses were extracted from routine datasets from pilot start to end of March 2018. Numbers of attendances since January 2009 were extracted and tested for trends before and after introduction of HPV vaccination. RESULTS: Overall, first dose uptake was 49.1 % (23 619/48 095), with clinics with highest data completeness achieving close to 90% uptake during the pilot period. Refusals were very low (3.5%). There was no evidence of increases in the number of GBMSM attendances at pilot SHC. CONCLUSIONS: HPV vaccination has not caused important deviations to expected attendance patterns of GBMSM at SHC throughout the pilot phase. Overall, recorded initiation has been encouraging given known issues with data recording, as is current status of second and third dose completion. Attendances, vaccination initiation and completion will continue to be monitored alongside surveillance of anogenital warts diagnoses and of rectal HPV prevalence.

Clinical impact and cost-effectiveness of primary cytology versus human papillomavirus testing for cervical cancer screening in England.

OBJECTIVES: In England, human papillomavirus (HPV) testing is to replace cytological screening by 2019-2020. We conducted a model-based economic evaluation to project the long-term clinical impact and cost-effectiveness of routine cytology versus HPV testing. METHODS: An individual-based model of HPV acquisition, natural history, and cervical cancer screening was used to compare cytological screening and HPV testing with cytology triage for women aged 25-64 years (with either 3- or 5-year screening intervals for women aged under 50 years). The model was fitted to data from England's National Health Service Cervical Screening Programme. Both clinical and economic outcomes were projected to inform cost-effectiveness analyses. RESULTS: HPV testing is likely to decrease annual cytology testing (by 2.76 million), cervical cancer incidence (by 290 cases), and health system costs (by £13 million). It may increase the number of colposcopies, although this could be reduced without leading to more cancers compared with primary cytology by increasing the interval between screens to 5 years. The impact in terms of quality-adjusted life-years (QALYs) depends on the quality of life weight given to colposcopies versus cancer. CONCLUSIONS: England's move from cytology to HPV screening may potentially be life-saving and cost-effective. Cost-effectiveness can be improved further by extending the interval between screens or using alternative triage methods such as partial or full genotyping.

Epidemiology of genital warts in the British population: implications for HPV vaccination programmes.

OBJECTIVES: To estimate the prevalence of, and describe risk factors for, genital warts (GWs) in the British population, following the introduction of the bivalent (human papillomavirus (HPV)-16/18) vaccination programme in girls, and prior to the switch to quadrivalent (HPV-6/11/16/18) vaccine (offering direct protection against GWs) and compare this with GW diagnoses in the prevaccination era. METHODS: Natsal-3, a probability sample survey in Britain, conducted in 2010-2012, interviewed 9902 men and women aged 16-44. Natsal-2, conducted in 1999-2001, surveyed 11 161 men and women aged 16-44. Both surveys collected data on sexual behaviour and sexually transmitted infection diagnoses using computer-assisted interview methods. RESULTS: In Natsal-3, 3.8% and 4.6% of sexually experienced men and women reported ever having a diagnosis of GWs, with 1.3% of men and 1.7% of woman reporting a GWs diagnosis in the past 5 years. GWs were strongly associated with increasing partner numbers and condomless sex. Diagnoses were more frequent in men who have sex with men (MSM) (11.6% ever, 3.3% past 5 years) and in women reporting sex with women (10.8% ever, 3.6% past 5 years). In the age group who were eligible for vaccination at the time of Natsal-3 (16-20 years), a similar proportion of same-aged women reported a history of GWs in Natsal-2 (1.9%, 1.1-3.4) and Natsal-3 (2.6%, 1.5-4.4). CONCLUSIONS: These data provide essential parameters for mathematical models that inform cost-effectiveness analyses of HPV vaccination programmes. There was no evidence of population protection against GWs conferred by the bivalent vaccine. Even with vaccination of adolescent boys, vaccination should be offered to MSM attending sexual health clinics.

Declines in anogenital warts diagnoses since the change in 2012 to use the quadrivalent HPV vaccine in England: data to end 2017.

OBJECTIVES: In 2008, a national human papillomavirus (HPV) vaccination programme for females was introduced in England using the bivalent vaccine (HPV16 and 18 only). In 2012, the programme changed to offer the quadrivalent vaccine that includes protection against the two HPV types that cause the majority of anogenital warts (AGW; HPV6 and 11). We present data reporting AGW diagnoses in sexual health clinics (SHCs) in England to the end of 2017, including diagnoses among birth cohorts offered the quadrivalent vaccine. METHODS: Using data from all SHCs across England, we performed ecological analyses to consider rates of AGW diagnoses by age, gender and sexual orientation. We tested for trends over time of diagnoses of AGW in young females, heterosexual males, and men who have sex with men (MSM) between the ages of 15 and 24 years during both bivalent (2009 to 2013) and quadrivalent (2014 to 2017) vaccine time periods using Poisson regression. RESULTS: Between 2014 and 2017, there was strong evidence for a decreasing trend in the rate of AGW diagnoses at SHC among females aged 15-17 years from 257.5 to 45.7 per 100 000 population (82.3% decline) and same aged heterosexual males from 59.1 to 19.1 per 100 000 population (67.7% decline). The reductions in the incidence of AGW diagnoses in MSM aged 15-17 years were less clear (decreased by 13.6% between 2014 and 2017, from 129.9 to 112.2 per 100 000 population). CONCLUSIONS: The moderate, unexpected declines in AGW seen since the introduction of a high-coverage HPV vaccination programme using the bivalent vaccine are being followed, as expected, by much larger declines among females offered the quadrivalent vaccine and same-aged heterosexual males. Surveillance plans are in place to continue to monitor AGW diagnoses to evaluate the impact of both female and targeted MSM HPV vaccination on early disease outcomes.

Implementation and evaluation of the human papillomavirus (HPV) vaccination pilot for men who have sex with men (MSM), England, April 2016 to March 2017.

BACKGROUND: Opportunistic human papillomavirus (HPV) vaccination for men who have sex with men (MSM) was piloted in sexual health clinics (SHC) in England between 2016 and 2018. AIM: to evaluate the pilot's first year (April 2016-March 2017) in terms of feasibility, acceptability, uptake, impact and equity and interpret the outcome in the context of wide HPV vaccination policy. METHODS: Attendance and uptake data from routine SHC surveillance datasets and a cross-sectional survey administered to individuals receiving the vaccine were analysed. RESULTS: Among 18,875 eligible MSM, 8,580 (45.5%) were recorded as having received one HPV vaccine dose, decreasing slightly with increasing age, and uptake was higher in rural than urban areas. Survey results suggested that of those receiving the first dose of HPV vaccine, 8% were new attendees and that among those, less than 11% attended just to receive the vaccine. Of those having their first HPV vaccination, 95% indicated they would like to receive the next vaccine doses at the same clinic and 85% of patients reported accessing other services when visiting SHC for the first dose of vaccine. CONCLUSION: An opportunistic HPV vaccination programme for MSM can be delivered in an acceptable and, as far as can be evaluated, equitable manner, without major disruption to SHC and HIV clinics.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

The Impact of the National HPV Vaccination Program in England Using the Bivalent HPV Vaccine: Surveillance of Type-Specific HPV in Young Females, 2010-2016.

Background: The national human papillomavirus (HPV) immunization program was introduced in England in September 2008 using the bivalent vaccine. Methods: We collected residual vulva-vaginal swab specimens from 16 to 24-year-old women attending for chlamydia screening between 2010 and 2016 and tested for HPV DNA. We compared changes in type-specific (vaccine and nonvaccine) HPV prevalence over time and association with vaccination coverage. For women with known vaccination status, vaccine effectiveness was estimated. Results: HPV DNA testing was completed for 15459 specimens. Prevalence of HPV16/18 decreased between 2010/2011 and 2016 from 8.2% to 1.6% in 16-18 year olds and from 14.0% to 1.6% in 19-21 year olds. Declines were also seen for HPV31/33/45 (6.5% to 0.6% for 16-18 year olds and 8.6% to 2.6% for 19-21 year olds). Vaccine effectiveness for HPV16/18 was 82.0% (95% confidence interval [CI], 60.6%-91.8%) and for HPV31/33/45 was 48.7% (95% CI, 20.8%-66.8%). Prevalence of HPV16/18 was compared to findings in 2007-2008 (prevaccination) and to predictions from Public Health England's mathematical model. Discussion: Eight years after the introduction of a national HPV vaccination program, substantial declines have occurred in HPV16/18 and HPV31/33/45. The prevalence of other high-risk HPV types has not changed.

Effect of HPV vaccination and cervical cancer screening in England by ethnicity: a modelling study.

BACKGROUND: Health equality is increasingly being considered alongside overall health gain when assessing public health interventions. However, the trade-off between the direct effects of vaccination and herd immunity could lead to unintuitive consequences for the distribution of disease burden within a population. We used a transmission dynamic model of human papillomavirus (HPV) to investigate the effect of ethnic disparities in vaccine and cervical screening uptake on inequality in disease incidence in England. METHODS: We developed an individual-based model of HPV transmission and disease, parameterising it with the latest data for sexual behaviour (from National Survey of Sexual Attitudes and Lifestyles [Natsal-3]) and vaccine and screening uptake by ethnicity (from Public Health England [PHE]) and fitting it to data for HPV prevalence (from ARTISTIC, PHE, Natsal-3) and HPV-related disease incidence (from National Cancer Registry [ONS]). The outcome of interest was the age-adjusted incidence of HPV-related cancer (both cervical and non-cervical) in all women in England in view of differences and changes in vaccination and screening uptake by ethnicity in England, over time. We also studied three potential public health interventions aimed at reducing inequality in HPV-related disease incidence: increasing uptake in black and Asian females to match that in whites for vaccination; cervical screening in women who turn 25 in 2018 or later; and cervical screening in all ages. FINDINGS: In the pre-vaccination era, before 2008, women from ethnic minorities in England reported a disproportionate share of cervical disease. Our model suggests that Asian women were 1·7 times (95% credibility interval [CI] 1·1-2·7) more likely to be diagnosed with cervical cancer than white women (22·8 vs 13·4 cases per 100 000 women). Because HPV vaccination uptake is lower in ethnic minorities, we predict an initial widening of this gap, with cervical cancer incidence in Asian women up to 2·5 times higher (95% CI 1·3-4·8) than in white women 20 years after vaccine introduction (corresponding to an additional 10·8 [95% CI 10·1-11·5] cases every year). In time, we predict that herd immunity benefits will diffuse from the larger white sub-population and the disparity will narrow. Increased cervical screening uptake in vaccinated women from ethnic minorities would lead to rapid improvement in equality with parity in incidence after 20 years of HPV vaccination. INTERPRETATION: Our study suggests that the introduction of HPV vaccination in England will initially widen a pre-existing disparity in the incidence of HPV-related cancer by ethnicity, partly due to herd immunity disproportionately benefiting subgroups with high vaccination rates. Although in time this induced disparity will narrow, increasing cervical screening uptake in girls from ethnic minorities should be encouraged to eliminate the inequality in cervical cancer incidence in the medium term. We recommend that dynamic effects should be considered when estimating the effect of public health programmes on equality. FUNDING: Cancer Research UK.