Rebecca Howell-Jones

Multi-site study of HPV type-specific prevalence in women with cervical cancer, intraepithelial neoplasia and normal cytology, in England

Background:Knowledge of the prevalence of type-specific human papillomavirus (HPV) infections is necessary to predict the expected, and to monitor the actual, impact of HPV immunisation and to design effective screening strategies for vaccinated populations.Methods:Residual specimens of cervical cytology (N=4719), CIN3/CGIN and cervical cancer biopsies (N=1515) were obtained from sites throughout England, anonymised and tested for HPV DNA using the Linear Array typing system (Roche).Results:The prevalence of HPV 16 and/or 18 (with or without another high-risk (HR) type) was 76% in squamous cell carcinomas, 82% in adeno/adenosquamous carcinomas and 63% and 91% in CIN3 and CGIN, respectively. Of all HR HPV-infected women undergoing cytology, non-vaccine HPV types only were found in over 60% of those with mild dyskaryosis or below, and in <20% of those with cancer. In women of all ages undergoing screening, HR HPV prevalence was 16% and HPV 16 and/or 18 prevalence was 5%.Conclusion:Pre-immunisation, high-grade cervical disease in England was predominantly associated with HPV 16 and/or 18, which promises a high impact from HPV immunisation in due course. Second-generation vaccines and screening strategies need to consider the best ways to detect and prevent disease due to the remaining HR HPV types.BACKGROUND Knowledge of the prevalence of type-specific human papillomavirus (HPV) infections is necessary to predict the expected, and to monitor the actual, impact of HPV immunisation and to design effective screening strategies for vaccinated populations. METHODS Residual specimens of cervical cytology (N=4719), CIN3/CGIN and cervical cancer biopsies (N=1515) were obtained from sites throughout England, anonymised and tested for HPV DNA using the Linear Array typing system (Roche). RESULTS The prevalence of HPV 16 and/or 18 (with or without another high-risk (HR) type) was 76% in squamous cell carcinomas, 82% in adeno/adenosquamous carcinomas and 63% and 91% in CIN3 and CGIN, respectively. Of all HR HPV-infected women undergoing cytology, non-vaccine HPV types only were found in over 60% of those with mild dyskaryosis or below, and in <20% of those with cancer. In women of all ages undergoing screening, HR HPV prevalence was 16% and HPV 16 and/or 18 prevalence was 5%. CONCLUSION Pre-immunisation, high-grade cervical disease in England was predominantly associated with HPV 16 and/or 18, which promises a high impact from HPV immunisation in due course. Second-generation vaccines and screening strategies need to consider the best ways to detect and prevent disease due to the remaining HR HPV types.

A Randomized, Observer-Blinded Immunogenicity Trial of Cervarix® and Gardasil® Human Papillomavirus Vaccines in 12-15 Year Old Girls

Background The current generation of Human Papillomavirus (HPV) vaccines, Cervarix® and Gardasil®, exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross-protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals. Methods and Findings Serum and genital samples were collected from 12–15 year old girls following vaccination with either Cervarix® (n = 96) or Gardasil® (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix®, compared to the Gardasil®, vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix® having a median 2.5 (inter-quartile range, 1.7–3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil® (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types. Conclusions These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross-neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines. Trial Registration ClinicalTrials.gov NCT00956553

Epidemiology of, and behavioural risk factors for, sexually transmitted human papillomavirus infection in men and women in Britain

Objectives Persistent infection with high-risk sexually transmitted human papillomaviruses (HR-HPVs) can lead to development of cervical and other cancers, while low-risk types (low-risk HPV) may cause genital warts. We explored the epidemiology of different HPV types in men and women and their association with demographic and behavioural variables. Methods We analysed data collected for the British National Survey of Sexual Attitudes and Lifestyles, a cross-sectional survey undertaken in 1999–2001. Half of all sexually experienced male and female respondents aged 18–44 years were invited to provide a urine sample. We tested 3123 stored urine samples using an in-house Luminex-based HPV genotyping system. Results HPV DNA was detected in 29.0% (95% CI 26.7% to 31.3%) of samples from women and 17.4% (95% CI 15.1% to 19.8%) from men. Any of 13 HR-HPV types was detected in 15.9% (95% CI 14.1% to 17.8%) of women and 9.6% (95% CI 8.0% to 11.6%) of men. HPV types 16/18 were found in 5.5% (95% CI 4.5% to 6.8%) of women and 3.0% (95% CI 2.1% to 4.3%) of men; and types 6/11 in 4.7% (95% CI 1.8% to 5.9%) of women and 2.2% (95% CI 1.5% to 3.1%) of men. In multivariate analysis, HR-HPV was associated with new partner numbers, in women with younger age, single status and partner concurrency, and in men with number of partners without using condom(s) and age at first intercourse. Conclusions HPV DNA was detectable in urine of a high proportion of the sexually active British population. In both genders, HR-HPV was strongly associated with risky sexual behaviour. The minority of HPV infections were of vaccine types. It is important to monitor HPV prevalence and type distribution following the introduction of vaccination of girls.

Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study

Objective To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18 for schoolgirls. Design Cohort study Setting 20 London universities and further education colleges. Participants 2185 sexually active female students, mean age 21 years (range 16-27), 38% from ethnic minorities, who took part in the POPI (prevention of pelvic infection) chlamydia screening trial in 2004-08 and who provided duplicate, self taken vaginal swabs and completed questionnaires at baseline. At follow-up, a median of 16 months later, 821 women (38%) returned repeat vaginal swabs by post. In 2009-10, stored samples were tested for HPV. Results Samples from 404/2185 (18.5% (95% CI 16.9% to 20.2%)) of the cohort were positive for carcinogenic HPV at baseline, including 15.0% (327) positive for non-vaccine carcinogenic genotypes. Reporting two or more sexual partners in the previous year and concurrent Chlamydia trachomatis or bacterial vaginosis were independent risk factors for prevalent vaginal HPV infection. Infection with one or more new HPV types was found in 17.7% (145/821) of follow-up samples, giving an estimated annual incidence of carcinogenic HPV infection of 12.9% (95% CI 11.0% to 15.0%). Incident infection was more common in women reporting two or more partners in the previous year, aged<20, of black ethnicity, or with C trachomatis vaginosis at baseline. Multiple partners was the only independent risk factor for incident infection (adjusted relative risk 1.99 (95% CI 1.46 to 2.72)). Of 143 women with baseline carcinogenic HPV infection, 20 (14% (8.3% to 19.7%) had infection with the same carcinogenic HPV type(s) detected after 12-28 months. Of these women, 13 (65%) had redetected infection with HPV 16 or 18, and nine (45%) with non-vaccine carcinogenic HPV genotypes. Conclusion In the first UK cohort study of carcinogenic HPV in young women in the community, multiple sexual partners was an independent predictor of both prevalent and incident infection. Infection with non-vaccine carcinogenic genotypes was common. Although current HPV vaccines offer partial cross protection against some non-vaccine carcinogenic HPV types, immunised women will still need cervical screening.

Prevalence of human papillomavirus (HPV) infections in sexually active adolescents and young women in England, prior to widespread HPV immunisation

INTRODUCTION The introduction of an HPV immunisation programme in England should result in a significant reduction in the prevalence of vaccine type infections in young women. Here we describe type-specific HPV prevalence in three samples of the young female population in England, prior to the beginning of mass immunisation in 2008. METHODS Residual vulva-vaginal swab samples from females aged under 25 years undergoing chlamydia testing as part of the National Chlamydia Screening Programme (NCSP) or Prevention of Pelvic Infection (POPI) trial were collected from sites across England, together with available demographic and sexual behaviour data. Residual samples were screened for HPV infection using the Hybrid Capture 2 (hc2) HPV DNA Test, including the high-risk (HR) and low-risk (LR) probes. Hc2 positive samples were genotyped using the Roche Linear Array (LA) HPV Genotyping Test. RESULTS A total of 3829 samples were included: 2369 from 16 to 24 year old NCSP participants, 275 from 13 to 15 year old NCSP participants and 1185 from 16 to 24 year old POPI participants. Variations in HPV prevalence between and within the different samples followed a pattern largely consistent with differences in sexual behaviour. The prevalence of total HR HPV infection, of HPV 16 and/or 18 (16/18) infection and of five HR HPV types closely related to HPV 16/18 (HPV 31, 33, 45, 52 or 58) amongst 16-24 year old NCSP participants was 35% (95% CI 33-37%), 18% (95% CI 16-19%), and 16% (95% CI 14-18%), respectively. Risk of HR HPV infection increased with age during the teen years and was higher in women who reported two or more sexual partners in the last year and in women with chlamydia infection. Approximately half of women with HPV 16/18 infection also had another non-vaccine HR HPV type present. CONCLUSIONS Prior to HPV immunisation, there was a high prevalence of HPV infections in the lower genital tract of young, sexually active females in England. The overall, type-specific, and multiple infection prevalence closely reflected age and sexual activity. These data provide a baseline against which the early impact of HPV immunisation on the prevalence of HPV 16/18 and closely related types in young women can be measured, in order to inform immunisation and cervical screening policies.

Neutralization of non-vaccine human papillomavirus pseudoviruses from the A7 and A9 species groups by bivalent HPV vaccine sera

Highlights ► We examined neutralizing antibody in girls immunized with bivalent HPV vaccine. ► Antibody cross-reactivity dependent on response to vaccine types. ► Significant cross-reactivity against HPV31, HPV33, HPV45. ► Cross-reactive levels are low at <1% of vaccine type antibody responses. ► Potential role for cross-reactive antibodies as surrogate of protection.

Human papillomavirus genotype detection and viral load in paired genital and urine samples from both females and males.

The ability to detect type‐specific high risk HPV (HR‐HPV) infections in samples from females and males is important for monitoring the epidemiology of HPV and the impact of vaccination. Type‐specific detection concordance between paired urine and genital samples from females (n = 264) undergoing routine colposcopy and males (n = 88) attending a genito‐urinary medicine clinic was evaluated using an in‐house genotyping assay. The overall inter‐rater agreement (κ) was 0.781 for female pairs and 0.346 for male pairs. Female urine had sensitivity for detection of HPV16/18 and HR‐HPV of 75% and 84%, respectively, while male urine had sensitivities of 13% and 28%, respectively. Genital samples had a higher HPV DNA copy number than urine although a small proportion (10%) of urine samples had a higher copy number than the corresponding genital sample. The proportion of females with normal cytology positive for HPV16/18 was 19%, increasing to 57% in moderate or severely dyskaryotic samples. The same trend was seen in the corresponding urine (19–43%) compounded by the reduced sensitivity of this sample type. The HPV16 viral load in female genital samples, but not in urine, was weakly associated with cervical disease stage. Despite reduced sensitivity, urine appears to be an appropriate surrogate sample for type‐specific HPV detection in females for epidemiological objectives. The lower sensitivity and lack of association between viral load and disease stage in urine suggest that urine may not be useful for clinical management of HPV infection. The utility of urine for type‐specific detection in males is less certain. J. Med. Virol. 83:1744–1751, 2011.

Does laboratory antibiotic susceptibility reporting influence primary care prescribing in urinary tract infection and other infections

OBJECTIVES Using a prospective interrupted time series design, our goal was to determine whether a change in urine antibiotic susceptibility reporting from co-amoxiclav to cefalexin to community clinicians served by Southmead General Hospital led to a change in antibiotic prescribing. METHODS We used longitudinal data on antibiotic prescribing using a clinician questionnaire to identify prescribing for urinary tract infections (UTIs) when a urine specimen was submitted to microbiology; MIQUEST computer search in general practices for prescribing for all UTIs in the community; and Prescribing Analysis and Cost (PACT) data to determine antibiotic prescribing for all infections. RESULTS Cefalexin and cephalosporin prescribing increased when cefalexin was reported and co-amoxiclav prescribing decreased when co-amoxiclav was not reported by the laboratory. This was seen for episodes of UTI in which a general practitioner (GP) sent a specimen as determined with: the questionnaire results (9-fold rise in cephalosporins, 70% fall in co-amoxiclav); episodes of UTI identified by MIQUEST searches in the practice (50% increase in cefalexin, 25% reduction in co-amoxiclav); and overall antibiotic prescribing in the practice determined with PACT data (20% increase in cefalexin, 8% reduction in co-amoxiclav). MIQUEST data indicated that prescribing reverted to pre-intervention levels once the change in antibiotic reporting had stopped. CONCLUSIONS Our data provide more evidence that changing laboratory antibiotic susceptibility reporting has a direct effect on antibiotic prescribing by GPs. Our data indicate that much of the change in prescribing was attributable to the use of cefalexin and co-amoxiclav for persistent or recurrent infections. Microbiology laboratories can influence antibiotic use by selectively reporting antibiotics they would prefer GPs to prescribe.

Overcoming the barriers to chlamydia screening in general practice—a qualitative study

BACKGROUND There is low uptake of chlamydia screening in general practices registered with the English National Chlamydia Screening Programme (NCSP). Aims. To explore staffs attitudes and behaviour around chlamydia screening and how screening could be optimized in general practice. METHODS A qualitative study with focus groups and interviews, in general practices in seven NCSP areas. Twenty-five focus groups and 12 interviews undertaken with a purposively selected diverse group of high and low chlamydia-screening practices in 2006-08. Data were collected and analysed using a framework analytical approach. RESULTS Higher screening practices had more staff with greater belief in patient and population benefits of screening and, as screening was a subjective norm, it was part of every day practice. Many staff in the majority of other practices were uncomfortable raising chlamydia opportunistically and time pressures meant that any extra public health issues covered within a consultation were determined by Quality Outcomes Framework (QOF) targets. All practices would value more training and feedback about their screening rates and results. Practices suggested that use of computer prompts, simplified request forms and more accessible kits could increase screening. CONCLUSION Practice staff need more evidence of the value of opportunistic chlamydia screening in men and women; staff development to reduce the barriers to broaching sexual health; simpler request forms and easily accessible kits to increase their ability to offer it within the time pressures of general practice. Increased awareness of chlamydia could be attained through practice meetings, computer templates and reminders, targets and incentives or QOF points with feedback.

Staphylococcus aureus carriage in care homes: identification of risk factors, including the role of dementia

The aim of this study was to investigate the prevalence and associated risk factors of methicillin-susceptible and methicillin-resistant Staphylocccus aureus (MSSA and MRSA) carriage in care homes, with particular focus on dementia. A point-prevalence survey of 748 residents in 51 care homes in Gloucestershire and Greater Bristol was undertaken. Dementia was assessed by the clock test or abbreviated mini-mental test. Nasal swabs were cultured for S. aureus on selective agar media. Multivariable analysis indicated that dementia was not a significant risk factor for MSSA (16.2%) or MRSA (7.8%); and that residents able to move around the home unassisted were at a lower risk of MRSA (P=0.04). MSSA carriage increased with increasing age (P=0.03) but MRSA carriage decreased with increasing age (P=0.05). Hospitalization in the last 6 months increased the risk of MSSA (P=0.04) and MRSA (P=0.10). We concluded that cross-infection through staff caring for more dependent residents may spread MRSA within care homes and from the recently hospitalized. Control of MSSA and MRSA in care homes requires focused infection control interventions.