Martin Donaghy

Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types

Background:In 2008, a national human papillomavirus (HPV) immunisation programme began in Scotland for 12–13 year old females with a three-year catch-up campaign for those under the age of 18. Since 2008, three-dose uptake of bivalent vaccine in the routine cohort aged 12–13 has exceeded 90% annually, while in the catch-up cohort overall uptake is 66%.Methods:To monitor the impact of HPV immunisation, a programme of national surveillance was established (pre and post introduction) which included yearly sampling and HPV genotyping of women attending for cervical screening at age 20. By linking individual vaccination, screening and HPV testing records, we aim to determine the impact of the immunisation programme on circulating type-specific HPV infection particularly for four outcomes: (i) the vaccine types HPV 16 or 18 (ii) types considered to be associated with cross-protection: HPV 31, 33 or 45; (iii) all other high-risk types and (iv) any HPV.Results:From a total of 4679 samples tested, we demonstrate that three doses (n=1100) of bivalent vaccine are associated with a significant reduction in prevalence of HPV 16 and 18 from 29.8% (95% confidence interval 28.3, 31.3%) to 13.6% (95% confidence interval 11.7, 15.8%). The data also suggest cross-protection against HPV 31, 33 and 45. HPV 51 and 56 emerged as the most prevalent (10.5% and 9.6%, respectively) non-vaccine high-risk types in those vaccinated, but at lower rates than HPV 16 (25.9%) in those unvaccinated.Conclusions:This data demonstrate the positive impact of bivalent vaccination on the prevalence of HPV 16, 18, 31, 33 and 45 in the target population and is encouraging for countries which have achieved high-vaccine uptake.

Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland

Background:In Scotland, a national HPV immunisation programme began in 2008 for 12- to 13-year olds, with a catch-up campaign from 2008 to 2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established.Methods:We analysed colposcopy data from a cohort of women born between 1988 and 1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20–21 in 2008–2012.Results:By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1; RR 0.71, 95% CI 0.58 to 0.87; P=0.0008), CIN 2 (RR 0.5, 95% CI 0.4 to 0.63; P<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58; P<0.0001) for women who received three doses of vaccine compared with unvaccinated women.Conclusions:To our knowledge, this is one of the first studies to show a reduction of low- and high-grade CIN associated with high uptake of the HPV bivalent vaccine at the population level. These data are very encouraging for countries that have achieved high HPV vaccine uptake.

A population-based record linkage study of mortality in hepatitis C-diagnosed persons with or without HIV coinfection in Scotland

Infection with the hepatitis C virus (HCV) is known to increase the risk of death from severe liver disease and, because HCV status is strongly associated with a history of injecting drug use, the effect of a key disease progression cofactor, infection with human immunodeficiency virus (HIV), is of interest. We examined all-cause, liver-related and drug-related mortality and excess risk of death from these causes in a large cohort of HCV-monoinfected and HIV-coinfected persons in Scotland. The study population consisted of 20,163 persons confirmed to be infected with hepatitis C through laboratory testing in Scotland between 1991 and 2005. Records with sufficient identifiers were linked to the General Register Office for Scotland death register to retrieve associated mortality data, and were further linked to a national database of HIV-positive individuals to determine coinfection status. A total of 1715 HCV monoinfected and 305 HIV coinfected persons died of any cause during the follow-up period (mean of 5.4 and 6.4 years, respectively). Significant excess mortality was observed in both HCV monoinfected and HIV coinfected populations from liver-related underlying causes (standardised mortality ratios of 25, 95% CI = 23—27; and 37, 95% CI = 26—52 for the two groups, respectively) and drug-related causes (25, 95% CI = 23—27; 39, 95% CI = 28—53. The risk of death from hepatocellular carcinoma, alcoholic or non-alcoholic liver disease, or from a drug-related cause, was greatly increased compared with the general Scottish population, with the highest standardised mortality ratio observed for hepatocellular carcinoma in the monoinfected group (70, 95% CI = 57—85). This study has revealed considerable excess mortality from liver- and drug-related causes in the Scottish HCV-diagnosed population; these data are crucial to inform on the clinical management, and projected future public health burden, of HCV infection.

Achieving high and equitable coverage of adolescent HPV vaccine in Scotland

Background and methods The national immunisation records of over 220 000 girls offered vaccine in the routine or catch-up programme of the Human papillomavirus (HPV) programme in Scotland were analysed. Descriptive statistics and multilevel modelling were used to determine individual and organisational factors associated with uptake. Age, school year, school denomination, deprivation and, for school-leavers, mode of delivery were explored. Additional aggregate data were used to examine the effect of late uptake of missed doses in the routine vaccination programme. Results School-based delivery initially achieved over 80% uptake of complete courses in routine and catch-up age groups. Within this context of generally high coverage, there was an association between individual level deprivation and lower uptake, and a decline in in-year course completion over time. However, later uptake of missed doses in the following year substantially decreased these effects. There was no influence on uptake of the type of school (non-denominational/denominational). Vaccination of school-leavers in the catch-up campaign had lower coverage, with 50% starting and 30% completing the course in-year. There was no clear advantage of vaccination through general practice or through Board-run clinics in reaching this group. Conclusions School-based vaccination can achieve high and equitable uptake of a multidose vaccine in a routine immunisation programme. Sustained high coverage with HPV vaccine across Scotland provides a stable platform for planning future strategies for cervical screening and understanding the impact of the vaccination at a population level.

HPV type-specific prevalence using a urine assay in unvaccinated male and female 11- to 18-year olds in Scotland

Background:We conducted a baseline prevalence survey of unvaccinated 11- to 18-year olds to inform effectiveness studies for the new human papillomavirus (HPV) immunisation programme in Scotland.Methods:Participants were recruited from schools and colleges and invited to provide demographic data and an anonymous urine sample for type-specific HPV testing.Results:Among females aged 11–14 years, the weighted prevalence was 1.1% overall; 0.9% for high-risk types and no infections were associated with types 16 and 18. Among 15- to 18-year old females, the weighted prevalence was 15.2% overall; 12.6% for high-risk types and 6.5% for types 16 and 18. Among females aged 16–18 years, infection was more frequently associated with attending college and rural schools, and showed a trend towards increasing prevalence with increasing social deprivation (P=0.045). Among males aged 11–14 years, the weighted prevalence was 1.4% overall; 1.0% for high-risk types and 0.7% for types 16 and 18. Among 15- to 18-year old males, the weighted prevalence was 3.9% overall; 2.4% for high-risk types and 0.7% for types 16 and 18.Conclusions:Human Papillomavirus prevalence is low among 11- to 14-year olds, which includes the age group targeted for routine vaccination. The prevalence in males and correlation with deprivation require further investigation.

Estimation of HPV prevalence in young women in Scotland; monitoring of future vaccine impact

BackgroundEstimation of pre-immunisation prevalence of HPV and distribution of HPV types is fundamental to understanding the subsequent impact of HPV vaccination. We describe the type specific prevalence of HPV in females aged 20–21 in Scotland who attended or defaulted from cervical screening using three specimen types; from attenders liquid based cytology and from defaulters urine or self-taken swabs.MethodsResidual liquid based cytology samples (n = 2148), collected from women aged 20–21 attending for their first smear were genotyped for HPV. A sample (n = 709) from women who had defaulted from screening was also made available for HPV testing through the use of postal testing kits (either urine samples (n = 378) or self-taken swabs (n = 331)). Estimates of prevalence weighted by deprivation, and for the postal testing kit, also by reminder status and specimen type were calculated for each HPV type. The distribution of HPV types were compared between specimen types and the occurrence of multiple high-risk infections examined. The influence of demographic factors on high-risk HPV positivity and multiple infections was examined via logistic regression.ResultsThe prevalence of any HPV in young women aged 20–21 was 32.2% for urine, 39.5% for self-taken swab, and 49.4% for LBC specimens. Infection with vaccine specific types (HPV 16, 18) or those associated with cross-protection (HPV 31, 33, 45, 51) was common. Individuals were more likely to test positive for high-risk HPV if they resided in an area of high deprivation or in a rural area. The overall distribution of HPV types did not vary between defaulters and attenders. Multiple infections occurred in 48.1% of high-risk HPV positive individuals. Excluding vaccine types the most common pairing was HPV 56 and 66.ConclusionsUnderstanding of the pre-immunisation prevalence of HPV in young women puts Scotland in a prime position to assess the early effect of vaccination as the first highly vaccinated cohorts of individuals enter the screening programme. Differences in results with different specimen types must be taken into account when monitoring the impact of vaccination programmes.

Acceptability and response to a postal survey using self-taken samples for HPV vaccine impact monitoring

Objective To assess the feasibility and acceptance of a postal survey to measure human papillomavirus (HPV) prevalence and monitor vaccine impact, using self-taken specimens from young women who do not attend their first cervical screening appointment. Methods Focus groups informed the survey design identifying factors that would influence acceptability. Postal testing kits were sent to a nationally representative sample of unscreened women. Overall response rate, the influence of different specimen types (urine or vaginal swab) and the receipt of a reminder letter on participation were calculated. Specimens were tested anonymously for HPV. Individual test results were not provided. Results Of 5500 kits sent, 725 were returned (13.2%). Fifty-two women actively opted out. There was a higher return rate for urine kits (13.7% vs 12%) and from those who received a reminder letter (15.5% vs 12.2%). Response was influenced by deprivation (10.3% in the most deprived quintile vs 16.2% in the least). Overall weighted HPV prevalence was 35.9% (40.0% from swab specimens and 31.9% from urine). Conclusions Some women were willing to participate in anonymised postal testing. However, the low uptake means that HPV prevalence results are difficult to interpret for ongoing surveillance. Monitoring HPV vaccine impact outwith the cervical screening programme remains challenging.

High uptake of HPV immunisation in Scotland--perspectives on maximising uptake.

In September 2008, Scotland introduced a national human papillomavirus (HPV) immunisation programme with bivalent HPV vaccine, to prevent cervical cancer. This school-based programme routinely vaccinates girls aged between 12 and 13 years. A catch-up campaign, running over three years, also began at this time, offering vaccination to all girls aged 13 years to under 18 years old. The HPV immunisation campaign presented challenges due to this vaccine being targeted to girls in school and older girls who had left school. Following a long and comprehensive planning process, this campaign was successfully implemented across Scotland, delivering high vaccine uptake of 91.4% for three doses of vaccine in the first year (September 2008 to August 2009) for the routine cohort and 90.1% in the second year (September 2009 to August 2010) for the routine cohort. We describe the planning process, challenges and implementation strategies employed to achieve this high uptake.

Effect of HPV assay choice on perceived prevalence in a population-based sample

Human papillomavirus (HPV) immunization programs clearly have considerable potential to reduce HPV-associated disease; they are also resource-intense; so, it is essential that their effectiveness is determined accurately and in a timely way. Measuring circulating HPV types in a population can provide an early measure of vaccine impact. We assessed the impact of HPV assay on the observed population prevalence of HPV in women who provided samples as part of a National HPV Immunisation Surveillance Exercise. A total of 1145 liquid-based cytology samples, 326 self-taken swabs, and 371 urine samples were tested with a line-blot assay (the Digene reverse hybridization HPV genotyping assay) and a luminex-based assay (the Mulitmetrix HPV genotyping assay). Assay agreement was determined for the different sample types. Positivity (according to assay) was compared at different levels ranging from positive for HPV 16 and/or 18 to positive for any one of the 18 HPV types common to both assays. The luminex assay consistently detected a higher prevalence of HPV—up to 10% for HPV types common to both assays. In addition, disagreement for HPV 16 and/or 18 was observed in around 9% of the overall sample, with an associated &kgr; score of 0.74. These data indicate that assay choice has a significant impact on observed prevalence of HPV, including vaccine types. The impact of any change of assay during longitudinal surveillance programs should thus be taken into account to avoid confounding the assessment of any vaccine-induced changes.

Q fever in migrant workers, Scotland.

To the Editor: Q fever is a zoonosis caused by infection with Coxiella burnetii and is most commonly associated with occupational exposure to animal-slaughtering facilities. C. burnetii is an obligate intracellular bacterium and causes highly variable disease, ranging from asymptomatic infection to fatal chronic infective endocarditis. In June 2006, the United Kingdom experienced its largest outbreak of Q fever with 138 cases associated with a slaughterhouse near Stirling in Scotland. The slaughterhouse had been processing post-parturition ewes in the lairage (place for keeping livestock temporarily) at the end of May. These animals were thought to be among the most likely to shed the organism (1). Further investigation showed that a ewe had aborted in the lairage toward the end of May. Although the sheep lairage was the most likely source of the infection, no microbiologic evidence confirmed this, as C. burnetii was not isolated from environmental samples. The outbreak was neither remarkable for its putative mode of transmission nor for the industry involved, but both the number and nationalities of migrant workers infected was noteworthy. Since 2004, 12 member states have joined the European Union and this has led to an influx of immigrants to the United Kingdom. The increase in migrant numbers has partly been a result of the government’s managed migration policy, expanding migration to fill vacancies in skilled and low-wage occupations. Employers have difficulty recruiting UK workers because of the jobs’ physical demands, long hours that limit social activities, and low pay. They therefore recruit international workers with a good work ethic and reliability; central and Eastern European workers are compared favorably with UK nationals (2). Migrants from Eastern and central Europe are now more likely to be found in low-wage occupations in agriculture, construction, hospitality, and au pair employment. Of the 138 cases of Q fever, 48 were immigrants from the following countries: Slovakia (41), Poland (3), Czech Republic (2), and Lithuania (2). Unsurprisingly, epidemiologic case interviews were beset with linguistic and logistic problems. The diagnosis of Q fever relies predominantly on its serologic legacy since asymptomatic seroconversion occurs in up to 60% of patients (3). Analysis of our cohort found that non-UK patients were significantly less likely than their UK counterparts to have symptoms (fever, muscle pain, joint pain, headache, and cough) and to subsequently have Q fever confirmed (Table, p<0.001). Twenty-two patients (15 UK, 7 non-UK) did not complete epidemiologic questionnaires and were therefore not included in this analysis. Table χ2 analysis of Q fever symptoms and GP registration by nationality* Furthermore, analysis of cases registered with general practitioners (GPs) identified a significant difference (Table, p<0.001) between UK and non-UK patients with the latter group less likely to be registered with a GP. Although most UK residents were registered with a general practice, only 11 of 43 non-UK cases were registered. Information on GP registration was not known for 17 patients, and these were not included in the analysis. Although the investigating health board took stringent steps to ensure follow-up of all patients, we believe that some asymptomatic non-UK patients may have permanently returned to their native countries with undiagnosed illness, and subsequently, cannot be traced. This unfortunate scenario has potentially catastrophic implications for these patients because proper follow-up clinical management of Q fever is necessary to prevent possible endocarditis (4), unnecessary surgery, and premature death. Persons with known occupational hazards have benefited from an effective Q fever vaccine; abattoir workers and farmers are routinely vaccinated in Australia (5). Given the aforementioned linguistic and coordination issues with follow-up of migrant workers and the potential gravity of inappropriate clinical follow-up, it may be prudent to consider Q fever vaccination for all employees who work within UK meat-processing industries. Public health practitioners should be aware of the continuously evolving multinational makeup of the local population and this should stimulate constant review of local translation services because census data seriously underrecognize the ethnic minority migrant worker population. Furthermore, many migrant workers are unsure of their rights to access primary and hospital care and the structure of healthcare is unfamiliar to many. GPs should consider zoonotic infections, such as Q fever, when patients with acute febrile illness report occupational livestock exposure, especially because migrant workers have become an important source of labor (sometimes preferred over domestic workers) in the agricultural workforce in the United Kingdom (2).