Cervical screening in HPV-vaccinated populations

Cervical screening with cytology has been the basis for substantial reductions in cervical cancer incidence and mortality in most high-income countries over the last few decades. More recently, there have been two key, parallel developments which have prompted a major re-consideration of cervical screening. The first is the emergence of evidence on the improved sensitivity of human papillomavirus (HPV) DNA testing compared to cytology, and the second is the large-scale deployment of prophylactic vaccination against HPV. A key challenge to be overcome before HPV screening could be introduced into national cervical screening programs was the specificity of an infection, for detection of precancerous lesions. This has been done in three ways: (1) by considering the appropriate age for starting HPV screening (30 years in unvaccinated populations and 25 years in populations with mature vaccination programs and high vaccine uptake) and the appropriate screening interval; (2) via development of clinical HPV tests, which are (by design) not as sensitive to low viral loads; and (3) by introducing effective triaging for HPV-positive women, which further risk-stratifies women before referral for diagnostic evaluation. This review discusses these major developments and describes how the benefits of HPV screening are being optimized in both unvaccinated and vaccinated populations

Impact of the National Cervical Screening Programme in New Zealand by age: analysis of cervical cancer trends 1985-2013 in all women and in Māori women

Background New Zealand is an example of a country with a well-established cytology-based screening program. New Zealand’s National Cervical Screening Programme (NCSP) commenced in 1990, and recommends three-yearly cytology-based screening for women aged 20–69 years. In 2018, the NCSP will transition to five-yearly HPV-based screening for women aged 25–69 years. The aim of this study was to assess the impact of the program to date in different groups, to provide a benchmark for the new program. Methods Analysis of cervical cancer trends in New Zealand by age and ethnicity over the period 1985–2013, and by morphology over the period 1997–2013, using data from the New Zealand Cancer Registry was conducted. Results The overall incidence of cervical cancer was 56% (95% CI 51–60%) lower in 2009–2013 than in 1985–1989, and significant reductions were observed in women aged 25–49, 50–69, and 70 + years. Relative reductions in cervical cancer were very similar for Māori and non-Māori women aged 25–49 (50% in Māori; 52% in non-Māori) and 50–69 years (65% in Māori; 69% in non-Māori). In contrast, incidence appeared to increase after around 1996 in women aged 20–24. The increasing trend was significant for women aged 20–24 overall and for non-Māori women (p < 0.01 in both cases). Conclusion There have been substantial reductions in cervical cancer among women aged 25 + years in New Zealand since the inception of the NCSP, and these reductions are similar in Māori and non-Māori women. Cervical cancer incidence among women 20–24 years has not declined since the NCSP began, and appears to be increasing.NZ MOHNZ MO

Participation in Cervical Screening by Older Asian and Middle Eastern Migrants in New South Wales, Australia

Background: There is little information on the detailed patterns of cervical screening uptake in older migrant women in Australia. This linkage study was performed to assess cervical screen-ing participation in older migrants.Methods: We linked year 2000-2001 records for 14,228 Middle Eastern/Asian-born women 40-64 years of age, and an age and area matched random sample of 13,939 Australian-born wom-en in the New South Wales (NSW) Admitted Patients Data Collection (APDC), which records country of birth, to screening register records. Screening behaviour after 1st July 2001 was as-sessed in women without a recorded prior cervical abnormalityResults: Compared to Australian-born women, women born in South Central Asia had a low-er screening participation rate (odds ratio for being screened at least once within a 3 year period 0.78, 95% CI 0.70-0.88). However, participation appeared relatively higher (17%-25%) in women born in the Middle East or other parts of Asia. Screening increased with increasing socioeconom-ic status (SES) in Australian-born women, but this trend was not observed in the migrant wom-en. When we broadly corrected for hysterectomy, the apparent excess of screening in women from the Middle East and other parts of Asia was substantially eliminated and in contrast, the apparent deficiency in screening in women from South Central Asia increased.Conclusions: Older women from the Middle East, and North East and South East Asian countries appeared to have similar overall screening participation to that of Australian-born women. Women from South Central Asia appeared less likely than Australian-born women to participate in cervical screening at the recommended interval

Potential for HPV vaccination and primary HPV screening to reduce cervical cancer disparities: Example from New Zealand

Background Cervical cancer rates are over twice as high, and screening coverage is lower, in Māori women compared to other women in New Zealand, whereas uptake of HPV vaccine is higher in Maori females. We aimed to assess the impact of HPV vaccination and the proposed transition to 5-yearly primary HPV screening in Māori and other women in New Zealand, at current participation levels; and additionally to investigate which improvements to participation in Māori females (in vaccination, screening, or surveillance for screening-defined higher-risk women) would have the greatest impact on cervical cancer incidence/mortality. Methods An established model of HPV vaccination and cervical screening in New Zealand was adapted to fit observed ethnicity-specific data. Ethnicity-specific models were used to estimate the long-term impact of vaccination and screening (vaccination coverage 63% vs 47%; five-year screening coverage 68% vs 81% in Maori vs European/Other women, respectively). Results Shifting from cytology to HPV-based screening is predicted to reduce cervical cancer incidence by 17% (14%) in Maori (European/Other) women, respectively. The corresponding reductions due to vaccination and HPV-based screening combined were 58% (44%), but at current participation levels long-term incidence would remain almost twice as high in Māori women (6.1/100,000 compared to 3.1/100,00 in European/Other women). Among strategies we examined, the greatest impact came from high vaccine coverage and achieving higher attendance by Māori women under surveillance for screen-detected abnormalities. Conclusion Relative reductions in cervical cancer due to vaccination and HPV-based screening are predicted to be greater in Maori than in European/Other women. While these interventions have the potential to substantially reduce between-group differences, cervical cancer incidence would remain higher in Maori women. These findings highlight the importance of multiple approaches and the potential influence of factors beyond HPV prevention

A revision of sexual mixing matrices in models of sexually transmitted infection

Two sexual mixing matrices previously used in models of sexually transmitted infections (STIs) are intended to calculate the probability of sexual interaction between age groups and sexual behaviour subgroups. When these matrices are used to specify multiple criteria for how people select sexual partners (such as age group and sexual behaviour class), their conditional probability structure means that they have in practice been prone to misuse. We constructed revised mixing matrices that incorporate a corrected conditional probability structure and then used one of them to examine the effect of this revision on population modelling of STIs. Using a dynamic model of human papillomavirus (HPV) transmission as an example, we examined changes to estimates of HPV prevalence and the relative reduction in age-standardised HPV incidence after the commencement of publicly funded HPV vaccination in Australia. When all other model specifications were left unchanged, the revised mixing matrix initially led to estimates of age-specific oncogenic HPV prevalence that were up to 11% higher than our previous models at certain ages. After re-calibrating the model by modifying unobservable parameters characterising HPV natural history, the revised mixing matrix yielded similar estimates to our previous models, predicting that vaccination would lead to relative HPV incidence reductions of 43% and 85% by 2010 and 2050, respectively, compared with 43% and 86% using the unrevised mixing matrix formulation. Our revised mixing matrix offers a rigorous alternative to commonly used mixing matrices, which can be used to reliably and explicitly accommodate conditional probabilities, with appropriate re-calibration of unobservable model parameter

Vulvar cancer in high-income countries: Increasing burden of disease

The aim of this study was to assess trends in the age-specific incidence of vulvar cancer in 13 high-income countries satisfying a priori conditions regarding the availability of cancer registry data over a 20-year period; these were Canada, the United States, nine European countries, Australia and Japan. Five-yearly incidence and population at risk were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents for the years 1988-1992 (Volume 7) to 2003-2007 (Volume 10). The 5-yearly average percent change (AvPC) over the period and standardised rate ratios (SRRs) for 2003-2007 versus 1988-1992 were used to assess changes in the age-standardised incidence rates of vulvar cancer for all ages, and for <60 years and 60+ years. During the study period, the 5-yearly AvPC across the 13 countries increased by 4.6% (p = 0.005) in women of all ages, and 11.6% (p = 0.02) in those <60 years. No change was observed in women aged 60+ years (5-yearly AvPC = 0.1%, p = 0.94). The SRR for 2003-2007 versus 1988-1992 was significantly elevated in women <60 years of age (SRR = 1.38, 95% CI: 1.30-1.46), but not in women of 60+ years (SRR = 1.01, 95% CI: 0.97-1.05). The increase in incidence in women <60 years of age drove a significant increase in the overall SRR in women of all ages (SRR = 1.14, 95% CI: 1.11-1.18). Some differences in the specific findings at the individual country level were observed. The findings are consistent with changing sexual behaviours and increasing levels of exposure to human papillomavirus (HPV) in cohorts born around/after about 1950, but younger cohorts offered HPV vaccination are likely to receive some protection against developing vulvar cancer in the future

Quantifying the impact of dissimilar HPV vaccination uptake among Manitoban school girls by ethnicity using a transmission dynamic model

BACKGROUND: Gardasil, a human papillomavirus (HPV) vaccine, began among grade 6 girls in Manitoba, Canada in 2008. In Manitoba, there is evidence that First Nations, Metis, and Inuit women (FNMI) have higher HPV prevalence, lower invasive cervical cancer (ICC) screening, and higher ICC incidence than all other Manitoban (AOM) women. We developed a mathematical model to assess the plausible impact of unequal vaccination coverage among school girls on future cervical cancer incidence. METHODS: We fit model estimated HPV prevalence and ICC incidence to corresponding empirical estimates. We used the fitted model to evaluate the impact of varying levels of vaccination uptake by FNMI status on future ICC incidence, assuming cervical screening uptake among FNMI and AOM women remained unchanged. RESULTS: Depending on vaccination coverage, estimated ICC incidence by 2059 ranged from 15% to 68% lower than if there were no vaccination. The level of cross-ethnic sexual mixing influenced the impact that vaccination rates among FNMI has on ICC incidence among AOM, and vice versa. The same level of AOM vaccination could result in ICC incidence that differs by up to 10%, depending on the level of FNMI vaccination. Similarly, the same level of FNMI vaccination could result in ICC incidence that differs by almost 40%, depending on the level of AOM vaccination. CONCLUSIONS: If we are unable to equalize vaccination uptake among all school girls, policy makers should prepare for higher levels of cervical cancer than would occur under equal vaccination uptak

Expenditure and resource utilisation for cervical screening in Australia

BACKGROUND The National Cervical Screening Program in Australia currently recommends that women aged 18-69 years are screened with conventional cytology every 2 years. Publicly funded HPV vaccination was introduced in 2007, and partly as a consequence, a renewal of the screening program that includes a review of screening recommendations has recently been announced. This study aimed to provide a baseline for such a review by quantifying screening program resource utilisation and costs in 2010. METHODS A detailed model of current cervical screening practice in Australia was constructed and we used data from the Victorian Cervical Cytology Registry to model age-specific compliance with screening and follow-up. We applied model-derived rate estimates to the 2010 Australian female population to calculate costs and numbers of colposcopies, biopsies, treatments for precancer and cervical cancers in that year, assuming that the numbers of these procedures were not yet substantially impacted by vaccination. RESULTS The total cost of the screening program in 2010 (excluding administrative program overheads) was estimated to be A$194.8M. We estimated that a total of 1.7 million primary screening smears costing$96.7M were conducted, a further 188,900 smears costing $10.9M were conducted to follow-up low grade abnormalities, 70,900 colposcopy and 34,100 histological evaluations together costing$21.2M were conducted, and about 18,900 treatments for precancerous lesions were performed (including retreatments), associated with a cost of $45.5M for treatment and post-treatment follow-up. We also estimated that$20.5M was spent on work-up and treatment for approximately 761 women diagnosed with invasive cervical cancer. Overall, an estimated $23 was spent in 2010 for each adult woman in Australia on cervical screening program-related activities. CONCLUSIONS Approximately half of the total cost of the screening program is spent on delivery of primary screening tests; but the introduction of HPV vaccination, new technologies, increasing the interval and changing the age range of screening is expected to have a substantial impact on this expenditure, as well as having some impact on follow-up and management costs. These estimates provide a benchmark for future assessment of the impact of changes to screening program recommendations to the costs of cervical screening in Australia

Type-specific oncogenic human papillomavirus infection in high grade cervical disease in New Zealand

BACKGROUND: The national Human Papillomavirus (HPV) Immunisation Programme in New Zealand was introduced in 2008, and involves routine vaccination of girls 12–13 years with a catch-up for females aged up to 19 years. The aims of this study were to measure the pre-vaccination prevalence of oncogenic HPV infection in women aged 20–69 years who were participating in the New Zealand National Cervical Screening Programme (NZ-NCSP) and who were: (1) referred with high grade cytology with a subsequent histologically-confirmed high grade cervical intraepithelial neoplasia (CIN2/3) or adenocarcinoma in situ (AIS); or (2) were in the wider group of women who had a cytological prediction of high grade squamous disease or glandular abnormality (ASC-H/ HSIL+/AGC/AIS). METHODS: Women aged 20–69 years appearing on the NZ-NCSP register between August 2009-February 2011 with a cytology record of ASC-H/HSIL+/AGC/AIS were invited to participate in the study. Liquid-based cytology specimens were tested for 37 HPV types using Linear Array genotyping. The prevalence of type-specific HPV infection was reported within women with histologically-confirmed CIN 2/3 and within the wider group with ASC-H/HSIL+/AGC/AIS cytology. Age-specific trends for the relative proportion of HPV 16/18 vs. other oncogenic types in CIN2/3 were assessed. RESULTS: A total of 594 women with ASC-H/HSIL+/AGC/AIS cytology and a valid HPV test were recruited; of these 356 (60%) had confirmed CIN2/3 and 6 (1%) had confirmed AIS or glandular dysplasia. Positivity rates for any oncogenic HPV infection and for HPV16 and/or 18 within confirmed CIN2/3-AIS were 95% (95%CI: 92-97%) and 60% (54-65%) respectively; in all women with ASC-H/HSIL+/AGC/AIS cytology it was 87% (84-89%) and 53% (49-57%), respectively. The most common reported HPV types in women with CIN 2/3 were 16 (51%), 52 (19%), 31 (17%), 33 (13%) and 18 (12%). A trend for higher rates of HPV 16/18 infection compared to other oncogenic types was observed in younger women (p=0.0006). CONCLUSIONS: The prevalence of HPV 16/18 in confirmed high grade disease in New Zealand is comparable to that observed in Australia and European countries. Test positivity rates for type 52 appear higher than in comparable studies in other developed countries. A greater proportion of high grade lesions in younger women appear to be associated with HPV 16/18 infection