Human papillomavirus-driven head and neck cancers in Japan during 2008-2009 and 2018-2019: The BROADEN study.

There is limited understanding of epidemiology and time trends of human papilloma virus (HPV)-driven head and neck cancers (HNC) in Japan, especially outside of the oropharynx. To assess HPV-driven HNC, a non-interventional study (BROADEN) of HNC patients diagnosed in 2008-2009 and 2018-2019 was conducted in Japan. Adult patients with oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal or oral cavity cancers were included in this study. HPV was centrally tested using p16INK4a immunohistochemistry, HPV-DNA PCR and HPV E6*I mRNA. HPV attributability required positivity in at least two tests (p16INK4a immunohistochemistry, HPV-DNA PCR, HPV E6*I mRNA) in the oropharynx, and HPV-DNA and HPV E6*I mRNA positivity for non-oropharynx sites. Nineteen hospitals included a total of 1108 patients, of whom 981 had valid samples. Men accounted for 82% of HNC diagnoses. Patients in the earlier cohort were younger and included a higher percentage of smokers. There was an increasing trend of HPV-driven oropharyngeal cancer over the last decade, from 44.2% to 51.7%. HPV attribution in nasopharyngeal cancers was 3.2% in 2008-2009 and 7.5% in 2018-2019; and 4.4% and 0% for larynx respectively. In total, 95.2% of HPV-driven HNC were attributed to HPV genotypes included in the 9-valent HPV vaccine being HPV16 the most prominent genotype. These results suggest that an epidemiologic shift is happening in Japan, with a decrease in smoking and alcohol use and an increase in HPV-driven HNC. The increasing trend of HPV-driven HNC in Japan highlights the need for preventive strategies to mitigate the rise of HPV-driven HNC.

Assessing the epidemiological impact on cervical cancer of switching from 4-valent to 9-valent HPV vaccine within a gender-neutral vaccination programme in Switzerland.

BACKGROUND: An infection with high-risk human papillomavirus (HPV) is the obligatory aetiological factor for the development of cervical cancer. In Switzerland, the prevention strategy for cervical cancer is based on primary prevention via HPV vaccination and secondary prevention with an opportunistic screening programme for precancerous lesions. Vaccination is recommended to 11-26 years old male and female persons. The objective of the study was to assess the epidemiological impact on cervical cancer of switching from the currently implemented programme with the 4-valent vaccine to the 9-valent vaccine, in an 11-26 years old gender-neutral vaccination programme in Switzerland. METHODS: A previously validated dynamic transmission model of HPV infections was adapted and calibrated to the Swiss setting assuming an 80% coverage rate in HPV-vaccination and lifelong vaccine type-specific protection. A gender-neutral vaccination programme (males and females) for 11-26 years old with a 9-valent HPV vaccine was compared with the current 11-26 years old gender-neutral 4-valent vaccination programme. Sensitivity analyses were conducted in order to test the impact of lower vaccination coverage rates and a shorter duration of protection on the model outcomes. RESULTS: In Switzerland, a 9-valent gender-neutral vaccination programme would result in an additional prevention of 2979 cervical cancer cases, 13,862 CIN3 and 15,000 CIN2 cases, compared with the 4-valent gender-neutral vaccination programme over 100 years. These additional disease cases avoided would correspond to a 24, 36 and 48% cumulative incidence decrease in cervical cancer, CIN3 and CIN2 cases, respectively. It would also prevent additional 741 cervical cancer-related deaths over 100 years. A substantial additional reduction in cervical cancer and precancerous lesions burden is still observed when varying the vaccination coverage rate from 30 to 60% or reducing the duration of protection from lifelong to 20 years. CONCLUSIONS: The switch to the 9-valent vaccine in Switzerland to prevent cervical diseases showed an important contribution in terms of public health impact compared with the 4-valent vaccine in an 11-26 years old gender-neutral population, even with very conservative assumptions such as low coverage rates or low duration of protection and limiting analysis to only cervical disease.

Literature review of the distribution of hepatitis C virus genotypes across Europe.

Recent advances in hepatitis C virus (HCV) therapies have transformed the treatment landscape for this disease. However, efficacy of current treatments depends on HCV genotype and individual patient characteristics. This review aimed to appraise observational studies reporting epidemiological outcomes to characterize HCV genotype distribution in Europe, in the general HCV population and various subpopulations of interest. MEDLINE and EMBASE entries published between November 2008 and November 2013 were systematically searched. Studies were grouped according to the patient populations of interest: general HCV population, HCV-HIV co-infected patients, patients with advanced fibrosis/cirrhosis, and liver transplant recipients. Thirty publications provided estimates of HCV genotype distribution in four distinct patient groups: general HCV population (n = 21), HCV-HIV co-infected patients (n = 6), liver transplant patients (n = 3), and patients with HCV-compensated cirrhosis (n = 1). Nationwide estimates of genotype distribution in the general HCV population were available for 10 countries, with genotypes 1 and 3 the most commonly reported. Romanian studies were found to have reported genotype 1 infections almost exclusively (98.0-99.8%). Considerable regional variation was reported in some countries (e.g., Italy), but not others (e.g., France). National and multi-national estimates for the HCV-HIV co-infected population suggested a different genotype distribution to that in the general HCV population. No studies reported nationwide genotype distribution in patients with advanced liver disease. Given the clinical importance of genotype in developing optimal HCV eradication strategies, further nationwide European studies are needed to fully characterize genotype distribution in both the general HCV population and in HCV subpopulations. J. Med. Virol. 88:2157-2169, 2016. © 2016 Wiley Periodicals, Inc.

Forecasting Disease Burden with a Dynamic Transmission Model of Human Papillomavirus and Recurrent Respiratory Papillomatosis in the United States.

Juvenile- and adult-onset recurrent respiratory papillomatosis (JORRP and AORRP) are rare but serious conditions that are caused by oral human papillomavirus (HPV) infections. The proliferation of wart-like growths throughout the respiratory tract can result in medical problems, including death. The current treatment scheme is surgery, though prevention of HPV infection through vaccination is available. A previously developed model for JORRP and AORRP was adapted to the United States using data on disease burden and HPV infection. The model was validated against post-vaccination reductions in disease and used to forecast the future burden of JORRP and AORRP, estimating the impact that HPV vaccination will have on these diseases. Between 2007 (the beginning of HPV vaccination in the US) and 2021, this model estimates that approximately 1393 lives, 22,867 Quality-Adjusted-Life-Years, and over USD 672 million in treatment costs have been saved by HPV vaccination. There is also a substantial reduction in JORRP and AORRP burden, with a 95% reduction in incidence by 2040. Moreover, between 2040 and 2121, the model predicts 3-11 total cases of HPV6/11-related JORRP in the US, and 36-267 total cases of HPV6/11-related AORRP. HPV vaccination in the United States has driven, and will continue to drive, substantial reductions in the public health and economic burden of HPV6/11-related JORRP and AORRP.

Global burden and economic impact of vaccine-preventable cancer mortality.

BACKGROUND: Infections are responsible for approximately 13% of cancer cases worldwide and many of these infections can be prevented by vaccination. Human papillomavirus (HPV) and hepatitis B virus (HBV) are among the most common infections that cause cancer deaths globally, despite effective prophylactic vaccines being available. This analysis aims to estimate the global burden and economic impact of vaccine-preventable cancer mortality across World Health Organization (WHO) regions. METHODS: The number of deaths and years of life lost (YLL) due to five different vaccine-preventable cancer forms (oral cavity, liver, laryngeal, cervical, and oropharyngeal cancer) in each of the WHO regions (African, Eastern Mediterranean, European, the Americas, South-East Asia Pacific, and Western Pacific) were obtained from the Institute for Health Metrics Evaluation global burden of disease dataset. Vaccine-preventable mortality was estimated considering the fraction attributable to infection, to estimate the number of deaths and YLL potentially preventable through vaccination. Data from the World Bank on GDP per capita were used to estimate the value of YLL (VYLL). The robustness of these results was explored with sensitivity analysis. Given that several Epstein-Barr virus (EBV) vaccines are in development, but not yet available, the impact of a potential vaccine for EBV was evaluated in a scenario analysis. RESULTS: In 2019, there were 465,740 potentially vaccine-preventable cancer deaths and 14,171,397 YLL across all WHO regions. The estimated economic impact due to this mortality was $106.3 billion globally. The sensitivity analysis calculated a range of 403,025-582,773 deaths and a range in productivity cost of $78.8-129.0 billion. In the scenario analysis EBV-related cancer mortality increased the global burden by 159,723 deaths and $32.4 billion. CONCLUSION: Overall, the findings from this analysis illustrate the high economic impact of premature cancer mortality that could be potentially preventable by vaccination which may assist decision-makers in allocating limited resources among competing priorities. Improved implementation and increased vaccination coverage of HPV and HBV should be prioritized to decrease this burden.

Burden and indirect cost of vaccine-preventable cancer mortality in Europe.

BACKGROUND: The economic and mortality burden of cancer is high worldwide. In Europe, cancer was responsible for 1.3 million deaths in 2020 and incurred an estimated cost of €50 billion from premature mortality. Human papillomavirus (HPV) and hepatitis B virus (HBV) are among the leading causes of infection-related cancers despite the availability of effective vaccines against these infections. This analysis estimated the mortality and productivity loss of HBV- and HPV-associated cancers that could be preventable through vaccination across European regions. MATERIALS AND METHODS: Institute for Health Metrics Evaluation (IHME) data were used to estimate mortality, years of life lost (YLL), and the value of years of life lost (VYLL) from five HBV- and HPV-related cancers (oral cavity, oropharynx, larynx, cervical, and liver cancers) across 40 European countries in 2019. Preventable deaths and YLL were estimated based on fractions attributable to infections. Data from the World Bank on GDP per capita were used to estimate the VYLL. The robustness of these results was explored with sensitivity and scenario analyses. RESULTS: In 2019, 31,906 cancer deaths resulted in an economic burden of €18,521,614,725 due to productivity losses across Europe. HPV-related cervical cancer had the highest mortality (19,473 deaths) and economic burden (€10,706,253,185). HBV-related liver cancer and HPV-related larynx, oral cavity, and oropharynx cancers also had a substantial burden, particularly in males. Eastern Europe had the highest YLL (308,179; 39%) and Western Europe was responsible for the greatest VYLL (€8,281,306,504; 45%), although the highest VYLL per death was in Northern Europe (€923,638). HPV-related oropharynx cancer had the highest VYLL per death (€656,607). CONCLUSION: HPV- and HBV-related cancer deaths are associated with substantial mortality and productivity losses in Europe, which could be reduced by the continued prioritization and implementation of prophylactic public health measures including systematic awareness, vaccination, and screening efforts.

Productivity costs due to human papillomavirus-related cancer mortality in the United Kingdom.

BACKGROUND: Human papillomavirus (HPV) causes several cancers such as cervical cancer and some head and neck (oral cavity, pharynx, and larynx), vulval, vaginal, anal, and penile cancers. As HPV vaccination is available, there is potential to prevent these cancers attributed to HPV and consequently the burden associated with them. The aim of this analysis was to estimate the number of HPV-related cancer deaths and the productivity costs due to years of life lost (YLL) in the United Kingdom (UK). METHOD: A model was developed utilizing UK 2019 mortality data sourced from country-specific databases for England, Scotland, Wales, and Northern Ireland for the following HPV-related cancers: head and neck (ICD-10 C00-14 and C32), cervix uteri (C53), vaginal (C51), vulval (C52), anal (C21), and penile (C60). The proportion of deaths and years of life lost (YLL) due to HPV were estimated using HPV attributable fractions for each anatomic location from the published literature. Labor force participation, retirement ages, and mean annual earnings, discounted at 3.5% annually, were applied to YLL to calculate the present value of future lost productivity (PVFLP). RESULTS: A total of 1817 deaths due to HPV-related cancers were reported in the UK in 2019 resulting in 31,804 YLL. Restricting to only YLL that occurred prior to retirement age yielded a total YPLL of 11,765 and a total PVFLP of £187,764,978. CONCLUSIONS: There is a high disease burden in the UK for HPV-related cancers, with a large economic impact on the wider economy due to productivity losses. Implementing and reinforcing public health measures to maintain high HPV vaccination coverage in both males and females may further facilitate reduction of this burden.

A systematic literature review of the human papillomavirus prevalence in locally and regionally advanced and recurrent/metastatic head and neck cancers through the last decade: The "ALARM" study.

AIMS: The aim of this systematic literature review was to provide updated information on human papillomavirus (HPV) prevalence in locally and regionally advanced (LA) and recurrent/metastatic (RM) head and neck cancer (HNC) worldwide. METHODS: Electronic searches were conducted on clinicaltrials.gov, MEDLINE/PubMed, Embase, and ASCO/ESMO journals of congresses for interventional studies (IS; Phase I-III trials) as well as MEDLINE and Embase for non-interventional studies (NIS) of LA/RM HNC published between January 01, 2010 and December 31, 2020. Criteria for study selection included: availability of HPV prevalence data for LA/RM HNC patients, patient enrollment from January 01, 2010 onward, and oropharyngeal cancer (OPC) included among HNC types. HPV prevalence per study was calculated as proportion of HPV+ over total number of enrolled patients. For overall HPV prevalence across studies, mean of reported HPV prevalence rates across studies and pooled estimate (sum of all HPV+ patients over sum of all patients enrolled) were assessed. RESULTS: Eighty-one studies (62 IS; 19 NIS) were included, representing 9607 LA/RM HNC cases, with an overall mean (pooled) HPV prevalence of 32.6% (25.1%). HPV prevalence was 44.7% (44.0%) in LA and 24.3% (18.6%) in RM. Among 2714 LA/RM OPC patients from 52 studies with available data, mean (pooled) value was 55.8% (50.7%). The majority of data were derived from Northern America and Europe, with overall HPV prevalence of 46.0% (42.1%) and 24.7% (25.3%) across studies conducted exclusively in these geographic regions, respectively (Northern Europe: 31.9% [63.1%]). A "p16-based" assay was the most frequently reported HPV detection methodology (58.0%). CONCLUSION: Over the last decade, at least one quarter of LA/RM HNC and half of OPC cases studied in IS and NIS were HPV+. This alarming burden is consistent with a potential implication of HPV in the pathogenesis of at least a subgroup of HNC, underscoring the relevance of HPV testing and prophylaxis to HNC prevention and management.

Estimating the prevalence of non-cervical human papillomavirus infection in mainland China (PROGRESS-Plus): protocol of a national cross-sectional study.

INTRODUCTION: Human papillomavirus (HPV) infection is the most common sexually transmissible infection worldwide. Although the prevalence of cervical HPV infection has been extensively reported in women worldwide, few epidemiological studies have examined the prevalence of non-cervical HPV infection among both women and men, especially in China. METHODS AND ANALYSIS: PROGRESS-Plus is a national, multisite, cross-sectional study that aims to estimate the prevalence of non-cervical HPV infection in women and men aged 18-60 years residing in mainland China. More specifically, PROGRESS-Plus will estimate the prevalence rate of HPV DNA in oral samples from both women and men, and that of anogenital samples from men. The secondary study objectives are to (1) report the aforementioned prevalence rates by HPV genotype, age and geographical region, (2) examine the concordance (ie, prevalence of the same HPV genotype) between the oral and anogenital samples among men, (3) explore risk factors associated with oral (in both women and men) and anogenital (in men only) HPV infection and (4) describe study participants' health-related quality of life, health behaviour, sexual behaviour and health status. ETHICS AND DISSEMINATION: The study protocol and all required documents have been submitted for review and approval to the Independent Ethics Committees of all the participating sites. All participants will provide their written informed consent on study entry, and all the recorded data will be treated as confidential.

Oral Human Papillomavirus Prevalence and Genotyping Among a Healthy Adult Population in the US.

Importance: In the US, oropharyngeal cancer, predominantly caused by high-risk (HR) human papillomavirus (HPV) infection, is the most frequent HPV-associated cancer, surpassing cervical cancer. However, little is known about oral HPV prevalence and genotype distribution in the general population. Objective: To assess oral HPV prevalence and factors associated with HR and low-risk infection in a general US population. Design, Setting, and Participants: PROGRESS (Prevalence of Oral HPV Infection, a Global Assessment) was a cross-sectional observational study conducted between November 2021 and March 2022 in 43 dental offices in the US (24 urban, 13 urban cluster, and 6 rural sites), spanning 21 states. Eligible participants were aged 18 to 60 years, visiting dental clinics for routine dental examination. Dental clinics used targeted sampling to recruit equal distributions of men and women and across age groups. Exposure: Participants provided an oral gargle specimen for HPV DNA and genotyping and completed behavioral questionnaires, and dentists reported oral health status. Detection of HPV DNA and genotyping was performed using the SPF10/DEIA/LiPA25 system at a central laboratory. Main Outcome: Oral HPV prevalence. Results: Of the 3196 participants enrolled, mean (SD) age was 39.6 (12.1) years, and 55.5% were women. Oral HPV prevalence was 6.6% (95% CI, 5.7%-7.4%) for any HPV genotype, and 2.0% (95% CI, 1.5%-2.5%), 0.7% (95% CI, 0.4%-1.0%), and 1.5% (95% CI, 1.1%-1.9%) for HR, HPV-16, and 9-valent-HPV vaccine types, respectively. Among HPV-positive participants, HPV-16 was the most prevalent genotype (12.4% among men and 8.6% among women). Prevalence of HPV was higher in men than women and highest among men aged 51 to 60 years (16.8%, 6.8%, and 2.1% for any HPV, HR HPV, and HPV-16, respectively). Factors associated with HR oral infection included being male (adjusted odds ratio [AOR], 3.1; 95% CI, 1.2-8.5), being aged 51 to 60 years (AOR, 3.3; 95% CI, 1.5-7.3), having 26 or more lifetime male sex partners (AOR, 6.5; 95% CI, 2.3-18.7), and having 6 to 25 lifetime female oral sex partners (AOR, 3.4; 95% CI, 1.3-8.7). Conclusions and Relevance: In this cross-sectional study, oral HPV burden was highest among older men who may be at higher risk of developing oropharyngeal cancer. In addition to male sex and older age, HR oral HPV infection was also associated with sexual behaviors, including increasing number of male sex partners and female oral sex partners.

Assessing the burden of HPV-related head and neck cancers in mainland China: protocol of a nationwide, multisite, cross-sectional study.

BACKGROUND: Persistent human papillomavirus (HPV) infection is a known cause of a subset of head and neck cancers (HNCs). In the last two decades, the proportion of HNCs attributable to HPV infection has increased worldwide, notably the oropharyngeal cancers. However, the trend of HPV-related HNC burden is not clearly understood yet in China. Thus, the absolute burden of HPV-related head and neck cancers in China (BROADEN-China) will be conducted to estimate the proportion of HNCs attributable to HPV infection, per anatomic site, by genotype, in three time periods (2008-2009, 2013-2014 and 2018-2019). METHODS AND ANALYSIS: BROADEN-China is a nationwide, multisite, cross-sectional study. A stratified, multistage, non-randomised cluster sampling method will be used to select 2601 patients with HNC from 14 hospitals across seven regions, based on population density in China. Patients with formalin-fixed paraffin-embedded tissue samples collected prior to treatment induction during three time periods will be included, and factors (eg, smoking status, alcohol consumption, betel nut chewing, Epstein-Barr virus, teeth loss, etc) associated with HNC will be assessed. HPV testing (HPV-DNA, HPV-mRNA and p16INK4a immunohistochemistry) and histological diagnosis of the tissue samples will be conducted at a central laboratory.The study protocol and all required documents have been submitted for review and approval to the Independent Ethics Committees of all the participating sites. The informed consent was waived for all participants and all the recorded data will be treated as confidential.We have included 14 hospitals as our participating sites, of which Henan Cancer Hospital is the leading site. The study has been approved by the independent ethics committees of the leading site on 3 December 2020. The other 13 participating site names of ethics committee and IRB that have approved this study.

The BROADEN study: The design of an observational study to assess the absolute burden of HPV-related head and neck cancers.

BACKGROUND: Persistent human papillomavirus (HPV) infection is an important risk factor for a subset of head and neck cancers (HNCs). However, estimates of the HPV-attributable fraction of oropharyngeal cancers vary greatly, and the proportion is increasing. Growing evidence indicates smaller proportions of oral cavity and laryngeal cancers are also HPV-attributable, but this requires further investigation. The primary objective of the BROADEN study is to estimate the fraction of HNCs attributable to HPV in selected European and Asian countries by anatomic site. Secondary objectives are to determine HPV genotypes involved and to describe primary tumor and patient characteristics by HPV status. METHODS: BROADEN is a non-interventional, cross-sectional study of patients with HNC in China, France, Germany, Italy, Japan, Portugal, and Spain. The HPV-attributable HNC fraction will be determined within pre-defined time-periods (2008-2009, 2013-2014 [China only], 2018-2019). Approximately 9000 patients from an estimated 90 hospitals with reference HNC diagnostic units and local reference pathology laboratories will participate. Sample size estimates were generated by grouped anatomic site (oropharynx, oral cavity, nasopharynx, hypopharynx, and larynx) and country. HPV testing (HPV-DNA and p16 immunohistochemistry [IHC]) will be performed at a central laboratory on formalin-fixed paraffin-embedded tissue samples. All HPV-DNA-positive samples and HPV-DNA-negative/p16 IHC-positive samples, plus 10% of remaining HPV DNA-negative (control) samples will be tested for HPV mRNA. DISCUSSION: BROADEN is a large global epidemiologic study to estimate current and recent past HPV burden in oropharyngeal and non-oropharyngeal HNCs. BROADEN is expected to provide robust estimates of HPV attributability by anatomic site in participating countries.

Oral human papillomavirus (HPV) and associated factors among healthy populations: The design of the PROGRESS (PRevalence of Oral hpv infection, a Global aSSessment) study.

BACKGROUND: Head and neck cancers are increasingly associated with human papillomavirus (HPV) infection. Previous studies of oral HPV indicate considerable heterogeneity across geographic regions and by sex, but studies differ in methodologies used and risk groups included. Understanding the natural history of oral HPV in the general population is important to assess HPV-related disease burden and plan effective prevention programs. In this study, we aim to assess the prevalence, incidence, and persistence of oral HPV among adult men and women. Factors independently associated with oral HPV will also be evaluated. METHODS: The PROGRESS (PRevalence of Oral hpv infection, a Global aSSessment) study is a non-interventional study of 7877 healthy men and women aged 18-60 years, from France, Germany, Spain, the United Kingdom (UK) and the United States (US). Oral HPV prevalence will be measured using a commercially available PCR DNA test. In the US, participants will be followed prospectively every 6 months for 24 months to assess incidence, clearance, and persistence of oral HPV infection. Eligible individuals presenting for regular dental check-ups will be recruited from participating dental offices via systematic consecutive sampling. Participant dentists will collect clinical characteristics, and participants will complete self-reported study questionnaires and provide an oral rinse and gargle (ORG) specimen for HPV-DNA detection and genotyping at each study visit. HPV-DNA detection and genotyping will be performed in two reference laboratories, using the SPF10/DEIA/LiPA25 system. DISCUSSION: PROGRESS study aims to fill knowledge gaps concerning the natural history of oral HPV using a standardized methodology. PROGRESS will also assess factors associated with oral HPV prevalence and natural history in the general population.

Landscape assessment for gender neutral human papillomavirus vaccination recommendations including head and neck cancer burden data.

INTRODUCTION: Head and neck cancers (HNC) accounted for over 450,000 deaths and 900,000 cases in 2018 worldwide. Of those, 38,000 cases were attributable to human papillomavirus (HPV). HNC is two to four times more prevalent in men than in women. The incidence of oropharyngeal cancers (OPC) and oral cavity cancers caused by HPV has increased in recent decades. Given the substantial burden of HPV-related HNC in males, this study aimed to assess whether and how national agencies included HPV-related HNC when evaluating HPV genderneutral vaccination (GNV) programs. METHODS: A systematic literature review was conducted in MEDLINE® and EMBASE®, and on the websites of selected national agencies. RESULTS: Searches identified a potential 205 records; seventeen were eligible for the review. Seventy percent of assessments were published by European countries and most were recent (2014-2019). Eleven (65%) reports considered OPC when discussing HNC, and a few included other anatomic sites. All reports that considered incidence data were in consensus that incidence of OPC was higher in men and showed that the mortality rates for HPV-related HNC were also higher in men. When looking at the economic impact, the incremental cost-effectiveness ratios in the assessments varied widely, as the inputs into the analyses were heterogeneous. However, several reports concluded GNV programs were likely to be cost-effective versus not vaccinating males. CONCLUSION: The burden of HPV-related HNC in the general male population has been recognized by several Heatlth Technology Assessment (HTA) agencies and National Immunization Technical Advisory Groups (NITAGs) when evaluating HPV GNV programs. The assessments identified on GNV programs strongly indicate a cost-effective clinical benefit. Nevertheless, the epidemiological burden of HNC may have been underestimated in some countries due to limited data. Further research is crucial to obtain more robust data that will help address the information gap in epidemiological and economic burden of HPV-associated HNC in men.

Health Impact and Cost-Effectiveness of Implementing Gender-Neutral Vaccination With the 9-Valent Human Papillomavirus Vaccine in Belgium.

Background: Routine human papillomavirus (HPV) immunization in Belgium is currently regionally managed, with school-aged girls receiving the 9-valent HPV (9vHPV) vaccine in Flanders and Wallonia-Brussels with a national catch-up program for females only. This study will assess whether expanding these programs to gender-neutral vaccination (GNV) with the 9vHPV vaccine is a cost-effective strategy in Belgium. Methods: A validated HPV-type transmission dynamic model estimated the potential health and economic impact of regional vaccination programs, comparing GNV versus female-only vaccination (FOV) with the 9vHPV vaccine in individuals aged 11-12 years in Flanders, GNV with the 9vHPV vaccine versus FOV with the 2-valent HPV (2vHPV) vaccine in individuals aged 12-13 years in Wallonia-Brussels, and national catch-up GNV versus FOV with the 9vHPV vaccine for those aged 12-18 years. Vaccination coverage rates of 90, 50, and 50% in both males and females were used in the base cases for the three programs, respectively, and sensitivity analyses were conducted. All costs are from the third-party payer perspective, and outcome measures were reported over a 100-year time horizon. Results: GNV with the 9vHPV vaccine was projected to decrease the cumulative incidence of HPV 6/11/16/18/31/33/45/52/58-related diseases relative to FOV in both Flanders and Wallonia-Brussels. Further reductions were also projected for catch-up GNV with the 9vHPV vaccine, including reductions of 6.8% (2,256 cases) for cervical cancer, 7.1% (386 cases) and 18.8% (2,784 cases) for head and neck cancer in females and males, respectively, and 30.3% (82,103 cases) and 44.6% (102,936 cases) for genital warts in females and males, respectively. As a result, a GNV strategy would lead to reductions in HPV-related deaths. Both regional and national catch-up GNV strategies were projected to reduce cumulative HPV-related disease costs and were estimated to be cost-effective compared with FOV with incremental cost-effectiveness ratios of €8,062, €4,179, and €6,127 per quality-adjusted life-years in the three programs, respectively. Sensitivity analyses were consistent with the base cases. Conclusions: A GNV strategy with the 9vHPV vaccine can reduce the burden of HPV-related disease and is cost-effective compared with FOV for both regional vaccination programs and the national catch-up program in Belgium.

Impact of hospitalization on health-related quality of life in atrial fibrillation patients in Canada and the United States: results from an observational registry.

BACKGROUND: Hospitalization is recognized as an important end point in atrial fibrillation (AF). The association between hospitalization and reduced health-related quality of life (HRQOL) has not been previously studied. METHODS: The FRACTAL study was a prospective observational registry of patients enrolled in the United States and Canada with new-onset AF diagnosed by electrocardiogram. HRQOL was assessed with the SF-12 and the AF Symptom Checklist at baseline, 3, 6, 12, 24 and 30 months. Mixed linear regression models were fitted to estimate the impact of hospitalization on HRQOL summary scores, adjusting for demographic and baseline comorbid conditions known to influence HRQOL in this population. RESULTS: Of 933 subjects who completed questionnaires and were not hospitalized during the baseline study visit, 303 (32%) were hospitalized a total of 490 times during a mean of 2.0 years of follow-up. Most admissions (64%) were for cardiovascular causes. The adjusted effect of any hospital admission (vs none) on symptom frequency and severity scores over time was +1.3 and +1.1 points, respectively (P < .01 for both). The adjusted effect of any admission on the SF-12 physical score was -2.7 points (P < .0001) and on health state utility, -0.03 (P < .0001). In contrast, hospitalization had little effect on longitudinal Short Form 12 mental scores (-0.7 points, P = .15). CONCLUSIONS: Within 2 years after AF diagnosis, hospitalizations were associated with increased AF symptomatology and decrements in generic physical HRQOL and utilities. Based on these results, interventions that reduce admissions in AF patients may also improve or preserve HRQOL.

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.

BACKGROUND: Nivolumab was the first programmed death receptor 1 (PD-1) immune checkpoint inhibitor to demonstrate long-term survival benefit in a clinical trial setting for advanced melanoma patients. OBJECTIVE: To evaluate the cost effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. METHODS: A Markov state-transition model was developed to estimate the lifetime costs and benefits of nivolumab versus ipilimumab and dacarbazine for BRAF mutation-negative patients and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-positive patients. Covariate-adjusted parametric curves for time to progression, pre-progression survival, and post-progression survival were fitted based on patient-level data from two trials and long-term ipilimumab survival data. Indirect treatment comparisons between nivolumab, ipilimumab, and dacarbazine were informed by these covariate-adjusted parametric curves, controlling for differences in patient characteristics. Kaplan-Meier data from the literature were digitised and used to fit progression-free and overall survival curves for dabrafenib and vemurafenib. Patient utilities and resource use data were based on trial data or the literature. Patients are assumed to receive nivolumab until there is no further clinical benefit, assumed to be the first of progressive disease, unacceptable toxicity, or 2 years of treatment. RESULTS: Nivolumab is the most cost-effective treatment option in BRAF mutation-negative and mutation-positive patients, with incremental cost-effectiveness ratios of £24,483 and £17,362 per quality-adjusted life year, respectively. The model results are most sensitive to assumptions regarding treatment duration for nivolumab and the parameters of the fitted parametric survival curves. CONCLUSIONS: Nivolumab is a cost-effective treatment for advanced melanoma patients in England.

The importance of baseline viral load when assessing relative efficacy in treatment-naïve HBeAg-positive chronic hepatitis B: a systematic review and network meta-analysis.

BACKGROUND: To date no network meta-analysis (NMA) has accounted for baseline variations in viral load when assessing the relative efficacy of interventions for chronic hepatitis B (CHB). We undertook baseline-adjusted and unadjusted analyses using the same data to explore the impact of baseline viral load (BVL) on CHB treatment response. METHODS: We searched Embase, Medline, Medline in Process and the Cochrane CENTRAL databases for randomised clinical trials (RCTs) of monotherapy interventions at licensed doses for use in CHB. Search strategies comprised CHB disease and drug terms (a combination of controlled vocabulary and free text terms) and also a bespoke RCT filter.The NMA was undertaken in WinBUGs using fixed and random effects methods, using data obtained from a systematic review. Individual patient data (IPD) from an entecavir clinical trial were used to quantify the impact of different baseline characteristics (in particular undetectable viral load (UVL) at 1 year) on relative treatment effect. Study level mean baseline values from all identified studies were used. Results were generated for UVL and presented as relative risks (RRs) and 95% credible intervals (CrIs) using entecavir as reference treatment. RESULTS: Overall, for all eight relevant interventions we identified 3,000 abstracts. Following full text review a total of 35 (including the contents of six clinical study reports) met the inclusion critera; 19 were in hepatitis B e antigen (HBeAg)-positive patients and 14 of the 19 contained outcome information of relevance to the NMA.Entecavir and tenofovir studies had heterogeneous patient populations in terms of BVL (mean values 9.29 and 8.65 log10 copies/ml respectively). After adjusting UVL for BVL using an informative prior based on the IPD analysis, the difference between entecavir and tenofovir was not statistically significant (RR 1.27, 95% CrI 0.96 to 1.47-fixed effects). A similar conclusion was found in all sensitivity analyses. Adjusted tenofovir results were more consistent with observed clinical trial response rates. CONCLUSIONS: This study demonstrates the importance of adjusting for BVL when assessing the relative efficacy of CHB interventions in achieving UVL. This has implications for both clinical and economic decision making.

Chronic hepatitis B treatment initiation and modification patterns in five European countries: a 2-year longitudinal, non-interventional study.

BACKGROUND: Chronic hepatitis B (CHB) is an important health concern, but there are few studies describing its management in different countries. This prospective, longitudinal, non-interventional study aimed to assess differences in CHB management in five European countries (Germany, France, Poland, Romania and Turkey). METHODS: Data were collected from CHB patients' records between 2008 and 2010. Patients were stratified by treatment status at baseline (treated or untreated). The primary objective was to estimate the probability of a CHB management modification (treatment initiation or change) among patients from each country during a 2-year follow-up. RESULTS: A total of 1,267 patients were included (567 treated, 700 untreated). Baseline characteristics between countries and treatment status groups were broadly comparable. Most patients had an alanine aminotransferase measurement in the 12 months prior to baseline; proportions of patients with an HBV DNA assessment varied by country and treatment status. The Kaplan-Meier-estimated probability of any treatment modification ranged from 9.4% (Turkey) to 30.1% (Poland) at 12 months and 10.0% (Turkey) to 40.0% (Poland) at 24 months. Modifications were more common in treated than untreated patients. The most frequently reported reasons for modifying treatment were HBV-DNA-related. The majority of treated patients were treated with monotherapy; however, choice of therapy differed between countries. CONCLUSIONS: This is the first longitudinal study describing CHB management in European countries. Differences were observed in treatment and monitoring between countries, but alanine aminotransferase and HBV DNA levels consistently emerged as key tests in the management of CHB in all five countries.

Chronic hepatitis B monitoring and treatment patterns in five European countries with different access and reimbursement policies.

BACKGROUND: In Europe, health-care policies are determined at a national level and differ between countries. This analysis from a prospective, longitudinal, non-interventional study aimed to describe patterns in the clinical monitoring and treatment of chronic hepatitis B (CHB) in five European countries. METHODS: Country-specific cohorts of adult patients with compensated CHB managed in clinics in Germany, France, Poland, Romania and Turkey were followed for up to 2 years between March 2008 and December 2010. RESULTS: A total of 1,267 patients were included. Baseline age and gender distribution were similar across countries for patients who were treated (n=567) and untreated (n=700) at baseline. Most treated patients were receiving monotherapy at baseline, most frequently with entecavir or tenofovir in Germany, France and Turkey, and with lamivudine in Poland and Romania. Use of pegylated interferon was more frequent in Poland and Romania than in other countries. In Romania monotherapy with entecavir increased after it became reimbursed in 2008. Hospitalizations during follow-up were more frequent in Romania (1.45 hospital days/patient-year) and Poland (1.81 days/patient-year) than in Turkey, France and Germany (0.00, 0.05 and 0.10 days/patient-year, respectively); clinic visits were more frequent in Poland (3.20 versus 0.30-1.78 visits/patient-year across other countries). CONCLUSIONS: These results illustrate country-specific patterns in the management of CHB patients across Europe. Observed monitoring patterns, hospitalization rates and other health-care utilization may be related to cost and reimbursement issues; however, further study in individual countries would be required to confirm these (post hoc) observations.