Marc Brisson

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

BACKGROUND Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. METHODS We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure. FINDINGS We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. INTERPRETATION Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. FUNDING The Canadian Institutes of Health Research.

The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study

Background: Vaccination against herpes zoster is being considered in many countries. We conducted a multicentre prospective study to describe the impact of herpes zoster and postherpetic neuralgia on health-related quality of life. Methods: From October 2005 to July 2006, 261 outpatients aged 50 years or older with herpes zoster were recruited from the clinical practices of 83 physicians within 14 days after rash onset. The Zoster Brief Pain Inventory was used to measure severity of pain and interference with activities of daily living because of pain. The EuroQol EQ-5D assessment tool was used to measure quality of life. These outcomes were assessed at recruitment and on days 7, 14, 21, 30, 60, 90, 120, 150 and 180 following recruitment. Results: Acute herpes zoster interfered in all health domains, especially sleep (64% of participants), enjoyment of life (58%) and general activities (53%). The median duration of pain was 32.5 days. The median duration of interference with activities of daily living because of pain varied between 27 and 30 days. Overall, 24% of the participants had postherpetic neuralgia (pain for more than 90 days after rash onset). Anxiety and depression, enjoyment of life, mood and sleep were most frequently affected during the postherpetic neuralgia period. The mean EQ-5D score was 0.59 at enrolment and remained at 0.67 at all follow-up points among participants who reported clinically significant pain. Interpretation: These data support the need for preventive strategies and additional early intervention to reduce the burden of herpes zoster and postherpetic neuralgia.

The cost-effectiveness of varicella vaccination in Canada

A deterministic realistic age-structured model was used to predict the impact of vaccination on the incidence of varicella and zoster. Unit costs, estimated from literature, were applied to the predicted health outcomes. Various vaccination programs were investigated and a sensitivity analysis was performed. Assuming no impact of vaccination on zoster, varicella vaccination is estimated to cost 45,000 dollars, 51,000 dollars and 18,000 dollars per life-year gained from the health payers perspective for infant, infant with catch-up campaign, and preteen programs, respectively. From the societal perspective, mass infant varicella vaccination was estimated to be highly cost saving in Canada. Importantly, infant varicella vaccination could result in a short- to medium-term increase of zoster incidence and thus cause vaccination to be highly cost-ineffective (118,000 dollars per life-year gained) under the health payers perspective. From a health payers perspective the preteen vaccination is the only strategy that is deemed cost-effective. The cost-effectiveness of infant vaccination rests heavily on the unknown relationship between varicella and zoster.

Economic Evaluation of Human Papillomavirus Vaccination in Developed Countries

Background: With promising efficacy results from randomized control trials of human papillomavirus (HPV) vaccines and the availability of new screening paradigms, policymakers are being asked to make recommendations and decisions regarding the optimal strategies to reduce HPV infection and disease. Such decisions are increasingly being made with significant input from mathematical and economic models. The demand for modeling has resulted in the publication of numerous mathematical models looking at the cost-effectiveness of HPV vaccination. Objective: To review published models that have been used to evaluate the cost-effectiveness of HPV vaccination in developed countries and highlight points of consensus and disagreement in methods and findings. Methods: This review consists of cost-effectiveness studies published in the peer-reviewed literature before August 2008. Results: Despite variations in methods, modeling studies are producing consistent conclusions: (1) vaccinating young girls against HPV is likely to be cost- effective; (2) vaccinating boys will most likely not be cost- effective in countries that can reach high coverage rates in girls, and (3) results are most sensitive to the duration of vaccine protection. However, results from analyses examining the effectiveness and cost-effectiveness of vaccinating boys when coverage rates are low (≤80%) and catch-up strategies have reached conflicting conclusions.

Incremental Impact of Adding Boys to Current Human Papillomavirus Vaccination Programs: Role of Herd Immunity

Our aim was to examine the potential incremental impact of vaccinating boys against human papillomavirus (HPV) on vaccine-type infection in females and males, using an individual-based HPV transmission-dynamic model. Under base assumptions (vaccine efficacy = 99%, duration of protection = 20 years, coverage = 70%), vaccinating 12-year-old boys, in addition to girls, resulted in an incremental reduction in HPV-16/18 (HPV-6/11) incidence over 70 years of 16% (3%) in females and 23% (4%) in males. The benefit of vaccinating boys decreased with improved vaccination coverage in girls. Given the important predicted herd immunity impact of vaccinating girls under moderate to high vaccine coverage, the potential incremental gains of vaccinating boys are limited.

Cost-effectiveness of female human papillomavirus vaccination in 179 countries: a PRIME modelling study

BACKGROUND Introduction of human papillomavirus (HPV) vaccination in settings with the highest burden of HPV is not universal, partly because of the absence of quantitative estimates of country-specific effects on health and economic costs. We aimed to develop and validate a simple generic model of such effects that could be used and understood in a range of settings with little external support. METHODS We developed the Papillomavirus Rapid Interface for Modelling and Economics (PRIME) model to assess cost-effectiveness and health effects of vaccination of girls against HPV before sexual debut in terms of burden of cervical cancer and mortality. PRIME models incidence according to proposed vaccine efficacy against HPV 16/18, vaccine coverage, cervical cancer incidence and mortality, and HPV type distribution. It assumes lifelong vaccine protection and no changes to other screening programmes or vaccine uptake. We validated PRIME against existing reports of HPV vaccination cost-effectiveness, projected outcomes for 179 countries (assuming full vaccination of 12-year-old girls), and outcomes for 71 phase 2 GAVI-eligible countries (using vaccine uptake data from the GAVI Alliance). We assessed differences between countries in terms of cost-effectiveness and health effects. FINDINGS In validation, PRIME reproduced cost-effectiveness conclusions for 24 of 26 countries from 17 published studies, and for all 72 countries in a published study of GAVI-eligible countries. Vaccination of a cohort of 58 million 12-year-old girls in 179 countries prevented 690,000 cases of cervical cancer and 420,000 deaths during their lifetime (mostly in low-income or middle-income countries), at a net cost of US

Population-Level Impact of the Bivalent, Quadrivalent, and Nonavalent Human Papillomavirus Vaccines: A Model–Based Analysis

4 billion. HPV vaccination was very cost effective (with every disability-adjusted life-year averted costing less than the gross domestic product per head) in 156 (87%) of 179 countries. Introduction of the vaccine in countries without national HPV vaccination at present would prevent substantially more cases of cervical cancer than in countries with such programmes, although the disparity has narrowed since 2012. If 71 phase 2 GAVI-eligible countries adopt vaccination according to forecasts, then in 2070 GAVI Alliance-funded vaccination could prevent 200,000 cases of cervical cancer and 100,000 deaths in some of the highest-burden countries. INTERPRETATION Large between-country disparities exist for HPV vaccination, with countries with the most to gain yet to introduce national HPV vaccination. Support from the GAVI Alliance could help to reduce such disparities, but a substantial burden will remain even after presently projected vaccine introductions. FUNDING WHO.

Dynamic transmission modeling: A report of the ISPOR-SMDM modeling good research practices task force-5

BACKGROUND Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines. METHODS We developed an individual-based, transmission-dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada. RESULTS Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers. CONCLUSIONS The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer.

Accounting for methodological, structural, and parameter uncertainty in decision-analytic models: a practical guide.

Abstract The transmissible nature of communicable diseases is what sets them apart from other diseases modeled by health economists. The probability of a susceptible individual becoming infected at any one point in time (the force of infection) is related to the number of infectious individuals in the population, will change over time, and will feed back into the future force of infection. These nonlinear interactions produce transmission dynamics that require specific consideration when modeling an intervention that has an impact on the transmission of a pathogen. Best practices for designing and building these models are set out in this article.

Understanding differences in predictions of HPV vaccine effectiveness: a comparative model-based analysis.

Accounting for uncertainty is now a standard part of decision-analytic modeling and is recommended by many health technology agencies and published guidelines. However, the scope of such analyses is often limited, even though techniques have been developed for presenting the effects of methodological, structural, and parameter uncertainty on model results. To help bring these techniques into mainstream use, the authors present a step-by-step guide that offers an integrated approach to account for different kinds of uncertainty in the same model, along with a checklist for assessing the way in which uncertainty has been incorporated. The guide also addresses special situations such as when a source of uncertainty is difficult to parameterize, resources are limited for an ideal exploration of uncertainty, or evidence to inform the model is not available or not reliable. Methods for identifying the sources of uncertainty that influence results most are also described. Besides guiding analysts, the guide and checklist may be useful to decision makers who need to assess how well uncertainty has been accounted for in a decision-analytic model before using the results to make a decision.