Structured Literature Review to Identify Human Papillomavirus's Natural History Parameters for Dynamic Population Models of Vaccine Impacts.

Human papillomavirus (HPV) is a common sexually transmitted virus that can cause cervical cancer and other diseases. Dynamic transmission models (DTMs) have been developed to evaluate the health and economic impacts of HPV vaccination. These models typically include many parameters, such as natural history of the disease, transmission, demographic, behavioral, and screening. To ensure the accuracy of DTM projections, it is important to parameterize them with the best available evidence. This study aimed to identify and synthesize data needed to parametrize DTMs on the natural history of HPV infection and related diseases. Parameters describing data of interest were grouped by their anatomical location (genital warts, recurrent respiratory papillomatosis, and cervical, anal, vaginal, vulvar, head and neck, and penile cancers), and natural history (progression, regression, death, cure, recurrence, detection), and were identified through a systematic literature review (SLR) and complementary targeted literature reviews (TLRs). The extracted data were then synthesized by pooling parameter values across publications, and summarized using the range of values across studies reporting each parameter and the median value from the most relevant study. Data were extracted and synthesized from 223 studies identified in the SLR and TLRs. Parameters frequently reported pertained to cervical cancer outcomes, while data for other anatomical locations were less available. The synthesis of the data provides a large volume of parameter values to inform HPV DTMs, such as annual progression rates from cervical intraepithelial neoplasia (CIN) 1 to CIN 2+ (median of highest quality estimate 0.0836), CIN 2 to CIN 3+ (0.0418), carcinoma in situ (CIS) 2 to local cancer+ (0.0396), and regional to distant cancer (0.0474). Our findings suggest that while there is a large body of evidence on cervical cancer, parameter values featured substantial heterogeneity across studies, and further studies are needed to better parametrize the non-cervical components of HPV DTMs.

Cost-effectiveness of nonavalent HPV vaccination in the Netherlands.

BACKGROUND: A bivalent human papillomavirus vaccine (2vHPV) is currently used in the Netherlands; a nonavalent vaccine (9vHPV) is also licensed. RESEARCH DESIGN AND METHODS: We compared the public health and economic benefits of 2vHPV- and 9vHPV-based vaccination strategies in the Netherlands over 100 years using a validated deterministic dynamic transmission metapopulation model. RESULTS: Compared to 2vHPV, the 9vHPV strategy averted an additional 3,245 cases of and 825 deaths from 9vHPV-strain-attributable cancers, 4,247 cases of and 190 deaths from recurrent respiratory papillomatosis (RRP), and 1,009,637 cases of anogenital warts (AGWs), with an incremental cost-effectiveness ratio (ICER) of €4,975 per quality-adjusted life year (QALY) gained. The ICER increased in a scenario with increased HPV vaccination coverage rates and was relatively robust to one-way deterministic sensitivity analyses, with variation in the disease utility parameter having the most impact. When catch-up vaccination for individuals ≤26 years of age was added to the model, vaccinating with 9vHPV averted additional cancers and AGWs compared to 2vHPV vaccination. CONCLUSION: Our analyses predict that transitioning from a 2vHPV- to a 9vHPV-based vaccination strategy would be cost-effective in the Netherlands.

Health impact and cost effectiveness of implementing gender-neutral HPV vaccination in Japan.

OBJECTIVE: To assess the public health impact and cost effectiveness of gender-neutral vaccination (GNV) versus female-only vaccination (FOV) with human papillomavirus (HPV) vaccination in Japan. METHODS: We modeled the public health impact and cost effectiveness of GNV versus FOV to prevent HPV-associated diseases in Japan over the next 100 years. We used one-way sensitivity analyses to examine the impact of varying key model input parameters and conducted scenario analyses to explore the effects of varying the vaccination coverage rate (VCR) of each cohort. RESULTS: In the base-case analysis, GNV averted additional cancer cases (17,228 female/6,033 male) and deaths (1,892 female/1,849 male) compared to FOV. When all HPV-associated diseases were considered, GNV had an incremental cost-effectiveness ratio of ¥4,732,320 (US$35,987)/quality-adjusted life year gained compared to FOV. The model was most sensitive to the discount rate and the disutility associated with HPV-related diseases. GNV had greater relative public health benefits when the female VCR was lower and was cost effective at a female VCR of 30%. CONCLUSIONS: Immediate implementation of GNV would reduce the disease burden and mortality associated with HPV in Japan, and would be cost effective compared to FOV if the female VCR remains low (30%).

Human papillomavirus (HPV) is a common sexually transmitted infection and, in Japan, the prevalence of HPV infection and the incidence of its associated diseases are high among both men and women. In the present manuscript we modeled the public health impact and cost effectiveness of gender-neutral vaccination versus female-only vaccination to prevent HPV-associated diseases in Japan over the next 100 years and found that immediate implementation of a gender-neutral vaccination strategy would reduce the burden and mortality associated with HPV in Japan.

Public health impact and cost-effectiveness of switching from bivalent to nonavalent vaccine for human papillomavirus in Norway: incorporating the full health impact of all HPV-related diseases.

AIM: The objective of this study was to estimate and compare the cost-effectiveness of switching from a bivalent to a nonavalent human papillomavirus (HPV) vaccination program in Norway, incorporating all nonavalent vaccine-preventable HPV-related diseases and in the context of the latest cervical cancer screening program. METHODS: A well-established dynamic transmission model of the natural history of HPV infection and disease was adapted to the Norwegian population. We determined the number of cases of HPV-related diseases and subsequent number of deaths, and the economic burden of HPV-related disease under the current standard of care conditions of bivalent and nonavalent vaccinations of girls and boys aged 12 years. RESULTS: Compared to bivalent vaccination, nonavalent vaccination averted an additional 4,357 cases of HPV-related cancers, 421,925 cases of genital warts, and 543 cases of recurrent respiratory papillomatosis (RRP) over a 100-year time horizon. Nonavalent vaccination also averted an additional 1,044 deaths over the 100-year time horizon when compared with bivalent vaccination. Total costs were higher for the nonavalent strategy (10.5 billion NOK [€1.03 billion] vs. 9.3-9.4 billion NOK [€915-925 million] for bivalent vaccination). A switch to nonavalent vaccination had a higher vaccination cost (4.4 billion NOK [€433 million] vs. 2.7 billion NOK [€266 million] for bivalent vaccination) but resulted in a savings of 627-694 million NOK [€62-68 million] in treatment costs. A switch to nonavalent vaccination demonstrated an incremental cost-effectiveness ratio of 102,500 NOK (€10,086) per QALY versus bivalent vaccination. CONCLUSIONS: Using a model that incorporated the full range of HPV-related diseases, and the latest cervical cancer screening practices, we found that switching from bivalent to nonavalent vaccination would be considered cost-effective in Norway.

Human papillomavirus (HPV) is a sexually transmitted infection that is common in Norway. Vaccination against HPV has substantially reduced the burden of HPV-related diseases globally. The HPV vaccine is available in bivalent, quadrivalent, and nonavalent forms. The bivalent vaccine is currently used in the Norwegian national immunization program, but the nonavalent vaccine is also licensed in Norway. In order to gain a more complete understanding of the benefits of nonavalent vaccination, it is necessary to evaluate the cost-effectiveness of switching from the bivalent vaccine to the nonavalent vaccine in light of the full array of vaccine-preventable diseases, including both cervical and noncervical cancers, genital warts, and recurrent respiratory papillomatosis (RRP). Our results show that, when the full range of HPV-related diseases is considered, nonavalent vaccination would be cost-effective relative to bivalent vaccination in Norway. Compared to bivalent vaccination, nonavalent vaccination averted an additional 4,357 cases of HPV-related cancers, 421,925 cases of genital warts, and 543 cases of RRP over a 100-year time horizon. Nonavalent vaccination also averted an additional 1,044 deaths over the 100-year time horizon when compared with bivalent vaccination. While total costs were higher for the nonavalent strategy (10.5 billion NOK [€1.03 billion] vs. 9.3-9.4 billion NOK [€915­925 million] for bivalent vaccination), switching to the nonavalent strategy resulted in a savings of 627­694 million NOK [€62­68 million] in treatment costs compared to the bivalent strategy.

Assessing the Health and Economic Outcomes of a 9-Valent HPV Vaccination Program in the United Kingdom.

Background: The United Kingdom (UK) switched from using the 4-valent human papillomavirus (HPV) vaccine (Gardasil®) to the 9-valent vaccine (Gardasil 9®) in 2021. Objective: To estimate and compare the health and economic outcomes of 2 HPV vaccination programs in the UK targeting girls and boys aged 12-13 years from the perspective of the UK National Health Service. The 2 vaccination strategies were (1) universal vaccination 4-valent (UV4V), using the 4-valent HPV vaccine (4vHPV), and (2) universal vaccination 9-valent (UV9V), using the 9-valent HPV vaccine (9vHPV). Methods: A deterministic heterosexual compartmental disease transmission model was used to track health and economic outcomes over a 100-year time horizon. Outcomes were discounted at an annual rate of 3.5% and 1.5%. All costs were adjusted to 2020 British pounds (£). Health outcomes were measured in quality-adjusted life-years (QALYs), and the summary results were presented as incremental cost-effectiveness ratios (£/QALY gained) when comparing UV4V with UV9V. Results: Using the same vaccine coverage for both programs, the total cumulative cases of HPV-related health outcomes tracked over the 100-year horizon indicated that the relative number of cases averted (UV9V vs UV4V) ranged from 4% (anal male cancers and deaths) to 56% (cervical intraepithelial neoplasia [CIN1]). Assuming that 9vHPV cost £15.18 more than 4vHPV (a cost differential based on discounted list prices), the estimated incremental cost-effectiveness ratio was £8600/QALY gained when discounted at 3.5%, and £3300/QALY gained when discounted at 1.5%. The estimated incremental cost-effectiveness ratios from the sensitivity analyses remained <£28000/QALY over a wide range of parameter inputs and demonstrated that disease utilities, discount rate, and vaccine efficacy were the 3 most influential parameters. Discussion: Consistent with other published studies, the results from this study found that the 9vHPV vaccine prevented a substantial number of cases when compared with the 4vHPV vaccine and was highly cost-effective. Conclusions: These results demonstrate that replacing universal 4vHPV with 9vHPV can prevent a substantial additional number of HPV-related cases/deaths (in both women and men) and remain cost-effective over a range of 9vHPV price premiums.

Public health impact and cost-effectiveness of catch-up 9-valent HPV vaccination of individuals through age 45 years in the United States.

The Advisory Committee on Immunization Practices (ACIP) recommended catch-up 9-valent Human Papillomavirus (HPV) vaccination through age 26 years, and shared clinical decision-making for adults aged 27-45 years, compared with catch-up through age 26 years and 21 years for females and males, respectively (status quo; pre-June-2019 recommendations). This study assessed the public health impact and cost-effectiveness of expanded catch-up vaccination through age 45 years (expanded catch-up) compared with status quo. We used an HPV dynamic transmission infection and disease model to assess disease outcomes and incremental cost-effectiveness ratio (ICER) of expanded catch-up compared with status quo. Costs (2018 USD), calculated from a healthcare sector perspective, and quality-adjusted life years (QALY) were discounted at 3% annually. Historical vaccination coverage was estimated using NIS-TEEN survey data (NHANES data for sensitivity analysis). Alternative scenario analyses included restricting upper age of expanded catch-up through 26 years (June-2019 ACIP recommendation), 29 years, and further 5-year increments. Our results show expanded catch-up vaccination would prevent additional 37,856 cancers, 314,468 cervical intraepithelial neoplasia-2/3s, 1,743,461 genital warts, and 10,698 deaths compared with status quo over 100 years at cost of $141,000/QALY. With NHANES coverage, the ICER was $96,000/QALY. The June-2019 ACIP recommendation also provided public health benefits with an ICER of $117,000/QALY, compared with status quo. The ICER for expanded vaccination through age 34 years was $107,000/QALY. Expanding catch-up vaccination program through age 45 years-old in the US is expected to provide public health benefits, and cost-effectiveness improves with expanding catch-up through age 34.

Assessing the impact of aggregating disease stage data in model predictions of human African trypanosomiasis transmission and control activities in Bandundu province (DRC).

Since the turn of the century, the global community has made great progress towards the elimination of gambiense human African trypanosomiasis (HAT). Elimination programs, primarily relying on screening and treatment campaigns, have also created a rich database of HAT epidemiology. Mathematical models calibrated with these data can help to fill remaining gaps in our understanding of HAT transmission dynamics, including key operational research questions such as whether integrating vector control with current intervention strategies is needed to achieve HAT elimination. Here we explore, via an ensemble of models and simulation studies, how including or not disease stage data, or using more updated data sets affect model predictions of future control strategies.

Assessing Strategies Against Gambiense Sleeping Sickness Through Mathematical Modeling.

Background: Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment. Methods: Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings. Results: Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings. Conclusions: There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs.

The dynamics of vector-borne relapsing diseases.

In this paper, we describe the dynamics of a vector-borne relapsing disease, such as tick-borne relapsing fever, using the methods of compartmental models. After some motivation and model description we provide a proof of a conjectured general form of the reproductive ratio R0, which is the average number of new infections produced by a single infected individual. A disease free equilibrium undergoes a bifurcation at R0=1 and we show that for an arbitrary number of relapses it is a transcritical bifurcation with a single branch of endemic equilibria that is locally asymptotically stable for R0 sufficiently close to 1. Furthermore, we show there is no backwards bifurcation. We then show that these results can be extended to variants of the model with an example that allows for variation in the number of relapses before recovery. Finally, we discuss implications of our results and directions for future research.

Speed choice and driving performance in simulated foggy conditions.

Driving in fog is a potentially dangerous activity that has been investigated in a number of different ways; however, most have focused on identifying the underlying perceptual changes that result in an inability to perceive speed of vehicle motion. Although the previous research has identified the perceptual changes associated with driving in fog and shows that people are highly likely to perceive their speed to be higher than it actually is, these research studies have not investigated driving behavior when drivers are allowed to maintain speed as they feel appropriate and make use of the vehicle's speedometer. In addition, much of the existing research focuses on speed perception and presents a limited view of other driving performance metrics in terms of lane keeping and event detection. The current study addresses these issues utilizing a driving simulator-based method where fog is simulated as a distance dependent contrast reduction while having participants drive at speeds they feel are appropriate. A number of different instructions and speed feedback mechanisms were tested in order to determine how drivers react when driving in varying levels of fog. Results also include lane keeping measures in order to assess whether drivers are willing to drive at speeds where their lane keeping performance is degraded due to the reduced visibility. Results indicate that, in general, drivers do not tend to slow down significantly until visibility distance is drastically reduced by fog; however, lane keeping ability is maintained throughout most of the range of visibility distances. Lane keeping ability was reduced only when fog results in visibility distances <30 m. Overall, the current study shows that drivers are willing and able to maintain vehicular control at high speed when driving in fog; however, it is important to note that drivers chose to drive at speeds where they would be incapable of stopping to avoid obstacles in the roadway even if they were to identify and react to the obstacle immediately at the border of visibility distance. This research suggests that safety benefits may be gained by convincing drivers to slow down more than they would on their own when driving in fog or enhancing a vehicle's ability to identify and react to hazards that are not visible to the driver. In order to further understand the effects of driving in fog, future naturalistic driving research should focus on identifying and mitigating risky behaviors associated with driving in foggy conditions.