Lenvatinib Versus Sorafenib as First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Cost-Utility Analysis.

BACKGROUND: In a global, phase III, open-label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10 years to receive approval as first-line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost-effectiveness of lenvatinib and sorafenib as a first-line therapy of unresectable HCC. MATERIALS AND METHODS: A state-transition model of unresectable HCC was developed in the form of a cost-utility analysis. The model time horizon was 5 years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model. RESULTS: Lenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost-saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy. CONCLUSION: Lenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost-saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost-saving if a significantly cheaper generic sorafenib becomes available. IMPLICATIONS FOR PRACTICE: This analysis suggests an actionable clinical policy that will achieve cost saving. This cost-utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost-saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10 years in Canada provides an important opportunity for clinicians, researchers, and health care decision-makers to explore potential modifications in recommendations and practice guidelines.

Carcinogenicity of Human Papillomavirus (HPV) Types in HIV-Positive Women: A Meta-Analysis From HPV Infection to Cervical Cancer.

Background: Data on the relative carcinogenic potential of human papillomavirus (HPV) types among women infected with human immunodeficiency virus (HIV) (WHIV) are needed to inform prevention programs for this population. Methods: A systematic literature review and meta-analysis of high-risk HPV-type distribution in 19883 HIV-positive women was performed. The women, from 86 studies worldwide, included 11739 with normal cytological findings; 1784 with atypical squamous cells of undetermined significance (ASCUS); 2173 with low-grade and 1282 with high-grade squamous intraepithelial lesions (HSILs) diagnosed cytologically; 1198 with cervical intraepithelial neoplasia grade 1 (CIN1), 456 with CIN2, and 455 with CIN3 diagnosed histologically; and 796 with invasive cervical cancers (ICCs). A large proportion of WHIV, and almost all with ICCs, were from Africa. Results: In Africa, HPV 16 accounted for 13% of HPV-positive WHIV with normal cytological findings, but this proportion increased through ASCUS, low-grade squamous intraepithelial lesions, CIN1, and CIN2 (18%-25%), up to 41%-47% for CIN3 and ICCs. Only HPV 16, HPV 18, and HPV 45 accounted for a greater proportion of HPV infections in ICCs compared with normal cytological findings (ICC:normal ratios, 3.68, 2.47, and 2.55, respectively). Other high-risk types accounted for important proportions of low- and/or high-grade lesions, but their contribution dropped in ICCs, with ICC:normal ratios in Africa ranging from 0.79 for HPV 33 down to 0.38 for HPV 56. Findings for HPV 16 and HPV 18 in Europe/North America, Asia, and Latin America were compatible with those from Africa. Conclusions: HPV 16 and HPV 18 in particular, but also HPV 45, at least in Africa, warrant special attention in WHIV. Broad consistency of findings with those in HIV-uninfected population would suggest that the risk stratification offered by partial HPV genotyping tests also have relevance for HIV-positive women.

CAR T-cell Therapy for Diffuse Large B-cell Lymphoma in Canada: A Cost-Utility Analysis.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a novel cell therapy for treating non-Hodgkin lymphoma. The development of CAR T-cell therapy has transformed oncology treatment by offering a potential cure. However, due to the high cost of these therapies, and the large number of eligible patients, decision makers are faced with difficult funding decisions. Our objective was to assess the cost-effectiveness of tisagenlecleucel for adults with relapsed/refractory diffuse large B-cell lymphoma in Canada using updated survival data from the recent JULIET trial. METHODS: We developed an individual-simulated discrete event simulation model to assess the costs and quality-adjusted life-years (QALY) of tisagenlecleucel compared with salvage chemotherapy. Survival estimates were obtained from a published clinical trial and retrospective analysis. If patients remained progression free for 5 y, they were assumed to be in long-term remission. Costing and utility data were obtained from reports and published sources. A Canadian health care payer perspective was used, and outcomes were modeled over a lifetime horizon. Costs and outcomes were discounted at 1.5% annually, with costs reported in 2021 Canadian dollars. A probabilistic analysis was used, and model parameters were varied in 1-way sensitivity analyses and scenario analyses. RESULTS: After we incorporated the latest clinical evidence, tisagenlecleucel led to an additional cost of $503,417 and additional effectiveness of 2.48 QALYs, with an incremental cost-effectiveness ratio of $202,991 compared with salvage chemotherapy. At a willingness-to-pay threshold of $100,000/QALY, tisagenlecleucel had a 0% likelihood of being cost-effective. CONCLUSIONS: At the current drug price, tisagenlecleucel was not found to be a cost-effective option. These results heavily depend on assumptions regarding long-term survival and the price of CAR T. Real-world evidence is needed to reduce uncertainty. HIGHLIGHTS: For patients with diffuse large B-cell lymphoma who failed 2 or more lines of systemic therapy, CAR T was not found to be a cost-effective treatment option at a willingness-to-pay threshold of $100,000.These results heavily depend on the expected long-term survival. The uncertainty in the model may be improved using real-world evidence reported in the future.

Coevolution of risk perception, sexual behaviour, and HIV transmission in an agent-based model.

Risk perception shapes individual behaviour, and is in turn shaped by the consequences of that behaviour. Here we explore this dynamics in the context of human immunodeficiency virus (HIV) spread. We construct a simplified agent-based model based on a partner selection game, where individuals are paired with others in the population, and through a decision tree, agree on unprotected sex, protected sex, or no sex. An individual's choice is conditioned on their HIV status, their perceived population-level HIV prevalence, and the preferences expressed by the individual with whom they are paired. HIV is transmitted during unprotected sex with a certain probability. As expected, in model simulations, the perceived population-level HIV prevalence climbs along with actual HIV prevalence. During this time, HIV- individuals increasingly switch from unprotected sex to protected sex, HIV+ individuals continue practicing unprotected sex whenever possible, and unprotected sex between HIV+ and HIV- individuals eventually becomes rare. We also find that the perceived population-level HIV prevalence diverges according to HIV status: HIV- individuals develop a higher perceived HIV prevalence than HIV+ individuals, although this result is sensitive to how much information is derived from global versus local sources. This research illustrates a potential mechanism by which distinct groups, as defined by their sexual behaviour, HIV status, and risk perceptions, can emerge through coevolution of HIV transmission and risk perception dynamics.

Understanding the Feasibility of Implementing CAR T-Cell Therapies from a Canadian Perspective.

In Canada, chimeric antigen receptor (CAR) T-cell therapy was recommended for funding for the treatment of select hematological cancers. Canadian hospitals have limited experience and capacity in administrating this therapy. We conducted a qualitative interview-based study with stakeholders in Canada. Questions were asked related to the development, administration, implementation and logistical planning of CAR T-cell therapy. Results were summarized into four main themes: (i) novel; (ii) patient characteristics and the delivery of care; (iii) processes from "bench-to-bedside"; and (iv) the future state, including both challenges and recommendations to ensure sustainability. Valuable perspectives from stakeholders highlight some of the unique challenges to implementing a highly personalized and expensive-to-deliver therapy.

Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model.

PURPOSE: The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future. The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma. METHODS: A health system-level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma. Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality. RESULTS: Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time. CONCLUSION: We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system. Wait times may be prolonged if system resource availability does not match the demand. Strategies must be developed to minimize the impact of delays and reduce complications during waiting.

Multiplayer games and HIV transmission via casual encounters.

Population transmission models have been helpful in studying the spread of HIV. They assess changes made at the population level for different intervention strategies. To further understand how individual changes affect the population as a whole, game-theoretical models are used to quantify the decision-making process. Investigating multiplayer nonlinear games that model HIV transmission represents a unique approach in epidemiological research. We present here 2-player and multiplayer noncooperative games where players are defined by HIV status and age and may engage in casual (sexual) encounters. The games are modelled as generalized Nash games with shared constraints, which is completely novel in the context of our applied problem. Each player's HIV status is known to potential partners, and players have personal preferences ranked via utility values of unprotected and protected sex outcomes. We model a player's strategy as their probability of being engaged in a casual unprotected sex encounter (USE), which may lead to HIV transmission; however, we do not incorporate a transmission model here. We study the sensitivity of Nash strategies with respect to varying preference rankings, and the impact of a prophylactic vaccine introduced in players of youngest age groups. We also study the effect of these changes on the overall increase in infection level, as well as the effects that a potential prophylactic treatment may have on age-stratified groups of players. We conclude that the biggest impacts on increasing the infection levels in the overall population are given by the variation in the utilities assigned to individuals for unprotected sex with others of opposite HIV status, while the introduction of a prophylactic vaccine in youngest age group (15-20 yr olds) slows down the increase in HIV infection.

Effect of age-difference between heterosexual partners on risk of cervical cancer and human papillomavirus infection.

BACKGROUND: Age difference (Adiff) within a heterosexual couple may influence a woman's risk of being HPV-positive and developing cervical cancer (CC). METHODS: We assessed the relationship between Adiff within the first and current sexual partnership and risk of CC and HPV infection in 1495 cases and 1358 control women from 6 countries included in IARC's multicentric case-control study (median age: 48 years). RESULTS: Large Adiff within the first partnerships was associated with increased CC risk (OR≥3 vs. ≤2 years=1.49, CI: 1.26-1.75); this association disappeared after correction for age at first sexual intercourse (OR=1.03, 0.86-1.24). The relationship between Adiff within the current partnership and HPV-positivity was opposite (OR≥3 vs. ≤2 years=0.59, 0.41-0.86) and not affected by adjustment for sexual confounding. The influences of Adiff on CC risk and HPV-positivity were consistent across age groups and countries. CONCLUSION: The association between CC risk and large Adiff in the first sexual partnership is mostly explained by young age at first intercourse. Conversely, the negative association between Adiff in current partnership and HPV-positivity is probably related to decreased infectiousness of the male partner with age. The study of Adiff in sexual partnerships helps elucidate HPV circulation in different populations.

A Filtering Approach for Image-Guided Surgery With a Highly Articulated Surgical Snake Robot.

GOAL: The objective of this paper is to introduce a probabilistic filtering approach to estimate the pose and internal shape of a highly flexible surgical snake robot during minimally invasive surgery. METHODS: Our approach renders a depiction of the robot that is registered to preoperatively reconstructed organ models to produce a 3-D visualization that can be used for surgical feedback. Our filtering method estimates the robot shape using an extended Kalman filter that fuses magnetic tracker data with kinematic models that define the motion of the robot. Using Lie derivative analysis, we show that this estimation problem is observable, and thus, the shape and configuration of the robot can be successfully recovered with a sufficient number of magnetic tracker measurements. RESULTS: We validate this study with benchtop and in-vivo image-guidance experiments in which the surgical robot was driven along the epicardial surface of a porcine heart. CONCLUSION: This paper introduces a filtering approach for shape estimation that can be used for image guidance during minimally invasive surgery. SIGNIFICANCE: The methods being introduced in this paper enable informative image guidance for highly articulated surgical robots, which benefits the advancement of robotic surgery.

Effect of HIV Infection on Human Papillomavirus Types Causing Invasive Cervical Cancer in Africa.

OBJECTIVES: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type. DESIGN: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa. METHOD: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR). RESULTS: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV. CONCLUSIONS: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models.

BACKGROUND: Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination. METHODS: We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). FINDINGS: 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46-0·68) and 0·36 (0·28-0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90-1·00) and 0·83 (0·75-1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13-0·32) and 0·35 (0·27-0·39) for 40% coverage, and 0·07 (0·00-0·10) and 0·16 (0·01-0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). INTERPRETATION: Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time. FUNDING: Canadian Institutes of Health Research.

Sexual behavior, risk perception, and HIV transmission can respond to HIV antiviral drugs and vaccines through multiple pathways.

There has been growing use of highly active antiretroviral treatment (HAART) for HIV and significant progress in developing prophylactic HIV vaccines. The simplest theories of counterproductive behavioral responses to such interventions tend to focus on single feedback mechanisms: for instance, HAART optimism makes infection less scary and thus promotes risky sexual behavior. Here, we develop an agent based, age-structured model of HIV transmission, risk perception, and partner selection in a core group to explore behavioral responses to interventions. We find that interventions can activate not one, but several feedback mechanisms that could potentially influence decision-making and HIV prevalence. In the model, HAART increases the attractiveness of unprotected sex, but it also increases perceived risk of infection and, on longer timescales, causes demographic impacts that partially counteract HAART optimism. Both HAART and vaccination usually lead to lower rates of unprotected sex on the whole, but intervention effectiveness depends strongly on whether individuals over- or under-estimate intervention coverage. Age-specific effects cause sexual behavior and HIV prevalence to change in opposite ways in old and young age groups. For complex infections like HIV-where interventions influence transmission, demography, sexual behavior and risk perception-we conclude that evaluations of behavioral responses should consider multiple feedback mechanisms.

Demonstration of transoral surgery in cadaveric specimens with the medrobotics flex system.

OBJECTIVES/HYPOTHESIS: Using human cadavers, we investigated the feasibility of using a new robotic platform, the Medrobotics Flex System, for laryngeal access and flexible tool delivery to facilitate the performance of pharyngolaryngeal procedures without laryngeal suspension. Our initial trials specifically assess the utility of this experimental robotic system for epiglottectomy and base of tongue resection. STUDY DESIGN: Feasibility; Level of evidence: NA. METHODS: Using standard mouth retractors, the Flex™robot was driven via the physician controller to the supraglottic region. Non-crossing, flexible endoscopic tools were inserted through the robot's external tool channels to retract, cauterize, and remove tissue in each procedure type. Mock surgical procedures were performed on the laryngopharyngeal complex including epiglottectomy, base of tongue resection, and vocal cord excision. Time-to-tissue exposure was noted for each procedure. Each epiglottectomy was timed to determine operation duration. RESULTS: Epiglottectomy, base of tongue resection, and vocal cord excision were successfully performed without suspension laryngoscopy. Individual surgeons improved the procedure time significantly (P = 0.03) between first and second attempts. Epiglottectomies were performed in an average time of 42 minutes (N = 5, σ = 28 minutes). CONCLUSIONS: The Medrobotics Flex System demonstrates great potential as a surgical tool in head and neck oncology. Compared to other surgical robots, the Flex System offers facilitated access, vision, and triangulation of flexible tools for procedures in the endolarynx. LEVEL OF EVIDENCE: N/A.

A transoral highly flexible robot: Novel technology and application.

OBJECTIVES/HYPOTHESIS: Organ preservation surgery is a major focus in head and neck oncology. Current approaches are aimed toward improving quality of life and decreasing treatment-related morbidity. Transoral robotic surgery was developed to overcome the limitations of traditional surgical approaches. The most widely used robotic system is the da Vinci Surgical System. Although the da Vinci offers clear surgical advantages over traditional approaches, its rigid operative arms prevent complex maneuverability in three-dimensional space. The ideal surgical robot would configure to the anatomy of the patient and maneuver in narrow spaces. We present the first cadaveric trials of the use of a highly flexible robot able to traverse the nonlinear upper aerodigestive tract and gain physical and visual access to important anatomical landmarks without laryngeal suspension. STUDY DESIGN: Feasibility. METHODS: Using human cadavers, we investigated the feasibility of visualizing the endolarynx transorally with a highly flexible robot without performing suspension of the larynx. Two fresh and four preserved human specimens were used. RESULTS: Unhampered visualization of the endolarynx was achieved in all specimens without performing laryngeal suspension. Standard mouth retractors facilitated the delivery of the robot into the endolarynx. CONCLUSIONS: The flexible robot technology mitigates laryngeal suspension and the limitations of current robotic surgery with rigid line-of-sight-directed instruments. Having demonstrated the feasibility of physical and visual access to the endolarynx, future work will study the feasibility of using the highly flexible robot in transoral robotic procedures with flexible instrumentation placed in the robot's available working ports.

Time for change? An economic evaluation of integrated cervical screening and HPV immunization programs in Canada.

Many jurisdictions have implemented universal human papillomavirus (HPV) immunization programs in preadolescent females. However, the cost-effectiveness of modified cervical screening guidelines and/or catch-up immunization in older females in Canada has not been evaluated. We conducted a cost-utility analysis of screening and immunization with the bivalent vaccine for the Canadian setting from the Ministry of Health perspective. We used a dynamic model to capture herd immunity and included cross-protection against strains not included in the vaccine. We found that adding catch-up immunization to the current program would be cost-effective, and that combining catch-up immunization with delaying the age at which screening is first initiated could result in cost savings and net health gains.