Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.

Time From Infection to Disease and Infectiousness for Ebola Virus Disease, a Systematic Review.

We systematically reviewed the literature to estimate the incubation and latent periods of Ebola virus disease. We found limited epidemiological data from individuals with discrete 1-day exposures. Available data suggest that the incubation and latent periods may differ, and mathematical models may be improved by distinguishing between the two periods.

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.

Public health impact of 2-, 4-, and 9-valent HPV vaccination in females on cervical and noncervical diseases in men and women under different coverage scenarios in China: A simulation study.

The high prevalence of human papillomavirus (HPV) infection in China suggests there would be a substantial positive health impact of widespread vaccination against HPV. We adapted a previously described dynamic transmission model of the natural history of HPV infection and related diseases to the Chinese setting to estimate the public health impact in China of 2-valent (with and without cross-protection), 4-valent, and 9-valent HPV vaccination strategies. The model predicted the incidence and mortality associated with HPV-related diseases, including cervical and noncervical cancers, genital warts, and recurrent respiratory papillomatosis (RRP), based on the various vaccination coverage rate (VCR) scenarios, over a 100-year time horizon. The public health impact of the 4 vaccination strategies was estimated in terms of cases and deaths averted compared to a scenario with no vaccination. Under the assumption of various primary and catch-up VCR scenarios, all 4 vaccination strategies reduced the incidence of cervical cancer in females and noncervical cancers in both sexes, and the 4-valent and 9-valent vaccines reduced the incidence of genital warts and RRP in both sexes. The 9-valent vaccination strategy was superior on all outcomes. The number of cervical cancer cases averted over 100 years ranged from ~ 1 million to ~ 5 million while the number of cervical cancer deaths averted was ~ 345,000 to ~ 1.9 million cases, depending on the VCR scenario. The VCR for primary vaccination was the major driver of cases averted.

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.

Cost-effectiveness of axicabtagene ciloleucel versus lisocabtagene maraleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the US.

AIMS: This study evaluated from a US payer perspective the cost-effectiveness of two chimeric antigen receptor T (CAR T) cell therapies, axicabtagene ciloleucel (axi-cel) versus lisocabtagene maraleucel (liso-cel), for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following two or more systemic therapy lines. METHODS: We developed a 3-state (i.e., pre-progression, post-progression, death) partitioned survival model to estimate patients' lifetime outcomes. Mixture cure models were used for survival extrapolation to account for long-term remission. Survival inputs were based on a matching-adjusted indirect comparison (MAIC) that reweighted the ZUMA-1 population (receiving axi-cel) to match patient characteristics in TRANSCEND-NHL-001 (assessing liso-cel). Costs included apheresis, drug acquisition, and administration for conditioning chemotherapy and CAR T therapies, monitoring, transplant, hospitalization, adverse events, routine care, and terminal care, per published literature and databases. Utilities were derived from ZUMA-1 and literature. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, axi-cel was associated with more QALYs (7.76 vs. 5.94) and greater costs overall ($611,440 vs. $597,174) than liso-cel, at $7,843/QALY gained. The incremental costs (+$14,266) were largely driven by higher routine care costs (+$18,596) due to longer survival and hospitalization (+$10,993) but partially offset by reduced costs of CAR T acquisition (‒$11,300) and terminal care (‒$4,025). Sensitivity analyses consistently suggested robustness of base-case results. LIMITATIONS: This study relied on an MAIC in which trial design differences and unobserved confounders could not be accounted for. Future real-world studies for recently approved CAR T are warranted to validate our results. Due to a lack of data, we assumed equivalent use of transplants and treatment for B-cell aplasia between the two therapies based on clinicians' opinions. CONCLUSIONS: In the US, axi-cel is a potentially cost-effective treatment option compared with liso-cel for adult patients with r/r LBCL after two or more systemic therapy lines.

Cost-effectiveness of intravenous vedolizumab vs subcutaneous adalimumab for moderately to severely active ulcerative colitis.

BACKGROUND: The efficacy of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab for the treatment of moderately to severely active ulcerative colitis (UC) was assessed in the VARSITY clinical trial, which demonstrated for the first time in a head-to-head clinical trial setting the superiority of IV vedolizumab with respect to clinical remission and endoscopic improvement. Both therapies offer better clinical outcomes compared with immunomodulators and corticosteroids but are often more expensive than other pharmacologic treatment options. Thus, payers and decision makers face the task of leveraging finite resources for optimal health benefits, which can be aided by the use of cost-effectiveness models. OBJECTIVE: To assess the cost-effectiveness of IV vedolizumab vs SC adalimumab from a US payer perspective using head-to-head data from the VARSITY trial. METHODS: A cohort decision tree was developed to estimate the costs and clinical outcomes associated with IV vedolizumab vs SC adalimumab to treat adults with moderately to severely active UC. Simulated cohorts began the model at treatment induction and continued to maintenance treatment with vedolizumab or adalimumab unless experiencing nonresponse or serious adverse drug reaction (ADR), in which case those patients transitioned to second-line treatment with tofacitinib, infliximab, or golimumab, where they could achieve response and/or remission or not. Those who still did not achieve response or remission or who had a serious ADR transitioned to a state of nonresponse for the remainder of the model or received surgery. The process was modeled for patients who were treatment naive and treatment experienced at baseline separately. Efficacy and safety inputs for vedolizumab and adalimumab were taken from the VARSITY trial, and corresponding inputs for other biologics were derived from a network meta-analysis. All clinical inputs were extrapolated over 2 years. Direct medical costs (expressed in 2019 US dollars) included those related to drug acquisition and administration, ADRs, routine monitoring, and additional treatment procedures. Outcomes were not discounted given the short time horizon. Univariate sensitivity and scenario analysis were applied to evaluate the robustness of the model to underlying parameter and structural uncertainty. RESULTS: Initial treatment with vedolizumab was associated with a higher remission rate at 2 years (73.5% vs 71.5%) and higher persistence (22.0% vs 14.4%) compared with adalimumab. Total direct medical costs were lower for the vedolizumab cohort ($100,022 vs $151,133), primarily driven by the lower annual drug acquisition cost of vedolizumab ($85,953 vs $137,492). When endoscopic improvement was used as the outcome measure, IV vedolizumab was also associated with higher endoscopic remission and lower overall costs. CONCLUSIONS: With better clinical outcomes and lower direct medical costs over a 2-year model horizon, vedolizumab IV was the dominant treatment strategy vs adalimumab SC in adults with moderately to severely active UC. Outcomes were driven primarily by the probability of major ADRs and induction response. DISCLOSURES: This study was supported by Takeda Pharmaceuticals U.S.A., Inc. (Lexington, MA). Schultz and Turpin are employees of Takeda Pharmaceuticals U.S.A., Inc. Turpin has stock or stock options in Takeda Pharmaceuticals. Diakite, Carter, and Snedecor are employees of OPEN Health (Bethesda, MD), which received payment from Takeda for the design and execution of this study. This study was presented at the European Crohn's and Colitis Organisation (ECCO) 2020 Congress and Digestive Disease Week (DDW), 2020 Virtual Congress.

Cost Effectiveness of Vericiguat for the Treatment of Chronic Heart Failure with Reduced Ejection Fraction Following a Worsening Heart Failure Event from a US Medicare Perspective.

OBJECTIVE: Given the high economic burden of disease among adult patients with chronic heart failure with reduced ejection fraction (HFrEF) following a worsening heart failure event in the US, this study aimed to estimate the cost effectiveness of vericiguat plus prior standard-of-care therapies (PSoCT) versus PSoCT alone from a US Medicare perspective. METHODS: A four-state Markov model (alive prior to heart failure hospitalization, alive during heart failure hospitalization, alive post-heart failure hospitalization, and death) was developed to predict clinical and economic outcomes, based on the results of the VICTORIA trial, in which patients with chronic HFrEF following a worsening heart failure were randomized to placebo or vericiguat, in addition to PSoCT, which consisted of ß-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan. Risks of heart failure hospitalization and cardiovascular mortality were based on multivariable regression models derived from VICTORIA data. Utilities were derived from VICTORIA EQ-5D data and the literature. Costs included drug acquisition, heart failure hospitalization, routine care, and terminal care. Primary outcomes included heart failure hospitalization, cardiovascular mortality, life-years, quality-adjusted life-years (QALYs), and incremental costs per QALY gained over a 30-year lifetime horizon, discounted at 3.0% annually. RESULTS: For the VICTORIA overall intent-to-treat population, compared with PSoCT, vericiguat plus PSoCT resulted in 19 fewer heart failure hospitalizations and 13 fewer cardiovascular deaths per 1000 patients, as well as 0.28 QALY gained per patient at an incremental cost of $23,322, leading to $82,448 per QALY gained. CONCLUSIONS: Based on the results of VICTORIA, patients treated with vericiguat had lower rates of heart failure hospitalization and cardiovascular death. The addition of vericiguat to PSoCT was estimated to increase QALYs and to be cost effective at a willingness-to-pay threshold of $100,000 per QALY gained.

Cost effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the United States.

AIMS: To assess from a US payer perspective the cost-effectiveness of the chimeric antigen receptor T (CAR T)-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) to treat relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following ≥2 systemic therapy lines. METHODS: A three-state (i.e. pre-progression, post-progression, and death) partitioned survival model was used to estimate the quality-adjusted life-years (QALYs) and costs for patients on each treatment over a lifetime horizon. Progression-free survival (PFS) and overall survival (OS) were based on a matching-adjusted indirect treatment comparison (MAIC) that accounted for differences in trial population baseline characteristics. Mixture cure models (MCMs) were used to account for long-term survivors. Costs included drug acquisition and administration for the CAR T-cell therapies and conditioning chemotherapy, apheresis, CAR T-specific monitoring, transplant, hospitalization, adverse events, routine care, and terminal care. Health state utilities were derived from trial and published data. Sensitivity analyses included probabilistic sensitivity analyses (PSAs) and an analysis of extremes that assessed the results across a vast array of combinations of parametric OS and PFS curves across the two therapies. RESULTS: Compared to tisa-cel, axi-cel resulted in 2.31 QALYs gained and a cost reduction of $1,407 in the base case. In the PSA, the cost per QALY gained was ≤$31,500 in 95% of the 1,000 simulations. In the analysis of extremes, the cost per QALY gained was ≤$7,500 in 99% of the 1,296 combinations of MCMs and ≤$40,000 in 95% of the 1,296 combinations of standard models. LIMITATIONS: In absence of head-to-head comparative data, we relied on a MAIC, which cannot account for all possible confounders. Moreover, some outcomes (i.e. transplantations, hospitalizations, adverse events (AEs)) were not adjusted in the MAIC. CONCLUSIONS: In this simulation, axi-cel was a superior treatment option as it is predicted to achieve better outcomes at lower or minimal incremental costs versus tisa-cel.

Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model.

BACKGROUND: During the 2014 Ebola virus disease (EVD) outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT) was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel "ordered stepped-wedge cluster trial" (OSWCT) designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model's projection of first case occurrence was robust to changes in disease natural history parameters. CONCLUSIONS/SIGNIFICANCE: Ordering clusters in a step-wedge trial based on the cluster's underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints.