Introduction to OpenMalaria Drug-based interventions

Resources Pathogenesis model description (when and how someone gets sick) Smith T, Ross A, Maire N, Rogier C, Trape JF, Molineaux L An epidemiologic model of the incidence of acute illness in Plasmodium falciparum malaria. Am J Trop Med Hyg 75:56-62. https://github.com/SwissTPH/openmalaria/wiki/ModelClinical Case management model description (when and how someone is treated) Tediosi F, Maire N, Smith T, Hutton G, Utzinger J, Ross A, Tanner M (2006) An approach to model the costs and effects of case management of Plasmodium falciparum malaria in sub-saharan Africa. Am J Trop Med Hyg 75:90-103. https://github.com/SwissTPH/openmalaria/wiki/ScenarioHealthSyste m

Model assumptions Probability of clinical episode based on pyrogenic threshold The health system acts on events as driven by the clinical illness model Immunity acts by suppressing parasite densities Infectivity of humans to mosquitoes a function of asexual parasite densities 10, 15 and 20 days previously, allowing for a delay resulting from the time course of gametocytaemia All events occur within a five-day timeframe Case management Access to treatment Diagnosis Effectiveness of treatment

Method 1: drugs deployed through the health system Describes drug effectiveness, compliance, and access to treatment for uncomplicated and severe illness Linked to clinical illness model, on a five day timestep, starting from model initialization Model will be calibrated, and immunity in the population acquired, with the described health system in place Can also be an “intervention” to change health system to a new description (i.e. introduction of new first line treatment)

Method 1: drugs deployed through the health system Two methods for parameterization: Method A: Based on sector (public, private, etc) Method B: Based on drugs Why use Method A? You want to use the original OpenMalaria Tanzania parameterization Public sector is the main entry point for case management You plan to conduct a cost-effectiveness analysis Why use method B? There are multiple drugs in the market you would like to describe Treatment through many different channels There exists data on access to and effectiveness of each drug (i.e. an ACTwatch country) Detailed documentation: https://github.com/SwissTPH/openmalaria/wiki/ScenarioHealthSystem

Health system – parameter descriptions Detailed documentation: https://github.com/SwissTPH/openmalaria/wiki/ScenarioHealthSystem

Method 2: drugs deployed through a stand-alone intervention Deploy at specified time points to specific age groups or cohorts and/or Continuously when someone reaches a certain age Stand-alone or “bundled” with a group of interventions With or without a diagnostic (deterministic or stochastic)

Drug administration glossary (operational definitions) Intervention Definition Test? Primary goal MSAT Mass screen and treat Test community for malaria parasites. If positive, give drug. Y Clear parasites MTAT Mass test and treat Same as MSAT MDA Mass drug administration Drug distribution at the community level N Clear parasites & prevention IST Intermittent screen and treat Test specific groups for malaria parasites. If positive, give drug. FSAT* Focal screen and treat Test a radius around an identified case (hotspots). If positive, give drug. SMC Seasonal malaria chemoprophylaxis Drug distribution to community to prevent malaria during main transmission season. Prevention IPTi Intermittent Preventive therapy of infants Drug distribution to infants to prevent malaria. Given in 3 rounds. IPTp Intermittent preventive therapy of pregnant women Drug distribution to pregnant women to prevent malaria. Given in 3 rounds. *Not possible to simulate with OpenMalaria – no explicit spatial component

Method 2: drugs deployed through a stand-alone intervention Specify separate drug action per timestep on blood and liver stages (or both) or Specify an initial effectiveness of drug action and a decay function (like a vaccine) Transmission-blocking Prevents infection from human to mosquito (gametocytes) Blood stage Decreases number of parasites in the blood (trophozoites) Pre-erythrocytic Kills liver stage parasites (merozoites) *Exception: Ivermectin (deployed like a vector control intervention)

Stand-alone drug interventions – parameter descriptions Initial efficacy (proportion of infections cured) – either total, or for separate blood and liver stages Duration of efficacy (either time to half or full decay) Decay function Diagnostic: Cutoff for parasites per Microlitre or Specificity and 50% density Detailed documentation: https://github.com/SwissTPH/openmalaria/wiki/ScenarioHealthSystem

Example Research question To predict the incremental cost-effectiveness of mass screen and treat (MSAT) campaigns as a strategy for malaria disease-burden reduction in sub-Saharan African settings with varying receptivity and access to case management, compared to the absence of MSAT

OpenMalaria parameterization Health system parameterization First-line treatment with Artemether-lumefantrine (Coartem) Drug effectiveness (% of infections cleared): 85% Compliance to drug regimen: 90% For patients who did not comply, treatment 20% effective MSAT parameterization One round of treatment per year at different timing Peak, month before peak, trough, month before trough, month after trough Coverage: 85%

OpenMalaria experiment design Assuming Namawala, Tanzania transmission setting Starting annual average EIR: 2, 20, 50 LLIN coverage: 40%, 60%, 80% Fevers accessing treatment using: 20%, 35%, 55% Outcome measure Incremental cost effectiveness ratio (ICER) per uncomplicated case averted from the comparator

Results MSAT averted the most episodes where the number of episodes in the comparator was intermediate (different combinations of EIR and LLIN coverage) MSAT has comparable cost-effectiveness to scaling up case management or LLINs at intermediate coverage levels of those interventions