Background
A not-so-trivial question: transmission-blocking or vector control?
Defining the ideal context for ivermectin use for malaria control
Residual transmission
Insecticide resistance
High transmission settings
Elimination settings
Additional factors
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The presence of artemisinin resistance
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The specific susceptibility of the local vectors to ivermectin
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The local transmission pattern
Selecting the right proof-of-concept scenario: where is it testable?
Residual transmission | Insecticide resistance | Transmission | Targeted for elimination | Artemisinin resistance | Burden of malaria | Testable | |
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Elimination in the GMS | +++ | + | + | +++ | +++ | + | Possibly |
Elimination in selected areas of sub-Saharan Africa | ++ | +++ | +++ | +++ | – | +++ | Yes |
Reduce disease burden in high-transmission areas | + | Any | +++ | + | +++ | Yes | |
Stem insecticide resistance in well-defined areas | Any | ++++ | Any | + | Any | + | Difficult |
Elimination from hotspots in the endgame | ++ | +++ | +++ | +++ | Any | +++ (local) | Doubtful |
Stem of outbreaks | + | Any | ++ | Any | Any | + | Doubtful |
Elimination in the Greater Mekong Sub-region
Elimination in selected areas of countries with a heterogeneous transmission
Reduce disease burden in areas of high vectorial capacity
Stem insecticide resistance in well-defined areas with high resistance intensity
Elimination from hotspots in the endgame
Control of outbreaks
Selecting ivermectin-based strategies for malaria control: factors affecting the potential impact
The plasma levels reached as a factor of the LC50
The duration of effective mosquitocidal concentrations
The population coverage
The proportion of vectors feeding on alternative blood sources
The magnitude and duration of beneficial sublethal effects of the drug on the mosquitoes
Selecting ivermectin-based strategies for malaria control: how to use it?
Using the current oral formulation
Potential novel formulations
Target coverage
Examples of possible use
Using the current oral formulation at high doses for a short period of time
Using the current oral formulation at Onchocerca-approved doses at intervals
Novel, slow release formulations of ivermectin
Regimen | Efficacy | Safety | Acceptability | Compliance | Programmatic difficulty | R&D costs | Implementation costs |
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High dose, single encounter | To be assessed | To be assessed | + | +++ | + | + | Similar to ACT MDA |
Existing dose, multiple encounters | To be assessed | + | +++ | + | +++ | + | Similar to SMC |
Novel long-lasting formulation, single encounter | To be assessed | To be assessed | To be assessed | +++ | + | +++ | Similar to SMC but high R&D costs and longer timeframe to availability |
Timing the intervention: when could ivermectin be most useful?
Study design for a proof-of concept of ivermectin MDA to achieve a measurable transmission reduction
Potential outcomes
Outcome measure | Rationale | Method | Advantages | Disadvantages | |
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In Humans | Clinical incidence | Of primary importance for the target population | Clinical case definition and laboratory confirmation | Unequivocal and tangible reflection of benefit for the population The earliest measurable clinical end-point reflecting transmission reduction | Requires robust baseline data Must reflect seasonal variations |
Parasite prevalence | Directly related to the EIR and VC | Consensus needed Options include: microscopy RDT PCR RT-PCR QT-NASBA [75] LAMP [76] | Robust measure Used across many settings Tangible reflection of benefit at population level | Laborious. Requires robust baseline data Must reflect seasonal variations Some methods are not suitable for the field. Method must be tailored according to the local prevalence | |
Gametocytaemia | A measure of infectiousness to mosquitoes (k) [63] | Consensus needed Options include: RT-PCR (RNA vs DNA) LAMP QT-NASBA | Robust measure of transmission | Must collect baseline data May not reflect population benefit May not reflect the independent effect of ivermectin | |
Variations in population level serology [77] | Indirect measure of transmission | Consensus needed on mosquito and parasite antigens | Direct reflection of exposure to malaria vectors and parasites Most useful in very low-transmission settings Useful without baseline data | May not reflect clinical benefit Must reflect seasonal variations | |
Molecular force of infection [78] | Indirect measure of transmission | PCR | Reliable and easier to determine than FOI | May not reflect clinical benefit Seasonality Inter-cluster variations | |
Entomological | Entomological inoculation rate [66] | A direct measure of transmission intensity. Likely to reflect the additional effect of ivermectin | Human landing catches vs light traps for biting rate Dissection, ELISA or PCR for sporozoite rate | Most useful in high transmission settings | Requires extensive knowledge of the local vectors. Very laborious. Minimum EIR of 5-10 needed for reliability [64] Ethics of human landing catches Must avoid contamination from control sites |
Vectorial capacity | Would additionally reflect the daily survival of vectors, a more direct effect of ivermectin | As above plus determination of the daily survival and assessment of the extrinsic incubation period | The most direct assessment of transmission | Requires extensive knowledge of the local vectors. Very laborious. Minimum EIR of 5-10 needed for reliability [64] Ethics of human landing catches Must avoid contamination from control sites |
Potential comparators
Community standard core vector control interventions alone (LLINs/IRS vs LLINs/IRS + ivermectin)
MDA with anti-malarials (ACT MDA+LLINs+/−IRS vs ACT MDA +LLINs/+/−IRS + ivermectin)
Transmission-blocking interventions
Potential trial design
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A vector control package representative of strategies and epidemiology for that region must be included.
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Appropriate surveillance system for identification of cases and appropriate response systems must be in place. This includes reporting systems to ensure timely facility-based reporting.
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The impact of ivermectin MDA is modelled to be proportionally higher in areas of high transmission [44, 56], giving a theoretical power advantage to that context, although trials under different scenarios (higher endemicity to accelerate the path to elimination and at low levels of endemicity to accelerate crashing transmission) have been considered and would be valuable in different context.
Go/No-Go criteria for pre-clinical and early clinical development
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Cumulative 3-day mosquito mortality: reflecting a quick reduction in vector densities and with direct implication on an effect on human-to-mosquito transmission.
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Cumulative 9-day mosquito mortality (before completion of sporogony): reflecting the reduction in infectious vectors.
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The duration of the above effects.
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Definitive proof of impact on human health will likely be required at later development stages given its importance for communities and policy makers.