Table 2 Summary of key findings

Measuring and monitoring resistance

Drug resistance is but one of many factors that determine the efficacy of IPTp, IPTi, SMC and MDA

Clinical trials that measure health outcomes are the gold standard for measuring chemoprevention efficacy

Drug treatment efficacy is not a reliable surrogate for chemoprevention efficacy

Molecular markers accurately indicate the presence of drug resistant parasites, and can serve as useful but imperfect means of predicting chemoprevention efficacy

Specific resistance markers must be validated independently as predictors of efficacy for each different chemoprevention regimen

Impact of IPTp on resistance

IPTp-SP appears to select for antifolate resistance mutations associated with low to moderate increases in drug resistance, but there is no convincing evidence of selection favouring the key mutations associated with higher level antifolate resistance and loss of ITPp-SP efficacy

Impact of resistance on IPTp

Despite some evidence that high level antifolate resistance at least partially compromises IPTp-SP efficacy, a worst-case scenario of harmful effects in the presence of SP resistance was not borne out by subsequent studies

The evidence supporting a recommendation to withhold ITPp-SP where the prevalence of dhps A581G exceeds a threshold of 10% is not strong

Impact of IPTi on resistance

While IPTi-SP has been accompanied by overall increases in the prevalence of some antifolate resistance markers, there is little evidence of significant selection of the forms of resistance known to compromise SP efficacy for treatment or chemoprevention

Impact of resistance on IPTi

The evidence supporting a recommendation that IPTi-SP should not be deployed where prevalence of dhps K540E exceeds 50% remains limited

Impact of SMC on resistance

While some studies have reported that SMC is followed by increased prevalence of resistance markers, other studies found no such evidence of selection

There is no evidence that SMC results in increased prevalence of the higher-level resistance mutations that most severely impair SP efficacy, nor does SMC appear to select for parasites carrying mutations associated with amodiaquine resistance

Impact of resistance on SMC

Unless and until high-level resistance mutations become more prevalent in areas where SMC is used, it will not be possible to draw conclusions about the impact of resistance on SMC efficacy

Impact of MDA on resistance

There is no evidence that MDA in the modern era using highly effective ACTs results in increased drug resistance

Impact of resistance on MDA

In the past, drug resistance has diminished the efficacy of MDA when drugs have been used in sub-curative formulations and dosing regimens

However, in the twenty-first century, MDA with highly effective combination drugs has proven efficacious even in the face of high levels of resistance

Other chemoprevention strategies

Evidence that seasonal malaria chemoprevention in school-age children increases drug resistance does not stand up to careful scrutiny

Selection of clinically relevant forms of resistance by chemoprevention is not inevitable

Managing and mitigating resistance

Standardized protocols for measuring and monitoring chemoprevention efficacy are needed

With imperfect evidence, practical considerations can help guide recommendations on when and where to deploy chemoprevention strategies

Using different drugs for chemoprevention and treatment and combining drugs with countervailing resistance mechanisms may help to preserve efficacy

The best approach for mitigating and managing drug resistance to protect the efficacy of chemoprevention strategies is to ensure a pipeline of safe and effective new malaria drugs with diverse mechanisms of action and resistance