Update on antimalarial drug efficacy and resistance in the GMS Drug Efficacy and Response Unit MPAC meeting 17-19 October 2018
• Update on artemisinin-resistance markers • Relation between partial artemisinin resistance and partner drug failure • Spread of DHA-piperaquine resistance • Efficacy of other ACTs
Associated and validated K13 mutations 2018 Validated Candidates/associated F446I P441L N458Y G449A M476I C469F Y493H A481V R539T P527H I543T N537I P553L G538V R561H V568G C580Y P574L F673I A675V Ariey et al., Nature 2013 Other less frequent variants were reported to be associated with delayed clearance but without statistical significance due to few number of cases: D452E, C469Y, K479I, R515K, S522C, N537D, R575K, M579I, D584V, P667T, H719N.
Distribution of K13 mutants in the GMS Line between artemisinin- resistance regions F446I M476I R561H N458YI R539T P553L Y493H C580Y I543T
Distribution of C580Y mutations worldwide C580Y reported Possible “ permissive ” or compensatory background mutations Miotto et al. , Nature Genetics 2015
Relation between partner drug efficacy & K13 mutations Year Site ACT N Efficacy 28/42 K13 mutant (%) Pfmdr1 days (%) (n > 1) (%) 2011 Pailin Artesunate- 29 100 75.9 6.9 Cambodia mefloquine (C580Y) 2012-13 Dak Nong Dihydro- 33 100 72.7 N/A Viet Nam piperaquine (C580Y; Y493H) 2014 Yingjiang county Dihydro- 23 100 91.3 N/A Yunnan, China piperaquine (F446I) 2014-15 Champassak Artemether- 29 93.2 83.3 N/A Lao PDR lumefantrine (C580Y; R539T) 2014-16 Kratie, Siam Artesunate- 305 100 94.2 < 5 Riep, Pursat, mefloquine (C580Y) P. Vihear Cambodia
Relation between partner drug efficacy & K13 mutations Year Site ACT N Efficacy 28/42 K13 mutant (%) days (%) 2016 Kampong Speu, Artesunate- 69 100 95.6% Kratie mefloquine (C580Y) 2017 Kampong Speu, Artesunate- 170 99.5 78.2% Pursat, mefloquine (C580Y, R539T, Stungtreng Y493H) 2017 Ratanakiri, Artesunate- 123 97.6 72.4 Mondulkiri pyronaridine (C580Y) 2017 Kachin, N. Shan Artemether- 71 97.2 43.7 lumefantrine (F446I, R561H)
DHA-PIP efficacy in Cambodia: role of each component K13 WT PIP WT (n=268) K13 WT PIP MUT (n=14) K13 MUT PIP WT (n=208) K13 MUT PIP MUT (n=235) (N = 725) Witkowski et al., Lancet Inf. Disease 2016
Spread of DHA-piperaquine in GMS
Therapeutic efficacy and changes in national malaria drug policies
Spread of DHA-piperaquine in GMS DHA-PIP used until recently for MDA and clinical trials in Cambodia! Increase of piperaquine resistance: increase of Pm2 CN and 2 new Pfcrt mutations; Difficult to expect PIPR reversal similarly to MQR. What about reversal of AR?
Efficacy of ACTs in the GMS between 2010-2017 Years N of Treatment Treatment studies failures min failures min Myanmar Artemether-lumefantrine 2010-17 24 0.0 6.0 Artesunate-mefloquine 2011-13 5 0.0 2.2 Artesunate-pyronaridine 2017-17 2 0.0 0.0 DHA-piperaquine 2010-17 15 0.0 4.8 Cambodia Artesunate-mefloquine 2010-17 13 0.0 1.7 Artesunate-pyronaridine 2014-17 5 0.0 18.0 Lao PDR Artemether-lumefantrine 2010-17 9 0.0 17.2 DHA-piperaquine 2016-17 2 13.3 47.4 Viet Nam DHA-piperaquine 2010-17 39 0.0 46.3 Artesunate-pyronaridine 2017-on-going 5 N = 136; TF = 4.4%
Conclusions • The data reaffirm the need for an urgent and continued intensive regional malaria elimination campaign in the GMS; • Surveillance for artemisinin and partner drug resistance needs to be continued and strengthened in the GMS; • There is a critical need for surveillance outside the GMS to detect potential de novo resistance or the potential introduction of resistant parasites; • Where surveillance signals a potential threat to leading ACTs, effective alternative ACTs should be identified and implemented before resistance reaches critical levels.
Suggested actions needed to prevent and respond to resistance Limit the number of Ensure that drug pressure Contain and eliminate resistant strains deemed to be a parasites exposed to on a parasite population is potential threat to public health drug pressure not from one drug only Limit cases by drugs Limit the likelihood Lower the risk of Minimise the total Use a range of different other than the ones of any transmission exportation number of malaria cases antimalarial drugs in an area to which resistance by other means than the Interventions: Interventions: has developed use of antimalarial drugs Interventions: • Detect cases early • Targeted diagnosis • Treat with combination (for pf prior to Interventions: and treatment at Interventions: therapies; gametocyte borders or in • Vector control; Treatment, • Use different drugs for development); migrant chemoprevention or • Housing improvements; • Gametocidal drug different interventions; MDA with different populations. • Environmental • Remove oral monotherapies. for falciparum; drugs. management. • Targeted vector control 1 3 6 Minimise any public health impacts of antimalarial 4 5 2 drug resistance Limit the number of parasites Stop the onward Limit the number of parasites exposed to exposed to a drug to which transmission of resistant subtherapeutic levels of antimalarial drugs they are not fully sensitive parasites Ensure that the drugs used are Lower the risk that a Limit the risk of an individual Limit the number of patients highly efficacious recrudescent case transmits with low levels of antimalarial treated with a substandard or malaria drug in the blood being incomplete treatment Interventions: Interventions: infected by malaria Interventions: • Monitor efficacy and drug • Follow-up /track cases; • Provision of QA drugs at a resistance; Interventions: • Rapid treatment with second- dosage ensuring clearance of • Only use drugs known to have • Ensure testing before line treatment and asexual blood stage high efficacy. treatment; gametocidal drug. parasites; • Prevent reinfection among • Private sector regulation; patients with subtherapeutic • Health staff capacity building; levels of antimalaria drugs in • Improve adherence. the blood.
Conclusions • There is a good understanding of what different factors can play a role in the development of drug resistance. However, it is less clear which of these factors are the main drivers of resistance development. • Drug resistance prevention has to a large extent been framed as merely a matter of implementation of good malaria control lacking consensus on more proactive ways to delay resistance. • Therefore we propose an Evidence Review Group on: • Main drivers of drug resistance development; • Proactive ways to delay the development of drug resistance.
Thank you for your attention
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