Update on antimalarial drug efficacy and resistance in the GMS

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Donna Norman
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1 Update on antimalarial drug efficacy and resistance in the GMS Drug Efficacy and Response Unit MPAC meeting October 2018

2 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 F446I N458Y M476I Y493H R539T I543T P553L R561H C580Y Candidates/associated P441L G449A C469F A481V P527H N537I G538V V568G P574L F673I A675V

3 Associated and validated K13 mutations 2018 Validated F446I N458Y M476I Y493H R539T I543T P553L R561H C580Y Candidates/associated P441L G449A C469F A481V P527H N537I G538V V568G 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.

4 Distribution of K13 mutants in the GMS Line between artemisininresistance regions F446I M476I R561H N458YI R539T P553L C580Y Y493H I543T

5 Distribution of C580Y mutations worldwide C580Y reported Possible permissive or compensatory background mutations Miotto et al., Nature Genetics 2015

6 Relation between partner drug efficacy & K13 mutations Year Site ACT N Efficacy 28/42 days (%) K13 mutant (%) Pfmdr1 (n > 1) (%) 2011 Pailin Cambodia Artesunatemefloquine (C580Y) Dak Nong Viet Nam Dihydropiperaquine (C580Y; Y493H) N/A 2014 Yingjiang county Yunnan, China Dihydropiperaquine (F446I) N/A Champassak Lao PDR Artemetherlumefantrine (C580Y; R539T) N/A Kratie, Siam Riep, Pursat, P. Vihear Cambodia Artesunatemefloquine (C580Y) < 5

7 Relation between partner drug efficacy & K13 mutations Year Site ACT N Efficacy 28/42 days (%) K13 mutant (%) 2016 Kampong Speu, Kratie 2017 Kampong Speu, Pursat, Stungtreng 2017 Ratanakiri, Mondulkiri Artesunatemefloquine Artesunatemefloquine Artesunatepyronaridine % (C580Y) % (C580Y, R539T, Y493H) (C580Y) 2017 Kachin, N. Shan Artemetherlumefantrine (F446I, R561H)

8 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

9 Spread of DHA-piperaquine in GMS

10 Therapeutic efficacy and changes in national malaria drug policies

11 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?

12 Efficacy of ACTs in the GMS between Myanmar Years N of studies Treatment failures min Treatment failures min Artemether-lumefantrine Artesunate-mefloquine Artesunate-pyronaridine DHA-piperaquine Cambodia Artesunate-mefloquine Artesunate-pyronaridine Lao PDR Artemether-lumefantrine DHA-piperaquine Viet Nam DHA-piperaquine Artesunate-pyronaridine 2017-on-going 5 N = 136; TF = 4.4%

13 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.

14 Suggested actions needed to prevent and respond to resistance Limit the number of parasites exposed to drug pressure Ensure that drug pressure on a parasite population is not from one drug only Contain and eliminate resistant strains deemed to be a potential threat to public health Minimise the total number of malaria cases by other means than the use of antimalarial drugs Vector control; Housing improvements; Environmental management. Use a range of different antimalarial drugs in an area Treat with combination therapies; Use different drugs for different interventions; Remove oral monotherapies. Limit cases by drugs other than the ones to which resistance has developed Treatment, chemoprevention or MDA with different drugs. Limit the likelihood of any transmission Detect cases early (for pf prior to gametocyte development); Gametocidal drug for falciparum; Targeted vector control Lower the risk of exportation Targeted diagnosis and treatment at borders or in migrant populations Minimise any public health impacts of antimalarial drug resistance Limit the number of parasites exposed to subtherapeutic levels of antimalarial drugs Limit the number of parasites exposed to a drug to which they are not fully sensitive Stop the onward transmission of resistant parasites Limit the risk of an individual with low levels of antimalarial drug in the blood being infected by malaria Ensure testing before treatment; Prevent reinfection among patients with subtherapeutic levels of antimalaria drugs in the blood. Limit the number of patients treated with a substandard or incomplete treatment Provision of QA drugs at a dosage ensuring clearance of asexual blood stage parasites; Private sector regulation; Health staff capacity building; Improve adherence. Ensure that the drugs used are highly efficacious Monitor efficacy and drug resistance; Only use drugs known to have high efficacy. Lower the risk that a recrudescent case transmits malaria Follow-up /track cases; Rapid treatment with secondline treatment and gametocidal drug.

15 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.

16 Thank you for your attention

ERG on multidrug-resistant P. falciparum in the GMS

ERG on multidrug-resistant P. falciparum in the GMS Minutes of ERG meeting Presented by D. Wirth, Chair of the ERG Geneva, 22-24 March 2017 MPAC meeting Background At the Malaria Policy Advisory Committee