Update on antimalarial drug efficacy and resistance in the GMS Drug - - PowerPoint PPT Presentation

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 N458Y M476I Y493H R539T I543T P553L R561H C580Y 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.

Distribution of K13 mutants in the GMS

F446I M476I R561H P553L R539T N458YI I543T Y493H C580Y

Line between artemisinin- resistance regions

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 days (%) K13 mutant (%) Pfmdr1 (n > 1) (%) 2011 Pailin Cambodia Artesunate- mefloquine 29 100 75.9 (C580Y) 6.9 2012-13 Dak Nong Viet Nam Dihydro- piperaquine 33 100 72.7 (C580Y; Y493H) N/A 2014 Yingjiang county Yunnan, China Dihydro- piperaquine 23 100 91.3 (F446I) N/A 2014-15 Champassak Lao PDR Artemether- lumefantrine 29 93.2 83.3 (C580Y; R539T) N/A 2014-16 Kratie, Siam Riep, Pursat,

• P. Vihear

Cambodia Artesunate- mefloquine 305 100 94.2 (C580Y) < 5

Year Site ACT N Efficacy 28/42 days (%) K13 mutant (%) 2016 Kampong Speu, Kratie Artesunate- mefloquine 69 100 95.6% (C580Y) 2017 Kampong Speu, Pursat, Stungtreng Artesunate- mefloquine 170 99.5 78.2% (C580Y, R539T, Y493H) 2017 Ratanakiri, Mondulkiri Artesunate- pyronaridine 123 97.6 72.4 (C580Y) 2017 Kachin, N. Shan Artemether- lumefantrine 71 97.2 43.7 (F446I, R561H)

Relation between partner drug efficacy & K13 mutations

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)

Witkowski et al., Lancet Inf. Disease 2016

(N = 725)

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 studies Treatment failures min Treatment 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%

• 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.

Conclusions

Minimise any public health impacts of antimalarial drug resistance

Ensure that drug pressure

• n a parasite population is

not from one drug only

Use a range of different antimalarial drugs in an area Interventions:

• Treat with combination

therapies;

• Use different drugs for

different interventions;

• Remove oral monotherapies.

Contain and eliminate resistant strains deemed to be a potential threat to public health

Limit cases by drugs

• ther than the ones

to which resistance has developed Interventions: Treatment, chemoprevention or MDA with different drugs. Limit the likelihood

• f any transmission

Interventions:

• Detect cases early

(for pf prior to gametocyte development);

• Gametocidal drug

for falciparum;

• Targeted vector

control Lower the risk of exportation Interventions:

• Targeted diagnosis

and treatment at borders or in migrant populations.

Limit the number of parasites exposed to drug pressure

Minimise the total number of malaria cases by other means than the use of antimalarial drugs Interventions:

• Vector control;
• Housing improvements;
• Environmental

management.

Limit the number of parasites exposed to subtherapeutic levels of antimalarial drugs

Limit the risk of an individual with low levels of antimalarial drug in the blood being infected by malaria Interventions:

• 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 Interventions:

• Provision of QA drugs at a

dosage ensuring clearance of asexual blood stage parasites;

• Private sector regulation;
• Health staff capacity building;
• Improve adherence.

Limit the number of parasites exposed to a drug to which they are not fully sensitive

Ensure that the drugs used are highly efficacious Interventions:

• Monitor efficacy and drug

resistance;

• Only use drugs known to have

high efficacy.

2 1 3 4 6

Suggested actions needed to prevent and respond to resistance Stop the onward transmission of resistant parasites

Lower the risk that a recrudescent case transmits malaria Interventions:

• Follow-up /track cases;
• Rapid treatment with second-

line treatment and gametocidal drug.

5

• 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

• f good malaria control lacking consensus on more

proactive ways to delay resistance.

• Therefore we propose an Evidence Review Group
• n:
• Main drivers of drug resistance development;
• Proactive ways to delay the development of drug

resistance.

Conclusions

Thank you for your attention