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Antimalarial Drug Responses and Factors That Affect Clinical Outcome After Treatment SGC-McGill-MMV Malaria Symposium June 20, 2016 Antimalarial drug responses and factors that affect clinical outcome after treatment Thomas E. Wellems, MD, PhD National Institute of Allergy and Infectious Diseases Bethesda, MD Cinchona Qinghaosu Global Malaria Incidence and Deaths, 1990-2013 Murray et al. (2014) Lancet PMID: 25059949 Malaria Death Rates in the 20th Century chloroquine introduced chloroquine resistance spreads in Africa deaths deaths (annual per 10,000) Carter and Mendis (2002) Clin.Microbiol.Rev. 15:564-594; Wellems et al. (2009) J.Clin.Invest. 199:2496-2505 The Route to Chloroquine Quinine & pre-chloroquine synthetic antimalarial drugs H H N H Quinine HO OCH3 N Methylene blue, 1891 N S N N (Paul Ehrlich) C2H5 N C H N 2 5 N Pamaquine, 1926 OCH3 C2H5 N C H Mepacrine, 1931 N 2 5 OCH3 (atebrin; quinacrine) Cl N Chloroquine designated antimalarial-of-choice, 1945 C2H5 N C H Chloroquine, 1936 N 2 5 (Resochin; SN-7618) Cl N Spread of Chloroquine Resistant Malaria Wellems Nat.Med. (2004) 10:1169-71 Mapping the CQR Gene in a P. falciparum Cross CQ-sensitive clone CQ-resistant clone Mosquitoes Chimpanzee Independent Progeny Locate & Identify Gene Wellems et al. (1990) Nature 345:253-255 Chloroquine Structure-Activity Relationships Resistance: tuned to structure of side chain Pf Chloroquine Resistance Transporter Action: ring structure sandwiches with hematin De et al. (1996) Am.J.Trop.Med.Hyg. 55: 579-583; Vippagunta et al. (1999) J.Med.Chem. 42:4630-4639 Compounds Active against CQ-Resistant P. falciparum N N N N Cl N N Cl Chloroquine Piperaquine N OH N N N O Cl N Pyronaridine Ferroquine Hybrid 4-amino-7-chloroquinoline + imipramine Artemisinin (Qinghaosu) from Traditional Chinese Medicine Recrudescences Combination Treatment with Artemisinins Li et al. (1994) TRSTMH 88 Suppl 1:5-6 Increasing Use of ACTs for Malaria Treatment World Malaria Report (2014) Murray et al. (2014) Lancet PMID: 25059949 Dihydroartemisinin-Piperaquine Failure in Cambodia Saunders et al. (2014) N.Engl.J.Med. 371: 484-5 Threat to Artemisinin Combinations? Delayed parasite clearances observed in Cambodia DELAYED CLEARANCE Western Cambodia 100 Wang Pha (2.7 h)* Pailin (5.4 h)* 10 Pursat (6.3 h)** 1 *Nosten, Dondorp & White 0.1 (Mahidol-Oxford Research Unit) NORMAL CLEARANCE density Parasite 0.01 **Amaratunga & Fairhurst (NIAID, NIH) Western Thailand (%admission) on value of 0.001 parasitemia (% admission) 0 12 24 36 48 60 72 84 96 108 120 Hours time (hours) Reports and projects on artemisinin resistance (2001–2011) A P. falciparum Genetic Cross to Investigate Artemisinin Responses Cambodian African Gametocytes Gametocytes 803 (Cambodian) GB4 (Ghanaian) Isolated in 2009 Isolated in 1990s Mosquitoes AS PCT >100 hrs African PCT K13 C580Y K13 C580 Not infective to Aotus Chimpanzee Infects Aotus monkeys Blood forms Progeny Monkey models of infection Assess artemisinin responses and drug treatment in vivo and in vitro; genetic mapping Chromosome Patterns Confirm Independent Recombinant Progeny 3,124 SNPs distinguish the 803 and GB4 parents Chr 1 Chr 2 Chr 3 Chr 4 Chr 5 Chr 6 Chr 7 Chr 8 Chr 9 Chr 10 Chr 11 Chr 12 Chr 13 Chr 14 1.0 Chr 13 SNP Data: 803 GB4 0.8 803e l e l GB4l A 34F53 0.6 0 43H38 f o 43A6 y c 44E8n e 24G11u 0.4 q e r 36D5F 36E5 39C30.2 85D3 46G9 39A40.0 38G5 0.0 0.5 0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 40E7 Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) 76H10 Chr 1 Chr 2 Chr 3 Chr 4 Chr 5 Chr 6 Chr 7 Chr 8 Chr 9 Chr 10 Chr 11 Chr 12 Chr 13 Chr 14 11C2 0.0 0.5 1.0 1.5 2.0 2.5 3.0 48C11.0 61E8 39C5 0.8 e l Chr 1 Chr 2 Chr 3 Chr 4 Chr 5 Chr 6 Chr 7 Chr 8 Chr 9 Chr 10 Chr 11 Chr 12 Chr 13 Chr 14 e l l A 3 0.6 0 8 f 10 o y c n 9 e u 0.4 q e r 8 F s r 7 0.2e v o s 6 s o r C 5 0.0f o r 0.0 0.5 0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 4 e b Position (Mb) Position (Mb) Position (Mb) Position (Mb) m Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Position (Mb) Number Position (Mb) u 3 N 0.0 0.5 1.0 1.5 2.0 2.5 3.0 2 1 0 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0Chr0.5 1 0.0 Ch0.5r 21.0 0.0 Ch0.5r 31.0 0.0 0.5Chr1.0 4 1.5 0.0 0.5Chr1.0 5 1.5 0.0 0.5Chr1.0 6 1.50.0 0.5Chr1.0 7 1.5 Chr 8 Chr 9 Chr 10 0.0 0.5Ch1.0r 11.51 2.0 0.0 0.5Ch1.0r 1.5122.0 0.0 0.5 1.0Ch1.5r 132.0 2.5 0.0 0.5 1.0Ch1.5r2.0 142.5 3.0 Chromosome 10 9 8 s r 7 e v o s 6 s o r C 5 f o r 4 e b m u 3 N 2 1 0 0.0 0.5 0.0 0.5 1.0 0.0 0.5 1.0 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.50.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Recrudescences Regardless of K13 580 Codon C 5 8 0 C 5 8 0 Y 5 5 ) ) 4 4 % % ( ( a a i i 3 3 m m e e t t i i 2 2 s s a a r r a a 1 1 P P 0 0 0 1 0 2 0 3 0 0 1 0 2 0 3 0 D a y s P o s t 1 s t A S T re a tm e n t D a y s P o s t 1 s t A S T re a tm e n t Observations . Reductions in malaria M&M today reminiscent of those from chloroquine in the 1950s and 1960s – Lessons from the evolution of chloroquine resistance – Sustainable gains require elimination of the immense reservoir of parasites in asymptomatic individuals . Combination therapy imperative – Artemisinin remains effective but requires good partners – Recrudescences in Aotus model independent of K13 – New partner drug discovery vital for the future . Much more than technological innovation is required – Community empowerments for malaria control – Educational, economic, health infrastructure advances Breaking the Health-Poverty Trap The Economist October 20, 2012 .
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