Shunmay Yeung LSHTM Malaria Day talk April 29, 2010 The problem with drugs…. ……..is they don’t last forever

Overview What’s the problem? Previous drug resistance Artemisinin resistance/tolerance What’s being done? Challenges, questions and priorities Shunmay Yeung –LSHTM malaria day

Chloroquine resistance  First reported on the Thai-Cambodia border in 1957  Burma 1969  Africa in 1978 Payne, 1987 Drug resistance – emerged from here before and spread to Africa Shunmay Yeung –LSHTM malaria day

Antimalarial resistance results in…. Longer time to recovery Treatment failure Severe malaria Continued infectiousness of patients and therefore continued transmission Increased costs to health services and patients Increased deaths! Shunmay Yeung –LSHTM malaria day

Increased mortality “…the proportion of deaths attributable to chloroquine treatment was 69%…..These 4 years of data provide strong evidence that continued use of chloroquine in areas with resistance is contributing to excess Plasmodium falciparum- related deaths” (The mortality consequences of the continued use of chloroquine in Africa: experience in Siaya, western Kenya. Zucker JR et al. Am J Trop Med Hyg Apr;68(4):386-90)Zucker JR “After the emergence of chloroquine resistance, the risk of malaria death among children 0-9 years old in the three populations was multiplied by 2.1, 2.5 and 5.5, respectively.” (Impact of chloroquine resistance on malaria mortality. Trape JF, et al CR Acad Sci ) Trape JF Shunmay Yeung –LSHTM malaria day

Non-malaria mortality in under 5’s fell in the 1990’s Malaria mortality increased in East and Southern Africa and remained static in West Africa % of deaths dues to malaria increased Korenromp et al Lancet Infect Dis 2003; 3: Shunmay Yeung –LSHTM malaria day

Artemisinins - the “new” hope Rapid killing Broad stage specificity Reduces gametocyte carriage Oral/injectable/rectal Well tolerated Once a day treatment Shunmay Yeung –LSHTM malaria day

WHO Technical Consultation on “Antimalarial Combination Therapy” – April 2001 ….. but have to be given in combination with another effective antimalarial as an Artemisinin based Combination Therapy (ACT) to: Ensure adherence (3 days instead of 7 days as monotherapy) an To protect against drug resistance Ideally in one tablet as a Fixed Dose Combination Shunmay Yeung –LSHTM malaria day

Lots of evidence that they worked and were safe.. Shunmay Yeung – LSHTM malaria day

CURE RATE (%) CQ SP Q M 25 QT AM M 15 Sustained high cure rates and a decline in resistance (in-vitro) Shoklo Malaria Research Unit, Thailand Shunmay Yeung – LSHTM malaria day

Myint et al, 2004 Lancet 2004:363;9-17 Day 28 failure rates Shunmay Yeung – LSHTM malaria day

(World Malaria report 2009) Shunmay Yeung – LSHTM malaria day

Just when things were looking up… Shunmay Yeung – LSHTM malaria day

Thai-Cambodia border Thai-Myanmar border Dondorp, NEJM, 2009 p= for  slopes between sites Prolonged parasite clearance time in Western Cambodia Shunmay Yeung – LSHTM malaria day

Conventional In-vitro Drug Sensitivity testing does not pick up the resistant phenotype; new tests are urgently needed Dondorp, NEJM, 2009 Shunmay Yeung – LSHTM malaria day

Artemisinin Quinine 48 hours Mechanism of artemisinin resistance? Shunmay Yeung – LSHTM malaria day

Clearance rate is a heritable trait …. Anderson et al. JID 2010 But no molecular marker has yet been identified Immawong et al. submitted Shunmay Yeung – LSHTM malaria day

Why Western Cambodia? History of political turmoil Lots of population movement Weak public health system Drug pressure Long history of artemisinin use Widespread availability of artesunate monotherapy Long delay in availability of effective fixed dose combination tablet - first line is still co-blistered artesunate and mefloquine Sub-therapeutic dosing (poor provider and patient adherence) Fake and sub-standard drugs Shunmay Yeung – LSHTM malaria day

If artemisinin resistance follows in the path of previous antimalarial drug resistance - potentially disastrous for global malaria control What to do?!? Shunmay Yeung – LSHTM malaria day

“Containment” programme launched 2009 Shunmay Yeung Shunmay Yeung – LSHTM malaria day

Objectives 1.Reducing drug pressure 2.Eliminate malaria through early detection and treatment 3.Target mobile and migrant population 4.Vector control 5.Information and education and behaviour change communication 6.Strengthening management and surveillance capacity 7.Operational research Shunmay Yeung – LSHTM malaria day

Reducing drug pressure Ban on oral artemisinin monotherapies Strengthening capacity of drug regulatory and enforcement Limited switch to co-formulated DHA-piperaquine Piloting of Affordable Medicine Facility malaria Piloting of Public-Private initiatives ? Role of Atovaquone and Proquanil Shunmay Yeung – LSHTM malaria day

Eliminating malaria through detection and treatment Passive case detection: – Community based diagnosis and treatment through village malaria workers and malaria health posts – Attempts to improve case management in public health facilities Active case detection – ? Mass drug administration/Mass Screening and treatment Type of diagnosis (none/microscopy/RDT/PCR) ACT or Malarone? Primaquine? (Safety, dose, timing…..) Feasibility/acceptability/sustainability? Effectiveness/cost-effectiveness? – ? Focal screening and treatment – ?Active case investigation and response Shunmay Yeung – LSHTM malaria day

Migrant and mobile population Qualitative research Engagement of employers of migrant workers IEC (billboards, mass media, community events) Border health posts (Thailand) and Mobile Malaria Workers (Cambodia) Official border crossingNot so official…. Shunmay Yeung

Challenges Tools Delay in availability of choice in fixed dose combination ACT Primaquine – concerns re. haemolysis Lack of very sensitive point of contact diagnostic test for screening Health systems Weak public health system and infrastructure in Cambodia Financial and human resource constraints especially peripherally Co-ordination and management Between WHO, NMCP, NGOs and multiple partners Political Cross border tensions eg. Preah Vihear temple dispute Cross border control and the mobile population Porous borders Very heterogeneous population Highest risk populations are hardest to reach Many unknowns Shunmay Yeung – LSHTM malaria day

Challenges – global level How far it’s spread? – Not yet to Western Thailand or Bangladesh – No evidence of spread ≠ Evidence of no spread Difficult to define and difficult to measure – In-vivo clinical response to artemisinin monotherapy Misunderstandings – Tolerance not full-blown resistance – “Artemisinin” rather than “ACT” – ACTs still very effective – including in Western Cambodia Need for urgent action to limit spread and prevent emergence else where but this does not mean reducing access to good quality ACTs to those who need them. Shunmay Yeung – LSHTM malaria day

Priorities – Define limits of spread – Global mechanism with mandate and adequate funds to plan and coordinate appropriate response – Action on artemisinin monotherapies and sub- standard/fake drugs – Fast-tracking of development of priority drugs? – Research Development of screening tools Understanding underlying mechanism New drugs/dosing regimes to overcome artemisinin tolerance? Operational research on containment/elimination Shunmay Yeung – LSHTM malaria day

THANK YOU Shunmay Yeung Shunmay Yeung – LSHTM malaria day