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Monitoring antimalarial drug efficacy and resistance: challenges Dr P. Ringwald Global Malaria Programme 1| RBM Case Management Group, 13 May 2017 What is antimalarial drug resistance? Ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject” (WHO, 1973). The drug must gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action (WHO, 1986). Drug resistance treatment failure (host and/or parasite factors) 2| RBM Case Management Group, 13 May 2017 Consequences of antimalarial drug resistance Increased morbidity and mortality – including anaemia, low birth weight Increased of transmission – switch to effective drug combinations in situations of low to moderate endemicity has always resulted in a dramatic decrease in transmission Economic impact – increases cost to health services (to both provider and patient) because of returning treatment failures Greater frequency and severity of epidemics Modification of malaria distribution Greater reliance on informal private sector – with the risk of using monotherapies, sub-standard and counterfeit medicines which in turn will increase drug resistance 3| RBM Case Management Group, 13 May 2017 Monitoring antimalarial drug efficacy fits squarely within WHO’s six core functions • Providing leadership on matters critical to health and engaging in partnerships where joint action is needed; • Shaping the research agenda and stimulating the generation, translation and dissemination of valuable knowledge; • Setting norms and standards, and promoting and monitoring their implementation; • Articulating ethical and evidence-based policy options; • Providing technical support, catalysing change, and building sustainable institutional capacity; • Monitoring the health situation and assessing health trends. 4| RBM Case Management Group, 13 May 2017 Surveillance of antimalarial drug resistance 1. Avoiding emergence of drug resistance 2. Monitoring drug efficacy 3. Containing of drug resistance 5| RBM Case Management Group, 13 May 2017 1. Strategies to avoid drug resistance – Use of combination therapy – Effective ACTs of good quality • widely accessible • correctly used, particularly in the private sector, which includes: – education of the practitioners – increase compliance by use of co-package or co-formulated ACTs. – supervised drug administration can help to back up adherence (similar to DOT) • Better diagnosis of the disease to avoid misuse of the medicines • Fight against drugs of poor quality – Transmission control to reduce the burden and the use of antimalarial drugs (less drug pressure) – vector control and bed-nets (South Africa) – reduction of reservoir of infection (responsible for the spread of drug resistance) in improving therapeutic practice, in particular early diagnosis, effective treatment, and use of gametocytocidal drugs. – vaccine 6| RBM Case Management Group, 13 May 2017 2. Monitoring drug efficacy Countries must closely monitor the efficacy of antimalarial medicines recommended in their treatment guidelines and rapidly change drug policy when no longer effective, to avoid emergence of multidrug-resistance. 7| RBM Case Management Group, 13 May 2017 WHO role Template protocol – English, French – According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and cleared by ERC – Inclusion, exclusion criteria, sampling methodology, CRF, informed consent, SAE reporting… Standardized data entry and data analysis methodology – Excel programme + SOP (English, French, Spanish) – Improves quality of the data by double entry, cross check, automatic analysis of the data Funding – USAID – WWARN/WHO Antimalarial medicines for monitoring efficacy free of charge Training – Protocol and microscopy (+++) Report and publication 8| RBM Case Management Group, 13 May 2017 WHO/GMP Guidelines PK 2009 2007 2008 9| RBM Case Management Group, 13 May 2017 MM 2009 2010 Major achievements of WHO's coordination and global database on drug efficacy 77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests Report on global monitoring GFATM changed choice of drug procurement Detection of artesunate resistance at Thai-Cambodia border 10 | RBM Case Management Group, 13 May 2017 Countries which need ACT policy Countries which adopted ACT 11 | RBM Case Management Group, 13 May 2017 Threshold levels for changing malaria treatment policy % clinical failures (14 d f/up) Change 25% % failures (14 d f/up) Parasitological failures + Action 15% Clinical failures 25% Parasitological failures 15% 10% Alert 5% 5% Grace 0 WHO criteria 1998 12 | % failures (28 d f/up) RBM Case Management Group, 13 May 2017 0 WHO criteria 2003 0 WHO criteria 2005 Major achievements 77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests Report on global monitoring GFATM changed choice of drug procurement Detection of artesunate resistance at Thai-Cambodia border 13 | RBM Case Management Group, 13 May 2017 Countries which need ACT policy Countries which adopted ACT Preventing drug resistance is a global public good and monitoring drug efficacy is WHO's responsibility Global database on therapeutic efficacy of antimalarials: www.who.int/malaria/ resistance.htm 14 | RBM Case Management Group, 13 May 2017 Major achievements 77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests Report on global monitoring GFATM changed choice of drug procurement Detection of artesunate resistance at Thai-Cambodia border 15 | RBM Case Management Group, 13 May 2017 Countries which need ACT policy Countries which adopted ACT 16 | RBM Case Management Group, 13 May 2017 Major achievements 77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests Report on global monitoring GFATM changed procurement policy Detection of artesunate resistance at Thai-Cambodia border 17 | RBM Case Management Group, 13 May 2017 Countries which need ACT policy Countries which adopted ACT Proportion with treatment failure (2001-2007) in Cambodia 18 | RBM Case Management Group, 13 May 2017 Proportion of positive cases on day 3 (2001-2007) 19 | RBM Case Management Group, 13 May 2017 PCT in Pailin study 2007 20 | FULLY SENSITIVE PARASITES time (hours) RBM Case Management Group, 13 May 2017 time (hours) 120 108 96 84 0.001 72 120 108 96 84 72 60 48 36 24 12 0.0001 0.01 60 0.001 0.1 48 0.01 1 36 0.1 10 24 1 100 12 10 1000 0 parasitaemia as % from admission (individual data) 100 0 parasitaemia as % from admission (geometric mean) AS 2 mg/kg AS 4 mg/kg & MQ Potential for collaboration between WHO/GMP & WARN WHO activities – Monitoring antimalarial drug efficacy Possible points of collaboration with WARN* • Technical and financial support to regional sub-regional networks (workshops) • Capacity strengthening in countries through technical (training) and financial support • Provision of quality assured medicines and other relevant supplies • QC of data (through site visits at beginning, middle and end of the study and data review and validation-CRF, parasitology) • Collection of data from countries • Collection of blood samples for in vitro, MM, and PK • Participation of WARN members to promote WARN activities • Participation of consultants designated within WARN • • Promote country data sharing with WARN Disseminate samples to WARN reference labs – Review of research and updating methodologies – Updating and publishing WHO Global Drug Resistance Database and its applications • Co-sponsored meeting on an ad-hoc basis • WARN as one source of information • Publication of drug resistance report • Update of recommendations on medicine policy 21 | RBM Case Management Group, 13 May 2017 *WHO collaborations with WARN will not be exclusive but open to all the scientific community Networks supported by WHO Mekong RAVREDA 22 | RBM Case Management Group, 13 May 2017 HANMAT African regional networks HANMAT RAOTAP 1 RAOTAP 2 RACTAP EANMAT RER-OI SANMAT 23 | RBM Case Management Group, 13 May 2017 3. Containment of drug resistance Strengthening the strategies to avoid the emergence of drug resistance Remove the pressure of the resistant medicines Operational research – depends on the local situation Development of new antimalarial medicines 24 | RBM Case Management Group, 13 May 2017 Recommendations to countries and partners Monitoring antimalarial drug efficacy – partners to invest in monitoring antimalarial drug efficacy Support and improve access to early and effective treatment – increase use of diagnosis – increase use of good ACTs Remove the sale and use of monotherapies – support surveys on drug quality Support transmission reduction 25 | RBM Case Management Group, 13 May 2017 Structure of GMP's Technical Expert Groups (TEGs) Vector Control Chemotherapy of malaria Economics, Finance and Impact, Implementation and Scaling Up Co-chair persons Malaria Case Management Drug resistance Preventive chemotherapy Core Members + Co-opted Members 26 | RBM Case Management Group, 13 May 2017