Parasite Resistance to Artemisinins
WHO/MMV ARTEMISININ CONFERENCE 2009 "Ensuring Sustainable API Supply to Meet Global ACT Demand"
28th – 30th September 2009 in Mumbai, India
Dr Kamini Mendis Global Malaria Programme 80 countries are using ACTs as first-line malaria treatment
Countries with P.falciparum and no ACT Countries which adopted ACT as 1st-line treatment
GLOBAL 2 | MALARIA PROGRAMME Parasite Resistance to Artemisinins
Could reverse the malaria control achievements of the past decade…….
But not inevitable, if the correct course of action is taken
GLOBAL 3 | MALARIA PROGRAMME 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).
Therapeutic efficacy is used to detect resistance
Treatment failure ≠ drug resistance (host and/or parasite factors)
GLOBAL 4 | MALARIA PROGRAMME Experience in Thailand with successive drug regimens
Mefloqu ine Quinin e Sulphadoxine- pyrimethamine Chloroqui ne
GLOBAL 5 | MALARIA PROGRAMME Rapid development of resistance to monotherapies Year of 1st case Antimalarial introducti of drug on resistance Quinine 1632 1910
Chloroquine 1945 1957 12 years
Proguanil 1948 1949 1 year
Sulfadoxine-pyrimethamine 1967 1967 <1 year
Mefloquine 1977 1982 5 Artemisinin derivatives 1990 - 2000 2009 years 9-20 years? GLOBAL 6Atovaquone | 1996 MALARIA 1996 <1 year PROGRAMME Paper on resistance Artemisinin resistance
GLOBAL 8 | MALARIA PROGRAMME Events leading up to the confirmation of artemisinin resistance Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO – 2003 and 2005 High failure rate and increase parasite clearance time with ACTs detected Lao PDR
Thailand
Paili n Tra t
Vietnam Proportion with treatment failure (2001-2007) in Cambodia Proportion of positive cases on day 3 (2001-2007) „ETF“ with AS/MEF
Treatment failures with 7 days artesunate monotherapies
Noedl. et al. New England Journal of Medicine, 2009, 361: 5401. Paili n Tra t
GLOBAL 14 MALARIA | PROGRAMME Parasite clearance time with AS+MQ in Trat province No of P. falciparum positives cases PCT Province Year N D2 D3 D7 (days)
Trat 2003 44 14 (31%) 7 (15.9%) 2 (4.5%) 2.0
Trat 2004 15 2 (13.3%) 2 (13.3%) 0 2.1
Trat 2005 22 7 (31.8%) 2 (9%) 1(4.5%) 2.3
Trat 2006 32 10 (31.2%) 7(21.8%) 0 3.3
Trat 2007 31 14(45.1%) 5 (16.1%) 0 3.7
GLOBAL 15 MALARIA | PROGRAMME Mae Sot
Trat PCR-adjusted parasitological efficacy of MAS3 at Day 42
100
n=170 n=280 95 n=482 n=276 n=406 n=252 n=212 n=176 90 n=338 n=29 n=400
85
parasitological efficacy (in %) n=98 3
MAS 80 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Years
GLOBAL 17 MALARIA | PROGRAMME Higher drug concentrations needed to inhibit parasite growth
Noedl. et al. New England Journal of Medicine, 2009, 361: 5401. Pfmdr1 (≥ 2) copy number trend
70%
60%
50%
40%
30%
Increased in copy number (2+)cn 20%
10% Increased copy number in %
0% 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Years Mae Sot
Trat
GLOBAL 20 MALARIA | PROGRAMME Events leading up to the confirmation of artemisinin resistance Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO – 2003 and 2005 High failure rate and increase parasite clearance 2005time - WHO with raisedACTs detected concern over artesunate resistance in "Drug Resistance Global Report" 2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure 2006 - AFRIMS detected 2 suspected cases of artesunate resistance in Tasanh (published in 2008) Events leading up to the confirmation of artemisinin resistance Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO – 2003 and 2005 High failure rate and increase parasite clearance 2005time - WHO with raisedACTs detected concern over artesunate resistance in "Drug Resistance Global Report" 2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure 2006 - AFRIMS detected 2 suspected cases of artesunate resistance2007 January in Tasanh - WHO (published informal consultationin 2008) on containment of malaria multidrug resistance on Cambodia-Thailand border, Phnom Penh 2007 November - ARC3 project funded by BMGF (3.2 M) Objectives of the ARC3 project
Confirm clinically relevant artemisinin resistance – Characterize clinically relevant artemisinin resistance in-vivo by conducting clinical and pharmacokinetic-pharmacodynamic assessments of artesunate, at sites where artemisinin resistance has been reported, where parasite clearance is prolonged but treatment failure not yet manifest, and where artesunate efficacy is preserved; – Establish a reference repository of parasite isolates from clinically validated cases of resistance. If clinical resistance is confirmed, further characterize this resistance to define resistant in vitro phenotypes and genotypes for use in global surveillance for artemisinin resistance To establish the prevalence on substandard and fake drugs on the Thai-Cambodia border Develop strategies to combat the spread of artemisinin resistant malaria within SoutheastGLOBAL Asia and 23 internationally MALARIA | PROGRAMME ARC3 project
Funded by BMGF (3.2 M) Coordinated by GMP/HQ Major partners: – Wellcome Trust-Mahidol University, Oxford Tropical Medicine Research Programme, Bangkok, THAILAND – US Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, THAILAND – Réseau des Instituts Pasteur, Cambodge, Phnom Penh, CAMBODIA – University of Vienna, Vienna, AUSTRIA – University of Maryland School of Medicine, Baltimore, Maryland, USA – University of South Florida, Tampa, Florida, USA – USP, Rockville, Madison, USA – National Malaria Control Programme, Phnom Penh, CAMBODIA – National Malaria Control Programme, Bangkok, THAILAND – WHO Mekong project, Bangkok, THAILAND – Western Pacific Regional Office, Manila, PHILIPPINES
GLOBAL 24 MALARIA | PROGRAMME (Bandarban )University of Vienna Artesunate 2 mg/kg vs 4 mg/kg vs quinine+tetracycline over 7 days
(Mae Sot )SMUR (completed) Same design as Pailin
(Tasahn )AFRIMS Artesunate 2 mg/kg vs 4 mg/kg vs 6 mg/kg over 7 days
(Pailin )MORU( )Completed Artesunate 2 mg/kg over 7 days vs artesunate 4 mg/kg over 3 days + sequential mefloquine 25 mg/kg over 2 days If< 6 patients with PCT < 96 h Artesunate 6 mg/kg/over 7 days → vs artesunate 8 mg/kg over 3 days + sequential mefloquine 25 mg/kg (over 2 days )split PCT in Pailin study 2007
AS 2 mg/kg FULLY SENSITIVE AS 4 mg/kg & MQ PARASITES
100 1000 10 100
1 10 1 0.1 0.1
0.01 (individual data) 0.01 (geometric mean) 0.001 0.001 0.0001 0 parasitaemia as % from admission 0 96 24 60 72 84 12 36 48 parasitaemia as % from admission 84 96 72 12 24 36 48 60 108 120 108 120 time (hours) time (hours)
GLOBAL 26 MALARIA | PROGRAMME Parasite Clearance (p=0.0001 for ∆ slopes between sites)
Thai- Cambodia border
Thai- Myanmar border PCT in Pailin with artesunate 6 and 8 mg/kg/d
N=4 0 Mechanism of artemisinin resistance?
48 hours
Artemisinin Quinine Inexorable, contiguous spread of chloroquine resistance from limited foci following rare, complex genetic event Spread of chloroquine resistant P.falciparum
GLOBAL 31 MALARIA | PROGRAMME Preliminary conclusions
• The proportion of patients who are parasitaemic on day 3 is the best measure of slow parasite clearance from available clinical trial data. • The in vivo phenotype does not correlate to standard in vitro assays: • There is no correlation between artesunate IC50s and PRR at 24 h and 48 h, proportions of patient still parasitemic on day 1, day 2 or day 3 or PCT; • The lack of in vitro correlation may be because we are using the wrong tool, therefore there is a need to develop novel in vitro studies. • There was no correlation between a number of different mutations (pfSERCA or mtDNA mutations - coxIII gene) or pfmdr1 copy number and clinical GLOBAL 32 MALARIA outcomes. | PROGRAMME Artemisinin resistance: research priorities
• What is it? • What is it caused by? • How can it be readily detected? • How far has it spread? • How should artemisinin resistance infections be treated? • How can it be eliminated?
GLOBAL 33 MALARIA | PROGRAMME Artemisinin resistance
GLOBAL 34 MALARIA | PROGRAMME Events leading up to the confirmation of artemisinin resistance Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO – 2003 and 2005 High failure rate and increase parasite clearance 2005time - WHO with raisedACTs detected concern over artesunate resistance in "Drug Resistance Global Report" 2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure 2006 - AFRIMS detected 2 suspected cases of artesunate resistance2007 January in Tasanh - WHO (published informal consultationin 2008) on containment of malaria multidrug resistance on Cambodia-Thailand border, Phnom Penh 2007 November - ARC3 project funded by BMGF (3.2 M) 2008 January - WHO meeting on containment of artemisinin tolerance, Geneva 2008 February - ARC3 Clinical trial meeting, Bangkok – Informal consultation to define strategy to contain/eliminate P. falciparum parasites with altered response to artemisinin, Bangkok Thailand 2008 June - Informal consultation on resource mobilisation for the containment of artemisinin tolerant malaria on the Cambodia-Thailand border 2008 November - Containment project funded by BMGF (22.5 M) Structure of the containment project Objectives of containment project 1. To eliminate artemisinin tolerant parasites by detecting all malaria cases in target areas and ensuring effective treatment and gametocyte clearance 2. To decrease drug pressure for selection of artemisinin resistant malaria parasites (including monotherapy ban) 3. To prevent transmission of artemisinin tolerant malaria parasites by mosquito control and personal protection 4. To limit the spread of artemisinin tolerant malaria parasites by mobile/migrant populations 5. To support containment/elimination of artemisinin resistant parasites through comprehensive behavior change communication (BCC), community mobilization and advocacy 6. To undertake basic and operational research to fill knowledge gaps and ensure that strategies applied are evidence-based 7. To provide effective management, surveillance and coordination to enable rapid and high quality implementation of the strategy Dealing with the threat of parasite resistance
WHO strategies to prevent and contain parasite resistance
GLOBAL 38 MALARIA | PROGRAMME Global Malaria Portfolio - May 2008
Research Translational Development Launch* Lead Opt Preclinical Phase I Phase II Phase III Registration
Pyridones Macrolides Tafenoquine Artemifone Pyramax Coartem-D Coartem GSK GSK Artemifone Falcipains Nat Product Iv Coarsucam Isoquine Eurartesim GSK NITD artesunate AS/AQ Macrolide Biartemides Pyridone Blue AQ Pyramax AS/MQ GSK NITD 932121 Azithromyci DHFR DHODH MK4815 Ferroquine n NITD Fosmidomyci chloroquine Aminoindole AQ13 OZ439 n Broad/Genzyme Immtech Azithromycin HSP90 SAR116242 SAR97276 Arterolane Broad/Genzyme Trioxanes Choline PQP Immucillins NPC1161c Einstein Mississippi MMV projects Mirincamyci Other projects n Unprecedented Likelihood to 14% 27% 38% 72% 90% targets Launch *Note 1: Lead Optimisation projects only includes MMV 2: Launch following registration by stringent authority or WHO-PQ Consequences of antimalarial
Increased morbiditydrug and resistance 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
GLOBAL 40 MALARIA | PROGRAMME To deal with the threat of drug resistance
Develop new medicines
. Monitor drug efficacy
Avoid emergence of drug resistance
Contain the spread of drug resistance
GLOBAL 41 MALARIA | PROGRAMME Surveillance of drug resistance
Early detection of tolerance / resistance to artemisinins Routinely monitor therapeutic efficacy of ACTs – In vivo studies on ACTs
WHO supported routine surveillance of drug resistance – Standardized methodologies, tools and technical assistance – To countries and regional and sub-regional networks
GLOBAL 42 MALARIA | PROGRAMME Regional and sub-regional networks on monitoring drug efficacy
Mekong
RAVREDA HANMAT
GLOBAL 43 MALARIA | PROGRAMME WHO/GMP Guidelines
2003
2007 2008 2009
Planned: guidelines on pharmacokinetic and molecular markers for drug resistance
GLOBAL 44 MALARIA | PROGRAMME 2. Monitoring drug efficacy
Countries must closely monitor the efficacy of antimalarial medicines recommended in their treatment guidelines to detect resistance early, and rapidly change drug policy when no longer effective, to avoid the further selection and spread of multidrug-resistance.
GLOBAL 45 MALARIA | PROGRAMME WHO's 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 GLOBAL 46 MALARIA | PROGRAMME New report in 2009 Preventing drug resistance is a global public good and monitoring drug efficacy is WHO's responsibility
Global database on therapeutic efficacy of antimalarials: Preventing drug resistance is a global public goodwww.who.int/malaria/ resistance.htm GLOBAL 47 MALARIA | PROGRAMME change Instrument of policy
GLOBAL 48 MALARIA | PROGRAMME Major achievements of WHO's coordination and global database on drug efficacy 80 endemic countries changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoring
GFATM changed choice of drug procurement Countries with P.falciparum and no ACT Countries which adopted ACT as 1st-line treatment Detection of artesunate resistance GLOBAL 49at Thai-Cambodia MALARIA border| PROGRAMME Threshold levels for changing malaria treatment policy
% clinical failures (14 d f/up) % failures (14 d f/up) % failures (28 d f/up)
Change Parasitological failures 25% + 25% Action Clinical failures Parasitological 15% 15% failures Alert 10% 5% 5% Grace 0 0 0 WHO criteria 1998 WHO criteria 2003 WHO criteria 2005
GLOBAL 50 MALARIA | PROGRAMME Network of scientists to strengthen the scientific underpinnings of drug resistance & improve its detection and management GLOBAL 51 MALARIA | PROGRAMME Dealing with the threat of drug resistance
Develop new medicines
Monitor drug efficacy
Avoid. emergence of drug resistance
Contain the spread of drug resistance
GLOBAL 52 MALARIA | PROGRAMME 1. Strategies to avoid drug resistance Use of combination therapy TOTAL PARASITES
1012 m
1010 Drug level
8 10 n 106 x A y 104
102
B B1 0 0 1 2 3 4
October 7, 2009 WEEKS 1. Strategies to avoid drug resistance Use of combination therapy 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-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 Dealing with the threat of drug resistance
Develop new medicines
Monitor drug efficacy
Avoid emergence of drug resistance
.Contain the spread of drug resistance
GLOBAL 57 MALARIA | PROGRAMME 3. Containment of drug resistance Remove the pressure of the resistant medicines – Atovaquine-proguanil (malarone TM) is being used on the eastern border of Thailand
Operational research – depends on the local situation
Development of new antimalarial medicines
GLOBAL 58 MALARIA | PROGRAMME 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 quality ACTs
Remove the sale and use of monotherapies and sub- standard medicines – support surveys on drug quality
Increase efforts to reduce transmission
Ensure a steady and robust pipeline of new antimalarial GLOBAL 59combination medicines MALARIA | PROGRAMME Tackling antimalarial drug resistance
Contain drug resistance Confirm drug es resistance Monitor therapeutic efficacy Activiti
Avoid emergence of resistance
Develop new drugs
time
GLOBAL 60 MALARIA | PROGRAMME