Update on malaria prevention, diagnosis and treatment RBM PSM WG Meeting Geneva, Switzerland 10-11 June 2014 Silvia Schwarte Diagnosis, Treatment and Vaccines Global Malaria Programme schwartes@who.int
Outline WHO guidelines, 3 rd edition - Transmission blocking: primaquine as gametocytocide Diagnosis - Diagnostics in low transmission settings - RDT Product Testing Programme: Round 5 Report Treatment - Prequalified medicines - Artemisinin resistance - Oral artemisinin-based monotherapies
Update of WHO Guidelines for the Treatment of Malaria February 2013: Scoping meeting to define areas for review May 2013: Commission of reviews of available evidence July 2013: Proposal for MTG review approved by WHO Guideline Review Committee (GRC) November 2013: Completion of the systematic reviews and Grade tables* and 1 st TEG meeting to review and reach consensus on the draft recommendations 2 nd TEG meeting (drafting meeting) (25-27 June 2014) Finalisation and submission to MPAC (10-12 September 2014) Final clearance through the WHO GRC and other WHO in-house processes (3 rd quarter 2014) Publication, translations and dissemination expected in October/November 2014 * Major rate limiting step is the availability of systematic reviews of the evidence in a format to which GRADE methodology can be easily applied. 3
Single-dose primaquine as gametocytocide in Plasmodium falciparum malaria Single dose of primaquine at 0.25mg base/kg: is effective in transmission blocking is unlikely to cause serious toxicity in subjects with any of the G6PD variants MPAC recommendation => new treatment guidelines: in areas threatened by artemisinin resistance where single dose primaquine as a gametocytocide for P. falciparum malaria is not being implemented, and in elimination areas which have not yet adopted primaquine as a gametocytocide for P. falciparum malaria: A single 0.25 mg base/kg primaquine dose should be given to all patients with parasitologically- confirmed P. falciparum malaria on the first day of treatment in addition to an ACT, except for pregnant women and infants <1 year of age. http://www.who.int/malaria/pq_updated_policy_recommendation_en_102012.pdf?ua=1
WHO policy brief on malaria diagnostics in low transmission settings (1) Symptomatic parasitemia Asymptomatic parasitemia Who are we missing with microscopy and RDTs? What factors influence the asymptomatic reservoir? What is its contribution to transmission? When and how to target it? December 2013: Evidence Review Group Meeting on Malaria Diagnosis in Low Transmission Settings March 2014: Malaria Policy Advisory Committee recommendation
WHO policy brief on malaria diagnostics in low transmission settings (2) 1. Quality-assured RDT and microscopy are the primary diagnostic tools for the confirmation and management of suspected clinical malaria in all epidemiological situations, including areas of low transmission, due to their high diagnostic performance in detecting clinical malaria, their wide availability and relatively low cost. Similarly, RDT and microscopy are appropriate tools for routine malaria surveillance (of clinical cases) in the majority of malaria-endemic settings. 2. A number of nucleic acid amplification (NAA) techniques are available and are more sensitive in detection of malaria compared to RDTs and microscopy. Generally, the use of more sensitive diagnostic tools should be considered only in low transmission settings where there is already widespread implementation of malaria diagnostic testing and treatment and low parasite prevalence rates (e.g. < 10%). Use of NAA-based methods should not divert resources away from malaria prevention and control interventions and strengthening of the health care services, including the surveillance system. 3. Sub-microscopic Plasmodium falciparum and P. vivax infections are common in low as well as high transmission settings. The use of NAA methods by malaria programmes should be considered for epidemiological research and surveys aimed at mapping sub-microscopic infections in low transmission intensity. There may also be a use for NAA methods for identifying foci for special intervention measures in elimination settings.
WHO policy brief on malaria diagnostics in low transmission settings (3) 4. The majority of infections with asexual parasites have gametocytes detectable by molecular amplification methods, at low density not detectable by microscopy or RDTs. Most malaria infections (microscopic and sub-microscopic) should be considered as potentially infectious and able to contribute to ongoing transmission. There is no need for routine detection of gametocytes using sensitive NAA methods in malaria surveys or clinical settings. 5. Common standards for nucleic acid based assays should be developed, including use of the WHO International Standard for P. falciparum DNA NAA assays and development of standards for other Plasmodium species, particularly P. vivax should be undertaken. A standard operating procedure should be developed which defines methods for sample collection, extraction, and the recommended equivalent quantity of blood to be added to the assay. Development of an international, external quality assurance system is strongly recommended to ensure that data obtained from nucleic acid amplification assays are reliable and comparable. 6. In order to establish the role of serological assays in epidemiological assessments, there is a need for standardisation and validation of reagents (antigens and controls), assay methodologies and analytical approaches.
WHO policy brief on malaria diagnostics in low transmission settings (4) Applications of malaria diagnostic tests in low transmission setting Operational characteristics and performance of different NAA diagnostic techniques
WHO policy brief on malaria diagnostics in low transmission settings (5) Symptomatic parasitemia Asymptomatic parasitemia the use of microscopy and RDTs is sufficient for clinical management of patients with suspected malaria, routine surveillance and passive detection in low transmission areas. NAA-based diagnostic methods are not required for these applications.
WHO/FIND/CDC RDT Product Testing Programme Rounds 1-5 Round 1 Round 2 Round 3 Round 4 Round 5 Number of products 41 29 50 48 42 Number of manufacturers 21 13 23 27 34 Resubmissions - 1 23 13 23 Median Pf PDS at 200 p/μl (range) 70.2% (1.3-100%) 82% (22.0-98.0%) 83.84% (2.02-98% ) 89.34% (32.7-100%) available Q2/2014 Median Pv PDS at 200p/μl (range) 30% (0-100%) 75% (0-95%) 51.43% (0-97.1%) 61.80% (0-100%) available Q2/2014 Median false positives against clean negatives (range) 1.8% (0-28.0%) 2.0% (0.0-37%) 1.0% (0.0-44%) 1.10% (0.0-99.1%) available Q2/2014
RDT performance in Phase 2 of Rounds 1 4 against wild type (clinical) samples containing P. falciparum at low (200 parasites/μl) and high (2000 or 5000 parasites/μl) parasite densities and clean-negative samples PDS at 2000 parasites/μl PDS at 200 parasites/μl False Positive Rate Invalid Rate Updated WHO Information Note on recommended selection criteria for the procurement of malaria rapid diagnostic tests (RDTs) English: http://www.who.int/entity/malaria/publications/atoz/rdt_selection_criteria_en.pdf French: http://www.who.int/entity/malaria/publications/atoz/rdt_selection_criteria_fr.pdf
WHO prequalified medicines (last updated 27.05.204) Fixed-dose combinations (FDCs) - artemether/lumefantrine: Ajanta, Cipla, Ipca, Macleods, Mylan Laboratories, Novartis, Strides - artemether/lumefantrine dispersibles: Ajanta, Novartis - artemether/lumefantrine 40mg/240mg: Mylan Laboratories - artesunate/amodiaquine: Ajanta, Cipla, Sanofi, Guilin, Ipca - artesunate/mefloquine: DNDi/Cipla Co-Blisters (Co-B) - artesunate + amodiaquine: Cipla, Guilin, Ipca, Strides - artesunate + sulfadoxine/pyrimethamine: Guilin Injectables Eurartesim (DHA-PPQ) (Uncomplicated Pf malaria) EMA approval; Caveat: Cardiotoxicity Pyramax (AS + pyronaridine) EMA Article 58 positive opinion; Caveat: Hepatotoxicity AQ+SP (Seasonal Malaria Chemoprevention) SP (Intermittent Preventive Treatment in Pregnancy) Rectal AS (Pre-referral treatment of severe malaria in children < 5 years) - AS powder for injection: Guilin (60mg, 30mg, 120mg)
Oral artemisinin-based monotherapies (oamts) National Drug Regulatory Authorities and Manufacturers 9 National Drug Regulatory Authorities still allow oamts (last updated May 2014) Manufacturing sites / place of registration of 30 oamts producers (last updated May 2014) 13
WHO/GMP Status Report on Artemisinin Resistance (January 2014) Foci of artemisinin resistance: five countries in the Greater Mekong subregion, mainly along international borders (Cambodia, the Lao People s Democratic Republic, Myanmar, Thailand and Viet Nam) Additional foci of artemisinin resistance suspected in Suriname, Guyana and French Guiana (France) - studies ongoing Recently identified molecular marker: mutations in the Kelch 13 (K13) propeller domain have been shown to be associated with delayed parasite clearance both in vitro and in vivo http://www.who.int/malaria/publications/atoz/status_rep_artemisinin_resistance_jan2014.pdf?ua=1 14
Emergence and spread of artemisinin resistance calls for intensified efforts to withdraw oamts from the market WHO/GMP briefing paper http://www.who.int/malaria/public ations/atoz/oral-artemisinin-basedmonotherapies-1may2014.pdf includes generic guide and checklist Asian Pacific Leaders' Malaria Alliance (APLMA) Access to Quality Medicines and Other Technologies Task Force (AQMTF) Meeting in Sydney, March 2014 WHO Drug Information 15
Thank you 16 GMP staff meeting 26 July 2013 Global Malaria Programme