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Multi-Drug Resistant Malaria: Plasmodium falciparum at our door step Vani Vannappagari, MBBS, MPH, PhD. WorldWide Epidemiology , GlaxoSmithKline Presented at the 41st Annual Symposium“Global Movement of Infectious Pathogens and Improved Laboratory Detection” Eastern PA Branch-American Society for Microbiology November 17, 2011 Thomas Jefferson University, Philadelphia
Malaria: Morbidity and Mortality There are ~250 million malaria cases annually ~A million malaria related deaths annually 85% of deaths occur among the <5 year age group – By some calculations a child dies of malaria, every 30 seconds Over 3.2 Billion people are at risk for malaria and over 1.2 billion people are at high risk for malaria.
Protozoa from the Plasmodium genus Five species causing human disease – Plasmodium falciparum – Plasmodium vivax – Plasmodium ovale – Plasmodium malariae – Plasmodium knowlesi P. falciparum, the most virulent, accounts for >75% of malaria cases in SSA where ~80% of malaria cases and ~90% of malaria deaths occur P. vivax accounts for 10-20% of malaria cases in SSA; outside of SSA, it accounts for >50% of all malaria cases
Malaria Cases Due to Plasmodium falciparum World Malaria Report, 2008
Malaria Cases Due to Plasmodium falciparum and Plasmodium vivaxFeachem, Lancet. 2010 November 6; 376(9752): 1566–1578
Diagnosis of MalariaPrompt and accurate diagnosisIdeal diagnostic tests need to be rapid, affordable,low-maintenance, minimal training, able to detectlow density parasitemia and distinguish speciesThere are several methods of diagnosing malariaincluding: – Clinical – Microscopy – Rapid Diagnostic Tests – Polymerase Chain Reaction (PCR) – Other tests
Clinical Symptoms as a Guide to Diagnosis WHO recommendations for laboratory-confirmed diagnosis of malaria infections prior to treatment in all cases Clinical features cannot reliably distinguish severe malaria from other severe viral and bacterial infections in children Specificity of clinical diagnosis (i.e. declared fever) is only 20-60% compared with microscopy 127 (6%) of 2048 children admitted to hospital in Kenya and Mozambique with severe falciparum malaria had concurrent positive blood cultures (Bassat, 2009) At autopsy, seven of 31 (22.6%) Malawian children with a clinical diagnosis of cerebral malaria were found to have died from other causes. (Taylor, 2004)
MicroscopyOperational Gold Standard for malaria diagnosisUnder optimum conditions, microscopy can detect 20-50parasites per μL bloodAdvantages of using microscopy include parasitequantification and species identificationAchieving high sensitivity requires training and qualitycontrol of microscopists, adequate equipment, andmaintenance
P. falciparum panel detection score of malaria RDTs at low (200) and high (2000or 5000) parasite density (parasites/μl) according to target antigen type (HRP2or pLDH)
Polymerase Chain Reaction (PCR) Tests –GoldStandard Numerous PCR assays have been developed for the laboratory diagnosis of malaria, including nested and real-time PCR techniques PCR-based assays are highly specific and sensitive, capable of detecting as few as 5 parasites per μL of blood PCR can readily detect mixed-species infections and may be automated to enable the processing of large numbers of samples. PCR tests are mostly used in research settings for diagnostic confirmation and identification of molecular markers of resistance In areas with high transmission, detection of low-level parasitaemia may not be clinically relevant
Nucleic Acid Lateral Flow Immunoassay (NALFIA) NALFIA is a simple readout system for nucleic acids and has been successfully applied for the detection of food-borne pathogens such as Bacillus cereus and Salmonella Rapid immunochromatographic test to detect labeled amplicon products on a nitrocellulose stick coated with specific antibodies Lower detection limit is 0.3 to 3 parasites/μL, 10-fold more sensitive than gel electrophoresis analysis More sensitive than microscopy and a good alternative to detect PCR products while circumventing using electricity or expensive equipment First step toward molecular field diagnosis
Loop-Mediated Isothermal Amplification (LAMP) LAMP (Loop-mediated isothermal amplification), allows rapid amplification and detection of a target genetic sequence with minimal instrumentation and simplified sample processing Can detect 1-6 parasites / l with minimal sample processing that requires no sophisticated equipment and the results can be read with the naked eye Early results have proved the utility of this approach for (-) (+) identifying parasite-positive individuals in population surveys, even at low transmission intensities Currently prototype still under study
Other Diagnostic Methods Fluorescence microscopy Flow cytometry Life lens smart phone application – Smartphone application. – A user takes a photo of a blood sample using a phone and the high resolution imaging sensor determines whether the blood is infected with malarial parasites
Frequently Used Diagnostic Methods Clinical diagnosis - least expensive and most commonly used method in most malaria endemic areas Globally, ~73% of reported suspected malaria cases in 2009 were parasitologically-confirmed before treatment In SSA, only ~35% confirmed before treatment Fosters drug resistance Microscopy - most popular parasitological method of detecting malaria infection Only available in better-equipped clinics Use of RDTs also on the rise, but still remain out of reach to many due to cost
Recommended Treatments for UncomplicatedP. falciparum MalariaFirst-line treatments Artemisinin-based combination treatments (ACTs) Recommended ACTs include: artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunate plus sulfadoxine-pyrimethamineSecond-line treatments Alternative ACT known to be effective in that particular region Artesunate plus tetracycline or doxycycline or clindamycin Quinine plus tetracycline or doxycycline or clindamycin
Recommended Treatments for Severe P. falciparumMalaria First-line treatment Parenteral artesunate Second-line treatment Artemether or quinine if parenteral artesunate is not available
P. falciparum Drug Resistance P. falciparum has become variably resistant to all drug classes except artemisinin derivatives Particularly resistant to former first-line drugs chloroquine (median treatment failure rate up to 100%) and sulfadoxine-pyrimethamine (median treatment failure rate as high as 52.8% in some areas) Chloroquine remains effective only in Central America
P. Falciparum Resistance to Former First-line Treatments
Multi-Drug Resistance Multi-drug resistance has been established in southeast Asia, South America, and SSA There is high and increasing global resistance of P. falciparum to amodiaquine, mefloquine and lumefantrine
Factors Contributing to Development ofResistance Uncontrolled use of combination therapies Monotherapy Sub-therapeutic levels, substandard and counterfeit drugs.
Delaying the Development and Spread of Resistance Early diagnosis and appropriate treatment of malaria – Treatment: prompt provision of antimalarial drugs (ACTs for P. falciparum and chloroquine and primaquine for P. vivax). Optimizing insect vector control (Indoor residual spraying of insecticide, insecticide treated bed nets) Strengthening disease management and surveillance systems and monitoring for drug resistance
Vaccine Targets based on the life cycle of theparasitePre-erythrocyticvaccinesBlood-stage vaccinesTransmission-blockingvaccines
Challenges in Developing a Malaria Vaccine Parasite has developed immune evasion strategies Each infection presents thousands of antigens Different antigens at different stages of the life cycle Multiple infections (different strains and/or different species) Inadequate data on the immune response to infection
Most Advanced Vaccine Candidate - RTS,S Malaria RTS,S is a fusion protein of a portion of the circumsporozoite protein (CSP) with the hepatitis B surface antigen produced as a recombinant particle and combined with a proprietary adjuvant AS02 (GlaxoSmithKline) Phase II trials showed reduction of clinical malaria by 35% -55% and severe malaria by 49% Phase 3 trials begun in 2009 to recruit up to 16,000 children in 7 African countries Results expected in 2012
Population at risk for malaria in 2009 according to World Health Organization RegionsRegion Population* Population at risk Population at risk for malaria* (low & for malaria* (high high) (%) only) (%)Africa 821.8 696.3 (84.7) 567.0 (69.0)Americas 543.3 158.5 (29.2) 42.1 (7.7)East Mediterranean 555.2 307.3 (55.3) 115.9 (20.9)Europe 276.9 2.6 (0.9) 0.2 (0.1)South-East Asia 1,783.3 1,249.2 (70.0) 449.5 (25.2)Western Pacific 1,637.8 866.4 (52.9) 68.5 (4.2)Total 5,618.2 3,280.3 (58.4) 1,243.2 (22.1)*-MillionsSource: World Malaria Report 2010
Estimated numbers of malaria cases (in millions) and deaths (in thousands) by WHO Region, 2008Region No. of malaria No. of deaths * % of deaths cases * under 5 yearsAfrica 208 (155-276) 767 (621-902) 88The Americas 1 (1-1) 1 (1-2) 30East Mediterranean 9 (7-11) 52 (32-73) 77Europe 0 0 3South-East Asia 24 (20-29) 40 (27-55) 34Western Pacific 2 (1-2) 3 (2-5) 41Total 243 (190-311) 863 (708-1003) 85*-(5th-95th Percentile) Source: World Malaria Report 2009
Countries with the highest number of confirmed P. falciparum cases in 2009 Microscopy/RDTs Microscopy/RDTs P. falciparumCountry Population taken positive cases*Uganda 32,709,864 3,6112,418 1,301,337 1,275,310India 1,198,003,273 103,395,721 1,563,344 837,130Ghana 23,837,261 2,899,497 1,104,370 924,095Ethiopia 82,824,732 1,328,114 1,036,316 594,751Benin 8,934,986 --- 889,597 534,590Liberia 3,954,977 1,003,961 839,581 212,657Indonesia 229,964,721 2,461,428 544,470 212,501Togo 6,618,613 734,303 391,338 191,357Myanmar 50,019,774 940,050 436,068 121,636Congo 3,683,181 203,160 92,855 92,855 Note: Microscopy slides/RDTs taken may be lower than microscopy slides/RDTs positive if a country did not report number of RDTs examined (taken), * Proportion of P. falciparum out of total confirmed malaria cases Source: World Malaria Report 2010
Populations at high risk for malaria infection High transmission areas – Children under five years – Pregnant women – HIV infected individuals – Travellers from non-endemic areas Low transmission areas – All age groups – Travellers from non-endemic areas
Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency G6PD is required by all cells for protection from damage by oxidation. For the red cell, this is the sole source of protection against oxidant damage in the form of free radicals generated by the conversion of oxy- to deoxyhemoglobin and by peroxides generated by phagocytosing granulocytes. Approximately 330 million people worldwide affected with highest prevalence in individuals of African, Mediterranean and Asian heritage. Since this is an X-linked gene, prevalence among females is higher but they are generally asymptomatic. Many variants of G6PD alleles have been identified
Global distribution of G6PD deficiency Nkhoma et al, 2009
G6PD variants • Class I: severely deficient, associated with chronic nonspherocytic hemolytic anemia – • Class II: severely deficient (1%-10% residual activity), associated with acute intermittent hemolytic anemia (G6PD Mediterranean) – • Class III: moderately deficient (10%-60% residual activity) - intermittent hemolysis usually associated with infection or drugs • Class IV: normal activity (60%-100%) • Class V: increased activity (>100%-150%)
Treatment of Malaria Objectives of treatment include: – Prevent progress to severe disease and complications – Prevent development of antimalarial drug resistance – Reduce transmission
Treatment guidelines for uncomplicated falciparum malaria Artemisinin-based combination therapies (ACT) are the recommended treatments for uncomplicated falciparum malaria. ACTs should include at least 3 days of treatment with an artemisinin derivative The following ACTs options are recommended: – Artemether + lumefantrine; artesunate + amodiaquine; artesunate + mefloquine; artesunate + sulfadoxine-pyrimethamine; and dihydroartemisinin + piperaquine . Second-line antimalarial treatment: – Alternative ACT known to be effective in the region; – Artesunate plus tetracycline or doxycycline or clindamycin. – Quinine plus tetracycline or doxycycline or clindamycin. Source: WHO Guidelines for the Treatment of Malaria, 2010
Treatment guidelines for severe falciparum malaria For adults, artesunate i.v. or i.m – Quinine remains an acceptable alternative For children (especially in the malaria endemic areas of Africa) the following options are recommended as there is insufficient evidence to recommend any of these antimalarial medicines over another: – artesunate i.v. or i.m.; quinine (i.v. infusion or divided i.m. injection); artemether i.m. Give parenteral antimalarials for a minimum of 24hrs once started (irrespective of the patients ability to tolerate oral medication earlier), and, thereafter, complete treatment by giving a complete course of: – an ACT; artesunate + clindamycin or doxycycline; quinine + clindamycin or doxycycline Source: WHO Guidelines for the Treatment of Malaria, 2010
Treatment guidelines for special populations –pregnantwomen First trimester: – Quinine + clindamycin – An ACT is indicated only if this is the only treatment immediately available, or if treatment with quinine + clindamycin fails or compliance issues with a 7-day treatment. Second and third trimesters: – ACT known to be effective in the country/region or artesunate + clindamycin or quinine + clindamycin Source: WHO Guidelines for the Treatment of Malaria, 2010
Treatment guidelines for other special populations Lactating women – Lactating women should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines. Infants and young children – ACTs with attention to accurate dosing and ensuring Travellers returning to non-endemic countries: – atovaquone-proguanil – Artemether +lumefantrine – dihydroartemisinin + piperaquine – quinine + doxycycline or clindamycin. Source: WHO Guidelines for the Treatment of Malaria, 2010
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