K S Labaran, CPIPP ABU Zaria Treatment of malaria K S Labaran, CPIPP ABU Zaria

MALARIA: THE PROBLEM Every year: worldwide > 200 million clinical cases > 2 million deaths from malaria mainly in Africa DRUGS ARE FAILING Pilot implementation of RTS,S/AS01 vaccine

Female Anopheles mosquito

Several species of the Plasmodium protozoan parasite can infect humans under natural circumstances – P. falciparum (frequently fatal malignant tertian malaria: drug- resistance) P. vivax, P. o v a l e, (“benign” relapsing) P. malariae (chronic childhood infection: nephrotic syndrome) P. knowlesi .

Malaria diagnosis: Microscopy Rapid diagnostic test (RDT) Thin blood films: better for morphology Thick blood films are 10x more sensitive than thin Rapid diagnostic test (RDT)

Morbidity due to infection with P Morbidity due to infection with P. falciparum can range from mild febrile illness which is difficult to distinguish clinically from other similar illnesses, to life-threatening disease with coma, respiratory distress, severe anaemia or circulatory shock. In young children and non-immune adults in particular, the clinical picture can change within 24 hours, from an apparently mild condition to a life-threatening illness.

Severe morbidity and mortality from falciparum malaria result from sequestration of infected erythrocytes and associated vital organ dysfunction. Sequestration causes microvascular obstruction-related brain pathology, metabolic acidosis compounded by severe anaemia due to accelerated erythrocyte destruction, hypoglycaemia, circulatory shock, and in older children and adults, renal failure and pulmonary oedema.

Symptoms High fever Profuse sweating Vomiting Headache Cold shivers Muscle pains Convulsions Diarrhoea Cough

Blood stages: responsible for pathology Fever is associated with synchronous bursting of the infected blood cells Anaemia: loss of blood cells Cerebral malaria: cytoadherence in brain capillaries Late stage infected red cells block brain capillaries

Morbidity and mortality control Prompt diagnosis and drug treatment

Suggestion to control malaria? Preventing mosquito bites Prevention of man-mosquito contacts Pyrethroid-impregnated bed-net Repellants Residual insecticide house-spray Health education

How does the infection persist? The only reservoir is man, since mosquito populations loose their infections within weeks in the absence of infective humans Persistence in man depends on the persistence in the blood stage P. falciparum up to 3 years P. malariae > 50 years Persistence in the liver P. vivax and P. ovale, the dormant parasite may remain in the liver for up to 5 years

P. Vivax and P. ovale Some sporozoites become dormant hypnozoites and delay development for 3,6 or more months up to 5 years

Drug treatment Therapeutic: speedy effect on growing blood forms Hypnozoitocide/gametocytocide: kills dormant forms in liver or blood Sporontocide: kills growing mosquito stages Radical cure: therapeutic + hypnozoitocide for relapsing malarias, therapeutic alone for non-relapsing malarias

Drug treatment Choice of regimen is based on: Availability Cost Drug resistance pattern of P. falciparum Known allergies Age pregnancy

Blood schizontocides Used for therapeutic cure Some are also used in suppressive prophylaxis Attack haemoglobin-digesting blood stages only Chloroquine Quinine Mefloquine Halofantrine Lumefantrine Artemisinins

Prophylaxis Suppressive prophylaxis: prevent growth of blood forms Causal prophylaxis: prevent growth of liver forms

The chloroquine-resistance problem Chloroquine was introduced for malaria treatment and prevention in the late 1940s It was safe and effective P. falciparum resistance to chloroquine, was first seen in 1950-60 in SE Asia and S. America

Possibility of artemisinin resistance Artemisia annua “Qinghao” Source of artemisinin No 100% confirmed cases of artemisinin resistance seen yet The first reports of higher recrudescence rates of P. falciparum malaria after treatment with ACTs emerged in Cambodia since 2004 Reduced susceptibility to artemether in French Guianan isolates

Possibility of artemisinin resistance Artemisia annua “Qinghao” Source of artemisinin December 2008 showed the strongest indication of potential artemisinin resistance yet in Cambodia Parasites persisted 7 days after artesunate treatment or re- emerged 28 days after treatment All pharmacology results were normal – i.e. drug reached required concentration in patients

Possibility of artemisinin resistance Artemisia annua “Qinghao” Source of artemisinin May be linked to widespread availability of artemisinin monotherapy and multidrug resistance

The management of malaria and avoiding drug resistance Diagnosis Minimising the development of resistance The strategic use of drugs Previous treatment regimens ACT combinations WHO recommendations

Diagnosis Prompt and accurate diagnosis of malaria is part of effective disease management and will if implemented effectively help reduce unnecessary use of antimalarial medicines

Diagnosis Clinical diagnosis Least expensive and the most widely practiced Traditional among medical doctors It is based on signs and symptoms and on physical findings and examination

A clinical diagnosis of malaria is still challenging because of the non-specific nature of the signs and symptoms, which overlap considerably with other common, as well as potentially life-threatening diseases, e.g. common viral or bacterial infections, and other febrile illnesses. The overlapping of malaria symptoms with other tropical diseases impairs diagnostic specificity, which can promote the indiscriminate use of antimalarials and compromise the quality of care for patients with non-malarial fevers in endemic areas

Diagnosis Laboratory diagnosis Detection of the causative parasite or its products The most commonly used being microscopic diagnosis and more recently rapid diagnostic tests (RDT) based on immunochromatographic techniques.

Development of resistance Point mutations leading to amino acid change and resistance occur at most once in a million cell divisions. In the absence of drug pressure they are unfit and die out. Intensive use of drugs selects these rare changes. Level of drug resistance may increase by sequential mutations. So inadequate treatment courses can predispose to resistance development.

Controlling the spread of resistance Reduce transmission overall, using insecticide-impregnated bed nets and mosquito control activities Use primaquine to kill the sexual stages in the blood to prevent mosquitos getting infected (care in G6PD deficient- haemolysis) Qinghaosu (Artemisinin) drugs also reduce numbers of sexual stages. These drugs are especially useful in combination with other antimalarials

Make sure FULL COURSE of treatment and PROPER DOSING (BY WEIGHT) is adhered to

Artemisinin COMBINATION therapies (ACTs) First line treatment of malaria Promote rational drug use abandon the use of oral artemisinin MONOTHERAPIES

Features of ACT Rapid resolution of clinical symptoms Rapid parasite clearance Rapid and substantial reduction of the parasite biomass Effective action against multi-drug resistant P. falciparum Reduction of gametocyte carriage, which potentially reduces transmission of resistant alleles

WHO recommendations 1. artemether + lumefantrine 2. artesunate + amodiaquine 3. artesunate + sulfadoxine/pyrimethamine (where SP efficacy is high) 4. amodiaquine + sulfadoxine/pyrimethamine, in areas where efficacy of all three drugs remains high 5. artesunate + mefloquine 6. dihydroartemisinin + piperaquine

P. vivax Use chloroquine Clear erthrocytic stages of the parasite but has no effect on the liver stage Use course of primaquine for radical cure Patient may suffer a relapse which will occur weeks, months or sometimes years after the original attack

Malaria in pregnancy Malaria in pregnancy poses a substantial risk to the mother, the fetus and the newborn infant Pregnant women are less capable of coping with and clearing malaria infections Attacks of severe malaria, which may result in stillbirths or spontaneous abortions, or the death of the mother

Malaria in pregnancy In areas of high transmission, levels of acquired immunity tend to be high and women may have asymptomatic infections, which may result in maternal anaemia and placental parasitaemia. These conditions can lead to low birth weight, an important contributor to neonatal mortality

Intravenous artesunate should be used in preference to quinine for the treatment of SEVERE P. falciparum malaria in adults Rapid administration of quinine is unsafe. Each dose of parenteral quinine must be administered as a slow, rate- controlled infusion

Prophylaxis Travellers to malaria risk areas (tropical and subtropical areas) Over 100 countries About 30,000 international travelers fall ill annually Fever occurring in a traveler one week or more after entering a malaria risk area, and up to 3 months after departure, is a medical emergency that should be investigated urgently.

Children travelers are at special risk Chloroquine +(or) proguanil HCl remains the drug of choice in areas where malaria remains sensitive Mefloquine is the preferred agent in chloroquine-resistant areas Doxycycline

Protection against bites Permethrin impregnated mosquito nets Diethyltoluamide (DEET) lotions, sprays or roll on formulations Long sleeves and trousers

Mosquirix™ Pilot implementation program Young children P. falciparum Ghana, Kenya, Malawi