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

2. 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

3. Female Anopheles mosquito

5. 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 .

6. 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)

8. 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.

9. 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.

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

11. 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

12. Morbidity and mortality control
Prompt diagnosis and drug treatment

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

14. 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

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

16. 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

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

18. 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

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

20. 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 in SE Asia and S. America

21. 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

22. 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

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

24. 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

25. 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

26. 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

27. 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

28. 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.

29. 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.

30. 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

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

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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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.

40. 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

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

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