Malaria Programmes and Implication on Strengthening the overall Health System

Malaria treatment (Current WHO recommendations & guidelines)

Copenhagen 31 January 20067.31

Malaria distribution and reported case of resistance or treatment failure2

Treatment efficacy at Thai-Burmese borderFirst demonstration project in Thailand3Thailand has been known for two decades as the country, where one antimalarial treatment after another has become ineffective following around 10 years of use. Thus, by the mid-1990s, the efficacy of mefloquine 25 mg/kg in western Thailand was as low as 75% (parasitological cure rate in 42 day tests). The combination of quinine and tetracycline (QT) has maintained its efficacy relatively well, but is considered far from satisfactory because of the long duration of the regimen (7 days), which leads to poor adherence. Following a number of clinical trials, it was decided to introduce a combination of artesunate 4mg/kg/day x 3 with mefloquine 25mg/kg in the most multi-drug resistant areas in the west of the country from 1996. This regimen has maintained a 42 day parasitological cure rate of around 95% since it was introduced. This is a truly remarkable achievement, and must be related to the artesunate, which is short-acting and to which no true resistance has been detected so far, somehow protecting the long-acting mefloquine, which has a long terminal half-life and is very vulnerable to the development of resistance.Countries with falciparum malaria Few countries deployed ACTs in selected provinces/districts Adoption of ACT as first-line treatment in 20004Countries with falciparum malaria Countries which adopted ACT as 1st-line treatment ACT as first-line malaria treatment in 20065ContinentCountriesDrugLineAFRICABurundi, Cameroon, Cte d'Ivoire, DRC, Eq.Guinea, Gabon, Ghana, Guinea, Liberia, Madagascar, Senegal, ST&P, Sierra Leone, Sudan (S), ZanzibarAS + AQ1stAngola, Benin, Burkina Faso, Comoros, Ethiopia, Gambia, Guinea Bissau, Kenya Mali, Namibia, Niger, Nigeria, Rwanda, Uganda, S. Africa, Tanzania, Togo, Zambia AL1stCte d'Ivoire, Gabon, Mozambique, Sudan (N), ST&P, Zanzibar AL2ndMozambique, Sudan (N), South Africa (Mpumalanga) AS + SP1stASIA

Cambodia, Thailand AS + MQ1stBangladesh, Bhutan, Laos, MyanmarAL1stIndonesia AS + AQ1st Afghanistan, India (5 Provinces), Iran, Tajikistan, Yemen AS + SP1stViet Nam DP1stPapua New Guinea AS + SP2ndPhilippines, Iran AL2ndSOUTHAMERICA Ecuador, Peru AS + SP1stBolivia, Peru, Venezuela AS + MQ1stBrazil, Guyana, Suriname AL1stUpdated 15 Jan. 2006 AQ=amodiaquine; AL=artemether/lumefantrine; AS=artesunate; DP=dihydroartemisinin/piperaquine; MQ=mefloquine; SP=sulfadoxine/pyrimethamine 56 countries have adopted ACTs6ContinentCountriesDrugLineAFRICABurundi, Cameroon, Cte d'Ivoire, DRC, Eq.Guinea, Gabon, Ghana, Guinea, Liberia, Madagascar, Senegal, ST&P, Sierra Leone, Sudan (S), ZanzibarAS + AQ1stAngola, Benin, Burkina Faso, Comoros, Ethiopia, Gambia, Guinea Bissau, Kenya Mali, Namibia, Niger, Nigeria, Rwanda, Uganda, S. Africa, Tanzania, Togo, Zambia AL1stCte d'Ivoire, Gabon, Mozambique, Sudan (N), ST&P, Zanzibar AL2ndMozambique, Sudan (N), South Africa (Mpumalanga) AS + SP1stASIA

Cambodia, Thailand AS + MQ1stBangladesh, Bhutan, Laos, MyanmarAL1stIndonesia AS + AQ1st Afghanistan, India (5 Provinces), Iran, Tajikistan, Yemen AS + SP1stViet Nam DP1stPapua New Guinea AS + SP2ndPhilippines, Iran AL2ndSOUTHAMERICA Ecuador, Peru AS + SP1stBolivia, Peru, Venezuela AS + MQ1stBrazil, Guyana, Suriname AL1st29% deployingAQ=amodiaquine; AL=artemether/lumefantrine; AS=artesunate; DP=dihydroartemisinin/piperaquine; MQ=mefloquine; SP=sulfadoxine/pyrimethamine 60% deploying71% deployingUpdated 15 Jan. 2006 26 countries are deploying ACTs7WHO definition of Antimalarial CombinationTherapy (Use of Antimalarial Drugs - Nov 2000)

Antimalarial Combination Therapy = simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite: fixed-dose or multiple-therapyWhat is NOT antimalarial combination therapy:

antimalarial drug with a drug that enhances its action (e.g. CQ plus chlorpheniramine)

use of a blood schizonticidal drug with a gametocytocidal drug (CQ plus primaquine)

combinations in which components have no significant schizonticidal effect (e.g. SP, chlorproguanildapsone, atovaquoneproguanil)8WHO Technical consultation on Antimalarial Combination Therapy (April 2001)

Combinations reviewed:Chloroquine + Sulphadoxine-pyrimethamine Amodiaquine + Sulphadoxine-pyrimethamineMefloquine + Sulphadoxine-pyrimethamineQuinine + Tetracycline or doxycyclineArtemisinin based combinationArtesunate +chloroquineArtesunate + amodiaquineArtesunate + suphadoxine-pyrimethamineArtesunate + mefloquineArtemether-lumefantrine

9Which combination therapies ?WHO Technical Consultation on Antimalarial Combination Therapy April 2001Based on available safety and efficacy data the following therapeutic options, currently available, have the potential for deployment (in priority order) regardless of cost: artemether-lumefantrine artesunate (3 days) + amodiaquine artesunate (3 days) + SP where SP is still effective amodiaquine + SP where amodiaquine and SP are still efficaciousartesunate (3 days) + mefloquine in areas of low transmission

10THERAPEUTIC OPTIONS NOT RECOMMENDED BY WHOWITH OBJECTIVE OF DELAYING RESITANCEchloroquine based combinations (CQ + SP and CQ + artesunate)one day treatment of artesunate + SP mefloquine based combinations (e.g. mefloquine + artesunate) in areas of high malaria transmission one day treatment of artesunate + mefloquine in the acute phase of complex emergencieschlorproguanil/dapsone as monotherapy in Africa11Malaria diagnosisParasitological confirmation (microscopy or RDT) before treatment

Exceptions:children under 5 years of age, from areas of high transmission where treatment is based on clinical diagnosissuspected severe malaria where parasitological confirmation is not immediately possible12Changing antimalarial treatment policyTreatment failure of >10% (as assessed through monitoring of therapeutic efficacy at 28 days)

New treatment an average cure rate of > 95% as assessed in clinical trials13ANTIMALARIALS DEVELOPED SO FAR

14Treatment of uncomplicated falciparum malariaArtemisinin-based combination therapies (ACT) are the treatments recommended for all cases of uncomplicated falciparum malaria including:in infants, in people living with HIV/AIDS for home-based management of malaria pregnant women in the 2nd and 3rd trimesters Exception:1st trimester of pregnancy

15Treatment of uncomplicated falciparum malariaThe following ACTs are presently recommended:artemether-lumefantrineartesunate + amodiaquineartesunate + mefloquineartesunate + sulfadoxine-pyrimethamineEfficacy of ACTs depend on the efficacy of the partner medicine

The artemisinin derivatives (oral formulations) and partner medicines of ACTs are not recommended as monotherapy 16Treatment of uncomplicated falciparum malariaSecond-line treatment:alternative ACT quinine + tetracycline or doxycycline or clindamycin 17Treatment of severe falciparum malariaAny of the following antimalarial medicines are recommended Artesunate i.v. or i.m artemether i.m. quinine (i.v. infusion or i.m. injection).

Full course of ACT or quinine + clindamycin or doxycycline when patient can tolerate oral treatment18Dosage and administration Coartem (Artemether 20 mg/Lumefantrine 120mg) for uncomplicated malaria falciparumAge groupWeight groupBlistercolor(Day 1)(Day 2)(Day 3)4 months 5 years5 14 kgYellow1 tb R,1 tb R,1 tb R,1 tb Z1 tb Z1 tb Z6 11 years15 -24 kgBlue2 tb R,2 tb R,2 tb R,2 tb Z2 tb Z2 tb Z12 14 years25 34 kgOrange3 tb R,3 tb R,3 tb R,3 tb Z3 tb Z3 tb Z> 14 years>34 kgGreen4 tb R,4 tb R,4 tb R,4 tb Z4 tb Z4 tb ZSource: Guideline for the treatment of malaria, WHO; 200619Coartem Dosage Schedule

Source: WHO, 200720Artesunate+AmodiaquineAmodiaquine A tablet contains: 153.1mg of base as Chlorohydrate or 200mg of base as Hydrochloride

Artesunate A tablet contains: 50mg of Sodium Artesunate Dosing Schedule The total recommended treatment is as follow: 4mg/kg body weight of Artesunate 10mg/kg body weight of Amodiaquine

Both must be given once a day, at the same time, for three days21Artesunate+AmodiaquineAgeDose in mg (No of tablets)Artesunate AmodiaquineDay 1Day 2Day 3Day 1Day 2Day 35 mnt 11 mnts25 mg25 mg25 mg76 mg76 mg76 mg 1 6 years50 mg50 mg

50 mg

153 mg153 mg

153 mg

7 13 years100 mg100 mg

100 mg

306 mg306 mg306 mg

Over 13 years200 mg200 mg

200 mg

612 mg612 mg

612 mg

22MECHANISM OF ACTION Exerts antimalarial activity by iron-mediated cleavage of the peroxide bridge and generation of an organic free radical. The interaction of artemisinin with haem in the parasite may turn out to be essential. Haem bound iron (but also free iron) may serve as a catalyst. The artemisinin radical binds subsequently to membrane proteins, and alkylation reactions eventually cause destruction of the parasite. (Vries et al, Drugs, 199623ANTIMALARIAL EFFICACY Rapidly acting blood schizontocidal antimalarials against chloroquine sensitive and chloroquine resistant falciparum as well as vivax malaria They quickly arrest the ring or the trophozoite development and also prevent pathological sequelae Fever subsides and parasites are cleared rapidly Defervescence occurs within 2-3 days after drug administration Ninety percent clearance of asexual erythrocytic parasitaemia is usually observed within 4 hours (Valecha N. et al., Indian Journal of Pharmacology, 1997)

24ARTEMISININ DERIVATIVES EFFECTS ON ROSETTING AND CYTOADHERANCEThe process whereby erythrocytes containing mature forms of P. falciparum ahdere to microvascular endothelium is called cytoadherance. It thus disappears from circulation, known as sequestration. Erythrocytes containing mature parasites also adhere to uninfected parasites, leading to the formation of rosettes. Cytoadherance and rosetting lead to microcirculatory obstruction in falciparum malaria, the consequence of which are reduced oxygen and substrate supply, anaerobic glycolysis and lactic acidosis, finally leading to complications of malaria. (Manson, 1997)All artemisinin drugs prevent the development of ring stage parasites to the more mature pathogenic stages that rosette and cytoadhere to capillaries (The use of artemisinin and its derivatives as antimalarial drugs - Report of a Joint CTD/DMP/TDR- WHO, 1998)

25EFFICACY OVER OTHER ANTIMALARIALSArtesunate and artemether have been shown to clear parasitaemias more effectively than chloroquine and sulfadoxine/pyrimethamineMeta analysis of mortality in trials indicated that a patient treated with artemether had at least an equal chance of survival as a patient treated with quinineArtemisinin drugs cleared parasites faster than quinine in patients with severe malaria but fever clearance was similar Parenteral artemether and artesunate are easier to use than quinine and do not induce hypoglycaemia (The use of artemisinin and its derivatives as antimalarial drugs - Report of a Joint CTD/DMP/TDR- WHO, 1998)

26Treatment of other malaria casesDuring PregnancyORAL QUININE ALL TRIMESTERSIt safe in all trimestersIt is a 7-day treatmentIt is taken as 10mg/kg to a maximum of 600mg or 2 tablets, three times daily.Can reduce doses to 5 7.5mg/kg (i.e 2 tablets twice daily) after three daysACTs 2ND AND 3RD TRIMESTERS ONLYThe use of ACTs in the second and third trimester have not been found to be associated with any teratogenic or mutagenic effect.27Children less than 5 kgOral Quinine 10mg/kg 8 hourly for 7 days (No enough evidence on the use of ACTs)ChemoprophylaxisSickle Cell AnaemiaDaily ProguanilNon Immune VisitorsMefloquineDoxycyclineAtovaquone-Proguanil28Dosage and administration of Chloroquine and Primaquine for malaria vivax.Age Group* Weight group (Kg)CHLOROQUINE(150 mg base) 10 mg/kg on the first two days. 5 mg/kg on day 3PRIMAQUINE(15 mg base) 0.5 mg/kg bwGive for 3 days

Start concurrently with CQ and give daily for 14 days

Day 1Day 2Day 34 months up to 12 months4 -