Malaria, Något nytt att berätta?

• Malaria minskar – men fortfarande 660.000 dödsfall– Minskning med 25% sedan 2000 (I Afrika 33%)

• Test, Treat and Track !• Diagnos före behandling• Behandling bygger på Artemisininpreparat• Sängnät, Indoor spraying• Läkemedelsprofylax på tapeten igen !• Vaccin inget genombrott• Hot

– Artemisininresistens– Pyrethrum resistens

Malaria• Mal Aria – dålig luft• Beskriven 500 BC i Italien• Hippokrates skiljde ut olika febrar: tertiana och quartana• Kinaträdets bark; Mot feber i Peru upptäcktes av spanjorerna på

1600-talet, rek.av Linné mot frossa• 1880-talet: Myggor för med gift från sumpmarker• Kring 1900 malariacykeln fastställdes• Malaraläkemedel krigens läkemedel

– 1930 talet Klorokin anv. av amerikaner 1947– 1940 talet Proguanil (Paludrin), Pyrimethamin (Daraprim)

Sulphonamide+Pyrimethamine (SP eller Fansidar)– 1970 talet Meflokvin (Lariam)

• 1990 talet Atovaquone+ Proguanil (Malarone)

• 1970 – 2000 Artemesininpreparat

Malariaprogram• Malaria eradication - 1955 -1970-tal• Malaria control - 1980 tal• Roll Back Malaria – 2001 -

– ”Halvera morbiditet och mortalitet i malaria 2010 jämfört med år 2000”

– Abudja deklarationen 2000– Global Fund to Fight AIDS, TBC and

Malaria– Bill Gates donation– 2011 nya mål

• Malaria dödlighet i Afrika minskar

Roll Back malaria- Nya mål 2011

• (RBM) targets were updated in June 2011.

– reduce global malaria deaths to near zero by end 2015;

– reduce global malaria cases by 75% from 2000 levels by end-2015; and

– eliminate malaria by end 2015 in 10 new countries since 2008,

Malaria 2012

1.8 miljarder US dollar för malaria kontroll 2012Beräknat behov 5,1 miljarder USD

Malaria 2012

• Antal fall i världen 220 milj• Döda 650.000• 56 % av hushåll i Sub Saharan Afrika har

myggnät. De används i 95 % av dessa• Metoder att minska malariasjuklighet

– Effektiv behandling – LongLasting Insecticide Nets – Pyrethroids– Indoor spraying– IPTp till gravida och små barn IPTi (SP)

Malaria 2013 - Hot

• Minskande eller otillräckliga resurser

• Resistens mot insekticider särskilt pyrethroids (enda medel i LLIN)– Har påvisats i 64 länder med malaria

transmission

• Resistens mot Artemisin– Har påvisats i Thailand, Cambodja, Burma

och Vietnam

Roll Back Malaria

• Test– Alla fall ska ha en säker diagnos

• Snabbtest eller Microskopi

• Treat– Behandla med effektiva antimalariamedel i

Afrika; Artemisinin PREPARAT

• Track– Öka ansträngningar att förhindra nya fall

• Bednets, Indoor spraying, profylax

AKTUELLA DOKUMENT

•

The artemisinin storyIn the tomb of the Han nobleman, "Marquis of Dai", living 2200 years ago ….

• Chairman Mao : Find new treatment of malaria ! The chinese army had a problem in the Vietnam war

• 1972; Tu Youyou discovered artemisinin in the leaves of Artemisia annua (annual wormwood; kinesisk sommarmalört). The drug is named Qinghaosu in Chinese.

• It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history.

Artemisinin derivat

• Artemether• Riamet=artemether –lunefantrin ( I Tanzania-ALU)

• Artesunate

• Artemotil• Dihydroartemisinin• Kombinationer;

• artesunat+amodiaquine eller mefloquine eller SP

Artemisininderivat vs Kinin

Severe malaria

•Severe malaria is most commonly caused by infection

with Plasmodium falciparum, although P. vivax and

P. knowlesi can also cause severe disease. –The risk is increased if treatment of an uncomplicated attack of malaria caused by these parasites is delayed.–Recognizing and promptly treating uncomplicated malaria is therefore of vital importance–Sometimes, however, especially in children,severe P. falciparum malaria may develop so rapidly that early treatment of uncomplicated malaria is not feasible.

Clinical features of severe malaria

• impaired consciousness (including unrousable coma);• prostration, i.e. generalized weakness so that the patientis unable to sit, stand or walk without assistance;• multiple convulsions: more than two episodes within 24h;• deep breathing and respiratory distress (acidotic breathing);• acute pulmonary oedema and acute respiratory distress

syndrome;• circulatory collapse or shock, systolic blood pressure< 80mm Hg in adults and < 50mm Hg in children;• acute kidney injury;• clinical jaundice plus evidence of other vital organ

dysfunction; and• abnormal bleeding.

Severe malaria

Severe malaria- lab findings

• hypoglycaemia (< 2.2mmol/l or < 40mg/dl);• metabolic acidosis (plasma bicarbonate < 15mmol/l);• severe normocytic anaemia (haemoglobin < 5g/dl, packed

cell volume < 15% in children; <7g/dl, packed cell volume < 20% in adults);

• haemoglobinuria;• hyperlactataemia (lactate > 5mmol/l);• renal impairment (serum creatinine > 265μmol/l); and• pulmonary oedema (radiological).

Hög andel smittade röda blodkroppar. >2.5% ökar risken men i högendemiska områden kan man se 20%

Severe malaria

• Pl Falciparum but also Pl Knowlesis• Microscopy is gold standard

– Few parasites does not rule out severe mal.– Where microscopy is unavailable or unfeasible, a

rapid diagnostic test (RDT) should be used. RDTs for detecting HRP2 antigen

• can be useful for diagnosing malaria in patients who have recently received antimalarial treatment and in whom bloodfilms are transiently negative for malaria parasites.

– If both the slide and the RDT are negative, the patient is extremely unlikely to have malaria

Severe Malaria• Make a rapid clinical assessment, with specialattention to the general condition and level ofconsciousness, blood pressure, rate and depth ofrespiration and pallor. Assess neck stiffness andexamine for rash to exclude alternative diagnoses.

• Admit the patient to an acute illness ward or room;or next to the nurses’ station in a general ward forclose monitoring. However if indicated and available,admit the patient to an intensive care unit.

• Make a rapid initial check of the blood glucoselevel, correct hypoglycaemia if present, andthen monitor frequently for hypoglycaemia.

Severe Malaria -HypoglucaemiaIf hypoglycaemia (threshold for intervention, 3mmol/l)is detected by blood testing or suspected on clinicalgrounds, give

Adults: - 25g of dextrose (preferably as 10% dextrose) over a few

minutes..• Children

– Immediately give 5ml/kg of 10% dextrose through a peripheral line, and ensure enteral feeding or if not possible maintain with up to 5ml/kg per hour of 10% dextrose.

.• Continue to monitor blood glucose levels (with arapid ‘stix’ method if available) in order to regulate thedextrose infusion. Remember that hypoglycaemia mayrecur even after treatment with intravenous dextrose.

Artesunate – new recommendationapril 2011

• The AQUAMAT trial, Lancet 2010; 376: 1647–57 • a multi-centre study conducted in African children

hospitalized with severe malaria. This very large randomized controlled trial, which enrolled 5425 children < 15 years of age across Africa,

• a significant mortality reduction by 22.5% in the artesunate group when compared to the quinine group.

• The incidence of convulsions, coma, and hypoglycaemia developing after hospital was also significantly reduced.

• Importantly there was no significant difference in the incidence of severe neurological sequelae

Severe malaria anti – malaria treatment

• For adults and children, artesunate 2.4 mg/kg body weight IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment.

• Artemether, or quinine, is an alternative if parenteral artesunate is not available:

– artemether 3.2 mg/kg BW IM given on admission then 1.6 mg/kg BW per day ; or

– quinine 20 mg salt/kg BW on admission (IV infusion or divided IM injection), then 10 mg/kg BW every 8 h; infusion rate should not exceed 5 mg salt/kg BW per hour.

• Give parenteral treatment for 24 h. – complete treatment by giving a full course of oral artemether plus

lumefantrine or other available combination

– Broad spectrum Antibiotics also indicated to all cases of severe malaria

Pre referral treatment of severe malaria

• If complete treatment for severe malaria is not possible patients with severe malaria should be given pre-referral treatment and referred immediately to an appropriate facility for further treatment.

• – The following are options for pre-referral treatment:rectal artesunate • quinine IM • artesunate IM

artemether IM.• – In young children of less than 5 years of age, the use

of the use of rectal artesunate (10 mg/kg) has been shown to reduce the risk of death and permanent disability.

Severe malaria – pregnant women

• Increased risk– Hypogkucemia and pulmonary oedema– Mortality rate 50%– Artesunate is the drug of choice. – If this is not available, artemether is referable

to quinine in later pregnancy because – quinine is associated with a 50% risk for

hypoglycaemia

Severe malaria-seizures

• Treat seizures with a benzodiazepine (intravenous diazepam,). If a seizure episode persists longer than 10min after the first dose, give a second dose of a benzodiazepine– Total dose benzodazepim 1 mg/kg per 24 h

• Seizures that persist (status epilepticus) despite the use of two doses of benzodiazepam, give phenytoin– Phenytoin (Epanutin) 18mg/kg body weight intravenously, or– Phenobarbitone (Fenemal)15mg/kg body weight intramuscularly

or intravenously if it is the only available option. • Monitor breathing repeatedly. High dose of phenobarbitone

(20mg/kg body weight) has been linked to an increased risk for death and the patient may need assisted ventilation.

Treatment of uncomplicated malaria

Artemisinin-based combination therapies (ACTs) are the recommended treatments for uncomplicated P. falciparum malaria. Fixed combinations för three days

■ artemether plus lumefantrin ALU (Riamet) Adults 4 tabl 6 trimes 0,8,24,36,48 and 60 h

• The recommended treatment is a 6-dose regimen over a 3-day period.• (5–14 kg: 1 tablet; 15–24 kg: 2 tablets; 25–34 kg: 3 tablets; and > 34 kg: 4

tablets),• given twice a day for 3 days.

• Other ACT■ artesunate plus amodiaquine,■ artesunate plus mefloquine,■ artesunate plus sulfadoxine-pyrimethamine,■ dihydroartemisinin plus piperaquine.

Malaria - behandling

• Nytt hopp för Klorokin ??– Malawi var 50% av allla Pl falc. Resistenta

1993 mot klorokin– Helt stopp i användningen av klorokin– Molekylär markör för klorokinres borta 2001– 2006 jmf studie 210 barn medd okomplicerad

malaria. • Klorokin failure 1 /80.• Fansidar failure 71/87

RTS S vaccin

Sporocoitantigen kopplat tillHBsAg och adjuvans AS01

Utvecklat av GSKMelinda o Bill Gates har satsat miljarder

• Malariavaccin

Malariavaccin projekt

Malaria vaccin

Strategic goal• By 2025, develop and licensea malaria vaccine that has aprotective efficacy of more than80% against clinical disease andlasts longer than four years.

Landmark• By 2015, develop and license afirst-generation malaria vaccine thathas a protective efficacy of morethan 50% against severe diseaseand death and lasts longer thanone year.

The current status of malaria vaccine research WHO Nov 2012

• No licensed malaria vaccines.• Over 20 vaccine in clinical trials. • The vaccine RTS,S/AS01

•against Plasmodium falciparum, with no protection expected against P. vivax malaria.•a partnership between GlaxoSmithKline Biologicals and •Malaria Vaccine Initiative (MVI), with funds from the Bill & Melinda Gates Foundation. •The clinical testing of RTS,S is at least 5-10 years ahead of other candidate malaria vaccines.

Malariavaccin RTS,S/AS01

• Sporocoitantigen

• Hepatit B s antigen (HBsAg)

• Ny och potent adjuvans

• Fas 3 studie startade 2009– 15460 barn inkluderade’– Sju länder i Sub-Saharan Africa– Kontrollgruppen fick Meningokock eller

Rabies vaccin

RTS,S/AS01 delstudie 5-17 mån vid dos 13 doser 1 mån intervall

Follow-up 12 mån efter sista dos N Engl J Med 2011; 365:1863-1875 Nov 17 2011

• Incidence of the first or only episode of clinical malaria was 0.44 per person-year in the RTS,S/AS01 group and 0.83 per person-year in the control group (Rabies vaccin, per protocol analysis)

• efficacy against clinical malaria 55.8%• severe malaria 47.3%

– The efficacy over a 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Tidig studie i Kenya)

• Ingen skillnad i dödlighet mellan grupperna• Samma frekvens biverkningar men fler krampanfall i RTS,S gruppen

RTS,S/AS01, delstudie 6-12 veckor vid dos 13 doser, 1mån intervall

Follow up 12 mån efter första dosN Engl J Med 2012; 367:2284-2295 December 13, 2012

• The incidence of the first or only episode of clinical malaria was 0.37 per person-year in the RTS,S/AS01 group and 0.48 per person-year in the control group, (Meningokockvaccine, per protocol analysis)

• efficacy against clinical malaria 31.3%

• against severe malaria 36.6% – Adverse events similar frequency– Meningitis 9/4358 vs 2/2179