malaria treatment in Nigeria: malaria drugs in Nigeria

What is the current guideline of malaria treatment in Nigeria? What is the best method of malaria treatment in Nigeria?

Facts about malaria in Nigeria

• In Nigeria, malaria is endemic.
• Accounts for 60% of outpatient visits.
• Responsible for 30% of under-5 mortality.
• Resurgence of malaria is observed in recent times.
• Resurgence due to increasing resistance to chloroquine & sulfadoxine-pyrimethamine.
• A therapeutic efficacy test in 2002 indicated efficacy < 75% for CQ & SP (FMH, Nigeria). Prompted revision of antimalarial drug treatment policy in 2005 in Nigeria (FMH, Nigeria).

laboratory diagnosis of malaria in Nigeria

BLOOD FILM MICROSCOPY

• Thick & thin smears are usually prepared.
• The thick film shows parasite density/parasite load.
• The thin film shows the causative specie.
• Giemsa stained thick blood smears are the basis for microscopic diagnosis with a standard of looking at 100 fields at a magnification of 600-700 (equivalent to 0.25ul of blood).
• Limit of detection is usually 10-20 parasites per microlitre of blood.
• The Plus System of reporting; inappropriate for monitoring treatment of severe disease.
• Report as parasite count per WBC (Parasite Density).
• In hospitalized patients, repeat MP at 24, 48 &72 hours after initiating therapy.
• In general, parasitaemia will drop very quickly within the first 2 hours.

PARASITE COUNT PER WBC
(PARASITE DENSITY)

• Parasites are counted against 200 WBC on the thick film & this is converted to parasite / microlitre using the formula:
• Parasite/ul = No parasite counted x Total WBC divided by No of WBC counted.
• Where the patient’s total WBC is unknown, an average of figure of 800 is used as total WBC.

fluorescent microscopy

• The Quantitative Buffy Coat(QBC) method.
• The Kawamoto Acridine Orange(KAO) process.
• Benzothiocarboxypurine (BCP) procedure.
• Principle: Certain fluorescent dyes have affinity for the nucleic acids in the parasite nucleus. When excited by UV light at an appropriate wavelength, nucleus fluoresces, enabling visualization of the parasite.

rapid immunodiagnostic tests

• Based on the detection of malaria antigens by immuno-chromatography.
• Available as kits & easy to perform.
• Two antigens currently focused on are:
• Plasmodium lactate dehydrogenase & Plasmodium falciparum Histidine Rich Protein2(PfHR2).

other lab investigations

• Polymerase Chain Reaction: Can detect <5 parasites/ul with 100% sensitivity& specificity
• The Immuno-chromatographic test (ICT Malaria P.f. test): Detects circulating antigen of P. falciparum in whole blood. Test takes about 8 minutes.
• Intra-leucocyte malaria pigment: The pigment-containing neutrophil count is a simple marker of disease severity in childhood malaria.

Names of malaria drugs in Nigeria

• Cinchona alkaliods: quinine
• 4-aminoquinolines: chloroquine, amodiaquine
• Chloroquine and 41 other antimalarial drugs have been banned in Nigeria.
• 8-aminoquinolines: primaquine, pamaquine
• Biguanides: proguanil, chlorproguanil
• Diaminopyrimidines: pyrimethamine
• Sulphonamides and sulphones
• Quinoline-methanols: mefloquine
• Antibiotics: tetracycline, erythromycin

Newer antimalarial drugs in Nigeria

• Sesquiterpene-lactone endoperoxides: artemether, artesunate
• Aryl amino alcohols: lumefantrine
• Phenanthrene methanol: halofantrine
• Hydroxynaphthoquinones: atovaquone
• Naphthridine derivatives: pyonaridine

Malaria treatment guidelines in Nigeria

• Malaria manifests in two clinical forms:
• Uncomplicated (non-severe) malaria.
• Complicated (severe) malaria
• The clinical form determines choice of treatment

Current treatment of malaria in Nigeria

• Uncomplicated malaria is defined as symptomatic malaria with no life-threatening manifestations.
• Treatment of choice is Artemisinin-based Combination Therapy (ACT).
• The use of ACT is recommended at various levels: home, community, primary health care centres, secondary & tertiary health institutions in Nigeria

What are ACTs

ACT, which means artemisinin- based combination therapy is defined as the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite (WHO, 2006).

Currently recommended ACTs in Nigeria are:

• Artemether-lumefantrine (AL)
• Artesunate plus Amodiaquine (AS + AQ)
• Artesunate plus Mefloquine (AS +MQ)
• Artesunate plus Sulfadoxine-pyrimethamine (AS +SP)
• In Nigeria, Artemeter-Lumefantrine is the ACT of choice while AS + AQ and AS + MQ are the second line.

Dosage of artemeter-lumefantrine (National drug of choice)

Key: BD= twice daily

Other options of malaria treatment in Nigeria

AQ + SP may be considered as an interim option in situations where ACTs cannot be made available.

rationale for use of artemisinin based combination therapy in nigeria

The concept is based on the synergistic or additive potential of 2 or more drugs to:

Improve treatment efficacy

Retard the development of resistance to the individual components of the combination.

treatment of uncomplicated malaria in special groups

• Children < 3 months old or weigh < 5 kg: Oral quinine 10mg/kg 8 hourly for 7days is recommended as data on the use of artesunate in this age group is lacking.

management of malaria treatment failures in Nigeria

• If fever and parasitaemia fail to resolve or recur within 2 weeks of treatment, then is considered a treatment failure(WHO,2006).
• Treatment failure must be confirmed parasitologically.
• Molecular genotyping using PCR technology should be used to distinguish recrudescent parasites from newly acquired infections.
• Treatment failures may result from drug resistance, poor adherence, under-dosing, poor quality drugs, expired drugs, fake drugs & unusual pharmacokinetic properties in that individual.
• Treatment failures within 14 days; treat with second- line antimalarial.

second-line treatments of malaria in Nigeria

• Alternative ACT known to be effective in this regard.
• Children; Artesunate + Clindamycin (clindamycin is given as 5-20mg/kg/day in 7 divided doses) OR
• Children; Quinine + Clidamycin. Quinine is given 10mg/kg/day in dextrose infusion for 7 days. It can be given alone if clindamycin is not available.
• For Adults; Artesunate + tetracycline OR
• Adults; Quinine + tetracycline or clindamycin
• Tetracycline is contraindicated in children < 12years.
• In order of preference as recommended by Guidelines Development Group of WHO, 2006

Severe malaria treatment in Nigeria

DEFINITION: In patients with P. falciparum asexual parasitaemia and no other obvious cause of their symptoms, presence of one or more of the following clinical or laboratory features classifies the patients as suffering from severe malaria (WHO,2000).

CLINICAL MANIFESTATIONS

• Prostration
• Impaired consciousness
• Respiratory distress (acidotic breathing)
• Multiple convulsions
• Circulatory collapse
• Pulmonary oedema (radiological)
• Abnormal bleeding
• Jaundice
• Haemoglobinuria
• Persistent vomiting (inability to retain any food or fluid)

LABORATORY TEST

• Severe anaemia (Hb <5g/dl)
• Hypoglycemia (<2.2mmol/L)
• Acidosis (HCO<15mmol/L; arterial pH <7.35)
• Renal impairment (Cr >265mmol/L, urine output <0.5ml/kg/hr)
• Hyperlactaemia (>5mmol/L)
• Hyperparasitaemia (non-immune = or > 4%; partially-immune >20%)

objectives of treatment in severe malaria in Nigeria

• Primary objective, prevent death; secondary is to prevent recrudescence, transmission, or emergence of resistance & disabilities.
• Achieve quickly but safely high concentration of antimalarial drug in parasitized RBCs.
• Ensure that the concentration is maintained throughout the time required to achieve a rapid clearance of parasitaemia.

specific antimalarial treatment for severe malaria in nigeria

According to the World Health Organisation. The treatment regimen for severe malaria is as follows;

First Line

• IV artesunate; 2.4mg/kg at 0 hour, 12 hours, and 24 hours for the first day. For day 2, give 2.4mg/kg/day until the patient can tolerate orally. Then switch to the appropriate ACT regimen.

Second Line of severe malaria treatment in Nigeria

• IM artemeter; 3.2mg/kg on the first day. Then 1.4mg/kg for a maximum of 3 days until the child can tolerate orally then switch to ACT regimen.

Third Line (used as first line in most hospitals in severe malaria treatment in Nigeria)

• IV Quinine: given 20mg/kg as loading dose in 10% dextrose water over a period of 4 hours. Then a quinine-free period of 4hours, just dextrose infusion. Now a dose of 10mg/kg is given in dextrose fluid at 8 hourly intervals until patient can tolerate orally. Switch to a 3-day course of ACT.
• Ideal IV fluid is either 10% dextrose water or 8% dextrose in one-fifth saline. Quinine causes hypoglycemia.

Prognosis of severe malaria

The poor prognostic factors in severe malaria are;

• Age < 3 years
• Acidosis
• Cerebral malaria
• Renal impairment
• Delay in institution of treatment
• Hypoglycemia
• Presence of secondary bacteria infection such as septicaemia or UTI

treatment of hyperparasitaemic patient

• If no other signs of severe disease, treat with oral ACT under the following condition:
• Patients must be monitored closely first 48 hours after start of treatment.
• If patient does not retain oral medication, parenteral treatment should be given without delay.
• Non-immune patients with parasitaemia >20%, treat with parenteral antimalaria.

pre-referral malaria treatment in Nigeria

• Risk of death from severe malaria is greatest in the first 24 hours.
• The following may be given:
• Artesunate or artemisinin rectally
• Artesunate artemether I.M.
• Quinine I.M.

children specifically at risk of having severe malaria

In malaria endemic regions, malaria chemoprophylaxis is recommended for the following categories of children only:

• Those with sickle cell anaemia.
• Non-immune immigrants
• Proguanil (3mg/kg/ day) is the drug of choice for chemoprophylaxis.

chemoprophylaxis for non-immune visitors

Those visiting malaria endemic region should start prophylatic therapy one week before arrival,continue during their stay and up to 6wks after departure.

mass malaria chemoprophylaxis for under-fives in Nigeria

In malaria endemic area, not recommended for the following reasons:

• Not feasible to achieve continuous suppression on a large scale.
• May interfere with development of protective immunity.
• May accelerate development of drug resistance.
• Risk of cumulative toxicity.

intermittent preventive treatment- treatment of malaria in pregnancy in Nigeria

In pregnancy, give sulfadoxine-pyrimethamine for intermittent preventive treatment in accordance with the National Antimalarial Treatment Policy and Guidelines as per the Roll Back Malaria Programme in Nigeria.

• First dose from 16 weeks of gestation.
• 2^nd dose at least 4 weeks after 1^st dose up to 36wks.

hiv/aids & malaria in children .

Conflicting reports:

• In advanced immunosuppression, more episodes of clinical malaria & higher parasite densities (Taha T et al,1994)
• In areas of unstable malaria, more severe disease, or coma (Grimwade K et al, 2003)
• No association between Plasmodium falciparum &HIV infection in children in Kinshasa (Nguyen-Dinh et al,1987)
• Confirmatory parasitological diagnosis mandatory to avoid misdiagnosis & wrong treatment.
• Possible toxicity between halofantrine & NRTIs (delavidine). Artemeter-lumefantrine & antiretrovirals may have similar potential to interact.
• Those on cotrimoxazole prophylaxis should be managed with non-sulfa antimalarials.

Prevention and Control of Malaria in Nigeria

• Bacillus thuringiensis var israelensis H-14 (Bti)
• A biological weapon for vector control.
• When mosquito larvae ingest Bti spore along with their diet of algae, Bti releases toxins which destroy the midgut of the larvae, causing its death.
• Gene therapy: In this anti-vector measure, genetically engineered mosquitoes are introduced into the ecosystem to displace the receptive female anopheles species, thus depriving plasmodium of its vector transmission.
• Insecticide-Treated Nets (ITNs):
• ITNs use reduce under-five mortality by 20%.
• Saves about 6 lives per thousand under-fives protected each year.
• Hinder mosquito transmission.
• It’s a cost-effective
• In Nigeria, government is promoting the use of ITNs.

progress towards a malaria vaccine

• Any viable vaccine should comprise antigens derived from most or all the developmental stages.
• A candidate vaccine of this composition is under study in Malaria Research Group at New Delhi, India (component of International Centre for Genetic Engineering and Biotechnology).
• This candidate vaccine comprises two blood stage antigens, the Plasmodium falciparum merozoites surface protein-1(PfMSP-1) and the 17kDa erythrocyte binding antigen(EBA-175) both are essential for RBC invasion.
• Similar combination vaccine of antigens produced in the Parasitology Lab, Institute of Tropical Medicine, Cuba comprising the RTS, S/AS02A polypeptides of Plasmodium falciparum.
• Field trial in Mozambique proved safe and well tolerated but showed low immunogenicity (Rivero LR et al, 2005)
• The most promising malaria vaccine so far introduced into field trials remains the RTS, SIA02A developed by GlaxoSmithKline Biologicals.
• Phase two clinical trials began in 2003, using 2000 Mozambican children (Gulland A, 2003)

Development of resistance to malaria drugs in Nigeria

Be aware that malaria treatment in Nigeria is prone to resistance of self prescription. Currently no bedside tests for determining malaria parasite susceptibility to antimalarials. Monitoring is needed to determine geographical trends. Information obtained will help guide treatment choices & predictions of future resistance patterns. Greatest problem of drug resistance is with P. falciparum.

• Antimalarial drug resistance (AMDR) is defined as the ability of a parasite strain to survive and/or multiply despite the proper administration and absorption of an antimalarial drug in the dose normally recommended (WHO, 2006)

emergency and spread of antimalarial resistance

• Development of resistance can be considered in 2 parts:
• The initial genetic event, producing resistant mutants;
• The subsequent selective process, leading to survival advantage and preferential transmission of resistant mutants and spread of resistance.

predisposing factors to malaria drug development in Nigeria

• Intense frequency of occurrence of genetic changes.
• Degree of resistance (shift in concentration-effect relationship, conferred by the genetic change.
• Fitness of the resistance mechanism
• Proportion of all transmissible infections that are exposed to the drug (the selection pressure).
• Number of parasites exposed to the drugs
• Concentration of drug to which these parasites are exposed.
• Pharmacokinetic & pharmacodynamic properties of the antimalarial.
• Individual (dosing, duration, adherence) and community (quality, availability, distribution) patterns of drug use.
• Immunity profile of the community and individual
• Simultaneous presence of other antimalarials or substances in blood to which the parasite is not resistant.

monitoring of antimalarial drug resistance

• Therapeutic efficacy testing (also known as in vivo testing).
• In vitro studies of parasite susceptibility to drugs in culture.
• Studies of point mutations or duplications in parasite resistant genes with molecular methods (polymerase chain reaction).
• Animal models are also used but not routinely

pre-referral treatment

• Recommended at PHC level in line with IMCI
• Rectal artesunate or any recommended parenteral treatment as a single dose prior to referral to secondary health care level.

Any contributions on malaria treatment in Nigeria?

Malaria has been found to cause nephrotic syndrome.