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Artemether with Lumefantrine

Contents
Introduction: Malarial Epidemic in India Pathogens causing Malaria Malarial Life Cycle Clinical Features of Malaria Diagnosis Treatment Need of Combination Therapy Available Combinations in India Clinical Efficacy Studies Preventive Measures

Indian contribution to Malaria


Malaria remains one of the major killers of humans worldwide, threatening the lives of more than one-third of the worlds population1.
Indian contribution to Malaria in South East Asia

75%

Of the 2.48 million malaria cases reported annually from South Asia of which 75% cases are contributed by India alone2.
1. U.S. Department of health and human services national institutes of health 2. Infectious Diseases Chapter, Indian Academy of Pediatrics

In India High-risk population resides in:


Andhra Pradesh Chhatisgarh, Gujarat, Jharkhand, Madhya Pradesh Maharashtra Orissa Rajasthan The seven north-eastern states and Sikkim.

Approximately 95% of the countrys population lives in malariaendemic areas, 80% of malaria occurs among 20% of the population who are classified as high risk populations1.
1. Estimation of Malaria Disease Burden in India; Regional Office for South-East Asia WHO

Pathogens causing Malaria


Human malaria can be caused by four species of the genus Plasmodium: P. Falciparum, P. Vivax, P. Ovale and P. Malariae. Parasites majorly responsible for malaria in India Plasmodium Falciparum Plasmodium vivax P. falciparum malaria is more dangerous because the parasite can infect RBCs in all stages of development, leading to very high parasite levels in the blood

P. vivax parasites infect only young RBCs, which means the number of parasites in the blood does not reach the same high levels as seen in P. falciparum infection.

Malaria Causing Pathogens

Ref: Best Practice, BMJ, 2011

Seasonal variation of Malarial pathogens in India


From the study of Comprehensive-care, multi-specialty hospital in New Delhi

P. falciparum and P. vivax is malaria cases tends to be greatest in India


Ref: Malaria Jouranl 2009, 8:227

Acta Tropica 121 (2012) 267 273

Clinical features of different malarial Parasite


The normal incubation period is 10-21 days, which can be longer. The temperature often reaches 41c which is accompanied by the rigor and drenching sweats.
Malarial Parasite P. falciparum Clinical Features It may cause serious complication and the vast majority of malaria deaths are due P. falciparum. Patients can deteriorate rapidly, and children may go to coma and death within hours. Illness is relatively Mild, Anemia develops slowly, and there may be tender to hepatosplenomegaly. Spontaneous recover usually occurs within 2-6 weeks, but hypnozoites in the liver can cause relapses for many years after infection.

S.No. 1.

2.

P. vivex

Malarial Life Cycle

Mosquito bites, infects human Transmission to Mosquito Gametocytes produced in Blood


cont.

Sporozoites enter blood stream

Malarial Life cycle


Reached Liver & Multiply into Merozoites

Ruptured RBC & produce more Merozoites

Back to Bloodstream

Signs & Symptoms


Fever with chills and shivering is the cardinal symptom of malaria. It can be intermittent with or without periodicity or continuous. Fever is often accompanied by headache,s myalgia, arthralgia, anorexia, nausea and vomiting. At times, symptoms of malaria can be non-specific and mimic other diseases like viral infections, enteric fever etc

Malarial Complications
CNS Renal
Blood Respiratory Metabolic Gastrointestinal

Cerebral malaria (coma, convulsion) Haemoglobinuria (Black water fever, Oliguria, uremia) Severe anemia (Haemolysis and dyserthropoisis) Acute Respiratory distress syndrome
Hypoglycemia Diarrhea, Jaundice, splenic rupture

Ref: Kumar and Clark, Clinical Medicine 5th Edition; Page No. 100

Diagnosis of malaria
All clinically suspected malaria cases should be investigated immediately by microscopy and/or Rapid Diagnostic Test (RDT).

Microscopy

Malaria Parasites Amid Red Blood Cells The invasion has begun

Diagnosis of Malaria cont.


Advantages of Microscopy The sensitivity is high. It is possible to detect malarial parasites at low densities. It also helps to quantify the parasite load. It is possible to distinguish the various species of malaria parasite and at their different stages.
Malaria Parasites Amid Red Blood Cells The invasion has begun

Diagnosis of Malaria cont.


Rapid Diagnostic Test
Rapid Diagnostic Tests are based on the detection of circulating parasite antigens. Several types of RDTs are available. Some of them can only detect P. falciparum, while others can detect other parasite species also. The latter kits are expensive and temperature sensitive. RDTs are produced by different companies, so there may be differences in the contents and in the manner in which the test is done.
Guidelines for diagnosis and Treatment of malaria in India 2009 (Government of India)

Management of Malaria
Aim of the Malaria Management

Complete cure
Prevention of progression of uncomplicated malaria

to severe disease
Prevention of deaths Interruption of transmission Minimizing risk of selection and spread of drug resistant parasites.
Guidelines for diagnosis and Treatment of malaria in India 2009 (Government of India)

Treatment Goal
Balance between provision of early diagnosis and prompt treatment, and minimising the development of antimalarial drug resistance.

Goal: reduce morbidity and mortality Broad access to antimalarias Emphasis on community and household management Requires high sensitivity of diagnosis

Goal: reduce and delay resistance Restrictive access to antimalarial drugs Emphasis on regulation and control management of drug use Requires high specificity of diagnosis

Report of a Technical Consultation, WHO, Geneva, 4-5 April 2001

Management of Malaria in Pregnancy


According guidelines,
Treatment in the first trimester of

to

current

WHO

pregnancy is quinine.
Artemisinin Combination Therapy can be given in the second and third trimester of pregnancy.
Guidelines for diagnosis and Treatment of malaria in India 2009 (Government of India)

Developing Resistance to Monotherapy

ICMR Bulletin, 2008, 38(7-9)

Need of Combination therapy


INFECTIOUS DISEASES CHAPTER, INDIAN ACADEMY OF PEDIATRICS

Parasites would not be exposed to subtherapeutic levels of the drug


According to WHO, one of the partner in combination therapy should be an artemisinin derivative due to its: High killing rate (reduces parasite number 10,000 fold per cycle whereas other antimalarial reduces 100 to 1000 fold per cycle). Lack of serious side effects. Relatively low level of resistance. Rapid elimination rate.

Protection against emergence of drug resistance


Combinations also protect against emergence of drug resistance

Need of Combination
INFECTIOUS DISEASES CHAPTER, INDIAN ACADEMY OF PEDIATRICS

Better Treatment Adherence


When artemesinin derivatives are combined with slowly eliminated antimalarials [lumefantrine], shorter courses of treatment (3 days) are effective which ensures better treatment adherence.

Complete eradication of the infection


The number of parasites exposed to long acting drug. Thus, residual parasites are exposed to relatively high levels of long acting drugs and even if susceptibility was reduced, these levels may be sufficient to eradicate the infection.

Emergence of Chloroquine resistant falciparum malaria Monotherapy with Artesunate will further increase the resistance

Combinations Available in India


Artether +Lumefantrine
Sulphamethopyrazine + Pyrimethamine Artesunate + Mefloquine Kit

Artesunate + Pyrimethamine+ Sulphadoxine Kit

Artemether + Lumefantrine
Artemether Lumefantrine 80mg 480mg

WHO-Recommends Artemisinin based fixed dose combination therapy

Expectations from Antimalarials Treatment

Artemether Lumefantrine Vs. Artesunate - Mefloquine


N = 490 patients with malaria

Treatment = Artemether-Lumefantrine (n = 245) or Artesunate Mefloquine (AST MF) (n = 245) and were followed for 42 days. Result =

1. High Cure Rate


ARM -LM results in high cure rate
100.00% 98.00% 96.00% 94.00% ARM -LM AST -MF 98.80% 96.30%

2. Lower Recrudescence
Lower Recrudescence with ARM- LM
10 5 0 ARM -LM AST -MF 2 8

Artesunate Lumefantrine achieves higher cure rate as well as Lowers recrudescence than Artesunate -Mefloquine.
Ref: Malaria Journal 2005, 4:46

Artemether Lumefantrine Vs. Artesunate - Mefloquine


Cont . N = 470 patients with malaria

Treatment = Artemether-Lumefantrine or Artesunate Mefloquine (AST MF). Result =

Lowers Adverse effects


Adverse Events
30.00% 20.00% 10.00% 0.00% ARM -LM AST -MF 18.40% 27.80%

Artesunate Lumefantrine less adverse effects than Mefloquine-Artesunate.


Ref: Am J Trop Med Hyg, 79(5), 2008; 655661

Artemether Lumefantrine Vs. Artesunate - Mefloquine


Cont . N Result
PCT:

= The review of six trial (1698 participants) =

Treatment = Artemether-Lumefantrine or Artesunate Mefloquine (AST MF).

Faster Gametocyte Clearance


Effects of Artemether -Lumefantrine
100 Hours 50 0 29 31 72 85

GCT:

Parasite Clearance Time, Gametocyte Clearance Time

PCT
ARM -LM AST -MF

GCT

Parasite and Gametocyte clearance time was found to be shorter with the treatment of Artemether- Lumefantrine as compared to Artesunate Mefloquine therapy.
Ref: Tropical Medicine and International Health, 2004 Feb, 9 (2); 192199

Artemether-Lumefantrine Vs. Artesunate- SulphadoxinePyrimethamine


N = 786 Patients <5 years old with uncomplicated P. falciparum

Treatment = Artemether- Lumefantrine (ARM-LM) and ArtesunateSulphadoxine- Pyrimethamine (AST- SP)


Result = 95% 94% 93% 92% 91% 90% 89%

ARM -LM results in Cure Rate


94% 91%

ARM-LM

AST-SP

Artesunate Lumefantrine achieves higher cure rate than Artesunate- Sulphadoxine- Pyrimethamine.
Ref: Gutman, Julie (2009)

Artemether-Lumefantrine Vs. Artesunate- SulphadoxinePyrimethamine Cont .


Treatment = A Randomized control trial compared Artemether Lumefantrine with Artesunate- Sulphadoxine Pyrimethamine for 28 days. =
12% 10% 8% 6% 4% 2% 0%

Result

Failure rate associated with ARM- LM


10%

0% ARM-LM AST-SP

Artesunate Lumefantrine shows less failure rate than Artesunate- Sulphadoxine- Pyrimethamine.
Ref: Best Practice, BMJ, 2008

Artemether-Lumefantrine Vs. Artesunate- SulphadoxinePyrimethamine Cont .


Treatment = A Randomized control trial compared Artemether Lumefantrine (6-dose regimen; 106 children) with ArtesunateSulphadoxine Pyrimethamine (91 children) for 28 days. = 30% 20% 10% 13%

Result

Recurrent parasitaemias
25%

0%
ARM-LM AST-SP

Artesunate Lumefantrine is associated with lower rate of recurrent parasitaemia as compared to Artesunate- SulphadoxinePyrimethamine.
Ref: Best Practice, BMJ, 2008

Artemether-Lumefantrine Vs. Different Combinations

Artesunate Lumefantrine achieves higher cure rate.


Ref: Am J Trop Med Hyg 2007, 77:1005-1009

Benefits of Artemether Lumefantrine combination


Against Artesunate- Mefloquine
High Cure Rate Lower Adverse Effects Lower Recrudescence Faster Gametocyte Clearance

Against Artesunate Sulphadoxine Pyrimethamine High Cure Rate


Lower Failure Rate Lower Recurrent Parasitaemia

Dosage & Administration

Malaria Prevention
Indoor Residual Spraying (IRS) is being carried out in identified High Risk villages. Two regular rounds of IRS are being carried out every year during transmission season. Weekly spraying of larvicides (Temephos, Fenthion, etc.) on mosquito breeding places is being carried out in urban areas. Use Guppy fish at suitable mosquito breeding places.

Malaria Prevention cont.


Rely on anti-malaria prescriptions when traveling to malaria prone areas. Prevent the development of the eggs into adult mosquitoes. It is common habit to throw the unutilized utensils , buckets, bottles, tyres, tender coconut shells etc. into the open. During the rains, water gets collected in these containers and provides ample breeding locations for the female anopheles mosquito.

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