WHO Guidelines for

the treatment of malaria

Dr.Ramya.k
1
07-02-2011
 Road map
 Introduction
 Clinical Disease-malaria
 Anti malarial drugs
 WHO strategies
 Diagnosis
 Objectives of treatment
 Resistence to antimalarial drugs
 Anti malarialial treatment policies
 Treatment for p.falciparum
 Treatment for other species
 Resistence to anti malarial drugs
 Treatment failures
 conclusion

2

 Introduction


Malaria: an important cause of death &
illness in children & adults, especially in
tropical countries

Disease now affects more than half a
billion in world and kills more than a
million people every year



3
 Clinical disease &
epidemiology

4
 Clinical disease &
epidemiology
Caused by parasites of the
species Plasmodium


vP. falciparum (highest mortality)


vP. vivax (most common)

vP. ovale

vP. malariae
v
vP.knowlesi
5
 Life cycle
plappp
of
Plasmodium

6
7
 Drugs classification
True casual prophylactics
Casual prophylactics –hepatic cycle-
primary tissue schizonticides
Primaquine, pyrimethamine, proguanil
Suppressives-erythrocytic stage-
schizonticides
Quinine, 4-aminoquinolines, mefloquine,
artemisinin, proguanil, pyrimethamine,
tetracycline
Radical curatives- both phases
primaquine, proganil


Gametocytocidal drugs
Primaquine-all species
8
Chloroquine, quinine, artesunate(except
falciparum)
 Clinical Manifestations
Malaria parasites multiply rapidly in the liver,
then in red blood cells.


Symptoms commonly include:



Fever
Headache
Chills
Malaise
Joint pain
Vomiting


9
 …clinical
manifestations


If not treated promptly with effective medicines,

malaria may cause mortality by infecting &
destroying red blood cells which clog the
capillaries carrying blood to the brain or other
vital organs potentially causing the following:


Renal failure
Hypoglycemia
Anemia
Pulmonary edema
Shock and coma


10
 Cerebral malaria
Seizures
Fatal if untreated; mortality 20% with Rx
10% treated have neurologic sequelae
Risk factors:
 - Young & old
 - Pregnancy
 - Poor nutrition
 - HIV

11
 WHO strategies
Malaria control requires an integrated
approach, including
Prevention (primarily vector control)
Prompt treatment with effective
antimalarials

WHO urges 4 main strategies to tackle
malaria
Prevention
Treatment
Special effort-young children , pregnant
woman
12 Pre empting epidemics by detecting them
 …WHO
strategies
WHO Guidelines for the treatment of
malaria-first published in 2006

Provide global, evidence-based
recommendations on the case
management of malaria

Targeted policy-makers at country level


13
 Recommendations on
parasitological diagnosis
Prompt parasitological confirmation by
microscopy, or RDT s, is recommended in
all patients suspected of malaria before
treatment is started

Treatment solely on the basis of clinical
suspicion should only be considered when
a parasitological diagnosis is not
accessible

14
Objectives of treatment-
Uncomplicated malaria


Objective: Cure the infection as rapidly as



possible


Cure: defined as “elimination of parasites that

caused illness from the body”
Prevents progression to severe disease &
additional morbidity associated with
treatment failure

15
 …Objectives of treatment-
Uncomplicated malaria
Public health goal of treatment:
To reduce transmission of the infection to
others
To reduce the infectious reservoir
To prevent the emergence and spread of
resistance



Other considerations:
Adverse effect profile
Tolerability of antimalarial medicines
Speed of therapeutic response


16 
Objectives of treatment-Severe
malaria
Primary objective: prevent death


Cerebral malaria: prevention of neurological deficit

Severe malaria in pregnancy-saving the life of the
mother

Secondary objective:


In all cases -prevention of recrudescence,

avoidance of minor adverse effects are
secondary

17
 medicines
Resistance: Major threat to malaria control


Indiscriminate use of antimalarials exerts a

strong selective pressure on malaria parasites


Resistance: prevented by
Combining antimalarials with different
mechanisms of action
Full adherence to correct dose regimens



Drug resistance with Plasmodium falciparum:

lethal
Chloroquine resistance does occur in P. vivax,
Very few reports of resistance in P. malariae or P.
18
ovale
 Antimalarial treatment
policy
Aims to offer highly effective antimalarials


Main determinants of antimalarial treatment

policy:


Therapeutic efficacy of antimalarial medicine

Changing patterns of malaria-associated
morbidity and mortality
Consumer and provider dissatisfaction with the
current policy
Availability of alternative medicines, strategies
and approaches

19
 …antimalarial
treatment policy
Duration of post-treatment follow-up is based
on:
 Elimination half-life antimalarial medicine

Current recommended duration of follow-up:

Minimum of 28 days for all antimalarial
medicines
Extended for longer duration depending on
elimination half-life
42 days for combinations with
mefloquine and piperaquine

20
 WHO GUIDELINES FOR THE TREATMENT
OF MALARIA
2nd Edition, 2010

21
 Treatment of uncomplicated
P. falciparum malaria
Uncomplicated malaria : Defined as
Symptomatic malaria without signs of
severity or evidence (clinical or
laboratory) of vital organ dysfunction

The signs and symptoms of
uncomplicated malaria are
nonspecific.
Malaria is, therefore, suspected
clinically mostly on the basis of
fever or a history of fever
22
Rationale for antimalarial
combination therapy
Antimalarial combination therapy:
Simultaneous use of two or more blood
schizontocidal medicines with independent
modes of action

Rationale is twofold:
Combination is often more effective
If a mutant parasite resistant to one of the
medicines arises de novo during the course
of the infection, this resistant parasite will be
killed by the other antimalarial medicine

This mutual protection is thought to prevent or
23
to delay the emergence of resistance
 Treatment of
uncomplicated
P. falciparum malaria
 Artemisinin-based combination therapies
(ACTs) - recommended treatments



24
 Artemisinin-based
combination therapy
Artemisinins produce rapid clearance of
parasitaemia and rapid resolution of
symptoms, by reducing parasite numbers
100- to 1000-fold per asexual cycle of the
parasite


7-day course is required:

Artemisinin and its derivatives are
eliminated rapidly, when given alone or in
combination with rapidly eliminated
compounds (tetracyclines, clindamycin)

3-day course can be used:
25
In combination with slowly eliminated
 Artemisinin-based
combination therapy
Additional advantage from: ability of the
artemisinins to reduce gametocyte carriage
⇨↡ transmissibility of malaria ⇨ malaria
control in areas of low-to-moderate
endemicity


Shorter courses of 1–2 days not

recommended:
Leads to a larger proportion of
parasitaemia for clearance by the partner
medicine
Less efficacious (except when the partner
drug is highly effective)
26
Less effect on gametocyte carriage
Provide less protection of the slowly
 Artemisinin-based
combination therapy

The choice of ACT - based on the level of

resistance of the partner medicine in the
combination

Artemisinin and its derivatives should not be
used as monotherapy

Non-artemisinin based combination
therapy: inferior in efficacy: hence no
longer recommended
27

 Fixed dose combinations
Fixed-dose combination (FDC) formulations
are strongly preferred and recommended
over blistered co-packaged or loose tablets
combinations to


Promote adherence to treatment

To reduce the potential selective use of the
medicines as monotherapy

Fixed-dose combination formulations are
now available for all recommended ACTs,
except artesunate plus SP.

28
 Second-line antimalarial
treatment

Alternative ACT known to be effective in the
region

Artesunate plus tetracycline or doxycycline
or clindamycin-7 days

Quinine plus tetracycline or doxycycline or
clindamycin-7 days


29
 Additional considerations for
clinical management

Can the patient take oral medication?


Use of antipyretics

Use of antiemetics

Management of seizures

30
 Operational issues in
treatment management

31
 Home-based management of
malaria
Recommended to improve access to prompt
and effective treatment of malaria-trained
community members

Coverage of the health services for malaria to
extend beyond the reach of health facilities

Effective and appropriate treatment with
first-line ACTs- guidance on referral criteria-
provided at the community level

Rectal artesunate and RDTs recommended

32
 HMM?...
 Trained community providers (CHWs,

Medicine Sellers or Retailers) should

be provided with:
ACTs for treatment of

uncomplicated malaria
Rectal artemisinin

suppositories for pre-referral

treatment of severe malaria
Rapid diagnostic tests where

applicable

33
Information, Education and
 Treatment of uncomplicated
P. falciparum malaria in
special risk groups


Pregnancy


First trimester:
Quinine plus clindamycin - 7 days
(artesunate plus clindamycin - 7 days
indicated if fails)

During pregnancy, infection with P.
falciparum, (in p.vivax also)reduces
birth weight and increases the risk of
neonatal death due to
34
Chronic anaemia
 Treatment of uncomplicated
P. falciparum malaria in
Pregnancy
An ACT is indicated –
If this is the only treatment immediately
available
If treatment with 7-day quinine plus
clindamycin fails
Uncertainty of compliance with a 7-day
treatment


Second and third trimesters:



ACTs known to be effective in the

35
country/region
Artesunate plus clindamycin-7 days
 Treatment of uncomplicated P.
falciparum malaria…
 Lactating women
Lactating women - standard antimalarial
treatment (including ACTs) except for
dapsone, Primaquine and tetracyclines

 Infants and young children:
ACTs - first-line treatment - accurate
dosing and ensuring -administered dose
retained

Travellers returning to non-endemic


countries
Atovaquone-proguanil;
36
Artemether-lumefantrine;
 HIV infection- uncomplicated P.
falciparum malaria
Treatment or intermittent preventive treatment
with sulfadoxine-pyrimethamine should not be
given to HIV patients receiving cotrimoxazole
(trimethoprim plus sulfamethoxazole)
prophylaxis


Treatment in HIV patients on zidovudine or
efavirenz should, if possible, avoid
amodiaquine-containing ACT regimens

37
 Malaria - Treatment

38 Artemisinin
 TREATMENT OF SEVERE P.
FALCIPARUM MALARIA

39
 Severe falciparum malaria
Presence of one or more of the following
clinical or laboratory features
Clinical features:
– Impaired consciousness
– Generalized weakness, failure to feed
– multiple convulsions – more than 2 in
24 h
– respiratory distress (acidotic breathing)
– circulatory collapse or shock
– clinical jaundice, other vital organ
dysfunction
– haemoglobinuria
– abnormal spontaneous bleeding
40
– pulmonary oedema (radiological)
 …Severe falciparum
malaria
Laboratory findings:


– hypoglycaemia (blood glucose < 40 mg/dl)

– metabolic acidosis (bicarbonate < 15
mmol/l)
– severe normocytic anaemia (Hb < 5 g/dl)
– haemoglobinuria
– hyperparasitaemia (> 2%/100 000/μl )
– hyperlactataemia (lactate > 5 mmol/l)
– renal impairment (s.creatinine > 265
μmol/l)

41
…Treatment of severe P.
falciparum malaria
Severe malaria -medical emergency
Full doses of parenteral antimalarial
treatment without delay

 Adults
 Artesunate IV or IM
 Quinine an alternative

 Children ( endemic areas of africa)

 Artesunate IV or IM
 Quinine (IV infusion or divided IM )
 Artemether IM ( absorption - erratic)
42
 …Treatment of severe P.
falciparum malaria
Give parenteral antimalarials - for a minimum
of 24 h, once started


Complete treatment by giving a complete

course of:
An ACT;
Artesunate plus clindamycin or
doxycycline;
Quinine plus clindamycin or doxycycline.



43
 …Treatment of severe P.
falciparum malaria
If complete treatment is not possible,
patients should be given pre-referral
treatment

Referred to an appropriate facility for
further treatment

Options for pre-referral treatment :
rectal artesunate, quinine IM,
artesunate IM, artemether IM


44
 Treatment of Plasmodium
vivax, P. ovale and P.
malariae infections

45
 Treatment of p.vivax malaria
Plasmodium vivax


Objectives of treatment of vivax malaria are

two fold:
To terminate the acute blood infection
To cure the clinical symptoms
To clear hypnozoites from the liver to
prevent future relapses-radical cure

 Standard oral regimen
Chloroquine monotherapy (25 mg base/kg
body weight over 3 days) is recommended
as the standard treatment for vivax
malaria
46
 ….Treatment of p.vivax
malaria
Primaquine (0.25 or 0.5 mg base/kg body
weight in a single daily dose for 14 days) is
used as a supplement to the standard
treatment for the purpose of eradicating
dormant parasites in the liver and
preventing relapses


14-day regimen of primaquine is superior in
preventing relapses


47
 Treatment of uncomplicated
P. vivax malaria
Chloroquine with primaquine
-treatment of choice -chloroquine-
sensitive infections

In mild-to-moderate G6PD deficiency,
primaquine 0.75 mg base/kg body
weight - once a week for 8 weeks

In severe G6PD deficiency,
primaquine is contraindicated

48
…Treatment of uncomplicated P.
vivax malaria
ACT (exception AS+SP) -adopted as
first-line treatment for P. falciparum

May also be used for P. vivax malaria
in combination with primaquine for
radical cure

Artesunate plus sulfadoxine-
pyrimethamine is not effective
against P. vivax in many places


49
 Treatment of chloroquine-
resistant P. vivax
Antimalarials that are effective against P.
falciparum are generally effective against
the other human malarias



The exception to this is sulfadoxine-

pyrimethamine to which P. vivax is
commonly resistant


Owing to the high prevalence of dhfr
mutations in P. vivax (Pvdhfr), resistance to
50 sulfadoxine-pyrimethamine develops faster
 chloroquine- resistant P.
vivax

Artemisinins, combined with an effective

partner medicine-excellent cure rates in
both chloroquine sensitive & resistant
strains of P. vivax

In areas of CQ resistance, two
ACTs,DHA+PPQ and AS+AQ , in
combination with primaquine, have
provided high cure rates

ACTs with partner medicines that have

51
longer half-lives, such as DHA+PPQ, are
more effective in reducing relapses than
 … Treatment of
chloroquine- resistant P.
vivax


Mild nausea,vomiting and abdominal pain

are the commonly reported adverse
reactions

Mefloquine (15 mg base/kg body weight as
a single dose) has been found to be highly
effective with a treatment success of 100%

Doxycycline alone (100 mg twice a day for
7 days) provides poor cure rates in P. vivax

52
 … Treatment of
chloroquine- resistant P.
 vivax
Artemisinin derivatives, such as
monotherapy for 3–7 days, have shown poor
efficacy in vivax malaria The addition of
primaquine to these regimes improved the day
28 cure rates to 100%

Quinine (10 mg salt/kg body weight three
times a day for 7 days) is also effective
against CQ resistant P. vivax, but it is not an
ideal treatment because of its toxicity and
consequent poor adherence to this regimen
53
 … Treatment of chloroquine-
resistant P. vivax


Wide a range treatment of vivax malaria

with quinine leads to early relapses

This may be because quinine has a short
half-life, and no antihypnozoite activity

The best combinations for the treatment of
P. vivax are those containing primaquine
when given in antihypnozoite doses

The recommended treatments for CQ
resistant P. vivax are, therefore, ACTs (with
54 the exception of AS+SP) combined with
 … Treatment of chloroquine-
resistant P. vivax


If the recurrence appears within 16 days of

starting treatment of the primary infection,
it is almost certainly a recrudescence due
to therapeutic failure

A recurrence between days 17 and 28 may
be either a recrudescence by chloroquine-
resistant parasites or a relapse

Beyond day 28, any recurrence probably
55 represents a relapse in an infection of
chloroquine-sensitive P. vivax
 Preventive therapy for
relapses


Primaquine is the only available and marketed drug
that can eliminate the latent hypnozoite reservoirs
of P. vivax and P. ovale that cause relapses




Hypnozoites of many strains of P. vivax are
susceptible to a total dose of 210 mg of
primaquine

unsupervised 14-day primaquine therapy can be
56
overcome effectively through patient education
 …Preventive therapy for
relapses



Alternative drugs are much needed for the
radical treatment of P. vivax malaria
resistant to chloroquine and/or primaquine


New drugs, tafenoquine and bulaquine, are
currently being evaluated as an alternative
to primaquine in the prevention of relapses
-this too has haemolytic potential in G6PD-
deficient individuals


57


 Treatment of severe and
complicated vivax malaria


Prompt and effective management should
be the same as for severe and complicated
falciparum malaria

58
 Treatment of malaria caused
by P. ovale and P. malariae

The recommended treatment for radical
cure of P. ovale, relapsing malaria, is the
same as that for P. vivax, i.e. with
chloroquine and primaquine


P. malariae forms no hypnozoites, and so it
does not require radical cure with
primaquine



59

 Adverse effects and
contraindications


Chloroquine is generally well tolerated.

Common side effects include mild
dizziness, nausea, vomiting, abdominal
pain and itching


Primaquine can induce a life-threatening
haemolysis in those who are deficient in
the enzyme G6PD


60
 Adverse effects and
contraindications
Abdominal pain and/or cramps are
commonly reported when primaquine is
taken on an empty stomach.

Gastrointestinal toxicity is dose-related, and
it is improved by taking primaquine with
food. Primaquine may cause weakness,
uneasiness in the chest, haemolytic
anaemia, leukopenia, and suppression of
myeloid series



61
 Mixed malaria infections
ACTs are effective against all malaria
species, and they are the treatment of
choice

Radical treatment with primaquine should be
given to patients with confirmed P. vivax
and P. ovale infections, except in high
transmission settings where the risk of re-
infection is high


62
 Practical aspects of
treatment with
recommended ACTs
Artemether plus lumefantrine
Fixed-dose formulation with dispersible or
standard tablets containing 20 mg of
artemether and 120 mg of lumefantrine
Therapeutic dose. 6-dose regimen over a 3-day

period


Dosing based on the number of tablets per dose

according to pre-defined weight bands (5–14 kg:
1 tab; 15–24 kg: 2 tabs; 25–34 kg: 3 tabs; > 34
63
kg: 4 tabs) given twice a day for 3 days
Drugs Therapeutic dose Duration
mg/kg
artesunate + 4 once a day for
amodiaquine 10 3 days
Artesunate + 4 once a day for
mefloquine 8.3 3 days
Artesunate + 4 OD 3 days
Sulphadoxine 25/ Single administration
pyrimethamine 1.25 on day 1st
Dihydroartemisinin + 4 OD for 3
piperaquine 18 days
Artesunate 2 OD For
Tetracycline/ 4 QID 7
Doxycycline/ 3.5 OD days
clindamycin 10 BID
64
 Management of treatment
failures
Recurrence - P. falciparum malaria-re-
infection, or a recrudescence(i.e. failure)

If fever and parasitaemia fail to resolve or
recur within two weeks of treatment-failure
of treatment

Treatment failures-drug resistance, poor
adherence or inadequate drug exposure,
substandard medicines

Patient’s history- confirmed parasitologically –
65 blood slide examination (as P. falciparum
 ….Management of
treatment failures

Failure within 14 days



Treatment failures within 14 days of initial

treatment should be treated with a second-
line antimalarial
Failure after 14 days
Recurrence - more than two weeks after
treatment could result either from
recrudescence or new infection

This distinction can only be made through
parasite genotyping by PCR.

66
 …Management of
treatment failures


Treatment failures after two weeks of initial

treatment - new infections-treated with the
first-line ACT

If failure is a recrudescence, then the first-
line treatment should still be effective in
most cases


Reuse of mefloquine within 60 days of first

treatment is associated with an increased
risk of neuropsychiatric reactions

67 In cases where the initial treatment was
 Conclusions and
recommendations


For the radical cure of chloroquine-sensitive

P. vivax malaria in patients with no G6PD
deficiency


The standard oral regimen of


Chloroquine of 25 mg base/kg body weight
-3 days
 Plus
Primaquine at either a low (0.25 mg base/kg
body weight per day for 14 days) or

High (0.5–0.75 mg base/kg body weight per
68
day for 14 days) dose is effective and safe
 recommendations
Where infections of drug-resistant P.
falciparum and/or P. vivax are common,
An artemisinin-based combination treatment
(dihydroartemisinin +piperaquine) that
does not include sulfadoxine-
pyrimethamine would be a good choice


Use of high-dose primaquine (0.5–0.75 mg

base/kg body weight/day -14 days), with
either chloroquine or another effective
antimalarial, to prevent relapses of
primaquine-resistant or primaquine-
tolerant P. vivax
69
 recommendations

A primaquine regimen of 0.75 mg base/kg
body weight once per week for 8 weeks is
recommended as anti-relapse therapy for
P. vivax and P. ovale malaria in patients
with mild G6PD deficiency



Increased efforts are needed to evaluate
alternative treatments for P. vivax strains
that are resistant to chloroquine

70
 Malaria - Prevention

71
 References
 Guidelines for the treatment of malaria, WHO, 2nd ed.
Geneva:world press; 2010. p.1-210.
(http://whqlibdoc.who.int/publications/2010/9789241547925_en
g.pdf)

 Vinetz JM, ClainJ, Bounkeua V, Eastman RT, Fidock D.
Chemotherapy of Malaria. In: Hardman.J.G, Limbird.L.E,
Gilman.A.J Editors. Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill;
2011.P.1383-1418.


 Satoskar RS, Bhandarkar SD, Rege NN. Chemotherapy of Malaria.

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Thank you
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