Transcript Chloroquine resistance in Sudan latest results

Malaria Endemic Areas and Drug Resistance
Chloroquine resistance
SP resistance
Multi-drug resistance
Plasmodium life cycle
Introduction
• Chloroquine had became the treatment
of choice since its discovery in 1930 due
to the following facts:
• Cheap
• Safe
• Initially highly effective drug
• it was the cornerstone of the effort to
eradicate malaria in the 1950s and 1960s
Chloroquine resistance
• CQ-resistant Plasmodium falciparum
arose and was first detected in Southeast
Asia and South America in the late 1950s
(Peters, 1969),
• Reaching Africa two decades later (Campbell et
al., 1979; Fogh et al., 1979, 1984; Jepsen et al., 1983).
Chloroquine resistance
• Within 10 years, CQ resistance began to reach high
levels in many parts of Southern and Eastern Africa.
• In response to unacceptably high rates of CQ failure, in
1993 Malawi became the first sub-Saharan African
country to discontinue the use of CQ and shift to
sulfadoxine–pyrimethamine nationwide (Bloland et al., 1993).
• Subsequently, Kenya, Botswana and Tanzania also
adopted the policy change from chloroquine to
sulfadoxine–pyrimethamine nd other combination
Drug resistance- definition:
It is the “ability of a parasite strain to
survive and/or multiply despite the
administration and absorption of a drug
given in doses equal to or higher than
those usually recommended but within
tolerance of the
subject”.
Degree of resistance: assessment
WHO has developed a simple scheme
for estimating the degree of the resistance
that involves studying the parasitemia over
28 days.
Smears on day 2 , 7 and 28 are done
to grade the resistance as RI to RIII.
Sensitive (S): The asexual parasite count
reduces to 25% of the pre-treatment
level in 48 hours after starting the
treatment and complete clearance after
7
days,
without
subsequent
recrudescence - Complete Recovery.
RI, Delayed Recrudescence: The asexual
parasitemia reduces to < 25% of pretreatment level in 48 hours, but
reappears between 2-4 weeks.
RI, Early Recrudescence: The asexual
parasitemia reduces to < 25% of pretreatment level in 48 hours, but
reappears earlier.
RII
Resistance: Marked reduction in
asexual parasitemia (decrease >25%
but <75%) in 48 hours, without
complete clearance in 7 days.
RIII Resistance: Minimal reduction in
asexual parasitemia, (decrease <25%)
or an increase in parasitemia after 48
hours.
WHO modified in vivo test
•Minimum follow up 14 days
Early treatment failure (ETF):
Development of danger signs or severe malaria on Day 1,2,3 in the
presence of parasitaemia
Late clinical failure (LCF)
Development of danger signs or severe malaria after day 3 in the
presence of parasitaemia
Late parasitological failure (LPF):
Presence of parasitaemia on any day from day 7 to day 28 and
temp below 37.5 oC
Adequate clinical and parasitological response (CPR):
Absence of parasitaemia on day 28 irrespective of auxiliary temp
Molecular basis of CQ resistance
• CQ is thought to exert its antimalarial effect by
interfering with hematin detoxification in the
digestive vacuole of the parasite.
• PfCRT is a predicted transporter located on the
digestive vacuole membrane and may be
responsible for modulating CQ accumulation
within vacuole.
• Mutation of PfCRT is strongly associated with in
vitro resistant isolates
Factors associated with resistance
1.
2.
3.
4.
5.
6.
Longer half-life.
Genetic mutation.
Poor compliance
Host immunity.
Number of people using these drugs.
Poor compliance.
Malaria Endemic Areas and Drug Resistance
Chloroquine resistance
SP resistance
Multi-drug resistance
Treatment of drug-resistant malaria
Treatment of drug-resistant malaria-new
policy
•
This strategy is based on use of
combination therapy based on
artemisinin derivatives offers hope to
preserving the efficacy of antimalaria
drugs and prolonging their useful
therapeutic.
1.
2.
3.
Artemether+Sulfadoxine/pyrimethamine (1st line)
Artesunate +lumefantrine(2nd line)
Quinine (3rd line as well a the drug of choice for
treatment of severe malaria)
The current situation of malaria in Sudan
•
80 % of the population in Sudan are living in
malarial endemic areas.
•
In spite of presence of all type of Malaria parasite,
Plasmodium falciparum causes
80-90% of infections.
•
Prevalence of malaria ranged between
(17.4 – 44.8%) in out – patient clinics and (9.636.3.8%) in in-patients.
•
Death rate is ranging between (0.9 – 6.9%) .
(Federal Ministry of Health, 2003).
Chloroquine resistance in Sudan
Historic background 1
• The presence of CQ resistant parasites
strains in Sudan was first suggested by
Omer A. M. and Moyou, S, (1979) in Gezira area
and by Kouznestov, A. A. et al.,1979) in Sennar.
• This was later confirmed by an in vitro
study at Gezira area (Ibrahim (1986).
Chloroquine resistance in Sudan
Historic background 2
• Later was reported in Khartoum State (Al
Tawil & Akood M A 1983). The report indicated
that the level of resistance was up to RIII
levels.
• Further studies carried out by Baynoumi, R. A
et al., (1989) have indicated the emergence
of chloroquine resistance in eastern part of
Sudan.
Chloroquine resistance in Sudan
latest results
• In north and central part of Sudan the level
of CQ resistance is near 50%
Report on sentinel sites , National malaria
administration 1999
• Out of 50 patients 12(50%) were classified
as resistance in Gedaref state
Babiker et al JID 2001 V 183
Important factors that are
associated with resistance:
1.
2.
3.
4.
5.
6.
Physiological adaptation.
Single mutation for resistance.
Longer half –life.
Host immunity.
Number of people using these drugs.
Poor compliance.
Chloroquine resistance in Sudan
latest results
• In South the levels of CQ resistance is regaining
from 15-80%
Stivanello E et al, Trop int. health
Bachy C, MSF report 2003
• 75.9% CQ resistance cases reported in Gedaref
area.
• 32.1% CQ resistance cases reported in Hag
Yousif area
Tagelsir et al. acta tropical 2006 V 79
Remerging of chloroquine
susceptibility
• Vietname study by Jacquire etal 1983
• The use of CQ was deceased in Vietnam
since 1975.
• Out of 68 patients included in the study the
rate cure was 90%
• The good clinical response was attributed
to the decreased use of CQ since 1975.
Remerging of chloroquine
susceptibility
• Other studies conducted later had
conflicting out comes and this attributed to
the fact that the removal of CQ in Vietnam
was incomplete due to its continued use
for treatment of P.vivax which is absence
or present in low percentage in subSaharan Africa
Remerging of CQ susceptibility-African
experience
• Malawi was the first country to switch from CQ to
Fansidar for the 1st line of treatment in 1993.
• 5 years after this change clinical isolates were
tested in vitro for CQ susceptibility
The results indicated that:
• 65% of the isolates were sensitive to CQ.
• 31% were border line resistance
• 3% were resistant cases.
In vitro study- Blantyre, Malawi
Remerging of chloroquine
Future
• These studies if they confirmed by well
designed controlled clinical studies,
several opportunities for managing
malaria drug resistance problem become
possible
• Reintroducing of CQ as monothreapy is
highly inadvisable