REPUBLIC OF THE SUDAN

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REPUBLIC OF THE SUDAN
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Inter Country workshop on monitoring Therapeutic
Efficiency of Antimalarial Drugs Sanaa Rep. of
Yemen 21 25 April 2002. Research Activities
conducted in Sudan for assessments of
antimalarial resistance county experience in
establishing sentinel sites surveillance for
monitering therapeutic efficiency of antimalarial
drugs using WHO modified protocol. Dr. Abdel
latif M. Salih Q. A. of Diag. And Treatment
NMA Dr. Abu Algasim Abdel Rahim Omer Director
of Malaria Unit South Kordofan
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Introduction- Sudan is the largest country in
Africa and the Middle East, with an area of 2.7
million km2 and 30 million population, 60 are
rural, 10 nomads and 30 are urban. The country
is divided into 26 States, 112 Provinces and 700
Localities. Malaria is the major health problem
in the country. Annual cases 7.5 million annual
deaths 35000. The whole population is at risk of
developing the disease, generally two main
epidemiological situation are identified stable
(perennial transmission and unstable with
epidemic prone (constitutes gt 65 of
population). The main vector is A. Arabiensis
and Dominant parasite is P.F. gt 90 followed by
P.V. which is now increasing specially in the
east of Sudan.
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• Endemicity of Malaria-
• Going from North to the South of Sudan could be
  divided into-
• Meso endemic.
• Hypo endemic.
• Hyper endemic.
• Holo endemic.

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• Now RBM programme is adopted in Sudan. The
  programme is built on partnership.
• Main strategies are-
• Early diagnosis and prompt treatment.
• Multiple preventive measures inducing personal
  protection.
• Early detection and containment of epidemics,
• Focused researches.
• RBM is the responsibility of NMA at the Federal
  level and malaria units at State levels.

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NMSLA
L. Cor. M. Con. S. Con


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Malaria treatment- Malaria is recognized when
there is fever with ring stage in peripheral
blood. i.e. the clinical picture is confirmed
by laboratory examination RDTs are now
introduced but in a narrow scale. Malaria
is differentiated into simple and complicated
malaria.
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• National Protocol for Treatment of Malaria-
• Two workshops were held in Sudan on this topic,
  as a result the National Malaria Protocol was
  agreed upon. According to the National Protocol
  the disease is treated as follows-
• Simple Malaria (Specific treatment)-
• 1st line treatment is Chloroquine (total dose for
  adults is 1500mg tab or 7 injection of 200mg.
  Children according to body weight 25mg/kg.
• 2nd line is Fansidar (S/P) or oral Quinine in
  case of pregnancy.
• 3rd line treatment is either mefloquine or oral
  Quinine
• Severe malaria is treated specifically with
  Quinine or Artemether injections.
• There are other antimalarials which are not
  included in the Protocol but still they are
• prescribed by some practioners e.g. Halofantrine.
• In practice resistance to chloroquine is observed
  by practioners. Resistance to other antimalraials
  is doughtfull. Chloroquine is still the 1st line
  drug in common use.
• The National Protocol is to be revised and the
  1st line of treatment will be changed according
  to studies on Plasmodium sensibility to
  chloroquine.

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Drug Resistance- Drug resistance of malaria
parasites has been defined as the ability of a
parasite strain to multiply and/ or survive in
the presence of concentration of a drug that
normally destroys parasites of the same species
or prevent their multiplication (Bruce-Chawat, L.
J. ed (1981). This definition has been further
qualified into relative resistance, i.e. yielding
to increased, doses of the drug tolerated by the
host, or complete resistance, i.e withstanding
maximum doses tolerated by the host. Nowadays the
common use of the term drug resistance related to
complete resistance and is based on
parasitological features. When speaking of
resistance to antimalarials, attention is
generally focused on P.falciparum, since failure
or success of medication may determine the
patients survival. This is rarely so in
infections with the other human-pathogenic
Plasmodium species.
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Drug resistance in Sudan (1)- In 1978, the
chloroquine sensitivity of P.falciparum was
studied in two areas of Sudan. In the Gezria,
99.4 of the patients treated responded
completely to the drug. Two patients (0.4) and
one patient (0.2) showed, respectively RI and
RII responses (Abdel Hamid Sayed Omer). In the
district of Sennar, the results of in vivo test
showed parasite resistant at the RI level only,
but the mean clearance time of trophozoies from
the blood was higher than for strains found in
many other areas of tropical Africa. (KouzneTsov,
et al 1980). In vivo assessment of the
sensitivity of P.falciparum to chloroquine was
carried out in 63 patients in eastern Sudan
Standard triple dose therapy with chloroquine
(25mg base/Kg body wt) failed in curing 30
patients, all grades of resistance were
demonstrated in the study in the area. (Saeed-BO
et al. 1990). In the 1992 study reports on
chloroquine resistance of P.falciparum among
Sudanese children (6 month to 16 years) living at
Wad Medani, Central Sudan. All levels of
resistance response were confirmed (Ibrahim-AM
et al 1992).
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• Drug resistance in Sudan (2)-
• Of 56 children lt 5 years old seen between
  December 1994 and January 1995 in Waat, Uper Nile
  province, who had pure P.falciparum malaria, 50
  were followed up for 14 days after treatment with
  chloroquine (10mg/kg on day 1 and 2, 5mg/Kg on
  day 3). Three were still positive on day 7 (RII
  resistance), and 2 others who were negative on
  day 3 and 7 became positive again on day 14 (RI
  resistance). (Guthman-PJ et al, 1996).
• Fansidar
• Resistance to S/P has been reported in Central
  Sudan (Ibrahim et al 1991).
• But in vitro study in Eastern Sudan showed 100
  sensitivity (Khalil 1995).
• Quinine-
• In vitro resistance of P.falciparum to quinine
  was also reported in Eastern part of Sudan
  (Khalil 1995).
• In practice Quinine and Fansidar are still
  effective drugs. Chloroquine is still prescribed
  as the 1st line treatment for un complicated
  malaria.

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• Research activities for assessment of
  antimalarial resistance-
• Some researches are conducted by Department of
  Biochemistry (U. of K.) (in vivo test) for
  sensitivity of P.F to Chloroquine/ Fansidar and
  Quinine in New Halfa in the East of the Sudan
  (the attached study).
• The Study conclusion-
• Chloroqunine resistance is worsening.
• Quinine resistance is emerging.
• Fansidar is fully effective.
• Other researches are conducted in Gezira
  University
• PhD research on chlororquine and fansidar
  assessment outcome in the treatment of un
  complicated malaria by Mr. Bakri Yousif. Other
  researches are conducted by the same researcher
  are
• The in vivo and in vitro sensitivity of quinine
  in the treatment of severe malaria in Madani
  teaching Hospital.
• The therapeutic efficacy of chloroquine
  primaquine to prevent relapse of P. vivax in
  Gezira.
• A randomised trial of oral artemether plus
  chloroquine in the treatment of uncomplicated P.
  F. malaria in Central Sudan.
• Researches to obtain MD from U of G by 3
  malariologists on efficacy of antimalarials in
  Gadarif, Madani and Sinnar areas

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Experience in establishing sentinel sites using
WHO protocol- A workshop was organized in BNTRI
in Gezira in 1997 to develop a system for
monitoring therapeutic efficacy of antimalarial
drugs against P.F infections in Sudan. There
are no permanent sentinel sites. Studies are
carried out in different parts of the country
with a hope to develop a sensitivity map of P.F
to antimalarial drugs, chloroquine is targeted
mainly at the present. 18 sentential sites are
suggested.
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• The ongoing studies are at the following sites-
• Northern State.
• Khartoum State.
• Gezria State.
• White Nile State.
• Nourth Kordofan State.
• Blue Nile State.

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Summary of results of some studies carried out
under NMA supervision
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• Problems in establishing sentinel sites-
• Lack of training.
• Lack of close supportive supervision.
• Unstable staff.
• Poor incentives (for both team work and patients).

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Modified WHO Protocol for Assessment of
Therapeutic Efficacy of Chloroquine for
Uncomplicated Falciparum Malaria (In Vivo Test
Guidelines)
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Introduction Malaria is the first public health
problem in Sudan. Chloroquine is the first line
drug for treatment since very early time. Many
studies targeting Chloroquine efficacy were done
with different results. All proved that there is
some degree of resistance. For the National and
State Malaria Administration (NMA SMA) there is
high need for reassessing the efficacy. The
modified standardized in vivo test for testing
the response of Plasmodium falciparum to drugs is
used. The test follows a set of criteria for the
selection of patients, the administration of
standard treatment regimens of the appropriate
drug, and daily parasitological blood
examination. In order to assess the therapeutic
efficacy of routine treatment regimens, the test
should be carried out only in persons suffering
from clinically manifested, microscopically
confirmed falciparum malaria. The test system
expected to provide information required for
guiding drug policies and for monitoring the
efficacy of antimalarial drugs overtime.
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• Objective (1)-
• To assess the efficacy of Chloroquine as a first
  line drug for treatment of uncomplicated
  falciparum malaria.
• Materials and Methods
• Study type
• This is a cross-sectional community-based study
• Study area
• To avoid selection bias the following should be
  considered
• The study should be carried out in an isolated
  area, preferably in a rural setting. The rural
  health center or dispensaries are the most
  suitable sites. An outpatient department (OPD) of
  a rural hospital comes second and then the urban
  health center or OPD of teaching or urban
  hospital.
• The chosen health facilities are better to be at
  a relatively short distance i.e in one district.
• The study team should avoid awareness campaign
  and should select a health facility, which
  usually receive at least 15-20 febrile patients/
  day.
• Efforts should be made to include all febrile
  patients in the area.

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Objective (2)- Study population The study
population comprises all attendance whose illness
proved to be uncomplicated falciparum malaria
clinically (febrile) and microscopically. Sample
size- The sample size varies depending on the
financial, institutional and personnel resources
available. Sample size can be determined by using
LQAS (Lot Quality Assurance Sampling). According
to this method the National Malaria
Administration will look seriously in any study
based on a sample size not less than 100
patients i.e to negotiate changing Chloroquine as
a first line drug. This sample size corresponds
with an upper threshold level of clinical failure
(Po) equal to 25 and a lower level (Pa) of 0.75
and with the power of test equal to 80.
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• Sampling
• The selection of the required sample size should
  be based on the following criteria
• Inclusion criteria
• Age above 6 months
• Mono-infection with P. falciparum
• Parasite count of 500 100.000/ cumm (asexual
  stages).
• Presence of fever or history of fever during the
  previous 48 hours
• Ability to come for the stipulated follow-up
  visits.
• Easy access to health facility.
• Informed consent

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• Exclusion criteria
• Presence of severe complicated malaria or general
  danger signs-
• Not able to drink or breastfeed
• Vomiting everything
• Recent history of convulsions
• Lethargic or unconscious state
• Unable to sit or stand up
• Axillary temperature gt39.5
• Pregnancy
• Febrile diseases other than malaria

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• The test system
• Test Schedule (See annex I)
• A pre-treatment assessment, which includes
  recording essential patient information, clinical
  assessment including body temperature and
  parasitaemia.
• The body weight should be taken at Day 0 and then
  the supervised treatment with the recommended
  drug and dose and treatment schedule will be
  given (Annex IV).
• If the patient meets all the required criteria,
  the patient is recorded in a logbook and entered
  in the record form.
• Clinical assessment with measuring of body
  temperature is to be done on Days 1, 2, 3, 7 and
  14.
• Parasitological examination on Days 0, 3, 7 and
  14.

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• Follow up procedure
• The representativeness of the study diminishes
  with an increasing number of drop-outs. An
  accepted drop-out should be less than 10.
• Thus a need for the precise registration of the
  patient address at enrolment and for the tracing
  of patients who fail to show up on the scheduled
  days (Annex III).
• Those who are excluded because of developing
  exclusion criteria during follow up are not
  included in the calculation of the drop-out rate.
• The patient is expected to be followed on Days
  1, 2, 3, 7and 14. So drop-out rate will be
  calculated by relating those who are excluded to
  the total patients enrolled.

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• Methods of measuring body temperature and body
  weight
• The patient will be weighed on a reliably
  calibrated scale. The weight is recorded to the
  nearest kg.
• The body temperature is recorded to one decimal
  point, preferably with electronic thermometer. If
  the axillary temperature is less than 36.0o C,
  the measurement must be repeated.

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• Methods of blood examination
• For microscopic examination, two slides should be
  taken from each patient.
• Thick and thin blood film should be prepared in
  the same slide.
• One of the slides should be stained with 10 of
  Giemsa stain and examined for the presence of
  infection. Parasite count will be determined by
  counting the parasite against 200 WBCs. The
  parasite count will be calculated using the
  formula
• Parasitaemia (per cumm) No. Of parasites X 5000
  / 200
• The second slide should be kept for further
  reexamination by the control lab of the NMA
• Presence of gametocyte is not necessary in the
  evaluation of the test.
• All slides should be kept for reexamination by
  the NMA.

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• Classification of the therapeutic response
• Three categories can be identified
• ETF (Early treatment failure)
• Development of danger signs or severe malaria on
  Day 1, 2 or 3 in the presence of parasitaemia.
• Parasitaemia on Day 3 gt 25 of Day 0.
• LTF (Late treatment failure)
• Those are patients not classified as ETF up to
  Day 3 then they developed one of the following
• Danger signs parasitaemia
• Unscheduled return due to deterioration
  parasitaemia
• Presence of parasitaemia in the follow up visits
  on Day 7 or 14.
• ACR (Adequate clinical response)
• Patients not classified as ETF or LTF.

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• Data Analysis and Interpretation of Test Results
• Data will be analyzed using SPSS software.
• ETF, LTF and ACR should be calculated in each
  health facility out of the total patients
  followed.
• The proportion of treatment failure is the sum of
  ETF and LTF out of the total.

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Please notice that any treatment failure level
above 25 necessitate changing the Chloroquine as
a first line drug.
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• Organization of the Work
• This work is a collaboration between SMA and the
  NMA and it is fully financed by the NMA / WHO.
• A State team of 3 4 persons will do the work.
  The team is headed by the Medical Officer in
  charge of the health facility were the test is
  performed and composed of Lab. Technician and a
  Nurse. There is a chance for consultants to join
  this work with a chance of full utilization of
  its results.
• The Medical Officer is responsible about
  financing and so clearance by the end of the
  period and so he will be paid at last.
• Regular supervisory visits will be organized by
  NMA concerned staff (At least 3 visits).
• The equipment required by one study team will be
  procured partially by the NMA building on the
  available in the study site (Annex 5a).
• The supplies required for patients will be
  procured fully by the NMA (Annex 5b).

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Endemicity of Malaria in Sudan
High transmission Irrigated Urban Riverine Rural,
high seasonal