Treatment of Severe Malaria: How will countries cope with changes in national malaria treatment policies?

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Treatment of Severe Malaria How will countries
cope with changes in national malaria treatment
policies?

• Karen I Barnes
• Division of Pharmacology
• University of Cape Town

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Problem statement

• Malaria infects approximately 250 million people
  and results in 1- 2 million deaths each year, the
  majority among children lt 5 years.
• Malaria morbidity and mortality in Africa is
  rising, and this is principally a result of
  increasing chloroquine and sulfadoxine-pyrimethami
  ne (SP) resistance in Plasmodium falciparum and
  delays in access to effective therapy.
• Many patients who cannot tolerate oral treatment
  do not have ready access to health facilities
  able to provide injectable treatment. Delay in
  access to prompt therapy can be fatal.

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Treatment of Severe Malaria How will countries
cope with NO change in national malaria treatment
policies?
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Malaria Epidemiology in KZN
High level SP treatment failure (together with
insecticide resistance in the vector), resulted
in the urgent need for replacement of first line
therapy. Similar levels of SP failure reported
in Malawi, Tanzania, Burundi. Temporal
association between increased antimarial
resistance and increased malaria deaths in KZN,
Senegal, Kenya.
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Malaria Case Fatality Rates

• Severe malaria 10-40
• Moderately severe malaria 3
• Uncomplicated malaria lt1
• How would it be most feasible and cost-effective
  to intervene, to reduce malaria mortality?

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Reduce malaria mortality by

• Early access to effective parenteral Rx and
  modern intensive care, particularly
  haemofiltration and ventilation for patients with
  severe malaria1.
• Rectal formulations for patients unable to
  tolerate oral treatment and who do not have
  access to parenteral treatment
• Early access to effective treatment for
  uncomplicated malaria
• Community IEC
• Effective durable treatment policy
• Delay resistance through combinations,
  particularly artemisinin-based combinations.
• Reduce malaria transmission
• Mosquito Vector control
• Artemisinin-based combination therapy
• 1White NJ (2003). The management of severe
  falciparum malaria. Am J Resp Crit Care Med 167
  673-674.

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Reducing malaria mortalityEvidence for and
implementation of rational malaria treatment
policies
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Severe malaria meta-analysis2653 patients in
16 trialsOlliaro P, Cochrane review 2002

• Artemether IM
• PCT more rapid, but clinically equivalent.
• Coma recovery time and neurological sequelae
  similar
• Better survival than quinine (mortality odds
  ratio 0.61 0.46 0.82)

• Quinine IV/IM
• Constant rate infusion / painful IM injection
• Narrow therapeutic range
• Hypoglycaemia, CVS, CNS toxicity

But IV / IM artesunte is likely to be
significantly better than IM artemether.
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Severe malaria

• Randomized comparison of artesunate and quinine
  in the treatment of severe falciparum malaria.
• Newton PN, Angus BJ, Chierakul W, Dondorp A,
  Ruangveerayuth R, Silamut K, Teerapong P,
  Suputtamongkol Y, Looareesuwan S, White NJ.
• 113 adults with clinically severe falciparum
  malaria in western Thailand.
• Mortality was 12 with artesunate and 22 with
  quinine treatment
• (relative risk, 0.53 95 confidence interval,
  0.23-1.26 P.22).
• Parasite clearance time was much shorter among
  artesunate-treated patients (P.019).
• Fewer patients became hypoglycemic during
  artesunate therapy (10) than during quinine
  therapy (28) (P.03).
• Artesunate is at least as effective as quinine in
  the treatment of adults with severe malaria.
  Larger trials are required to determine whether
  mortality is reduced among patients treated with
  artesunate.

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Hyperparasitaemia

• Patients with greater than 4 parasitaemia, but
  with no other features of severe malaria, are at
  an increased risk of developing severe malaria
  and have a 3 mortality rate.
• Oral artesunate was found to be clinically and
  parasitologically superior to intravenous
  quinine.
• Luxemborger C, Thwai KL, Raimond SD,
  Chongsuphajaisiddhi T, White NJ (1995). Oral
  artesunate in the treatment of uncomplicated
  hyperparasitaemic falciparum malaria. Am J Trop
  Med Hyg, 53 522-525.

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Efficacy of rectal artesunate

• SA Adults (n35) Malawian children (n109)
• Percentage of baseline parasitaemia during
  initial 24 hours following rectal artesunate vs
  IM quinine, in patients with moderately severe
  malaria.
• Rectal artesunate resulted in more rapid parasite
  clearance, and clinically equivalent to IM
  quinine.
• Pharmacokinetic and or pharmacodynamic evidence
  of adequate absorption of rectal artesunate shown
  in all patients with moderately severe malaria.
• Barnes KI, Mwenechanya J, Tembo M, McIlleron H,
  Folb PI, Ribeiro I, Little F, Gomes M, Molyneux
  ME Efficacy of rectal artesunate in the initial
  treatment of moderately severe malaria in African
  children and adults. Lancet 2004 (In press)

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Artemisinin-based combination therapy in
uncomplicated malaria
Improve clinical cure rates Delay emergence of
resistance Reduce transmission
Widespread use of 1st line Rx with Artemisinin-ba
sed Combination Therapy
Cost effective
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ACT delays resistance in NW Thailand
Nosten F, et al (2000). Effects of artesunate
mefloquine combination on incidence of Plasmodium
falciparum malaria and mefloquine resistance in
western Thailand a prospective study. Lancet
356 297-302.
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ACT acts synergistically with vector control to
decrease malaria transmission in KwaZulu Natal,
South Africa
A DDT reintroduced
B IRS southern Mozambique
C Artemether-lumefantrine implemented
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How did ACT decrease malaria case load in KZN?

• Significantly Improved Cure rates
• Significantly Decreased Gametocyte Carriage

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Hospital admissions for malaria in 3 sentinel
rural district hospitals in KwaZulu Natal in 2000
2001
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Overcoming Challenges in Implementation

• Drug regulation and registration.
• Pricing and sustainable funding.
• Strengthening the healthcare system.
• Ongoing training and supervision.
• Monitoring and evaluation and FEEDBACK.

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Future research questionsin severe malaria

• Efficacy and effectiveness of rectal artesunate
  in severe malaria.
• Large scale multi-centre study of intravenous
  artesunate vs. quinine in severe malaria.
• Feasible methods for enhancing referral systems
  in resource poor settings.
• Effect of widespread use of ACTs on hospital
  malaria admissions in areas of higher intensity
  malaria transmission.
• Outcome studies of interventions to promote early
  treatment seeking in malaria, particularly in
  more severe malaria.

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Key Lessons Learnt Policy Implications

• Artemisinins can play an important role in
  decreasing malaria mortality in children (and
  adults).
• Potential to decrease mortality from more severe
  malaria when artesunate is administered
  intravenously (and possibly rectally).
• Rectal artesunate in moderately severe malaria
  allows earlier access to effective treatment in
  patients unable to tolerate oral treatment.
• Artemisinin-based combination therapy for
  uncomplicated malaria should lead to a decrease
  the inpatient malaria burden by improving cure
  rates, delaying antimalaial resistance, and
  decreasing malaria transmission.

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