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Karen I Barnes Division of Pharmacology University of Cape Town

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. Problem statement.

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Karen I Barnes Division of Pharmacology University of Cape Town

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  1. 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

  2. Problem statement Malaria infects approximately 250 million people and results in 1- 2 million deaths each year, the majority among children < 5 years. Malaria morbidity and mortality in Africa is rising, and this is principally a result of increasing chloroquine and sulfadoxine-pyrimethamine (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.

  3. Treatment of Severe Malaria: How will countries cope with NO change in national malaria treatment policies?

  4. Malaria Epidemiology in KZN High level SP treatmentfailure (together with insecticide resistance in the vector), resulted in the urgent need forreplacement of first linetherapy. Similar levels of SP failure reported in Malawi, Tanzania, Burundi…. Temporal association between increased antimarial resistance and increased malaria deaths in KZN, Senegal, Kenya….

  5. Malaria Case Fatality Rates • Severe malaria 10-40% • Moderately severe malaria 3% • Uncomplicated malaria <1% How would it be most feasible and cost-effective to intervene, to reduce malaria mortality?

  6. Reduce malaria mortality by: • Early access toeffective 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.

  7. Reducing malaria mortality:Evidence for and implementation of rational malaria treatment policies

  8. Quinine IV/IM Constant rate infusion / painful IM injection Narrow therapeutic range Hypoglycaemia, CVS, CNS toxicity 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) Severe malaria meta-analysis:2653 patients in 16 trialsOlliaro P, Cochrane review 2002 But IV / IM artesunte is likely to be significantly better than IM artemether.

  9. 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.

  10. 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.

  11. SA Adults (n=35) Malawian children (n=109) 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) Efficacy of rectal artesunate

  12. 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-based Combination Therapy Cost effective

  13. 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.

  14. 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

  15. How did ACT decrease malaria case load in KZN? • Significantly Improved Cure rates • Significantly Decreased Gametocyte Carriage

  16. Hospital admissions for malaria in 3 sentinel rural district hospitals in KwaZulu Natal in 2000 & 2001

  17. 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.

  18. 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.

  19. 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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