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Emerging trends malaria

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  • 1. Emerging trends in the therapy of Malaria Better clarity, Better outcomes Dr. B. K. Iyer
  • 2. Introduction
    • Malaria scenario is dynamic -
      • Changes in parasite transmission
      • Increasing drug & insecticide resistance resistance
      • Climatic changes
      • New drugs
    • Over-reliance on quinoline & antifolate Base Drugs: (Cross) Resistance
    • Therapy must be up to date with current situation
  • 3. Cause
    • Next to mosquitoes the biggest cause of malaria is
    This is because success is influenced by resistance patterns “ Ignorance”
  • 4. Malaria – roadmap of today What we know What we may not know What we need to know
    • Africa and malaria today
    • Needs of today
    • Criteria for combinations
    • The difference between the various artemisinins
    • The relatively superior artemisinin
    Add- vantage of Artesunate over other artemisinins Today’s review
  • 5. Antimalarials Developed So Far
    • Over-reliance on quinoline & antifolate Base Drugs: (Cross) Resistance
    2003 1990s 1980s 1970s 1960s 1950s 1940s 1930s <1930 Chlorproguanil-dapsone Atovaquone-proguanil Halofantrine Artemisinin Sulfa-Pyrimethamine Pyrimethamine Proguanil Mepacrine Pamaquine Artemether-lumefantrine Pyronaridine Primaquine Amodiaquine Chloroquine Quinine Mefloquine Artemether Artesunate Not adopted by malaria programs Being abandoned due to resistance
  • 6. Antimalarials on the Horizon In response to the antimalarial drug resistance situation, WHO recommends that treatment policies for falciparum malaria in all countries experiencing resistance to monotherapies, should be combination therapies, preferably those containing an artemisinin derivative (ACT – artemisinin-based combination therapy ). 2003 1990s 1980s 1970s 1960s 1950s 1940s 1930s <1930 Chlorproguanil-dapsone Atovaquone-proguanil Halofantrine Artemisinin Sulfa-Pyrimethamine Pyrimethamine Proguanil Mepacrine Pamaquine Artemether-lumefantrine Pyronaridine Primaquine Amodiaquine Chloroquine Quinine Mefloquine Artemether Artesunate Not adopted by malaria programs Being abandoned due to resistance Fixed Dose Combinations
  • 7. Therapeutic Efficacy of SP in Africa: Evidence to Guide Action West Central East THRESHOLD FOR CHANGE 15
  • 8. Antimalarial Drug Resistance Implications Chloroquine resistance S/P resistance Mefloquine resistance Policy Revision Policy revision underway Evidence collection & policy dialogue
  • 9. Implications in Africa Policy change in Africa: choice of 1st-line treatment CQ SP/AQ CQ AQ+SP CQ/SP ACT INTERIM <1993 1998 1999 2000 2001 2002 2003 CQ CQ+SP Malawi S.Africa Kenya Botswana Tanzania Ethiopia Zimbabwe Uganda S.Africa Rwanda DRC Burundi Zambia Eritrea Zanzibar Cameroon (AQ) Coartem Burundi Gabon Comores Mozambique Senegal Côte d’Ivoire
  • 10. Combination Therapies: Definition What Parallel use of 2 or more antimalarials as free / fixed combinations to delay antimalarial drug resistance in Falciparum malaria Hypertension Cancer Diabetes Tuberculosis AIDS Combination therapy
  • 11. Combination Therapies: As Defined by WHO
    • Simultaneous use of 2 or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite
    from “Use of Antimalarial Drugs” - Nov 2000 What Free Combinations Fixed Dose Combinations To improve efficacy, To delay development of drug-resistance To prolong the useful therapeutic life of antimalarial drugs
  • 12. Combination Therapies: As Perceived by WHO What Antimalarial agents in combination therapy should
    • enhance the efficacy of medication [of agents which are not sufficienty effective on their own]
    • e.g. S/P in the case of first grade resistance to pyrimethamine, or
    • artesunate + mefloquine in the case of mefloquine resistance]
    speed up clinical / therapeutic response, or Both
  • 13. Combination Therapies: As Rejected by WHO from “Use of Antimalarial Drugs” - Nov 2000 What WHAT IS NOT “ antimalarial combination therapy” Antimalarial drug with a drug that enhances its action ( e.g. CQ plus chlorpheniramine ) Use of a blood schizonticidal with a gametocytocidal drug ( CQ plus primaquine )
    • Combinations in which neither components could be given alone, e.g.
    • S+P,
    • Atovaquone / proguanil &
    • LAP/DAP
  • 14. Combination Therapies: Principles What Dosages Contra- indications Ease of Use Principles
  • 15. Combination Therapies: Fixed Dose Combinations
    • Fixed Dose Combinations
    Who Artemisinin based Combinations under Review Existing Coartem ? LapDap AS / AQ AS / MQ AS / LAPDAP AS / SP Short term AQ / SP DHA / Piperaquine WHO Technical Consultation on “ Antimalarial Combination Therapy” – April 2001 AS / Pyonaridine ACTS as recommended By WHO
  • 16. Observations of International Studies
    • Data from Thailand suggest that for combination Therapy in malaria, Artemisinin derivatives are particularly effective combination partners as -
      • They are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle;
      • They reduce malaria transmissibility;
      • No resistance to these drugs has been reported yet.
      • Halts the progression of resistance
      • No adverse side effects from artesunate/artemether and safe for use in 2 nd /3 rd trimesters
    Who Antimalarial drug resistance and combination chemotherapy, Philos Trans R Soc Lond B Biol Sci. 1999 Apr 29;354(1384):739-49, White N.
  • 17. Benefits of Adding artemisinins to Current monotherapy
    • Accelerates therapeutic response and so, deterioration of the patient's condition to severe malaria is extremely unusual
    Why
    • Superior cure rate / enhanced efficacy rate;
    • Greater parasite killing and more rapid parasite clearance;
    • Reduced gametocyte carriage and hence low recrudescence rates;
    • Shortened duration of therapy
    • No added overt toxicity
  • 18. Mean parasite response with artemisinin derivatives Why
  • 19. Why Not Artemisinin Derivatives As monotherapy?
    • If artemisinin or one of its derivatives is given alone, completion of a 7-day treatment course is needed because:
      • Cure rate of Artemisinin derivatives as monotherapy depends on:
        • Dosage used
        • Duration of treatment
        • Severity of patients
    Why
  • 20. Artemisinins Under Review in ACTs
    • Artemether
    • Artesunate
    • Dihydroartemisinin
    • Arteether
    • Arteflene
    Why
    • Artemotil
  • 21. Artemisinin studies Under Review
    • Artemisinins vs. DHA
    • Quinine vs. Artesunate
    • Artemether vs. Artesunate
    • Artemether+lumefantrine vs. Artesunate+Mefloquine
    • Amodiaquine + Artesunate
    • Amodiaquine + SP
    Why
  • 22. Artemisinins with reference to DHA
    • Use of dihydroartemisinin could be beneficial in 2 ways: [1] Easy to make and [2] Low cost
    • All Artemisinin derivatives act after being converted into dihydroartemisinin [DHA] which has intrinsically greater antimalarial activity than artes unate.
    • In terms of the current-in-vitro 50% inhibitory concentrations for P. falciparum in western Thailand, artesunate has approx. 70% of the potency of DHA .
    How Then, why is DHA still not popular over artemether or artesunate?
  • 23. Artemisinins With Reference to DHA Antimicrobial Agents and Chemotherapy, April 2002, p. 1125-1127, Vol. 46, No. 4 How
    • The time of dissolution of the relatively insoluble DHA tablet is higher providing:
      • A higher lag time and
      • Longer time to maximum antimalarial activity ( T max ).
  • 24. Quinine / Artesunate
    • In one comparative study, 1461 patients with severe malaria were recruited from Bangladesh, Indonesia, India, and Myanmar into a randomised controlled trial comparing artesunate with quinine.
    • Half the patients were assigned IV artesunate and half IV quinine.
    • The investigators found that mortality from severe malaria was 15% in artesunate recipients compared with 22% in quinine recipients.= [A reduction of 35%]
    How Lancet, 27 August 2005
  • 25. Quinine / Artesunate : Conclusion:
    • The World Health Organization this week announced that it will recommend artesunate as the first-line treatment for adults with severe malaria after a study found that the drug might be more effective than quinine at treating the disease,
    How Aug 31, 2005
  • 26. Artemether + Lumefantrine
    • Initial response of Coartem in malaria is determined by Artemether but,
    • The principal determinant of overall cure rate is Lumefantrine AUC.
    How Antimicrob Agents Chemother. 2000 March; 44 (3): 697–704 Artemether.
    • A fixed combination of artemether and lumefantrine in 3 different study regimens have all shown a rapid initial response with comparable parasite clearance time ( PCT ) and fever clearance time ( FCT ) although they vary in cure rates.
    Clin Drug Invest 19(5):343-348, 2000 .
  • 27. Artemether + Lumefantrine Negative points How
    • Lumefantrine’s long half-life could also increase the risk of resistance to treatment developing more rapidly.
      • Indeed, a study in Zanzibar, which recently began using co-artemether, has already shown that the malarial parasite is mutating in response to the treatment.
    Sisowath C et al,J Infect Dis. 191(6):1014-7, 2005.
    • Lumefantrine oral bioavailability is dependent on food and is consequently poor in acute malaria but improves markedly with recovery.
  • 28. Artemether + Lumefantrine Dosage observations
    • The Cochrane Review shows that the 6 dose regimen ( 480 mg of artemether + 2,880 mg of lumefantrine) is more effective as compared to the 4 dose regimen of artemether-lumefantrine (320 mg of artemether + 1,920 mg of lumefantrine) but the failure rates with the 4 dose regimen was very high and the 6-dose regimen is largely untested.
    How The Cochrane Database of Systematic Reviews 2005 Issue 3
    • It is worth noting that artemether is liposoluble and not hydrophilic unlike artesunate.
  • 29. Artemether + Lumefantrine Comparative studies
    • In one comparative study, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether.
    • The oral antimalarial bioavailability following artemether was significantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.
      • British journal of clinical pharmacology, volume 52 issue 6 page 655  - December 2001.
    How
  • 30. Artemether + lumefantrine vs. Artesunate + mefloquine
    • In one open-label, two-arm, randomized study comparing oral artemether-lumefantrine and mefloquine-artesunate in 490 patients for the treatment of uncomplicated falciparum malaria with 42 days of follow up, the following was observed:
    • All patients had rapid initial clinical and parasitological responses.
    • In both groups, the PCR adjusted cure rates by day 42 were high.
    • Both regimens were very well tolerated with no serious adverse events observed attributable to either combination.
      • Malaria Journal 2005, 4:46, A randomized trial of artemether-lumefantrine versusmefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparumon the western border of Thailand by Robert Hutagalung et al.
    How
  • 31. Combination Therapies: Alternatives: AQ + ART
    • Excellent efficacy reported on parameters of:
      • Fever clearance rates
      • Parasite clearance rates
      • Gametocyte carriage rates
      • Recrudescence rates
      • Success rates
      • Low failure rates
    • Why not SP combination? With SP as first line therapy, resistance / treatment failure are already prevalent and expected to increase rapidly.
    How
    • For AQ and ART, both are given according to the usual weight-specific dosage schedules for a minimum period of 3 days.
  • 32. Combination Therapies: Alternatives: AQ + S/P
    • Efficacy reported as superior to amodiaquine alone and S/P alone in an area of full chloroquine resistance and incipient S/P resistance (in this area amodiaquine alone was superior to S/P alone)..
    • Both are given according to the usual weight-specific dosage schedules and S/P (single dose) given with the first dose of amodiaquine.
    How Efficacy of AQ alone and combined with SP and of SP combined with AS. Am J Trop Med Hyg. 2003 Jun;68(6):743-7, Rwagacondo CE, Niyitegeka F, et al.
  • 33. Combination Therapies: Alternatives: How Prices may come down as demand increases
  • 34. Combination Therapies: Conclusion:
    • WHO recommends consideration of alternative artemisinin-based combination therapies to artemether-lumefantrine, based on susceptibility of the local malaria parasites. They include:
      • Artesunate (3 days) + amodiaquine,
      • Artesunate (3 days) + sulfadoxine / pyrimethamine (SP) in areas where SP efficacy remains high; &
      • Artesunate (3 days) + mefloquine in areas of low to moderate transmission.
    How WHO Information note draft 6 December 2004)
  • 35. Amqunate studies
    • In one study, 941 children patients who were 10 years or older and who had uncomplicated P falciparum malaria were observed and studied
      • 400 in Kenya,
      • 321 in Sénégal, and
      • 220 in Gabon.
    • Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days).
    How Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.
  • 36. Amqunate studies How Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.
  • 37. Amqunate studies
    • The primary endpoints were measured at days 14 and 28 also.
    • Artesunate + amodiaquine combination improved treatment efficacy across all the common end points.
    How Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.
  • 38. Amqunate studies
    • In an individual patients’ data meta-analysis conducted as recently as 2004, 16 randomized trials with 5948 patients were reviewed.
    • It was seen that addition of 3 days of artesunate to standard therapies resulted in a 70% reduction in the absolute risk of treatment failure.
    How International Artemisinin study group, artesunate combinations for treatment of malaria, meta-analysis, Lancet, 2004, volume 363, page 9-17.
  • 39. Amqunate studies
    • This analysis also showed that artesunate generally lowered gametocyte counts in peripheral blood potentially reducing the risk of transmission.
    How International Artemisinin study group, artesunate combinations for treatment of malaria, meta-analysis, Lancet, 2004, volume 363, page 9-17.
  • 40. One Vital Question Treatment of Uncomplicated Falciparum Malaria in Southern Vietnam: Can chloroquine or sulfadoxine-pyrimethamine be reintroduced in combination with artesunate? Clinical Infectious Diseases    2003;37:1461-1466 How Can Conventional antimalarial Resistance Be Reversed in Combination With artesunate? The successful reintroduction of conventional therapies in combination with artesunate depends on epidemiological and / or parasitological factors and is not predictable since it varies from place to place.
  • 41. Combination Therapies: Brand: Amqunate How
  • 42. Combination Therapies: Adult Dosing: Amqunate How
  • 43. Combination Therapies: Dosing in children: Amqunate How
  • 44. Combination Therapies: Comparative Parameters How AS+MQ AS+lap / dap AS+Lumefantrine Recrudescence rate Gametocyte carriage Parasite clearance times [positivity after day 3] Fever duration [Fever after 3 days] DHA+Piperaquine AS+AQ AS+SP Parameters
  • 45. Conclusion
    • New combination in niche market.
    • Rationally sound dosage forms.
    • High safety profile / very low side effects.
    • Good success rates > 90%.
    • Faster efficacy - 90% of parasitaemia is cleared within 24 hours.
    • Economical.
    How
  • 46. Thank You!