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  • Emerging trends in the therapy of Malaria

    Better clarity, Better outcomes

    Dr. B. K. Iyer

  • 2

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Introduction

    Malaria scenario is dynamic -1. Changes in parasite transmission2. Increasing drug & insecticide resistance

    resistance3. Climatic changes4. New drugs

    Over-reliance on quinoline & antifolate Base Drugs: (Cross) Resistance

    Therapy must be up to date with current situation

  • 3

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Cause

    Next to mosquitoes the biggest cause of malaria is

    Ignorance

    This is because success is influenced by resistance patterns

  • 4

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Malaria roadmap of today

    What we know

    What we may not know

    What we need to know

    1.Africa and malaria today

    2.Needs of today

    3.Criteria for combinations

    1.The difference between the various artemisinins

    2.The relatively superior artemisinin

    Add- vantage of Artesunate

    over other artemisinins

    Todays review

  • 20031990s1980s1970s1960s1950s1940s1930s
  • 20031990s1980s1970s1960s1950s1940s1930s
  • 7

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    0

    5

    10

    15

    20

    25

    30

    35

    40

    45

    50

    % F

    ailu

    res

    ParasitologicalClinical

    West Central East

    THRESHOLD FOR CHANGE15

    Therapeutic Efficacy of SP in Africa: Evidence to Guide Action

  • 8

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Chloroquine resistanceChloroquine resistance

    S/P resistanceS/P resistance

    Mefloquine resistanceMefloquine resistance

    Antimalarial Drug ResistanceImplications

    Policy Revision

    Policy revision underway

    Evidence collection & policy dialogue

  • Implications in Africa

    Policy change in Africa: choice of 1st-line treatment

    CQ SP/AQ

    CQ AQ+SP

    CQ/SP ACT

    Malawi

    S.Africa

    Kenya

    Botswana

    Tanzania

    Ethiopia

    Zimbabwe

    Uganda

    INTE

    RIM

    S.Africa

    Rwanda

    DRC

    Burundi

    Zambia

    Eritrea

    Zanzibar

    Cameroon

    (AQ)

  • 10

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies:Definition

    WhatWhat

    Parallel use of 2 or more antimalarials as free / fixed combinations to delay antimalarial drug

    resistance in Falciparum malaria

    HypertensionHypertension

    CancerCancer

    DiabetesDiabetesTuberculosisTuberculosis

    AIDSAIDSCombination Combination

    therapytherapy

  • 11

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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

    WhatWhat

    Free CombinationsFree Combinations Fixed Dose CombinationsFixed Dose Combinations

    To improve efficacy,

    To delay development of drug-resistance

    To prolong the useful therapeutic life of antimalarial drugs

  • 12

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies:As Perceived by WHO

    WhatWhat 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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies:As Rejected by WHO

    from Use of Antimalarial Drugs - Nov 2000

    WhatWhat 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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies:Principles

    WhatWhat

    Principles

    Dosages

    Contra-

    indications

    Ease of

    Use

  • 15

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies: Fixed Dose Combinations

    WhoWho

    Fixed Dose Combinations

    Artemisinin based Artemisinin based Combinations under Review Combinations under Review

    ExistingExisting

    Coartem ? LapDap

    AS / AQ AS / MQ

    AS / LAPDAP

    AS / SP

    Short termShort term

    AQ / SP

    DHA / Piperaquine

    WHO Technical Consultation on

    Antimalarial Combination Therapy

    April 2001

    ACTS as recommendedBy WHO

    AS / Pyonaridine

  • 16

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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 2nd/3rd trimesters

    WhoWho

    Antimalarial drug resistance and combination chemotherapy, Philos Trans R Soc Lond B Biol Sci. 1999 Apr 29;354(1384):739-49, White N.

  • 17

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Benefits of Adding artemisinins to Current monotherapy

    Accelerates therapeutic response and so, deterioration of the patient's condition to severe malaria is extremely unusual

    WhyWhy 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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Mean parasite response with artemisinin derivatives

    WhyWhy

  • 19

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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

    WhyWhy

  • 20

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemisinins Under Review in ACTs

    Artemether Artesunate Dihydroartemisinin Arteether ArtefleneWhyWhy

    Artemotil

  • 21

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemisinin studies Under Review

    1. Artemisinins vs. DHA2. Quinine vs. Artesunate3. Artemether vs. Artesunate4. Artemether+lumefantrine vs.

    Artesunate+Mefloquine5. Amodiaquine + Artesunate 6. Amodiaquine + SP

    WhyWhy

  • 22

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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 artesunate.

    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.

    HowHow

    Then, why is DHA still not popular over artemether or artesunate?

  • 23

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemisinins With Reference to DHA

    Antimicrobial Agents and Chemotherapy, April 2002, p. 1125-1127, Vol. 46, No. 4

    HowHow

    The time of dissolution of the relatively insoluble DHA tablet is higher providing: A higher lag time and Longer time to maximum antimalarial

    activity (Tmax).

  • 24

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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%]

    HowHow

    Lancet, 27 August 2005

  • 25

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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,

    HowHow

    Aug 31, 2005

  • 26

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemether + Lumefantrine

    Initial response of Coartem in malaria is determined by Artemether but,

    The principal determinant of overall cure rate is Lumefantrine AUC.

    HowHow

    Antimicrob Agents Chemother. 2000 March; 44 (3): 697704 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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemether + Lumefantrine Negative points

    HowHow

    1. Lumefantrines 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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    The Cochrane Database of Systematic Reviews 2005 Issue 3

    It is worth noting that artemether is liposoluble and not hydrophilic unlike artesunate.

  • 29

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

  • 30

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Artemether + lumefantrinevs. 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.

    HowHow

  • 31

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    For AQ and ART, both are given according to the usual weight-specific dosage schedules for a minimum period of 3 days.

  • 32

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Prices may come down as demand increases

    Combination Therapies: Alternatives:

    HowHow

  • 34

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    WHO Information note draft 6 December 2004)

  • 35

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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 Sngal, 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).

    HowHow

    Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.

  • 36

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Amqunate studies

    HowHow

    Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.

  • 37

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    Lancet, volume 359, number 9315, page 1365-1372, 20 April 2002.

  • 38

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

    International Artemisinin study group, artesunate combinations for treatment of malaria, meta-analysis, Lancet, 2004, volume 363, page 9-17.

  • 39

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Amqunate studies

    This analysis also showed that artesunate generally lowered gametocyte counts in peripheral blood potentially reducing the risk of transmission.

    HowHow

    International Artemisinin study group, artesunate combinations for treatment of malaria, meta-analysis, Lancet, 2004, volume 363, page 9-17.

  • 40

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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

    HowHow

    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

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies: Brand: Amqunate

    HowHow

  • 42

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies: Adult Dosing: Amqunate

    HowHow

  • 43

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies: Dosing in children: Amqunate

    HowHow

  • 44

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    Combination Therapies: Comparative Parameters

    AS+MQAS+lap / dap

    AS+Lumefantrine

    Recrudescence rate

    Gametocyte carriage

    Parasite clearance times [positivity after day 3]

    Fever duration [Fever after 3 days]

    DHA+Piperaquine

    AS+AQAS+SPParameters

    HowHow

  • 45

    WhatWhat

    WhoWho

    WhyWhy

    HowHow

    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.

    HowHow

  • Thank You!

    Emerging trends in the therapy of Malaria Better clarity, Better outcomesIntroductionCauseMalaria roadmap of todayAntimalarials Developed So FarAntimalarials on the HorizonTherapeutic Efficacy of SP in Africa: Evidence to Guide Action Antimalarial Drug ResistanceImplications in AfricaCombination Therapies: DefinitionCombination Therapies: As Defined by WHOCombination Therapies: As Perceived by WHOCombination Therapies: As Rejected by WHOCombination Therapies: PrinciplesCombination Therapies: Fixed Dose CombinationsObservations of International StudiesBenefits of Adding artemisinins to Current monotherapyMean parasite response with artemisinin derivativesWhy Not Artemisinin Derivatives As monotherapy?Artemisinins Under Review in ACTsArtemisinin studies Under ReviewArtemisinins with reference to DHAArtemisinins With Reference to DHA Quinine / ArtesunateQuinine / Artesunate: Conclusion:Artemether + LumefantrineArtemether + Lumefantrine Negative pointsArtemether + Lumefantrine Dosage observations Artemether + Lumefantrine Comparative studies Artemether + lumefantrine vs. Artesunate + mefloquineCombination Therapies: Alternatives: AQ + ARTCombination Therapies: Alternatives: AQ + S/PCombination Therapies: Alternatives:Combination Therapies: Conclusion:Amqunate studiesSlide 36Slide 37Slide 38Slide 39One Vital QuestionCombination Therapies: Brand: AmqunateCombination Therapies: Adult Dosing: AmqunateCombination Therapies: Dosing in children: AmqunateCombination Therapies: Comparative ParametersConclusionThank You!

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Emerging trends in the therapy of Malaria Better clarity, Better outcomes Dr. B. K. Iyer
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