Download - Emerging trends malaria

Emerging trends in the therapy of Malaria

Better clarity, Better outcomes

Dr. B. K. Iyer

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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

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Cause

Next to mosquitoes the biggest cause of malaria is

“Ignorance”

This is because success is influenced by resistance patterns

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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

Today’s review

20031990s1980s1970s1960s1950s1940s1930s<1930

Chlorproguanil-dapsone

Atovaquone-proguanil

HalofantrineArtemisininSulfa-Pyrimethamine

PyrimethamineProguanilMepacrinePamaquine

Artemether-lumefantrine

PyronaridinePrimaquineAmodiaquineChloroquineQuinine

Mefloquine

Artemether

Artesunate

Not adopted by malaria programs Being abandoned due to resistance

Antimalarials Developed So Far

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

20031990s1980s1970s1960s1950s1940s1930s<1930

Chlorproguanil-dapsone

Atovaquone-proguanil

HalofantrineArtemisininSulfa-Pyrimethamine

PyrimethamineProguanilMepacrinePamaquine

Artemether-lumefantrine

PyronaridinePrimaquineAmodiaquineChloroquineQuinine

Mefloquine

Artemether

Artesunate

Not adopted by malaria programs Being abandoned due to resistance

Antimalarials on the Horizon

Fixed DoseCombinations

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, preferablypreferably those containing an artemisinin derivative (ACT – artemisinin-based combination therapy).

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50

% F

ailu

res

Parasitological

Clinical

West Central East

THRESHOLD FOR CHANGE

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Therapeutic Efficacy of SP in Africa: Evidence to Guide Action

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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

INTERIM

S.Africa

Rwanda

DRC

Burundi

Zambia

Eritrea

Zanzibar

Cameroon

(AQ)

<1993 1998 1999 2000 2001 2002 2003

Coartem Burundi

Gabon

Comores

Mozambique

Senegal

Côted’Ivoire

CQ CQ+SP

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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

AIDSAIDS

Combination Combination therapytherapy

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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

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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

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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

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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

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Combination Therapies:Principles

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Principles

Dosages

Contra-

indications

Ease of

Use

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Combination Therapies: Fixed Dose Combinations

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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

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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

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Antimalarial drug resistance and combination chemotherapy, Philos Trans R Soc

Lond B Biol Sci. 1999 Apr 29;354(1384):739-49, White N.

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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

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Mean parasite response with artemisinin derivatives

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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

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Artemisinins Under Review in ACTs

Artemether Artesunate Dihydroartemisinin Arteether ArtefleneWhyWhy

Artemotil

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Artemisinin studies Under Review

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

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

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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.

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

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Artemisinins With Reference to DHA

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

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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).

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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%]

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Lancet, 27 August 2005

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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,

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Aug 31, 2005

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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): 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.

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Artemether + Lumefantrine Negative points

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1. 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.

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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.

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The Cochrane Database of Systematic

Reviews 2005 Issue 3

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

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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.

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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.

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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.

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

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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.

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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.

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Prices may come down as demand increases

Combination Therapies: Alternatives:

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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.

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WHO Information note draft 6 December 2004)

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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).

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

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Amqunate studies

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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.

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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.

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

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Amqunate studies

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

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

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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

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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.

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Combination Therapies: Brand: Amqunate

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Combination Therapies: Adult Dosing: Amqunate

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Combination Therapies: Dosing in children: Amqunate

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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

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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.

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Thank You!