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
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
Therapeutic Efficacy of SP in Africa: Evidence to Guide Action West Central East THRESHOLD FOR CHANGE 15
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
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
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
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
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.
Atovaquone / proguanil &
Combination Therapies: Principles What Dosages Contra- indications Ease of Use Principles
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
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,
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.
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.
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.
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.
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.
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.