Early and effective chemotherapy for malaria has a pivotal role in reducing morbidity and mortality especially since a vaccine is unlikely to emerge within the next decade. Multidrug resistance has been reported from most parts of the world and as a result, monotherapy or some of the available combination chemotherapies for malaria are either ineffective or less effective. New antimalarial regimens are, therefore, urgently needed and antimalarial combination chemotherapy is widely advocated. Antimalarial combinations can increase efficacy, shorten duration of treatment (and hence increase compliance), and decrease the risk of resistant parasites arising through mutation during therapy.
Combination therapy with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. The concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination.
Artemisinin based combinations are known to improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant parasites. The total effect of artemisinin combinations (which can be simultaneous or sequential) is to reduce the chance of parasite recrudescence, reduce the within-patient selection pressure, and prevent transmission.
| Anti Malarial Drug Combinations | |
| Artemisinin based combinations | |
| Artesunate + Chloroquine | |
| Efficacy | Very high chloroquine failure rates (>60%) and sub-optimal efficacy of the combination (<85% cure rate) |
| Status | Not approved; Not a viable option in areas with pre-existing moderate to high levels of P. falciparum resistance to Chloroquine |
| Artesunate + Amodiaquine | |
| Efficacy and advantages | Better efficacy than amodiaquine alone (cure rate >90%); Well tolerated |
| Disadvantages | ?Neutropenia; Pharmacokinetic mismatch |
| Dose | Artesunate 4mg/kg and amodiaquine 10mg base/ kg once a day 3 days |
| Status | Approved |
| Artesunate + Mefloquine | |
| Efficacy and advantages | In use for many years and the first-line treatment in several parts of SE Asia |
| Disadvantages | Pharmacokinetic mismatch; Mefloquine induced neuropsychiatric effects, cardiotoxic effects, incidents of vomiting in children; but combination with artesunate results in less adverse reactions than the use of mefloquine alone |
| Dose | Artesunate (4mg/kg once daily) for 3 days + mefloquine (25mg base/kg) as a split dose of 15mg/kg on Day 2 and 10mg/kg on Day 3. (Alternatively 8mg/kg mefloquine daily for three days) |
| Status | Not approved; Not considered a viable option as first-line therapy in Africa |
| Artesunate + Sulfadoxine-Pyrimethamine (SP) | |
| Efficacy and advantages | Well tolerated; Efficacy dependent on the level of pre-existing resistance to SP |
| Disadvantages | Pharmacokinetic mismatch; adverse effects to SP |
| Dose | Artesunate 4mg/kg once daily for 3 days and SP single dose of 25mg/kg and 1.25mg/kg respectively |
| Status | Approved (in areas where SP efficacy is high); Resistance to SP limits the use |
| Artemether + Lumefantrine (Coartem,TM RiametTM) | |
| Efficacy and advantages | As effective, and better tolerated, as artesunate plus mefloquine; No serious adverse reactions documented |
| Disadvantages | ?Irreversible hearing impairment |
| Dose | Artemether 1.5mg/kg and Lumifantrine 9mg/kg at 0, 8, 24, 36, 48 and 60 hours |
| Status | Approved; Not recommended for use in pregnancy and lactating women |
| Chlorproguanil + Dapsone + Artesunate (DacartTM) | |
| Status | Withdrawn at development stage by GSK for fears of hemolytic anemia in G6PD deficiency [See Press Release, News Report, Another Report] |
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| Non-Artemisinin based combinations | |
| Sulfadoxine-Pyrimethamine based combinations | |
| Sulfadoxine-Pyrimethamine (SP) | |
| Efficacy and advantages | Single dose; Cheap |
| Disadvantages | Drug resistance; Serious adverse effects |
| Dose | Sulfadoxine 25mg/kg and Pyrimethamine 1.25mg/kg as single dose |
| Status | Not approved; Considered as single drug |
| SP + Chloroquine | |
| Advantages | Cheap; Similar pharmacokinetic profiles, with varied modes of action on different biochemical targets in the parasite |
| Disadvantages | Drug resistance; Serious adverse effects to SP |
| Dose | Chloroquine 25mg/kg over 3 days; SP single dose as above |
| Status | Not approved; an be used where resistance to SP is not a problem |
| SP + Amodiaquine | |
| Advantages | Similar pharmacokinetic profiles |
| Disadvantages | Adverse effects of amodiaquine and SP |
| Dose | Amodiaquine 10mg/kg daily for 3 days; SP single dose as above |
| Status | Approved (In areas where efficacy of both amodiaquine and SP remain high – countries in West Africa) |
| SP + Quinine | |
| Advantages | Effective where resistance to SP is not a problem |
| Disadvantages | Drug resistance; Serious adverse effects |
| Dose | Quinine 15mg/kg 12 hourly for 3 days; SP single dose as above |
| Status | Not approved |
| SP + Mefloquin (FansimefTM) | |
| Advantages | Fixed dose pill, single dose |
| Disadvantages | Not an additive or synergistic combination; Each drug has a different pharmacokinetic profile; Expensive; Resistance known |
| Dose | Mefloquine 15mg/kg and SP as above single dose |
| Status | Not approved; Not recommended for general use since 1990 |
| Atovaquone + Proguanil (MalaroneTM) | |
| Advantages | Synergistic activity; Good safety and tolerability in children and adults |
| Disadvantages | High cost; Restricted availability; Contra-indicated in case of hypersensitivity or renal insufficiency |
| Dose | Atovaquone 20mg/kg and Proguanil 8mg/kg once daily for 3 days |
| Status | Approved; Highly efficacious against P. falciparum, including strains that are resistant to chloroquine and mefloquine, with cure rates of 94-100% |
| Chlorproguanil + Dapsone (LapDapTM) | |
| Advantages | Well tolerated; Efficacious |
| Disadvantages | Dapsone induced methaemoglobinaemia and haemolysis in G6PD deficiency; Potential cross-resistance with SP |
| Dose | Chlorproguanil 2mg/kg and Dapsone 2·5mg/kg once daily for 3 days |
| Status | Withdrawn by GSK for fears of hemolytic anemia in G6PD deficiency [See Press Release, News Report, Another Report] |
| Quinine based Combinations | |
| Quinine + Tetracycline | |
| Advantages | Efficacious |
| Disadvantages | 7-day course, multiple doses daily; Cinchonism; Tetracyclines contraindicated in children and pregnant women; Emergence of resistance |
| Dose | Quinine 10mg/kg 8 hourly and Tetracycline 4mg/kg 6 hourly for 7 days |
| Status | Not approved; Difficult to recommend as a first-line treatment for uncomplicated malaria |
| Quinine + Clindamycin | |
| Advantages | Good efficacy; Safe in children and pregnant women; Lesser risk of resistance |
| Disadvantages | Cinchonism |
| Dose | Quinine 15mg/kg 12 hourly and Clindamycin 20mg/kg in three doses for 3 days |
| Status | Not approved |
| New Combinations | |
| Piperaquine + Dihydroartemisinin + Trimethoprim (ArtecomTM) and ArtecomTM plus Primaquine (CV8TM) (CV = China-Viet Nam) | |
| Advantages | Efficacy consistently above 93% |
| Disadvantages | Animal toxicology studies indicate additive toxicity; No serious adverse events observed in human studies |
| Status | Trials; May prove to be more affordable |
| Chlorproguanil+ Dapsone + Artesunate (CDATM or Lapdap plusTM ) | |
| Status | No adequate data available yet |
| Fosmidomycin+ Clindamycin | |
| Advantages | Both drugs act on the parasite’s apicoplast; Rapid clearance and 100% cure rates reported |
| Status | Trials on |
- Clinical experience for many of the combinations is limited and more studies are needed
- Artemisinin-based combinations produce rapid clinical and parasitological cure, parasite resistance is yet to be documented, reduce gametocyte carriage rate, and are generally well tolerated. However, the cost of treatment could be higher by a factor of up to 10-fold and this may be a hindrance in poor communities.
- Based on available safety and efficacy data, the following therapeutic options are available now and have potential for deployment (in prioritized order) if costs were not an issue:
- Artemether-lumefantrine (CoartemTM)
- Artesunate (3 days) plus amodiaquine
- Artesunate (3 days) plus SP in areas where SP efficacy remains high
- SP plus amodiaquine in areas where efficacy of both amodiaquine and SP remain high. This is mainly limited to countries in West Africa.
- These combination options need continued documentation of safety and efficacy as part of any potential implementation process, especially among very young children, pregnant women, and breastfeeding mothers and their babies.
- Options that are not recommended for policy at this time include:
- Chloroquine-based combinations (CQ + SP and CQ + artesunate)
- One-day treatment of artesunate + SP
- Mefloquine-based combinations (e.g. mefloquine plus artesunate) in areas of high malaria transmission
- One-day treatment of artesunate plus mefloquine in the acute phase of a complex emergency or malaria epidemics
References:
- Antimalarial Drug Combination Therapy: Report of a WHO Technical Consultation. 4-5 April 2001. Available at http://mosquito.who.int/cmc_upload/0/000/015/082/use_of_antimalarials2.pdf
- http://www.paho.org/English/AD/DPC/CD/mal-adct.htm
- Kremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004 Jul 17;364(9430):285-94.
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