2.1 Co-administered (non-fixed) combinations used in the past or present

Table 20 shows the status of combinations in this category.

Chloroquine or amodiaquine plus sulfadoxine-pyrimethamine:

These combinations have been shown to have higher cure rates than sulfadoxine- pyrimethamine alone (332).

Artemether or lumefantrine:

This combination is currently used as the first-line treatment in KwaZulu Natal, North Province of South Africa.

2.2 Co-administered (non-fixed) combinations under trial involving available drugs

Table 21 shows the status of combinations in this category.

Sulfadoxine-pyrimethamine plus artesunate

Sulfadoxine-pyrimethamine is expected to fail rapidly in areas of chloroquine resistance in East Africa and more gradually in West Africa. The combination of sulfadoxine-pyrimethamine with artesunate may reduce the rate of emergence of sulfadoxine-pyrimethamine resistance. In two trials in Africa (in Gambia [224, 225] and Kenya) a 3-day artesunate regimen seems to be necessary to optimize treatment efficacy. In Gambia, the effect on gametocyte carriage was similar with either one or three days of artesunate.

It is important to decide whether sulfadoxine-pyrimethamine resistance has progressed too far in parts of Africa to warrant the high cost of implementing artemisinin-based combination therapy that includes sulfadoxine-pyrimethamine (SP ACT). Sulfadoxine-pyrimethamine resistance is strongly associated with mutations in parasite dhfr, the gene that encodes parasite dihydrofolate reductase (DHFR) (333-335). While three mutations are now common in many parts of Africa (333, 336), a fourth mutation, providing complete resistance to sulfadoxine- pyrimethamine, has not been reported, although codon 164 mutations may already exist at low frequency (337). Using epidemiological modelling, it is possible that SP ACT will still delay the rate of selection of the quadruple mutant, if implemented widely before this genotype becomes prevalent (IM Hastings, WM Watkins, NJ White, unpublished data). However, dhfr triple mutant infections would still be common, requiring treatment with SP ACT, since this genotype is of borderline susceptibility to sulfadoxine-pyrimethamine (338). It is debatable whether, with this background of sulfadoxine-pyrimethamine resistance, SP ACT should be used (with all its implications) or whether other more efficacious combinations should be introduced. Candidates include amodiaquine ACT, artemether-lumefantrine and ACTs under development e.g. LapDap ACT.

It is important to take into consideration the fact that it would be extremely difficult to eliminate sulfadoxine-pyrimethamine monotherapy from the market as it is cheap, well-known and produced by many generic drug producers.

Amodiaquine plus artesunate

The 3-day regimen of both components is currently co-administered although coformulation is feasible. Amodiaquine has a greater efficacy than chloroquine in Africa. However, the rate of development and spread of amodiaquine resistance is unknown and cross-resistance with chloroquine may be a limiting factor for long-term efficacy. In addition, amodiaquine toxicity following repeated doses requires further evaluation. In clinical trials of around 960 patients, amodiaquine as monotherapy or combined with 3 days of artesunate was well tolerated. There was no evidence of significant hepatotoxicity. However, it is not yet known whether hepatotoxicity may develop after repeated treatments.

2.3 Potential combinations under consideration or trial with drugs that are not yet available

Table 22 shows the status of combinations in this category.

Chlorproguanil-dapsone (Lapdap)

This is a fixed-ratio synergistic drug association that has been shown to be efficacious in field trials in patients whose P. falciparum infections have failed to respond to sulfadoxine- pyrimethamine, since parasites with the triple dhfr mutation retain sensitivity to Lapdap. However, it is likely that it will not be effective against parasites with a quadruple dhfr mutation. The half-life is much shorter than that of sulfadoxine-pyrimethamine and a 3-day treatment is required. As both chlorproguanil and dapsone are rapidly eliminated, the combination is likely to exert a small selection pressure. Multicentre phase III trials are under way in Africa and preclinical safety testing is at an advanced stage. The combination is expected to be available in early 2002.

Chlorproguanil-dapsone-artesunate (Lapdap plus)

Phase I and phase II trials with Lapdap plus artesunate are due to start late 2001.

Pyronaridine-artemisinin derivative

This is being developed as a fixed combination. The rate of development of resistance was high in the mouse model. If a dosage regimen can be designed with a maximum of three daily doses, this may become a practicable ACT regimen.

Dihydroartemisinin-piperaquine-trimethoprim (Artecom ^®)

This has advantages over mefloquine plus artesunate. It is cheaper, has fewer adverse effects, and is available as a co-formulated tablet. Piperaquine has a short half-life.

Dihydroartemisinin-piperaquine-trimethoprim-primaquine (CV8)

This is the co-administration of primaquine and Artecom ^®.