To counter the threat of resistance of P. falciparum to monotherapies, and to improve treatment outcome, combinations of antimalarials are now recommended by WHO for the treatment of falciparum malaria.
Antimalarial combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. The concept is based on the potential of two or more simultaneously administered schizontocidal drugs with independent modes of action to improve therapeutic efficacy and also to delay the development of resistance to the individual components of the combination.
7.2.2 What is not considered to be combination therapy
Drug combinations such as sulfadoxine-pyrimethamine, sulfalene-pyrimethamine, proguanil-dapsone, chlorproguanil-dapsone and atovaquone-proguanil rely on synergy between the two components. The drug targets in the malaria parasite are linked. These combinations are operationally considered as single products and treatment with them is not considered to be antimalarial combination therapy. Multiple-drug therapies that include a non-antimalarial medicine to enhance the antimalarial effect of a blood schizontocidal drug (e.g. chloroquine and chlorpheniramine) are also not antimalarial combination therapy.
7.2.3 Rationale for antimalarial combination therapy
The rationale for combining antimalarials with different modes of action is twofold: (1) the combination is often more effective; and (2) in the rare event that a mutant parasite that is resistant to one of the drugs arises de novo during the course of the infection, the parasite will be killed by the other drug. This mutual protection is thought to prevent or delay the emergence of resistance. To realize the two advantages, the partner drugs in a combination must be independently effective. The possible disadvantages of combination treatments are the potential for increased risk of adverse effects and the increased cost.
7.2.4 Artemisinin-based combination therapy (ACT)
Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydro-artemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10 000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented.
EVIDENCE: trials comparing monotherapies with ACTsa
Interventions: single drug (oral AQ, MQ or SP) compared with single drug in combination with AS (both oral)
Summary of RCTs: one meta-analysis of 11 RCTs has been conducted. This found a clear benefit of adding 3 days of AS to AQ, MQ or SP for uncomplicated malaria. The combination treatment resulted in fewer parasitological failures at day 28 and reduced gametocyte carriage compared to the baseline value. Adding AS treatment for 1 day (6 RCTs) was also associated with fewer treatment failures by day 28 but was significantly less effective than the 3-day regimen (OR: 0.34; 95% CI: 0.24-0.47; p <0.0001).
Expert comment: the addition of AS to standard monotherapy significantly reduces treatment failure, recrudescence and gametocyte carriage.
Basis of decision: systematic review.
Recommendation: replace monotherapy with oral ACTs given for 3 days.
a See also Annex 7.1.
In 3-day ACT regimens, the artemisinin component is present in the body during only two asexual parasite life-cycles (each lasting 2 days, except for P. malariae infections). This exposure to 3 days of artemisinin treatment reduces the number of parasites in the body by a factor of approximately one hundred million (104 × 104 = 108). However, complete clearance of parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed. Thus the partner compounds need to be relatively slowly eliminated. As a result of this the artemisinin component is "protected" from resistance by the partner medicine provided it is efficacious and the partner medicine is partly protected by the artemisinin derivative. Courses of ACTs of 1-2 days are not recommended; they are less efficacious, and provide less protection of the slowly eliminated partner antimalarial.
The artemisinin compounds are active against all four species of malaria parasites that infect humans and are generally well tolerated. The only significant adverse effect to emerge from extensive clinical trials has been rare (circa 1:3000) type 1 hypersensitivity reactions (manifested initially by urticaria). These drugs also have the advantage from a public health perspective of reducing gametocyte carriage and thus the transmissibility of malaria. This contributes to malaria control in areas of low endemicity.
7.2.5 Non-artemisinin based combination therapy
Non-artemisinin based combinations (non-ACTs) include sulfadoxine-pyrimethamine with chloroquine (SP+CQ) or amodiaquine (SP+AQ). However, the prevailing high levels of resistance have compromised the efficacy of these combinations. There is no convincing evidence that SP+CQ provides any additional benefit over SP, so this combination is not recommended; SP+AQ can be more effective than either drug alone, but needs to be considered in the light of comparison with ACTs. The evidence is summarized next page.
EVIDENCE: trials comparing monotherapies with non-ACTsa
Interventions: oral SP+CQ compared with oral SP
Summary of RCTs: no RCTs with reported results for day 28 outcomes. Five subsequent RCTs found insufficient evidence of any difference in rates of treatment failure at days 14 and 21, respectively, between CQ+SP and SP alone, and gave no information on adverse events.
Expert comment: increasing resistance to CQ in all settings means that neither of the options is recommended.
Basis of decision: RCT.
Recommendation: do not use CQ+SP.
Interventions: oral SP+AQ compared with oral AQ or oral SP
Summary of RCTs: one systematic review of SP+AQ compared with AQ alone with day 28 follow-up found no significant difference in day 28 outcomes.
Three subsequent RCTs also found no significant differences in cure rates and levels of adverse events.
One systematic review of SP+AQ compared with SP alone, found no significant difference in rates of day 28 cure or adverse events. One subsequent RCT found higher rates of day 28 cure and mid-adverse events with the combination compared to SP alone.
Expert comment: in some areas where AQ+SP has been deployed, failure rates of this combination have increased rapidly.
Basis of decision: systematic review.
Recommendation: if more effective medicines (ACTs) are not available and AQ and SP are effective,b AQ+SP may be used as an interim measure.
a See also Annex 7.2.
b Efficacy >80%.
EVIDENCE: trials comparing ACTs with non-ACTsa
Interventions: oral ACTs compared with oral non-artesunate combinations
Summary of RCTs: 1 RCT compared AS(for 3 days)+SP with AQ+SP. The total failure excluding new infections at day 28 was similar in the 2 groups (13% in the AS+SP group compared to 22% in the AQ+SP group; OR: 0.59; 95% CI: 0.29-1.18); total number of recurrent infections, including reinfections, was higher with AS+SP (29% with AS+SP, 17% with AQ+SP, OR: 0.49; 95% CI: 0.27-0.87).
Expert comment: the above result is probably due to the efficacy of AQ that remains high, while SP failure is on the increase. In areas where AQ+SP has been adopted as first-line treatment, the impression is that there has been rapid development of resistance to AQ. This also makes both AQ and SP unavailable for use as an ACT component.
Basis of decision: expert opinion.
Recommendation: if more effective ACTs are not available and both AQ and SP are effective, b then AQ+SP may be used as an interim measure.
a See also Annex 7.3.
b Efficacy >80%.