2.1 Definitions

Combination therapy with antimalarial drugs (CT) is the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite.

Artemisinin-based combination therapy (ACT) is antimalarial combination therapy with an artemisinin derivative as one component of the combination.

Combination therapies can be either fixed-combination medicinal products, in which the components are co-formulated in the same tablet or capsule, or multiple-drug therapy, in which the components are co-administered in separate tablets or capsules.

Note 1. In accordance with these definitions, the following multiple-drug therapies are NOT considered to be combination therapy:

• use of an antimalarial drug with a non-antimalarial drug that may enhance its action
  (e.g. chloroquine plus chlorpheniramine),
• use of a blood schizonticidal drug with a tissue schizonticidal or gametocytocidal drug
  (e.g. chloroquine plus primaquine).

Note 2. Certain medicinal products that strictly speaking fit the criteria of synergistic fixed-dose combinations are operationally considered as single synergistic products in that neither of the individual components in itself would be given alone for antimalarial therapy. Examples include:

• sulfadoxine-pyrimethamine,
• chlorproguanil-dapsone,
• atovaquone-proguanil.

2.2 Rationale for the use of combination therapy

Fixed-combination and multiple-drug therapies are used to exploit the synergistic and additive potential of individual drugs. The aim is to improve efficacy and to retard the development of resistance to the individual components of the combination. This concept has been realized in multiple-drug therapy for leprosy, tuberculosis and cancer and, more recently, in antiretroviral treatments. It has also already been realized to some extent in the field of malaria with the development of such drugs as sulfadoxine-pyrimethamine, atovaquone-proguanil and mefloquine-sulfadoxine-pyrimethamine.

Because of the continued increase of resistance to antimalarial drugs in many regions of the world, with the resultant effect on morbidity and mortality (23), it is essential to ensure rational deployment of the few remaining effective drugs, to maximize their useful therapeutic life while still ensuring that safe, effective and affordable treatment is accessible to those at risk. This requirement has resulted in a re-examination of the potential of combinations of existing products and the development of new combination drugs.

The rationale for the impact of CT on drug resistance is based on the assumption that drug resistance essentially depends on mutation. Provided that the constituent drugs administered in the combination have independent modes of action, the probability that a mutant will arise that is simultaneously resistant to both drugs is the product of the respective mutation rates, multiplied by the number of parasite cells exposed to the drugs (8, 10, 44). For example, if two drugs are used, and for each one a single mutational event confers complete resistance and such events occur with a frequency of 1:10 ¹⁰ nuclear divisions, then the probability of a mutation resistant to both drugs is 1:10 ²⁰ . The number of asexual parasites (parasite biomass) during an acute malaria infection is usually between 10 ⁹ and 10 ¹⁴ (44).

2.3 Artemisinin-based combination therapy

The particular features of ACT relate to the unique mode of action of the artemisinin component, which includes the following:

• rapid and substantial reduction of the parasite biomass,
• rapid parasite clearance,
• rapid resolution of clinical symptoms,
• effective action against multidrug-resistant P. falciparum,
• reduction of gametocyte carriage, which potentially reduces transmission of resistant alleles.

There are also few reported adverse clinical effects (45), although preclinical toxicology data on many artemisinin derivatives are limited.

Because of the short half-life of artemisinin derivatives, their use as monotherapy requires daily doses over a period of 7 days. Combination of one of these drugs with a longer half-life partner antimalarial drug allows a reduction in the duration of antimalarial treatment while at the same time enhancing efficacy and reducing the likelihood of resistance development. The major immediate effect of the artemisinin component is to reduce the parasite biomass. The residual biomass is exposed to maximum concentrations of the partner drug, well above its minimum inhibitory concentration, resulting in a lesser likelihood of resistant mutations breaking through.

In most of the artemisinin-based combinations currently in use or being evaluated, e.g. artesunate-mefloquine, the partner drug is eliminated slowly. The partner drug is therefore unprotected once the artemisinin has been eliminated from the body and operates a selective pressure on new infections. The implications of this "pharmacokinetic mismatch" are not fully understood at present, particularly in areas of high transmission in Africa. The safest approach is to use a drug partner that has a residual half-life as short as possible, while still enabling parasite clearance with a 3-day treatment. However, this is difficult to achieve given the limited range of antimalarial drugs available.

There is a growing interest in using antimalarial combinations containing an artemisinin derivative as first-line treatment. The aim is to provide efficacious and safe antimalarial drug treatment while probably delaying the onset and spread of resistance to both drugs in the combination. This interest results from experience with the combination of artesunate and mefloquine on the Thai-Myanmar border (12, 13, 46-49). Following the introduction of the combination there have been four principal clinical and epidemiological effects:

• the efficacy of the combination has exceeded 95% at a time when high-dose mefloquine was showing a failure rate of approximately 25%,
• this high efficacy has been sustained over the past 7 years,
• the transmission of P. falciparum has been reduced (with reduced gametocyte carriage from the artesunate),
• the in vitro sensitivity of mefloquine has increased, suggesting that the combination has reversed the previous decline in mefloquine sensitivity.

These studies have been conducted in areas where there is a high level of medical service provision and malaria transmission is low. It is not yet known whether similar results can be achieved in Africa and other high-transmission regions. Moreover, evidence of the effectiveness of ACT in delaying the development of resistance is not yet available in Africa. Clinical trials using combinations of artesunate with amodiaquine, chloroquine, sulfadoxine-pyrimethamine or mefloquine are currently in progress to assess the efficacy and safety of ACT for treating uncomplicated falciparum malaria in Africa, South America and Asia.

Factors for and against the introduction of ACT are summarized in Table 5. ACT should be considered in two different settings. In places where the combination is presently more efficacious than available monotherapies, such as parts of South-East Asia, it has a clear role. In areas where monotherapy is still efficacious but where this may change if the drug concerned is not protected from resistance, the justification for introducing ACT is less clear at the operational level. Although the general theory behind the promotion of ACT is widely accepted, doubts remain about the quantitative impact it will have in real-life situations. Ministries of health are therefore reluctant to commit to a high-cost ACT strategy where the merits of the different options available remain unclear and significant operational barriers still need to be overcome.

Time is a major constraint to this process: a change is needed now in several countries where chloroquine has poor efficacy. There are profound concerns that a change from chloroquine to sulfadoxine-pyrimethamine monotherapy might affect the future utility of some ACTs, in particular sulfadoxine-pyrimethamine plus artesunate, and chlorproguanil-dapsone (LapDap) plus artesunate. Urgent information is needed on the effectiveness of chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine as a possible interim measure while attempts are made to assess and improve on the cost-effectiveness of ACTs in the African context.

2.4 Implementation of combination therapy--operational issues

It would appear logical that, if CT is to delay the development of resistance, existing monotherapy with either of its components should cease, although this has not been rigorously proven. In order to minimize monotherapy with the components of a particular CT, therefore, it is necessary to guarantee consistent access to the CT and restrict access to related drugs throughout the health sector, both private (formal and informal) and public. Fixed-combination products are preferred to multiple-drug therapy as this will improve the ease of use and compliance, while minimizing the potential use of components of the combination as mono-therapy. Price to the user and to the health system must be competitive with alternatives and affordable to the poorest, otherwise the public health value of CT may be compromised.

Other areas where improvement is critical for successful implementation of CT relate to generic issues of policy implementation. They include training and motivation of health workers, public confidence in and use of health facilities, reliable drug supplies, a regulated private sector and good quality control to prevent infiltration of counterfeit drugs.

With the increased use of new combinations, safety assessments, monitoring of potential drug interactions and strategies for the treatment and protection of pregnant women are urgently required. Similar strategies for application in complex emergency situations, with a particular emphasis on compliance, are also essential. With support from external agencies, implementation of CT in the short term, in defined areas, may be feasible. However, greater efforts and resources are needed in isolated areas with poor services to ensure the sustainability of policies and programmes.

It is anticipated that, in some settings, CT could be introduced to protect the life span of a still effective antimalarial monotherapy. In these cases, CT will be of long-term benefit to the community rather than of immediate benefit to the patient. The substantially higher cost of CTs is probably the major obstacle to the implementation of this strategy, especially in sub-Saharan Africa. As a public health measure subsidies could be justified, but assurance is needed that financial mechanisms will be sustainable.