Assessment of Antimalaria Drugs Susceptibility Testing for an Effective Management of Infected Patients in Sub-Sahara Africa

Malaria incidence has increased two- to three-folds over the past four decades, and nearly half the world's population now lives in regions endemic for malaria: In Asia, Africa, and South America. A global annual estimate of 300-500 clinical cases of malaria and mortality in the range of 1-2 million is reported, 90% of which occurs in sub-Saharan Africa. In Cameroon, malaria remains the number one public health problem with more than one million five hundred cases and three thousand one hundred and sixty two deaths in health facilities per year. Indeed, 45-50% of consultations, 23% of hospitalizations and 35% of deaths among children under 5 years are attributable to malaria Early diagnosis and treatment for malaria remain the most acceptable strategy for malaria control. Mortality is rising and approaching three million malarial deaths each year, in large parts because of increasing resistance to antimalarial drugs. The emergence and spread of P. falciparum resistance to conventional monotherapies such as chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), sulfadoxine-pyrimethamine (SP) resulted in the request of more effective and accessible antimalaria drugs to the entire population living in endemic areas.

In Cameroon, prior to 2002, CQ and SP were the first and second line antimalarial drugs respectively. Studies conducted in different ecological settings in Cameroon revealed marked decline of these drugs with 67% clinical failure for CQ alone . This led to an interim adoption of AQ by the Ministry of Public Health. A series of randomised, open controlled trial revealed that AQ was still effective when administered as monotherapy or in combination with SP since only 10.2 %, 13.6 % and 0% clinical failures were recorded for AQ, SP and SP+AQ respectively. However, studies conducted in Guinea Savannah showed decline rates of these antimalarials drugs with clinical failures of 40%, 20%, and 13.6% for AQ, SP and AQ+SP combination.

Widespread resistance of malaria parasite to these commonly available antimalaria drugs has necessitated country to review and deploy new antimalarial drug policies to ensure effective case management. The World Health Organization (WHO) currently recommends artemisinin-based combination therapies (ACTs) as the best first-line treatment for uncomplicated falciparum malaria, but studies to ensure that current regimens are optimal are incomplete. Artemisinine-based combination therapies (ACTs) are most preferred for their enhancement of efficacy and their potential to lower malaria incidence and the rate at which resistance emerges and spread\. Due to their rapid clearance time, treating early cases of uncomplicated malaria with ACTs may prevent its progression to severe malaria with consequent reduction in severe cases and malaria mortality rate. Although the National Malaria Control Programme (NMCP) of Cameroon adopted amodiaquine plus artesunate (AQ+AS) and arthemether plus lumefantrine (ART+LUM) for the treatment of uncomplicated malaria in 2004, there was no local data in support of the policy. In series of subtrials to constitute a database of anti-malarial drug efficacy in Cameroon, AQ was proposed to be the most rational partner of artesunate; likewise, a single arm study provided preliminary evidence of safety and efficacy of AQ+AS but with low statistical power to detect rare events and no PCR corrections to distinguish re-infection from recrudescence. Meta-analysis studies have shown ART-LUM to be highly effective and safe when the twice daily doses (total of six doses) are administered under supervision, but there are concerns that six doses of ART-LUM over three days may reduce compliance. Nevertheless, relatively few numbers of patients complained of physical fatigue during ART-LUM treatment but trials comparing it to order ACTs are few. AS+AQ combination is less expensive and subsidized by the Cameroonian Government, it is believed that its cure rate may be lower than that of ART-LUM because of parasite resistance to AQ and as such, its inclusion in ACTs is likely going to fail. In addition, the minor, transient side effects of AQ may lead to poor compliance and subsequent decline in AQ efficacy. In Southeast Asia, where P. falciparum is the most drug-resistant in the world, three-day artesunate-mefloquine treatment is generally the preferred treatment for uncomplicated malarial infection. Studies in Laos, suggest that artesunate plus mefloquine (AS-MQ) and ART-LUM combinations are both effective and are superior to CQ plus SP in the treatment of uncomplicated falciparum malaria. However, ASMQ has been limited by the high cost, the frequency of adverse effects associated with mefloquine, and the lack of a formulation combining both antimalarials in a single tablet. In addition, reduced efficacy of artesunate-mefloquine has been reported recently from the southeastern border of Thailand.

Artemether plus lumefantrine has fewer adverse effects but is also relatively expensive. A global analysis of a series of randomized studies of anti-malarial treatment efficacy conducted in Cameroon between 2003 and 2007 ART-LUM to be the most effective ACT with no treatment failure due to recrudescence (98.3% cure rate PCR corrected), followed by dihydroartemisinin-piperaquine with 92.7% cure rate. After PCR adjustment, 28 days cure rates was 91.7% for AS-SP 88.7% for artesunate-amodiaquine, and 76% for artesunate-chlorproguanil-dapsone. Clinical trials in Cambodia and Vietnam suggest that the dihydroartemisinin plus piperaquine (DHA+PQ) combination is highly effective against P. falciparum parasites with few adverse effect in both children and adult. In Cambodia, the 28-days cure rates were 98.6% in children and 92.3% in adult and in Vietnam, using dihydroartemisinin-piperaquine-trimethoprim combination, the 56-days cure rates in children and adults were 97-98% (Tran et al., 2004). In addition, it is relatively inexpensive compare to other ACTs, at 1 $ US per treatment course (Mutabingwa et al., 2005).

Therefore if it is demonstrated that DHA-PQ is an effective antimalaria in Cameroon, with fewer adverse effects in comparison to AS-MQ and ART-LUM, it may be an alternative treatment available to the Government of Cameroon with the advantages of being coformulated and available at lower cost than the other ACTs.