Department of Pharmacology and Therapeutics, University of Ibadan, Nigeria.
Dr. O.S. Michael
Department of Pharmacology and Therapeutics,
University of Ibadan,
Artemisinin based combination therapies (ACTs) are the corner stone of current efforts aimed at the management and control of malaria globally.1 In 2004, Nigeria adopted the recommendation of the World Health Organization and made two ACTs (artemetherlumfanthrine and artesunate Amodiaquine) the first line malaria therapies. Several studies have confirmed the high efficacies of these therapies.2 However, in 2009, resistance to Artemisin was reported from South-east Asia.3 Since then, fears of resistance to artemisinin in sub-saharan Africa have been entertained. Recent publications from workers in Nigeria are pointing towards a decline in malaria parasite susceptibility to artemisinin-based combination therapies.4 These reports are worrisome and there is a need for interventions and methods that will delay the development of artemisinin resistance in the sub region. This letter describes an observation that suggests the need for prolonged follow up of malaria patients after treatment with artemisinin-based therapies in order to monitor properly the pattern of recrudescence to ACT therapies. The following report will contribute to background data and the need for prolonging the follow up period in antimalarial studies that may be essential to the monitoring of recent trends to artemisinin-based therapies in Nigeria.
In a study conducted at the University College Hospital, Ibadan, in Southwest Nigeria in 2004, one hundred and ten (110) children aged below 12 years (mean age 5.9 ± 2.9 years with acute uncomplicated malaria received Artesunate-Mefloquine (AMq) and were followed up for 42 days. The study was approved by the Institutional Ethics Review Board and all participants gave written informed consent. The follow-up schedule included blood smears for microscopy and Polymerase Chain Reaction (PCR) for genotyping of parasites on days 1, 2, 3, 7, 14, 21, 28, 35, and 42. Enrolled children had parasitemia of 2000/ uL or greater. The children were treated with a standard dose of Artesunate (4mg/kg) and Mefloquine (25mg/kg) combination for three days. Drugs were administered orally. Parasite clearance time in days before parasite cleared from the peripheral blood film was determined. Parasite genomic DNA was extracted from blood samples collected on filter paper using the Chelex extraction method according to the method described by Plowe et al 1995.5 In the study, polymorphism in block 3 of merozoite surface protein 2 (MSP2) in P. falciparum isolates was used for parasite genotyping. Analyses of treatment outcome (reinfection vs. recrudescence) was carried out using parasite MSP2 loci that exhibited repeat numbers of polymorphisms to detect the complexity of infection in individual patient isolate as well as distinguish true treatment failure (recrudescence) from new infection
The results showed that the geometric mean parasite density was 85,089 parasites/μL, parasite clearance time was 1.4 ± 0.5 days and parasite reduction ratio was 75.4 x 103 per day for the children studied. During the course of follow-up children remained without patent parasitemia until day 21 at which time nine late treatment failures occurred as shown in the table. Analysis of parasite genotypes showed that five of the late treatment failures were recrudescence, while four were re-infections. There was no occurrence of mixed re-infection and recrudescence in any of the children that failed therapy.
The occurrence of late parasite recrudescence was unexpected at the time the study was carried out. At that time, there was a general tendency to attribute parasite re-infections to late treatment failures and recrudescence to treatment failure before day 14 of antimalarial therapy. At about the same period, studies starts showing that distinguishing re-infection and recrudescence was better done by molecular differentiation and not by attributing late treatment failures to re-infection and early treatment failures to recrudescent parasites.6 In light of recent decline in susceptibility to ACTs in Nigeria4 it has become imperative suggest compliance to a follow up period of 42 days minimum and mandatory molecular differentiation of parasite recrudescence and reinfection in all antimalarial studies. The relevance of longer durations of follow up in the setting of current malaria drug trials have been described in a few studies7, however studies are still being conducted in the sub-region and globally with follow up periods of 28 days, many times on account of financial implications and participants’ inability to completing the study.