Author: Hayder Giha
Position: No occupation was given
Institution: College of Medicine and Health Sciences, Arabian Gulf University. and Malaria Research Centre
E-mail: gehaha2002@yahoo.com
Submitted Date: September 14, 2007
Published Date: September 18, 2007
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The intermittent preventive treatment (IPT) for malaria is currently employed for pregnant women and is being studied for infants (IPTi). O'Meara et al., 2006 [1] have used a mathematical model to study the implication of (IPT) on spread of drug resistance. The model predicts that, in high-transmission areas, drugs to which little or no resistance exists and drugs with long half-life, are not advisable for IPT and that IPTi rather than IPT in pregnancy is likely to accelerate the spread of resistance. Based on clinical and molecular data, we proposed the application of IPT (chloroquine) for reduction of fatal cerebral malaria in adults during epidemics in areas of low, seasonal and unstable malaria transmission.

The global climatic changes have a serious impact in human health [2], the effect is more pronounced in the poor countries predominantly in Africa and Southeast Asia. This year, 2007, the unprecedented floods in many countries might precipitate serious malaria epidemics. The semi-immune population living areas of hypo and mesoendemic malaria are more prone to develop severe complications during epidemics. In Sub-Saharan Africa the major complications that associates with fatal severe malaria (SM) are cerebral malaria (CM) and severe malaria anemia (SMA) [3]. In settings where the malaria transmission is seasonal and unstable e.g. Sudan, Ethiopia, Yemen and etc, the adults are prone to develop fatal SM, predominantly CM [4], while in hyperendemic regions children with SMA are the principal victims.

Chloroquine (CQ) was abandoned in most African countries and replaced by artemisinin-based combinations therapy (ACT), because of the progressively declining efficacy of the former. The major gene implicated in resistance to chloroquine (pfcrt) has been identified [5], and a role of another gene, pfmdr1, in augmenting the level of resistance has been proved [6]. The pfcrt mutation was found to be associated (linked) with sulphadoxine / pyrimethamine (SP)-resistance genes mutation, dhfr/dhps [7]. Recent work suggested that multiple pfcrt and or dhfr/dhps mutations are associated with reduced parasite fitness and virulence [7, 8], and that fatal CM is preferentially caused by CQ-sensitive parasites [8]. Furthermore, the multiple dhfr/dhps mutations enhance the immunological clearance of the parasites [9]. In addition, of the lessons learnt from the imported malaria among non-immune Europeans, is that patients who take prophylaxis are less likely to die of SM [10]. It is possibly that, chemoprophylaxis prevents new infections with sensitive strains but not with the resistant strains (mutant), and the later are less virulent and easily washed out by the immune system [8, 9].

For treatment of CQ sensitive parasites in SM, the QN is superior to CQ, mainly because QN have faster onset of action and stronger killing effect. Accordingly, the prophylaxis (before infection) with CQ might be comparable to QN treatment (during infection) for CQ sensitive infections (virulent strains). By considering all the above, CQ might be effective in reduction of CM death rate, and can be the rescue for floods aftermath. The other advantages of prophylaxis with CQ in this specific situation are:

1. low toxicity
2. low price
3. fair compliance
4. In the Sudan, CQ was formally withdrawn from malaria treatment protocols in 2004, so, the frequency of wild strains is expected to increase by 2007. In 2001, the frequency of pfcrt/pfmdr1 mutations was approximately 85%, while 60% of the deaths were caused by pfcrt/pfmdr1wild infections [8]
5. Finally, not much will be lost if this plan doesn’t work. However, people should be informed that this CQ is not for prevention of malaria but to reduce the fatality, and they should seek medical advice if they have fever.

The suggested dosage is to give full course presumptive treatment, followed by weekly smaller dose (5 mg/kg) until the epidemic comes down. The expected outcome will be 1. Reduced fatality attributed to CM but not that due to SMA 2. The selection of mutant parasites (resistant parasites) by CQ will keep boosting the immunity against malaria, unlike the complete parasite eradication (effective drugs) 3. The use of CQ by small children (less than 3-4 years) might increase the number of SMA cases, and the spread of the pfcrt/pfmdr1 gene mutations [1], so it is not advisable. This approach might not suits areas where malaria is hyper-endemic or the transmission is continuous. Finally, the use of CQ for prophylaxis is not going to replace the other preventive measures such as the use of the impregnated bed nets, insecticides or other control measures

Hayder A. Giha

1 Department of Medical Biochemistry, Faculty of Medicine and Medical Sciences, Arabian Gulf University (AGU), P.O. Box 26671, Manama, Kingdom of Bahrain.
2 Malaria Research Centre (MalRC) - Department of Biochemistry, and Department of Microbiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

References

1. Prudhomme O'Meara W, Smith DL, McKenzie FE (2006) Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria. PLoS Med 3(5): e141. At http://dx.doi.org/10.1371...
2. Pielke R Jr, Prins G, Rayner S, Sarewitz D (2007) Climate change 2007: lifting the taboo on adaptation. Nature 445: 597-608.
3. World Health Organization, Communicable Diseases Cluster (2000) Severe falciparum malaria. Trans R Soc Trop Med Hyg 94: S1–S90.
4. Giha HA, Elghazali G, A-Elgadir TM, A-Elbasit IE, Eltahir EM, et al. (2005) Clinical pattern of severe Plasmodium falciparum malaria in Sudan in an area characterized by seasonal and unstable malaria transmission. Trans R Soc Trop Med Hyg 99: 243-251.
5. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, et al. (2000) Mutations in the P. falciparum digestive vacuole trans-membrane protein pfcrt- and evidence for their role in chloroquine resistance. Mol Cell 6: 861-871.
6. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, (2000) Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403: 906-909.
7. Osman ME, Mockenhaupt FP, Bienzle U, Elbashir MI, Giha HA (2007) Field-based evidence for linkage of mutations associated with chloroquine (pfcrt/pfmdr1) and sulfadoxine-pyrimethamine (pfdhfr/pfdhps) resistance and for the fitness cost of multiple mutations in P. falciparum. Infect Genet Evol 7: 52-59.
8. Giha HA, Elbashir MI, A-Elbasit IE, A-Elgadir TM, ElGhazali GE, et al. (2006) Drug resistance-virulence relationship in Plasmodium falciparum causing severe malaria in an area of seasonal and unstable transmission. Acta Trop 97: 181-187.
9. A-Elbasit IE, Alifrangis M, Khalil IF, Bygbjerg IC, Masuadi EM, et al. (2007) The implication of dihydrofolate reductase and dihydropteroate synthetase gene mutations in modification of Plasmodium falciparum characteristics. Malar J 6: 108
10. Krause G, Schoneberg I, Altmann D, Stark K (2006) Chemoprophylaxis and malaria death rates. Emerg Infect Dis 3: 447-451.