Current challenges in drug-resistant malaria
NJ Gogtay1, NA Kshirsagar1, AB Vaidya2,
1 Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India
2 Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, USA
N J Gogtay
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai
|How to cite this article:|
Gogtay N J, Kshirsagar N A, Vaidya A B. Current challenges in drug-resistant malaria.J Postgrad Med 2006;52:241-242
|How to cite this URL:|
Gogtay N J, Kshirsagar N A, Vaidya A B. Current challenges in drug-resistant malaria. J Postgrad Med [serial online] 2006 [cited 2020 Jul 6 ];52:241-242
Available from: http://www.jpgmonline.com/text.asp?2006/52/4/241/28142
Malaria is an ancient disease that has influenced human evolution and history. Though the malaria parasite cycle was discovered in 1897 and the concept of eradication was adopted by the World Health Organization in 1955, the disease continues to remain a major public health problem. Most estimates suggest the global annual estimate of 300-500 million clinical cases and 2-3 million deaths. Four parasite species account for most human malaria infections worldwide- P. falciparum, P. vivax, P. malariae and P. ovale . The biology of each parasite presents unique challenges for diagnosis, management, drug development and policy-making. The present issue of the journal contains five articles by participants at a National Consultation on Drug Resistance - malaria, TB and HIV-AIDS held in September 2005 in Mumbai (Bombay), which touch upon a multitude of challenges in malaria control.
Drug resistance is seen in both P. vivax and P. falciparum . With vivax, resistance to the first-line drug chloroquine has been reported from Papua New Guinea, Irian Jaya (Indonesia), parts of Asia including India and South America.,, The low prevalence of 1-2% resistance in vivax still permits the use of chloroquine as the drug of first choice in these patients. This is particularly important for countries like India where between 60-70% of the cases are caused by vivax. However, the problem of morbidity associated with relapses of vivax malaria is of greater concern and this was addressed by several speakers at the meeting. Primaquine, an 8-aminoquinoline is currently the drug of choice for prevention of relapses and is recommended by the World Health Organization in the dose of 15 mg/d for 14 days. While this appears to prevent relapses in the majority of cases, sporadic reports and a randomized controlled trial with polymerase chain reaction genotyping have documented possible resistance to this regime.,
There are significant difficulties, however, in classifying the secondary parasitemia as recrudescence, relapse or re-infection in geographical regions where determination needs to be made in the face of continued transmission. Genotyping of parasites from the initial and subsequent episodes of vivax malaria with highly polymorphic markers could provide important information. If the genotypes of parasites from the primary and subsequent malaria episodes are identical, it may be safe to assume that it is either recrudescence or relapse. On the other hand, different genotypes of the primary and subsequent parasites could be due to new infection or recrudescent or relapsing parasites that happen to be emerging from an initial mixed genotype infection., Thus the estimates of drug failure based on identical genotypes of parasites from subsequent infections may be underestimates and such observations should be carefully evaluated prior to deciding treatment policies. Other antimalarials that have been assessed as antirelapse include azithromycin, which was shown to be ineffective in a small study, elubaquine (formerly bulaquine or CDRI 80/53), which is marketed as antirelapse in India and tafenoquine. The limited number of options for antirelapse in the face of primaquine resistance warrant the search and development of other antirelapse drugs with ongoing monitoring of primaquine effectiveness.
Chloroquine was introduced in the 1940s, but today resistance to the drug occurs wherever falciparum occurs. Switch to the next first-line, antifolate sulfadoxine pyrimethamine, has led to declining sensitivity to this combination as well in several parts of the world. Resistance commonly develops within 10-15 years after an antimalarial is introduced. However, resistance to mefloquine was reported as early as five years after its introduction as a prophylactic agent in parts of Thailand and atovaquone resistance was reported in the same year of its introduction., With resistance developing to both inexpensive and the more expensive monotherapy agents, combination therapy with drugs with differing mechanisms of action is now the preferred approach to the management of malaria. The most widely advocated combinations are the ACTs (Artemisinin-based combination therapies). The artemisinins act rapidly, are safe and well tolerated, have a high intrinsic effectiveness, reduce gametocyte carriage and thus are good transmission blocking agents. The choice of the artemisinin and its partner drug have led to several ACTs being evaluated. Artemether-lumefantrine is a co-formulated ACT that is highly efficacious and may countries in Africa now use this combination. Artesunate-mefloquine was recently introduced in Burma as first-line treatment and DHA-piperaquine showed similar efficacy to Artesunate-mefloquine although the latter was less effective in preventing gametocytemia. The choice of the appropriate ACT for falciparum malaria and national policy would thus need the results of more such comparisons and also comparisons with non-ACT combinations.
Green et al . in this issue have also addressed the problem of counterfeiting in malaria. The types of counterfeiting include use of fake artesunate holograms, "artesunate" tablets containing chloroquine, but no artesunate and "mefloquine" tablets containing sulfadoxine pyrimethamine but no mefloquine., The use of antimalarials not containing the active ingredient or containing less than the specified amount (substandard drugs) would result in inefficacy and thus significant morbidity and mortality. At the other end of the spectrum, too much of the active ingredient can also lead to toxicity, for example with drugs like quinine that have a narrow therapeutic margin., It is likely that the high cost of ACTs and the large consumption and use of antimalarials in tropical countries has encouraged their counterfeiting. Against this backdrop, the work by Ro et al and the production of artemisinic acid in engineered yeast is particularly encouraging. The engineering Saccharomyces cerevisiae by the introduction of just three Artemisia genes resulted in the production of a high concentration of artemisinic acid. Optimizing this process and scaling up the production could eventually lead to a larger availability and reduction in costs of ACTs.
Drug-resistant malaria remains the greatest challenge to any malaria-control program. The focus of management today relies on the use of combinations rather than monotherapy. Since the parasite has to mutate at several sites for it to become resistant to the combination, this prolongs the life of the drugs used. The current drug development portfolio in malaria includes a wide range of combinations such as chloroproguanil-dapsone-artesunate, co-artemether (artemether-lumefantrine) and Dihydroartemisinin-piperquine among others. The development of individual drugs such as isoquine and aminoquinoline with an improved safety profile, DB289 an aromatic diamidine and OZ277 a synthetic artemisinin derivative hold the promise that new drugs and new drug combinations will become widely available in the next few years. It is also important to remember that while advances in science may hold promise for the management of the disease, economics always seems to dictate policy, particularly in developing countries. The impact of such potentially imperfect policy on drug resistance emergence and disease management remains significant.
|1||WHO. Malaria fact sheet no 94. World Health Organization: Geneva; 1996. |
|2||Baird JK. Chloroquine resistance in Plasmodium vivax . Antimicrob Agents Chemother 2004;48:4075-83.|
|3||Garg M, Gopinathan N, Bodhe PV, Kshirsagar NA. Vivax malaria resistant to chloroquine- case reports from Bombay. Trans R Soc Trop Med Hyg 1995;89:656-7.|
|4||Philips EJ, Keystone JS, Kain KC. Failure of combined chloroquine and high-dose primaquine therapy for Plasmodium vivax malaria acquired in Guyana, South America. Clin Infect Dis 1996;23:1171-3.|
|5||Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis 2004;39:1336-45.|
|6||Rajgor DD, Gogtay NJ, Kadam VS, Kamtekar KD, Dalvi SS, Chogle AR, et al . Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India. Trans R Soc Trop Med Hyg 2003;97:438-40.|
|7||Craig AA, Kain KC. Molecular analysis of Plasmodium vivax from paired primary and relapse infections . J Infect Dis 1996;174:373-9.|
|8||Kirchgatter K, del Portillo HA. Molecular analysis of Plasmodium vivax relapses using the MSP1 molecule as a genetic marker. J Infect Dis 1998;177:511-5. |
|9||Ranque S, Badiaga S, Delmont J, Brouqui P. Triangular test applied to the clinical trial of azithromycin against relapses in Plasmodium vivax infections. Malar Jr 2002;1:13.|
|10||Gogtay NJ, Kamtekar KD, Dalvi SS, Chogle AR, Aigal U, Kshirsagar NA. Preliminary report of the evaluation of the gametocytocidal action of bulaquine, in adult patients with acute, Plasmodium falciparum malaria. Ann Trop Med Parasitol 2004;98:525-8. |
|11||Walsh DS, Wilairatana P, Tang DB, Heppner DG Jr, Brewer TG, Krudsood S, et al . Randomized trial of 3-dose regimens of tafenoquine (WR238605) versus low-dose primaquine for preventing Plasmodium vivax malaria relapse. Clin Infect Dis 2004;39:1095-103. |
|12||Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Inf Dis 2002;2:209-18.|
|13||Greenwood BM, Bojang K, Whitty CJM, Targett GA. Malaria. Lancet 2005;365:1487-98.|
|14||Kremsner PG, Krishna S. Antimalarial combinations. Lancet 2004;364: 285-94.|
|15||Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, et al . Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunat-mefloquine in falciparum malaria: An open label randomized comparison. Lancet 2006;367:2075-85.|
|16||Duffy PE, Mutabingwa TK. Artemisinin combination therapies. Lancet 2006;367:2037-9.|
|17||Green MD. Antimalarial drug resistance and the importance of drug quality monitoring. J Postgrad Med 2006;52:288-90.|
|18||Rozendaal J. Fake anti malarials circulating in Cambodia. Mekong Malaria Forum 2000;7:62-9.|
|19||Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, et al . Manslaughter by fake artesunate in Asia- will Africa be next? PloS Med 2006;3:e197.|
|20||Taylor RB, Shakoor O, Behrens RH, Everard M, Low AS, Wangboonskul J, et al . Assessment of pharmacopoeial quality of drugs supplied by Nigerian pharmacies . Lancet 2001;357:1933-6.|
|21||Newton PN, Green MN, Fernandez FM, Day NPJ, White NJ. Counterfeit anti-infective drugs. Lancet Inf Dis 2006;6:602-13.|
|22||Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, et al . Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 2006;440:940-3.|
|23||Biagini GA, O'Neill PM, Bray PG, Ward SA. Current drug development portfolio for antimalarial therapies. Curr Opin Pharmacol 2005;5:473-8.|