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Treatment failure and resistance to sulfadoxine-pyrimethamine in Malawi
- Pascal RINGWALD (12 March 2004)
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Is sulfadoxine-pyrimethamine safe as a first line therapy
- Zaki Hussain Khan (18 March 2004)
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Sulfadoxine-pyrimethamine is not working in Malawi
- Nicholas J White (1 April 2004)
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Sustained clinical efficacy of Sulfadoxine-pyrimethamine in malawi after 10 years: recommendations should be interpreted with caution.
- Ayokunle .T. Abegunde (6 April 2004)
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Authors' response
- Christopher V. Plowe, James G. Kublin, Fraction K. Dzinjalamala, Deborah S. Kamwendo, Rabia A. G. Mukadam, Malcolm E. Molyneux, Terrie E. Taylor (7 April 2004)
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SP Failure rates similar in Blantyre, Malawi and KwaZulu Natal, South Africa
- Karen I Barnes, Brian L Sharp, David N Durrheim (15 April 2004)
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Pascal RINGWALD, Medical officer, Roll Back Malaria Department, WHO 1211 Geneva 27, Switzerland
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I read with interest the article by Plowe et al. (1) on the sustained clinical efficacy of sulfadoxine-pyrimethamine in Malawi. Studies assessing long term trends of drug efficacy are rare, and are useful for updating antimalarial treatment policies. Nevertheless, I would like to add some comments on the methods applied to enhance the interpretation of the data. WHO has developed several standardized protocols to assess the efficacy of antimalarial drugs. Although the outcomes were classified in the 1973 guideline as RI-RII-RIII levels of resistance, later and current protocols are intended to determine treatment failures and not resistance patterns of the parasite. Treatment failure is not identical to parasite resistance. Some treatment failures may be due to incomplete absorption or rapid clearance of the drug; conversely treatment success can be recorded in semi-immune adults infected with resistant parasites. Recently, WHO published a revised standardized protocol for the assessment of antimalarial drug efficacy, giving clear indications of outcome classifications, the target groups to be monitored and the duration of the follow-up according to the drug tested (2). The new classification is appropriate for symptomatic patients, and includes not only clinical but also parasitological criteria. Since Adequate Clinical and Parasitological Response (ACPR), Late Parasitological Failure (LPF), Late Clinical Failure (LCF) and Early Treatment Failure (ETF) results are most often similar to the previous RI- II-III classification, it becomes redundant now to classify the response based on both classifications. But, an examination of WHO's database on antimalarial drug efficacy has shown that LCF and LPF correspond closely to RI, and ETF to RIII + RII, contradicting the authors' claim that ETF is systematically overestimating the true early failure rate. Regardless of the intensity of the malaria transmission, any evaluation should focus on treatment efficacy in children under 5 years. Even in populations with little acquired immunity, younger children have less favourable therapeutic response to antimalarial drugs than do older children and adults. Adults have been included in this survey; it would be interesting to analyse the data focusing only on young children. Results of the therapeutic efficacy test is only one of the factors that can lead to the decision to change current drug policy; increased malaria-associated morbidity and mortality may also be indicators of failure of the existing policy. It has been clearly demonstrated that persistent parasitaemia is associated with anaemia, increased risk of clinical recrudescence and increased gametocyte carriage. A technical meeting convened by WHO/AFRO in Harare, 14-15 August 2003, agreed that, in intense transmission areas, asymptomatic parasitological failure (quoted as LPF in the new protocol) should be an additional indicator for the interpretation of the test. It was also agreed that an unacceptable level of failures is reached when clinical failure at day 14 (ETF+LCF) >= 15% and total failure (ETF+LCF+LPF) >=25% (2). The authors’ data in table 2 show that these thresholds have been reached in Ndirande since 1999. There is clear evidence that the resistance of P. falciparum to sulfadoxine-pyrimethamine has increased in Malawi over the last ten years. According to Plowe et al. sulfadoxine-pyrimethamine resistance was absent in Malawi in 1990 before the drug became the first line treatment but it emerged, with 14 day recrudescence rates (RI, RII, RIII combined), up to 36% in 1995 and 1996 in the town of Karonga (3).The level of cumulative RI -RII-RIII parasitological failure probably reached a peak in Ndirande in 1999. Similar failure rates with chloroquine in 6 sites in Malawi led to policy change and the adoption in 1993 of sulfadoxine-pyrimethamine as first line treatment (4). The authors had previously demonstrated that the triple mutations in dhfr gene and the double mutant in dhps gene, which are good markers of sulfadoxine and pyrimethamine resistance, are highly prevalent in Malawi (3). It would be misleading to try to correlate the prevalence of mutants and the results of WHO therapeutic efficacy test using the previous 1996 outcome classification, because this test did not consider asymptomatic parasitological failures at D14, and instead classified them under Adequate Clinical Response. Sulfadoxine-pyrimethamine efficacy data in Malawi is a subject of scientific debate. Behind this debate, there is a real public health issue of delivering fully effective drugs to the population. 1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, Chimpeni P, et al. Sustained clinical efficacy of sulfadoxine- pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 2004;328:545-8. 2. World Health Organization (WHO). Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva, Switzerland:WHO/HTM/RBM/2003.50. 3. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, et al. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J Infect Dis 1997;176:1590- 6. 4. Khoromana CO, Campbell CC, Wirima JJ, Heymann DL. In vivo efficacy of chloroquine treatment for Plasmodium falciparum in Malawian children under five years of age. Am J Trop Med Hyg 1986;35:465-71. Competing interests: None declared |
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Zaki Hussain Khan, Resident medical officer yr 1 Ziauddin medical university hospital, Karachi, Pakistan
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Is sulfadoxine-pyrimethamine safe as a first line therapy,is the main question here. Although it show satisfactory efficacy but what about its side effects.As a doctor belong to the country where the rate of malaria is also high and use of sulfadoxine-pyrimethamine is not uncommon specially by the local GPs, i had seen many severe side effect of this drug which is also too frequent namely the aplastic anemia and other hematological disorder.Patient may get rid of malaria by the sulfadoxine- pyrimethamine use but its stay in hospital usually increases and mortality also increases because of the side effect of this drug. I feel that use of cholorquine is still remain the first line therapy in uncomplicated cases of falciparum malaria in adults. If you encounter the complicated case then its better to deal it with quinine or halofantrine. Use of this drug as a first line therapy is not recommended and specially in poor countries. Competing interests: None declared |
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Nicholas J White, Professor of Tropical Medicine Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok, 10400, Thailand
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Dear Sir I wonder if the article by Plowe et al (BMJ 6 March 328; 545-8) 1 might not be better titled “Sustained lack of efficacy of sulfadoxine- pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment; five year prospective study”. As the authors and others 1,2 have documented, by the start of the study period five years ago Plasmodium falciparum in Malawi had already acquired significant resistance to SP; parasites with quintuple mutations in the genes encoding the drug targets (3 mutations in Pfdhfr and 2 in Pfdhps) were already widely prevalent. Infections with such parasites in non- immune patients are associated with high failure rates. This explains the sustained lack of efficacy in Malawi documented carefully, in large numbers of patients in this report; cure rates in children with acute falciparum malaria assessed at 28 days remained steadily less than 40% over the five year study period. This is confirmed by the Malawi component of the recent WHO-TDR multicentre evaluation of artemisinin combination treatment (with some authors common to both reports); the cure rate assessed 28 days following observed administration of SP was only 23%3, and this for one of the major killing diseases of childhood. A 77 % failure rate is amongst the worst SP responses ever documented! Only 7% (5/71) of reported trials on SP have had failure rates worse than this4. Reinfection was not a major confounder; the PCR genotyping corrected 28 day cure rate was 32%. Before SP was introduced widely it was very effective in Malawi5 , but, since then, efficacy has fallen dramatically1,3,6-9 (Table). The front page of the BMJ was wrong; SP is not “still working”. A drug giving a cure rate of consistently less than 40% for a potentially life-threatening infection cannot be described as having “good efficacy”. Particularly when highly effective alternatives exist. Can you imagine endorsing an antibiotic with a more than 60% failure rate for use in European or American children with those words? These figures reflect dangerously poor efficacy. It is the immune response which is “still working”. In Malawi, where children may receive an infection each week or even more frequently, there is clearly intense exposure to malaria, and immunity is gained in early childhood. But malaria is still a major cause of childhood death. Children die from malaria because they do not have sufficient immunity to the particular parasite causing their infection, and because they do not receive effective treatment. They may well have immunity to many other parasites, and, as severe malaria occurs in only a small minority of infections, the majority of infections are controlled by the host’s defences10. Treatment responses appear to be satisfactory for ineffective drugs, particularly with the blinkered assessment provided by the blunt tool of “clinical response” assessed at 14 days. But demographic surveillance system data from Eastern and Southern Africa suggest that malaria attributable mortality in children almost doubled between 1990 and 1998, whereas by contrast non-malaria related mortality fell. The use of ineffective drugs, such as SP in Malawi, may well be to blame11. Professor NJ White
Table Declining therapeutic responses to sulphadoxine –pyrimethamine in Malawian children with acute falciparum malaria; 1987 -2003 Author Day 7 assessment Day 14 assessment Day 21 or Day 28 assessment of cure Heymann D et al 19875 100% 100% (D21) Nwanyanwu et al 19966 98% 98% Verhoeff et al 19977 98% 90.5% Nwanyanwu et al 20008 89% 81-93% MacArthur et al 20009 80% WHO –TDR study 2000-23 53% 23%* (D28) Plowe et al 20041 78-88% 61-73% 27-39% (D28) * The true success rate, confirmed with PCR genotyping was 36/113; 32% References 1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, Chimpeni P, Molyneux ME, Taylor TE. Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ. 2004 ;328:545-8. 2. Bwijo B, Kaneko A, Takechi M, Zungu IL, Moriyama Y, Lum JK, Tsukahara T, Mita T, Takahashi N, Bergqvist Y, Bjorkman A, Kobayakawa T. High prevalence of quintuple mutant dhps/dhfr genes in Plasmodium falciparum infections seven years after introduction of sulfadoxine and pyrimethamine as first line treatment in Malawi. Acta Trop. 2003; 85: 363-73. 3. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N; International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004; 363: 9-17. 4. Myint HY, Tipmanee P, Nosten F, Pukrittayakamee S, Day NPJ, Looareesuwan S, White NJ. A systematic overview of published antimalarial drug trials. Trans R Soc Trop Med Hyg; 2004, 98: 73-81. 5. Heymann DL, Khoromana CO, Wirima JJ, Campbell CC. Comparative efficacy of alternative primary therapies for Plasmodium falciparum infections in Malawi. Trans R Soc Trop Med Hyg. 1987; 81: 722-4. 6. Nwanyanwu OC, Ziba C, Kazembe P, Chitsulo L, Wirima JJ, Kumwenda N, Redd SC.Efficacy of sulphadoxine/pyrimethamine for Plasmodium falciparum malaria in Malawian children under five years of age. Trop Med Int Health. 1996;1: 231-5. 7. Verhoeff FH, Brabin BJ, Masache P, Kachale B, Kazembe P, Van der Kaay HJ. Parasitological and haematological responses to treatment of Plasmodium falciparum malaria with sulphadoxine-pyrimethamine in southern Malawi. Ann Trop Med Parasitol. 1997; 91: 133-40. 8. Nwanyanwu OC, Ziba C, MacHeso A, Kazembe P. Efficacy of sulphadoxine-pyrimethamine for acute uncomplicated malaria due to Plasmodium falciparum in Malawian children under five years old. Trop Med Int Health. 2000; 5: 355-8. 9.MacArthur J, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D, Barat LM, Kazembe PN, Ruebush TK 2nd.Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998. Am J Trop Med Hyg. 2001; 65: 679-84. 10. Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med. 1998;4: 358-60. 11. Korenromp EL, Williams BG, Gouws E, Dye C, Snow RW. Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy. Lancet Infect Dis. 2003; 3: 349-358. Competing interests: None declared |
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Ayokunle .T. Abegunde, senior medical officer University of Lagos medical centre,Lagos,Nigeria.
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Editor, Plowe et al(1)validate anecdotal reports which have suggested that Sulfadoxine-pyrimethamine is still efficacious in Malawi despite considerable evidence that suggests otherwise.(2,3) How long this efficacy would last can only be left to speculation. They are correct in stating that regional studies on drug efficacy and not predictions based on experiences in very different epidemiological settings should form the basis of rational antimalarial drug policy.(1) This is evident from the differing levels of Chloroquine(CQ) and Sulfadoxine-pyrimethamine(SP) resistance seen in East Africa when compared to West Africa. However I disagree with the statement that "countries still using CQ despite high resistance, but where SP remains efficacious should consider switching to SP as an interim drug while waiting for more effective combination therapies." This statement should be interpreted with caution,because for a West African country such as Nigeria, SP and CQ resistance has been reported over a decade ago.(4-6) However, both drugs still demonstrate varying degrees of efficacy even in the face of perennial transmission of malaria and drug pressure.(7) A policy shift to SP monotherapy as first line now would only result in the squandering of limited resources for health,because in a few years time there may be a need to change policy again. Combination therapy is the logical and urgent alternative to help reduce malaria incidence,prevent the emergence of drug resistance and possibly extend the useful therapeutic life of standard antimalarials.(including SP)(8) However the cost implications of implementing the available Artesunate Combination Therapies(ACT)is daunting for most countries in sub-saharan Africa. A recent meta-analysis showed that 3 days artesunate combined with standard antimalarials reduced treatment failures in Africa.(9) This positive effect was especially noticeable with SP, other antimalarial drug combinations have also been found to be effective and much cheaper than ACT's. Amodiaquine-Sulfadoxine-pyrimethamine was superior to Artesunate-Sulfadoxine -pyrimethamine for preventing late recrudescent infections in Uganda.(10) I would argue that these alternative combination therapies e.g (Amodiaquine/SP)may prove the best candidates as "short term strategy" until cheaper ACT's with proven safety in pregnancy are available, not Sulfadoxine-pyrimethamine monotherapy. AT Abegunde References 1. Plowe CV, Kublin JG, Dzinjalamala FK et al. Sustained efficacy of sulfadoxine -pyrimethamine for uncomplicated malaria in Malawi after 10years as first line treatment:Five year prospective study. BMJ 2004;328(7439):545 2.Verhoeff FH, Brabin BJ, Masache P et al. Parasitological and haematological responses to treatment of Plasmodium falciparum with Sulfadoxine-pyrimethamine in southern Malawi. Ann.Trop.Med.Parasitol. 1997;91:133-40 3.Nwanyanwu OC,Ziba C, Macheso A et al. Efficacy of Sulfadoxine- pyrimethamine for acute uncomplicated malaria in Malawian children under five years old. Trop. Med.Int.Health 2000;5:355-8 4.Lege-oguntoye L,Adagu SI, Werblinska B et al. Resistance of Plasmodium Falciparum to sulfadoxine -pyrimethamine combination in semi- immune children in Zaria,northern Nigeria. Trans.R.Soc.Trop.Med.Hyg 1990;84(4): 505-6 5.Adagu SI, Okoyeh JN, Lege-Oguntoye L et al. Efficacy of a 3 day oral regimen of Quinine in an area of northern Nigeria with low grade resistance of Plasmodium falciparum to Chloroquine and Sulfadoxine- pyrimethamine.J.Trop.Med.Hyg 1995;98(5):296-8 6. Happi CT,Gbotosho GO, Sowunmi A et al. Molecular analysis of Plasmodium Falciparum recrudescent malaria infections in children treated with Choroquine in Nigeria. Am.J.Trop.Med.Hyg 2004;70(1): 20-6 7.Sowunmi A, Fehintola FA, Adedeji AA et al. Comparative efficacy of Chloroquine plus chlorpheniramine alone and in sequential combination with sulfadoxine-pyrimethamine for the treatment of acute uncomplicated falciparum malaria in children. Ann.Trop.Med.Parasitol. 2000;94(3):209-17 8.Nosten F, Brasseur P.Combination therapy for malaria: The way foward. Drugs 2002;62:1315-29 9.Adjiuk M,Babiker A,Garner P et al;International Artemisinnin study group.Artesunate combinations for the treatment of malaria:A meta- analysis. Lancet 2004;363(9402):9-17 10.Dorsey G, Njama D, Kamya MR et al. Sulfadoxine-pyrimethamine alone or with Amodiaquine or Artesunate for the treatment of uncomplicated malaria: A longitudinal randomised controlled trial.Lancet 2002;360:2031- 38 Competing interests: None declared |
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Christopher V. Plowe, Associate Professor University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore MD 21044 USA, James G. Kublin, Fraction K. Dzinjalamala, Deborah S. Kamwendo, Rabia A. G. Mukadam, Malcolm E. Molyneux, Terrie E. Taylor
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Dear Sir, In his letter of 1 April 2004, Professor NJ White characterizes sulfadoxine-pyrimethamine (SP) as ineffective in Malawi and refers to the proportion of persons with no parasites 28 days after SP treatment of uncomplicated falciparum malaria as a “cure rate”. How is the reader to reconcile our article’s report of a sustained 80% efficacy1 with Professor White’s assertion that we found sustained cure rates of less than 40%? We reported our results using the standard definition of antimalarial therapeutic efficacy in high transmission areas, which is based on follow- up through 14 days after treatment.2 If this is a “blinkered assessment” it was blinkered by expert consensus and widely used and accepted as the standard definition until less than one year ago, after the study we reported was concluded. We also reported parasitaemia prevalences at 28 days after treatment, but these data do not provide cure rates in any accepted or standard sense, particularly since our study did not distinguish between reinfections and recrudescences. In high transmission settings, the proportion of persons with malaria infections increases over time following a treatment episode, so the “cure rate” declines as the definition of efficacy is extended from 14 days to 28 days or longer. Not surprisingly, even lower “cure rates” for drugs (including artemisinin- based combination therapy) are found when follow-up is extended beyond 28 days, even after genotyping to correct for reinfections.3 Which measure of drug efficacy – adequate clinical response or complete eradication of the initial parasite population by 28 days – more accurately predicts a drug’s usefulness in the long term against the important endpoints in a community, namely severe disease and mortality? Actual data are lacking by which to answer this question. White argues that severe and fatal disease are a consequence of absence of specific immunity to a new parasite, and that the drug used for treatment is therefore the principal determinant of the outcome. These are plausible suggestions, but they would be greatly strengthened if supported by data acquired in a high-transmission setting. A longitudinal study compared the efficacy of SP and chlorproguanil- dapsone over time in Malawi from 1997 to 1999.4 This study used a non- standard definition of efficacy, but it was conducted in the same clinic at the same time as our study, and found that SP had an efficacy rate of 80%, in close agreement with our contemporaneous standard measure of SP efficacy. Chlorproguanil-dapsone, a short-acting antifolate combination, had 95% efficacy. In Malawi, children treated with SP for all episodes of malaria over the course of a year had no more episodes of uncomplicated malaria, anemia or severe malaria than those treated for all malaria episodes with chlorproguanil-dapsone, despite the latter’s much higher efficacy. The benefit of chlorproguanil-dapsone’s higher efficacy was effectively cancelled out by the prolonged prophylactic effect of the longer acting but less efficacious SP. Radical cure, which can be achieved with short-acting, highly efficacious combinations, should be the goal in low transmission settings where the risk of reinfection is low, but this study demonstrates that over time, children in areas of high transmission may do as well or better with a longer acting drug with mediocre efficacy than with a short acting regimen with high efficacy. In addition to efficacy, factors including epidemiology, pharmacokinetics, pharmacodynamics, compliance, and economic considerations must all be taken into account in assessing the benefit of antimalarial treatment regimens. Large longitudinal studies are required to demonstrate a benefit of more complex first-line drug regimens against the end-points that matter most – severe malaria and child mortality. Assumptions that the best approach to malaria therapy in one setting can be extrapolated, in the absence of data, to all other settings, are unwise. Nevertheless, we share the concerns expressed by Professor White and Dr. Pascal Ringwald and agree with the editorial by Professor Brian Greenwood that the observed degree of efficacy (however it is defined) reported in our study is less than satisfactory. Hence the statement in our paper that the efficacy levels we reported for SP ‘do not warrant complacency about seeking alternative treatments for its replacement’. (We are currently working with the national programme to identify the best alternatives for Malawi). Of particular concern is the risk of anemia and recurrent clinical episodes that comes with impaired treatment efficacy, as noted by Dr. Ringwald. In low transmission settings, highly curative treatment regimens are clearly better than treatments with impaired efficacy. In Africa, however, the health benefit of treatment regimens is not solely a function of curative efficacy. Professor White ends his letter by blaming the use of SP for increases in malaria-attributable morbidity and mortality in Eastern and Southern Africa between 1990 and 1998. Malawi introduced SP as the first line antimalarial in 1993. This was accompanied by a 20% reduction in infant mortality and a 22% reduction in child mortality from 1990 through 2000,5 despite increasing rates of HIV mortality during this period, and in contrast to increasing infant and child mortality in the rest of the region, where other countries continued to use chloroquine. It is likely that the continued use of chloroquine in the face of truly dismal efficacy rates, while waiting for long delayed alternative treatments, was responsible for higher mortality among children in other countries of this region. It may indeed be too late now for other countries to enjoy the benefit from switching to SP that Malawi did, but it seems likely that had these countries joined Malawi in this switch in 1993, large numbers of children’s lives would have been saved. The situation is changing, and all countries must now seek to introduce optimal first-line treatments and to monitor their effectiveness against malaria-attributable mortality in children. References 1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, Chimpeni P et al. Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 2004. 2. WHO. Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated Falciparum malaria in areas with intense transmission. 1996. Geneva, World Health Organization, Division of Control of Tropical Diseases. 3. Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke SG et al. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 2002;360:2031-8. 4. Sulo J, Chimpeni P, Hatcher J, Kublin JG, Plowe CV, Molyneux ME et al. Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial. Lancet 2002;360:1136-43. 5. Millenium Indicators Database. http://unstats.un.org/unsd/mi/mi_goals.asp. Statistics Division, World Health Organization, Geneva. Competing interests: None declared |
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Karen I Barnes, Senior Lecturer University of Cape Town Division of Pharmacology, Anzio Road, Cape Town, 7925, South Africa, Brian L Sharp, David N Durrheim
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Dear Sir We read the article by Plowe et al (1) (BMJ 6 March 2004, 328: 545-8) with interest as ongoing monitoring of the therapeutic efficacy of drugs included in a national malaria treatment policy is essential for ensuring optimal patient management. However, we are surprised that these authors interpret their findings as sustained clinical efficacy of sulfadoxine- pyrimethamine (SP). The extremely high levels of parasitological failure reported confirm that acquired immunity (and antipyretic use) is a more important determinant of the resolution of clinical signs of malaria (most commonly fever) than SP treatment. Thus, Plasmodium falciparum infection in Malawi in non-immunes (such as infants or travellers) would be associated with high treatment failure rates, and high mortality if there is no ready access to more effective drugs. The authors compare their findings with those we reported in KwaZulu Natal, South Africa(2), and suggest that SP resistance arose more quickly in KwaZulu Natal, where transmission intensity and thus immunity are lower than in Malawi. However, the apparent “longer useful therapeutic life” of SP reported in Malawi reflects differences in methodology and interpretation, rather than the impact of variable transmission intensity. In 2001 we reported a parasitological failure rate following SP treatment of 88% after 42 days of follow up. The longer period of follow up is necessary to capture all recrudescences (given the long elimination half-life of SP). We reanalysed our data from 2000 (12 years after SP implementation) at day 14 and day 28, using internationally standardised methods for assessing antimalarial drug efficacy (3), to allow comparison with the findings of Plowe et al in Malawi (10 years after SP implementation). In KwaZulu Natal, intention to treat analysis of 129 patients recruited showed that the SP parasitological failure rate observed by day 14 was 45% (95% Confidence Interval: 36 – 54%), compared with 38% in Malawi. After 28 days of follow up, the parasitological failure rate was 81% (95% Confidence Intervals 72 - 89%), compared with 73% in Malawi. Potentially lethal high grade treatment failures (R3 response) occurred in between 10 and 15% of patients over the five year Malawi study, compared with 8.5% in KwaZulu Natal. This comparison of the therapeutic efficacy of SP in Malawi and KwaZulu Natal ten and twelve years after implementation, respectively, suggests that SP resistance had progressed to a similarly high level after a decade in Malawi, despite the higher intensity of malaria transmission. The interpretation of the failure rates differs considerably between Malawi and KwaZulu Natal. Plowe et al report that the observed levels of treatment failure “may before long fall to unacceptable levels”. In marked contrast, similar very high failure rates in KwaZulu Natal were considered so serious that SP was replaced with an artemisinin-based combination, artemether-lumefantrine within 6 months (4). Plowe et al’s advice on the interim utility of sulfadoxine-pyrimethamine in African countries awaiting implementation of combination antimalarial treatment, is potentially misleading as this is not supported by their data, and as existing data, including that from Malawi, suggest that full implementation of a malaria treatment policy change usually takes at least 18-24 months(5). Karen I Barnes
Brian L Sharp
David N Durrheim
1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RAG, Chimpeni P, Molyneux ME, Taylor TE. Sustained clinical efficacy of sulfadoxine-pyrimathamine for uncomplicated falciparum malaria after 10 years as first line treatment: five year prospective study. Brit Med J 2004; 328: 545-8. 2. Bredenkamp BL, Sharp BL, Mthembu SD, Durrheim DN, Barnes KI. Failure of sulfadoxine-pyrimathamine in treating Plasmodium falciparum malaria in KwaZulu Natal. S Afr Med J 2001; 91: 970-2. 3. World Health Organisation (WHO). Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva, Switzerland: WHO/HTM/RBM/2003.50. 4. Baker L, Barnes K. New antimalarials treatment for KwaZulu Natal. S Afr Med J 2001; 91(5): 358-9. 5. Bloland PB and Ettling M. Making malaria-treatment policy in the face of drug resistance. Ann Trop Med Parasitol 1999; 93: 5-23. Competing interests: None declared |
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