Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatme
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《英国医生杂志》
1 Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF1-480, Baltimore, MD 21044, USA, 2 Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi, 3 Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, 4 College of Osteopathic Medicine, Michigan State University, Lansing, MI, USA
Correspondence to: C V Plowe cplowe@medicine.umaryland.edu
Abstract
In 1993 Malawi became the first African country to change its first line antimalarial drug from chloroquine to sulfadoxine-pyrimethamine on a nationwide basis in the face of rising rates of resistance to chloroquine.1 At the time, this was a controversial decision. On the basis of the rapid selection for mutant Plasmodium falciparum parasites resistant to these antifolate drugs and the precipitous decline in efficacy of sulfadoxine-pyrimethamine after it was introduced in South America and Southeast Asia, experts predicted that sulfadoxine-pyrimethamine would have a useful therapeutic life of only about five years in Africa and might fail even more quickly because of higher rates of transmission of malaria and of use of the drug.2 Neighbouring countries were concerned that resistance to sulfadoxine-pyrimethamine would develop in Malawi and spread to their countries, so that when they were eventually forced to drop chloroquine, sulfadoxine-pyrimethamine would already be compromised. Because other countries in Africa continued to rely on chloroquine and only a few have begun to change their policies within the past few years, Malawi serves as a sentinel site for failure of sulfadoxine-pyrimethamine for the rest of the continent.
We began monitoring the efficacy of sulfadoxine-pyrimethamine at one site in Malawi in 1998. We treated patients (mostly children) with uncomplicated falciparum malaria and measured their parasitological and therapeutic responses to the drug.
Methods
We enrolled 1377 patients into the study. Characteristics on enrolment were similar over the five years of study (table 1), although parasite density on presentation apparently increased in 2001 and 2002. One thousand and eighteen (73.9%) of the enrolled participants completed 14 days of follow up; 246 (17.9%) were lost to follow up before day 14, 30 (2.2%) withdrew consent to continue in the study, 40 (2.9%) were withdrawn owing to protocol violations, and 43 (3.1%) had incomplete follow up for unspecified reasons. Most protocol violations were receipt of curative treatment for malaria from sources other than study investigators. We could not determine therapeutic efficacy for 95 (9%) of 1054 participants for whom parasitological outcomes could be determined. This was because of clinical judgments made to treat persistent or recurrent malaria infections that did not meet criteria for treatment failures—that is, treatment of symptomatic but afebrile parasitaemias between day 4 and day 14. No trends towards increasing rates of withdrawal or loss to follow up occurred throughout the course of the study.
Table 1 Characteristics at time of treatment for uncomplicated falciparum malaria
As shown in the figure and table 2, the 14 day efficacy remained stable over the five year study period, with adequate clinical response rates remaining above 80% (top left of figure: P = 0.44, odds ratio 0.95, 95% confidence interval 0.82 to 1.09). Among participants followed for 28 days, the rate of adequate clinical response decreased from 73% in 1998 to 60% in 2002 (bottom left: P = 0.02, odds ratio 0.86, 0.75 to 0.98). Rates of sensitive or RI parasitological responses at both 14 and 28 days also decreased significantly over the five year study period (top right: P = 0.015, odds ratio 0.84, 0.73 to 0.97; bottom right: P = 0.004, odds ratio 0.81, 0.71 to 0.94). Neither parasitological resistance nor therapeutic failure was associated with age in this population with a median age of 2.4 years.
Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Top left: therapeutic efficacy at 14 days; bottom left: therapeutic efficacy at 28 days; top right: parasitological resistance at 14 days; bottom right: parasitological resistance at 28 days. ACR=adequate clinical response; LTF=late treatment failure; ETF=early treatment failure; S=sensitive; RI-RIII=parasitological resistance at the RI-RIII levels
Table 2 Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Values are numbers (percentages)
Haematological recovery rates between days 0 and 14 did not differ between cases of adequate clinical response and those with treatment failure or between sensitive cases and those with RI-RIII resistance (data not shown). In univariate analyses, anaemia (haemoglobin < 10 g/dl) at day 14 was associated with both treatment failure (odds ratio 2.05, 1.15 to 3.65, P = 0.009) and RI-RIII resistance (odds ratio 1.46, 1.01 to 2.10, P = 0.034). However, when we included treatment failure and parasitological resistance separately in a logistic regression model with parasite density at day 0 and age as covariates, only the association between age and anaemia at day 14 remained significant (P < 0.001). Anaemia was more common at day 28 among children with adequate clinical response and asymptomatic parasitaemia than in children with adequate clinical response and no parasites (42.4% v 26.7%; relative risk 1.59, 1.23 to 2.05, P < 0.001). This association remained significant after we controlled for age and initial parasitaemia in a regression model (P = 0.009).
We found excellent agreement between measures of therapeutic efficacy and parasitological resistance. With adequate clinical response corresponding to sensitivity or RI resistance, late treatment failure corresponding to RI or RII resistance, and early treatment failure corresponding to RIII resistance, we found only 10/959 (1%) cases of discordance among cases for which both efficacy and resistance could be determined. One sensitive case and two RI cases met non-parasitological criteria for early treatment failure, and seven cases met criteria for RII resistance but had adequate clinical responses (one case) or were late treatment failures (six cases) because fever did not always accompany persistent parasitaemia.
Discussion
Bloland PB, Lackritz EM, Kazembe PN, Were JB, Steketee R, Campbell CC. Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa. J Infect Dis 1993;167: 932-7.
Nzila AM, Nduati E, Mberu EK, Hopkins SC, Monks SA, Winstanley PA, et al. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 2000;181: 2023-8.
Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria in areas with intense transmission. Geneva: World Health Organization, Division of Control of Tropical Diseases, 1996.
Chemotherapy of malaria and resistance to antimalarials. Geneva: World Health Organization, 1973. (WHO technical report series 529.)
Plowe CV, Doumbo OK, Djimde A, Kayentao K, Diourte Y, Doumbo SN, et al. Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: parasitologic resistance versus therapeutic efficacy. Am J Trop Med Hyg 2001;64: 242-6.
Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 1990;87: 3018-22.
Triglia T, Menting JGT, Wilson C, Cowman AF. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 1997;94: 13944-9.
Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, et al. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 2002;185: 380-8.
Kublin JG, Cortese JF, Njunju EM, Mukadam RAG, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria following cessation of chloroquine use in Malawi. J Infect Dis 2003;187: 1870-5.
Plowe CV, Kublin JG, Doumbo OK. P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates. Drug Resist Update 1998;1: 389-96.
Cortese JF, Plowe CV. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutants expressed in yeast. Mol Biochem Parasitol 1998;94: 205-14.
Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 1997;94: 1124-9.
Bloland PB, Ettling M, Meek S. Combination therapy for malaria in Africa: hype or hope? Bull World Health Organ 2000;78: 1378-88.
Bloland PB. A contrarian view of malaria therapy policy in Africa. Am J Trop Med Hyg 2003;68: 125-6.
Bredenkamp BL, Sharp BL, Mthembu SD, Durrheim DN, Barnes KI. Failure of sulphadoxine-pyrimethamine in treating Plasmodium falciparum malaria in KwaZulu-Natal. S Afr Med J 2001;91: 970-2.
Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, et al. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 2003;361: 1174-81.
((Christopher V Plowe, asso)
Correspondence to: C V Plowe cplowe@medicine.umaryland.edu
Abstract
In 1993 Malawi became the first African country to change its first line antimalarial drug from chloroquine to sulfadoxine-pyrimethamine on a nationwide basis in the face of rising rates of resistance to chloroquine.1 At the time, this was a controversial decision. On the basis of the rapid selection for mutant Plasmodium falciparum parasites resistant to these antifolate drugs and the precipitous decline in efficacy of sulfadoxine-pyrimethamine after it was introduced in South America and Southeast Asia, experts predicted that sulfadoxine-pyrimethamine would have a useful therapeutic life of only about five years in Africa and might fail even more quickly because of higher rates of transmission of malaria and of use of the drug.2 Neighbouring countries were concerned that resistance to sulfadoxine-pyrimethamine would develop in Malawi and spread to their countries, so that when they were eventually forced to drop chloroquine, sulfadoxine-pyrimethamine would already be compromised. Because other countries in Africa continued to rely on chloroquine and only a few have begun to change their policies within the past few years, Malawi serves as a sentinel site for failure of sulfadoxine-pyrimethamine for the rest of the continent.
We began monitoring the efficacy of sulfadoxine-pyrimethamine at one site in Malawi in 1998. We treated patients (mostly children) with uncomplicated falciparum malaria and measured their parasitological and therapeutic responses to the drug.
Methods
We enrolled 1377 patients into the study. Characteristics on enrolment were similar over the five years of study (table 1), although parasite density on presentation apparently increased in 2001 and 2002. One thousand and eighteen (73.9%) of the enrolled participants completed 14 days of follow up; 246 (17.9%) were lost to follow up before day 14, 30 (2.2%) withdrew consent to continue in the study, 40 (2.9%) were withdrawn owing to protocol violations, and 43 (3.1%) had incomplete follow up for unspecified reasons. Most protocol violations were receipt of curative treatment for malaria from sources other than study investigators. We could not determine therapeutic efficacy for 95 (9%) of 1054 participants for whom parasitological outcomes could be determined. This was because of clinical judgments made to treat persistent or recurrent malaria infections that did not meet criteria for treatment failures—that is, treatment of symptomatic but afebrile parasitaemias between day 4 and day 14. No trends towards increasing rates of withdrawal or loss to follow up occurred throughout the course of the study.
Table 1 Characteristics at time of treatment for uncomplicated falciparum malaria
As shown in the figure and table 2, the 14 day efficacy remained stable over the five year study period, with adequate clinical response rates remaining above 80% (top left of figure: P = 0.44, odds ratio 0.95, 95% confidence interval 0.82 to 1.09). Among participants followed for 28 days, the rate of adequate clinical response decreased from 73% in 1998 to 60% in 2002 (bottom left: P = 0.02, odds ratio 0.86, 0.75 to 0.98). Rates of sensitive or RI parasitological responses at both 14 and 28 days also decreased significantly over the five year study period (top right: P = 0.015, odds ratio 0.84, 0.73 to 0.97; bottom right: P = 0.004, odds ratio 0.81, 0.71 to 0.94). Neither parasitological resistance nor therapeutic failure was associated with age in this population with a median age of 2.4 years.
Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Top left: therapeutic efficacy at 14 days; bottom left: therapeutic efficacy at 28 days; top right: parasitological resistance at 14 days; bottom right: parasitological resistance at 28 days. ACR=adequate clinical response; LTF=late treatment failure; ETF=early treatment failure; S=sensitive; RI-RIII=parasitological resistance at the RI-RIII levels
Table 2 Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Values are numbers (percentages)
Haematological recovery rates between days 0 and 14 did not differ between cases of adequate clinical response and those with treatment failure or between sensitive cases and those with RI-RIII resistance (data not shown). In univariate analyses, anaemia (haemoglobin < 10 g/dl) at day 14 was associated with both treatment failure (odds ratio 2.05, 1.15 to 3.65, P = 0.009) and RI-RIII resistance (odds ratio 1.46, 1.01 to 2.10, P = 0.034). However, when we included treatment failure and parasitological resistance separately in a logistic regression model with parasite density at day 0 and age as covariates, only the association between age and anaemia at day 14 remained significant (P < 0.001). Anaemia was more common at day 28 among children with adequate clinical response and asymptomatic parasitaemia than in children with adequate clinical response and no parasites (42.4% v 26.7%; relative risk 1.59, 1.23 to 2.05, P < 0.001). This association remained significant after we controlled for age and initial parasitaemia in a regression model (P = 0.009).
We found excellent agreement between measures of therapeutic efficacy and parasitological resistance. With adequate clinical response corresponding to sensitivity or RI resistance, late treatment failure corresponding to RI or RII resistance, and early treatment failure corresponding to RIII resistance, we found only 10/959 (1%) cases of discordance among cases for which both efficacy and resistance could be determined. One sensitive case and two RI cases met non-parasitological criteria for early treatment failure, and seven cases met criteria for RII resistance but had adequate clinical responses (one case) or were late treatment failures (six cases) because fever did not always accompany persistent parasitaemia.
Discussion
Bloland PB, Lackritz EM, Kazembe PN, Were JB, Steketee R, Campbell CC. Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa. J Infect Dis 1993;167: 932-7.
Nzila AM, Nduati E, Mberu EK, Hopkins SC, Monks SA, Winstanley PA, et al. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 2000;181: 2023-8.
Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria in areas with intense transmission. Geneva: World Health Organization, Division of Control of Tropical Diseases, 1996.
Chemotherapy of malaria and resistance to antimalarials. Geneva: World Health Organization, 1973. (WHO technical report series 529.)
Plowe CV, Doumbo OK, Djimde A, Kayentao K, Diourte Y, Doumbo SN, et al. Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: parasitologic resistance versus therapeutic efficacy. Am J Trop Med Hyg 2001;64: 242-6.
Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci USA 1990;87: 3018-22.
Triglia T, Menting JGT, Wilson C, Cowman AF. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 1997;94: 13944-9.
Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, et al. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 2002;185: 380-8.
Kublin JG, Cortese JF, Njunju EM, Mukadam RAG, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria following cessation of chloroquine use in Malawi. J Infect Dis 2003;187: 1870-5.
Plowe CV, Kublin JG, Doumbo OK. P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates. Drug Resist Update 1998;1: 389-96.
Cortese JF, Plowe CV. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutants expressed in yeast. Mol Biochem Parasitol 1998;94: 205-14.
Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 1997;94: 1124-9.
Bloland PB, Ettling M, Meek S. Combination therapy for malaria in Africa: hype or hope? Bull World Health Organ 2000;78: 1378-88.
Bloland PB. A contrarian view of malaria therapy policy in Africa. Am J Trop Med Hyg 2003;68: 125-6.
Bredenkamp BL, Sharp BL, Mthembu SD, Durrheim DN, Barnes KI. Failure of sulphadoxine-pyrimethamine in treating Plasmodium falciparum malaria in KwaZulu-Natal. S Afr Med J 2001;91: 970-2.
Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, et al. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 2003;361: 1174-81.
((Christopher V Plowe, asso)