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Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial
Research Letters
Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial David Schellenberg, Clara Menendez, John J Aponte, Elizeus Kahigwa, Marcel Tanner, Hassan Mshinda, Pedro Alonso
Lancet 2005; 365: 1481–83 See Comment page1443
Stopping antimalarial chemoprophylaxis can be followed by increased risk of malaria, suggesting that it interferes with the development of antimalarial immunity. We report analysis of extended follow-up until age 2 years of a randomised, placebo-controlled double-blind trial of intermittent preventive antimalarial treatment in infants. The rate of clinical malaria (events per person-year at risk, starting 1 month after final dose of intermittent treatment) was 0·28 in the sulfadoxine-pyrimethamine group and 0·43 in the placebo group (protective effect 36%, 95% CI 11–53). Intermittent treatment produced a sustained reduction in the risk of clinical malaria extending well beyond the duration of the pharmacological effects of the drugs, excluding a so-called rebound effect and suggesting that such treatment could facilitate development of immunity against Plasmodium falciparum. Infection with Plasmodium falciparum kills about a million African children every year. Trials of malaria chemoprophylaxis in endemic settings have shown the potential of antimalarial drugs to protect children from malaria episodes and death.1 However, several studies have documented an increase in the incidence of clinical malaria in children after prophylaxis stopped—the socalled rebound effect.1 In a safety and efficacy trial of intermittent antimalarial preventive treatment in infants,2 we have reported that sulfadoxinepyrimethamine delivered at the time of routine vaccinations reduced the incidence of clinical malaria by 59% (95% CI 41–72), and halved the incidence of severe anaemia (defined by a packed cell volume 25%) in the first year of life. Here, we present analyses of extended follow-up to assess the possibility of a rebound effect after this treatment. The setting and methodology are described in detail elsewhere.2 In brief, this study was a double-blind, individually randomised, placebo-controlled trial based at the Ifakara Mother and Child Health clinic in southern Tanzania. Children of consenting parents were recruited between August, 1999, and April, 2000, and given sulfadoxine-pyrimethamine or placebo when attending for vaccination with diphtheria-pertussistetanus and oral polio at ages 2 months and 3 months, and measles vaccination at age 9 months. Doses of sulfadoxine-pyrimethamine or placebo, administered according to bodyweight, were crushed and mixed with water on a tablespoon. Iron supplements (target dose of 2·5 mg kg–1 day–1) were dispensed to all children at recruitment and when attending a routine weighing clinic at age 4 months. Parents were encouraged to bring sick children to project clinical officers at the St Francis Designated District Hospital. Standardised clinical information was recorded and, if there was a history of fever in the preceding 24 h or axillary temperature was 37·5ºC or higher, capillary blood was taken for malaria parasite examination and measurement of packed cell volume. Malaria was treated with sulfadoxinewww.thelancet.com Vol 365 April 23, 2005
pyrimethamine unless presentation was within 14 days of such treatment or placebo, in which case treatment was with quinine. Children were followed up until the youngest members of the cohort were aged 18 months, by which time 40% were aged 2 years or older. Weight, packed cell volume, and P falciparum parasitaemia were measured at 18 months of age. Standard procedures2 established the presence and density of sexual and asexual malaria parasites on blood films, and packed cell volumes were measured in centrifuged microcapillary tubes. Protection against measles was determined by antibody titres in a simple random sample of blood specimens obtained at 12 months and measured unaware of treatment allocation with commercial ELISA kits (DiaSorin, Hycor Biomedical GmbH, Kassel, Germany); we present results of all samples evaluated in the trial. Clinical malaria defined as an axillary temperature 37·5ºC or higher with asexual P falciparum parasitaemia of any density has an estimated sensitivity and specificity of 100% and 97%, respectively.2 The primary purpose of the analysis was to exclude a rebound increase in the risk of clinical malaria following intermittent antimalarial preventive treatment. We estimated that a sample size of 700 would provide 80% power to detect a 50% increase in the incidence of the first or only episode of clinical malaria from 0·7 to 1·05 episodes per person-year at risk between 10 and 18 months of age at a 5% significance level, and allowing 20% loss to follow-up. The analyses are based on children who received three doses of intermittent preventive treatment, and started time at risk 1 month after the third dose of such treatment. Unlike the survival analyses presented previously, children were included irrespective of malaria episodes in the first 10 months of life. Individuals contributed to the time at risk until end of follow-up or when censored as a result of withdrawal or death. The protective effect was estimated from the hazard ratio (HR) in Cox regression models as 100(1–HR)% for analyses of first or only episodes, and as
Centre for International Health, Institut d’Investigacions Biomedicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain (D Schellenberg MRCP, C Menendez MD, J J Aponte MD, P Alonso MD); Ifakara Health Research and Development Centre, Kilombero, Tanzania (D Schellenberg, E Kahigwa MSc, H Mshinda PhD); Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK (D Schellenberg); and Swiss Tropical Institute, Basel, Switzerland (Prof M Tanner PhD) Correspondence to: Dr David Schellenberg, IHRDC, PO Box 78373, Dar es Salaam, Tanzania [email protected]
1481
Research Letters
See Lancet Online for webfigure and webtable
We have shown a continuing reduction in the risk of first or only episodes of clinical malaria in children aged 10 months to 2 years from intermittent preventive antimalarial treatment for infants. This finding increases the potential public-health benefits of such treatment and raises intriguing questions about the underlying mechanisms. The sustained protection seems to have had two components. Firstly, intermittent treatment decreased the risk of a first malaria episode, which itself is a major risk factor for subsequent episodes. This increased risk is not just due to increased exposure: adjustment for known risk factors for malaria in this area3 (use of mosquito nets and distance between home and hospital, reflecting proximity to vector breeding sites4) had a small, non-significant effect on the efficacy estimate. Illness-causing P falciparum infections in infants might not only fail to induce protective immunity but also enhance the risk of subsequent malaria illness. This situation emphasises the importance of protecting young infants from malaria. The second component of the sustained benefit of intermittent treatment is not related to a child’s experience of clinical malaria, since analysis controlling for previous episodes still yielded evidence of a reduction in malaria risk. This effect is unlikely to be due to the pharmacological action of sulfadoxine or pyrimethamine because their half-lives are roughly 7 days and 4 days, respectively,5 and time at risk for these analyses started 30 days after the final dose. A study of the efficacy of sulfadoxine-pyrimethamine in 1999 showed that, although there were no late treatment failures, 31% of children were parasitaemic by day 14 of follow-up.6 It is likely that most children were aparasitaemic when they received intermittent treatment because the parasite prevalence in placebo recipients was only 9% (25 of 274) in children aged 18 months, and is likely to have been even lower at the time of treatment doses. Hence, the most frequent interaction between P falciparum and sulfadoxine-pyrimethamine as intermittent preventive treatment might have arisen when children with subtherapeutic drug concentrations developed new infections. We postulate that the combined antiplasmodial effects of sulfadoxine-pyrimethamine, maternal immunity, and fetal haemoglobin effectively prevented new blood-stage infections developing into clinical episodes. Furthermore, parasites could have
100(1–rate ratio)% for assessments of multiple malaria episodes based on Poisson regression models with random effects to take into account between-child and within-child variation. Children were not regarded as at risk for 28 days after each presentation with malaria. Nutritional indices based on weight and age were generated with EPINUT tables (EPI Info version 6, CDC Atlanta, GA, USA). We randomly assigned 701 children either sulfadoxinepyrimethamine or placebo. A similar number of children in each group received all three doses of drug or placebo and completed extended follow-up (webfigure). The webtable shows baseline characteristics. During extended follow-up, the rate of first or only clinical malaria episodes was higher for recipients of placebo than for recipients of sulfadoxine-pyrimethamine: the protective effect was 36% (table). Between 10 months and 2 years of age, recipients of preventive treatment remained at lower risk of clinical malaria than recipients of placebo, and the survival curves diverged with time (figure). Adjustments for sex, distance of residence from the hospital, use of mosquito net, haemoglobin genotype, age at recruitment, and nutritional status at recruitment altered the efficacy estimate by less than 0·5%. Adjustment for previous malaria episodes reduced the estimate to 27% (95% CI –1 to 47), largely because of an increase of 2·5 (1·7 to 3·6, p0·0001) times in the risk of clinical malaria in those who had had a previous clinical malaria episode. There was no significant interaction between treatment group and previous malaria episode (p=0·222). Extending the scope of the analysis to include all episodes of malaria yielded a 23% reduction in clinical malaria after intermittent treatment, and controlling for previous malaria episodes reduced this estimate to 11% (95% CI –18 to 33). The incidence of severe anaemia was very similar in the two groups. At 18 months of age, the prevalences of fever, parasitaemia, severe anaemia, and parasite densities, mean packed cell volume, and anthropometric indices did not differ in the two groups (data not shown). At the same time, the prevalence of gametocytaemia was 3% (nine of 294) in recipients of placebo and 1% (three of 294) in recipients of sulfadoxine-pyrimethamine (p=0·08). The prevalence of protective antibody titres against measles was 92% (142 of 155) and 86% (140 or 162), respectively (Fisher’s exact p=0·155). Placebo (n=278)
Sulfadoxine-pyrimethamine (n=277)
Events
Person years at risk Rate
Events
Person years at risk
Rate
216·0
0·43
65
236·3
0·28
263·2
0·42
88
269·9
248·9
0·11
30
263·3
Malaria First or only episode 93 Adjusted for previous malaria episodes All episodes 111 Severe anaemia Severe anaemia (packed cell volume 25%) 27
Protective effect (95% CI)
p value
0·33
36% (11 to 53) 27% (–1 to 47) 23% (–5 to 43)
0·006 0·053 0·097
0·11
–5% (–77 to 38)
0·852
Table: Rate of clinical malaria from 1 month after dose three until end of follow-up
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www.thelancet.com Vol 365 April 23, 2005
Research Letters
Free of disease (%)
100
90 Sulfadoxine-pyrimethamine
Conflict of interest statement All authors are members of the IPTi (Intermittent Preventive antimalarial Treatment in infants) consortium, which is financially supported by the Bill and Melinda Gates Foundation and funds some of our research activities, but not the project reported here.
80 Placebo 70 p value for logrank test: 0·006 60 0 0
2
4
6
8
10
12
14
Time since 30 days after dose three (months) Number at risk 265 Placebo Sulfadoxine- 277 pyrimethamine
249
235
213
192
146
121
66
263
250
235
222
172
126
96
Figure: Kaplan-Meier survival curve
been attenuated in vivo, providing the immune system with an enhanced opportunity to generate protective responses. Some support for this hypothesis comes from experience of P yoelli in mice.7 If our hypothesis is correct, drugs with greater parasitocidal effectiveness might produce less pronounced sustained effects when used as intermittent preventive treatment than less effective drugs. It seems unlikely that the documented differences in malaria risk were due to selection bias: the baseline characteristics and completeness of follow-up of the two groups in this randomised study were similar. Although all children lived within 6 km of the hospital, and curative services were provided free of charge, passive case detection might have missed some malaria episodes. The unlikely event that the proportion of undetected episodes varied between the two groups could have biased our results. The sustained reduction in the risk of clinical malaria in children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine enhances the potentially considerable value of such treatment for malaria control, and suggests a novel approach for facilitation of the development of protective immunity to malaria. Contributors All authors contributed to definition of the rationale and study design. D Schellenberg and E Kahigwa were responsible for all field and hospital-based activities, as well as supervision of data management and quality control. Data analysis was led by J Aponte with contributions
www.thelancet.com Vol 365 April 23, 2005
from all authors, especially D Schellenberg, C Menendez, and P Alonso. H Mshinda and M Tanner contributed to all aspects of the trial and supported the running of the Ifakara Centre. The report received inputs from all authors, but the writing was led by D Schellenberg, C Menendez, and P Alonso. C Menendez and P Alonso coordinated the research team.
Acknowledgments We are indebted to the mothers and families of study children, the medical director and ward staff of St Francis Designated District Hospital, the Kilombero District medical officer and Ifakara Mother and Child Health Clinic staff for their collaboration within this project. The work of the clinical officers, field supervisors, assistant data manager, and laboratory coordinator was important for the successful completion of the study. Josep Vidal did serological assays in the department of microbiology of the Hospital Clinic, Barcelona. We are very grateful to M Corachan who independently monitored the trial and provided invaluable support and guidance. We acknowledge HoffmanLa Roche for providing sulfadoxine-pyrimethamine (fansidar) and placebo, and UNICEF for providing iron syrup. This investigation received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). The study protocol was approved by the Ifakara Health Research & Development Centre’s scientific and ethical review committees, the Tanzania Medical Research Co-ordinating Committee (Ref NIMR/ HQ/R.8a/VOL.VII/45) and by WHO (ref M24/181/185/ID: 980483). The funding source had no role in data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. References 1 Geerligs PDD, Brabin B, Eggelte TA. Analysis of the effects of malaria chemoprophylaxis in children on haematological responses, morbidity and mortality. Bull World Health Organ 2003; 81: 205–16. 2 Schellenberg D, Menendez C, Kahigwa E, et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebocontrolled trial. Lancet 2001; 357: 1471–77. 3 Schellenberg D, Aponte J, Kahigwa E, et al. The incidence of clinical malaria detected by active case detection in children in Ifakara, southern Tanzania. Trans R Soc Trop Med Hyg 2003; 97: 647–54. 4 Drakeley C, Schellenberg D, Kihonda J, et al. An estimation of the entomological inoculation rate for Ifakara: a semi-urban area in a region of intense malaria transmission in Tanzania. Trop Med Int Health 2003; 8: 767–74. 5 Compendium of data sheets and summaries of product characteristics 1999–2000. London: Datapharm publications, 1999. 6 Schellenberg D, Kahigwa E, Drakeley C, et al. The safety and efficacy of sulphadoxine-pyrimethamine, amodiaquine and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 2002; 67: 17–23. 7 Belnoue E, Costa F, Frankenberg T, et al. Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatment. J Immunol 2004; 172; 2487–95.
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Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial David Schellenberg, Clara Menendez, John J Aponte, Elizeus Kahigwa, Marcel Tanner, Hassan Mshinda, Pedro Alonso
Lancet 2005; 365: 1481–83 See Comment page1443
Stopping antimalarial chemoprophylaxis can be followed by increased risk of malaria, suggesting that it interferes with the development of antimalarial immunity. We report analysis of extended follow-up until age 2 years of a randomised, placebo-controlled double-blind trial of intermittent preventive antimalarial treatment in infants. The rate of clinical malaria (events per person-year at risk, starting 1 month after final dose of intermittent treatment) was 0·28 in the sulfadoxine-pyrimethamine group and 0·43 in the placebo group (protective effect 36%, 95% CI 11–53). Intermittent treatment produced a sustained reduction in the risk of clinical malaria extending well beyond the duration of the pharmacological effects of the drugs, excluding a so-called rebound effect and suggesting that such treatment could facilitate development of immunity against Plasmodium falciparum. Infection with Plasmodium falciparum kills about a million African children every year. Trials of malaria chemoprophylaxis in endemic settings have shown the potential of antimalarial drugs to protect children from malaria episodes and death.1 However, several studies have documented an increase in the incidence of clinical malaria in children after prophylaxis stopped—the socalled rebound effect.1 In a safety and efficacy trial of intermittent antimalarial preventive treatment in infants,2 we have reported that sulfadoxinepyrimethamine delivered at the time of routine vaccinations reduced the incidence of clinical malaria by 59% (95% CI 41–72), and halved the incidence of severe anaemia (defined by a packed cell volume 25%) in the first year of life. Here, we present analyses of extended follow-up to assess the possibility of a rebound effect after this treatment. The setting and methodology are described in detail elsewhere.2 In brief, this study was a double-blind, individually randomised, placebo-controlled trial based at the Ifakara Mother and Child Health clinic in southern Tanzania. Children of consenting parents were recruited between August, 1999, and April, 2000, and given sulfadoxine-pyrimethamine or placebo when attending for vaccination with diphtheria-pertussistetanus and oral polio at ages 2 months and 3 months, and measles vaccination at age 9 months. Doses of sulfadoxine-pyrimethamine or placebo, administered according to bodyweight, were crushed and mixed with water on a tablespoon. Iron supplements (target dose of 2·5 mg kg–1 day–1) were dispensed to all children at recruitment and when attending a routine weighing clinic at age 4 months. Parents were encouraged to bring sick children to project clinical officers at the St Francis Designated District Hospital. Standardised clinical information was recorded and, if there was a history of fever in the preceding 24 h or axillary temperature was 37·5ºC or higher, capillary blood was taken for malaria parasite examination and measurement of packed cell volume. Malaria was treated with sulfadoxinewww.thelancet.com Vol 365 April 23, 2005
pyrimethamine unless presentation was within 14 days of such treatment or placebo, in which case treatment was with quinine. Children were followed up until the youngest members of the cohort were aged 18 months, by which time 40% were aged 2 years or older. Weight, packed cell volume, and P falciparum parasitaemia were measured at 18 months of age. Standard procedures2 established the presence and density of sexual and asexual malaria parasites on blood films, and packed cell volumes were measured in centrifuged microcapillary tubes. Protection against measles was determined by antibody titres in a simple random sample of blood specimens obtained at 12 months and measured unaware of treatment allocation with commercial ELISA kits (DiaSorin, Hycor Biomedical GmbH, Kassel, Germany); we present results of all samples evaluated in the trial. Clinical malaria defined as an axillary temperature 37·5ºC or higher with asexual P falciparum parasitaemia of any density has an estimated sensitivity and specificity of 100% and 97%, respectively.2 The primary purpose of the analysis was to exclude a rebound increase in the risk of clinical malaria following intermittent antimalarial preventive treatment. We estimated that a sample size of 700 would provide 80% power to detect a 50% increase in the incidence of the first or only episode of clinical malaria from 0·7 to 1·05 episodes per person-year at risk between 10 and 18 months of age at a 5% significance level, and allowing 20% loss to follow-up. The analyses are based on children who received three doses of intermittent preventive treatment, and started time at risk 1 month after the third dose of such treatment. Unlike the survival analyses presented previously, children were included irrespective of malaria episodes in the first 10 months of life. Individuals contributed to the time at risk until end of follow-up or when censored as a result of withdrawal or death. The protective effect was estimated from the hazard ratio (HR) in Cox regression models as 100(1–HR)% for analyses of first or only episodes, and as
Centre for International Health, Institut d’Investigacions Biomedicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain (D Schellenberg MRCP, C Menendez MD, J J Aponte MD, P Alonso MD); Ifakara Health Research and Development Centre, Kilombero, Tanzania (D Schellenberg, E Kahigwa MSc, H Mshinda PhD); Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK (D Schellenberg); and Swiss Tropical Institute, Basel, Switzerland (Prof M Tanner PhD) Correspondence to: Dr David Schellenberg, IHRDC, PO Box 78373, Dar es Salaam, Tanzania [email protected]
1481
Research Letters
See Lancet Online for webfigure and webtable
We have shown a continuing reduction in the risk of first or only episodes of clinical malaria in children aged 10 months to 2 years from intermittent preventive antimalarial treatment for infants. This finding increases the potential public-health benefits of such treatment and raises intriguing questions about the underlying mechanisms. The sustained protection seems to have had two components. Firstly, intermittent treatment decreased the risk of a first malaria episode, which itself is a major risk factor for subsequent episodes. This increased risk is not just due to increased exposure: adjustment for known risk factors for malaria in this area3 (use of mosquito nets and distance between home and hospital, reflecting proximity to vector breeding sites4) had a small, non-significant effect on the efficacy estimate. Illness-causing P falciparum infections in infants might not only fail to induce protective immunity but also enhance the risk of subsequent malaria illness. This situation emphasises the importance of protecting young infants from malaria. The second component of the sustained benefit of intermittent treatment is not related to a child’s experience of clinical malaria, since analysis controlling for previous episodes still yielded evidence of a reduction in malaria risk. This effect is unlikely to be due to the pharmacological action of sulfadoxine or pyrimethamine because their half-lives are roughly 7 days and 4 days, respectively,5 and time at risk for these analyses started 30 days after the final dose. A study of the efficacy of sulfadoxine-pyrimethamine in 1999 showed that, although there were no late treatment failures, 31% of children were parasitaemic by day 14 of follow-up.6 It is likely that most children were aparasitaemic when they received intermittent treatment because the parasite prevalence in placebo recipients was only 9% (25 of 274) in children aged 18 months, and is likely to have been even lower at the time of treatment doses. Hence, the most frequent interaction between P falciparum and sulfadoxine-pyrimethamine as intermittent preventive treatment might have arisen when children with subtherapeutic drug concentrations developed new infections. We postulate that the combined antiplasmodial effects of sulfadoxine-pyrimethamine, maternal immunity, and fetal haemoglobin effectively prevented new blood-stage infections developing into clinical episodes. Furthermore, parasites could have
100(1–rate ratio)% for assessments of multiple malaria episodes based on Poisson regression models with random effects to take into account between-child and within-child variation. Children were not regarded as at risk for 28 days after each presentation with malaria. Nutritional indices based on weight and age were generated with EPINUT tables (EPI Info version 6, CDC Atlanta, GA, USA). We randomly assigned 701 children either sulfadoxinepyrimethamine or placebo. A similar number of children in each group received all three doses of drug or placebo and completed extended follow-up (webfigure). The webtable shows baseline characteristics. During extended follow-up, the rate of first or only clinical malaria episodes was higher for recipients of placebo than for recipients of sulfadoxine-pyrimethamine: the protective effect was 36% (table). Between 10 months and 2 years of age, recipients of preventive treatment remained at lower risk of clinical malaria than recipients of placebo, and the survival curves diverged with time (figure). Adjustments for sex, distance of residence from the hospital, use of mosquito net, haemoglobin genotype, age at recruitment, and nutritional status at recruitment altered the efficacy estimate by less than 0·5%. Adjustment for previous malaria episodes reduced the estimate to 27% (95% CI –1 to 47), largely because of an increase of 2·5 (1·7 to 3·6, p0·0001) times in the risk of clinical malaria in those who had had a previous clinical malaria episode. There was no significant interaction between treatment group and previous malaria episode (p=0·222). Extending the scope of the analysis to include all episodes of malaria yielded a 23% reduction in clinical malaria after intermittent treatment, and controlling for previous malaria episodes reduced this estimate to 11% (95% CI –18 to 33). The incidence of severe anaemia was very similar in the two groups. At 18 months of age, the prevalences of fever, parasitaemia, severe anaemia, and parasite densities, mean packed cell volume, and anthropometric indices did not differ in the two groups (data not shown). At the same time, the prevalence of gametocytaemia was 3% (nine of 294) in recipients of placebo and 1% (three of 294) in recipients of sulfadoxine-pyrimethamine (p=0·08). The prevalence of protective antibody titres against measles was 92% (142 of 155) and 86% (140 or 162), respectively (Fisher’s exact p=0·155). Placebo (n=278)
Sulfadoxine-pyrimethamine (n=277)
Events
Person years at risk Rate
Events
Person years at risk
Rate
216·0
0·43
65
236·3
0·28
263·2
0·42
88
269·9
248·9
0·11
30
263·3
Malaria First or only episode 93 Adjusted for previous malaria episodes All episodes 111 Severe anaemia Severe anaemia (packed cell volume 25%) 27
Protective effect (95% CI)
p value
0·33
36% (11 to 53) 27% (–1 to 47) 23% (–5 to 43)
0·006 0·053 0·097
0·11
–5% (–77 to 38)
0·852
Table: Rate of clinical malaria from 1 month after dose three until end of follow-up
1482
www.thelancet.com Vol 365 April 23, 2005
Research Letters
Free of disease (%)
100
90 Sulfadoxine-pyrimethamine
Conflict of interest statement All authors are members of the IPTi (Intermittent Preventive antimalarial Treatment in infants) consortium, which is financially supported by the Bill and Melinda Gates Foundation and funds some of our research activities, but not the project reported here.
80 Placebo 70 p value for logrank test: 0·006 60 0 0
2
4
6
8
10
12
14
Time since 30 days after dose three (months) Number at risk 265 Placebo Sulfadoxine- 277 pyrimethamine
249
235
213
192
146
121
66
263
250
235
222
172
126
96
Figure: Kaplan-Meier survival curve
been attenuated in vivo, providing the immune system with an enhanced opportunity to generate protective responses. Some support for this hypothesis comes from experience of P yoelli in mice.7 If our hypothesis is correct, drugs with greater parasitocidal effectiveness might produce less pronounced sustained effects when used as intermittent preventive treatment than less effective drugs. It seems unlikely that the documented differences in malaria risk were due to selection bias: the baseline characteristics and completeness of follow-up of the two groups in this randomised study were similar. Although all children lived within 6 km of the hospital, and curative services were provided free of charge, passive case detection might have missed some malaria episodes. The unlikely event that the proportion of undetected episodes varied between the two groups could have biased our results. The sustained reduction in the risk of clinical malaria in children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine enhances the potentially considerable value of such treatment for malaria control, and suggests a novel approach for facilitation of the development of protective immunity to malaria. Contributors All authors contributed to definition of the rationale and study design. D Schellenberg and E Kahigwa were responsible for all field and hospital-based activities, as well as supervision of data management and quality control. Data analysis was led by J Aponte with contributions
www.thelancet.com Vol 365 April 23, 2005
from all authors, especially D Schellenberg, C Menendez, and P Alonso. H Mshinda and M Tanner contributed to all aspects of the trial and supported the running of the Ifakara Centre. The report received inputs from all authors, but the writing was led by D Schellenberg, C Menendez, and P Alonso. C Menendez and P Alonso coordinated the research team.
Acknowledgments We are indebted to the mothers and families of study children, the medical director and ward staff of St Francis Designated District Hospital, the Kilombero District medical officer and Ifakara Mother and Child Health Clinic staff for their collaboration within this project. The work of the clinical officers, field supervisors, assistant data manager, and laboratory coordinator was important for the successful completion of the study. Josep Vidal did serological assays in the department of microbiology of the Hospital Clinic, Barcelona. We are very grateful to M Corachan who independently monitored the trial and provided invaluable support and guidance. We acknowledge HoffmanLa Roche for providing sulfadoxine-pyrimethamine (fansidar) and placebo, and UNICEF for providing iron syrup. This investigation received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). The study protocol was approved by the Ifakara Health Research & Development Centre’s scientific and ethical review committees, the Tanzania Medical Research Co-ordinating Committee (Ref NIMR/ HQ/R.8a/VOL.VII/45) and by WHO (ref M24/181/185/ID: 980483). The funding source had no role in data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. References 1 Geerligs PDD, Brabin B, Eggelte TA. Analysis of the effects of malaria chemoprophylaxis in children on haematological responses, morbidity and mortality. Bull World Health Organ 2003; 81: 205–16. 2 Schellenberg D, Menendez C, Kahigwa E, et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebocontrolled trial. Lancet 2001; 357: 1471–77. 3 Schellenberg D, Aponte J, Kahigwa E, et al. The incidence of clinical malaria detected by active case detection in children in Ifakara, southern Tanzania. Trans R Soc Trop Med Hyg 2003; 97: 647–54. 4 Drakeley C, Schellenberg D, Kihonda J, et al. An estimation of the entomological inoculation rate for Ifakara: a semi-urban area in a region of intense malaria transmission in Tanzania. Trop Med Int Health 2003; 8: 767–74. 5 Compendium of data sheets and summaries of product characteristics 1999–2000. London: Datapharm publications, 1999. 6 Schellenberg D, Kahigwa E, Drakeley C, et al. The safety and efficacy of sulphadoxine-pyrimethamine, amodiaquine and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 2002; 67: 17–23. 7 Belnoue E, Costa F, Frankenberg T, et al. Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatment. J Immunol 2004; 172; 2487–95.
1483