Assessment of the Role of Intermittent Preventive Treatment for Malaria in Infants Letter Report (2008) / Chapter Skim
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I am pleased to report the findings and recommendations of the committee, which reflect committee deliberations based on these presentations, additional analyses from the IPTi Consortium and the committee, and other relevant scientific literature. This report begins with a summary of the committee's key messages, followed by background information on malaria, intermittent preventive treatment, the possibility of a rebound effect, and the Expanded Program on Immunization.
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The purpose of the IOM review is to provide guidance to the Bill and Melinda Gates Foundation on a number of scientific, clinical, and programmatic issues related to IPTi, including whether the efficacy data from these studies support continued investment in IPTi-SP as a potentially useful tool to reduce morbidity from malaria in infants in some regions of subSaharan Africa. The Consortium (a group of autonomous institutions involved with malaria research in Africa, Europe, and the United States)
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If the decision is made to begin programmatic implementation, the committee recommends that IPTi-SP first be implemented in perennial, high- or moderate-intensity transmission areas in sub-Saharan Africa where the disease burden in infancy is high and SP resistance is not high, in order to obtain the greatest public health impact. In considering the current and future role of IPTi-SP, one must be cognizant that in many areas of sub-Saharan Africa there is a trend for the malaria disease burden to be diminishing and particularly among infants.
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2006. Intermittent preventive treatment for malaria control administered at the time of routine vaccinations in Mozambican infants: A randomized, placebo-controlled trial.
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The committee does not offer perspectives on other strategies for malaria prevention and control, such as the use of insecticide-treated bed nets or indoor residual insecticide spraying. Those interested may find a more detailed discussion of the history of malaria, of its clinical description, of the options for its treatment, and of the strategies and initiatives used to control it in a previous IOM report entitled Saving Lives, Buying Time (IOM, 2004)
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In this systematic review, nine randomized controlled trials of IPTp-SP in Africa were matched on the basis of country and time of trial with treatment studies of SP in symptomatic children. Protective efficacy of ITPp-SP was determined by comparing the different control groups (chloroquine prophylaxis, placebo (case management)
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. Intermittent Preventive Treatment in Infants As indicated in this report, IPTi involves the administration of full therapeutic doses of an antimalarial to asymptomatic infants in conjunction with some of the infant's healthcare visits to receive immunizations; IPTi-SP is IPTi with SP as the antimalarial.
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SOURCE: Aylward et al., 2004; WHO, 2004b. Intermittent Preventive Treatment in Children and Seasonal Intermittent Preventive Treatment Intermittent preventive treatment in children (IPTc)
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In contrast, experts are uncertain as to what happens after cessation of continuous chemoprophylaxis of children. In particular, given the limited data, there is not a consensus on whether interference with attainment of immunity during the period of continuous prophylaxis will lead to an increase in clinical malaria infections after cessation of chemoprophylaxis.
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Indeed, "the frequency of clinical malaria in the 8 weeks after prophylaxis stopped was about twice as high as that seen in the placebo group at any time during the intervention period" (Menendez, 1997, p.
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In that trial of continuous chemoprophylaxis in infants, the frequency of clinical malaria was significantly reduced compared with the frequency of clinical malaria in the control group during the treatment period. During the continuing follow-up after cessation of prophylaxis, however, the situation reversed: Children who had received continuous chemoprophylaxis experienced significantly higher rates of clinical malaria than did the control group of children who had previously received placebo.
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. SP delayed the median time to the first episode of clinical malaria from 38.5 days to 68 days but, similar to the chemoprophylaxis trial by Mendendez et al.
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Stated in another way, whatever the protective effect of SP during the intervention period, because of the long periods of time between the last two doses (either the time between the ages of 4 and 9 months or the time between the ages 9 and 15 months) , one would expect the children to have considerable exposure to infected mosquitoes during periods when they do not have protective blood levels of the drug, and therefore they presumably will have repetitive immunologic stimulation by Plasmodium.
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Methods Used to Detect Clinical Outcomes of Interest in the IPTi-SP studies Local conditions and logistical considerations led to differences among the six studies with respect to the active and passive follow-up methods used to detect relevant outcomes such as cases of malaria, anemia, hospitalizations of children with malaria parasites and all-cause hospitalization. As a convenience for the reader, Box 1 summarizes the different methods used in the six trials.
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LETTER REPORT 15 BOX 1 A Summary of the Methods Used in Each IPTi-SP Study to Detect Critical Outcomes Including Clinical Malaria and (Depending on the Specific Study) Anemia, Hospitalization of Patients with Malaria Parasites, and All Cause Hospitalizations Study Surveillance Methods Ifakara Passive and active (three-monthly cross-sectional surveys including blood smears)
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16 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS BOX 1 Continued passive case detection surveillance, the assessment of safety was conducted through home visits to assess morbidity 1 week after each dose, through specific registration of dermatological complaints of children attending the hospital, and through blood tests performed 1 month after receipt of the second IPTi dose." Kumasi Passive and active (monthly cross-sectional surveys including blood smears) : Kobbe "Episodes of clinical malaria, anemia, and adverse events were monitored 2007 monthly through active follow-up visits (20,733 visits in total)
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LETTER REPORT 17 Time Periods and Method of Analysis Taken into Consideration in Assessing Efficacy In the view of the committee, estimates of the efficacy of IPTi-SP should take into account both the period spanning the dosings with SP and a further follow-up extending for months after the last dose of SP, the latter period representing when rebound might be expected to occur. The ideal length of follow-up after cessation of treatment with SP or placebo to detect rebound can be debated: Too short a period might exclude true cases of rebound.
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Lancet 2001, 2005 BMJ 2005 JID 2006 CID 2007 JID 2007 AAC 2007 Recruitment (years) 1999–2000 2000–2002 2002–2004 2003–2005 2004–2005 2003 Entire study period 8/1999–4/2001 9/2000–6/2004 9/2002–2/2004 1/2003–9/2005 12/2002–8/2006 3/2003–7/2005 EIR/year 29 418 38 400 50 Not available Transmission Perennial Highly seasonal Perennial with Perennial Perennial with Perennial with seasonal peaks seasonal peaks seasonal peaks Predicted annual incidence of 0.43 1.0 0.55 1.29 0.22 0.88 clinical malaria in placebo group (all episodes)
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. These additional analyses examined the incidence of all episodes of clinical malaria, hospitalizations with malaria parasites and other outcomes over various time periods with person-years at risk as the denominators for the treatment and control groups.
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. The primary outcome was "prevention of clinical malaria in the first year of life" (IPTi Consortium, 2008a)
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Assumptions – Control group: 0.63 incidence N/A Placebo incidence rate = Assumptions not Placebo proportions -- anemia: Assumptions not protocol clinical malaria/PYAR; 0.42 0.33 case/yr presented 0.28; malaria: 0.60 presented incidence severe malaria/PYAR; 30% reduction in SP Assumptions- Control group: 0.36 clinical Incidence in placebo group Same as protocol Assumptions not Same as protocol for anemia; Assumptions not manuscript malaria/PYAR; 0.28 episodes of 25% presented no mention of malaria presented severe malaria/PYAR Power-protocol Protocol says "adequate" N/A 80% power to detect a Power not in protocol. 80% to detect a protective No power calculation protective efficacy of 30% Method of analysis efficacy of 30% against against having at least one not clearly defined having at least one episode of episode of malaria anemia and 16% for malaria Power-manuscript 80% 95% power to detect a 25% Same as protocol Study designed with Same as protocol for anemia; Sample size adequate to reduction (cluster 80% power to detect no mention of malaria detect 25% reduction in randomization)
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To compare results across the six trials, the committee used the estimates of 12-month protective efficacy whenever the data were available in the publications. As Table 4 shows, all the studies except the Lambaréné trial demonstrate a statistically significant reduction in the probability of contracting clinical malaria; for two of those five trials (Ifakara and Tamale)
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. Combined estimates were obtained using meta-analysis with random effects.
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Because the committee did not have access to raw data, we could not confirm the analyses. On the other hand, if the analyses are corroborated by an independent audit, they provide very instructive information with respect to the ability of IPTi-SP to exert a protective effect against all episodes of clinical malaria through 11 months of age.
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c Combined estimates are based on random-effects meta-analyses. d Range: lowest and highest estimated protective efficacy for the sensitivity analyses.
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As a consequence of the lack of acquisition of immunity in this theoretical scenario, when children who are no longer receiving intermittent SP therapy are subsequently exposed to the bites of infected mosquitoes, they would develop symptomatic malaria illness and more severe clinical malaria illness at a higher rate than would children of the same age who had not received IPTi-SP during the first year of life. On the other hand, some researchers contend that the intermittent nature of IPTi-SP dosing may allow infants to acquire immunity despite the three spaced doses of SP administered during infancy (Schreiber et al., 2007)
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The monthly follow-up visits allowed assessment of whether the infants had experienced clinical malaria or sub-clinical P falciparum infection in the period between 3 and 9 months of age.
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. Among the six trials, the most favorable outcome was seen in the initial IPTi studies in Ifakara, which showed a protective efficacy of 36 percent against the first or only episode of clinical malaria and of 23 percent for all episodes of malaria after the last dose of IPTi-SP in children aged 10 months (1 month after the last dose)
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b 8b (–5, 19) b NOTE: CI: confidence interval; NR: not reported; Pbo: placebo; PE: protective efficacy.
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Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Kumasi, Ghana Lambaréné, Gabon Tamale, Ghana Placebo Episodes 23 147 33 53 10 30 PYAR 25 107 49 40 40 51 Incidence 0.92 1.4 0.67 1.3 0.25 0.58 IPTi with SP Episodes 2 33 10 25 6 5 PYAR 26 107 51 41 40 53 Incidence 0.08 0.31 0.20 0.61 0.15 0.09 Efficacy (95% CI)
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, the point estimates of protective effect (42 percent and 19 percent, respectively) had lower limits of the 95 percent CI that were just slightly below zero (–1.2 percent and –1.3 percent, respectively)
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in Kumasi, Lambaréné, and Tamale until the next dose of IPTi administered at 9 months of age. SOURCE: Reprinted with permission from the Statistical Working Group (IPTi Consortium, 2007b)
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. For outcomes for which the SWG did not provide pooled estimates of protective efficacy, the committee used Stata to calculate pooled estimates of protective efficacy from random-effects meta-analyses from unpublished data of the Consortium.
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34 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS significant. The pooled estimate of protective efficacy was 18 percent with a 95 percent CI of (9, 27)
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for Outcomes During the 5 Months After Last Dose of SP or Placebo Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Kumasi, Ghana Lambaréné, Gabon Tamale, Ghana Overall Number of Subjects Placebo 344 1216 755 159 446 561 IPTi-SP 344 1197 748 162 459 556 Episodes of Clinical Malaria Placebo 87 443 191 298 24 436 IPTi-SP 62 436 192 301 34 442 % PE 30 0 –6 –3 –36 0 0 95 CI (%)
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. TABLE 13 Risk of Anemia from Randomization Up to 5 Months After the Last Dose of SP Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Kumasi, Ghana Lambaréné, Gabon Tamale, Ghana Overall Placebo Episodes 31 234 87 316 110 347 Subjects 351 1225 748 535 507 599 Risk (%)
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. TABLE 15 Incidence of All-Cause Hospital Admissions from Randomization Up to 5 Months After the Last Dose of SP Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Kumasi, Ghana Lambaréné, Gabon Tamale, Ghana Overall Placebo Episodes 172 445 359 94 NA 73 PYAR 303 1400 632 710 NA 714 Incidence 0.57 0.32 0.57 0.13 NA 0.10 IPTi with SP Episodes 138 397 298 92 NA 49 PYAR 303 1405 637 709 NA 707 Incidence 0.46 0.25 0.47 0.13 NA 0.07 Efficacy (95% CI)
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As seen in Table 17, three of the sites had relevant data. For each outcome, the combined estimate of protective efficacy was in the direction of benefit; the 95 percent confidence intervals, however, showed lower limits that were either just above zero (0.8 percent for episodes of malaria and 0.2 percent for all-cause hospitalizations)
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for Outcomes During the 11 Months After Last Dose of SP or Placebo Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Number of Subjects Placebo 344 1216 755 IPTi-SP 344 1197 748 Episodes of Clinical Malaria Placebo 166 826 336 IPTi-SP 146 854 344 % PE 14 –5 –16 95 CI (%)
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for Outcomes from Randomization Through 11 Months After Last Dose of SP or Placebo Location, Country Ifakara, Tanzania Navrongo, Ghana Manhiça, Mozambique Overall Number of Subjects Placebo 351 1225 748 IPTi-SP 350 1221 755 Episodes of Clinical Malaria Placebo 259 1871 576 IPTi-SP 180 1570 564 % PE 32 16 2 17 95 CI (%)
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The cumulative efficacy during these distinct periods results in an overall net benefit from IPTi-SP. Finding for measured outcome events other than clinical malaria: The committee found that the cumulative data supporting an effect on hospitalization with malaria parasites, anemia and all-cause hospitalization were more modest and less consistent across the trials than the effect on episodes of clinical malaria.
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With respect to clinical malaria, the primary outcome of interest, the combined estimate of protective efficacy using random-effects meta-analysis was 0 percent with a 95 percent CI of (–10, 9; p>0.99)
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. Recommendation: In view of the importance of the unpublished analyses by the SWG in showing a net benefit for IPTI-SP, and whereas the committee had no information about how the SWG or the individual study teams ensured quality control of the individual study data and hence the uniformly defined outcomes, the committee recommends that the SWG obtain an independent technical audit of the accuracy of the study-level data and analyses included in the pooled analysis.
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If the evidence of IPTi-SP in preventing clinical malaria is deemed sufficient to propose instituting pilot implementations, there may not be sufficient equipoise to justify large controlled trials of IPTi-SP to evaluate its ability to prevent anemia, hospitalizations with malaria, or all-cause hospitalizations. One possible solution might be to nest case-control studies within large-scale, population based pilot implementations of IPTi-SP.
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. The subsequent trials all reported approximately 20–30 percent protective efficacy against clinical malaria.
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. IPTi-SP and the Promotion of Resistance The long clearance times of SP give it potential value as a practical intermittent preventive treatment for malaria in infants; however, the long clearance times also establish potentially selective levels of SP-resistant parasites in the bloodstream.
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Safety of Intermittent Preventive Treatment in Infants with Sulfadoxine-Pyrimethamine Use of SP is known to cause hypersensitivity reactions including nonspecific rashes, urticaria (hives) , and other adverse effects.
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. The evidence presented from the IPTi trial for safety monitoring was based primarily on passive reports in the six efficacy trials and in the additional trial in Kisumu, but the surveillance methods varied as noted in Table 19 (and Box 1)
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to detect adverse reactions that may arise when recipients of IPTi-SP in infancy subsequently receive cotrimoxazole or other sulfa drugs. Pharmacokinetics of Sulfadoxine-Pyrimethamine Ideally, data on the pharmacokinetics of SP in healthy African infants would be useful; however, little information is available on the pharmacokinetics of antimalarial drugs, including SP, in the first year of life.
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The serological study, with guidance from the WHO Advisory Committee, was designed as a set of non-inferiority studies nested into five IPTi, randomized-controlled trials that were already underway to assess the protective efficacy of IPTi against clinical malaria and anemia. The sites included three Consortium IPTi sites (Navrongo, Ghana; Manhiça, Mozambique; and Kisumu, Kenya)
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Results from the pooled analyses showed a highly significant formal test of non-inferiority (p<0.001) for the primary outcome.
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The findings show that even though men are involved in matters related to child health, mothers have relative freedom in health decision-making because the mothers are ultimately responsible for taking the children to health clinics. The southern Tanzanian investigators concluded that there is uncertainty regarding the level of male influence when the health intervention is provided at home and not at the health facility (IPTI Consortium, 2008d)
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Other barriers identified from the preliminary data collected from the UNICEF sites include the requirement to cut the SP tablet, the need for intensive supervision of the program, the continuity of the drug supply, and the EPI shortages or cold-chain disruption that led to temporary cessation of child vaccinations (IPTi Consortium 2008e)
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Investigators used 2006 Tanzanian prices to calculate intervention costs and excluded the costs associated with research and with operation of clinical trials. Cost-effectiveness ratios (using efficacy results from the 2 individual trials and excluding cost savings from less severe malaria cases)
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; $4 to $29 for intermittent preventive treatment in pregnancy (Goodman et al., 1999) ; $32 to $41 for indoor residual insecticide spraying (Morel et al., 2005)
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Conclusion about continued investment in IPTi: On the basis of the evidence presented, the committee concluded that a decrease in the malaria burden in infancy would be expected to ensue after programmatic implementation of IPTi-SP in areas with high incidence of clinical malaria. The greatest public health impact of IPTi-SP will almost certainly be observed in areas of sub-Saharan Africa with high- and moderate intensity, perennial transmission.
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Thus, the committee finds the data supporting the efficacy and the safety of IPTi-SP against episodes of clinical malaria to be sufficiently persuasive to endorse continued investment in IPTi-SP and to believe that this intervention is ready to progress to another level. The committee is also acutely aware that the epidemiology of malaria in many areas of sub-Saharan Africa appears to be undergoing change, resulting in diminished exposure of local populations to infective mosquitoes and a diminished burden of clinical disease, particularly among infants.
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As additional evidence is generated from pilot projects, step-wise implementations, and focused studies to fill knowledge gaps and to expand the existing knowledge base about IPTi, its relative value as a control measure will become more clear. The IOM Committee on the Perspectives on the Role of Intermittent Preventive Treatment for Malaria in Infants appreciates the opportunity to provide input into the global health initiatives of the Bill and Melinda Gates Foundation.
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The cumulative efficacy during these distinct periods results in an overall net benefit from IPTi-SP. • The committee found that the cumulative data supporting an effect on hospitalization with malaria parasites, anemia and all-cause hospitalization were more modest and less consistent across the trials than the effect on episodes of clinical malaria.
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With respect to clinical malaria, the primary outcome of interest, the combined estimate of protective efficacy using random-effects meta-analysis was 0 percent with a 95 percent CI of (–10, 9; p>0.99)
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Program Management of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine • The committee found that many issues relevant to programmatic management of IPTi-SP were not well-explored in the studies presented. To enhance the acceptability and sustainability of IPTi-SP, the committee concluded that systematic capture of this information can help support continued improvement of a stepwise strategy for increasingly larger-scale implementation of IPTi-SP in relevant areas of sub-Saharan Africa if public health authorities implementing IPTi-SP are asked to regularly share information related to logistics, policy and program implementation, monitoring and evaluation, mode of delivery, and acceptability.
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In areas of low or seasonal transmission, where the greatest burden of malaria occurs after the first year of life, the public health benefit of IPTi may be less. The committee further concluded that continued investment in the strategy appears warranted but cautions that drug supply and logistics, monitoring and resistance, and community acceptance and reaction to IPTi-SP could arise as problems in conjunction with large-scale implementation.
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The provision of stronger evidence on these issues would be invaluable; the committee, however, recognizes that trying to estimate these parameters may involve an ethical challenge. If the evidence of IPTi-SP in preventing clinical malaria is deemed sufficient to propose instituting pilot implementations, there may not be sufficient equipoise to justify large controlled trials of IPTi-SP to evaluate its ability to prevent anemia, hospitalizations with malaria, or all-cause hospitalizations.
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64 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS Sincerely, Myron M Levine, Chair Committee on the Perspectives of the Role of Intermittent Preventive Treatment for Malaria in Infants Attachments Appendix A Committee Members and Staff, 65 Appendix B References, 66 Appendix C Glossary, 74 Appendix D Meeting Agenda, 76 Appendix E Reviewers, 79 Appendix F List of Tables, Figures, and Boxes, 80
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