INSTITUTE OF MEDICINE

Board on Global Health

June 30, 2008

A. David Brandling-Bennett, M.D., D.T.P.H.

Senior Program Officer

Infectious Diseases Development, Global Health Program

Bill and Melinda Gates Foundation

PO Box 23350 Seattle, WA 98102

Dear Dr. Brandling-Bennett:

At the request of the Bill and Melinda Gates Foundation, the Institute of Medicine (IOM) convened an expert committee to evaluate the evidence concerning intermittent preventive treatment for malaria in infants with sulfadoxine-pyrimethamine (IPTi-SP) and provide guidance on the value of continued investment in IPTi-SP. As this letter report describes in detail, the committee finds sufficient evidence to conclude that IPTi-SP is a valuable strategy for decreasing morbidity from malaria infections among infants who are at high risk because they reside in malaria-endemic areas in sub-Saharan Africa.

The committee greatly appreciated the briefing you provided on behalf of the Bill and Melinda Gates Foundation. The committee was also pleased with the comprehensiveness and clarity of the presentations made by the principal investigators of several of these IPTi studies, as well as with the lucid, inclusive, and extremely informative presentation made by a representative of the World Health Organization (WHO). We also appreciated the presentations given by others who have conducted related research or who have been involved in global policy deliberations related to IPTi. 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. The remaining sections present the committee’s findings and recommendations, organized by the following topics:

  • Efficacy of IPTi with Sulfadoxine-Pyrimethamine (based on review of individual and combined clinical trial results during treatment and follow-up periods)

  • Potential collateral effects of IPTi-SP (resistance to SP, drug safety, relationship with childhood immunization programs, programmatic management, cost effectiveness)

  • The potential value of continued investment in IPTi-SP

A complete list of the committee’s conclusions and recommendations is compiled in Boxes 2 and 3 before the Appendixes.



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Board on Global Health June 30, 2008 A. David Brandling-Bennett, M.D., D.T.P.H. Senior Program Officer Infectious Diseases Development, Global Health Program Bill and Melinda Gates Foundation PO Box 23350 Seattle, WA 98102 Dear Dr. Brandling-Bennett: At the request of the Bill and Melinda Gates Foundation, the Institute of Medicine (IOM) convened an expert committee to evaluate the evidence concerning intermittent preventive treatment for malaria in infants with sulfadoxine-pyrimethamine (IPTi-SP) and provide guidance on the value of continued investment in IPTi-SP. As this letter report describes in detail, the committee finds sufficient evidence to conclude that IPTi-SP is a valuable strategy for decreasing morbidity from malaria infections among infants who are at high risk because they reside in malaria-endemic areas in sub-Saharan Africa. The committee greatly appreciated the briefing you provided on behalf of the Bill and Melinda Gates Foundation. The committee was also pleased with the comprehensiveness and clarity of the presentations made by the principal investigators of several of these IPTi studies, as well as with the lucid, inclusive, and extremely informative presentation made by a representative of the World Health Organization (WHO). We also appreciated the presentations given by others who have conducted related research or who have been involved in global policy deliberations related to IPTi. 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. The remaining sections present the committee’s findings and recommendations, organized by the following topics: • Efficacy of IPTi with Sulfadoxine-Pyrimethamine (based on review of individual and combined clinical trial results during treatment and follow-up periods) • Potential collateral effects of IPTi-SP (resistance to SP, drug safety, relationship with childhood immunization programs, programmatic management, cost effectiveness) • The potential value of continued investment in IPTi-SP A complete list of the committee’s conclusions and recommendations is compiled in Boxes 2 and 3 before the Appendixes. 1 500 Fifth Street, NW Washington DC, 20001 www.national-academies.org

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2 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS SUMMARY OF KEY MESSAGES The Institute of Medicine (IOM) convened a committee with the following charge: (1) to review clinical trial methods and data analyses used in the studies conducted by the Intermittent Preventive Treatment in Infants (IPTi) Consortium (the Consortium); (2) to formulate consensus conclusions as to the advisability of further investment in IPTi using sulfadoxine-pyrimethamine (SP), on the basis of the results of six efficacy studies conducted over the last decade (or, if the evidence is sufficient, to consider investment with alternative drugs more recently studied); and (3) to consider drug safety (of prophylactic antimalarial drug use in infants in general and of treatment with SP in particular) and drug resistance; dosage regimens; potential collateral effects on other childhood healthcare programs (e.g., immunization); cost-effectiveness; and program management. As time and resources did not allow independent audits of trial conduct, data management, or analysis, the charge to the committee required it to assume, for the studies presented, that data collection and management were consistent with quality practices and that the analyses presented were correctly performed. The exception to this was the committee’s undertaking to conduct limited analyses to confirm some of the results of unpublished data from the Consortium. 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 sub- Saharan Africa. The Consortium (a group of autonomous institutions involved with malaria research in Africa, Europe, and the United States) is funded by the Bill and Melinda Gates Foundation. The committee reviewed the published results of six IPTi-SP Consortium field trials as well as unpublished pooled analyses by the Statistical Working Group (SWG) of the Consortium. Based on these analyses, the committee found substantial evidence indicating that IPTi-SP significantly diminished the incidence of clinical malaria in infants living in areas of high and moderate intensity of transmission. Reported data showed that IPTi-SP diminished the incidence of clinical malaria episodes by approximately 20–30 percent in infants who received IPTi-SP rather than a placebo and who were followed from the time of their first dose until a point 5 months and 5 weeks after receipt of their last dose.1 Data for the same period showed suggestive trends but not substantive evidence that IPTi-SP reduces the incidence of hospitalizations of patients with malaria parasites, anemia, and all-cause hospitalizations. The committee found that the extent of rebound is small compared to the overall benefit of IPTi-SP. A 20-30 percent reduction in incidence of clinical malaria in these epidemiologic settings is comparable to the levels of efficacy observed for the use of impregnated bed nets (Lengeler, 2004), which have translated to important improvements in child survival when bed nets were implemented en masse (Schellenberg et al., 2001). The committee therefore concludes that an intervention with results of this magnitude is worthy of further investment as part of a public health strategy to decrease morbidity from malaria infections in infants. 1 The 5-month follow-up period began 5 weeks after receipt of the last dose in order to allow time for the protective effect to wear off. Inclusion of the follow-up period is necessary to look for a rebound effect—that is, an increase in morbidity or mortality after treatment ends compared to a control group that had not received continuous chemoprophylaxis or intermittent therapy.

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LETTER REPORT 3 The committee was satisfied that the pooled analyses were done appropriately but had no information about how the SWG or the individual study teams ensured quality control of the uniformly defined outcomes or of data provided for the pooled analysis. Thus, 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. The committee was not asked whether, when, or where IPTi-SP should be implemented. However, if an independent technical audit confirms the results presented, the committee would support the notion that IPTi-SP is ready to move to a new level. 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. This might ultimately lead to changes in the desirable schedule for IPT-SP for infants and children. The committee recommends that public health authorities monitor evidence for possible increases or decreases of SP resistance in areas or regions of implementation. However, the decreasing use of SP for treatment of malaria in favor of artemisinin-based combination therapy will likely lessen the threat of dissemination of resistance to SP. If public health authorities elect to implement IPTi-SP, the committee recommends that monitoring efforts be undertaken in conjunction with initial implementation in select districts and countries to assess safety, effectiveness, cost-effectiveness, acceptability and sustainability at the community level, and logistical practicality; such efforts will help develop guidelines for larger-scale implementation. One important gap in the information about IPTi-SP is that there are not yet data to show its impact on infant and young-child mortality. An important goal should therefore be to try and gather such information, perhaps in conjunction with focal implementations and large-scale pilot projects. Strengthening the evidence base related to programmatic implementation and management could assist country- level decision makers at key decision points with respect to the national initiation, expansion, maintenance, or discontinuation of IPTi-SP. This approach can generate additional information on a variety of programmatic and pragmatic issues when IPTi-SP is used under real-life conditions. BACKGROUND INFORMATION Committee Process The committee held a 3-day meeting to gather data and information as well as to discuss (1) the implications of the data and the peer-reviewed literature presented by the Consortium, and (2) other relevant literature available in the public domain. After the meeting, discussions continued by means of two teleconferences involving all committee members, as well as by frequent and highly detailed e-mail communications. There were also email communications and conference calls between the committee and members of the Consortium after the meeting. The primary focus of this review was a collection of work completed by members of the Consortium (a group of 17 leading, autonomous institutions involved with malaria research in

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4 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS Africa, Europe, and the United States and funded by the Bill and Melinda Gates Foundation) as well as by two United Nations agencies—the World Health Organization and the United Nations Children’s Fund (IPTi Consortium, 2007a). These organizations came together in 2003 to “generate rigorous and compelling evidence to guide policy on IPTi” (IPTi Consortium, 2007a). Most of the work under consideration came from six peer-reviewed published studies2 that were initiated by independent researchers, in most cases prior to the establishment of the Consortium. These studies were conducted in six separate locations across sub-Saharan Africa between 1999 and 2005. The Consortium has added value to the separate studies in a variety of ways: It has conducted pooled analyses and has made those analyses available to the IOM committee. Because some of the work has not yet gone through the usual peer-review process that occurs prior to publication in a reputable journal, the IOM committee performed a careful assessment that included a multidisciplinary review of not only the results of the studies and of their interpretation by the Consortium researchers, but also of the relevant protocols and (where available) of safety monitoring reports. During the meeting, the committee also received an extensive briefing by the WHO on its latest technical and programmatic deliberations concerning the potential use of IPTi-SP in WHO’s Global Malaria Program. The committee’s conclusions and recommendations relied upon currently available study reports and analyses that the Consortium provided, on discussions of unpublished data of the Consortium, on further analyses of the unpublished data by the committee, and on other publicly available literature. Because time and resources did not allow independent audits of trial conduct, data management, or statistical analyses, the committee was charged to assume that the data collection and management methods for the studies presented were consistent with high-quality practices and that the analyses presented were performed correctly. We requested and received limited additional analyses by the Consortium of some efficacy and safety data. Within this report the committee has identified which analyses come from the published papers, which analyses come from unpublished material from the Consortium, and which analyses the 2 Schellenberg, D., C. Menendez, E. Kahigwa, J. Aponte, J. Vidal, M. Tanner, H. Mshinda, and P. Alonso. 2001. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: A randomised, placebo-controlled trial. Lancet 357(9267):1471- 1477; Schellenberg, D., C. Menendez, J. J. Aponte, E. Kahigwa, M. Tanner, H. Mshinda, and P. Alonso. 2005. Intermittent preventive antimalarial treatment for Tanzanian infants: Follow-up to age 2 years of a randomised, placebo-controlled trial. Lancet 365(9469):1481-1483. Chandramohan, D., S. Owusu-Agyei, I. Carneiro, T. Awine, K. Amponsa-Achiano, N. Mensah, S. Jaffar, R. Baiden, A. Hodgson, F. Binka, and B. Greenwood. 2005. Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ 331(7519):727-733. Macete, E., P. Aide, J. J. Aponte, S. Sanz, I. Mandomando, M. Espasa, B. Sigauque, C. Dobano, S. Mabunda, M. DgeDge, P. Alonso, and C. Menendez. 2006. Intermittent preventive treatment for malaria control administered at the time of routine vaccinations in Mozambican infants: A randomized, placebo-controlled trial. J Infect Dis 194(3):276-285. Kobbe, R., C. Kreuzberg, S. Adjei, B. Thompson, I. Langefeld, P. A. Thompson, H. H. Abruquah, B. Kreuels, M. Ayim, W. Busch, F. Marks, K. Amoah, E. Opoku, C. G. Meyer, O. Adjei, and J. May. 2007. A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Clin Infect Dis 45(1):16-25. Grobusch, M. P., B. Lell, N. G. Schwarz, J. Gabor, J. Dornemann, M. Potschke, S. Oyakhirome, G. C. Kiessling, M. Necek, M. U. Langin, P. K. Klouwenberg, A. Klopfer, B. Naumann, H. Altun, S. T. Agnandji, J. Goesch, M. Decker, C. L. Salazar, C. Supan, D. U. Kombila, L. Borchert, K. B. Koster, P. Pongratz, A. A. Adegnika, I. Glasenapp, S. Issifou, and P. G. Kremsner. 2007. Intermittent preventive treatment against malaria in infants in Gabon--a randomized, double-blind, placebo-controlled trial. J Infect Dis 196(11):1595-1602. Mockenhaupt, F. P., K. Reither, P. Zanger, F. Roepcke, I. Danquah, E. Saad, P. Ziniel, S. Y. Dzisi, M. Frempong, P. Agana-Nsiire, F. Amoo- Sakyi, R. Otchwemah, J. P. Cramer, S. D. Anemana, E. Dietz, and U. Bienzle. 2007. Intermittent preventive treatment in infants as a means of malaria control: A randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrob Agents Chemother 51(9):3273-3281.

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LETTER REPORT 5 committee itself performed. A list of all materials reviewed by the committee is available to the general public through the National Academies’ Public Access and Records Office (to contact by phone, 202-334-3543; by e-mail, PARO@nas.edu). Malaria Epidemiology and the Burden of Malaria in Infants Malaria is a leading cause of death among children in the developing world. According to WHO’s estimates, 350–500 million cases of malaria occur each year worldwide; of the more than 1 million people who die of malaria each year, over 80 percent are young children in sub- Saharan Africa (Global Partnership to Roll Back Malaria and UNICEF, 2005). In Africa, malaria is estimated to cause 18 percent of childhood deaths (Rowe et al., 2006). Global public health initiatives to control malaria include WHO’s Partnership to Roll Back Malaria, with its goal of decreasing the malaria burden by half by 2010 through a focus on treatment, prevention, and response. Goal six of the United Nation’s Millennium Development Goals is to halt the spread of malaria and to begin the reversal of the incidence of malaria and other major diseases by 2015 (United Nations, 2008). This report discusses clinical manifestations and consequences of malaria only in infants. 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) available at www.nap.edu. Human malaria is caused by infection with one of four Plasmodium species transmitted by the bites of female Anopheles mosquitoes. Of the four human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale) known to cause infections in humans, P. falciparum is the most common species found in sub-Saharan Africa; it is associated with severe disease and high case fatality. In malaria-naïve individuals, infection frequently leads to clinical illness and is associated with a high risk of death. As children in malaria-endemic areas experience repeated episodes of malaria infection, they progressively acquire increasing degrees of immunity. Having acquired some degree of immunity, individuals may still become infected (i.e., may have asexual parasites evident in their erythrocytes) after being bitten by infected anophelines; in such partially immune people, however, overt clinical disease is less common, and severe disease is rare. The age at which children living in malaria-endemic areas achieve partial immune status is determined by the intensity and seasonality of malaria transmission. The intensity of malaria transmission is classified as low, moderate, or high on the basis of either entomological inoculation rates (EIRs) or measures of parasite prevalence (e.g., cross-sectional surveys with examination of blood smears). Transmission patterns are further classified as either perennial (conditions that favor year-round exposure and infection) or seasonal (conditions that favor only periodic exposure and infection). Immunity is acquired most rapidly in perennial and high- intensity transmission settings. In areas of highest exposure, children younger than 2 years of age are at the highest risk for severe disease and death. For example, in areas of high malaria transmission in Tanzania, 70–80 percent of hospitalizations among infants younger than 1 year of age are due to severe malaria. As transmission decreases and seasonality increases, the burden

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6 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS of clinical disease is spread over a wider age distribution. Thus, in moderate-transmission settings approximately 70 percent of hospitalizations for severe malaria occur during the first 5 years of life. In low-transmission venues the severe malaria burden is distributed over an even wider age range, as approximately 65 percent of hospitalizations for severe malaria occur among children 0–14 years of age (Reyburn et al., 2005). In sub-Saharan Africa, where the malaria burden is highest, most deaths due to malaria occur in children under 5 years of age. The two common clinical presentations of severe malaria in children are severe anemia and cerebral malaria. These forms of severe disease are associated with a case-fatality rate of up to 20 percent. Severe anemia, defined as a hemoglobin concentration less than 5 g/dL, occurs in the first or second year of life, while cerebral malaria is more commonly diagnosed in older children. As exposure to malaria decreases in childhood, the age at which children develop cerebral malaria increases (Reyburn et al., 2005). The relative but evident protection observed among infants during the first few months of life, even in areas of high transmission intensity, is believed to be mediated by several factors including transplacentally acquired maternal antibodies and the relatively high hemoglobin F content of the very young infant’s erythrocytes (Riley et al., 2001). In areas of high transmission, however, even infants younger than 6 months of age can become infected. For example, one study showed that during the wet (malaria) season in Navrongo, Ghana, nearly half of the children younger than 6 months of age had parasitemia; the study did not report the incidence of clinical malaria illness (Chandramohan et al., 2007). Interventions to decrease exposure to malaria infection can lead to an increase in the age at which infants and young children acquire their first infections (Greenwood, 2006). Intermittent Preventive Treatment Intermittent preventive treatment (IPT) is the administration of a full therapeutic course of an antimalarial drug at defined intervals to at-risk individuals, regardless of the presence or absence of malaria infection (parasitemia) or symptoms. This treatment may provide benefit by completely or partially clearing any existing asexual erythrocytic stage parasites in the bloodstream at the time of administration or by subsequently preventing or reducing the biomass of new malaria infections until the drug level decays below inhibitory levels (O’Meara et al., 2005). Intermittent Preventive Treatment in Pregnancy Intermittent preventive treatment of malaria in pregnancy (IPTp), which is administered at the time of antenatal clinic visits, is recommended by WHO for preventing malaria during pregnancy. For IPTp, WHO currently recommends the use of SP (WHO, 2004a). A review conducted by ter Kuile et al. (2007) examined the effects of SP resistance on the efficacy of IPTp-SP. 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), or monthly IPT regimen) with a treatment group defined as receiving 2 doses of SP during pregnancy. Treatment failures of SP in

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LETTER REPORT 7 symptomatic children from the matched pediatric treatment studies were used to determine the protective efficacy of IPTp-SP vis-à-vis different levels of SP resistance. In these studies, the “assessment of the treatment response of children to SP was based on standard WHO criteria and defined as the proportion of total treatment failures by day 14, which combines clinical and parasitologic failure” (ter Kuile et al., 2007, p. 2605). Interestingly, the authors found that even given poor SP curative efficacy for the treatment of symptomatic disease in children (i.e., SP treatment failures as high as 30 percent in some areas), there was no strong decline in the protective efficacy of IPTp-SP (ter Kuile et al., 2007). 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. The infant immunization schedule followed in almost all countries in sub-Saharan Africa is shown in Table 1 (Aylward et al., 2004). The recommended schedule of IPTi generally proposed by the Consortium (in particular for settings of high and perennial transmission where the disease burden is high in infants) is to administer doses in conjunction with the 10-week, 14-week, and ~9-month Expanded Program on Immunization (EPI) visits (see Table 1). Some studies have assessed IPT- SP doses given up to age 15 months (Grobusch et al., 2007a; Kobbe et al., 2007; Mockenhaupt et al., 2007). Administering a dose of SP in the second year of life, at 15 months of age in some of the studies, is relevant to areas where malaria transmission is highly seasonal. In the one Consortium trial site where malaria is highly seasonal, the last dose of SP or placebo was administered at 12 months of age. Targeting administration of doses of IPTi beyond 12 months of age in sub-Saharan Africa, however, is not currently practical: Regular EPI contacts are not scheduled beyond 9 to 12 months of age, although occasional mass campaigns (which include toddlers) with the measles vaccine or with the oral polio vaccine are carried out. In the future, an immunization contact may be added to the second year of life (e.g., to administer an additional dose of certain conjugate vaccines and a second dose of measles vaccine). Should such a change in the EPI schedule occur, information on IPTi-SP administered during the second year of life becomes of practical importance. Taking these points into consideration, the committee primarily focused its review on IPTi-SP in infants up to 1 year of age, a focus that is both consistent with the proposed IPTi-SP schedule in Table 1 and compatible with current EPI practices in most of sub-Saharan Africa.

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8 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS TABLE 1 World Health Organization—Recommended EPI Schedule EPI Contact Age of Infant Intervention Proposed contacts for IPTi-SP 1 Birth BCG, OPV (monovalent HBVat birth is recommended in areas where HBV seroprevalence is high and maternal-infant vertical transmission represents a public health problem) DPT, HBVa, Hib conjugate, OPV 2 6 weeks DPT, HBVa, Hib conjugate, OPV 3 10 weeks + DPT, HBVa, Hib conjugate, OPV 4 14 weeks + 9 months b 5 Measles and vitamin A (yellow + fever vaccine is recommended for infants living in highly endemic areas) NOTE: BCG = Bacille Calmette Guerin vaccine against tuberculosis; DPT = diphtheria toxoid, whole-cell pertussis, and tetanus toxoid vaccine combination; HBV = hepatitis B vaccine; Hib = Haemophilus influenzae type b conjugate vaccine; OPV = oral polio vaccine. Currently, many countries in sub-Saharan Africa are using a “pentavalent vaccine” at 6, 10, and 14 weeks (contacts 2–4) that delivers DPT, HBV, and Hib in a single inoculation. a An acceptable alternative regimen for HBV is to give monovalent HBV at birth and at 6 and 14 weeks. However, this somewhat logistically complicated schedule (because of the skipped HBV dose at 10 weeks of age) is becoming less common as tetravalent (DPT, HBV) and pentavalent (DPT, HBV, Hib) combination vaccines (which require only a single injection) are becoming ever more popular. b 9–12 months in areas where measles in infants has become uncommon. SOURCE: Aylward et al., 2004; WHO, 2004b. Intermittent Preventive Treatment in Children and Seasonal Intermittent Preventive Treatment Intermittent preventive treatment in children (IPTc) refers to the use of IPT in children up to 5 years of age (Chandramohan et al., 2007). Seasonal IPT (sIPT) is defined as the administration of IPT to infants or children for a limited calendar period that coincides with the intense but highly seasonal transmission of malaria in certain ecologies, as in parts of West Africa. In practical terms, IPTc and sIPT often coincide, as seen in several studies that have investigated the relatively short-term use of IPT in children up to 5 to10 years of age during periods of marked seasonal transmission (Cisse et al., 2006; Dicko et al., 2004). Concern About a Possible Rebound Effect Theoretically, by delaying the acquisition of natural immunity, administering anti- malarial drugs either continuously or intermittently might lead to a “rebound”—an increase in morbidity or mortality after treatment ends compared to a control group that had not received continuous chemoprophylaxis or intermittent therapy. The committee carefully addressed concerns about continuous chemoprophylaxis by reviewing pertinent literature. For intermittent therapy, we considered in detail, both published and unpublished evidence provided by the IPTi Consortium.

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LETTER REPORT 9 Greenwood (2006, p. 983) has defined (continuous) chemoprophylaxis as “the administration of a drug in such a way that its blood concentration is maintained above the level that inhibits parasite growth, at the pre-erythrocytic or erythrocytic stage of the parasite’s life cycle, for the duration of the period at risk.” Experts in malaria (Greenwood, 2006; White, 2005) unequivocally conclude that chemoprophylaxis provides benefits to children living in malaria- endemic areas during the period of prophylaxis, in particular citing the diminution of episodes of clinical malaria. 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. If there is such an increase, malariologists do not agree on whether the overall burden of clinical malaria assessed from initiation of prophylaxis to completion of extended follow-up post-cessation of drug will be less than in a placebo group followed for the same time period. Surprisingly, very few well-designed and executed studies are available to address this important question. Three recent comprehensive reviews on continuous chemoprophylaxis have been published (Geerligs et al., 2003; Meremikwu et al., 2005, 2008). All three reviews identified just a few controlled trials of continuous chemoprophylaxis that were considered to be of sufficient rigor of design and description as to shed light on the question of rebound. The IOM committee only considered trials that (1) had a control group, (2) looked at clinical events as well as parasitemia, and (3) compared the treatment group during pre- and post-chemoprophylaxis to an appropriate control group. These reports are inconsistent as to whether continuous chemoprophylaxis renders infants or children more vulnerable to develop clinical malaria than children in the control group after the prophylaxis period has ended (Greenwood et al., 1995; Menendez et al., 1997; Otoo et al., 1988). A “worst-case” situation with respect to the impedance of acquisition of immunity and to the potential for rebound occurring would be chemoprophylaxis of infants in an area of perennial moderate or high intensity transmission. The IOM committee concluded that the one modern well-designed and -executed study that illustrates this worst-case situation was carried out by Menendez et al. (1997) in Ifakara, Tanzania, which at the time of the study was a perennial, high-intensity transmission area; IPTi-SP was subsequently tested at this site (Schellenberg et al., 2001, 2005). At 8 weeks of age, 832 infants were randomly allocated to one of four groups (i.e., 204– 213 infants per group) to receive: (1) 2.5 ml of pyrimethamine-dapsone syrup (3.13 mg pyrimethamine and 25 mg dapsone per 5 ml) plus oral placebo (the DP group), (2) 2.5 ml of pyrimethamine-dapsone syrup plus oral iron syrup (the DI group), (3) oral iron syrup plus oral placebo (the IP group), and (4) two types of placebo syrup, (the PP group). The oral iron or similar-appearing placebo was given daily, whereas the anti-malarial or its placebo was given weekly from 8 weeks of age though 52 weeks of age. Episodes of malaria during that period of follow-up were considered to have occurred during the intervention period. A second period of follow-up proceeded for all groups from 53 weeks of age through 92 weeks of age. During the intervention period, pyrimethamine-dapsone prevented 60.5 percent (95 percent CI, 48.2–69.9; p<0.001) of first or only episodes and 64.4 percent (95 percent CI, 53.3– 73.0; p<0.001) of multiple episodes of clinical malaria compared with results in the placebo group. However, children who had received pyrimethamine-dapsone during the intervention period had significantly higher rates of first or only malaria episodes during the post-therapy

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10 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS follow-up period (relative risk, 1.8; 95 percent CI, 1.3–2.6; p<0.001). The effect for multiple (two or more) malaria episodes was nearly the same: with a relative risk of two or more post- therapy malaria episodes of 1.8 (95 percent CI, 1.3–2.5, and p<0.001) in the chemoprophylaxis group. In the analysis of all subjects in the cohort, including the analysis of those children who had been withdrawn during the intervention follow-up period, there remained a significantly higher clinical malaria rate among recipients of pyrimethamine-dapsone compared with the rate among the controls (relative risk, 1.4; 95 percent CI, 1.1–1.7; p=0.02). The study investigators concluded that “the moderate efficacy against clinical malaria afforded by chemoprophylaxis during the first year of life was sufficient to impair the development of naturally acquired immunity” (Menendez, 1997, p. 848). Menendez et al. (1997) also pointed out that the rebound effect appeared within a few weeks of the cessation of therapy. 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. 848). The authors attributed this increase to delaying risk of exposure in the absence of drug until an age when the protective effect of maternal antibodies had completely disappeared and little or no immunity had been acquired from malaria infections during infancy. They also concluded that continuous malaria prophylaxis during infancy just delayed the risk of malaria to an older age. This clear (albeit worst-case) example, of rebound with continuous chemoprophylaxis, has led some stakeholders to question whether IPTi may also lead to rebound, and if so, its relative importance with respect to the overall net benefit of IPTi. Expanded Program on Immunization Because IPTi-SP programs use the Expanded Program on Immunization (EPI) to distribute SP, this letter report comments on the status of the global EPI, which WHO initiated in 1974 after the success of the Smallpox Eradication Program. An estimate produced by WHO found that only about 5 percent of children were receiving three doses of the diphtheria, pertussis, and tetanus combination vaccine (DPT) and the oral polio vaccine (OPV) in 1974; a decade later, the coverage had increased to approximately 40 percent. As a result of the efforts made to strengthen immunization services in developing countries in the early 1980s, an estimated 70 percent of infants were receiving three doses of DPT (DPT3 coverage) by the late 1980s; however, DPT3 coverage did not increase further over the next decade. With the launch of the Global Alliance for Vaccines and Immunization or GAVI in 2000, unprecedented financial resources, political will, and managerial expertise became available to strengthen immunization services in the world’s poorest countries. Consequently, DPT3 coverage by 2005 reached 79 percent globally—67 percent among the countries of sub-Saharan Africa (Arevshatian et al., 2007)— with greater homogeneity of coverage than previously within most developing countries. In the early 1980s, a detailed review of numerous published studies of optional immunization schedules (Halsey and Galazka, 1985) led to the recommendation of a standard immunization schedule for EPI (Henderson et al., 1988). The selected schedule of 6, 10, and 14 weeks for DPT administration was based on starting at the earliest age at which no detrimental effect of early immunization had been observed; the second and third doses would then be administered at the shortest interval that would achieve close to 100 percent protection against

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LETTER REPORT 11 diphtheria and tetanus. Each country selects the immunization schedule to use for its children. Although several different schedules are used throughout the world, almost all countries in the areas of high and moderate malaria transmission in Africa have adopted the immunization schedule shown in Table 1 (WHO, 2008a). Supplemental immunization activities, first introduced through the polio eradication program, were subsequently also adopted for control of measles mortality. For measles, an initial campaign to provide an extra dose to all children regardless of past immunization status targets children from 9 months to 14 years of age. Subsequent campaigns, held approximately every four years, target children from 1 to 4 years of age to provide a second dose to children born after the initial campaign. After these campaigns have reached 95–98 percent of eligible children in many districts, dramatic declines in the transmission of measles have occurred in many African countries (CDC, 2007). A recent review estimates that immunizations save more than 3 million lives each year (Brenzel et al., 2006). A number of non-vaccine interventions have been added for programmatic administration through the EPI infrastructure. These include vitamin A supplementation, iodine supplementation, and distribution of insecticide-treated bed nets for control of malaria (Grabowsky et al., 2005, 2007). The administration of vitamin A through use of the EPI infrastructure has had variable success (Arevshatian et al., 2007; Dalmiya et al., 2006; WHO/CHD, 1998). Further analysis of factors associated with successful supplementation with vitamin A would be useful for assessing the potential of the proposed IPTi-SP program. EFFICACY OF IPTi WITH SULFADOXINE-PYRIMETHAMINE Framing the Discussion To help frame the discussion about the efficacy of IPTi-SP, the committee considered as a benchmark the above-mentioned experience of a randomized, placebo-controlled trial of continuous chemoprophylaxis of infants (albeit with drugs other than SP) that was carried out in Ifakara, Tanzania (Menendez et al., 1997). Some of the same investigators who would become leaders in the Consortium subsequently tested IPTi-SP at this Tanzanian site. 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. Much of the excess risk of malaria occurred within the first two months after chemoprophylaxis was stopped. The authors concluded that continuous chemoprophylaxis of infants in a site of perennial malaria transmission prevented the acquisition of immunity. Thus, the risk of developing malaria was delayed until the time when drug was no longer being administered (Menendez et al., 1997). The fundamental tenet of IPTi-SP is that the administration to infants of a few (three) full therapeutic doses of SP (administered concomitantly when the infants receive routine EPI vaccines) will significantly diminish the incidence of malaria morbidity but will not substantially reduce the acquisition of immunity. In practical terms, this means that IPTi-SP must significantly protect infants from malaria when the doses of IPTi are administered but that this intervention

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54 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS Finding and Conclusion about programmatic management of IPTI-SP: 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. Cost-Effectiveness of IPTi-SP Methodology Using standard cost-effectiveness methodology based on a societal perspective, the Consortium presented incremental cost-effectiveness ratios (the change in costs of a therapeutic intervention to the change in effects of the intervention) based on the IPTi intervention compared with a “do-nothing” alternative. Health effects were estimated by using the efficacy results of the intervention and were combined with malaria incidence in the target population to estimate malaria cases averted for two sites—Ifakara, Tanzania and Manhiça, Mozambique. Cost- effectiveness ratios included cost per malaria episode averted, cost per malaria death averted and cost per Disability-Adjusted Life-Year (DALY) averted. Age-weighted DALYs were based on averted morbidity measured from the trials with mortality having an assumed case-fatality rate of 2 percent. Intervention costs included start-up and recurrent costs related to planning, delivery, and monitoring of IPTi. Treatment costs of inpatient and outpatient care (used to estimate resource savings) were collected from the study sites at the time of the trials. Costing Data The conditions of the Ifakara trial and the Manhiça trial did not reflect the actual practice of IPTi-SP delivery or the costs incurred. The researchers therefore also relied upon recently collected cost data from an effectiveness study being conducted in a community IPTi-SP trial in the Mtwara and Lindi regions of southern Tanzania. The Consortium reported using the same data for Mozambique because of the country’s similarity to Tanzania in health systems, resources available, and pricing, with the only difference being the actual cost of SP. 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) were reported in 2006 U.S.$: per DALY averted US$ 3.7 (1.61–12.20) in Ifakara (Tanzania) and US$ 11.2 (3.58–92.0) in Manhiça (Mozambique) when only gross intervention costs were considered. When savings due to treatment averted (with the assumption of uncomplicated treatment for outpatient malaria cases and complicated treatment for inpatient

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LETTER REPORT 55 cases) are included in the analysis, these will outweigh the costs of the intervention (cost per malaria episode averted was US$ 1.6 (0.8–4.0) and US$ 4.7 (1.7–30.3) for Ifakara and Manhiça, respectively). Costs per death averted were reported at US$ 100.0 (43.0–330.9) and US$ 301.0 (95.6–2498.4) for Ifakara and Manhiça, respectively. Sensitivity analyses were performed by the Consortium to explore the robustness of the results. Cost-effectiveness of IPTi Relative to Other Malaria-Control Interventions While costing methodologies vary significantly between the two sites, the study indicated that IPTi is cost-effective relative to many other malaria-control interventions in sub-Saharan Africa. Specifically, studies in sub-Saharan Africa, as reported in cost per DALY (all in U.S. dollars), include: $10 to $12 for reported case management with artemisinin-based combination therapy (Morel et al., 2005); $3 to $41 for chemoprophylaxis for children (Goodman et al., 1999); $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); and $29 to $40 for provision and treatment of bed nets (Goodman et al., 1999; Morel et al., 2005). The estimates of IPTi cost- effectiveness estimates reported by the Consortium also fall well below the benchmark of US$ 30 for the highly cost-effective interventions recommended by the World Health Organization (WHO, 1996). Benchmarks and thresholds of cost-effectiveness are only a guide for those who make the decisions about monetary resources. With most African governments devoting less than US$ 5 per person annually to public health, an IPTi program (no matter how cost-effective) could only be sustained through the continuing infusion of substantial international funds. The critical issue for consideration, therefore, is whether the financing of IPTi-SP can be sustained as an intervention competing for limited healthcare resources. Finding and Conclusion about cost-effectiveness of IPTI-SP: The committee found that, in one study, IPTi-SP delivered through a robust EPI system with high levels of coverage and acceptability appears to be relatively cost effective and compares well with other malaria-control interventions. The committee therefore concluded that this preliminary finding suggests that IPTi-SP delivered through EPI could be considered as a potential intervention to be included in the malaria control tool kit for sub-Saharan Africa. Recommendation: If larger-scale implementation of IPTi-SP in a given country were to ensue, it should be accompanied by the collection of evidence under varying conditions that are likely to affect the cost-effectiveness of the intervention, including the extent to which there is excess capacity under EPI (e.g., staff time, equipment, and vehicle use) to implement IPTi-SP; malaria transmission intensities; the case-fatality rates; the unit prices of IPTi drugs; and the program start-up costs.

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56 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS THE POTENTIAL VALUE OF CONTINUED INVESTMENT IN IPTi-SP In areas where malaria in infancy is an important health problem, IPTi-SP is likely to decrease morbidity from malaria. The most recently available data have indicated that regions with high and perennial malaria transmission have the greatest burden of malaria in infancy. As effective treatment and control measures (including widespread use of insecticide-treated bed nets, indoor residual insecticide spraying, and artemisinin-based combination therapies) become more widely implemented, more areas of Africa will be moving toward lower transmission intensities and may experience a resultant decrease in the burden of disease in the first year of life. Chandramohan and colleagues conducted a secondary analysis of data from an IPT trial in Ghana to explore whether EPI-linked IPT is the best option for maximizing the benefits of IPT for children younger than 5 years of age. They found that the highly seasonal transmission of malaria as in parts of West Africa differs from that in some sites for the initial IPTi trials and suggested that perhaps only 10 percent of malaria episodes in infants would be averted with current EPI coverage rates in such areas of extremely seasonal transmission (Chandramohan et al., 2007). For this reason, the burden of malaria in infancy in a particular country is likely to affect the potential value of IPTi if adoption is considered. Chandramohan and colleagues concluded that in areas of seasonal transmission or high disease rates in children above 1 year of age, IPT outside of the EPI system may be considered. However, in most areas of sub-Saharan Africa it is not clear how IPT could be delivered in a practical, cost-effective, sustainable way outside the EPI. 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. 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. Recommendation: If large-scale implementation is to be pursued, the committee recommends that the first IPTi-SP programs should be used where the infant population is at high risk for malaria morbidity because of perennial, high- and moderate-intensity transmission. Support should be continued for current efforts to identify more precise parameters, such as transmission intensity, seasonality of transmission, DPT3 coverage, and severity of clinical disease for locations in which IPTi-SP is to be implemented. Additionally, if large-scale implementations proceed or wherever large pilot projects are carried out, the committee urges that attempts be made to evaluate the impact of IPTi-SP on mortality in infant and young children.

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LETTER REPORT 57 Recommendation: Because of the issues discussed in this document, plans for monitoring and evaluation should accompany the programmatic implementation of IPTi-SP. Indicators would include the burden of malaria in infancy, which is likely to change in response to ongoing and new interventions, SP resistance, side effects, and impact on EPI coverage. Post-implementation monitoring of IPTi-SP would benefit from a baseline assessment followed by regular measurements of the burden of malaria in infancy. This could be accomplished through surveillance at sentinel sites, including hospitals and primary-care centers; in different transmission settings; and in other inter-country networks with capacity for data collection. Once the policy is well established and large-scale implementation is shown to be effective, notable changes may be detected in the age distribution of the pediatric malaria burden that may warrant modification of the policy. For example, if the frequency of infant malaria begins to increase, programmatic shortcomings and the emergence of drug resistance would require investigation. If IPTi, in conjunction with other measures, is highly effective and infant malaria is dramatically reduced or eliminated, the program may be modified to target the appropriate vulnerable age groups, possibly to include older children. CONCLUSION Now is a propitious moment for the control of malaria in sub-Saharan Africa. A tool box of preventive and therapeutic interventions has been assembled, with each tool offering the potential to reduce a portion of the burden of malaria disease and deaths. Among those tools already operational are insecticide-treated bed nets, indoor spraying with safer residual insecticides, IPTp, and artemisinin combination therapies. None of these tools by itself represents a magic bullet for control of malaria; if, however, these tools are used collectively, they may well achieve heretofore unparalleled results for sub-Saharan Africa. Early in its review of the trial designs and the data from those trials that constitute the evidence base addressing efficacy, the committee noted that the IPTi-SP studies were powered to assess an approximate 20–30 percent reduction for outcome events (e.g., clinical malaria) in the primary aim, comparing the IPTi-SP and the placebo groups. Where the incidence of malaria in infants is high, if there is a well-functioning EPI, an intervention that could achieve a 20–30 percent reduction in malaria morbidity events in the target group would be considered substantial. 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. Continued investment in IPTi-SP could take several forms. One might be additional large-scale pilot implementations like the few that have already been undertaken in southern Tanzania and in several other countries (Benin, Ghana, Madagascar, Malawi, Mali and Senegal) in sub-Saharan Africa. Many practical lessons can be learned from such pilot projects. For example, the overall impact of IPTi-SP will depend not only on the incidence of malaria among infants in a population but on their access to EPI services, on the EPI coverage, and on how well

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58 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS SP drug therapy is integrated into the routine EPI at the local level. Investment might also take the form of generating evidence to fill remaining gaps. In the view of the committee, these would include having more extensive and robust data to quantify the impact of IPTi-SP on diminishing malaria hospitalizations, anemia, all-cause hospitalizations, and infant mortality. Additional evidence of this type would be invaluable to public health decision makers who must grapple with recommending where to implement IPTi-SP and under what set of conditions. The committee therefore envisions that IPTi-SP has great potential to serve as an additional tool to assist in the control of malaria among infants at high risk who live in areas of perennial, high- and moderate-intensity malaria transmission in sub-Saharan Africa and in regions where EPI services achieve reasonable coverage (e.g., DPT3 >50 percent). Box 2 and 3 below summarize the Committee's Findings, Conclusions and Recommendations. The Findings and Conclusions are in order of appearance in the report, while the Recommendations are in order of significance. The basis for the recommendations is explained in the text. 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. We would be pleased to brief you and your staff regarding the findings and recommendations provided in this letter.

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LETTER REPORT 59 BOX 2 List of Committee Findings and Conclusions by Order of Appearance in the Letter Report The committee’s findings and conclusions are based on the evidence presented to and reviewed by the committee including publicly available literature. Efficacy of Sulfadoxine-Pyrimethamine for Use in Intermittent Preventive Treatment • The committee found that the six IPTi-SP studies differed in their settings, intensity and seasonality of malaria transmission, use of insecticide-treated bed net coverage, prevalence of SP resistance and age at administration of doses of SP (or of placebo). The committee viewed this heterogeneity as a positive feature of the set of trials, concluding that IPTi-SP has been evaluated in several venues within sub-Saharan Africa that have different conditions, which allows generalizability to other sites in sub-Saharan Africa that have high or moderate intensity of transmission. Analysis of results from the different sites both shows the generalizability of IPTi- SP and identifies limitations that might not be detected if the conditions were more homogeneous. • The committee concluded that the trials had adequate power to assess the effect of IPTi-SP on the number of episodes of clinical malaria. Assuming the analyses of the data from the individual trials are correct, the substantial amount of data on this outcome provides convincing evidence of an overall net benefit of IPTi-SP. With respect to the incidence of malaria from randomization up to 5 months after the last dose, the combined estimate of protective efficacy using a random- effects meta-analysis was 21 percent with a 95 percent CI of (11, 29; p< 0.001). The committee also concluded that an intervention with an efficacy of approximately 20 percent in diminishing the incidence of clinical malaria in infancy is a potentially useful adjunctive tool to control morbidity from malaria in areas in sub-Saharan Africa where the incidence of malaria in infants is high and where a well-functioning EPI infrastructure with reasonable immunization coverage exists (e.g., DPT3 coverage >50 percent, the GAVI cut-off for new vaccine eligibility). • The committee concluded that the overall estimate of efficacy of IPTi-SP compared with placebo represents a composite of events that occurs during a number of distinct time periods. For example, in the long lag from the time a dose is given at 3 or 4 months of age until the next dose at 9 months of age, a high level of protection is observed during the first 35 days after the dose of SP. Although the efficacy falls considerably over the next few months, a modest level of protection appears to persist. Exposure to infected mosquitoes in the few months just before the dose at age 9 months may result in infections that stimulate the immune system before the dose at 9 months eliminates or suppresses the circulating parasites. After the last dose of IPTi and the drop in drug blood levels roughly 5 weeks later, a period of potential rebound occurs in which more cases may occur among children who previously received SP than among children who received placebo. 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. For hospitalizations of children with malaria parasites, analyses from randomization up to 5 months after the last dose of IPTi showed a net benefit in four of the six studies (estimated efficacies of 49, 37, 36 and 15 percent), with two being statistically significant. The other two sites showed an increased risk for this outcome with efficacies of –9 percent and –12 percent. The pooled estimate of protective efficacy was 21 percent with a 95 percent CI of (–2, 38). For all-cause hospitalizations, five studies had analyses from randomization through 5 months after the last dose; all showed a positive net effect with efficacies of 33, 24, 20, 11, and 2 percent; in two instances, these were statistically significant. The pooled estimate of efficacy in preventing all-cause hospitalizations was 18

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60 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS BOX 2 Continued percent with a 95 percent CI of (9, 27). Analyses from randomization up to 5 months of age after the last dose suggested a modest effect on preventing anemia. The efficacy estimate was positive for each of the six sites but in no single site was the result statistically significant. The pooled estimate of efficacy was 10 percent with a 95 percent CI of (4, 17). The committee found the estimated efficacy for these additional outcomes to be encouraging but less robust than the cumulative data for efficacy against clinical malaria. Accordingly, the committee remained cautious in drawing conclusions concerning the effect of IPTi-SP in preventing these other outcomes. The analyses from randomization through 5 months after the last dose of IPTi-SP leave open the possibility that studies with much larger sample sizes might have demonstrated a statistically more convincing protective effect. • Several analyses provided by the SWG of the Consortium were very useful in evaluating whether IPTi-SP leads to rebound malaria. In particular, for each study and for the combined studies using random-effects meta-analyses, the analyses of malaria episodes in the period 5 months after the last dose of IPTi (beginning 5 weeks after the dose) were very helpful. The overall combined estimates of efficacy against various outcomes are summarized in the table below. 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). For hospitalizations with malaria parasites the combined estimate of protective efficacy (using fixed- effects meta-analysis) was –20 percent with a 95 percent CI of (–60, 10; p=0.23). Similarly, for all-cause hospitalizations the combined estimate of protective efficacy was –11 percent (–30, 6; p=0.22). The combined estimate of protective effect against anemia using random effects meta- analysis was 2 percent with a 95 percent CI of (–8, 11; p=0.74). These analyses focus only on the period of risk for rebound, comparing the SP and placebo groups. A statistically more rigorous and clinically more relevant approach is to perform analyses from randomization through 5 months after the last dose of IPTi-SP. Those analyses (mentioned above) provide the net balance of effect between the treatment period and the potential rebound period. • Depending on the specific outcome event measured, the committee found mixed evidence regarding the existence of a rebound. In no case was the rebound sufficiently large to negate the overall benefit of IPTi-SP. Based on its review of all the data and the analyses presented, the committee concluded that the extent of rebound is small and that the benefits of IPTi-SP outweigh this negative effect. Drug Resistance and Sulfadoxine Pyrimethamine • On the basis of the evidence presented, the committee found that the clinical effectiveness of SP for treating acute malaria in children is not an accurate indicator of IPTi-SP effectiveness, and that IPTi-SP has measurable efficacy in the face of moderate to high prevalence of SP resistant parasites that are common in much of sub-Saharan Africa (40 to 80 percent prevalence of dhfr triple mutant). • Some selection for SP-resistant parasites is likely to occur in infections in infants who have recently received SP; however, the committee noted that IPTi did not result in increasing SP resistance at the population level in one setting. The committee concluded that concerns about accelerating the spread of SP resistance do not provide justifications for delay or limitation of IPTi implementation.

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LETTER REPORT 61 BOX 2 Continued Safety of Intermittent Preventive Treatment in Infants and Sulfadoxine Pyrimethamine • The committee found no evidence of additional benefit of IPT with SP among children receiving TS prophylaxis. No information is available on the risk of adverse events associated with coadministration of these antifolate medications. Because of this lack of information, the committee concluded that IPTi-SP should not be offered to infants or young children who are taking long-term, daily cotrimoxazole to prevent HIV-associated infections. • The committee found that although the pharmacokinetics of SP in infants and toddlers 3–15 months of age in IPTi have not been well studied, a wealth of data supports the benefits and safety of SP dosages currently recommended for these age groups as used in therapeutic and preventive regimens. The committee concluded that studying other drugs would be a reasonable avenue for further research as the evidence base for IPTi with drugs other than SP is still limited. Further, if trials are undertaken to study the efficacy of IPTi with antimalarial drugs other than SP, and if pharmacokinetic data in infants are not available for those drugs, nesting pharmacokinetic studies within the clinical trials could yield valuable information. Generating pharmacokinetic data on the new drugs in infants may provide information with which to design improved and more effective treatment schedules and dosage regimens. Impact of Expanded Program on Immunization Vaccines • On the basis of the evidence presented, the committee found that the studies were adequately powered to assess non-inferiority or seroequivalence and that the studies used appropriate serologic assays. The pooled analysis showed no evidence suggesting that SP has a negative impact on the serologic response to the EPI vaccine antigens evaluated to date. Thus, the committee concluded that the administration of SP with scheduled EPI visits has been demonstrated to be an effective means for implementing IPTi. The committee also concluded that, as other vaccine antigens (e.g., the rotavirus, Haemophilus influenzae type b, pneumococcal- conjugate, and meningococcal-conjugate vaccines) are added to the EPI for infants in sub- Saharan Africa in the future, it will be prudent to document that IPTi does not negatively impact the immunogenicity of those vaccines. Similarly, if an evidence base with IPTi that uses other antimalarials accumulates and proves to be as robust as the data for IPTi-SP, it will have to be shown (as has been done for IPTi-SP) that these other antimalarials do not adversely impact immune responses to EPI vaccines. 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. • The committee found that, in one study, IPTi-SP delivered through a robust EPI system with high levels of coverage and acceptability appears to be relatively cost effective and compares well with other malaria-control interventions. The committee therefore concluded that this preliminary finding suggests that IPTi-SP delivered through EPI could be considered as a potential intervention to be included in the malaria control tool kit for sub-Saharan Africa.

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62 INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA IN INFANTS BOX 2 Continued The Potential Value of 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. 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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LETTER REPORT 63 BOX 3 Committee Recommendations in Order of Significance 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. If this audit confirms the results presented, the committee would support the notion that IPTi-SP is ready to move to a new level. The committee’s confidence in the efficacy of IPTi-SP in preventing cases of clinical malaria is sufficient to encourage larger-scale pilot implementations and evaluations in areas where the incidence of malaria in infants is high (often areas of perennial, high- and moderate-level transmission areas) to assess the impact of the intervention under real- life conditions. 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. One possible solution might be to nest case-control studies within large-scale, population-based pilot implementations of IPTi-SP. Nested studies of various designs may allow assessment of the effectiveness of IPTi in preventing malaria hospitalizations, anemia, and infant deaths. Recommendation: If large-scale implementation is to be pursued, the committee recommends that the first IPTi-SP programs should be used where the infant population is at high risk for malaria morbidity because of perennial, high- and moderate-intensity transmission. Support should be continued for current efforts to identify more precise parameters, such as transmission intensity, seasonality of transmission, DPT3 coverage, and severity of clinical disease for locations in which IPTi-SP is to be implemented. Additionally, if large-scale implementations proceed or wherever large pilot projects are carried out, the committee urges that attempts be made to evaluate the impact of IPTi-SP on mortality in infant and young children Recommendation: The committee recommends that if programmatic implementation of IPTi-SP were to ensue, public health authorities should monitor evidence of possible increases or decreases of SP resistance in the areas or regions of implementation. Recommendation: Because of the issues discussed in this document, plans for monitoring and evaluation should accompany the programmatic implementation of IPTi-SP. Indicators would include the burden of malaria in infancy, which is likely to change in response to ongoing and new interventions, SP resistance, side effects, and impact on EPI coverage. Post-implementation monitoring of IPTi-SP would benefit from a baseline assessment followed by regular measurements of the burden of malaria in infancy. This could be accomplished through surveillance at sentinel sites, including hospitals and primary-care centers; in different transmission settings; and in other intercountry networks with capacity for data collection. Once the policy is well established and large-scale implementation is shown to be effective, notable changes may be detected in the age distribution of the pediatric malaria burden that may warrant modification of the policy. For example, if the frequency of infant malaria begins to increase, programmatic shortcomings and the emergence of drug resistance would require investigation. If IPTi, in conjunction with other measures, is highly effective and infant malaria is dramatically reduced or eliminated, the program may be modified to target the appropriate vulnerable age groups, possibly to include older children. Recommendation: If larger-scale implementation of IPTi-SP in a given country were to ensue, it should be accompanied by the collection of evidence under varying conditions that are likely to affect the cost- effectiveness of the intervention, including the extent to which there is excess capacity under EPI (e.g., staff time, equipment, and vehicle use) to implement IPTi-SP; malaria transmission intensities; the case-fatality rates; the unit prices of IPTi drugs; and the program start-up costs. Recommendation: Post-implementation monitoring should include pharmacovigilance with longer-term follow-up for children (e.g., 24 months) to detect adverse reactions that may arise when recipients of IPTi-SP in infancy subsequently receive cotrimoxazole or other sulfa drugs.

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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