Intermittent Preventive Treatment In Infants Research Articles

Mode of action and choice of antimalarial drugs for intermittent preventive treatment in infants

Intermittent preventive treatment in infants (IPTi) is an effective and safe malaria control strategy. However, it remains unclear what antimalarials should be used to replace sulfadoxine-pyrimethamine (SP) when and where SP is no longer an effective drug for IPTi. Work recently conducted in Tanzania, combined with the findings of previous studies, indicates that IPTi is essentially intermittent chemoprophylaxis; consequently, long-acting antimalarials that provide a long period of post-treatment prophylaxis will be the most effective alternative to SP. However, because of concerns about development of drug resistance, new combinations of long-acting drugs are urgently needed.

Cost-effectiveness of malaria intermittent preventive treatment in infants (IPTi) in Mozambique and the United Republic of Tanzania.

To estimate the cost-effectiveness of malaria intermittent preventive treatment in infants (IPTi) using sulfadoxine-pyrimethamine (SP). In two previous IPTi trials in Ifakara (United Republic of Tanzania) and Manhiça (Mozambique), SP was administered three times to infants before 9 months of age through the Expanded Programme on Immunization. Based on the efficacy results of the intervention and on malaria incidence in the target population, an estimate was made of the number of clinical malaria episodes prevented. This number and an assumed case-fatality rate of 1.57% were used, in turn, to estimate the number of disability-adjusted life years (DALY) averted and the number of deaths averted. The cost of the intervention, including start-up and recurrent costs, was then assessed on the basis of these figures. The cost per clinical episode of malaria averted was US$ 1.57 (range: US$ 0.8-4.0) in Ifakara and US$ 4.73 (range: US$ 1.7-30.3) in Manhiça; the cost per DALY averted was US$ 3.7 (range: US$ 1.6-12.2) in Ifakara and US$ 11.2 (range: US$ 3.6-92.0) in Manhiça; and the cost per death averted was US$ 100.2 (range: US$ 43.0-330.9) in Ifakara and US$ 301.1 (range: US$ 95.6-2498.4) in Manhiça. From the health system and societal perspectives, IPTi with SP is expected to produce health improvements in a cost-effective way. From an economic perspective, it offers good value for money for public health programmes.

Therapeutic and prophylactic effect of intermittent preventive anti-malarial treatment in infants (IPTi) from Ghana and Gabon

BackgroundIntermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) reduces the incidence of malaria episodes in young children. The exact mechanism by which the protective effect is mediated needs to be defined. This study aimed to investigate therapeutic, prophylactic, and possible exceeding effects of SP-based IPTi in two clinical trials.MethodsProtective efficacies from two IPTi trials performed in Kumasi, Ghana, and Lambaréné, Gabon, were assessed for overlapping time series of 61 days. For six-months periods after each of three IPTi doses a multivariate Poisson regression model with the respective cohort as co-variate was generated and effect modification of protective efficacy with time strata was evaluated by log-likelihood tests.ResultsProtective efficacies were not significantly different between the two study cohorts. Study-cohort corrected protective efficacy was highest for the first 61 days after each IPTi application and decreased continuously. For the first 61 days after IPTi-1, IPTi-2, and IPTi-3 the protective efficacy was 71%, 44%, and 43%, respectively. A reduction of the malaria incidence rate was detectable for the first 60, 30 and 40 days after IPTi-1, IPTi-2 and IPTi-3 drug application, respectively. After IPTi-3 a higher risk for malaria could be seen after day 60. This effect was mainly based on the overwhelming influence of the Kumasi cohort.ConclusionThe results suggest that SP-based IPTi mainly works through a therapeutic and prophylactic effect over 30 to 60 days after drug application and that a sustained effect beyond post-treatment prophylaxis might be very low.Trial registrationData analysis from clinical trials NCT ID # 00206739 (Kumasi Trial) and NCT ID # 00167843 (Lambaréné Trial), .

Intermittent preventive treatment for malaria and anaemia control in Tanzanian infants; the development and implementation of a public health strategy

Minimizing the time between efficacy studies and public health action is important to maximize health gains. We report the rationale, development and implementation of a district-based strategy for the implementation of intermittent preventive treatment in infants (IPTi) for malaria and anaemia control in Tanzania. From the outset, a research team worked with staff from all levels of the health system to develop a public-health strategy that could continue to function once the research team withdrew. The IPTi strategy was then implemented by routine health services to ensure that IPTi behaviour-change communication materials were available in health facilities, that health workers were trained to administer and to document doses of IPTi, that the necessary drugs were available in facilities and that systems were in place for stock management and supervision. The strategy was integrated into existing systems as far as possible and well accepted by health staff. Time-and-motion studies documented that IPTi implementation took a median of 12.4 min (range 1.6-28.9) per nurse per vaccination clinic. The collaborative approach between researchers and health staff effectively translated research findings into a strategy fit for public health implementation.

From strategy development to routine implementation: the cost of Intermittent Preventive Treatment in Infants for malaria control

BackgroundAchieving the Millennium Development Goals for health requires a massive scaling-up of interventions in Sub Saharan Africa. Intermittent Preventive Treatment in infants (IPTi) is a promising new tool for malaria control. Although efficacy information is available for many interventions, there is a dearth of data on the resources required for scaling up of health interventions.MethodWe worked in partnership with the Ministry of Health and Social Welfare (MoHSW) to develop an IPTi strategy that could be implemented and managed by routine health services. We tracked health system and other costs of (1) developing the strategy and (2) maintaining routine implementation of the strategy in five districts in southern Tanzania. Financial costs were extracted and summarized from a costing template and semi-structured interviews were conducted with key informants to record time and resources spent on IPTi activities.ResultsThe estimated financial cost to start-up and run IPTi in the whole of Tanzania in 2005 was US$1,486,284. Start-up costs of US$36,363 were incurred at the national level, mainly on the development of Behaviour Change Communication (BCC) materials, stakeholders' meetings and other consultations. The annual running cost at national level for intervention management and monitoring and drug purchase was estimated at US$459,096. Start-up costs at the district level were US$7,885 per district, mainly expenditure on training. Annual running costs were US$170 per district, mainly for printing of BCC materials. There was no incremental financial expenditure needed to deliver the intervention in health facilities as supplies were delivered alongside routine vaccinations and available health workers performed the activities without working overtime. The economic cost was estimated at 23 US cents per IPTi dose delivered.ConclusionThe costs presented here show the order of magnitude of expenditures needed to initiate and to implement IPTi at national scale in settings with high Expanded Programme on Immunization (EPI) coverage. The IPTi intervention appears to be affordable even within the budget constraints of Ministries of Health of most sub-Saharan African countries.

Molecular Markers of Resistance to Sulfadoxine‐Pyrimethamine during Intermittent Preventive Treatment for Malaria in Mozambican Infants

Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is a potential malaria control strategy. There is concern about the impact that increasing in vivo resistance to SP has on the efficacy of IPTi, as well as about the potential contribution of IPTi to increases in resistance. We compared the frequency of clinical episodes of malaria caused by P. falciparum parasites with mutations in dhfr and dhps among sick children who received SP or placebo in the context of a randomized, double-blind, placebo-controlled IPTi trial in Mozambique. Half of the children who received placebo harbored quintuple-pure mutant parasites. Nevertheless, the protective efficacy of IPTi within the 35 days after the third dose was 70.8% (95% confidence interval [CI], 40.7%-85.6%). Between month 2 after the third IPTi dose and the end of the follow-up period, children receiving SP harbored more dhps codon 437 mixed infections (odds ratio [OR], 10.56 [95% CI, 1.30-86.14]) and fewer dhps double-pure mutant parasites (OR, 0.43 [95% CI, 0.22-0.84]) than did placebo recipients. IPTi appears to be associated with some changes in the prevalence of genotypes involved in SP resistance. In the face of a high prevalence of quintuple-mutant parasites, SP exhibited a high level of efficacy in the prevention of new episodes of malaria in infants.

Impact of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine on Antibody Responses to Erythrocytic-StagePlasmodium falciparumAntigens in Infants in Mozambique

We evaluated the impact of intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP), which was given at ages 3, 4, and 9 months through the Expanded Program on Immunization (EPI), on the development of antibody responses to Plasmodium falciparum in Mozambique. Immunoglobulin M (IgM) and IgG subclass antibodies specific to whole asexual parasites and to recombinant MSP-1(19), AMA-1, and EBA-175 were measured at ages 5, 9, 12, and 24 months for 302 children by immunofluorescence antibody tests and by enzyme-linked immunosorbent assays. Antibody responses did not significantly differ between children receiving IPTi with SP and those receiving a placebo at any time point measured, with the exception of the responses of IgG and IgG1 to AMA-1 and/or MSP-1(19), which were significantly higher in the SP-treated group than in the placebo group at ages 5, 9, and/or 24 months. IPTi with SP given through the EPI reduces the frequency of malarial illness while allowing the development of naturally acquired antibody responses to P. falciparum antigens.

Duration of Protection against Malaria and Anaemia Provided by Intermittent Preventive Treatment in Infants in Navrongo, Ghana

BackgroundIntermittent preventive treatment for malaria in Infants (IPTi) has been shown to give effective and safe protection against malaria. It has been suggested that IPTi might have long-lasting beneficial effects but, in most settings, the protection provided by IPTi appears to be short-lived. Knowledge of the duration of protection given by IPTi would help interpret the results of existing trials and suggest optimal delivery schedules for IPTi. This study investigated how the protective efficacy of IPTi against malaria and anaemia changes over time.Methods and FindingsA secondary analysis of data from a cluster-randomised, placebo-controlled trial of IPTi using sulfadoxine-pyrimethamine (SP) in Ghana was conducted. In this trial IPTi was given to 2485 infants at 3, 4, 9 and 12 months of age; children remained in follow-up until two years of age. Poisson regression with a random effect to adjust for the cluster-randomised design was used to determine protective efficacy of IPTi against clinical malaria and anaemia in defined time strata following administration of IPTi. Analysis of first-or-only clinical malaria episode following the individual IPTi doses showed that some protection against malaria lasted between 4 to 6 weeks. A similar pattern was seen when the incidence of all malaria episodes up to 2 years of age was analysed in relation to the most recent IPT, by pooling the incidence of malaria after the individual IPTi doses. Protective efficacy within four weeks of IPTi was 75.2% (95% CI: 66–82) against malaria, 78.9% (95% CI: 69–86) against high parasite density malaria, and 93.8% (95% CI: 73–99) against anaemia. Protection against these outcomes was short-lived, with evidence of any effect lasting for only 6, 6 and 4 weeks respectively. Protection in children who were parasitaemic when receiving IPTi appeared to be of shorter duration than in uninfected children. There was no evidence of any benefit of IPTi after the immediate period following the IPTi doses.ConclusionsIntermittent preventive treatment provides considerable protection against malaria and anaemia for short periods, even in an area of intense seasonal transmission. Due to the relatively short duration of protection provided by each dose of IPTi, this treatment will be of most benefit when delivered at the time of peak malaria incidence.

Malaria incidence and efficacy of intermittent preventive treatment in infants (IPTi)

BackgroundIntermittent preventive antimalarial treatment in infants (IPTi) is currently evaluated as a malaria control strategy. Among the factors influencing the extent of protection that is provided by IPTi are the transmission intensity, seasonality, drug resistance patterns, and the schedule of IPTi administrations. The aim of this study was to determine how far the protective efficacy of IPTi depends on spatio-temporal variations of the prevailing incidence of malaria.MethodsOne thousand seventy infants were enrolled in a registered controlled trial on the efficacy of IPTi with sulphadoxine-pyrimethamine (SP) in the Ashanti Region, Ghana, West Africa (ClinicalTrial.gov: NCT00206739). Stratification for the village of residence and the month of birth of study participants demonstrated that the malaria incidence was dependent on spatial (range of incidence rates in different villages 0.6–2.0 episodes/year) and temporal (range of incidence rates in children of different birth months 0.8–1.2 episodes/year) factors. The range of spatio-temporal variation allowed ecological analyses of the correlation between malaria incidence rates, anti-Plasmodium falciparum lysate IgG antibody levels and protective efficacies provided by IPTi.ResultsProtective efficacy of the first SP administration was positively correlated with malaria incidences in children living in a distinct village or born in a distinct month (R2 0.48, p < 0.04 and R2 0.63, p < 0.003, respectively). Corresponding trends were seen after the second and third study drug administration. Accordingly, IgG levels against parasite lysate increased with malaria incidence. This correlation was stronger in children who received IPTi, indicating an effect modification of the intervention.ConclusionThe spatial and temporal variations of malaria incidences in a geographically and meteorologically homogeneous study area exemplify the need for close monitoring of local incidence rates in all types of intervention studies. The increase of the protective efficacy of IPTi with malaria incidences may be relevant for IPTi implementation strategies and, possibly, for other malaria control measures.

Immune responses after single‐dose sulphadoxine–pyrimethamine indicate underestimation of protective efficacy of intermittent preventive treatment in infants

To assess how intermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) affects Immunoglobulin (IgG) immune responses against Plasmodium falciparum in infants from rural Ghana. Randomized, placebo-controlled and double-blinded clinical trial with participants randomized in blocks of 10 to receive either 250 mg sulphadoxine/2.5 mg pyrimethamine or placebo at the age of 3 (IPTi-1), 9 (IPTi-2) and 15 (IPTi-3) months and followed-up for 21 months. (i) Anti-P. falciparum IgG levels were measured in 180 children at the age of 9 months. (ii) Longitudinal study of the relationship between IgG levels and P. falciparum infections and/or clinical malaria in 17 naive children until they reached the age of 2 years. IgG antibody levels against crude P. falciparum lysate were dependent on the frequency of preceding infections and significantly lower in children treated with SP. Placebo-treated children had an indifferentially higher incidence of P. falciparum infections than clinically observed, which implicates an underestimation of the protective efficacy of IPTi. IgG profiles in 17 children followed up until the age of 2 years provided no evidence for impaired immune responses after a single dose of SP within the framework of IPTi.

Intermittent Preventive Treatment in Infants as a Means of Malaria Control: a Randomized, Double-Blind, Placebo-Controlled Trial in Northern Ghana

Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 months of age to assess morbidity and adverse events. During the intervention period (3 to 18 months of age), IPTi reduced the incidences of malaria and severe anemia by 22.5% (95% confidence interval, 12 to 32%) and 23.6% (95% confidence interval, 4 to 39%), respectively, and reduced hospitalizations and episodes of asymptomatic parasitemia by one-third. Protection was pronounced in the first year of life and not discernible in the second. The malaria-protective effect was largely confined to a period of 1 month after sulfadoxine-pyrimethamine treatments. Following the intervention, protection against asymptomatic parasitemia persisted. In contrast, a significant rebound of severe malaria, predominantly severe malarial anemia, occurred among children having received IPTi. Although the treatment was generally well tolerated, one case of moderately severe skin reaction followed sulfadoxine-pyrimethamine treatment. IPTi reduces malaria and anemia in infants in northern Ghana. Extension of IPTi into the second year of life by administering a dose at 15 months of age provided no substantial benefit beyond a 1-month prophylactic effect. Although this simple intervention offers one of the few available malaria-preventive measures for regions where malaria is endemic, the observed rebound of severe malaria advises caution and requires further investigation.

Review of intermittent preventive treatment for malaria in infants and children

Malaria is one of the greatest killers of children in the world. Treatment is available, but there are problems with affordability, availability, accessibility and increasing drug resistance. A new regime, intermittent preventive treatment in infants (IPTi) shows promise. It involves giving a treatment course of antimalarial drugs, regardless of parasitaemia, at intervals over the first year of life. The aim is to decrease the frequency of malarial illness while allowing the development of natural immunity. Its strength is that it can be linked with the childhood immunisation schedule. Early studies are encouraging, but much remains to be learned before its potential place in the prevention of malaria in children can be determined and it can safely be introduced as public policy. A review of the literature was performed in July 2006 for references relating to IPTi and other forms of personal prevention of malaria in infants and children.

Community response to intermittent preventive treatment delivered to infants (IPTi) through the EPI system in Manhiça, Mozambique

To describe attitudes to the expanded programme on immunization (EPI) and intermittent preventive treatment in infants (IPTi), and perceptions of the relationship between them. In particular, whether the introduction of IPTi negatively affects community attitudes to, or use of, EPI; or, conversely, whether and if so how, the concurrent delivery of IPTi and immunization influences perceptions of IPTi. Anthropological study carried out in the context of a trial of IPTi with sulphadoxine-pyrimethamine delivered alongside routine EPI vaccinations. We used open in-depth interviews, semi-structured interviews and participant observation, conducted in both community and clinic settings. IPTi was generally acceptable, in spite of initial resistance. Perceived negative aspects of IPTi did not affect perceptions of EPI, and IPTi was not misinterpreted as immunization against malaria, leading to a reduction of other preventive measures or delay in treatment seeking. Initial resistance was related more to the trial than to IPTi per se, but both rejection and acceptance were embedded in a complex constellation of local and wider contextual factors. IPTi delivered together with EPI was generally accepted after initial rejection. The factors that led to this rejection were largely local and trial related, but they did resonate with much wider cultural themes (rumours about research and health interventions, gender inequality and health-related decision making). The prior acceptance and routine administration of EPI played a key role in the acceptance of IPTi in this community. However, more studies, in different social and cultural settings and using different drugs and regimens, are needed before generalizations can be made. Although trial settings are different from actual implementation, it is necessary to study acceptability before implementation in order to anticipate problems and design information campaigns to ensure maximum community acceptance.

Intermittent Preventive Treatment for Malaria Control Administered at the Time of Routine Vaccinations in Mozambican Infants: A Randomized, Placebo‐Controlled Trial

There is an urgent need to deploy and develop new control tools that will reduce the intolerable burden of malaria. Intermittent preventive treatment in infants (IPTi) has the potential to become an effective tool for malaria control. We performed a randomized, double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine (SP) treatment in 1503 Mozambican children. Doses of SP or placebo were given at 3, 4, and 9 months of age. The intervention was administered alongside routine vaccinations delivered through the Expanded Program on Immunization (EPI). Hematological and biochemical tests were done when infants were 5 months old. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys when infants were 12 and 24 months old. IPTi was well tolerated, and no adverse events associated with SP were documented. During the first year of life, intermittent SP treatment reduced the incidence of clinical malaria by 22.2% (95% confidence interval [CI], 3.7%-37.0%; P=.020) and the rate of hospital admissions by 19% (95% CI, 4.0%-31.0%; P=.014). Although the incidence of severe anemia (packed cell volume of <25%) did not differ significantly between the 2 groups (protective effect, 12.7% [95% CI, -17.3% to 35.1%]; P=.36), there was a significant reduction in hospital admissions for anemia during the month after dosing for both the first and second dose. The serological responses to EPI vaccines were not modified by the intervention. IPTi with SP has been shown to moderately reduce the incidence of clinical malaria in Mozambican infants without evidence of rebound after stopping the intervention or of interactions with EPI vaccines. Its recommendation as a malaria control strategy in Mozambique needs to be balanced against the scarcity of affordable control tools and the burden of malaria in children.

Intermittent Preventive Treatment in Infants—Adjusting Expectations and Seeing Opportunity

Antimalarial drugs have long been used to treat acute cases of malaria to cure infection and to prevent disease progression severe disease and death. They have also been used to prevent illness (e.g. chemoprophylaxis) and to reduce transmission (e.g. mass drug administration coupled with vector control measures). With each preventive strategy the balance of efficacy and long-term feasibility has led to progressively more focused use of the drug. That is mass drug administration and broad use of chemoprophylaxis in a population have been reduced to targeted drug administration to fewer people and only specific groups or to shorter time intervals to maximize benefits and to reduce costs poor adherence and the potential impact on drug resistance. Among pregnant women in settings where malaria is endemic who have long been a target population for chemoprophylaxis studies have demonstrated that a few treatment doses of a safe and efficacious antimalarial at intervals linked to routine antenatal clinic visits could produce a substantial reduction in rates of maternal anemia placental parasite infection and the attendant risk of low birth weight. This proactive and presumptive (not linked to symptoms or documentation of infection) use of treatment doses at a few specific intervals which is known as intermittent preventive treatment (IPT) during pregnancy has been widely adopted in many sub-Saharan African countries. (excerpt)

The IPTi Consortium: research for policy and action

The results of a randomized controlled trial in Tanzania suggest that intermittent preventive treatment in infants (IPTi), delivered through the Expanded Program on Immunization, might be a useful approach to controlling malaria in countries where it is endemic. An international consortium of research collaborations, involving the World Health Organization and United Nation's Children's Fund, is now evaluating IPTi in a range of different settings to generate robust and compelling evidence to guide policy. This review summarizes the available information on IPTi and presents the consortium's approach to determining whether IPTi might be a valuable additional strategy in programs to control malaria.

Editorial: Intermittent preventive treatment for malaria control in infants: moving towards evidence‐based policy and public health action

It is important to balance the urgency of implementing a new efficacious intervention on a public health scale against the need to acquire convincing evidence on safety and efficacy. Two studies in Tanzania have shown that intermittent preventive treatment in infants (IPTi) the administration of antimalarial drugs at pre-specified times during the first year of life regardless of the presence of clinical symptoms or Plasmodium falciparum parasitaemia reduces episodes of malaria and anaemia by over 50%. Children followed up to the age of 2 years showed a sustained 36% reduction in the risk of malaria. IPTi has the potential to become a major tool for malaria control in Africa as it may be delivered at the time of routine vaccination – through the Expanded Programme on Immunisation (EPI) – which increases the chance of long-term sustainability. Should IPTi now be recommended as a malaria control strategy for Africa? A group of research scientists WHO and UNICEF reviewed the evidence that was available in 2002 and agreed that information would be required in three key areas before a recommendation on the role of IPTi in national malaria control strategies could be made. First the efficacy of IPTi in reducing episodes of clinical malaria and anaemia in different epidemiological settings should be known. Secondly it should be demonstrated that IPTi has no adverse impact on serological responses to EPI vaccines. Thirdly the reassuring safety data that is currently available on IPTi with sulphadoxine-pyrimethamine (SP) should be consolidated. (excerpt)

Malaria vaccines: Evaluation and implementation

Development of an effective malaria vaccine that could be deployed widely in endemic areas has proved to be more difficult than was anticipated, when the first clinical trials of malaria vaccines were conducted 30 years ago. Substantial progress has been made during the past few years and one candidate vaccine, RTS,S/AS02, shows promise. However, during the period that malaria vaccine development has been taking place, alternative methods of malaria control including insecticide treated bednets and intermittent preventive treatment in infancy and childhood have been developed and shown to be partially effective. Malaria vaccines will need to be more effective or more cost effective than these alternative control strategies or be able to provide substantial added value, when deployed with them if they are to be adopted widely.

Malaria intermittent preventive treatment in infants, chemoprophylaxis, and childhood vaccinations

Malaria accounts for 1-3 million deaths yearly worldwide, mostly in children under 5 years of age in sub-Saharan Africa. Laboratory and clinical studies show an association between acute malaria and a decreased response to diphtheria and tetanus toxoids and to meningococcal, salmonella, and Haemophilus influenzae type b vaccinations. Malaria treatment, chemoprophylaxis, or other forms of parasite suppression might improve the immune response to childhood vaccinations. However, the antimalarial 4-aminoquinolones are immunodepressive, such that antimalarial drugs might depress the vaccine response. Last year, Julius Massaga and colleagues reported a randomised double-blinded placebo-controlled study in 291 infants aged 12-16 weeks in Tanzania (Lancet 2003; 361: 1853-60). At enrollment, children received their third dose of combined diphtheria-tetanus-pertussis and poliomyelitis expanded vaccines with the first of three daily doses of amodiaquine intermittent preventive treatment (IPTi) or placebo. After 60 days, children receiving amodiaquine had significantly fewer malaria fevers than controls. The increasing concordance of malaria control and vaccination, movement toward co-administration of IPTi with immunisation, and the increase in travellers to malarious areas who receive concurrent vaccinations and chemoprophylaxis warrant further study.