David Schellenberg

Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial

BACKGROUND Clinical malaria and severe anaemia are major causes of paediatric hospital admission and death in many malaria-endemic settings. In the absence of an effective and affordable vaccine, control programmes continue to rely on case management while attempting the large-scale deployment of insecticide-treated nets. We did a randomised, placebo-controlled trial to assess the efficacy and safety of intermittent sulphadoxine-pyrimethamine treatment on the rate of malaria and severe anaemia in infants in a rural area of Tanzania. METHODS We randomly assigned 701 children living in Ifakara, southern Tanzania, sulphadoxine-pyrimethamine or placebo at 2, 3, and 9 months of age. All children received iron supplementation between 2 and 6 months of age. The intervention was given alongside routine vaccinations delivered through WHOs Expanded Program on Immunisation (EPI). The primary outcome measures were first or only episode of clinical malaria, and severe anaemia in the period from recruitment to 1 year of age. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys at 12 and 18 months of age. Results were expressed in terms of protective efficacy (100 [1-hazard ratio]%) and analysis was by intention to treat. FINDINGS 40 children dropped out (16 died, 11 migrated, 12 parents withdrew consent, and one for other reasons). Intermittent sulphadoxine-pyrimethamine treatment was well tolerated and no drug-attributable adverse events were recorded. During the first year of life, the rate of clinical malaria (events per person-year at risk) was 0.15 in the sulphadoxine-pyrimethamine group versus 0.36 in the placebo group (protective efficacy 59% [95% CI 41-72]), and the rate of severe anaemia was 0.06 in the sulphadoxine-pyrimethamine group versus 0.11 in the placebo group (50% [8-73]). Serological responses to EPI vaccines were not affected by the intervention. INTERPRETATION This new approach to malaria control reduced the rate of clinical malaria and severe anaemia by delivering an available and affordable drug through the existing EPI system. Data are urgently needed to assess the potential cost-effectiveness of intermittent treatment in areas with different patterns of malaria endemicity.

Effectiveness and cost of facility-based Integrated Management of Childhood Illness (IMCI) in Tanzania

BACKGROUND The Integrated Management of Childhood Illness (IMCI) strategy is designed to address major causes of child mortality at the levels of community, health facility, and health system. We assessed the effectiveness of facility-based IMCI in rural Tanzania. METHODS We compared two districts with facility-based IMCI and two neighbouring comparison districts without IMCI, from 1997 to 2002, in a non-randomised study. We assessed quality of case-management for childrens illness, drug and vaccine availability, and supervision involving case-management, through a health-facility survey in 2000. Household surveys were used to assess child-health indicators in 1999 and 2002. Survival of children was tracked through demographic surveillance over a predefined 2-year period from mid 2000. Further information on contextual factors was gathered through interviews and record review. The economic cost of health care for children in IMCI and comparison districts was estimated through interviews and record review at national, district, facility, and household levels. FINDINGS During the IMCI phase-in period, mortality rates in children under 5 years old were almost identical in IMCI and comparison districts. Over the next 2 years, the mortality rate was 13% lower in IMCI than in comparison districts (95% CI -7 to 30 or 5 to 21, depending on how adjustment is made for district-level clustering), with a rate difference of 3.8 fewer deaths per 1000 child-years. Contextual factors, such as use of mosquito nets, all favoured the comparison districts. Costs of childrens health care with IMCI were similar to or lower than those for case-management without IMCI. INTERPRETATION Our findings indicate that facility-based IMCI is good value for money, and support widespread implementation in the context of health-sector reform, basket funding, good facility access, and high utilisation of health facilities.

Safety and Immunogenicity of RTS,S/AS02D Malaria Vaccine in Infants

BACKGROUND The RTS,S/AS malaria vaccine is being developed for delivery through the World Health Organizations Expanded Program on Immunization (EPI). We assessed the feasibility of integrating RTS,S/AS02D into a standard EPI schedule for infants. METHODS In this phase 2B, single-center, double-blind, controlled trial involving 340 infants in Bagamoyo, Tanzania, we randomly assigned 340 infants to receive three doses of either the RTS,S/AS02D vaccine or the hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received a vaccine containing diphtheria and tetanus toxoids, whole-cell pertussis vaccine, and conjugated Haemophilus influenzae type b vaccine (DTPw/Hib). The primary objectives were the occurrence of serious adverse events during a 9-month surveillance period and a demonstration of noninferiority of the responses to the EPI vaccines (DTPw/Hib and hepatitis B surface antigen) with coadministration of the RTS,S/AS02D vaccine, as compared with the hepatitis B vaccine. The detection of antibodies against Plasmodium falciparum circumsporozoite and efficacy against malaria infection were secondary objectives. RESULTS At least one serious adverse event was reported in 31 of 170 infants who received the RTS,S/AS02D vaccine (18.2%; 95% confidence interval [CI], 12.7 to 24.9) and in 42 of 170 infants who received the hepatitis B vaccine (24.7%; 95% CI, 18.4 to 31.9). The results showed the noninferiority of the RTS,S/AS02D vaccine in terms of antibody responses to EPI antigens. One month after vaccination, 98.6% of infants receiving the RTS,S/AS02D vaccine had seropositive titers for anticircumsporozoite antibodies on enzyme-linked immunosorbent assay (ELISA). During the 6-month period after the third dose of vaccine, the efficacy of the RTS,S/AS02D vaccine against first infection with P. falciparum malaria was 65.2% (95% CI, 20.7 to 84.7; P=0.01). CONCLUSIONS The use of the RTS,S/AS02D vaccine in infants had a promising safety profile, did not interfere with the immunologic responses to coadministered EPI antigens, and reduced the incidence of malaria infection. (ClinicalTrials.gov number, NCT00289185.)

Factors affecting home delivery in rural Tanzania

Background  Studies of factors affecting place of delivery have rarely considered the influence of gender roles and relations within the household. This study combines an understanding of gender issues relating to health and help‐seeking behaviour with epidemiological knowledge concerning place of delivery.

A research agenda for malaria eradication: diagnoses and diagnostics.

The Malaria Eradication Research Agenda (malERA) Consultative Group on Diagnoses and Diagnostics outline a research and development agenda to provide the diagnosis and diagnostic tools required for malaria eradication.

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials

BACKGROUND Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHOs Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING Bill & Melinda Gates Foundation.

The use of antenatal and postnatal care: perspectives and experiences of women and health care providers in rural southern Tanzania.

BackgroundAlthough antenatal care coverage in Tanzania is high, worrying gaps exist in terms of its quality and ability to prevent, diagnose or treat complications. Moreover, much less is known about the utilisation of postnatal care, by which we mean the care of mother and baby that begins one hour after the delivery until six weeks after childbirth. We describe the perspectives and experiences of women and health care providers on the use of antenatal and postnatal services.MethodsFrom March 2007 to January 2008, we conducted in-depth interviews with health care providers and village based informants in 8 villages of Lindi Rural and Tandahimba districts in southern Tanzania. Eight focus group discussions were also conducted with women who had babies younger than one year and pregnant women. The discussion guide included information about timing of antenatal and postnatal services, perceptions of the rationale and importance of antenatal and postnatal care, barriers to utilisation and suggestions for improvement.ResultsWomen were generally positive about both antenatal and postnatal care. Among common reasons mentioned for late initiation of antenatal care was to avoid having to make several visits to the clinic. Other concerns included fear of encountering wild animals on the way to the clinic as well as lack of money. Fear of caesarean section was reported as a factor hindering intrapartum care-seeking from hospitals. Despite the perceived benefits of postnatal care for children, there was a total lack of postnatal care for the mothers. Shortages of staff, equipment and supplies were common complaints in the community.ConclusionEfforts to improve antenatal and postnatal care should focus on addressing geographical and economic access while striving to make services more culturally sensitive. Antenatal and postnatal care can offer important opportunities for linking the health system and the community by encouraging women to deliver with a skilled attendant. Addressing staff shortages through expanding training opportunities and incentives to health care providers and developing postnatal care guidelines are key steps to improve maternal and newborn health.

Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial.

Stopping antimalarial chemoprophylaxis can be followed by increased risk of malaria, suggesting that it interferes with the development of antimalarial immunity. We report analysis of extended follow-up until age 2 years of a randomised, placebo-controlled double-blind trial of intermittent preventive antimalarial treatment in infants. The rate of clinical malaria (events per person-year at risk, starting 1 month after final dose of intermittent treatment) was 0.28 in the sulfadoxine-pyrimethamine group and 0.43 in the placebo group (protective effect 36%, 95% CI 11-53). Intermittent treatment produced a sustained reduction in the risk of clinical malaria extending well beyond the duration of the pharmacological effects of the drugs, excluding a so-called rebound effect and suggesting that such treatment could facilitate development of immunity against Plasmodium falciparum.

Age-Patterns of Malaria Vary with Severity, Transmission Intensity and Seasonality in Sub-Saharan Africa: A Systematic Review and Pooled Analysis

Background There is evidence that the age-pattern of Plasmodium falciparum malaria varies with transmission intensity. A better understanding of how this varies with the severity of outcome and across a range of transmission settings could enable locally appropriate targeting of interventions to those most at risk. We have, therefore, undertaken a pooled analysis of existing data from multiple sites to enable a comprehensive overview of the age-patterns of malaria outcomes under different epidemiological conditions in sub-Saharan Africa. Methodology/Principal Findings A systematic review using PubMed and CAB Abstracts (1980–2005), contacts with experts and searching bibliographies identified epidemiological studies with data on the age distribution of children with P. falciparum clinical malaria, hospital admissions with malaria and malaria-diagnosed mortality. Studies were allocated to a 3×2 matrix of intensity and seasonality of malaria transmission. Maximum likelihood methods were used to fit five continuous probability distributions to the percentage of each outcome by age for each of the six transmission scenarios. The best-fitting distributions are presented graphically, together with the estimated median age for each outcome. Clinical malaria incidence was relatively evenly distributed across the first 10 years of life for all transmission scenarios. Hospital admissions with malaria were more concentrated in younger children, with this effect being even more pronounced for malaria-diagnosed deaths. For all outcomes, the burden of malaria shifted towards younger ages with increasing transmission intensity, although marked seasonality moderated this effect. Conclusions The most severe consequences of P. falciparum malaria were concentrated in the youngest age groups across all settings. Despite recently observed declines in malaria transmission in several countries, which will shift the burden of malaria cases towards older children, it is still appropriate to target strategies for preventing malaria mortality and severe morbidity at very young children who will continue to bear the brunt of malaria deaths in Sub-Saharan Africa.

An estimation of the entomological inoculation rate for Ifakara: a semi-urban area in a region of intense malaria transmission in Tanzania.

Summary An entomological study on vectors of malaria and their relative contribution to Plasmodium falciparum transmission in the semi‐urban area of Ifakara, south‐eastern Tanzania, was conducted. A total of 32 houses were randomly sampled from the area and light trap catches (LTC) performed in one room in each house every 2 weeks for 1 year. A total of 147 448 mosquitoes were caught from 789 LTC; 26 134 Anopheles gambiae s.l., 615 A. funestus, 718 other anophelines and 119 981 culicines. More than 60% of the total A. gambiae s.l. were found in five (0.6%) LTCs, with a maximum of 5889 caught in a single trap. Of 505 A. gambiae s.l. speciated by polymerase chain reaction, 91.5% were found to be A. arabiensis. Plasmodium falciparum sporozoite enzyme‐linked immunosorbent assay tests were performed on 10 108 anopheles mosquitoes and 39 (0.38%) were positive. Entomological inoculation rate (EIR) estimates were generated using a standard method and an alternative method that allows the calculation of confidence intervals based on a negative binomial distribution of sporozoite positive mosquitoes. Overall EIR estimates were similar; 31 vs. 29 [95% confidence interval (CI): 19, 44] infectious bites per annum, respectively. The EIR ranged from 4 (95% CI: 1, 17) in the cool season to 108 (95% CI: 69, 170) in the wet season and from 54 (95% CI: 30, 97) in the east of the town to 15 (95% CI: 8, 30) in the town centre. These estimates show large variations over short distances in time and space. They are all markedly lower than those reported from nearby rural areas and for other parts of Tanzania.