Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting

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Study Justification:
– HIV-exposed, uninfected (HEU) infants have higher morbidity and mortality in the first year of life compared to HIV-unexposed, uninfected (HUU) infants.
– Limited data on the contribution of malaria to the health outcomes of HEU infants.
– This study aims to evaluate the incidence of febrile illnesses and malaria in a birth cohort of HEU infants living in a high malaria transmission setting.
Study Highlights:
– 361 HEU infants were enrolled, with 248 completing 12 months of follow-up.
– 1562 episodes of febrile illness and 253 episodes of malaria were recorded.
– The incidence of febrile illness was 5.12 episodes per person-year (PPY).
– The overall malaria incidence was 0.83 episodes PPY.
– Infants born to mothers with placental malaria were at higher risk of malaria.
– HEU infants had a lower incidence of malaria compared to HUU infants in other cohort studies from the same area.
Study Recommendations:
– Consider alternative causes of fever in HEU infants taking daily trimethoprim-sulfamethoxazole (TS) prophylaxis who present with fever.
– Further research is needed to understand the factors contributing to the lower incidence of malaria in HEU infants.
Key Role Players:
– Researchers and scientists conducting the study.
– Healthcare providers and clinics involved in the follow-up and treatment of the infants.
– Policy makers and government officials responsible for implementing interventions to reduce malaria burden in high-transmission settings.
Cost Items for Planning Recommendations:
– Funding for research and data collection.
– Personnel costs for researchers, healthcare providers, and support staff.
– Costs for diagnostic tests, medications, and treatment for febrile illnesses and malaria.
– Costs for training and capacity building of healthcare providers.
– Costs for community engagement and education programs.
– Costs for monitoring and evaluation of interventions.
Please note that the cost items provided are general categories and not actual cost estimates. The actual budget items would depend on the specific context and resources available.

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is relatively strong, but there are some areas for improvement. The study design is well-described, and the data collection methods are clearly outlined. The study includes a large sample size and provides detailed information on the incidence of febrile illnesses and malaria in a birth cohort of HIV-exposed uninfected infants. The study also compares the incidence of malaria in this cohort to other cohorts of HIV-exposed uninfected and HIV-unexposed uninfected infants in the same region. However, there are a few areas where the evidence could be strengthened. First, the abstract does not provide information on the statistical analysis methods used to assess risk factors for time to first episode of malaria. Including this information would enhance the transparency and reproducibility of the study. Second, the abstract does not mention any limitations of the study, such as potential biases or confounding factors. Including a brief discussion of the limitations would provide a more balanced assessment of the evidence. Finally, the abstract does not provide any recommendations for future research or implications for clinical practice. Including actionable steps to improve malaria prevention or treatment in HIV-exposed uninfected infants would enhance the practical relevance of the study.

Background: HIV-exposed, uninfected (HEU) infants suffer high morbidity and mortality in the first year of life compared to HIV-unexposed, uninfected (HUU) infants, but accurate data on the contribution of malaria are limited. Methods: The incidence of febrile illnesses and malaria were evaluated in a birth cohort of HEU infants. Infants were prescribed daily trimethoprim-sulfamethoxazole (TS) prophylaxis from 6 weeks of age until exclusion of HIV-infection after cessation of breastfeeding. Infants were followed for all illnesses using passive surveillance and routine blood smears were done monthly. Malaria was diagnosed as a positive blood smear plus fever. Placental malaria was determined by histopathology, placental blood smear and PCR. Risk factors for time to first episode of malaria were assessed using a Cox proportional hazards model. Malaria incidence among HEU infants aged 6-12 months was compared to that in other cohorts of HEU and HUU infants from the same region. Results: Among 361 HEU infants enrolled, 248 completed 12 months of follow-up resulting in 1562 episodes of febrile illness and 253 episodes of malaria after 305 person-years of follow-up. The incidence of febrile illness was 5.12 episodes per person-year (PPY), ranging from 4.13 episodes PPY in the first 4 months of life to 5.71 episodes PPY between 5 and 12 months of age. The overall malaria incidence was 0.83 episodes per person-year (PPY), increasing from 0.03 episodes PPY in the first 2 months of life to 2.00 episodes PPY between 11 and 12 months of age. There were no episodes of complicated malaria. The prevalence of asymptomatic parasitaemia was 1.2 % (19 of 1568 routine smears positive). Infants born to mothers with parasites detected from placental blood smears were at higher risk of malaria (hazard ratio = 4.51, P < 0.001). HEU infants in this study had a 2.4- to 3.5-fold lower incidence of malaria compared to HUU infants in other cohort studies from the same area. Conclusion: The burden of malaria in this birth cohort of HEU infants living in a high-transmission setting and taking daily TS prophylaxis was relatively low. Alternative etiologies of fever should be considered in HEU-infants taking daily TS prophylaxis who present with fever.

This was a planned secondary data analysis in a birth cohort of HEU infants born to HIV-infected mothers who were part of a randomized controlled trial of lopinavir/ritonavir versus efavirenz-based ART living in Tororo district, Uganda [Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women (PROMOTE-PIs), {"type":"clinical-trial","attrs":{"text":"NCT00993031","term_id":"NCT00993031"}}NCT00993031)] [13]. The study site is a high malaria transmission setting where transmission occurs year round with an average entomological inoculation rate of 310 infectious bites per person per year [14]. For this analysis, all infants who survived beyond the first 24 h of life and completed at least one visit to the study clinic after discharge from the hospital following birth were included. Gestational age was established using last menstrual period with confirmation by ultrasound [13]. Data from two other cohort studies conducted in the same region by the same researchers: Interactions Between HIV and Malaria in African Children (TCC, {"type":"clinical-trial","attrs":{"text":"NCT00527800","term_id":"NCT00527800"}}NCT00527800) [12] and Chemopreventive Therapy for Malaria in Ugandan Children (PROMOTE-Chemop, {"type":"clinical-trial","attrs":{"text":"NCT00948896","term_id":"NCT00948896"}}NCT00948896) [9], were included to enable comparisons with HUU infants and other HEU infants. Infants were followed from birth to 1 year of age. At birth, placental malaria status was determined from placental blood and tissue. Infants were seen at monthly routine visits and parents were instructed to bring their infants to a dedicated study clinic, open 7 days a week, for any fever or other illness. All study participants were given a long-lasting, insecticide-treated bed net (LLIN) at birth and prescribed daily TS prophylaxis from 6 weeks of age until they were confirmed to be HIV negative after cessation of breastfeeding. At each monthly visit, adherence to TS prophylaxis was assessed by 3-day recall and parents were asked if infants were sleeping under an LLIN. A thick blood smear for determination of malaria parasitaemia by microscopy was performed at every routine monthly visit. A febrile episode was defined as having a measured tympanic temperature of ≥38.0 °C or a history fever in the past 24 h. Study participants who presented to the study clinic with a febrile episode had a thick blood smear done for the detection of malaria parasites. If the blood smear was positive, they were diagnosed with malaria and a thin blood smear was taken off for identification of parasite species. Infants with uncomplicated malaria were treated with artemether–lumefantrine (AL) (tablets of 20 mg of artemether and 120 mg of lumefantrine: Coartem, Novartis) if they were ≥4 months old and weighing ≥5 kg. Infants with uncomplicated malaria who were <4 months old and weighing <5 kg were treated with quinine. Thick and thin blood smears were stained with 2 % Giemsa and examined for malaria parasites by trained microscopists. A blood smear was considered negative when the examination of 100 high power fields did not reveal asexual parasites. All slides were read by a second reader, and a third reader settled any discrepancies. Placental specimens were collected within 30 min of delivery in the hospital (or as early as possible, if delivery occurred at home). Thick blood smears made from placental blood collected from an incision on the maternal surface of placental tissue, were examined for parasites. Aliquots of approximately 25 µL of placental blood were also placed on filter paper, air dried and stored for DNA extraction and PCR testing for malaria parasites as earlier described [15]. Placental tissues were processed for histological evidence of placental malaria as described previously [13]. Histological slides were read in duplicate by two trained independent readers, and the results were recorded on a standardized case-record form; any discrepant results were resolved by a third reader. The rate of inter-reader agreement was 71.3 % (kappa, 0.48; P < 0.001). The readers were unaware of both the treatment assignment and the results of previous reads. Data were double-entered into Access database (Microsoft, Redmond, WA, USA) and analysed using Stata version 12 (Stata Corp, College Station, TX, USA). Follow-up time started at birth and ended at 1 year of age, or the time of premature withdrawal, or when the study was stopped prior to reaching 12 months of age because of limited funding. An incident episode of malaria was defined as having a febrile episode with a positive blood smear not preceded by any treatment for malaria in the prior 14 days. Comparisons of the incidence of malaria between 6 and 12 months of age were made between infants enrolled in this study and other cohorts enrolled in the same study site using the same methodology. Placental malaria status was categorized using a categorical variable as follows: no parasites or pigment detected by any method, only pigment detected by histopathology (no parasites), parasites detected by PCR or histopathology but not placental blood smear, parasites detected by placental blood smear. Time to an infant’s first episode of malaria was estimated using Kaplan–Meier survival analysis. Associations between risk factors assessed at the time of birth and time to first episode of malaria were assessed using a Cox proportional hazards model. In all analyses, a two-sided P value of <0.05 was considered to be statistically significant. This study was approved by the Uganda National Council of Science and Technology, the Makerere University School of Medicine Research Ethics Committee, and the University of California, San Francisco Committee for Human Research. Informed consent was obtained from all mothers at the time of enrolment.

Based on the provided information, it seems that the study is focused on understanding the burden of malaria in HIV-exposed, uninfected (HEU) infants in a high malaria transmission setting. The study also evaluates the effectiveness of daily trimethoprim-sulfamethoxazole (TS) prophylaxis in reducing the incidence of malaria in these infants.

Based on this study, here are some potential innovations that could be considered to improve access to maternal health:

1. Improved diagnostic tools: Develop and implement more accurate and efficient diagnostic tools for malaria, such as rapid diagnostic tests or point-of-care devices, to enable early detection and prompt treatment.

2. Enhanced surveillance systems: Establish robust surveillance systems to monitor the incidence of malaria and other febrile illnesses in pregnant women and infants, allowing for timely interventions and targeted healthcare services.

3. Integrated antenatal care: Integrate malaria prevention and treatment services into routine antenatal care visits, ensuring that pregnant women receive appropriate interventions and education on malaria prevention.

4. Community-based interventions: Implement community-based interventions, such as community health workers or mobile clinics, to provide access to maternal health services, including malaria prevention and treatment, in remote or underserved areas.

5. Health education and awareness: Conduct comprehensive health education campaigns to raise awareness about malaria prevention and the importance of early detection and treatment among pregnant women and their families.

6. Access to insecticide-treated bed nets: Ensure universal access to insecticide-treated bed nets for pregnant women and infants, as they are effective in reducing malaria transmission and protecting against mosquito bites.

7. Collaboration and partnerships: Foster collaboration between healthcare providers, researchers, policymakers, and community stakeholders to develop and implement comprehensive strategies for improving access to maternal health, including malaria prevention and treatment.

It is important to note that these recommendations are based on the information provided and may need to be further tailored to the specific context and needs of the target population.
AI Innovations Description
Based on the provided description, the recommendation to improve access to maternal health would be to implement a comprehensive malaria prevention and treatment program for HIV-exposed, uninfected (HEU) infants in high malaria transmission settings. This program should include the following components:

1. Prophylaxis: Provide daily trimethoprim-sulfamethoxazole (TS) prophylaxis to HEU infants from 6 weeks of age until exclusion of HIV-infection after cessation of breastfeeding. This can help reduce the incidence of malaria in these infants.

2. Bed nets: Distribute long-lasting, insecticide-treated bed nets (LLINs) to all study participants at birth. LLINs have been shown to be effective in preventing malaria transmission and can protect both the infants and their mothers.

3. Early diagnosis and treatment: Establish a dedicated study clinic open 7 days a week where parents can bring their infants for any fever or other illness. Conduct routine monthly visits to assess adherence to TS prophylaxis and perform thick blood smears for the detection of malaria parasites. If a febrile episode is detected, perform a thick blood smear for malaria diagnosis and provide appropriate treatment with artemether-lumefantrine (AL) or quinine, depending on the age and weight of the infant.

4. Placental malaria screening: Determine the placental malaria status of mothers using placental blood smears, histopathology, and PCR. Infants born to mothers with parasites detected from placental blood smears should be considered at higher risk of malaria and receive closer monitoring and prompt treatment if necessary.

5. Education and awareness: Provide education to mothers about the importance of adhering to TS prophylaxis, using bed nets, and seeking early medical care for febrile episodes. Raise awareness about alternative causes of fever in HEU infants taking TS prophylaxis to avoid unnecessary treatment for malaria.

By implementing this comprehensive program, the burden of malaria in HEU infants can be reduced, leading to improved maternal and infant health outcomes.
AI Innovations Methodology
To improve access to maternal health in a high malaria transmission setting, here are some potential recommendations:

1. Increase availability and distribution of insecticide-treated bed nets (ITNs): ITNs are a proven intervention to prevent malaria transmission. By ensuring that pregnant women have access to ITNs, the risk of malaria infection can be reduced, leading to improved maternal health outcomes.

2. Implement regular antenatal care (ANC) visits: ANC visits provide an opportunity for early detection and management of malaria in pregnant women. By promoting regular ANC visits, healthcare providers can monitor the health of pregnant women, provide appropriate preventive measures, and promptly treat any malaria infections.

3. Strengthen malaria testing and treatment services: Access to accurate and timely malaria testing and treatment is crucial for pregnant women. By improving the availability and quality of malaria diagnostic tools and antimalarial medications, healthcare providers can ensure that pregnant women receive appropriate treatment for malaria.

4. Enhance health education and community engagement: Raising awareness about the importance of malaria prevention and treatment during pregnancy is essential. By conducting health education campaigns and engaging with communities, pregnant women can be empowered to take proactive measures to protect themselves from malaria.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could include the following steps:

1. Define the target population: Identify the specific population of pregnant women in the high malaria transmission setting who would benefit from improved access to maternal health services.

2. Collect baseline data: Gather data on the current access to maternal health services, including ANC attendance rates, availability of ITNs, malaria testing and treatment services, and community knowledge and practices related to malaria prevention during pregnancy.

3. Develop a simulation model: Create a mathematical or computational model that simulates the impact of the recommended interventions on access to maternal health. The model should consider factors such as population size, coverage of interventions, and potential barriers to implementation.

4. Input intervention parameters: Specify the parameters of the recommended interventions, such as the percentage increase in ITN distribution, the frequency of ANC visits, the availability of malaria testing and treatment services, and the reach of health education campaigns.

5. Run simulations: Use the simulation model to project the potential impact of the interventions over a specified time period. The model can estimate outcomes such as the reduction in malaria incidence among pregnant women, the increase in ANC attendance rates, and the improvement in maternal health indicators.

6. Analyze results: Evaluate the simulation results to assess the effectiveness of the recommended interventions in improving access to maternal health. Identify key findings, trends, and potential challenges or limitations of the interventions.

7. Refine and iterate: Based on the simulation results, refine the intervention parameters and run additional simulations to explore different scenarios and optimize the impact of the interventions.

By using this methodology, policymakers and healthcare providers can gain insights into the potential benefits of implementing specific interventions to improve access to maternal health in high malaria transmission settings.

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