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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.
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