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Background: Observational studies suggest that blood concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with morbidity, viral suppression, and mortality among adults living with HIV.Objectives: We evaluated the effect of cholecalciferol (vitamin D3) supplementation on the risk of HIV disease progression, HIV-1 viral suppression, comorbidities, weight change, and depression among HIV-infected individuals that were initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania.Methods: We conducted a randomized, double-blind, placebo-controlled trial of vitamin D3 supplementation among 4000 HIV-infected adult men and nonpregnant women initiating ART with insufficient serum 25(OH)D concentrations (<30 ng/mL). Participants were randomly assigned to receive either weekly 50,000-IU doses for 4 wk followed by daily 2000 IU vitamin D3 until 1 y or a matching placebo regimen given in weekly followed by daily doses until 1 y. Participants were followed up at weekly visits for the first month followed by monthly visits thereafter. We conducted intent-to-treat analyses to assess the effect of vitamin D3 supplementation on the secondary trial outcomes of HIV progression or death, viral suppression, comorbidities, change in BMI, >10% weight loss, incident wasting, and depression.Results: During follow-up, 345 participants (17.2%) in the vitamin D3 group and 371 participants (18.6%) in the placebo group experienced HIV disease progression or death and there was no difference in risk between groups (RR: 0.91; 95% CI: 0.79, 1.06). Vitamin D3 supplementation did not affect the risk of an unsuppressed HIV-1 viral load (>1000 copies/mL) after 6 mo (RR: 1.10; 95% CI: 0.87, 1.41) and there was also no effect on change in BMI, risk of >10% weight loss, wasting, comorbidities, and depression (P values >0.05).Conclusions: Vitamin D supplementation did not affect the risk of HIV progression, viral suppression, common morbidities, weight-related indicators, or depression among adults initiating ART in Tanzania.This trial was registered at clinicaltrials.gov as NCT01798680. [ABSTRACT FROM AUTHOR]

Background: Hematological status may predict HIV disease progression and mortality among adults initiating highly active antiretroviral therapy (HAART).Objectives: We aimed to examine the relation of anemia and iron status at HAART initiation with survival and morbidity outcomes.Methods: We conducted a case-cohort study of 570 HIV-infected adults initiating HAART who were enrolled in a trial of multivitamins in Tanzania. Hemoglobin, serum ferritin, and hepcidin concentrations were assessed at HAART initiation and participants were followed up monthly. We adjusted serum ferritin for inflammation using a regression correction method to characterize hematological status. Cox proportional hazards models were used to estimate HRs for mortality and incident clinical outcomes.Results: We found an 83% prevalence of anemia, 15% prevalence of iron deficiency anemia, and 66% prevalence of anemia of chronic diseases (ACD). The prevalence of elevated iron was 33% and 19% had iron deficiency (ID). After multivariate adjustment, severe anemia (HR: 2.57; 95% CI: 1.49, 4.45) and ACD (HR: 4.71; 95% CI: 2.91, 7.62) were associated with increased risk of mortality as compared with nonanemic participants. In addition, both ID (HR: 2.65; 95% CI: 1.08, 7.78) and elevated iron (HR: 2.83; 95% CI: 2.10, 3.82) were associated with increased risk of mortality as compared with normal iron concentrations. Severe anemia and elevated iron concentrations were associated with incident wasting and >10% weight loss (P values <0.05).Conclusions: Anemia and both ID and elevated iron were associated with increased mortality among HIV-infected adults initiating HAART. Safety and efficacy studies including anemia etiology, timing of HAART initiation, and dose of iron supplementation among HIV patients appear warranted.This trial was registered at clinicaltrials.gov as NCT00383669. [ABSTRACT FROM AUTHOR]

Background: Zinc and vitamin A supplementation have both been shown to affect iron status, hemoglobin (Hb) concentration, and anemia in animal and human studies. However, evidence on their combined use in pregnancy, in the context of iron-folic acid (IFA) supplementation, remains limited.Objective: This study determined the effects of prenatal zinc, vitamin A, and iron supplementation on maternal hematologic and micronutrient status at delivery in Tanzania.Methods: We analyzed 2 large randomized controlled trials, using generalized estimating equations, and examined the effect of daily zinc (25 mg) and vitamin A (2500 IU) supplementation starting in the first trimester of pregnancy compared with placebo (n = 2500), and separately evaluated the safety and efficacy of daily iron (60 mg) supplementation among iron-replete pregnant women (n = 1500). Blood samples from baseline and delivery were tested for Hb, serum ferritin, soluble transferrin receptor, plasma zinc, and zinc protoporphyrin.Results: Zinc and vitamin A supplementation were associated with lower Hb concentrations at delivery of  -0.26 g/dL (95% CI: -0.50, -0.02 g/dL) and -0.25 g/dL (95% CI: -0.49, -0.01 g/dL), respectively. Vitamin A increased mean ferritin concentrations at delivery (14.3 μg/L, 95% CI: 1.84, 29.11 μg/L), but was associated with increased risk of severe anemia (RR: 1.41; 95% CI: 1.06, 1.88). Among women who were iron replete at baseline, iron supplementation reduced the risk of iron depletion at delivery by 47% (RR: 0.53; 95% CI: 0.43, 0.65). There was no effect of zinc or iron supplements on plasma zinc concentrations.Conclusions: Our findings support existing WHO guidelines on prenatal iron, vitamin A, and zinc supplementation among pregnant women. In this setting, scaling uptake of prenatal iron supplements is warranted, but prenatal zinc and vitamin A supplementation did not benefit maternal hematologic status at delivery. In settings where vitamin A deficiency is endemic, the efficacy and safety of the WHO recommended prenatal vitamin A supplementation require further evaluation. [ABSTRACT FROM AUTHOR]

Highlights • About one tenth of pregnant women had acute rubella infections. • IgM seropositivity decreased significantly with gestation age. • More than ¾ of IgM seropositive women had adverse pregnancy outcomes. • One tenth of IgM positive women delivered neonates with CRS. Abstract Objective This study investigated the adverse pregnancy outcomes among pregnant women with acute Rubella infections in the city of Mwanza, Tanzania. Methods A longitudinal study was conducted between 2014 and 2016 among pregnant women attending antenatal clinics. Women were screened for Rubella IgG and IgM antibodies using enzyme immunoassay (EIA). IgM seropositive pregnant women were followed up until the end of the pregnancy to determine Congenital Rubella Syndrome, congenital infections and other pregnancy outcomes. Results The median age of 685 enrolled pregnant women was 23 (IQR: 19–27) years. A total of 629(91.8%) were Rubella IgG seropositive while 61 (8.9%) were IgM seropositive. The IgM seropositivity was found to decrease significantly from first trimester to third trimester, p < 0.001. Forty six (83.6%) of 55 Rubella IgM seropositive women had adverse pregnancy outcomes and 6 (10.9%) delivered neonates with CRS, making the overall incidence of CRS to be 6/685 (0.87%). First trimester IgM seropositive women had significantly higher adverse pregnancy outcomes than those in second/third trimesters (70.4% vs. 35.7, p = 0.01). Conclusion There is one case of CRS in every 100 pregnancies necessitating additional strategies to reach a goal of elimination of CRS in developing countries. [ABSTRACT FROM AUTHOR]

OBJECTIVE Nine out of ten tuberculosis deaths occur in tuberculosis-burdened countries, particularly Sub Saharan Africa. In these setting mortality has not been fully described. We describe the magnitude and pattern of TB mortality in Tanzania. METHODS A multicenter prospective cohort study was conducted among HIV infected and uninfected pulmonary tuberculosis patients from time of anti-TB treatment initiation to completion. Patients were censored at the time of treatment completion, or at their last visit for those who did not complete TB treatment. Kaplan-Meier curves were used to estimate time to death; cox proportional hazards model was used to examine risk factors for mortality. RESULTS A total of 58 deaths out of 1696 patients (3.4%) occurred, two thirds (n = 39) during the first two months of treatment. Compared to HIV un-infected TB patients, mortality risk for TB/HIV co-infected patients was least when antiretroviral therapy (ART) was initiated after 14 days of anti-TB (RR = 3.55; 95% CI: 1.44, 8.73 p < 0.0001) and highest when ART was initiated 90 days or less prior to anti-TB and within the first 14 days of anti-TB therapy (RR = 10; 95% CI: 3.28, 30.54; p < 0.0001). CONCLUSION Meticulously planned and supervised antiretroviral therapy reduces mortality among TB/HIV patients. Among patients with TB/HIV naïve of ART, withholding ART until the third week of anti-tuberculosis therapy will likely reduce TB mortality in Tanzania. Patients on ART and later develop tuberculosis should be closely monitored. [ABSTRACT FROM AUTHOR]

Background Intact immune responses to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) represent a biologically and clinically relevant correlate of ‘immunological fitness’ in humans. However, there is a lack of knowledge concerning anti-EBV or anti-CMV responses in patients with pulmonary tuberculosis (TB), in whom aberrant immune responses may promote progression of clinical disease. Methods Venous blood samples were obtained at the time of (sputum smear positive) pulmonary TB diagnosis. A whole blood assay was performed by exposing PBMCs (peripheral blood mononuclear cells) to a panel of infectious antigens, including CMV, EBV and mycobacterial proteins. Cell culture supernatants were collected after seven days and interferon gamma (IFN-γ) was measured using a sandwich ELISA. Patients received standard first line anti-tuberculosis rifampicin (R)/isoniazid (H)/ethambutol (E)/pyrazinamide (Z) for two months followed by RH for four months. Results PBMCs from cured patients (after treatment completion) exhibited significantly stronger IFN-γ responses to CMV (p=0.035), EBV (p=0.006) or Mycobacterium tuberculosis ESAT-6 (p = 0.043) at the time of diagnosis as compared to patients who succumbed to TB during treatment. IFN-γ responses to other viral (H5N1, HSV-1) as well as other mycobacterial (Ag85A, Rv2958c, Rv0447c) antigens were not found to be significantly different among patients who were cured or those who succumbed to TB. Conclusions Increased cellular immune responses to CMV and EBV antigens at the time of diagnosis of pulmonary tuberculosis are associated with increased survival after a standard six months anti-TB therapy. CVM and EBV antigens may represent “intrinsic markers for immune fitness” and guide improved TB therapies including host-directed therapies. [ABSTRACT FROM AUTHOR]

Objectives: To identify risk factors, including maternal antiretroviral therapy (ART), for diarrhea in Tanzanian children exposed to HIV during the first 2 years of life.Study Design: Using generalized estimating equations, we analyzed data from a cohort of 2387 Tanzanian children exposed to HIV from age 6 weeks to 2 years, as well as data from their mothers, to determine risk factors for diarrhea in children. Mothers recorded diarrhea in a diary and reported results at visits scheduled every four weeks.Results: Body mass index was ≥18.5 in 95.6% of mothers. World Health Organization HIV stage was 1/2 for 1255 (87.8%) mothers. ART was received by 24.3% of mothers, most initiating ART during pregnancy. At baseline (6 weeks of age) 264 (11.3%) children were infected with HIV. In children whose mothers received ART, the relative risk of diarrhea in children was 0.79 (95% CI 0.68-0.92), after we adjusted for multiple factors, including child HIV status and exclusive breastfeeding duration. Exclusive breastfeeding (relative risk 0.67, 95% CI 0.56-0.80) also was protective.Conclusion: Our results provide additional support to increase ART coverage for all pregnant mothers, to control clinical HIV progression, reduce perinatal HIV infection, but also to reduce the risk of a major cause of death and morbidity in young children worldwide.Trial Registration: ClinicalTrials.gov: NCT00197730. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency is a highly prevalent micronutrient abnormality and the most common cause of anemia globally, worsening the burden of adverse pregnancy and child outcomes.Objective: We sought to evaluate the response of hematologic biomarkers to iron supplementation and to examine the predictors of the response to iron supplementation among iron-deficient pregnant women.Methods: We identified 600 iron-deficient (serum ferritin ≤12 μg/L) pregnant women, aged 18-45 y, presenting to 2 antenatal clinics in Dar es Salaam, Tanzania using rapid ferritin screening tests, and prospectively followed them through delivery and postpartum. All women received 60 mg Fe and 0.25 mg folate daily from enrollment until delivery. Proportions meeting the thresholds representing deficient hematologic status including hemoglobin <110 g/L, ferritin ≤12 μg/L, serum soluble transferrin receptor (sTfR) >4.4 mg/L, zinc protoporphyrin (ZPP) >70 mmol/L, or hepcidin ≤13.3 μg/L at baseline and delivery were assessed. The prospective change in biomarker concentration and the influence of baseline hematologic status on the change in biomarker concentrations were assessed. Regression models were estimated to assess the relation of change in biomarker concentrations and pregnancy outcomes.Results: There was significant improvement in maternal biomarker concentrations between baseline and delivery, with increases in the concentrations of hemoglobin (mean difference: 15.2 g/L; 95% CI: 13.2, 17.2 g/L), serum ferritin (51.6 μg/L; 95% CI: 49.5, 58.8 μg/L), and serum hepcidin (14.0 μg/L; 95% CI: 12.4, 15.6 μg/L) and decreases in sTfR (-1.7 mg/L; 95% CI: -2.0, -1.3 mg/L) and ZPP (-17.8 mmol/L; 95% CI: -32.1, 3.5 mmol/L). The proportions of participants with low hemoglobin, ferritin, and hepcidin were 73%, 93%, and 99%, respectively, at baseline and 34%, 12%, and 46%, respectively, at delivery. The improvements in biomarker concentrations were significantly greater among participants with poor hematologic status at baseline - up to 12.1 g/L and 14.5 μg/L for hemoglobin and ferritin concentrations, respectively. For every 10-g/L increase in hemoglobin concentration, there was a 24% reduced risk of perinatal mortality (RR = 0.76; 95% CI: 0.59, 0.99) and a 23% reduced risk of early infant mortality (RR = 0.77; 95% CI: 0.60, 0.99). The risk of anemia at delivery despite supplementation was predicted by baseline anemia (RR = 2.11; 95% CI: 1.39, 3.18) and improvements in ferritin concentration were more likely to be observed in participants who took iron supplements for up to 90 d (RR = 1.41; 95% CI: 1.13, 1.76).Conclusion: Iron supplementation decreases the risk of maternal anemia and increases the likelihood of infant survival among iron-deficient Tanzanian pregnant women. Interventions to promote increased duration and adherence to iron supplements may also provide greater health benefits. [ABSTRACT FROM AUTHOR]

Background: Antibodies to LPS and flagellin have been described as indirect measures of increased gastrointestinal permeability and may be markers of environmental enteric dysfunction (EED), which is a condition associated with poor child growth. Objective: We assessed whether LPS- and flagellin-specific immunoglobulin (Ig) concentrations were associated with poor growth in young Tanzanian children at risk of EED. Design: Blood samples were obtained from 590 children at 6 wk, 6 mo, and 12 mo of age. Serum LPS- and flagellin-specific Ig concentrations (IgA and IgG) were measured with the use of an ELISA. Growth was measured on a monthly basis for 18 mo. Results: Anti-LPS and anti-flagellin IgA and IgG concentrations increased over the first year of life and were higher than concentrations (measured at 9 mo of age) in healthy controls. Children with anti-flagellin IgA, anti-LPS IgA, anti-flagellin IgG, and anti-LPS IgG concentrations in the highest quartile at 6 wk of age were 2.02 (95% CI: 1.11, 3.67), 1.84 (95% CI: 1.03, 3.27), 1.94 (95% CI: 1.04, 3.62), and 2.31 (95% CI: 1.25, 4.27) times, respectively, more likely to become underweight (weight-for-age z score <-22) after adjustment for covariates (P-trend < 0.05) than were children with Ig concentrations in the lowest quartile. Children with increased concentrations of anti-flagellin IgA were also more likely to become wasted; however, there was no association between any of the markers and subsequent stunting. Conclusion: Serologic measures of increased intestinal permeability to bacterial components are associated with subsequent poor growth and could help identify children who may benefit most from preventive interventions. This trial was registered at clinicaltrials.gov as NCT00421668. [ABSTRACT FROM AUTHOR]

Background: Poor child growth increases risks of mortality and morbidity. Micronutrient supplements have the potential to improve child growth. Objective: We assessed the effect of daily zinc, multivitamin (vitamins C, E, and B-complex), and zinc and multivitamin (Zn+MV) supplementation on growth in infants in Tanzania. Design: In this randomized, 232 factorial, double-blind trial, 2400 infants were randomly assigned to receive zinc, multivitamins, Zn+MVs, or a placebo at 6 wk of age and were followed up for 18 mo with monthly growth measurements. Mixed-effects models with restricted cubic splines for the mean change in anthropometric z scores were fit for each group. Likelihood ratio tests were used to compare the effect of supplements on growth trajectories. Cox proportional hazards models were used to compare incidences of stunting, wasting, and underweight. Results: Children in all groups experienced growth faltering. At 19 mo of age, prevalences of stunting, wasting, and underweight were 19.8%, 6.0%, and 10.8%, respectively. Changes in weight-for-age z scores (WAZs) and weight-for-height z scores (WHZs) were significantly different across the 4 groups (P < 0.001 for both). The mean ± SE decline in the WAZ from baseline to the end of follow-up in the Zn+MV group was significantly less than in the placebo group (-0.36 ± 0.04 compared with -0.50 ± 0.04; P = 0.020), whereas the decline in the WHZ was significantly greater in the zinc-only group than in the placebo group (-0.57 ± 0.07 compared with 20.35 ± 0.07; P = 0.021). Supplements did not have a significant effect on mean change in the height-for-age z score or on rates of stunting, wasting, or underweight. Conclusions: Although there were small but significant improvements in the WAZ in the Zn+MV group, daily zinc supplementation alone, multivitamin supplementation alone, and the combined Zn+MV did not reduce the incidences of underweight, stunting, or wasting in Tanzanian infants. Alternative approaches to prevent growth faltering should be pursued. This trial was registered at clinicaltrials.gov as NCT00421668. [ABSTRACT FROM AUTHOR]

Background: Although various micronutrient regimens have been shown to prevent and treat common infectious diseases in children, the effects of daily multivitamin (MV) and/or zinc supplementation have not been widely evaluated in young African infants. Objective: The objective was to determine whether daily supplementation of HIV-unexposed Tanzanian infants with MVs or zinc reduces the risk of infectious morbidity compared with placebo. Methods: In a 2 x 2 factorial, double-blind, randomized controlled trial, 2400 infants who were 6 wk of age and born to HIV-negative mothers in a low-malaria setting were randomly assigned to receive daily oral supplementation of MVs (vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo. Morbidity was assessed by study nurses at monthly visits and by physicians every 3 mo and/or when the child was acutely ill. Results: No significant differences were found in the percentage of nurse visits during which diarrhea, cough, or any other symptom were reported throughout the previous month when receiving either zinc or MVs. However, physician diagnoses of all types of diarrhea (RR = 0.88; 95% CI: 0.81, 0.96; P = 0.003), dysentery (RR = 0.84; 95% CI: 0.74, 0.95; P = 0.006), and acute upper respiratory infection (RR = 0.92; 95% CI: 0.88, 0.97; P = 0.0005) were significantly lower for infants supplemented with zinc than for those who did not receive zinc. Among the 2360 infants for whom vital status was obtained, there was a nonsignificant increase in all-cause mortality among infants who received zinc (HR = 1.80; 95% CI: 0.98, 3.31; P = 0.06) compared with those who did not receive zinc. MVs did not alter the rates of any recorded physician diagnoses or mortality. Neither zinc nor MVs reduced hospitalizations or unscheduled outpatient visits. Conclusions: Daily zinc supplementation of Tanzanian infants beginning at the age of 6 wk may lower the burden of diarrhea and acute upper respiratory infections, but provision of MVs using the regimen in this trial did not confer additional benefit. This trial was registered at clinicaltrials.gov as NCT00421668. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is a potent immunomodulator, but its impact on morbidity and mortality among infants remains unclear. Objective: The objective of the study was to prospectively assess the association of vitamin D status with mortality, morbidity, and growth during the first 2 y of life. Methods: A prospective cohort of 253 HIV-infected and 948 HIV-exposed Tanzanian infants enrolled in a randomized trial of multivitamins (not including vitamin D) was studied. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 5--7 wk of age and infants were followed at monthly clinic visits until 24 mo. Physicians performed a clinical exam every 3 mo or when an illness was noted. Results: Serum 25(OH)D concentrations were (means ± SDs) 18.6 ± 10.3 ng/mL and 18.1 ± 9.2 ng/mL for HIV-infected and HIV-exposed infants, respectively. Unexpectedly, serum 25(OH)D concentrations ≥30 ng/mL were significantly associated with higher mortality as compared to the 20--29.9 ng/mL reference for HIV-infected (HR: 2.47; 95% CI: 1.13, 5.44; P = 0.02) and HIV-exposed (HR: 4.00; 95% CI: 1.67, 9.58; P < 0.01) infants after multivariate adjustment. We found no statistically significant association between 25(OH)D concentrations <10 ng/mL and mortality for HIV-infected (HR: 1.43; 95% CI: 0.74, 2.78; P = 0.29) and HIV-exposed (HR: 1.56; 95% CI: 0.60, 4.03; P = 0.36) infants. Among HIV-exposed infants, 25(OH)D concentrations ≥30 ng/mL were significantly associated with clinical [incidence ratio rate (IRR): 1.34; 95% CI: 1.06,1.70; P = 0.02] and confirmed (IRR: 1.71; 95% CI: 1.71; 1.15, 2.54; P < 0.01) malaria diagnoses, whereas concentrations of <10 ng/mL were associated with oral candidiasis (IRR: 1.47; 95% CI: 1.00--2.15; P = 0.046) and wasting (HR: 1.71; 95% CI: 1.20, 2.43; P < 0.01). Conclusion: The observational design of this study does not allow for causal interpretation; however, the results indicate a strong need for additional studies of vitamin D among HIV-infected and -exposed children, particularly in malaria-endemic settings. [ABSTRACT FROM AUTHOR]

Objective: Selenium supplementation for women infected with HIV may increase genital shedding of HIV-1, however, to our knowledge, no studies have examined the effect on viral shedding in breast milk. The aim of this study was to determine the effect of selenium supplementation on HIV-1 RNA detection in breast milk of HIV-infected women. Methods: HIV-infected pregnant women enrolled at 12 to 27 wk gestation in a randomized, double-blind, placebo-controlled trial of daily selenium (200 µg as selenomethionine) had cell-free HIV-1 RNA quantified in breast milk at 4 to 9 wk postpartum. All participants received high-dose multivitamins containing vitamin B complex, C, and E as standard of care. Results: The proportion of women with detectable (>50 copies/mL) HIV-1 RNA in breast milk appeared to be increased in the selenium group (36.4%) compared with those in the placebo group (27.5%) among the total cohort (N = 420), but results were borderline statistically significant (relative risk [RR], 1.32; 95% confidence interval [CI], 1.00-1.76; P = 0.05). In secondary analyses, the proportion of women with detectable HIV-1 RNA in breast milk was significantly greater in the selenium group (37.8%) compared with placebo group (27.5%) among women who did not receive highly active antiretroviral therapy (HAART; RR, 1.37; 95% CI, 1.03-1.82; P = 0.03). This relationship was primarily due to a significant effect of selenium among primiparous women (RR, 2.24; 95% CI, 1.30-3.86; P < 0.01), but not multiparous women (RR, 1.14; 95% CI, 0.81-1.59; P = 0.54) (P-value for interaction = 0.02). Too few women received HAART in this study (n = 12) to establish the effect of selenium supplementation. Conclusions: Selenium supplementation appears to increase HIV-1 RNA detection in breast milk among primiparous women not receiving HAART. Safety studies among pregnant women on HAART need to be conducted before administering selenium-containing supplements. [ABSTRACT FROM AUTHOR]

Background: The development of low-cost point-of-care technologies to improve HIV treatment is a major focus of current research in resource-limited settings. Objective: We assessed associations of body mass index (BMI; in kg/m²) at antiretroviral therapy (ART) initiation and weight change after 1 mo of treatment with mortality, morbidity, and CD4 T cell reconstitution. Design: A prospective cohort of 3389 Tanzanian adults initiating ART enrolled in a multivitamin trial was followed at monthly clinic visits (median: 19.7 mo). Proportional hazard models were used to analyze mortality and morbidity associations, whereas generalized estimating equations were used for CD4 T cell counts. Results: The median weight change at 1 mo of ART was +2.0% (IQR: -0.4% to +4.6%). The association of weight loss at 1 mo with subsequent mortality varied significantly by baseline BMI (P = 0.011). Participants with ≥2.5% weight loss had 6.43 times (95% CI: 3.78, 10.93 times) the hazard of mortality compared with that of participants with weight gains ≥2.5%, if their baseline BMI was <18.5 but only 2.73 times (95% CI: 1.49, 5.00 times) the hazard of mortality if their baseline BMI was ≥18.5 and <25.0. Weight loss at 1 mo was also associated with incident pneumonia (P = 0.002), oral thrush (P = 0.007), and pulmonary tuberculosis (P < 0.001) but not change in CD4 T cell counts (P > 0.05). Conclusions: Weight loss as early as 1 mo after ART initiation can identify adults at high risk of adverse outcomes. Studies identifying reasons for and managing early weight loss are needed to improve HIV treatment, with particular urgency for malnourished adults initiating ART. The parent trial was registered at clinicaltrials.gov as NCT00383669. [ABSTRACT FROM AUTHOR]

Growth faltering and micronutrient deficiencies commonly coexist in HIV-exposed children in sub-Saharan Africa, and correcting deficiencies, such as those of vitamins B-complex, C, and E, may improve HIV-related endpoints and child growth. We therefore examined the effect of daily oral supplementation of vitamins B-complex, C, and E on growth among 2341 children born to HIV-infected mothers in Tanzania. HIV-infected women pregnant at ≤32 wk of gestation were enrolled in the study. Children were randomized at age 6 wk to receive multivitamins or placebo until age 104 wk. All women received the same types of vitamins pre- and postnatally. At 6 wk, 256 children (11.1%) were HIV infected and the mean (SD) Z-scores for length for age (LAZ), weight for length (WLZ), and weight for age (WAZ) were -0.39 ± 1.20, -0.21 ± 1.23, and -0.52 ± 1.11, respectively. There was no overall treatment effect on LAZ, WLZ, or WAZ profiles during the follow-up (P > 0.15). There was no treatment effect from 6 to 104 wk on LAZ [(95% Cl: -0.14, 0.13); P = 0.94!, WLZ [(95% Cl: -0.17, 0.13); P = 0.78], or WAZ l(95% Cl: -0.15, 0.16); P = 0.97) or on the incidence of growth failure, defined as respective Z-scores < -2 (P ≥ 0.29). Among the subgroup of HIV-uninfected children, there was no treatment effect from 6 to 104 wk on LAZ, WLZ, and WAZ (P ≥ 0.71) or on the incidence of growth failure (P ≥ 0.16). Multivitamin supplements had no effect on growth among children born to HIV-infected women who were themselves receiving multivitamins. [ABSTRACT FROM AUTHOR]

Background: Multiple micronutrients (vitamin B complex and vitamins C and E) were effective at reducing infectious disease morbidity, HIV disease progression, and poor pregnancy outcomes in HIV-infected women. Objective: The objective was to evaluate whether direct supplementation of these micronutrients to HIV-exposed infants reduces mortality and morbidity. Design: Infants born to HIV-infected women from Dar es Salaam, Tanzania, were randomly assigned to receive daily oral supplementation of multiple multivitamins (vitamin B complex and vitamins C and E) or placebo from age 6 wk for 24 mo. All-cause mortality, hospitalizations, and unscheduled clinic visits were recorded. Morbidities were recorded during monthly follow-up visits. All mothers received multiple micronutrients throughout the study. Results: A total of 1193 infants were randomly assigned to receive micronutrients and 1194 to receive placebo. There were 138 child deaths in the multivitamin group and 124 deaths in the placebo group (HR: 1.13; 95% CI: 0.88, 1.44; P = 0.33). Hospitalizations (RR: 0.83; 95% CI: 0.62, 1.13; P = 0.23), unscheduled clinic visits (RR: 0.97; 95% CI: 0.85, 1.10; P = 0.59), and maternal reports of diarrhea (RR: 0.97; 0.87, 1.10; P = 0.64) were not significantly different between the 2 groups. Fever (P = 0.02) and vomiting (P = 0.007) were significantly lower in the multivitamin group. Among 429 children whose mothers received antiretroviral (ARV) therapy, multivitamin use had no effect on mortality but was associated with a significant reduction in hospitalizations (P = 0.035), episodes of fever (P = 0.005), and episodes of fever and cough (P = 0.019). Conclusions: In the setting of maternal micronutrient supplementation, supplementation of HIV-exposed infants with vitamin B and vitamins C and E does not reduce mortality. Studies of nutrition supplementation in ARV-exposed infants may be warranted. [ABSTRACT FROM AUTHOR]

Background: Despite the benefits of exclusive breastfeeding (EBF), exposure to HIV from breast milk has relegated EBF to an option only when formula feeding is not affordable, feasible, safe, and sustainable. Mixed feeding remains the norm in sub-Saharan Africa. Objective: We evaluated whether the duration of EBF was associated with mortality and HIV infection in children followed to ≤5 y of age. Methods: A total of 690 mother-infant pairs from the Trial of Vitamins with information on infant feeding, HIV status, and at least one visit in the first year were included in the analysis. The duration of EBF was defined in months as a time-varying covariate at each follow-up visit. Associations of the duration of EBF with mortality, HIV infection, and HIV infection or death were estimated by using Cox proportional hazards models and Kaplan-Meier survival curves. Results: A 1-mo increase in EBF was associated with a 49% reduction in early infant mortality in the first 6 mo of life (RR: 0.51 ; 95% CI: 0.28, 0.93) and a nonsignificant 15% reduction in risk of HIV infection or death (RR: 0.85; 95% CI: 0.71, 1.01; P = 0.07) over the first 5 y of life. EBF was not associated with HIV infection (RR: 0.93; 95% CI: 0.76, 1.15). Conclusion: Longer EBF by HIV-positive mothers was associated with reduced mortality in the first 6 mo of life without increased HIV infection, which makes EBF the best option for women who cannot sustain exclusive formula feeding. This trial was registered at clinicaltrials.gov as NCT00197743. [ABSTRACT FROM AUTHOR]

Abstract: Background: We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Methods: Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1mg intradermally (id), n =20, or 3.8mg intramuscularly (im), n =20, or placebo, n =20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (108 pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. Results: The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8+ and CD4+ T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01_AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. Conclusions: This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses. [Copyright &y& Elsevier]

Subclinical mastitis is common in HIV-infected women and is a risk factor for mother-to-child transmission of HIV. The purpose of this study was to examine the effect of vitamin supplementation [vitamin A + β-carotene, multivitamins (B complex, C, and E), or multivitamins, including vitamin A + β-carotene] on the risk of subclinical mastitis during the first 2 y postpartum among HIV-infected women. The study was a randomized; placebo-controlled, clinical trial including 674 HIV- infected, antiretroviral naive Tanzanian women who were recruited during pregnancy and followed-up after delivery. Breast milk samples were obtained approximately every 3 mo. Any subclinical mastitis was defined as a ratio of the sodium to potassium (Na:K) breast milk concentrations > 0.6 and further classified as either moderate (Na:K ⩾ 0.6 and ⩽ 1 (or severe (Na:K> 1.0). Fifty-eight percent of women had at least 1 episode of any subclinical mastitis. Women assigned to multivitamins (B complex, C, and E) had a 33% greater risk of any subclinical mastitis (P= 0.005) and a 75% greaterrisk of severe subclinical mastitis (P = 0.0006) than women who received the placebo. Vitamin A + β-carotene also increased the risk of severe subclinical mastitis by 45% (P = 0.03). Among women with CD4+ T-cell counts ⩾ 350 cells/μL, multivitamin intake resulted in a 49% increased risk of any subclinical mastitis (P = 0.006); by contrast, there were no treatment effects among women with CD4+ T-cell counts < 350 cells/μt )P- interaction for treatment x CD4+ T-cell count = 0.10). Supplementation of HIV-infected women with vitamins increased the risk of subclinical mastitis. [ABSTRACT FROM AUTHOR]

Background: In observational studies, the zinc status of HIV infected persons has been associated with both positive and adverse clinical outcomes. Such endpoints may affect the risk of adverse birth outcomes among HIV-infected women. Objective: We examined the effects of zinc supplements on birth outcomes, hematologic indicators, and counts of T lymphocyte subsets among 400 HIV-infected pregnant women. Design: Eligible women between 12 and 27 wk of gestation were randomly assigned to daily oral supplementation with either 25 mg Zn or placebo between recruitment and 6 wk after delivery. All women received iron, folic acid, and multivitamin supplements irrespective of the experimental assignment. Results: We observed no significant differences in birth weight, duration of gestation, or fetal and neonatal mortality betweenwomen in the zinc and placebo groups. Hemoglobin concentrations increased between baseline and 6 wk postpartum in both groups. However, the rise in hemoglobin over this period was significantly lower (P = 0.03) in the zinc group (x × SD: 11.5 × 17.9 g/L) than in the placebo group (15.2×18.6 g/L). Similarly, the changes in red blood cell count and in packed cell volume over the same period were significantly lower in the zinc group (P < 0.01 and P = 0.01, respectively). Zinc had no effect on CD4+, CD8+, or CD3+ cell counts during the follow-up period. Conclusion: Because of the lack of beneficial effects of zinc on adverse pregnancy outcomes and the likelihood of negative effects on hemoglobin concentrations, no compelling evidence exists to support the addition of zinc to prenatal supplements intended for pregnant HIV-infected women. [ABSTRACT FROM AUTHOR]

Objective: To examine whether daily zinc and/or multivitamin supplementation reduce biomarkers of environmental enteric dysfunction (EED), systemic inflammation, or markers of growth in a sample of infants from Dar es Salaam, Tanzania.Study Design: Subgroup analysis of infants participating in a randomized, double-blind, placebo-controlled trial received daily oral supplementation of zinc, multivitamins, zinc + multivitamins, or placebo for 18 months starting at 6 weeks of age. EED (anti-flagellin and anti-lipopolysaccharide immunoglobulins), systemic inflammation (C-reactive protein and alpha-1-acid glycoprotein), and growth biomarkers (insulin-like growth factor-1 and insulin-like growth factor binding protein-3) were measured via enzyme-linked immunosorbent assay in a subsample of 590 infants at 6 weeks and 6 months of age. EED biomarkers also were measured in 162 infants at 12 months of age.Results: With the exception of anti-lipopolysaccharide IgG concentrations, which were significantly greater in infants who received multivitamins compared with those who did not (1.41 ± 0.61 vs 1.26 ± 0.65, P = .006), and insulin-like growth factor binding protein-3 concentrations, which were significantly lower in children who received zinc compared with those who did not (981.13 ± 297.59 vs 1019.10 ± 333.01, P = .03), at 6 months of age, we did not observe any significant treatment effects of zinc or multivitamins on EED, systemic inflammation, or growth biomarkers.Conclusions: Neither zinc nor multivitamin supplementation ameliorated markers of EED or systemic inflammation during infancy. Other interventions should be prioritized for future trials.Trial Registration: Clinicaltrials.gov: NCT00421668. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the hypothesis that various maternal, socioeconomic, delivery, and infant nutritional characteristics are associated with early childhood development in young Tanzanian children.Study Design: We performed a prospective cohort study among 206 HIV-exposed, uninfected and 247 HIV-unexposed Tanzanian infants who had been enrolled in 2 separate micronutrient trials (NCT00197730 and NCT00421668). Trained nurses administered culturally modified Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III), to evaluate cognitive, motor, and language development at 15 months of age. This analysis explored predictors of BSID-III z-scores using multivariable linear regression.Results: Among maternal determinants, we found that low maternal height predicted all BSID-III domains in HIV-unexposed children; low maternal education predicted lower cognitive (standardized mean difference, -0.41; 95% CI, -0.74 to -0.08) and lower gross motor scores (standardized mean difference, -0.32; 95% CI, -0.61 to -0.04) in HIV-exposed children. Among delivery characteristics, facility delivery predicted higher cognitive scores (standardized mean difference, 1.36; 95% CI, 0.26-2.46); and oxytocin administration predicted lower fine motor scores (standardized mean difference, -0.48; 95% CI, -0.87 to -0.09) in HIV-exposed children. Higher length-for-age z-scores at 6 weeks of age predicted better cognitive (standardized mean difference, 0.15; 95% CI, 0.01-0.29) and expressive language scores (standardized mean difference, 0.16; 95% CI, 0.02-0.29) at 15 months in HIV-exposed infants.Conclusions: This hypothesis-generating study found significant associations between nutritional status and health of the mother and child, and maternal educational attainment, with direct measures of early childhood development at 15 months of age. In addition, several aspects of delivery (facility birth and oxytocin administration) were associated with early childhood development. Future intervention trials should focus on modifiable maternal, infant, and obstetric factors to strengthen the evidence base concerning early childhood development.Trial Registration: ClinicalTrials.gov: NCT00197730 and NCT00421668. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between breastfeeding initiation time and postneonatal mortality, morbidity, and growth through 24 months in a cohort of Tanzanian infants.Study Design: We included 4203 infants from 2 trials of micronutrient supplementation. We used Cox proportional hazards models or general estimating equations to estimate relative risks.Results: A total of 13% of infants initiated breastfeeding >1 hour after birth (n = 536). There was no association between breastfeeding initiation time and risk of all-cause or cause-specific mortality, nor infant growth failure, from 6 weeks to 2 years of age. However, delayed breastfeeding was associated with an increased risk of several common infectious morbidities in early infancy, including upper respiratory infection symptoms and vomiting. Compared with those who initiated breastfeeding within the first hour of birth, delayed breastfeeding initiation was associated with an 11% increased risk of cough (relative risk 1.11, 95% CI 1.02-1.21) and a 48% increased risk of difficulty breathing (relative risk 1.48, 95% CI 1.09-2.01) during the first 6 months. Delayed initiation was associated with a greater risk of difficulty breathing from 6 to 12 months of age, but it was not associated with risk of any other morbidity during this time, nor any morbidity between 12 and 24 months.Conclusion: Delayed breastfeeding initiation is associated with an increased risk of infant morbidity during the first 6 months of life. Early breastfeeding initiation, along with exclusive and prolonged breastfeeding, should be prioritized and promoted in efforts to improve child health. [ABSTRACT FROM AUTHOR]

Objective: To assess whether growth and biomarkers of environmental enteric dysfunction in infancy are related to health outcomes in midchildhood in Tanzania.Study Design: Children who participated in 2 randomized trials of micronutrient supplements in infancy were followed up in midchildhood (4.6-9.8 years of age). Anthropometry was measured at age 6 and 52 weeks in both trials, and blood samples were available from children at 6 weeks and 6 months from 1 trial. Linear regression was used for height-for-age z-score, body mass index-for-age z-score, and weight for age z-score, and blood pressure analyses; log-binomial models were used to estimate risk of overweight, obesity, and stunting in midchildhood.Results: One hundred thirteen children were followed-up. Length-for-age z-score at 6 weeks and delta length-for-age z-score from 6 to 52 weeks were associated independently and positively with height-for-age z-score and inversely associated with stunting in midchildhood. Delta weight-for-length and weight-for-age z-score were also positively associated with midchildhood height-for-age z-score. The 6-week and delta weight-for-length z-scores were associated independently and positively with midchildhood body mass index-for-age z-score and overweight, as was the 6-week and delta weight-for-age z-score. Delta length-for-age z-score was also associated with an increased risk of overweight in midchildhood. Body mass index-for-age z-score in midchildhood was associated positively with systolic blood pressure. Serum anti-flagellin IgA concentration at 6 weeks was also associated with increased blood pressure in midchildhood.Conclusions: Anthropometry at 6 weeks and growth in infancy independently predict size in midchildhood, while anti-flagellin IgA, a biomarker of environmental enteric dysfunction, in early infancy is associated with increased blood pressure in midchildhood. Interventions in early life should focus on optimizing linear growth while minimizing excess weight gain and environmental enteric dysfunction.Trial Registration: ClinicalTrials.gov: NCT00197730 and NCT00421668. [ABSTRACT FROM AUTHOR]

Objective: To compare health and growth outcomes in children infected with HIV, children exposed to but uninfected with HIV, and children unexposed to HIV.Study Design: Our cohort included 3554 Tanzanian children enrolled in 2 trials of micronutrient supplementation. Among infants born to mothers infected with HIV, 264 were infected with HIV and 2088 were exposed to but uninfected at 6 weeks of age. An additional 1202 infants were unexposed to HIV. Infants were followed until 18 months of age, death, or loss to follow-up. Morbidity and growth were assessed at monthly nurse visits.Results: Compared with unexposed infants, hazard ratios (95% CI) for all-cause mortality in infants infected with HIV and infants who were exposed to but uninfected with HIV were 28.99 (14.83-56.66) and 2.79 (1.41-5.53), respectively, after adjusting for demographic and nutritional covariates. Compared with infants unexposed to HIV, infants infected with HIV also had a significantly greater risk of all measured morbidities, while infants who were exposed to but uninfected with HIV were significantly more likely to suffer from cough, fever, unscheduled outpatient visits, and hospitalizations. Infants infected with HIV also were more likely to experience stunting, wasting, and underweight at baseline and during follow-up. Infants exposed to but uninfected with HIV were more likely to be underweight at baseline (adjusted relative risk, 2.05; 95% CI, 1.45-2.89), but on average, experienced slower declines in height-for-age z-score, weight-for-age z-score, and weight-for-height z-score as well as a lower rate of stunting over follow-up, compared with unexposed infants.Conclusion: In addition to preventing and treating HIV infection in infants, prevention-of-mother-to-child-transmission of HIV and child health services should also target children exposed to but uninfected with HIV to improve health outcomes in this vulnerable population.Trial Registration: Clinicaltrials.gov: NCT00197730 and NCT00421668. [ABSTRACT FROM AUTHOR]

Objective We sought to investigate the relationship between a panel of angiogenic and inflammatory biomarkers measured in midpregnancy and small-for-gestational-age (SGA) outcomes in sub-Saharan Africa. Study Design Concentrations of 18 angiogenic and inflammatory biomarkers were determined in 432 pregnant women in Dar es Salaam, Tanzania, who participated in a trial examining the effect of multivitamins on pregnancy outcomes. Infants falling below the 10th percentile of birthweight for gestational age relative to the applied growth standards were considered SGA. Multivariate binomial regression models with the log link function were used to determine the relative risk of SGA associated with increasing quartiles of each biomarker. Restricted cubic splines were used to test for nonlinearity of these associations. Results A total of 60 participants (13.9%) gave birth to SGA infants. Compared to those in the first quartile, the risk of SGA was reduced among those in the fourth quartiles of vascular endothelial growth factor-A (adjusted risk ratio [RR], 0.38; 95% confidence interval [CI], 0.19–0.74), placental growth factor (adjusted RR, 0.28; 95% CI, 0.12–0.61), soluble fms-like tyrosine kinase-1 (adjusted RR, 0.48; 95% CI, 0.23–1.01), monocyte chemoattractant protein-1 (adjusted RR, 0.48; 95% CI, 0.25–0.92), and leptin (adjusted RR, 0.46; 95% CI, 0.22–0.96). Conclusion Our findings provide evidence of altered angiogenic and inflammatory mediators, at midpregnancy, in women who went on to deliver SGA infants. [ABSTRACT FROM AUTHOR]