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Background: Combination antiretroviral therapy (cART) initiation during pregnancy reduces the risk of perinatal human immunodeficiency virus (HIV) transmission; however, studies have suggested that there may be unintended adverse consequences on birth outcomes for selected cART regimens.Methods: We analyzed adverse birth outcomes among a prospective cohort of 1307 pregnant women with HIV in Dar es Salaam who initiated cART during the first or second trimester of a singleton pregnancy. Our primary analysis compared birth outcomes by gestational age at cART initiation among these women initiating cART in pregnancy.Results: Among women who initiated cART in pregnancy, there was no relationship of gestational age at cART initiation with the risk of fetal death or stillbirth. However, women who initiated cART before 20 weeks of gestation compared with after 20 weeks had increased risk of preterm birth (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.03-1.67) but decreased risk of small-for-gestational age birth (RR, 0.71; 95% CI, .55-.93).Conclusions: With increasing use of cART preconception and early in pregnancy, clinicians should be aware of the benefits and potential risks of cART regimens to optimize birth outcomes. [ABSTRACT FROM AUTHOR]

Background We aimed to characterise the genetic determinants and context of two meropenem-resistant clinical isolates of Acinetobacter baumannii isolated from children hospitalised with bloodstream infections in Dar es Salaam, Tanzania. Methods Antimicrobial susceptibility was determined by disc diffusion E-test and broth microdilution. Genomes were completed using a hybrid assembly of Illumina and Oxford Nanopore Technologies sequencing reads and characterisation of the genetic context of resistance genes, multi-locus sequence types (STs) and phylogenetic analysis was determined bioinformatically. Results Twelve A. baumannii were isolated from 2226 blood cultures, two of which were meropenem-resistant. The two meropenem-resistant isolates, belonging to distinct STs, ST374 and ST239, were found to harbour bla NDM-1, which was chromosomally located in isolate DT0544 and plasmid-located in isolate DT01139. The genetic environment of bla NDM-1 shows the association of insertion sequence ISAba 125 with bla NDM-1 in both isolates. Both isolates also harboured genes conferring resistance to other β-lactams, aminoglycosides and cotrimoxazole. Conclusions This is the first report of New Delhi metallo-β-lactamase-producing isolates of A. baumannii from Tanzania. The genetic context of bla NDM-1 provides further evidence of the importance of ISAba 125 in the spread of bla NDM-1 in A. baumannii. Local surveillance should be strengthened to keep clinicians updated on the incidence of these and other multidrug-resistant and difficult-to-treat bacteria. [ABSTRACT FROM AUTHOR]

Objective: : To evaluate vitamin D levels/deficiency among malnourished children <5 years admitted at a tertiary care center, the Muhimbili National Hospital, Dar es Salaam, Tanzania. Children with malnutrition may have co-existing vitamin D deficiency (VDD), which may be severe.Methods: : Serum vitamin D and alkaline phosphatase were evaluated, and X-ray of the wrist was carried out on 134 children.Results: : VDD was found in 41 of 134 children (30.6%). The mean vitamin D level was 74.8 nmol/l. The mean alkaline phosphatase level was 176.6 U/l. Sixty-four (48%) children were found to have severe stunting, of whom 20 (31.2%) were vitamin D deficient. Marasmic children had higher odds of VDD compared with other forms of malnutrition.Conclusion: : The high prevalence of VDD in malnourished children underlines the need for active surveillance and aggressive management. [ABSTRACT FROM AUTHOR]

Objectives: The scale and impact of background isoniazid resistance in TB- and HIV-endemic countries requires definition to improve treatment success and guide the scale-up of isoniazid preventive therapy (IPT). We describe the effects of isoniazid resistance on TB treatment outcomes among patients with or without HIV infection in Dar es Salaam, Tanzania.Methods: A multicentre, prospective observational study was conducted among TB patients commencing WHO-recommended first-line TB treatment. In multivariate analysis we ascertained the relationship between isoniazid resistance at presentation with a composite of poor treatment outcomes (death, failure or default from TB therapy).Results: Of 861 patients, 250 (29.0%) were HIV infected and 23 (2.7%) had isoniazid resistance. Seven hundred and ninety-seven (92.6%) of the patients were successfully treated and 25 (2.9%) died. Isoniazid resistance [relative risk (RR) = 6.0; 95% CI = 1.9-18.7; P  <   0.01] and HIV infection with (RR = 2.3; 95% CI = 1.0-5.2; P  =   0.05) or without (RR = 3.1; 95% CI = 1.5-6.2; P  <   0.01) ART were independent predictors of poor treatment outcomes.Conclusions: Background isoniazid resistance and HIV infection adversely affected TB treatment outcomes. Early laboratory detection of isoniazid resistance is important for successful TB therapy. Studies on the impact of background isoniazid resistance on the efficacy of isoniazid prophylaxis are recommended. [ABSTRACT FROM AUTHOR]

The jury on transmission of HIV through breast-feeding is still on. Data from a clinical trial in children born to HIV-positive mothers were evaluated with respect to their relationship to mother-to-child transmission. A total of 1629 infants who were not infected at age 6 weeks, had HIV results available at 12 months and who were breast-fed were included in this study. Exclusive breast feeding (EBF) rates declined from 85% at 2 months to < 30% by 4 months. EBF was associated with a sustained and significant reduction in HIV infection. With every incremental month of EBF, HIV infection was reduced by 16% [multivariable (risk ratio) RR: 0.84, CI: 0.72-0.98, p = 0.03] from enrollment to 6 months of age and by 18% (multivariable RR: 0.82, CI: 0.72-0.94, p = 0.005) from enrollment to 12 months of age. EBF significantly reduces the risk of vertical HIV transmission through 12 months of age. [ABSTRACT FROM AUTHOR]

Objectives: There are few data on ART failure rates and drug resistance from Tanzania, where there is a wide diversity of non-B HIV subtypes. We assessed rates and predictors of virological failure in HIV-infected Tanzanians and describe drug resistance patterns in a subgroup of these patients.Methods: ART-naive, HIV-1-infected adults enrolled in a randomized controlled trial between November 2006 and 2008 and on ≥24 weeks of first-line NNRTI-containing ART were included. Population-based genotyping of HIV-1 protease and reverse transcriptase was performed on stored plasma from patients with virological failure (viral load >1000 copies/mL at ≥24 weeks of ART) and at baseline, where available.Results: A total of 2403 patients [median (IQR) age 37 (32-43) years; 70% female] were studied. The median (IQR) baseline CD4+ T cell count was 128 (62-190) cells/μL. Predominant HIV subtypes were A, C and D (92.2%). The overall rate of virological failure was 14.9% (95% CI 13.2%-16.1%). In adjusted analyses, significant predictors of virological failure were lower CD4+ T cell count (P = 0.01) and non-adherence to ART (P < 0.01). Drug resistance mutations were present in 87/115 samples (75.7%); the most common were M184V/I (52.2%) and K103N (35%). Thymidine analogue mutations were uncommon (5.2%). The prevalence of mutations in 45 samples pre-ART was 22%.Conclusions: High levels of early ART failure and drug resistance were observed among Tanzanian HIV-1-infected adults enrolled in a well-monitored study. Initiating treatment early and ensuring optimal adherence are vital for the success and durability of first-line ART in these settings. [ABSTRACT FROM AUTHOR]

Background: Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIV-exposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age.Methods: Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months.Results: Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16).Conclusions: Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden. [ABSTRACT FROM AUTHOR]

Background: Micronutrient deficiencies and in utero exposure to HIV may impair infant neurodevelopment.Objective: To evaluate the effect of daily multivitamin supplementation on the cognitive, language and motor development of HIV-exposed Tanzanian infants.Methods: A total of 2387 infants were randomized to receive daily oral supplementation of multivitamins (B-complex, C and E) or placebo from age 6 weeks for 24 months. The cognitive, language and motor scales of the Bayley Scales of Infant and Toddler Development, third edition, were administered to a subset of 206 infants at age 15 months.Results: Multivitamin supplementation did not improve measures of cognitive development, expressive or receptive language or gross motor capabilities. There was a trend toward improved fine motor skills among infants randomized to the multivitamin group (difference in mean score = 0.38; 95% CI = −0.01, 0.78, p = 0.06).Conclusion: Daily provision of multivitamins to HIV-exposed infants does not substantially improve developmental outcomes at age 15 months. [ABSTRACT FROM AUTHOR]

Background: Zinc supplementation prevents incident pneumonia in children; however, the effect for pneumonia treatment remains unclear.Methods: A randomized, double-blind, placebo-controlled trial of zinc supplements (daily 25 mg) adjunct to antibiotic treatment of radiology-confirmed acute pneumonia was conducted among hospitalized children (6–36 months) in Dar es Salaam, Tanzania.Results: The trial was stopped early due to low enrollment, primarily owing to exclusion of children outside the age range and >3 days of prior illness. Among children enrolled (n = 94), zinc supplementation indicated no beneficial effect on the duration of hospitalization (IRR: 0.69; 95% CI 0.45–1.06; p = 0.09) or the proportion of children who were hospitalized for <3 days (RR: 0.85; 95% CI: 0.57–1.25; p = 0.40) or <5 days (RR: 1.01; 95% CI: 0.83–1.23; p = 0.92) (IRRs and RRs >1.0 favor zinc).Conclusions: Although underpowered, this randomized trial provided no evidence for a beneficial effect of zinc supplementation adjunct to antibiotics for hospitalized children. [ABSTRACT FROM AUTHOR]

Vitamin D is essential for bone development and may also play an integral role in control of intracellular pathogens. Serum 25-hydroxyvitamin D levels were assessed at 6 months of age for 191 HIV-exposed uninfected infants enrolled in a trial of multivitamins (not including vitamin D) in Tanzania. A total of 66 infants (34.6%) were classified as vitamin D deficient (<20 ng/ml), 93 (48.7%) as vitamin D insufficient (20–30 ng/ml) and 32 (16.8%) as vitamin D sufficient (&geq;30 ng/ml). Independent risk factors for vitamin D deficiency were sampling during the rainy season and infant wasting. Infant breastfeeding, maternal CD4 T-cell count, maternal wasting status and maternal receipt of antiretroviral therapy were not associated with vitamin D deficiency. Low levels of vitamin D were highly prevalent among HIV-exposed uninfected infants in Tanzania, and longitudinal studies and clinical trials of supplementation are needed to assess the impact on child health. [ABSTRACT FROM PUBLISHER]

We prospectively determined the association between undernutrition and incidence of acute respiratory infections (ARIs) among 711 children born to HIV-infected women. Overall, underweight was associated with a 58% increased risk of ARI. Similarly, wasting (54%), very low birth weight (88%) and child HIV infection (62%) were significantly associated with increased risk of ARI during the first 2 years. Breastfeeding was associated with 52% reduction in risk of ARI only during the first 12 months of life. Among HIV-exposed, but uninfected, children, underweight, wasting and stunting were associated with 73%, 61% and 33% increased risk of ARI, respectively. Very low birthweight and advanced maternal disease stage were also associated with increased risk of ARI. Similar results were observed among HIV-infected children, except for stunting and very low birth weight. Prevention of child undernutrition could have major impact in reducing child ARI morbidity in settings of high HIV prevalence. [ABSTRACT FROM PUBLISHER]

Background. Prospective studies of serum albumin concentration measurement as a low-cost predictor of human immunodeficiency virus (HIV) disease progression are needed for individuals initiating antiretroviral therapy (ART) in resource-limited settings.Methods. Serum albumin concentration was measured at ART initiation for 2145 adults in Tanzania who were enrolled in a trial examining the effect of multivitamins on HIV disease progression. Participants were prospectively followed for mortality, morbidity, and anthropometric outcomes at monthly visits (median follow-up duration, 21.2 months). Proportional hazard models were used to analyze mortality, morbidity, and nutritional outcomes, while generalized estimating equations were used to analyze CD4+ T-cell counts.Results. Individuals with hypoalbuminemia (defined as a serum albumin concentration of <35 g/L) at ART initiation had a hazard of death that was 4.52 times (95% confidence interval, 3.37–6.07; P < .001) that of individuals with serum albumin concentrations of ≥35 g/L, after multivariate adjustment. Hypoalbuminemia was also independently associated with the incidence of pulmonary tuberculosis (P < .001), severe anemia (P < .001), wasting (P = .002), and >10% weight loss (P = .012). Secondary analyses suggested that serum albumin concentrations of <38 g/L were associated with increased mortality and incident pulmonary tuberculosis. There was no association between serum albumin concentration and changes in CD4+ T-cell counts (P = .121).Conclusions. Serum albumin concentrations can identify adults initiating ART who are at high risk for mortality and selected morbidities. Future research is needed to identify and manage conditions that reduce the serum albumin concentration. [ABSTRACT FROM AUTHOR]

Background. Maintaining vitamin D sufficiency may decrease the incidence of pulmonary tuberculosis and other infectious diseases. We present the first prospective study of vitamin D among human immunodeficiency virus (HIV)–infected adults receiving antiretrovirals in sub-Saharan Africa.Methods. Serum 25-hydroxyvitamin D (25(OH)D) level was assessed at antiretroviral therapy (ART) initiation for 1103 HIV-infected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania. Participants were prospectively followed at monthly visits at which trained physicians performed a clinical examination and nurses took anthropometric measurements and assessed self-reported symptoms. Cox proportional hazards models estimated hazard ratios (HRs) of morbidity outcomes.Results. After multivariate adjustment, vitamin D deficiency (defined as a concentration of <20 ng/mL) had a significantly greater association with incident pulmonary tuberculosis, compared with vitamin D sufficiency (HR, 2.89; 95% confidence interval [CI], 1.31–7.41; P = .027), but no association was found for vitamin D insufficiency (defined as a concentration of 20–30 ng/mL; P = .687). Deficiency was also significantly associated with incident oral thrush (HR, 1.96; 95% CI, 1.01–3.81; P = .046), wasting (HR, 3.10; 95% CI, 1.33–7.24; P = .009), and >10% weight loss (HR, 2.10; 95% CI, 1.13–3.91; P = .019). Wasting results were robust to exclusion of individuals experiencing pulmonary tuberculosis. Vitamin D status was not associated with incident malaria, pneumonia, or anemia.Conclusions. Vitamin D supplementation trials for adults receiving ART appear to be warranted. [ABSTRACT FROM PUBLISHER]

Objective To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children. Methods Newborn infants of HIV-infected mothers were enrolled at 6 weeks and followed for 2 years. HIV status was assessed by enzyme-linked immunosorbant assay and confirmed by HIV DNA polymerase chain reaction. Malaria was defined as (1) physician-diagnosed clinical malaria; (2) probable malaria, in which laboratory testing is requested for parasitemia; and (3) blood smear–confirmed malaria. Cox proportional hazards models estimated hazard ratios (HRs) for development of first and second malaria episodes, and generalized estimating equation models estimated malaria rate differences per 100-child-years in relation to time-updated HIV status. Results Child HIV infection was associated with clinical (HR, 1.34; 95% confidence interval [CI], 1.12–1.61), probable (HR, 1.47; 95% CI, 1.19–1.81), and confirmed (HR, 1.67; 95% CI, 1.18–2.36) malaria episodes. Per 100 child-years, HIV-infected children experienced 88 (95% CI, 65–113), 36 (95% CI, 19–53), and 20 (95% CI, 9–31) more episodes of clinical, probable, and confirmed malaria episodes, respectively, than HIV-uninfected children. Among children with ≥1 malaria episodes, those with HIV infection developed second clinical (HR, 1.28; 95% CI, 1.04–1.57), probable (HR, 1.60; 95% CI, 1.26–2.14), and confirmed (HR, 2.27; 95% CI, 1.06–3.89) malaria sooner than HIV-uninfected children. Conclusions HIV infection is a risk factor for the development of malaria. Proactive malaria disease prevention and treatment is warranted for all children, particularly those with HIV infection in settings of coendemicity. [ABSTRACT FROM PUBLISHER]

We examined the prospective associations between breast milk concentrations of erythropoietin, a factor with trophic effects on infant gut epithelia, and the risk of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) through breast-feeding in a study of 59 MTCT cases and 116 controls nested within a cohort of antiretroviral-naive HIV-infected Tanzanian women. Controls were matched to cases on the basis of the time from birth when the breast milk sample was collected. The risk of MTCT was inversely related to breast milk erythropoietin concentration (adjusted odds ratio for highest vs lowest erythropoietin concentration tertile, 0.34 [95% confidence interval, 0.14-0.82]; P = .02). These results suggest a protective effect of breast milk erythropoietin against MTCT. [ABSTRACT FROM AUTHOR]

We assessed age-specific CD4 T-cell counts and their determinants among Tanzanian children born to HIV-infected mothers to address a major research gap. A total of 474 HIV-uninfected and 69 HIV-infected children were followed until age of 12 months. Maternal predictors were measured during pregnancy and child predictors at birth and throughout the follow up. Child CD4 T-cell counts were evaluated at the age of 3 months and subsequent 3-month intervals; they decreased linearly among HIV-infected (β = –8 cells per week; 95% CI –12 to –4; P = 0.0003) and increased linearly among HIV-uninfected children (β = 4 cells/week; 95% CI 2–7; P = 0.0008). Decreased child counts were predicted by low child anthropometry, maternal HIV stage ≥2, and maternal mid-upper arm circumference <27 cm among HIV-infected children; and by weight-for-height <–2 z-score, maternal HIV stage ≥2, maternal erythrocyte sedimentation rate <81 mm/h and maternal haemoglobin <8.5 g/dl among HIV-uninfected children. The maternal and child predictors described may serve as intervention targets among HIV-exposed children. [ABSTRACT FROM PUBLISHER]

Selenium deficiency may increase risks of anemia and morbidity among people with human immunodeficiency virus infection. We therefore investigated the effect of selenium supplements (200 μg of selenomethionine) on these end points among 915 pregnant Tanzanian women. Hemoglobin concentration was measured at baseline (at 12-27 weeks of gestation) and at 6 weeks and 6 months postpartum, and morbidity data were collected during monthly visits to the clinic. Selenium supplements had no effect on hemoglobin concentrations during follow-up (mean difference, 0.05 g/dL; 95% confidence interval, -0.07 to 0.16 g/dL) but reduced diarrheal morbidity risk by 40% (relative risk, 0.60; 95% confidence interval, 0.42-0.84). There was no effect on the other morbidity end points. [ABSTRACT FROM AUTHOR]

Background. A human immunodeficiency virus (HIV) vaccine that limits disease and transmission is urgently needed. This clinical trial evaluated the safety and immunogenicity of an HIV vaccine that combines a plasmid-DNA priming vaccine and a modified vaccinia virus Ankara (MVA) boosting vaccine. Methods. Forty healthy volunteers were injected with DNA plasmids containing gp160 of HIV-1 subtypes A, B, and C; rev B; p17/p24 gagAand B, and RTmut B by use of a needle-free injection system. The vaccine was administered intradermally or intramuscularly, with or without recombinant granulocyte macrophage colony-stimulating factor, and boosted with a heterologous MVA containing env, gag, and pol of CRF01A_E. Immune responses were monitored with HIV-specific interferon (IFN)-γ and interleukin (IL)-2 ELISpot and lymphoproliferative assays (LPAs). Results. Vaccine-related adverse events were mild and tolerable. After receipt of the DNA priming vaccine, 11 (30%) of 37 vaccinees had HIV-specific IFN-γ responses. After receipt of the MVA boosting vaccine, ELISpot assays showed that 34 (92%) of 37 vaccinees had HIV-specific IFN-γ responses, 32 (86%) to Gag and 24 (65%) to Env. IFN-γ production was detected in both the CD8+ T cell compartment (5 of 9 selected vaccinees) and the CD4+ T cell compartment (9 of 9). ELISpot results showed that 25 (68%) of 37 vaccinees had a positive IL-2 response and 35 (92%) of 38 had a positive LPA response. Of 38 subjects, a total of 37 (97%) were responders. One milligram of HIV-1 DNA administered intradermally was as effective as 4mg administered intramuscularly in priming for the MVA boosting vaccine. Conclusion. This HIV-DNA priming-MVA boosting approach is safe and highly immunogenic. Trials registration. International Standard Randomised Controlled Trial number: ISRCTN32604572. [ABSTRACT FROM AUTHOR]