Anemia and Iron Supplementation in Relation to Viral Load and Mortality among 70,442 People Living with Human Immunodeficiency Virus in Tanzania.

BACKGROUND: Anemia may be associated with poor clinical outcomes among people living with human immunodeficiency virus (HIV) (PLHIV) despite highly active antiretroviral therapy (HAART). There are concerns that iron supplementation may be unsafe to prevent and treat anemia among PLHIV. OBJECTIVE: The objective of the study was to evaluate the associations of anemia and iron supplementation with mortality and viral load among PLHIV in Tanzania. METHODS: We analyzed data from a cohort of 70,442 nonpregnant adult PLHIV in Tanzania conducted between 2015 and 2019. Regression models evaluated the relationships between anemia severity and iron supplement use with mortality and unsuppressed HIV-1 viral load among all participants and stratified by whether participants were initiating or continuing HAART. RESULTS: Anemia was associated with an increased risk of mortality and unsuppressed viral load for participants who initiated or continued HAART. Iron supplement use was associated with reduced mortality risk but also had a greater risk of an unsuppressed viral load among participants continuing HAART. There was no association of iron supplement use with mortality, and unsuppressed viral load among PLHIV that were initiating HAART. There was a stronger negative association between iron supplement use and the risk of having an unsuppressed viral load among participants with stage III/IV disease compared with stage I/II disease. CONCLUSIONS: Anemia is associated with increased risk of mortality and unsuppressed viral load, but the benefits and safety of iron supplements appear to differ for those initiating compared with continuing ART as well as by HIV disease severity.

Rudi Kundini, Pamoja Kundini (RKPK): study protocol for a hybrid type 1 randomized effectiveness-implementation trial using data science and economic incentive strategies to strengthen the continuity of care among people living with HIV in Tanzania.

BACKGROUND: Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control. METHODS: The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania. Phase 1 of the study consists of a two-arm, cluster randomized trial across 32 health facilities to assess the effectiveness of a home visit plus one-time economic incentive on the proportion of out-of-care PLHIV with viral load suppression (< 1000 copies/ml) 6 months after enrollment (n = 640). Phase 2 is an individual 1:1 randomized controlled trial designed to determine the effectiveness of a short-term counseling and economic incentive program offered to in-care PLHIV who are predicted through machine learning to be at risk of disengaging from care on the outcome of viral load suppression at 12 months (n = 692). The program includes up to three incentives conditional upon visit attendance coupled with adapted counselling sessions for this population of PLHIV. Consistent with a hybrid effectiveness-implementation study design, phase 3 is a mixed methods evaluation to explore barriers and facilitators to strategy implementation in phases 1 and 2. Results will be used to guide optimization and scale-up of the incentive strategies, if effective, to the larger population of Tanzanian PLHIV who struggle with continuity of HIV care. DISCUSSION: Innovative strategies that recognize the dynamic process of lifelong retention in HIV care are urgently needed. Strategies such as conditional economic incentives are a simple and effective method for improving many health outcomes, including those on the HIV continuum. If coupled with other supportive services such as home visits (phase 1) or with tailored counselling (phase 2), economic incentives have the potential to strengthen engagement among the subpopulation of PLHIV who struggle with retention in care and could help to close the gap towards reaching global "95-95-95" goals for ending the AIDS epidemic. TRIAL REGISTRATION: Phase 1: ClinicalTrials.gov, NCT05248100 , registered 2/21/2022. Phase 2: ClinicalTrials.gov, NCT05373095 , registered 5/13/2022.

Impact of a post-partum family planning intervention on contraception and fertility in Tanzania: two-year follow-up of a cluster-randomised controlled trial.

PURPOSE: We evaluate contraceptive use and pregnancy two years following an intervention in Tanzania, which provided antenatal post-partum family planning counselling and post-partum intrauterine device (PPIUD) services following delivery. METHODS: We analyse data from five hospitals in Tanzania using a difference-in-difference cluster randomised design, with randomisation at the hospital level. We use women-level data collected at the index birth and a follow-up survey two years later among 6,410 women. Outcomes (overall modern contraceptive use, contraceptive type, pregnancy) are modelled with an intent-to-treat (ITT) approach using linear regression. We compare with the complier average causal effect (CACE) of the intervention among those counselled. RESULTS: The intervention increased long-term PPIUD use by 5.8 percentage points (95% CI: 0.7-11.2%) through substitution away from other modern methods. There was no impact on overall modern contraceptive prevalence or pregnancy. Only 29% of women reported receiving PPIUD counselling. When accounting for this in the CACE analysis we saw a larger impact with 25.7% percentage point increase in PPIUD use (95% CI: 22.7-28.6%). CONCLUSION: The intervention provided women an additional contraceptive choice, resulting in higher use of PPIUD over two years. Increase in PPIUD use was brought about by shifting methods, not creating new modern contraceptive users.

The post-partum family planning intervention in Tanzania offered women a new contraceptive option and increased sustained use of post-partum IUD. The intervention did not attract new modern contraception users and could have a greater impact if implemented more widely.

Renal outcomes in adults with HBV, HIV and HBV/HIV coinfection after 3 years of antiviral therapy in urban Tanzania.

BACKGROUND: An enhanced understanding of renal outcomes in persons with chronic HBV, HIV, and HBV/HIV coinfection is needed to mitigate chronic kidney disease in regions where HBV and HIV are endemic. OBJECTIVES: To investigate changes in estimated glomerular filtration rate (eGFR) in adults with HBV, HIV or HBV/HIV enrolled in a 3 year prospective cohort study of liver outcomes in Dar es Salaam, Tanzania and initiated on antiviral therapy. METHODS: We compared eGFR between and within groups over time using mixed-effects models. RESULTS: Four hundred and ninety-nine participants were included in the analysis (HBV: 164; HIV: 271; HBV/HIV: 64). Mean baseline eGFRs were 106.88, 106.03 and 107.18 mL/min/1.73 m2, respectively. From baseline to Year 3, mean eGFR declined by 4.3 mL/min/1.73 m2 (95% CI -9.3 to 0.7) and 3.7 (-7.8 to 0.5) in participants with HBV and HIV, respectively, and increased by 5.1 (-4.7 to 14.9) in those with HBV/HIV. In multivariable models, participants with HBV had lower eGFRs compared with those with HIV or HBV/HIV and, after adjusting for HBV DNA level and hepatitis B e antigen (HBeAg) status, significantly lower eGFRs than those with HBV/HIV at all follow-up visits. CONCLUSIONS: In this Tanzanian cohort, coinfection with HBV/HIV did not appear to exacerbate renal dysfunction compared with those with either infection alone. Although overall changes in eGFR were small, persons with HBV experienced lower eGFRs throughout follow-up despite their younger age and similar baseline values. Longer-term studies are needed to evaluate continuing changes in eGFR and contributions from infection duration and other comorbidities.

Antenatal depression and adverse birth outcomes among pregnant women living with HIV in Dar es Salaam, Tanzania.

BACKGROUND: Women who experience antenatal depression may be at increased risk of adverse birth outcomes. Few studies have examined this association among women living with HIV (WHIV). METHODS: We conducted a prospective cohort study of 2298 pregnant WHIV on antiretroviral therapy (ART) in Dar es Salaam, Tanzania, who were participants in a randomized trial of vitamin D3 supplementation. Depressive symptoms were assessed at 12-27 weeks gestation using the Hopkins Symptoms Checklist (HSCL-25). Generalized estimating equations to account for twins were used to assess the relative risks of adverse birth outcomes. RESULTS: Approximately 67 % of the women in our study population reported symptoms consistent with depression. We observed a 4.0 % prevalence of stillbirth and a 25.1 % prevalence of preterm birth. We found that low social support, higher education, and more recent initiation of ART were associated with a greater risk of antenatal depression. There was no association of antenatal depression with risk of fetal loss, stillbirth, low birth weight, birth weight, preterm birth, gestational age at delivery, or small-for-gestational age. LIMITATIONS: Depression was self-reported and only collected at one timepoint in pregnancy. Our findings may not be generalizable to all WHIV. CONCLUSIONS: Our findings illustrate the high risk of both depression and adverse birth outcomes among WHIV and underscore the need for interventions to improve their mental health and the health of their infants; however, the relationship between depression and birth outcomes remains unclear. Further research on this topic is merited, particularly examining the chronicity and timing of depression in pregnancy.

Associations Between Social Support and Symptoms of Antenatal Depression with Infant Growth and Development Among Mothers Living with HIV in Tanzania.

Children born to mothers living with HIV may experience greater risk of poor growth and development outcomes than their HIV-unexposed peers. Few studies have examined the relationship between maternal depression and social support with infant growth and development in the context of HIV. We conducted a prospective cohort study of 2,298 pregnant women living with HIV in Dar es Salaam, Tanzania, assessing antenatal depression (Hopkins Symptoms Checklist-25) and social support (Duke-UNC Functional Social Support Questionnaire) at 12-27 weeks of gestation. At one-year age, infant anthropometry and caregiver-reported infant development were assessed. Generalized estimating equations were used to assess mean differences (MD) and relative risks (RR) for growth and developmental outcomes. Symptoms consistent with maternal antenatal depression had 67% prevalence and were associated with infant wasting (RR 2.61; 95% confidence interval (CI) 1.03-6.65; z = 2.02; p = 0.04), but no other growth or developmental outcomes. Greater maternal social support was not associated with infant growth outcomes. Greater affective support was associated with better cognitive (MD 0.18; CI 0.01-0.35; z = 2.14; p = 0.03) and motor (MD 0.16; CI 0.01-0.31; z = 2.04; p = 0.04) development scores. Greater instrumental support was associated with better cognitive (MD 0.26; CI 0.10-0.42; z = 3.15; p < 0.01), motor (MD 0.17; CI 0.02-0.33; z = 2.22; p = 0.03), and overall (MD 0.19; CI 0.03-0.35; z = 2.35; p = 0.02) development scores. Depressive symptoms were associated with greater risk of wasting, while social support was associated with better infant development scores. Strategies to improve mental health and social support for mothers living with HIV during the antenatal period may benefit infant growth and development.

Assessing environmental enteric dysfunction via multiplex assay and its relation to growth and development among HIV-exposed uninfected Tanzanian infants.

BACKGROUND: Environmental enteric dysfunction (EED) may contribute to poor growth and development in young children. While validated EED biomarkers are currently lacking, multiplex assays are able to capture multiple domains of the condition. The purpose of this exploratory study was to examine the relationship between biomarkers of EED and subsequent growth and development among Tanzanian HIV-exposed uninfected (HEU) infants. METHODOLOGY: We enrolled 467 infants of mothers living with HIV who had participated in a trial of vitamin D3 supplementation during pregnancy. Infant serum samples collected at 6 weeks (n = 365) and 6 months (n = 266) were analyzed for anti-flagellin and anti-lipopolysaccharide (LPS) IgA and IgG via ELISA as well as the 11-plex Micronutrient and EED Assessment Tool (MEEDAT), which incorporates two biomarkers of EED [intestinal fatty acid-binding protein (I-FABP) and soluble CD14 (sCD14)]. Outcomes were 12-month growth [length-for-age z-score (LAZ), weight-for-length z-score (WLZ), and weight-for-age z-score (WAZ)] and development [Caregiver Reported Early Development Instruments (CREDI) z-scores] and were assessed using linear regression. FINDINGS: In primary analyses, higher quartiles of 6-month anti-LPS IgG concentrations were significantly associated with lower LAZ at 12 months (ptrend = 0.040). In secondary analyses, higher log2-transformed 6-week anti-flagellin IgA and 6-month anti-LPS IgA concentrations were significantly associated with lower LAZ at 12 months. No associations were observed between I-FABP or sCD14 and infant growth. However, higher log2-transformed 6-week sCD14 concentrations were significantly associated with lower overall CREDI z-scores, while higher log2-transformed 6-month I-FABP concentrations were significantly associated with higher overall CREDI z-scores. CONCLUSIONS: Unlike anti-flagellin and anti-LPS Igs, MEEDAT's biomarkers of EED (I-FABP and sCD14) were not associated with subsequent linear growth among HEU infants in Tanzania. The relationship between EED and infant development warrants further study.

The impact of a community health worker intervention on uptake of antenatal care: a cluster-randomized pragmatic trial in Dar es Salaam.

The provision of high-quality antenatal care (ANC) is important for preventing maternal and newborn mortality and morbidity, but only around half of pregnant women in Tanzania attended four or more ANC visits in 2019. Although there is emerging evidence on the benefit of community health worker (CHW) interventions on ANC uptake, few large-scale pragmatic trials have been conducted. This pragmatic cluster-randomized trial, implemented directly through the public sector health system, assessed the impact of an intervention that trained public sector CHWs to promote the uptake of ANC. We randomized 60 administrative wards in Dar es Salaam to either a targeted CHW intervention or a standard of care. The impact of the intervention was assessed using generalized estimating equations with an independent working correlation matrix to account for clustering within wards. A total of 243 908 women were included in the analysis of our primary outcome of four or more ANC visits. The intervention significantly increased the likelihood of attending four or more ANC visits [relative risk (RR): 1.42; 95% confidence interval (CI): 1.05, 1.92] and had a modest beneficial effect on the total number of ANC visits (percent change: 7.7%; 95% CI: 0.2%, 15.5%). While slightly more women in the intervention arm attended ANC in their first trimester compared with the standard-of-care arm (19% vs 18.7%), the difference was not significant (RR: 1.02; 95% CI: 0.84, 1.22). Our findings suggest that trained CHWs can increase attendance of ANC visits in Dar es Salaam and similar settings. However, additional interventions appear necessary to promote the early initiation of ANC. This study demonstrates that routine health system data can be leveraged for outcome assessment in trials and programme evaluation and that the results are likely superior, both in terms of bias and precision, to data that are collected specifically for science.

Iron status among HIV-infected adults during the first year of antiretroviral therapy in Tanzania.

BACKGROUND: The influence of inflammation on iron status among people living with HIV (PLWHIV) has not been well explored. We evaluated the trajectory of iron status among PLWHIV during the first year of highly active antiretroviral therapy (HAART), compared alternative approaches for inflammation correction, and assessed the associations of iron status with HIV-1 viral load and anthropometric outcomes. METHODS: We conducted a secondary analysis of data from a randomized trial among 400 adults initiating HAART in Tanzania. Ferritin and C-reactive protein (CRP) were measured at baseline, 1, 6 or 12 months. Ferritin was considered in four ways: unadjusted, and adjusted for inflammation using higher cut-off (HC), Thurnham-corrected (TC) and regression-corrected (RC) approaches. For unadjusted, TC and RC ferritin, iron deficiency (ID) was defined using ferritin < 15 µg/L and elevated iron status was defined using ferritin > 150 µg/L among females and > 200 µg/L among males. For HC ferritin, elevated iron status was defined based on serum ferritin > 500 µg/L, while ID was defined using ferritin < 70 µg/L in the presence of inflammation and < 15 µg/L in the absence of inflammation. Regression models evaluated the trajectory of ferritin concentration across categories of baseline characteristics, and assessed the association of iron status with viral and anthropometric outcomes. RESULTS: The prevalence of iron deficiency at HAART initiation was 9% for unadjusted, 17% for HC, 12% for TC and 22% for RC ferritin. The prevalence of elevated iron status was 42% for unadjusted, 18% for HC, 31% for TC, and 15% for RC ferritin. The prevalence of iron deficiency for all three methods increased during the first year of HAART, while the prevalence of elevated iron status decreased. Baseline elevated iron status defined using HC ferritin was associated with a greater risk of HIV-1 viral load > 1000 copies/mL [relative risk (RR) = 4.29, 95% CI: 1.38-13.3] and incidence of being underweight [body mass index (BMI) < 18.5 kg/m2 , hazard ratio (HR) = 3.65, 95% confidence interval (CI): 1.38-9.67]. Neither baseline-elevated iron status defined using TC or RC ferritin nor baseline iron deficiency defined using any of the three methods was associated with HIV-1 viral load or anthropometric outcomes. CONCLUSIONS: Whether and how inflammation correction is done influences findings of studies of iron status among PLWHIV.

The effect of a postpartum intrauterine device programme on choice of contraceptive method in Tanzania: a secondary analysis of a cluster-randomized trial.

Vertical global health programmes often evaluate success with a narrow focus on programmatic outcomes. However, evaluation of broader patient-centred and unintended outcomes is critical to assess impacts on patient choice and autonomy. Here, we evaluate the effects of a postpartum intrauterine device (PPIUD) intervention on outcomes related to contraceptive method choice. The stepped-wedge cluster randomized contolled trial (RCT) took place in five Tanzanian hospitals. Hospitals were randomized to receive immediate (Group 1; n = 11 483 participants) or delayed (Group 2; n = 8148 participants) intervention. The intervention trained providers on PPIUD insertion and counselling. The evaluation surveyed eligible women (18+, resided in Tanzania, gave birth at a study hospital) on provider postpartum contraceptive counselling during pregnancy or immediately postpartum. In our completed study, participants were considered exposed (n = 9786) or unexposed (n = 10 145) to the intervention based on the location and timing of their birth (no blinding). Our secondary analysis examined differences by intervention exposure on the likelihood of being counselled on IUD only, multiple methods, multiple method durations, a broad method mix; and on the number of methods women were counselled across two samples: all eligible women, and only women who reported receiving any contraceptive counselling. Among all eligible women, counselling on the IUD alone was 7% points higher among the exposed (95% confidence interal (CI): 0.02, 0.12). Among women who received any counselling, those exposed to the intervention were counselled on 1.12 fewer contraceptive methods (95% CI: 0.10, 2.34). The likelihood of receiving counselling on any non-IUD method decreased among those exposed, while the likelihood of being counselled on an IUD alone was 14% points higher among the exposed (95% CI: 0.06, 0.22), suggesting this intervention increased IUD-specific counselling but reduced informed contraceptive choice. These findings underscore the importance of broad metrics that capture autonomy and rights (in addition to programmatic goals) at all stages of health programme planning and implementation.

Rudi Kundini, Pamoja Kundini (RKPK): study protocol for a hybrid type 1 randomized effectiveness-implementation trial using data science and economic incentive strategies to strengthen the continuity of care among people living with HIV in Tanzania.

Background: Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at-risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control. Methods: The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania. Phase 1 of the study consists of a two-arm, cluster randomized trial across 32 health facilities to assess the effectiveness of a home visit plus one-time economic incentive on the proportion of out-of-care PLHIV with viral load suppression (<1000 copies/ml) 6 months after enrollment (n = 640). Phase 2 is an individual 1:1 randomized controlled trial designed to determine the effectiveness of a short-term counseling and economic incentive program offered to in-care PLHIV who are predicted through machine learning to be at-risk of disengaging from care on the outcome of viral load suppression at 12 months (n = 692). The program includes up to three incentives conditional upon visit attendance coupled with adapted counselling sessions for this population of PLHIV. Consistent with a hybrid effectiveness-implementation study design, phase 3 is a mixed methods evaluation to explore barriers and facilitators to strategy implementation in phases 1 and 2. Results will be used to guide optimization and scale-up of the incentive strategies, if effective, to the larger population of Tanzanian PLHIV who struggle with continuity of HIV care. Discussion: Innovative strategies that recognize the dynamic process of lifelong retention in HIV care are urgently needed. Strategies such as conditional economic incentives are a simple and effective method for improving many health outcomes, including those on the HIV continuum. If coupled with other supportive services such as home visits (phase 1) or with tailored counselling (phase 2), economic incentives have the potential to strengthen engagement among the subpopulation of PLHIV who struggle with retention in care and could help to close the gap towards reaching global '95-95-95' goals for ending the AIDS epidemic.Phase 1: Clinicaltrials.gov, NCT05248100, registered 2/21/2022 https://clinicaltrials.gov/ct2/show/NCT05248100Phase 2: Clinicaltrials.gov, NCT05373095, registered 5/13/2022 https://clinicaltrials.gov/ct2/show/NCT05373095.

Biomarkers of environmental enteric dysfunction and adverse birth outcomes: An observational study among pregnant women living with HIV in Tanzania.

BACKGROUND: Environmental enteric dysfunction (EED) may contribute to adverse birth outcomes in low-resource settings. We examined the associations of EED biomarkers with birth outcomes in pregnant women living with human immunodeficiency virus in Dar es Salaam, Tanzania. METHODS: We performed a cohort study of 706 HIV-infected pregnant women. Maternal serum samples collected at 32 weeks gestation were analyzed for markers of EED (anti-flagellin and anti-LPS immunoglobulins, intestinal fatty acid-binding protein [I-FABP] and soluble CD14), systemic inflammation (C-reactive protein and α1-acid glycoprotein [AGP]), and growth hormone resistance (insulin-like growth factor 1 [IGF-1] and fibroblast growth factor 21 [FGF21]. Associations of biomarkers categorized into quartiles with birth outcomes (birthweight, gestational duration, birthweight-for-gestational age, and stillbirth) were assessed using linear and log-binomial regression models adjusted for multiple sociodemographic and clinical variables. FINDINGS: Maternal EED biomarkers were not significantly associated with birthweight, gestation duration, or birthweight-for-gestational age. However, higher quintiles of I-FABP concentrations were associated with greater risk of stillbirth (ptrend=0·02). Higher AGP was associated with lower birthweight and was associated with increased risk of small-for-gestational age births. Higher IGF-1 was associated with higher birthweight and birthweight-for-gestational age while higher FGF21 was associated with shorter gestation and higher risk of preterm birth. INTERPRETATION: Maternal biomarkers of EED, systemic inflammation, and growth hormones were differentially associated with birth outcomes. Biomarkers of EED may be useful to identify pregnant women at risk of adverse birth outcomes, but further research is needed to confirm these findings and elucidate biological mechanisms. FUNDING: National Institutes of Health.

Timing of Antiretroviral Therapy: Initiation and Birth Outcomes Among Pregnant Women With Human Immunodeficiency Virus in Tanzania

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.

Cholecalciferol Supplementation Does Not Affect the Risk of HIV Progression, Viral Suppression, Comorbidities, Weight Loss, and Depression among Tanzanian Adults Initiating Antiretroviral Therapy: Secondary Outcomes of a Randomized Trial.

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.

Vitamin D3 supplementation during pregnancy and lactation for women living with HIV in Tanzania: A randomized controlled trial.

BACKGROUND: Observational studies suggest that vitamin D deficiency among people living with HIV is associated with a greater risk of disease progression and death. Low levels of vitamin D in pregnancy are also associated with poor fetal and infant growth. Therefore, vitamin D supplementation may improve clinical outcomes for pregnant women living with HIV and improve fetal and postnatal growth for their infants. METHODS AND FINDINGS: We conducted a randomized, triple-blind, placebo-controlled trial of vitamin D3 supplementation among pregnant and lactating women living with HIV in Dar es Salaam, Tanzania (ClinicalTrials.gov NCT02305927). Participants were randomized with 1:1 allocation stratified by study clinic to receive either daily 3,000 IU vitamin D3 supplements or matching placebo supplements from the second trimester of pregnancy (12-27 weeks) until 1 year postpartum. The primary outcomes were (i) maternal HIV progression or death, (ii) small-for-gestational-age (SGA) live births (<10th percentile), and (iii) infant stunting at 1 year of age (length-for-age z-score < -2). We also examined the effect of vitamin D3 supplementation on secondary maternal and infant health outcomes, maternal and infant serum 25-hydroxyvitamin D (25[OH]D) concentrations, and maternal hypercalcemia. An intent-to-treat analysis was used as the primary analytic approach. We enrolled 2,300 pregnant women between June 15, 2015, and April 17, 2018, and follow-up of mothers and infants was completed on October 20, 2019. There were 1,148 pregnant women randomly assigned to the vitamin D3 group, and 1,152 to the placebo group. The proportion of mothers lost to follow-up at 1 year postpartum was 6.6% in the vitamin D3 group (83 of 1,148) and 6.6% in the placebo group (76 of 1,152). The proportion of children lost to follow-up at 1 year of age was 5.5% in the vitamin D3 group (59 of 1,074 live births) and 5.2% in the placebo group (57 of 1,093 live births). There was no difference in the risk of maternal HIV progression or death, with 166 events during 1,461 person-years of follow-up in the vitamin D3 group and 141 events during 1,469 person-years of follow-up in the placebo group (hazard ratio 1.21, 95% CI 0.97 to 1.52, p = 0.09). There was no difference in the risk of SGA birth between the vitamin D3 (229 SGA births among 1,070 live births) and placebo groups (236 SGA births among 1,091 live births) (relative risk 1.03, 95% CI 0.87 to 1.22, p = 0.70). There was also no difference in the risk of infant stunting at 1 year of age between the vitamin D3 (407 events among 867 infants) and placebo groups (413 events among 873 infants) (relative risk 1.00, 95% CI 0.92 to 1.10, p = 0.95). In terms of adverse events, no cases of maternal hypercalcemia were identified. One hypersensitivity reaction to the trial supplements occurred for a pregnant woman in the placebo group. A limitation of our study is that our findings may not be generalizable to HIV-negative pregnant women or contexts where severe vitamin D deficiency is prevalent. CONCLUSIONS: The trial findings do not support routine vitamin D supplementation for pregnant and lactating women living with HIV in Tanzania. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02305927.

Iron supplementation and paediatric HIV disease progression: a cohort study among children receiving routine HIV care in Dar es Salaam, Tanzania.

BACKGROUND: Anaemia is common among HIV-infected children and iron supplementation is prescribed routinely for the prevention and management of anaemia among children. Limited evidence suggests iron supplementation may have adverse effects among HIV-infected populations. We aimed to estimate the effect of iron supplement use on mortality, disease progression and haematological outcomes among HIV-infected children in Dar es Salaam, Tanzania. METHODS: A prospective cohort study was conducted among HIV-infected children (aged 0-14 years) receiving antiretroviral treatment or supportive care between October 2004 and September 2014. Clinical data were recorded on morbidity and vital status, haematological status and prescriptions at each clinical visit. Cox proportional hazards models adjusted for time-varying covariates were used to estimate the association of time-varying iron supplementation on the hazard rate of mortality, HIV disease stage progression, tuberculosis incidence and anaemia and microcytosis persistence. RESULTS: In all, 4229 children were observed during 149 260 clinic visits for a mean follow-up of 2.9 years. After adjustment for time-varying clinical covariates, time-varying iron supplementation was associated with a 2.87 times higher hazard rate of mortality (95% CI: 1.70, 4.87) and a 1.48 times higher hazard rate of HIV disease stage progression (95% CI: 1.10, 1.98). Iron supplementation was also associated with a lower rate of anaemia persistence (HR = 0.47; 95% CI: 0.37, 0.61). No differences in the association between iron supplementation and clinical outcomes were observed by antiretroviral therapy or anaemia status. CONCLUSIONS: Iron supplementation may increase the risk of HIV disease stage progression and mortality among HIV-infected children, while reducing the risk of anaemia.

School readiness among children born to women living with HIV in Dar es Salaam, Tanzania: a cohort study protocol.

INTRODUCTION: Children who are born to women living with HIV are at a greater risk of suboptimal neurodevelopment; however, evidence from sub-Saharan Africa is limited and functional developmental outcomes are rarely assessed in this vulnerable population. The School Readiness among HIV-Exposed Children (SRHEC) cohort study aims to assess the school readiness of preschool aged children born to women living with HIV and to identify the biological, environmental and social factors that contribute to school readiness in this population. METHODS AND ANALYSIS: The SRHEC cohort is an observational follow-up study of children born to HIV-infected pregnant women who were previously enrolled in a maternal vitamin D supplementation randomised, placebo-controlled trial in Dar es Salaam, Tanzania. This parent trial enrolled 2300 pregnant women and followed mothers and infants up to 1-year postpartum. Mother/caregiver and child pairs will be eligible for the SRHEC follow-up study if the child is between 3 and 6.5 years of age at assessment, and the mother/caregiver provides informed consent. The International Development and Early Learning Assessment tool will be used to assess children's school readiness, including their early literacy, early numeracy, motor, socialemotional, and executive function skills. Data on maternal and child health and nutritional status (eg, anthropometry, blood pressure and diet) will be collected using standardised instruments and survey-based questionnaires. Data on maternal/caregiver depression and anxiety, maternal exposure to intimate partner violence, and HIV-related stigma will also be collected. Generalised linear and logistic regressions will be used to assess the relationship between child school readiness and biological, social, environmental factors. ETHICS AND DISSEMINATION: This study received ethical clearance from the Tanzanian National Institute of Medical Research, the Muhimbili University of Health and Allied Sciences, and the Harvard T.H. Chan School of Public Health. We will disseminate our results in the form of scientific conference presentations and peer-reviewed publications.

'I haven't heard much about other methods': quality of care and person-centredness in a programme to promote the postpartum intrauterine device in Tanzania.

BACKGROUND: Programmes promoting the postpartum intrauterine device (PPIUD) have proliferated throughout South Asia and sub-Saharan Africa in recent years, with proponents touting this long-acting reversible contraceptive (LARC) method's high efficacy and potential to meet contraceptive unmet need. While critiques of LARC-first programming abound in the Global North, there have been few studies of the impact of LARC-centric programmes on patient-centred outcomes in the Global South. METHODS: Here, we explore the impact of a PPIUD intervention at five Tanzanian hospitals and their surrounding satellite clinics on quality of contraceptive counselling and person-centred care using 20 qualitative in-depth interviews with pregnant women seeking antenatal care at one of those clinics. Using a modified version of the contraceptive counselling quality framework elaborated by Holt and colleagues, we blend deductive analysis with an inductive approach based on open coding and thematic analysis. RESULTS: Interpersonal aspects of relationship building during counselling were strong, but a mix of PPIUD intervention-related factors and structural issues rendered most other aspects of counselling quality low. The intervention led providers to emphasise the advantages of the IUD through biased counselling, and to de-emphasise the suitability of other contraceptive methods. Respondents reported being counselled only about the IUD and no other methods, while other respondents reported that other methods were mentioned but disparaged by providers in relation to the IUD. A lack of trained providers meant that most counselling took place in large groups, resulting in providers' inability to conduct needs assessments or tailor information to women's individual situations. DISCUSSION: As implemented, LARC-centric programmes like this PPIUD intervention may decrease access to person-centred contraceptive counselling and to accurate information about a broad range of contraceptive methods. A shift away from emphasising LARC methods to more comprehensive, person-centred contraceptive counselling is critical to promote contraceptive autonomy.

Depression and Viral Suppression Among Adults Living with HIV in Tanzania.

Limited information is available on the association between depression and viral suppression among people living with HIV (PLH) in sub-Saharan Africa. We conducted a prospective cohort study of 3996 adults initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. Log-binomial models were used to assess the association between depression and the risk of an unsuppressed viral load (> 400 copies/mL) after 6 months of ART. Women who had depression at both initiation and after 6 months of treatment had 1.94 times (95% CI 1.22, 3.09; z = 2.78, p < 0.01) the risk of an unsuppressed viral load after 6 months of treatment as compared to women who did not have depression at either time point. Men with the top tertile of depressive symptoms after 6 months of treatment had 1.58 times the risk of an unsuppressed viral load (95% CI 1.04, 2.38; z = 2.15, p = 0.03) as compared to the lowest tertile. Research should be pursued on interventions to prevent and address depression among adults initiating ART to potentially support achievement of viral suppression.

Long-term virological outcomes in women who started option B+ care during pregnancy for prevention of mother-to-child transmission of HIV in Dar es Salaam, Tanzania: a cohort study.

BACKGROUND: Option B+ marked a milestone in prevention of mother-to-child transmission (PMTCT) of HIV by recommending lifelong antiretroviral therapy (ART) for all pregnant women with HIV. Nevertheless, concerns remain regarding long-term outcomes in settings with a high HIV burden. We analysed long-term virological outcomes in women enrolled on option B+ in Tanzania. METHODS: In this prospective cohort study, we extracted data for pregnant women with HIV starting PMTCT care between Oct 1, 2014, and Sept 30, 2016, in routine health-care settings in Dar es Salaam, Tanzania, from national HIV and district health information system databases. We then excluded women who exited study sites before 6 months of ART follow-up and women who did not have a viral load test. Women were followed up until March 8, 2019. We used Poisson generalised estimating equations to examine trends in HIV viral suppression (<400 copies per mL) and virological failure (≥400 copies per mL), reporting relative risks (RRs) and 95% CIs adjusted for maternal age, gestational age, and several clinical characteristics. FINDINGS: We identified 15 586 pregnant women with HIV, of whom 10 161 were eligible for follow-up. Women were followed up for a median of 37 months (IQR 31-45) and a maximum of 53 months. The median age at PMTCT initiation was 31 years (IQR 27-35). At PMTCT enrolment, 1245 (17·0%) of 7318 women with available data were in their third trimester, 4901 (48·2%) of 10 161 women started ART at least 1 month before PMTCT enrolment, and 3380 (33·4%) of 10 131 women with available data had advanced HIV. Overall, a viral suppression rate of 88·2% (95% CI 87·8-88·7) was observed over the entire follow-up period, ranging from 85·1% (84·3-85·9) in viral load tests done at 0-11 months to 90·6% (89·7-91·4) at 36 months or longer since PMTCT enrolment. In a complete-case analysis (ie, including patients with <30% missing data; n=7306), the risk of virological failure among women who remained in HIV care decreased over time (adjusted RR 0·87 [95% CI 0·80-0·95] at 12-23 months since PMTCT enrolment; 0·65 [0·59-0·72] at 24-35 months; and 0·63 [0·55-0·71] at ≥36 months vs at 0-11 months). Younger women (aged <20 years: 1·76 [1·40-2·23] vs aged 30-39 years) and those starting PMTCT late in pregnancy (third trimester: 1·28 [1·10-1·50] vs first trimester) or with advanced HIV (1·33 [1·16-1·51] vs without advanced HIV) had increased risk of virological failure. Women who attended an antenatal care facility where more than 50% of attendees received couples HIV testing had a decreased risk of virological failure (adjusted RR 0·81 [0·65-0·99] vs <50% having couples testing). INTERPRETATION: High rates of viral suppression among women starting option B+ who remain in HIV care are sustainable, and might increase, at least up to 53 months. This rate might be further improved by addressing challenges of adolescent mothers, late presenters, and couples HIV testing at antenatal care. FUNDING: Swedish International Development Agency.