Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial.

BACKGROUND: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only. METHODS: We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] 0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45). INTERPRETATION: In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present. FUNDING: Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).This study was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development (DFID), the Wellcome Trust, and the UK Medical Research Council (MRC; G1100693). Additional funding support was provided by the PENTA foundation and core support to the MRC Clinical Trials Unit at University College London (London, UK; MC_UU_12023/23, MC_UU_12023/26). Cipla, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for the study and ready-to-use supplementary food was purchased from Valid International. The MRC Clinical Trials Unit has received other funding from Tibotec and Gilead Sciences for data safety monitoring board membership and lectures. The Malawi–Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (101113/Z/13/Z), and the KEMRI/Wellcome Trust Research Programme, Kilifi (203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust (UK)

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial.

This article has been accepted for publication in Clinical Infectious Diseases Published by Oxford University PressBackground: Severely immunocompromised human immunodeficiency virus (HIV)-infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods: The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts .1). Results: Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/µL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/µL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/µL), but low symptom burden and maintained fat mass. The remaining groups had 4%-6% mortality. Conclusions: Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up. Clinical Trials Registration: ISRCTN43622374.REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

Pesticidal efficacy of crude aqueous extracts of Tephrosia vogelii L., Allium sativum L. and Solanum incanum L. in controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)n controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)

Cabbage aphid (Brevicoryne brassicae L.) is one of the most problematic pests in smallholder vegetable production, causing significant yield losses in heavy infestations. Current control strategy focuses on use of synthetic pesticides that consequently lead to decimation of natural enemies, development of insect resistance and resurgence and upset biodiversity. Botanical pesticides have been used widely in smallholder farmers but not much documented literature exists on efficacy of these products. A field trial was done to assess the efficacy of crude aqueous extracts of Tephrosia vogelii, Allium sativum and Solanum incanum in controlling Brevicoryne brassicae in Brassica napus production. The trial was laid in a randomized complete block design (RCBD) with five treatments replicated four times. The five treatments used in the experiment were T. vogelii, A. sativum, S. incanum, dimethoate and control. Wingless adult female aphids were inoculated three weeks after transplanting of seedlings. Spraying and data collection were done weekly for four weeks. Data was collected on aphid nymph and adult counts on the third leaf from the aerial plant part of randomly selected plants from each treatment for 24 hours after the application of treatments and total plant fresh weight per each treatment. There were significant differences (p<0.05) in the efficacy of botanicals and synthetics in controlling aphids, with dimethoate being the most effective followed by T. vogelii, A. sativum, S. incanum and lastly the control. The treatments applied had a significant effect (p<0.05) on the yield of rape. It was concluded that T. vogelii, S. incanum and A. sativum aqueous crude extracts have some pesticidal effects on aphid in rape production

Pesticidal efficacy of crude aqueous extracts of Tephrosia vogelii L., Allium sativum L. and Solanum incanum L. in controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)n controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)

Cabbage aphid (Brevicoryne brassicae L.) is one of the most problematic pests in smallholder vegetable production, causing significant yield losses in heavy infestations. Current control strategy focuses on use of synthetic pesticides that consequently lead to decimation of natural enemies, development of insect resistance and resurgence and upset biodiversity. Botanical pesticides have been used widely in smallholder farmers but not much documented literature exists on efficacy of these products. A field trial was done to assess the efficacy of crude aqueous extracts of Tephrosia vogelii, Allium sativum and Solanum incanum in controlling Brevicoryne brassicae in Brassica napus production. The trial was laid in a randomized complete block design (RCBD) with five treatments replicated four times. The five treatments used in the experiment were T. vogelii, A. sativum, S. incanum, dimethoate and control. Wingless adult female aphids were inoculated three weeks after transplanting of seedlings. Spraying and data collection were done weekly for four weeks. Data was collected on aphid nymph and adult counts on the third leaf from the aerial plant part of randomly selected plants from each treatment for 24 hours after the application of treatments and total plant fresh weight per each treatment. There were significant differences (p<0.05) in the efficacy of botanicals and synthetics in controlling aphids, with dimethoate being the most effective followed by T. vogelii, A. sativum, S. incanum and lastly the control. The treatments applied had a significant effect (p<0.05) on the yield of rape. It was concluded that T. vogelii, S. incanum and A. sativum aqueous crude extracts have some pesticidal effects on aphid in rape production

Pesticidal efficacy of crude aqueous extracts of Tephrosia vogelii L., Allium sativum L. and Solanum incanum L. in controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)n controlling aphids (Brevicoryne brassicae L.) in rape (Brassica napus L.)

Cabbage aphid (Brevicoryne brassicae L.) is one of the most problematic pests in smallholder vegetable production, causing significant yield losses in heavy infestations. Current control strategy focuses on use of synthetic pesticides that consequently lead to decimation of natural enemies, development of insect resistance and resurgence and upset biodiversity. Botanical pesticides have been used widely in smallholder farmers but not much documented literature exists on efficacy of these products. A field trial was done to assess the efficacy of crude aqueous extracts of Tephrosia vogelii, Allium sativum and Solanum incanum in controlling Brevicoryne brassicae in Brassica napus production. The trial was laid in a randomized complete block design (RCBD) with five treatments replicated four times. The five treatments used in the experiment were T. vogelii, A. sativum, S. incanum, dimethoate and control. Wingless adult female aphids were inoculated three weeks after transplanting of seedlings. Spraying and data collection were done weekly for four weeks. Data was collected on aphid nymph and adult counts on the third leaf from the aerial plant part of randomly selected plants from each treatment for 24 hours after the application of treatments and total plant fresh weight per each treatment. There were significant differences (p<0.05) in the efficacy of botanicals and synthetics in controlling aphids, with dimethoate being the most effective followed by T. vogelii, A. sativum, S. incanum and lastly the control. The treatments applied had a significant effect (p<0.05) on the yield of rape. It was concluded that T. vogelii, S. incanum and A. sativum aqueous crude extracts have some pesticidal effects on aphid in rape production