Browsing by Author "Mulenga, Veronica"

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    Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial
    (The Lancet Infectious Diseases, 2016) Mulenga, Veronica; Musiime, Victor.; Kekitiinwa, Adeodata; Cook, Adrian D; Abongomera, George; Kenny, Julia; Chabala, Chisala; Mirembe, Grace; Asiimwe, Alice; Owen-Powell, Ellen; Burger, David; McIlleron, Helen; Klein, Nigel.; Chintu, Chifumbe; Thomason, Margaret J.; Kityo, Cissy.; Walker, Sarah A.; Gibb, Diana M
    Background WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fi xed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. Methods In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2–4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. Findings Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2–4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75–1·29]; abacavir vs stavudine: HR 0·88 [0·67–1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). Interpretation All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profi le and oncedaily dosing favours abacavir for African children, supporting WHO 2013 guidelines.
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    Development of tuberculosis treatment decision algorithms in children below 5 years hospitalised with severe acute malnutrition in Zambia and Uganda: a prospective diagnostic cohort study
    (Elsevier Ltd, 2024-07) Chabala, Chishala; Roucher, Clémentine; Ton Nu Nguyet, Minh Huyen; Babirekere, Esther; Inambao, Muleya; Businge, Gerald; Kapula, Chifunda; Shankalala, Perfect; Nduna, Bwendo; Mulenga, Veronica; Graham, Stephen; Wobudeya, Eric; Bonnet, Maryline; Marcy, Olivier; Marcy, Olivier; Serre, Angeline; Et.al
    In children with severe acute malnutrition (SAM) tuberculosis is common, challenging to diagnose, and often fatal. We developed tuberculosis treatment decision algorithms (TDAs) for children under the age of 5 years with SAM. In this prospective diagnostic study, we enrolled and followed up children aged <60 months hospitalised with SAM at three tertiary hospitals in Zambia and Uganda from 4 November 2019 to 20 June 2022. We included children aged 2–59 months with SAM as defined by WHO and hospitalised following the WHO clinical criteria. We excluded children with current or history of antituberculosis treatment within the preceding 3 months. They underwent tuberculosis symptom screening, clinical assessment, chest X-ray, abdominal ultrasound, Xpert MTB/RIF Ultra (Ultra) and culture on respiratory and stool samples with 6 months follow-up. Tuberculosis was retrospectively defined using the 2015 standard case definition for childhood tuberculosis. We used logistic regression to develop diagnostic prediction models for a one-step diagnosis and a two-step screening and diagnostic approaches. We derived scores from models using WHO-recommended thresholds for sensitivity and proposed TDAs. This study is registered with ClinicalTrials.gov, NCT04240990. Of 1906 children hospitalised with SAM during the study period, 1230 were screened, 1152 were eligible and 603 were enrolled. Of the 603 children enrolled–median age 15 (inter-quartile range (IQR): 11–20) months and 65 (11.0%) living with HIV–114 (18.9%) were diagnosed with tuberculosis, including 51 (8.5%) with microbiological confirmation and 104 (17.2%) initiated treatment at a median of 6(IQR: 2–10) days after inclusion. 108 children were retrospectively classified as having tuberculosis resulting in a prevalence of 17.9% (95% confidence intervals (CI): 15.1; 21.2). 75 (69.4%) children with tuberculosis reported cough of any duration, 32 (29.6%) cough ≥2 weeks and 11 (10.2%) tuberculosis contact history. 535 children had complete data and were included in the diagnostic prediction model. The one-step diagnostic model had 15 predictors, including Ultra, clinical, radiographic, and abdominal features, an area under the receiving operating curve (AUROC) of 0.910, and derived TDA sensitivity of 86.14% (95% CI: 78.07–91.56) and specificity of 80.88% (95% CI: 76.91–84.30). The two-step model had AUROCs of 0.750 and 0.912 for screening and diagnosis, respectively, and derived combined TDA sensitivity of 79.21% (95% CI: 70.30–85.98) and a specificity of 83.64% (95% CI: 79.87–86.82). Tuberculosis prevalence was high among hospitalised children with SAM, with atypical clinical features. TDAs achieved satisfactory diagnostic accuracy and could be used to improve diagnosis in this vulnerable group. Unitaid
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    Differences in body circumference, skin fold thickness and lipid profile measurements among HIV-infected children on and not on stavudine-based therapy in Uganda and Zambia in the CHAPAS-3 clinical trial
    (Joint Clinical Research Centre, 2013) Musiime, Victor; Cook, Adrian.; Kayiwa, Joshua; Zangata, Dorothy; Gibb, Diana M.; Kityo, Cissy; Kekitiinwa, Adeodata; Mulenga, Veronica; Nansubuga, Carol; Arach, Beatrice; Kenny, Julia; Wavamunno, Priscilla; Kabamba, Desiree; Asiimwe, Alice R.; Abongomera, George
    Lipodystrophy is a major side effect of antiretroviral therapy (ART) especially in adults, and although there have been some reports among HIV-infected children [1,2], paediatric data are limited Stavudine (d4T) has particularly been associated with lipodystrophy among HIVinfected adults owing to intracellular accumulation of the drug and its metabolites In HIV-infected children, d4T clearance is enhanced, potentially protecting them from these effects [3]. In addition, the relative d4T dose in paediatric fixed dosecombination “baby” tablets is lower than used in adults, and is also lower compared to the 4mg/kg licensed dose for children [4] Features of lipodystrophy have been observed to reverse when children have been switched from d4T-containing regimens [5]; however, clinical lipodystrophy ismore difficult to diagnose in growing children than in adults We compared body circumferences, skin-fold thickness (SFT) and lipid levels, as objective measures of lipodystrophy, among HIV-infected ART naïve vs experienced children at enrolment into the CHAPAS-3 trial, and in HIV-uninfected
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    Shorter Treatment For Minimal Tuberculosis (TB) In Children (SHINE): A Study Protocol For A Randomised Controlled Trial
    (Trials, 2018) Chabala, Chishala; Turkova, Anna; Thomason, Margaret J.; Wobudeya, Eric; Hissar, Syed; Mave, Vidya; Zalm, Marieke van der; Palmer, Megan; Kapasa, Monica; Bhavani, Perumal K.; Balaji, Sarath; Raichur, Priyanka A.; Demers, Anne-Marie; Hoddinott, Graeme; Powell, Ellen Owen; Kinikar, Aarti; Musoke, Philippa; Mulenga, Veronica; Aarnoutse, Rob; McIlleron, Helen; Hesseling, Anneke; Crook, Angela M.; Cotton, Mark; Gibb, Diana M.; on behalf of the SHINE trial team
    Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed.SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations.Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB.
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    Treatment of Young Children with HIV Infection: Using Evidence to Inform Policymakers
    (PLoS medicine, 2012) Prendergast, Andrew J.; Penazzato, Martina; Cotton, Mark; Musoke, Philippa; Mulenga, Veronica; Abrams, Elaine J.; Gibb, Diana M.
    Despite efforts to scale up prevention of mother-to-child transmission (PMTCT) of HIV, over 1,000 infants continue to be infected daily, particularly in sub-Saharan Africa [1]. Disease progression in infants is much more rapid than in older children and adults, with mortality exceeding 50% by 2 years of age in the absence of antiretroviral therapy (ART) [2]. Although combination ART has been available since 1997, diagnosis and treatment of infants is much more challenging compared to older children and adults (Box 1).Furthermore, until recently there was little evidence to guide treatment approaches in infants and young children, with international policymakers relying on data from cohort studies and expert opinion to inform guidelines. In the past 5 years, results have emerged from several randomized clinical trials of children with HIV under 2 years of age (Table 1) [3–8]; a systematic review of these trials has just been published [9]. Here, we consider the implications of research findings for forthcoming World Health Organization (WHO) guidelines and, ultimately, for policymakers, who will need to weigh efficacy and feasibility of interventions in their particular settings in low- and middle-income countries (LMIC).