Browsing by Author "Cotton, Mark"

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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).