Browsing by Author "Cotton, Mark"

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    Clinical trials of disease stages in COVID 19 : complicated and often misinterpreted
    (Elsevier, 2020-08-20) Park, Jay J. H.; Decloedt, Eric H.; Rayner, Craig R.; Cotton, Mark; Mills, Edward J.
    As of July 28, 2020, 1840 clinical trials were registered globally, with 1001 clinical trials recruiting patients for COVID-19 management.1 Despite this large number, only 30 trials have been published as peer-reviewed or preprint publications.2 Media reports and prepublications on medRxiv and bioRxiv represent the most frequent mechanism for data sharing, with wide public reach and usually with little detail. However, with inadequate details on the trials and only superficial scrutiny by the public and scientific decision makers, the consequences have had disastrous effects on other clinical trial funding, permissions, recruitment, and interpretation.
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    Isoniazid for preventing tuberculosis in HIV-infected children
    (John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration, 2017) Zunza, Moleen; Gray, Diane M.; Young, Taryn; Cotton, Mark; Zar, Heather J.
    Background: Tuberculosis (TB) is an important cause of illness and death in HIV‐positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV‐negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV‐positive children. Objectives: To summarise the effects of TB preventive treatment versus placebo in HIV‐positive children with no known TB contact on active TB, death, and reported adverse events. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017. Selection criteria: We included trials of HIV‐positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo. Data collection and analysis: Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE. Main results: We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow‐up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART). In HIV‐positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported. In HIV‐positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups. Authors' conclusions: Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV‐positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected.
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    Low vitamin-D levels combined with PKP3-SIGIRR-TMEM16J host variants is associated with tuberculosis and death in HIV-infected and -exposed infants
    (Public Library of Science, 2016) Gupta, Amita; Montepiedra, Grace; Gupte, Akshay; Zeldow, Bret; Jubulis, Jennifer; Detrick, Barbara; Violari, Avy; Madhi, Shabir; Bobat, Raziya; Cotton, Mark; Mitchell, Charles; Spector, Stephen; IMPAACT NWCS113 and P1041 Study Team
    Background: This study examined the associations of 25-hydroxyvitamin D and specific host genetic variants that affect vitamin D levels or its effects on immune function, with the risk of TB or mortality in children. Methods: A case-cohort sample of 466 South African infants enrolled in P1041 trial (NCT00080119) underwent 25-hydroxyvitamin D testing by chemiluminescent immunoassay. Single nucleotide polymorphisms (SNPs) that alter the effect of vitamin D [e.g. vitamin D receptor (VDR)], vitamin D levels [e.g. vitamin D binding protein (VDBP)], or toll like receptor (TLR) expression (SIGIRR including adjacent genes PKP3 and TMEM16J) were identified by real-time PCR. Outcomes were time to TB, and to the composite of TB or death by 192 weeks of follow-up. Effect modification between vitamin D status and SNPs for outcomes was assessed. Findings: Median age at 25-hydroxyvitamin D determination was 8 months; 11% were breastfed, 51% were HIV-infected and 26% had low 25-hydroxyvitamin D (<32ng/mL). By 192 weeks, 138 incident TB cases (43 definite/probable, and 95 possible) and 26 deaths occurred. Adjusting for HIV status and potential confounders, low 25-hydroxyvitamin D was associated with any TB (adjusted hazard ratio [aHR] 1.76, 95% CI 1.01–3.05; p = 0.046) and any TB or death (aHR 1.76, 95% CI 1.03–3.00; p = 0.038). Children with low 25-hydroxyvitamin D and TMEM 16J rs7111432-AA or PKP3 rs10902158-GG were at increased risk for probable/definite TB or death (aHR 8.12 and 4.83, p<0.05) and any TB or death (aHR 4.78 and 3.26, p<0.005) respectively; SNPs in VDBP, VDR, and vitamin D precursor or hydroxylation genes were not. There was significant interaction between low 25-hydroxyvitamin D and, TMEM 16J rs7111432-AA (p = 0.04) and PKP3 rs10902158-GG (p = 0.02) SNPs. Conclusions: Two novel SNPs, thought to be associated with innate immunity, in combination with low vitamin D levels were identified as increasing a young child’s risk of developing TB disease or death. Identifying high-risk children and providing targeted interventions such as vitamin D supplementation may be beneficial.
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    Low-dose stavudine trials: a public health priority for developing countries
    (AOSIS Publishing, 2012-03-13) Venter, W. D. Francois; Innes, Steve; Cotton, Mark
    The debate around relooking at stavudine dosing, both in terms of the adult low-dose stavudine study and more broadly, is welcome. The study being proposed to evaluate low-dose stavudine v. tenofovir is a fairly standard placebo-controlled non-inferiority study. The study design is not controversial; however, the choice of study drug has attracted critical attention.
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    Missed opportunities of inclusion in a cohort of HIV-infected children to initiate antiretroviral treatment before the age of two in West Africa, 2011 to 2013
    (International AIDS Society, 2016-03-23) Dahourou, Desire L.; Amorissani-Folquet, Madeleine; Coulibaly, Malik; Avit-Edi, Divine; Meda, Nicolas; Timite-Konan, Marguerite; Arendt, Vic; Ye, Diarra; Amani-Bosse, Clarisse; Salamon, Roger; Lepage, Philippe; Leroy, Valeriane; Cotton, Mark
    Introduction: The World Health Organization (WHO) 2010 guidelines recommended to treat all HIV-infected children less than two years of age. We described the inclusion process and its correlates of HIV-infected children initiated on early antiretroviral therapy (EART) at less than two years of age in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso. Methods: All children with HIV-1 infection confirmed with a DNA PCR test of a blood sample, aged less than two years, living at a distance less than two hours from the centres and whose parents (or mother if she was the only legal guardian or the legal caregiver if parents were not alive) agreed to participate in the MONOD ANRS 12206 project were included in a cohort to receive EART based on lopinavir/r. We used logistic regression to identify correlates of inclusion. Results: Among the 217 children screened and referred to the MONOD centres, 161 (74%) were included and initiated on EART. The main reasons of non-inclusion were fear of father’s refusal (48%), mortality (24%), false-positive HIV infection test (16%) and other ineligibility reasons (12%). Having previously disclosed the child’s and mother’s HIV status to the father (adjusted odds ratio (aOR): 3.20; 95% confidence interval (95% CI): 1.55 to 6.69) and being older than 12 months (aOR: 2.05; 95% CI: 1.02 to 4.12) were correlates of EART initiation. At EART initiation, the median age was 13.5 months, 70% had reached WHO Stage 3/4 and 57% had a severe immune deficiency. Conclusions: Fear of stigmatization by the father and early competing mortality were the major reasons for missed opportunities of EART initiation. There is an urgent need to involve fathers in the care of their HIV-exposed children and to promote early infant diagnosis to improve their future access to EART and survival.
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    Shorter treatment for minimal tuberculosis (TB) in children (SHINE) : a study protocol for a randomised controlled trial
    (BioMed Central, 2018-04-19) Chabala, Chishala; Turkova, Anna; Thomason, Margaret J.; Wobudeya, Eric; Hissar, Syed; Mave, Vidya; Van Der Zalm, Marieke; Palmer, Megan; Kapasa, Monica; Bhavani, Perumal K.; Balaji, Sarath; Raichur, Priyanka A.; Demers, Anne-Marie; Hoddinott, Graeme; Owen-Powell, Ellen; Kinikar, Aarti; Musoke, Philippa; Mulenga, Veronica; Aarnoutse, Rob; McIlleron, Helen; Hesseling, Anneke; Crook, Angela M.; Cotton, Mark; Gibb, Diana M.
    Background: 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. Methods/design: 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. Discussion: 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 smearnegative 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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    When to start antiretroviral therapy in infants and children
    (AOSIS OpenJournals, 2009-12) Cotton, Mark; Rabie, Helena; Feucht, Ute; Violari, Avy
    This articles provides a background for antiretroviral therapy in infants and children, incorporating both old and new data. There is increasing data favouring early therapy for all age groups. Below a year of age, all HIV-infected infants should commence therapy and thereafter at higher CD4 thresholds than previous recommendations