Browsing by Author "Prendergast, Andrew J."

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    Bacteremia, Causative Agents and Antimicrobial Susceptibility Among HIV-1–infected Children on Antiretroviral Therapy in Uganda and Zimbabwe
    (The Pediatric infectious disease journal, 2013) Musiime, Victor; Cook, Adrian; Bakeera-Kitaka, Sabrina; Vhembo, Tichaona; Lutakome, Joseph; Keishanyu, Rosette; Prendergast, Andrew J.; Lubwama, Sam; Robertson, Val; Hughes, Peter; Nathoo, Kusum; Munderi, Paula; Klein, Nigel; Musoke, Philippa; Gibb, Diana M.
    Bacteremia is common in HIV-infected children in Africa, including after start of antiretroviral therapy (ART), but there are limited data on causative pathogens and their antimicrobial sensitivity patterns in this population. Methods: We analyzed data on blood cultures taken from HIV-infected children developing acute febrile illness after enrollment to the Antiretroviral Research for Watoto (ARROW) clinical trial in Uganda and Zimbabwe. Patterns of bacterial pathogens and their antimicrobial susceptibilities were determined and bacteremia rates calculated over time from ART initiation. Results: A total of 848 blood cultures were obtained from 461 children, of which 123 (14.5%) from 105 children (median age 3.5 years, 51% girls) were culture positive, including 75 (8.8%) with clearly pathogenic organisms. The event rates for positive cultures with clearly pathogenic organisms after 0–1, 2–3, 4–11 and ≥12 months on ART were 13.3, 11.4, 2.1 and 0.3 per 1000 person-months of follow-up, respectively. The pathogens isolated (n; %) were Streptococcus pneumoniae (36; 28.3%), Staphylococcus aureus (11; 8.7%), Klebsiella pneumoniae (6; 4.7%), Pseudomonas aeruginosa (6; 4.7%), Salmonella spp (6; 4.7%), Escherichia coli (5; 3.9%), Haemophilus influenzae (1; 0.8%) and fungal spp (4; 3.1%). Other bacteria of doubtful pathogenicity (n = 52; 42%) were also isolated. Most isolates tested were highly (80–100%) susceptible to ceftriaxone, cefotaxime and ciprofloxacin; very few (~5%) were susceptible to cotrimoxazole; S. pneumoniae had high susceptibility to amoxicillin/ampicillin (80%). Conclusions: Rates of proven bacteremia were >20-fold higher immediately after starting ART compared with 12 months later in African HIV-infected children. S. pneumoniae was most commonly isolated, suggesting need for pneumococcal vaccination and effective prophylactic antibiotics.
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    Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy
    (The Journal of infectious diseases, 2016) Prendergast, Andrew J.; Szubert, Alexander J.; Berejena, Chipo; Pimundu, Godfrey; Pala, Pietro; Shonhai, Annie; Musiime, Victor; Bwakura-Dangarembizi, Mutsa; Poulsom, Hannah; Hunter, Patricia; Musoke, Philippa; Kihembo, Macklyn; Munderi, Paula; Gibb, Diana M.; Spyer, Moira; Walker, A. Sarah; Klein, Nigel
    Background. Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)–infected children. Methods. CD4+ T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. Results. There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunologicalresponse) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4–11.4 years) and 5.8 years (IQR, 2.3–9.3 years), respectively, and the median percentages of lymphocytes expressing CD4were 4% (IQR, 1%–9%) and 13% (IQR, 8%–18%), respectively. In multivariable logistic regression, cases had lower age-associatedCD4+ T-cell count ratio (calculated as the ratio of the subject’s CD4+ T-cell count to the count expected in healthy individuals of thesame age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4+ and CD8+ T-cellcount ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profoundimmunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8+ T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). Conclusions. While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.
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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).
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    Virological Response and Resistance Among HIV-Infected Children Receiving Long-Term Antiretroviral Therapy Without Virological Monitoring in Uganda and Zimbabwe: Observational Analyses Within the Randomised ARROW Trial
    (PLoS medicine, 2017) Szubert, Alexander J.; Prendergast, Andrew J.; Musiime, Victor; Musoke, Philippa; Bwakura-Dangarembizi, Mutsa; Nahirya-Ntege, Patricia; Thomason, Margaret J.; Nkanya, Immaculate; Senfuma, Oscar; Mudenge, Boniface; Walker, A. Sarah
    Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring. In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI −3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post–week 24 was spent with persistent low-level viraemia (80–5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years’ rebound. Nineteen out of 48 (40%) VLs 1,000–5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes. In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring.