NRU :: Browsing by Author "Gibb, Diana M."

Browsing by Author "Gibb, Diana M."

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Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children
(Europe PMC Funders Group, 2016) Kekitiinwa, Adeodata.; Musiime, Victor.; Thomason, Margaret J.; Mirembe, Grace; Lallemant, Marc; Nakalanzi, Sarah.; Baptiste, David.; Walker, Sarah A.; Gibb, Diana M.; Judd, Ali
Lopinavir/ritonavir ‘pellets’ were recently tentatively approved for licensing. We describe their acceptability for infants and children up to 48 weeks. Methods—CHAPAS-2 was a randomised, 2-period crossover trial comparing syrup and pellets in HIV-infected infants (n=19, group A, aged 3-<12 months) and children (n=26, group B, 1-<4yrs) and tablets and pellets in older children (n=32, group C, 4-<13yrs) from 2 clinics (“JCRC”, “PIDC”) in Uganda. At week 8, all groups chose which formulation to continue. Acceptability data were collected at weeks 0,4,8,12, and 48. Results—For groups A and B overall, the proportion preferring pellets increased between week 0 and week 12 and decreased at week 48 (group A 37%, 72%, 44%; group B 12%, 64% and 36% respectively), although there were marked differences between clinics. For group C, pellets were progressively less preferred to tablets over time: 41%,19%,13% at weeks 0,12,48 respectively. During follow-up unpleasant taste was similarly reported among young children taking pellets and syrups (37%/43% group A; 29%/26% group B), whereas among older children, pellets tasted worse than tablets (40%/2%). No participants reported problems with storage/transportation for pellets (0%/0%) unlike syrups (23%/13%). Conclusions—For children <4 years, pellets were more acceptable at week 12 but not week 48. Clinic differences could reflect bias among healthcare workers for different formulations. Pellets taste similar to syrup, are easier to store and transport than syrup, and represent an alternative formulation for young children unable to swallow tablets; improvements in taste and support for healthcare workers may help sustain acceptability
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.
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.
Co-Trimoxazole Or Multivitamin Multimineral Supplement For Post-Discharge Outcomes After Severe Anaemia In African Children: A Randomised Controlled Trial
(The Lancet Global Health, 2019) Maitland, Kathryn; Olupot, Peter Olupot; Kiguli, Sarah; Chagaluka, George; Alaroker, Florence; Opoka, Robert O.; Mpoya, Ayub; Walsh, Kevin; Engoru, Charles; Nteziyaremye, Julius; Mallewa, Machpherson; Nakuya, Margaret; Kennedy, Neil; Namayanja, Cate; Kayaga, Julianne; Nabawanuka, Eva; Sennyondo, Tonny; Aromut, Denis; Kumwenda, Felistas; Musika, Cynthia Williams; Thomason, Margaret J.; Bates, Imelda; Hensbroek, Michael Boele von; Evans, Jennifer A .; Uyoga, Sophie; Williams, Thomas N.; Frost, Gary; George, Elizabeth C.; Gibb, Diana M.; Walker, A. Sarah; the TRACT trial group
Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes.Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete.From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86–1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84–1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89–1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions).Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa.
Cost Effectiveness Analysis of Clinically Driven versus Routine Laboratory Monitoring of Antiretroviral Therapy in Uganda and Zimbabwe
(PloS one, 2012) Lara, Antonieta Medina; Kigozi, Jesse; Amurwon, Jovita; Muchabaiwa, Lazarus; Wakaholi, Barbara Nyanzi; Mota, Ruben E. Mujica; Walker, A. Sarah; Kasirye, Ronnie; Ssali, Francis; Reid, Andrew; Grosskurth, Heiner; Babiker, Abdel G.; Kityo, Cissy; Katabira, Elly; Munderi, Paula; Mugyenyi, Peter; Hakim, James; Darbyshire, Janet; Gibb, Diana M.; Gilks, Charles F.
Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated.Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12-weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial.3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm3) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95%CI:685,845], translating into an adjusted incremental cost of $7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent cost-drivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below $3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term.There is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test.
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
Differences in Factors Associated With Initial Growth, CD4, and Viral Load Responses to ART in HIV-Infected Children in Kampala, Uganda, and the United Kingdom/Ireland
(JAIDS Journal of Acquired Immune Deficiency Syndromes, 2008) Kekitiinwa, Addy; Lee, Katherine J.; Walker, Sarah; Maganda, Albert; Doerholt, Katja; Kitaka, Sabrina B.; Asiimwe, Alice; Judd, Ali; Musoke, Philippa; Gibb, Diana M.
Few studies have directly compared response to antiretroviral therapy (ART) between children living in well-resourced and resource-limited settings. In resource-limited settings non-HIV contributors could reduce the beneficial effects of ART. We compare predictors of short-term immunological, virological, and growth response to ART in HIV-infected children in the United Kingdom/Ireland and Kampala. Methods: We analyzed prospective cohort data from 54 UK/Irish hospitals (the Collaborative HIV Paediatric Study) and Mulago Hospital, Kampala, Uganda. Six- and 12-month responses are described among children initiating combination ART (≥3 drugs, ≥2 classes). Six months post-ART, predictors of viral load (VL) suppression <400 copies/mL, CD4% increases >10%, and height- and weight-for-age z-score increases ≥+0.5 were investigated using logistic regression.In all, 582 UK/Irish children (76% black African) were younger than 876 Kampala children at ART initiation (median 5.0 vs 7.6 years), with higher CD4% (14%, 8%), lower VL (172,491 and 346,809 copies/mL), and less stunting (−0.8, −2.8) and wasting (−0.6, −2.8). Post-ART, median 12-month changes in the United Kingdom/Ireland and Kampala in CD4% (+12%, +13%) and weight (+0.4, +0.5) were similar, but growth was less in Kampala (+0.20, +0.06, P < 0.001). Younger children in both cohorts had better immunological, weight, and growth responses (all P < 0.001). However, lower pre-ART CD4% predicted better immunological response in the United Kingdom/Ireland but poorer response in Kampala (heterogeneity P = 0.004). Although 70% children in both cohorts had suppressed <400 copies/mL at 6 months, adolescents starting ART in the United Kingdom/Ireland had somewhat poorer VL responses than those in Kampala (P = 0.15). In all, 582 UK/Irish children (76% black African) were younger than 876 Kampala children at ART initiation (median 5.0 vs 7.6 years), with higher CD4% (14%, 8%), lower VL (172,491 and 346,809 copies/mL), and less stunting (−0.8, −2.8) and wasting (−0.6, −2.8). Post-ART, median 12-month changes in the United Kingdom/Ireland and Kampala in CD4% (+12%, +13%) and weight (+0.4, +0.5) were similar, but growth was less in Kampala (+0.20, +0.06, P < 0.001). Younger children in both cohorts had better immunological, weight, and growth responses (all P < 0.001). However, lower pre-ART CD4% predicted better immunological response in the United Kingdom/Ireland but poorer response in Kampala (heterogeneity P = 0.004). Although 70% children in both cohorts had suppressed <400 copies/mL at 6 months, adolescents starting ART in the United Kingdom/Ireland had somewhat poorer VL responses than those in Kampala (P = 0.15).
The Impact of Different CD4 Cell-Count Monitoring and Switching Strategies on Mortality in HIV-Infected African Adults on Antiretroviral Therapy: An Application of Dynamic Marginal Structural Models
(American journal of epidemiology, 2015) Ford, Deborah; Robins, James M.; Petersen, Maya L.; Gibb, Diana M.; Gilks, Charles F.; Mugyenyi, Peter; Grosskurth, Heiner; Hakim, James; Katabira, Elly; Babiker, Abdel G.; Walker, A. Sarah
In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003–2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 personyears of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm3 or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks.
Pediatric Underdosing of Efavirenz: A Pharmacokinetic Study in Uganda
(JAIDS Journal of Acquired Immune Deficiency Syndromes, 2011) Fillekes, Quirine; Natukunda, Eva; Balungi, Jackie; Kendall, Lindsay; Bwakura-Dangarembizi, Mutsa; Keishanyu, Rosette; Ferrier, Alex; Lutakome, Joseph; Gibb, Diana M.; Burger, David M.; Walker, A. Sarah
Objectives: To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information. Design: Open-label, multicenter, PK study. Methods: Forty-one HIV-infected Ugandan children (3–12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to ,15, 15 to ,20, 20 to ,25, 25 to ,30 kg, respectively, using 200/50 mg capsules or halved 600 mg tablets in case of 300 and 350 mg doses. Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours postobserved ingestion) was performed at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24-hour sample). Results: Forty-one and 39 children had evaluable efavirenz profiles at PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3 were in the 10 to ,15, 15 to ,20, 20 to ,25, 25 to ,30 kg weight bands. The geometric mean (%CV) the area under the concentration– time curve 0–24 hours postdose was 50.8 (90.8%) and 55.5 (82.7%) h$mg$L-1 at PK1 and PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic C8h and/or C12h (,1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C24h ,1.0 mg/L (median (interquartile range) [range] 1.1 (0.7–2.9) [0.3–18.4]). Ten children at PK1 and 11 at PK2 had C8h and/or C12h .4.0 mg/L; 12 of 41 (29%) at either visit. Conclusions: African children aged 3–12 years, on efavirenz dosed according to 2006 WHO/manufacturer’s recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer’s leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.
Pharmacokinetics And Pharmacodynamics Of Azithromycin In Severe Malaria Bacterial Co-Infection In African Children (TABS-PKPD): A Protocol For A Phase II Randomised Controlled Trial
(Wellcome Open Research, 2021) Olupot, Peter Olupot; Okiror, William; Mnjalla, Hellen; Muhindo, Rita; Uyoga, Sophie; Mpoya, Ayub; Williams, Thomas N.; terHeine, Rob; Burger, David M.; Urban, Britta; Connon, Roisin; George, Elizabeth C.; Gibb, Diana M.; Walker, A. Sarah; Maitland, Kathryn
African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection.
Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial
(PLoS Med, 2012) Gibb, Diana M.; Kizito, Hilda; Russell, Elizabeth C.; Chidziva, Ennie; Zalwango, Eva; Nalumenya, Ruth; Spyer, Moira; Tumukunde, Dinah; Nathoo, Kusum; Munderi, Paula; Kyomugisha, Hope; Hakim, James; Grosskurth, Heiner; Gilks, Charles F.; Walker, Sarah; Musoke, Phillipa
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Methods and Findings: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths ($22 wk), and 137 (35%) terminations/miscarriages (,22 wk). Of 226 live-births, seven (3%) infants died ,2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p.0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers’ ART, 62/9/111 infants had no/20%–89%/$90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/ 182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p.0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Conclusions: Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
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.
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).
Virologic Response to First-Line Efavirenz- or Nevirapine-Based Anti-Retroviral Therapy in HIV-Infected African Children
(The Pediatric infectious disease journal, 2017) Kekitiinwa, Adeodata; Szubert, Alexander J.; Katuramu, Richard; Musiime, Victor; Kitaka, Sabrina Bakeera; Walker, Ann Sarah; Senfuma, Oscar; Gibb, Diana M.
Poorer virologic response to nevirapine vs efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies. We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ≥3 years of age initiating ART with clinician-chosen nevirapine vs efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/ml at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (p=0.1).
Whole blood versus red cell concentrates for children with severe anaemia: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial
(The Lancet Global Health, 2022) George, Elizabeth C.; Uyoga, Sophie; M’baya, Bridon; Kyeyune Byabazair, Dorothy; Kiguli, Sarah; Olupot-Olupot, Peter; Opoka, Robert O.; Chagaluka, George; Alaroker, Florence; Williams, Thomas N.; Bates, Imelda; Mbanya, Dora; Gibb, Diana M.; Walker, A. Sarah; Maitland, Kathryn
The TRACT trial established the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4–6 g/dL) and the optimal volume (20 vs 30 mL/kg whole blood or 10 vs 15 mL/kg red cell concentrates) for transfusion in children admitted to hospital with severe anaemia (haemoglobin <6 g/dL) on day 28 mortality (primary endpoint). Because data on the safety of blood components are scarce, we conducted a secondary analysis to examine the safety and efficacy of different pack types (whole blood vs red cell concentrates) on clinical outcomes. Methods This study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). TRACT was an open-label, multicentre, factorial, randomised trial conducted in three hospitals in Uganda (Soroti, Mbale, and Mulago) and one hospital in Malawi (Blantyre). The trial enrolled children aged between 2 months and 12 years admitted to hospital with severe anaemia (haemoglobin <6 g/dL). The pack type used (supplied by blood banks) was based only on availability at the time. The outcomes were haemoglobin recovery at 8 h and 180 days, requirement for retransfusion, length of hospital stay, changes in heart and respiratory rates until day 180, and the main clinical endpoints (mortality until day 28 and day 180, and readmission until day 180), measured using multivariate regression models. Findings Between Sept 17, 2014, and May 15, 2017, 3199 children with severe anaemia were enrolled into the TRACT trial. 3188 children were considered in our secondary analysis. The median age was 37 months (IQR 18–64). Whole blood was the first pack provided for 1632 (41%) of 3992 transfusions. Haemoglobin recovery at 8 h was significantly lower in those who received packed cells or settled cells than those who received whole blood, with a mean of 1·4 g/dL (95% CI –1·6 to –1·1) in children who received 30 mL/kg and –1·3 g/dL (–1·5 to –1·0) in those who received 20 mL/kg packed cells versus whole blood, and –1·5 g/dL (–1·7 to –1·3) in those who received 30 mL/kg and –1·0 g/dL (–1·2 to –0·9) in those who received 20 mL/kg settled cells versus whole blood (overall p<0·0001). Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion (odds ratio 2·32 [95% CI 1·30 to 4·12] for packed cells and 2·97 [2·18 to 4·05] for settled cells; p<0·001) and longer hospital stays (hazard ratio 0·94 [95% CI 0·81 to 1·10] for packed cells and 0·86 [0·79 to 0·94] for settled cells; p=0·0024). There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause. 823 (26%) of 3188 children presented with severe tachycardia and 2077 (65%) with tachypnoea, but these complications resolved over time. No child developed features of confirmed cardiopulmonary overload. Interpretation Our study suggests that the use of packed or settled cells rather than whole blood leads to additional transfusions, increasing the use of a scarce resource in most of sub-Saharan Africa. These findings have substantial cost implications for blood transfusion and health services. Nevertheless, a clinical trial comparing whole blood transfusion with red cell concentrates might be needed to inform policy makers.

Browsing by Author "Gibb, Diana M."

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