Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial.

BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. CONCLUSIONS: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study.

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

Cultural Adaption, Translation, Preliminary Reliability and Validity of Key Psychological and Behavioural Measures for 18 to 25 Year-Olds Living with HIV in Uganda: A Multi-Stage Approach.

HIV remains a significant public health issue among young adults living in Uganda. There is a need for reliable and valid measures of key psychological and behavioural constructs that are related to important outcomes for this population. We translated, adapted and tested the psychometric properties of questionnaires measuring HIV stigma, HIV disclosure cognitions and affect, antiretroviral therapy (ART) adherence, social support, personal values, and hope, using a multi-step process. This included: translation, back-translation, expert review, cognitive interviewing, readability and assessments of internal consistency with 93 young adults (18-25 years) living with perinatally acquired HIV in Uganda. Preliminary criterion validity was assessed by examining relationships between the adapted measures and wellbeing, HIV disclosure behaviour, HIV disclosure intention and viral load suppression. The measures all showed acceptable reliability and every questionnaire apart from the Agentic and Communal Value Scale was easy to read. Those scales measuring HIV disclosure affect and cognitions, social support, HIV stigma and hope showed relationships with other constructs suggestive of validity. There is preliminary evidence to support the use of these measures in research and clinical contexts for young adults living with perinatally acquired HIV in Uganda.

The HIV Empowering Adults' Decisions to Share: UK/Uganda (HEADS-UP) Study-A Randomised Feasibility Trial of an HIV Disclosure Intervention for Young Adults with Perinatally Acquired HIV.

Young adults with perinatally acquired HIV (PAH) face numerous challenges, including antiretroviral therapy (ART) adherence, managing onward HIV transmission risks and maintaining wellbeing. Sharing one's HIV status with others (onward HIV disclosure) may assist with these challenges but this is difficult. We developed and tested the feasibility of an intervention to help HIV status sharing decision-making for young adults with PAH. The study used a randomised parallel group feasibility design with 18-25-year-olds in Uganda and 18-29 year-olds in the UK. Participants were randomly assigned to intervention or standard of care (SOC) condition. The intervention consisted of four sessions (3 group, 1 individual) with follow-up support, delivered in person in Uganda and remotely in the UK. Assessments were carried out at: Pre-intervention /baseline; Post-intervention (intervention group only); Six-month follow-up. 142 participants were recruited (94 Uganda, 48 UK; 89 female, 53 male). At six-month follow-up, 92/94 (98%) participants were retained in Uganda, 25/48 (52%) in the UK. Multivariate analysis of combined data from both countries, showed a non-significant effect of intervention condition on HIV disclosure cognitions and affect (p = 0.08) and HIV disclosure intention (p = 0.09). There was a significant intervention effect on well-being (p = 0.005). This study addressed important gaps in understanding acceptable and feasible ways of delivering HIV status sharing support for young people living with PAH across two very different settings. The intervention was acceptable in both countries and feasible in Uganda. In the UK, retention may have been affected by its remote delivery.Trial registration: ISRCTN Registry, ISRCTN31852047, Registered on 21 January 2019.

Longitudinal Changes in Subclinical Vascular Disease in Ugandan Youth With Human Immunodeficiency Virus.

BACKGROUND: Prospective investigations on the risk of cardiovascular disease among youth with perinatally acquired human immunodeficiency virus (PHIV) in sub-Saharan Africa are lacking. METHODS: A prospective observational cohort study was performed in 101 youth (aged 10-18 years) with PHIV and 97 who were human immunodeficiency virus (HIV) uninfected (HIV-), from 2017 to 2021 at the Joint Clinical Research Center in Uganda. Participants with PHIV were receiving antiretroviral therapy (ART) and had HIV-1 RNA levels ≤400 copies/mL. The common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and at 96 weeks. Groups were compared using unpaired t-test, and potential predictors of IMT and PWV were assessed using quantile regression. RESULTS: Of the 198 participants recruited at baseline, 168 (89 with PHIV, 79 HIV-) had measurements at 96 weeks. The median age (interquartile range) age was 13 (11-15) years; 52% were female, and 85% had viral loads <50 copies/mL that remained undetectable at week 96. The baseline mean common carotid artery IMT was slightly higher in participants with PHIV compared with controls (P < .01), and PWV did not differ between groups (P = .08). At week 96, IMT decreased and PWV increased in the PHIV group (P ≤ .03); IMT increased in the HIV- group (P = .03), with no change in PWV (P = .92). In longitudinal analyses in those with PHIV, longer ART duration was associated with lower PWV (ß = .008 [95% confidence interval, -.008 to .003]), and abacavir use with greater IMT (ß = .043 [.012-.074]). CONCLUSIONS: In healthy Ugandan youth with PHIV, virally suppressed by ART, the common carotid artery IMT did not progress over 2 years. Prolonged and early ART may prevent progression of subclinical vascular disease, while prolonged use of abacavir may increase it.

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial.

BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration-time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.

First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial.

BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075.

Prevalence of neuropsychiatric adverse events and associated factors among adult patients on dolutegravir attending Mulago ISS clinic.

INTRODUCTION: Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor that is recommended by the World Health Organization as the preferred first-line and second-line antiretroviral therapy (ART) in patients with HIV. In 2018, Uganda started using DTG-based regimens as the preferred first-line ART. However, concerns regarding the potential neurotoxicity of DTG have been increasing. Data on the occurrence of neuropsychiatric adverse events (NPAEs) and the associated factors among adult patients who are initiated on or switched to DTG-based first-line or second-line ART in Uganda are limited. OBJECTIVE: This study aimed to determine the prevalence of NPAEs among adult patients on DTG and the factors associated with their occurrence. METHODS: We conducted a cross-sectional study using questionnaires administered by a trained research assistant between 15 November 2021 and 15 December 2021. The study included patients aged ≥18 years with HIV who were either initiated on or switched to a DTG-based ART regimen between 1 January 2018 and 31 October 2021. Informed consent and data were collected from 892 participants attending Mulago ISS clinic, including data on age, sex, marital status, disclosure status, current regimen, duration on ART, concurrent illness, concurrent medications, year of switch to DTG, duration on DTG, whether the onset of NPAEs was immediate or delayed, history of alcohol use or smoking, level of education, report of NPAEs while on DTG, and history of NPAEs while on previous regimen. Data were entered into Epidata version 4.6.0.2 then exported to Stata version 14 for analysis. RESULTS: Of the 892 adults on DTG attending Mulago ISS clinic, 41.7% (95% confidence interval [CI] 38.5%-44.9%) experienced at least one NPAE. DTG duration in years (adjusted prevalence [aPR] = 1.21, p = 0.024), disclosure status (aPR = 1.40, p = 0.042), concurrent medications (aPR = 1.31, p = 0.026), year of switch to DTG, and concurrent illness were associated with an increased occurrence of NPAEs. CONCLUSIONS: The prevalence of NPAEs was higher than that reported by any clinical trial. About 9.1% of participants had experienced severe to life-threatening NPAEs that required intervention from a healthcare professional to improve tolerability. The high prevalence requires that clinicians screen for NPAEs at very visit and reassure patients to maximize the benefits of long-term ART.

Prevalence and factors associated with hypothyroidism in children with sickle cell anemia aged 6 months - 17 years attending the Sickle Cell Clinic, Mulago Hospital, Uganda; a cross-sectional study.

PURPOSE: Hypothyroidism has been reported at a prevalence of 6% in children and adolescents with Sickle cell anemia. In this study, we determined the prevalence and factors associated with hypothyroidism among children with Sickle cell anemia attending the Sickle Cell Clinic, in Mulago hospital, Uganda. METHODS: A cross-sectional study was conducted among children aged 6 months - 17 years with a confirmed diagnosis of Sickle Cell Anemia, with no prior diagnosis of hypothyroidism and in steady state attending the Sickle Cell Clinic in Mulago hospital. Data was collected using a structured questionnaire and a blood sample was used to measure thyroid stimulating hormone and free thyroxine. RESULTS: Of the 332 children enrolled, sixty (18.1%) participants had sub-clinical hypothyroidism (95% CI: 14.3 - 22.6). Factors associated with hypothyroidism included constipation [adjusted odds ratio: 3.1, 95% CI:1.0 - 9.0, p = 0.043] and male sex [adjusted odds ratio:2.0, 95% CI:1.1- 3.5, p = 0.025]. CONCLUSION: Approximately 1 in 5 children (18.1%) had sub-clinical hypothyroidism. Males and children who presented with constipation were more likely to have sub-clinical hypothyroidism.

A retrospective evaluation of the presentation, prognostic factors and outcomes of neuroblastoma in Ugandan children.

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The complete burden and outcomes in Uganda are unknown. The study was a multicenter retrospective chart review of children aged between 0 to 15 years diagnosed with NB from 2010 to 2020. Demographic, clinical and tumor-related characteristics were extracted for analysis. Kaplan-Meier survival curves and Cox regression models were used to determine the one-year overall survival (OS) and identify prognostic factors. Seventy-five patients were evaluated, with a median age at diagnosis of 48 months (IQR 26-108 months). Fever (74.7%), weight loss (74.7%), high blood pressure (70.3%) and abdominal swelling/mass (65.3%) were the most common features at diagnosis. Suprarenal tumors (52%) and stage 4 disease (70.7%) were also common. The one-year OS was 60.0% (95%CI 56.8%; 64.3%) with a median survival time of 12.6 months (95% CI: 8.1; 20.8). The one-year OS for non-metastatic and metastatic disease was 67.3% and 42.6% (p = 0.11) respectively. Leukocytosis (p < 0.001) at diagnosis was of prognostic significance while clinical remission after induction chemotherapy (p < 0.001) provided survival advantages. Children who received maintenance chemotherapy had a longer median survival time of 38.5 months (range 10.8-69.5). Age (p = 0.001), lung metastasis (p < 0.001), and leukocytosis (p < 0.001) remained significant on multivariate analysis. In this Ugandan study, leukocytosis was a clinical predictor of prognosis, metastatic disease had management challenges and maintenance chemotherapy prolonged the survival time but not OS.

Ugandan children diagnosed with neuroblastoma present with advanced disease.Surgery and radiotherapy are under-utilized in the management of neuroblastoma, but have prognostic value in neuroblastoma outcomes.Children under the age of 12 months are under-diagnosed in Uganda, but those that do present for treatment fare poorer than older age groups.The overall survival is poor but the survival time can be increased with maintenance chemotherapy.

Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial.

BACKGROUND: Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. METHODS: We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. RESULTS: The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis. CONCLUSIONS: Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.

Relationship between maternal and/or newborn cholesterol levels and neonatal septicemia: protocol for a Ugandan cohort of mother-newborn pairs.

BACKGROUND: Many aspects of microbial dissemination appear to vary with host cholesterol levels. Since neonatal septicemia remains a leading cause of newborn admissions and mortality in resource-limited settings, the contribution of abnormal cholesterol levels in maternal and/or newborn blood to the risk of neonatal septicemia and outcome requires elucidation. We aim to determine a relationship between maternal serum and neonatal cord blood cholesterol levels and neonatal septicemia. METHODS: This will be a mother-newborn pair cohort study. Approximately 353 pregnant women who are eligible and consent to participate in the study will have blood drawn for a lipid profile. Upon delivery, we will analyse the cord blood cholesterol of their newborns and follow them for 28 days to determine whether the infants develop clinical signs and symptoms suggestive of neonatal septicemia. Relative risk will be used to determine the association between cholesterol and newborn septicemia. Poisson regression will be used to estimate the relative risk (with 95% confidence intervals) of developing septicemia. DISCUSSION: Findings from our study will contribute evidence to support the inclusion of lipid profile screening for pregnant women and newborns. Our study will determine whether newborns with abnormal cholesterol or those born to mothers with abnormal cholesterol will require rigorous follow-up in neonatal clinics.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

Neurocognitive function among HIV-infected children on protease inhibitor -based versus non-protease inhibitor based antiretroviral therapy in Uganda: a pilot study.

BACKGROUND: HIV infection is associated with significant neurocognitive deficits making maximization of cognitive function among children receiving antiretroviral therapy (ART) a public health imperative. Non-protease inhibitors (non-PIs) achieve higher drug levels in the cerebral spinal fluid (CSF) compared to PIs, potentially leading to better neurocognitive function by reducing CSF viral load and inflammation. ART that maximises children's neurodevelopment and school achievement could result in improved quality of life and productivity as adults, but little research to date has examined whether non-PI ART is associated with better neurocognitive outcomes. We compared the neurocognitive function between children living with HIV receiving PI-based and non PI-based ART. METHODS: We recruited a consecutive sample of clinically stable Ugandan children living with HIV aged 5-12 years who received PI-based or non PI-based ART for ≥ 1 year (viral load < 1000 copies). Neurocognitive function was assessed using the Kaufman Assessment Battery for Children, the Test of Variables of Attention, and Bruininks-Oseretsky Test of Motor Proficiency. Age-adjusted neurocognitive z-scores for the two groups were compared using linear regression models in STATA version 13. The Hommel's method was used to adjust for multiple testing. RESULTS: We enrolled 76 children living with HIV; 34 on PI ART and 42 on non-PI ART. Mean (±SD) age was greater in the non-PI vs. PI group (9.5 ± 1.9 vs. 8.5 ± 2.0) years (p = 0.03). Children in the non-PI group had lower socioeconomic scores (5.7 ± 3.3 vs. 7.4 ± 2.8, p = 0.02). There was no difference in neurocognitive function between the groups (adjusted p > 0.05) for KABC and TOVA. Children in the PI group had better total BOT scores than their counterparts (46.07 ± 1.40) vs. 40.51 (1.24), p = 0.03). CONCLUSIONS: We detected no difference in neurocognitive function among children on PI and non PI-based ART therapy based on KABC and TOVA tests. Children on PI based ART had better motor function than their counterparts. We recommend a prospective study with a larger sample size.

Specialty career preferences among final year medical students at Makerere University College of health sciences, Uganda: a mixed methods study.

BACKGROUND: Uganda has an imbalanced distribution of the health workforce, which may be influenced by the specialty career preferences of medical students. In spite of this, there is inadequate literature concerning the factors influencing specialty career preferences. We aimed to determine the specialty career preferences and the factors influencing the preferences among fifth year medical students in the School of Medicine, Makerere University College of Health Sciences (MakCHS). METHODS: A sequential explanatory mixed methods study design with a descriptive cross-sectional study followed by a qualitative study was used. A total of 135 final year medical students in MakCHS were recruited using consecutive sampling. Self-administered questionnaires and three focus group discussions were conducted. Quantitative data was analysed in STATA version 13 (StataCorp, College Station, Tx, USA) using descriptive statistics, chi-square tests and logistic regression. Qualitative data was analysed in NVIVO version 12 (QRS International, Cambridge, MA) using content analysis. RESULTS: Of 135 students 91 (67.4%) were male and their median age was 24 years (IQR: 24, 26). As a first choice, the most preferred specialty career was obstetrics and gynecology (34/135, 25.2%), followed by surgery (27/135, 20.0%), pediatrics (18/135, 13.3%) and internal medicine (17/135, 12.6%). Non-established specialties such as anesthesia and Ear Nose and Throat (ENT) were not selected as a first choice by any student. Female students had 63% less odds of selecting surgical related specialties compared to males (aOR = 0.37, 95%CI: 0.17-0.84). The focus group discussions highlighted controlled lifestyle, assurance of a good life through better financial remuneration and inspirational specialists as facilitators for specialty preference. Bad experience during the clinical rotations, lack of career guidance plus perceived poor and miserable specialists were highlighted as barriers to specialty preference. CONCLUSION: Obstetrics and Gynecology, Surgery, Pediatrics and Internal Medicine are well-established disciplines, which were dominantly preferred. Females were less likely to select surgical disciplines as a career choice. Therefore, there is a need to implement or establish career guidance and mentorship programs to attract students to the neglected disciplines.

Altered Intestinal Permeability and Fungal Translocation in Ugandan Children With Human Immunodeficiency Virus.

BACKGROUND: Children with perinatally acquired human immunodeficiency virus (HIV; PHIVs) face a lifelong cumulative exposure to HIV and antiretroviral therapy (ART). The relationship between gut integrity, microbial translocation, and inflammation in PHIV is poorly understood. METHODS: This is a cross-sectional study in 57 PHIVs, 59 HIV-exposed but uninfected children, and 56 HIV-unexposed and -uninfected children aged 2-10 years old in Uganda. PHIVs were on stable ART with HIV-1 RNA <400 copies/mL. We measured markers of systemic inflammation, monocyte activation, and gut integrity. Kruskal-Wallis tests were used to compare markers by group and the Spearman correlation was used to assess correlations between biomarkers. RESULTS: The mean age of all participants was 7 years and 55% were girls. Among PHIVs, the mean CD4 % was 34%, 93% had a viral load ≤20 copies/mL, and 79% were on a nonnucleoside reverse transcriptase inhibitor regimen. Soluble cluster of differentiation 14 (sCD14), beta-D-glucan (BDG), and zonulin were higher in the PHIV group (P ≤ .01). Intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide binding protein (LBP) did not differ between groups (P > .05). Among PHIVs who were breastfed, levels of sCD163 and interleukin 6 (IL6) were higher than levels in PHIV who were not breastfed (P < .05). Additionally, in PHIVs with a history of breastfeeding, sCD14, BDG, LBP, zonulin, and I-FABP correlated with several markers of systemic inflammation, including high-sensitivity C-reactive protein, IL6, d-dimer, and systemic tumor necrosis factor receptors I and II (P ≤ .05). CONCLUSIONS: Despite viral suppression, PHIVs have evidence of altered gut permeability and fungal translocation. Intestinal damage and the resultant bacterial and fungal translocations in PHIVs may play a role in the persistent inflammation that leads to many end-organ diseases in adults.Despite viral suppression, children with perinatally acquired human immunodeficiency virus (HIV) in Uganda have evidence of alterations in intestinal permeability and fungal translocation, compared to HIV-exposed but uninfected and HIV-unexposed children, which may play a role in HIV-associated chronic inflammation.

Subclinical Vascular Disease in Children With Human Immunodeficiency Virus in Uganda Is Associated With Intestinal Barrier Dysfunction.

BACKGROUND: The risk of cardiovascular disease (CVD) and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied. METHODS: Mean common carotid artery intima-media thickness (IMT) and pulse-wave velocity (PWV) were evaluated in 101 PHIV and 96 HIV-negative (HIV-) children. PHIV were on ART, with HIV-1 RNA levels ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation, oxidized lipids, and gut integrity. RESULTS: Overall median (interquartile range, Q1-Q3) age was 13 (11-15) years and 52% were females. Groups were similar by age, sex, and BMI. Median ART duration was 10 (8-11) years. PHIV had higher waist-hip ratio, triglycerides, and insulin resistance (P ≤ .03). Median IMT was slightly thicker in PHIVs than HIV- children (1.05 vs 1.02 mm for mean IMT and 1.25 vs 1.21 mm for max IMT; P < .05), while PWV did not differ between groups (P = .06). In univariate analyses, lower BMI and oxidized LDL, and higher waist-hip ratio, hsCRP, and zonulin correlated with thicker IMT in PHIV (P ≤ .05). After adjustment for age, BMI, sex, CD4 cell count, triglycerides, and separately adding sCD163, sCD14, and hsCRP, higher levels of intestinal permeability as measured by zonulin remained associated with IMT (ß = 0.03 and 0.02, respectively; P ≤ .03). CONCLUSIONS: Our study shows that African PHIV have evidence of CVD risk and structural vascular changes despite viral suppression. Intestinal intestinal barrier dysfunction may be involved in the pathogenesis of subclinical vascular disease in this population.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa.

BACKGROUND: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. METHODS: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality. RESULTS: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. CONCLUSIONS: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .).

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review.

INTRODUCTION: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. METHODS: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any longer or not including children with HIV/TB co-infection were excluded. All studies were assessed for quality. RESULTS: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted lopinavir/ritonavir (ratio 1:1) resulted in adequate lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only limited PK data of second-line TB drugs with ART in children who are HIV infected have been published. CONCLUSIONS: Whereas integrase inhibitors seem favourable in older children, there are limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.