Early Antiretroviral Therapy reduces the incidence of otorrhea in a randomized study of early and deferred antiretroviral therapy: Evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study

<p>Abstract</p> <p>Background</p> <p>Although otorrhea occurs commonly in HIV-infected infants, there are few data. We compared the incidence of otorrhea in infants receiving early vs deferred ART in the Children with HIV Early Antiretroviral (CHER) trial. Infants aged 6 to 12 weeks of age with confirmed HIV infection and a CD4 percentage greater than or equal to 25% were randomized to early or deferred ART at two sites in South Africa. Medical records from one study site were reviewed for otorrhea.</p> <p>Findings</p> <p>Data were reviewed from the start of the trial in July 2005 until 20 June 2007, when the Data Safety Monitoring Board recommended that randomization to the deferred arm should stop and that all infants in this arm be reviewed for commencing antiretroviral therapy. Infants entered the study at a median of 7.4 weeks of age. Eleven of 38 (29%) on deferred therapy and 7 of 75 (9%) in the early-therapy group developed otorrhea (risk ratio 3.1, 95% confidence interval (CI) 1.31-7.36; p = 0.01).</p> <p>Conclusions</p> <p>Early initiation of antiretroviral therapy is associated with significantly less otorrhea than when a deferred strategy is followed.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00102960">NCT00102960</a>. ClinicalTrials.Gov</p

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Factors influencing patient falls in a private hospital group in the Cape Metropole of the Western Cape

CITATION: Van Rensburg, R. J., Van Der Merwe, A. & Crowley, T. 2020. Factors influencing patient falls in a private hospital group in the Cape Metropole of the Western Cape. Health SA Gesondheid, 25:a1392, doi:10.4102/hsag.v25i0.1392.The original publication is available at https://hsag.co.za/index.php/hsagPublication of this article was funded by the Stellenbosch University Open Access FundBackground: The fall rate of patients in hospitals is a worldwide concern due to the impact falls have on patients, the family or relatives, as well as the healthcare setting. Factors influencing patient falls are categorised as intrinsic and extrinsic. Intrinsic factors refers to physical conditions and the extrinsic factors include the environment of the patient, nursing staffing levels and skill mix. Aim: The study aimed to determine the factors that influence patient falls. Setting: A private hospital group in the Cape Metropole of the Western Cape. Methods: A quantitative retrospective descriptive research approach was used by analysing 134 records of patients that have fallen from October 2016 to February 2018. Data was collected using a data extraction sheet and analysed using the Statistical Package for the Social Sciences (SPSS). Results: Intrinsic factors contributing to patient falls includedthe patient’s age, hypertension, co-morbidities and the use of benzodiazepines as a sedative. Extrinsic factors were the incorrect use of bed rails and the skill mix of the staff. In over half of the cases (n = 68; 50.7%), risk assessments were not performed according to the protocol. Only 5 (3.7%) patients sustained major injuries due to the falls. However, the risk of more severe falls increased 2.4 times with the lack of risk assessment. Conclusion: The lack of accurate and consistent patient fall risk assessments, use of benzodiazepines as a sedative and the staff skill mix were contributors to the fall rate in these hospitals.https://hsag.co.za/index.php/hsag/article/view/1392Publisher's versio

The importance of psychological characteristics in potentially talented adolescent long distance runners

Long distance running is a moderate to high-power activity supported by aerobic energy (Ward-Smith, 1999). Apart from the importance of aerobic conditioning, long distance running requires a great deal of mental toughness. The purpose of this study was to compare talented, with less talented distance runners, in order to identify the psychological characteristics exhibited by talented distance runners. A cross-sectional study design was used which consisted of 182 grade 8 pupils: 87 boys and 95 girls. Sport psychological skill levels were measured with the Athletic Copings Skills Inventory (ACSI-28). The Australian Talent Search Protocol was used to identify general sporting talent. The results of the beep test were used to identify the most talented potential distance runners. The top 30% (n=58) of the adolescents were assigned to group 1 (talented group) and the remaining adolescents to group 2 (n=107) (less talented). The results revealed that the talented group obtained significantly better results in 6 of the 8 variables which included adversity, pressure, goal-setting, concentration, coachability and the average coping ability (p<0.05). Moderate practical significance was found in 7 of the 8 variables which included adversity, pressure, goal-setting, concentration, confidence, coachability and coping ability, and a small practical significance was indicated for worry. It is therefore, important to consider psychological skill development in young long distance athletes to enhance their athletic performance

Neurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life

CITATION: Laughton, B. et al. 2019. Neurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life. Southern African Journal of HIV Medicine, 20(1):a1008, doi:10.4102/sajhivmed.v20i1.1008.The original publication is available at https://sajhivmed.org.zaBackground: Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described. Objectives: We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life. Method: Participants were enrolled from the public sector birth HIV-diagnosis programme. Inclusion criteria included the following: birth weight > 2000 g, infant commencing ART < 6 weeks and no infant cytomegalovirus disease. Antiretroviral therapy included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight > 3 kg and gestational age > 44 weeks, Abacavir replaced Zidovudine. The Griffiths mental development scales (GMDS) were administered at 10–12 months. Results: Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501 g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 h of birth. Median [interquartile range] viral load (VL) at diagnosis was 3904 [259–16 922] copies/mL, age starting ART was 6.0 [3–10] days and age at VL suppression was 19.1 [15–36] weeks. At the GMDS assessment, nine (31%) participants had detectable VL and 26 (90%) had World Health Organization (WHO) clinical stage I disease. The GMDS was performed at a mean age of 11.5 ± 0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6 ± 10.9 and mean quotients on the subscales ranged from lowest 95.9 ± 13.4 for locomotor to highest 112.8 ± 11.3 for hearing-and-language. Conclusion: Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV infection who started ART at a median of 6 days.Publisher's versio

Early severe HIV disease precedes early antiretroviral therapy in infants: Are we too late?

Objective: To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa. Design: This was a programmatic cohort study. Methods: Electronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t-test and Kaplan–Meier methods. Results: A total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2–9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% <25% or absolute CD4<1500 cells/mm3 or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2–11.9) weeks in Cape Town and 8.6 (IQR: 7.7–10.0) weeks in Soweto infants (p<0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (p<0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36–0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05–2.71). Conclusions: ART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality

Adjunctive Thalidomide Therapy of Childhood Tuberculous Meningitis: Possible Anti-Inflammatory Role

The objective of this study was to determine the safety and tolerability of the immunomodulatory agent thalidomide as adjunct therapy in children with tuberculous meningitis. Children with stage 2 tuberculous meningitis received oral thalidomide for 28 days in a dose-escalating study, in addition to standard four-drug antituberculosis therapy, corticosteroids, and specific treatment of complications such as raised intracranial pressure. Clinical and laboratory evaluations were carried out. Fifteen patients (median age, 34 months) were enrolled. Thalidomide was administered via nasogastric tube in a dosage of 6 mg/kg/day, 12 mg/kg/day, or 24 mg/kg/day. The only adverse events possibly related to the study drug were transient skin rashes in two patients. Levels of tumor necrosis factor-α in the cerebrospinal fluid decreased markedly during thalidomide therapy. Clinical outcome and neurologic imaging showed greater improvement than that experienced with historical controls. Thalidomide appeared safe and well tolerated in children with stage 2 tuberculous meningitis and could have important anti-inflammatory effects. These promising results have led us to embark on a randomized, double-blind, placebo-controlled trial of the efficacy of thalidomide in tuberculous meningitis. (J Child Neurol 2000;15:497-503)