Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV.

Background: Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment.

Methods: We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.

Clinical Subphenotypes of Staphylococcus aureus Bacteremia.

Background: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.

When should factorial designs be used for late-phase randomised controlled trials?

Background: A 2×2 factorial design evaluates two interventions (A versus control and B versus control) by randomising to control, A-only, B-only or both A and B together. Extended factorial designs are also possible (e.g.

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.

Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial.

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.

Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19 June to 28 October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

Objective: To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa.

Design: Longitudinal cohort study.

Methods: In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.

Predictors of recurrence, early treatment failure and death from Staphylococcus aureus bacteraemia: Observational analyses within the ARREST trial.

Objectives: Adjunctive rifampicin did not reduce failure/recurrence/death as a composite endpoint in the ARREST trial of Staphylococcus aureus bacteraemia, but did reduce recurrences. We investigated clinically-defined 14-day treatment failure, and recurrence and S. aureus-attributed/unattributed mortality by 12-weeks to further define their predictors.

Inflammatory biomarkers in HIV-infected children hospitalized for severe malnutrition in Uganda and Zimbabwe.

Objectives: A proportion of HIV-infected children with advanced disease develop severe malnutrition soon after antiretroviral therapy (ART) initiation. We tested the hypothesis that systemic inflammation underlies the pathogenesis of severe malnutrition in HIV-infected children.

Design: Cross-sectional laboratory substudy in 613 HIV-infected children initiating ART in Uganda and Zimbabwe.

Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation.

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue ( = 144) versus stop ( = 149) cotrimoxazole.

Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial.

Background: In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

Background: bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death.

Objectives: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation.

Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial.

Background: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.

Methods: We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe.

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

Background: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

Background: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

Methods: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals.

Virological response and resistance among HIV-infected children receiving long-term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: Observational analyses within the randomised ARROW trial.

Background: Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring.

Methods And Findings: In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART.

Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

Background: Poorer virologic response to nevirapine- versus efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies.

Methods: 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 versus 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.

Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy.

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.

Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.

Objectives: To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response.

Design: Observational analysis within the ARROW randomized trial.

Methods: sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART.

Pubertal development in HIV-infected African children on first-line antiretroviral therapy.

Objectives: To estimate age at attaining Tanner stages in Ugandan/Zimbabwean HIV-infected children initiating antiretroviral therapy (ART) in older childhood and investigate predictors of delayed puberty, particularly age at ART initiation.

Design: Observational analysis within a randomized trial.

Methods: Tanner staging was assessed every 24 weeks from 10 years of age, menarche every 12 weeks and height every 4-6 weeks.

Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results.

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy.