Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study.

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

Leukemic histiocytic sarcoma in a captive common squirrel monkey (Saimiri sciureus) with Saimiriine Gammaherpesvirus 2 (Rhadinovirus), Saimiri sciureus lymphocryptovirus 2 (Lymphocryptovirus) and Squirrel monkey retrovirus (ß-Retrovirus) coinfection.

Hematopoietic neoplasia other than lymphoma and leukemia is uncommon among non-human primates. Herein, we provide the first evidence of occurrence of leukemic histiocytic sarcoma in a captive common squirrel monkey with Saimiriine Gammaherpesvirus 2 (Rhadinovirus), Saimiri sciureus lymphocryptovirus 2 (Lymphocryptovirus), and Squirrel monkey retrovirus (ß-Retrovirus) coinfection.

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women.

AIMS: This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive (OC) in healthy women. METHODS: In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1-10 alone and with oral CAB 30 mg once daily Days 11-21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. RESULTS: Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07-1.18) and 1.05 (0.96-1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97-1.08) and 0.92 (0.83-1.03), respectively. Steady-state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. CONCLUSIONS: Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.

The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

No clinically significant pharmacokinetic interactions between dolutegravir and daclatasvir in healthy adult subjects.

BACKGROUND: Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. METHODS: To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days. RESULTS: The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively. CONCLUSIONS: DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment. TRIAL REGISTRATION: Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.

The time course of resolution of adhesions during fibrinolytic therapy in tetracycline-induced pleural injury in rabbits.

The time required for the effective clearance of pleural adhesions/organization after intrapleural fibrinolytic therapy (IPFT) is unknown. Chest ultrasonography and computed tomography (CT) were used to assess the efficacy of IPFT in a rabbit model of tetracycline-induced pleural injury, treated with single-chain (sc) urokinase plasminogen activators (scuPAs) or tissue PAs (sctPA). IPFT with sctPA (0.145 mg/kg; n = 10) and scuPA (0.5 mg/kg; n = 12) was monitored by serial ultrasonography alone (n = 12) or alongside CT scanning (n = 10). IPFT efficacy was assessed with gross lung injury scores (GLIS) and ultrasonography scores (USS). Pleural fluids withdrawn at 0-240 min and 24 h after IPFT were assayed for PA and fibrinolytic activities, α-macroglobulin/fibrinolysin complexes, and active PA inhibitor 1 (PAI-1). scuPA and sctPA generated comparable steady-state fibrinolytic activities by 20 min. PA activity in the scuPA group decreased slower than the sctPA group (kobs = 0.016 and 0.042 min(-1)). Significant amounts of bioactive uPA/α-macroglobulin (but not tPA; P < 0.05) complexes accumulated at 0-40 min after IPFT. Despite the differences in intrapleural processing, IPFT with either fibrinolysin was effective (GLIS ≤ 10) in animals imaged with ultrasonography only. USS correlated well with postmortem GLIS (r(2) = 0.85) and confirmed relatively slow intrapleural fibrinolysis after IPFT, which coincided with effective clearance of adhesions/organization at 4-8 h. CT scanning was associated with less effective (GLIS > 10) IPFT and higher levels of active PAI-1 at 24 h following therapy. We concluded that intrapleural fibrinolysis in tetracycline-induced pleural injury in rabbits is relatively slow (4-8 h). In CT-scanned animals, elevated PAI-1 activity (possibly radiation induced) reduced the efficacy of IPFT, buttressing the major impact of active PAI-1 on IPFT outcomes.

Establishment of biochemistry reference values for healthy Tanzanian infants, children and adolescents in Kilimanjaro Region.

OBJECTIVE: To establish common biochemistry reference intervals for Tanzanian infants, children and adolescents living in the Kilimanjaro Region. METHODS: We recruited healthy, HIV-uninfected Tanzanian infants, children and youth between the ages of 1 month and 17 years from local schools and clinics to participate in this study. Only afebrile children without signs of physical or chronic illness were enrolled. Nonparametric methods were used to determine 95% reference limits and their 90% confidence intervals, with outliers removed by the Tukey method. RESULTS: A total of 619 healthy infants, children and adolescents were enrolled into the study. Twenty-three biochemistry parameters were measured. Compared to US reference intervals, several of the biochemistry parameters showed notable differences, namely alkaline phosphatase, phosphorus, amylase and lipase. Comparing our data to the US National Institutes of Health (NIH) Division of AIDS (DAIDS) grading criteria for classification of adverse events, we found that for selected parameters, up to 15% of infants or children in certain age groups would have been categorised as having an adverse event as defined by DAIDS. CONCLUSIONS: Our study further confirms the need to use locally established reference intervals to define reference laboratory parameters among children in Africa, rather than relying on those derived from US or European populations. To our knowledge, this study provides the first set of locally validated biochemistry reference ranges for a paediatric population in Tanzania.

Advancing Research and Development of Anti-infectives for Children: A Clinical Development Perspective.

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programs, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged <4 weeks). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarize challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.

A Model-Based Approach Supporting Abacavir/Dolutegravir/Lamivudine Fixed-Dose Combination Approval in Children Living with HIV-1.

In March 2022, the US Food and Drug Administration expanded indications of TRIUMEQ, a once-daily fixed-dose combination (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) to include pediatric patients weighing at least 10 kg for the treatment of HIV-1. Prior to this extension, the ABC 600 mg/DTG 50 mg/3TC 300 mg FDC tablet was approved for use only in the adult/adolescent population, weighing ≥40 kg while each component of the FDC was approved for its use in pediatric patients at least 3 months and older. A new child-friendly formulation was developed as an FDC dispersible tablet (DT) of ABC 60 mg/DTG 5 mg/3TC 30 mg for pediatric patients with a body weight ≥ 6 kg. The present work demonstrates the utility of applying a model-informed drug development (MIDD) approach to expedite ABC/DTG/3TC FDC approval for pediatric patients (≥10 to <40 kg) based on data from the existing individual components and formulation bridging. Population pharmacokinetic models developed for pediatric participants across all three components of ABC/DTG/3TC FDC were employed for exposure prediction and incorporated relative bioavailability data. The predicted plasma exposures of ABC, DTG, and 3TC for FDC doses were consistent with those observed for the single entities in pediatric and adult studies. Thus, safety and efficacy observed in the individual component studies could be adequately extrapolated to the FDC that results in similar exposure. The current work demonstrates the significance of MIDD approaches in facilitating expedited access to child-friendly formulations in the HIV-1 therapeutic area.

Bridging dolutegravir clinical viral response across doses and formulations using model-based exposure-response analysis in pediatrics.

OBJECTIVE: Dolutegravir (DTG) is a once-daily HIV-1 integrase inhibitor approved for the treatment of HIV-1 infection in adults and children from 4 weeks of age. The posology of DTG in children has been driven by exposure-matching relative to the adult dose for efficacy and safety. However, higher variability in pediatric exposures raises concern that efficacy may not be reliably extrapolated from adult trials. Therefore, we evaluated the relationship between DTG exposure and virologic response in children. DESIGN/METHODS: A population exposure-response analysis using logistic regression for virologic response was undertaken based on DTG exposure and covariate data from 146 pediatric participants with HIV-1 from age at least 4 weeks to less than 18 years treated for up to 48 weeks with DTG in IMPAACT P1093 study. RESULTS: None of the DTG exposure metrics were predictive of virologic response over the range of exposures in this analysis. Of the covariates tested, viral load at least 100 000 copies/ml at enrolment was a significant predictor of virologic response showing a lower probability of achieving a virologic response of HIV-1 RNA less than 50 copies/ml compared with participants with viral load less than 100 000 copies/ml at enrolment. Baseline viral load was also a significant predictor at week 48 whereby the probability of achieving a virologic response at week 48 decreased with increasing baseline viral load. CONCLUSION: This exposure-response analysis suggests that DTG exposures in children are all above the plateau of the exposure-response relationship. These results suggest that matching pediatric pharmacokinetic exposure parameters to those in adults is a reasonable approach for dose determination of DTG-containing formulations in pediatrics.

Effect of Food on the Pediatric Dispersible Tablet Formulations of TRIUMEQ and DOVATO in Healthy Adult Participants.

This randomized food effect study in healthy adult participants examined dispersible tablet formulations of fixed-dose combinations of dolutegravir/abacavir/lamivudine (TRIUMEQ) and dolutegravir/lamivudine (DOVATO). While adult tablet formulations of these combinations are currently approved for the treatment of human immunodeficiency virus, alternate formulations for children are urgently needed to facilitate appropriate pediatric dosing for patients who may have difficulty swallowing a conventional tablet. This study compared the effect of a high-fat, high-calorie meal on the pharmacokinetics, safety, and tolerability of dispersible tablet (DT) formulations of the two-drug and three-drug regimens, with administration under fasting conditions. Both the two-drug and three-drug dispersible tablet formulations, administered under fasting conditions and following a high-fat, high-calorie meal, were well tolerated in healthy participants. There were no clinically relevant differences in drug exposure for either regimen when administered with a high-fat meal as compared to under fasting conditions. Safety observations were similar for both treatments, either in the fed or fasted state. Both TRIUMEQ DT and DOVATO DT formulations can be administer with or without food.

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents.

BACKGROUND AND OBJECTIVE: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. METHODS: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. RESULTS: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. CONCLUSIONS: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.

Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation study.

BACKGROUND: Child-friendly fixed-dose combination (FDC) antiretroviral therapy (ART) options are limited. We evaluated the pharmacokinetics, safety, and tolerability of dispersible and immediate-release FDC abacavir, dolutegravir, and lamivudine taken once per day in children younger than 12 years with HIV. METHODS: IMPAACT 2019 was an international, phase 1-2, multisite, open-label, non-comparative dose-confirmation study of abacavir, dolutegravir, and lamivudine in children younger than 12 years. Participants were enrolled across five weight bands: those weighing 6 kg to less than 25 kg received abacavir (60 mg), dolutegravir (5 mg), and lamivudine (30 mg) dispersible tablets (three to six tablets depending on body weight), and those weighing 25 kg to less than 40 kg received abacavir (600 mg), dolutegravir (50 mg), and lamivudine (300 mg) in an immediate-release tablet. At entry, participants were ART naive or ART experienced and virologically suppressed on stable ART for 6 months or more. Dose confirmation was based on pharmacokinetic and safety criteria in the first five to seven participants in each weight band to week 4; all participants were followed up to week 48. We present the results for the primary objectives to assess pharmacokinetics, confirm dosing, and evaluate safety through 24 weeks across all weight bands. The trial is registered with ClinicalTrials.gov (NCT03760458). FINDINGS: 57 children were enrolled and initiated study drug (26 [46%] female and 31 [54%] male; 37 [65%] Black, 18 [32%] Asian, and 1 [2%] had race reported as unknown). Within each weight band, 6 kg to less than 10 kg, 10 kg to less than 14 kg, 14 kg to less than 20 kg, 20 kg to less than 25 kg, and 25 kg or higher: the geometric mean dolutegravir area under the concentration time curve over the 24 h dosing interval (AUC0-24 h) was 75·9 h·µg/mL (33·7%), 91·0 h·µg/mL (36·5%), 71·4 h·µg/mL (23·5%), 84·4 h·µg/mL (26·3%), and 71·8 h·µg/mL (13·9%); dolutegravir concentrations 24 h after dosage (C24 h) were 0·91 µg/mL (67·6%), 1·22 µg/mL (77·5%), 0·79 µg/mL (44·2%), 1·35 µg/mL (95·5%), and 0·98 µg/mL (27·9%); abacavir AUC0-24 h was 17·7 h·µg/mL (38·8%), 19·8 h·µg/mL (50·6%), 15·1 h·µg/mL (40·3%), 17·4 h·µg/mL (19·4%), and 25·7 h·µg/mL (14·6%); lamivudine AUC0-24 h was 10·7 h·µg/mL (46·0%), 14·2 h·µg/mL (23·9%), 13·0 h·µg/mL (15·6%), 14·5 h·µg/mL (16·6%), and 21·7 h·µg/mL (26·2%), respectively. Pharmacokinetic targets and safety criteria were met within each weight band, and thus dosing of abacavir, dolutegravir, and lamivudine was confirmed at the originally selected doses. 54 (95%) of participants were treatment experienced and all who continued taking the study drug remained virologically suppressed (<200 copies per mL) through week 24. Virological suppression was achieved in two of three participants who were ART naive by week 24. There were no grade 3 or higher adverse events related to abacavir, dolutegravir, and lamivudine and no discontinuations because of toxicity to week 24. Both formulations were well tolerated. INTERPRETATION: Dosing of abacavir, dolutegravir, and lamivudine was confirmed in children weighing 6 kg to less than 40 kg, and both FDC formulations were safe, well tolerated, and efficacious through 24 weeks of treatment. These findings support global efforts to expand the availability of FDC abacavir, dolutegravir, and lamivudine to children with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, ViiV Healthcare, and GlaxoSmithKline.

Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children.

BACKGROUND: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS: The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS: As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS: These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial.

BACKGROUND: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing. FINDINGS: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir. INTERPRETATION: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.

Advances and failures in preventing perinatal human immunodeficiency virus infection.

An estimated 2.5 million children are currently living with HIV, the vast majority as a result of mother-to-child transmission. Prevention of perinatal HIV infection has been immensely successful in developed countries. A comprehensive package of services, including maternal and infant antiretroviral therapy, elective cesarean section, and avoidance of breast-feeding, has resulted in transmission rates of less than 2%. However, in developing countries, access to such services is often not available, as demonstrated by the fact that the vast majority of children with HIV live in Africa. Over the past few years, many developing nations have made great strides in improving access to much-needed services. Notably, in eastern and southern Africa, the regions most affected by HIV, mother-to-child-transmission coverage rates for HIV-positive women increased from 11% in 2004 to 31% in 2006. These successes are deserving of recognition, while not losing sight of the fact that much remains to be done; currently, an estimated 75% of pregnant women worldwide have an unmet need for antiretroviral therapy. Further work is needed to determine the optimal strategy for reducing perinatal transmission among women in resource-poor settings, with a particular need for reduction of transmission via breast-feeding.

Presumptive Primary Cerebral T-Cell Lymphoma in a White-Tailed Deer (Odocoileus virginianus).

Primary central nervous system (CNS) lymphomas are rare in humans and even more uncommon in animals. We report the clinical, pathological and immunohistochemical features of a presumptive primary cerebral T-cell lymphoma (PCTCL) in an aged female white-tailed deer (Odocoileus virginianus) that had chronic progressive neurological disease characterized by ataxia, claudication and eventual circling. The animal was euthanized due to poor prognosis. Grossly, a 2.5 cm dark red, friable nodule effaced the cortical neuroparenchyma of the left anterior cingulate cortex (LACC). Microscopically, the meningeal vasculature and adjacent grey and white matter cortical neuroparenchyma of the LACC were infiltrated by a poorly demarcated, unencapsulated and densely cellular round cell neoplasm with a consistent angiocentric pattern. The neoplasm was associated with extensive regions of haemorrhage and liquefactive necrosis. Neoplastic cells immunolabelled for CD3 antigen and had high proliferative activity, as indicated by Ki-67 labelling. Based on the cytohistomorphological and immunohistochemical features and absence of metastasis, a diagnosis of PCTCL was determined. This case indicates that PCTCL should be considered in the differential diagnosis of neurological disease and intracranial, intra-axial CNS masses in deer.

Precision targeting of the plasminogen activator inhibitor-1 mechanism increases efficacy of fibrinolytic therapy in empyema.

Plasminogen activator inhibitor-1 (PAI-1) is an endogenous irreversible inhibitor of tissue-type (tPA) and urokinase (uPA) plasminogen activators. PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) is designed to decrease the therapeutic dose of tPA and uPA, attenuating the risk of bleeding and other complications. Docking site peptide (DSP) mimics the part of the PAI-1 reactive center loop that interacts with plasminogen activators, thereby affecting the PAI-1 mechanism. We used DSP for PAI-1-TFT in two rabbit models: chemically induced pleural injury and Streptococcus pneumoniae induced empyema. These models feature different levels of inflammation and PAI-1 expression. PAI-1-TFT with DSP (2.0 mg/kg) converted ineffective doses of single chain (sc) tPA (72.5 µg/kg) and scuPA (62.5 µg/kg) into effective ones in chemically induced pleural injury. DSP (2.0 mg/kg) was ineffective in S. pneumoniae empyema, where the level of PAI-1 is an order of magnitude higher. DSP dose escalation to 8.0 mg/kg resulted in effective PAI-1-TFT with 0.25 mg/kg sctPA (1/8th of the effective dose of sctPA alone) in empyema. There was no increase in the efficacy of scuPA. PAI-1-TFT with DSP increases the efficacy of fibrinolytic therapy up to 8-fold in chemically induced (sctPA and scuPA) and infectious (sctPA) pleural injury in rabbits. PAI-1 is a valid molecular target in our model of S. pneumoniae empyema in rabbits, which closely recapitulates key characteristics of empyema in humans. Low-dose PAI-1-TFT is a novel interventional strategy that offers the potential to improve fibrinolytic therapy for empyema in clinical practice.

Establishment of haematological and immunological reference values for healthy Tanzanian children in Kilimanjaro Region.

OBJECTIVE: To determine the normal haematological and immunological reference intervals for healthy Tanzanian children. METHODS: We analysed data from 655 HIV-seronegative, healthy children from 1 month to 18 years of age from the Kilimanjaro Region of Tanzania for this cross-sectional study. Median and 95% reference ranges were determined for haematological and immunological parameters and analysed by age cohorts, and by gender for adolescents. RESULTS: Median haemoglobin (Hb) and haematocrit (Hct) for all age groups were higher than established East African reference intervals. Compared to U.S. intervals, reference ranges encompassed lower values for Hb, Hct, mean corpuscular volume, and platelets. Applying the U.S. National Institute of Health Division of AIDS (DAIDS) adverse event grading criteria commonly used in clinical trials to the reference range participants, 128 (21%) of 619 children would be classified as having an adverse event related to Hb level. CD4-positive T-lymphocyte absolute counts declined significantly with increasing age (P < 0.0001). For those aged under five years, CD4-positive T-lymphocyte percentages are lower than established developed country medians. CONCLUSIONS: Country-specific reference ranges are needed for defining normal laboratory parameters among children in Africa. Knowledge of appropriate reference intervals is critical not only for providing optimal clinical care, but also for enrolling children in medical research. Knowledge of normal CD4-positive T-lymphocyte parameters in this population is especially important for guiding the practice of HIV medicine in Tanzania.

Adverse life events, area socio-economic disadvantage, and adolescent psychopathology: The role of closeness to grandparents in moderating the effect of contextual stress.

The study, using data from 801 11-16-year-olds clustered in 68 schools across England and Wales, tested whether closeness to grandparents moderates the association between contextual stress and adolescent psychopathology and prosocial behavior, measured with the strengths and difficulties questionnaire (SDQ). Contextual stress was measured at both school area level (assessed with the index of multiple deprivation) and child level (assessed, as life stress, with the number of proximal and distal adverse life events experienced). At baseline, area stress (multiple deprivation) was unrelated to psychopathology (SDQ), and although both proximal (during the last 12 months) and distal (before the last 12 months) life stress was associated with broad and specific child psychopathology, the association with proximal life stress was stronger. Closeness to the most significant grandparent moderated both the effect of proximal life stress on hyperactivity and broad psychopathology, and the effect of the interaction between distal and proximal life stress on broad and externalizing psychopathology. These findings suggest that the role of grandparents deserves further attention in future investigations of the development of resilience in youth.