Background Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. Methods We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly. Results Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. Conclusions The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.)

Objectives We assessed the performance of two new devices (2D- and 3D-Mercy TAPE) to implement the Mercy Method for pediatric weight estimation, and contrasted their accuracy with the Broselow method. Methods We enrolled children 2 months through 16 years of age in this prospective, multi-center, observational study. Height/length, weight, humeral length and mid-upper arm circumference were obtained for each child using calibrated scales and measures. We then made measurements using blinded versions of the 2D- and 3D-TAPEs. Using height/length data, we calculated the weight estimated by the Broselow method. We contrasted measures with mean error, mean percentage error, and percent predicted within 10 and 20% of actual. Results 624 participants (median: 8.4 yr, 27.6 kg, 17.3 kg/m2) completed the study. Mean error (mean percentage error) was 0.3 kg (1.6%), 0.2 kg (1.9%), and −1.3 kg (−4.1%) for 2D, 3D, and Broselow, respectively. Concordance between both TAPE devices and the Mercy Method was >0.99. The proportion of children predicted within 10% and 20% of actual weight was 76% and 98% for the 2D tape, and 65% and 93% for the 3D tape. Excluding the 209 (33%) children who were too tall for the device, Broselow predictions were within 10% and 20% of actual weight in 59% and 91%. Conclusions The 2D- and 3D-Mercy TAPEs outperform the Broselow tape for pediatric weight estimation and can be used in a wider range of children.

Clindamycin is commonly prescribed to treat children with skin and skin structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]), yet little is known about the pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving intravenous clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. Median age (range) was 3.3 years (0–20). Median dosing was 9.9 mg/kg/dose (3.8–15.1). A 1-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (L/h)=13.7*(weight/70)0.75*(PMA3.1/(43.63.1+PMA3.1)); V (L)=61.8*(weight/70). Maturation reached 50% adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Background: Pts with higher-risk MDS and AML need treatment options that provide durable responses with sustained clinical benefit and favorable safety/tolerability. Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors but not on normal hematopoietic stem cells. Sabatolimab + HMA has been shown to deliver promising durable responses in a phase (Ph) Ib study in pts with vHR/HR-MDS or newly diagnosed (ND) AML (Wei et al. EHA 2021; NCT03066648). We report updated data from this study, including new analyses evaluating a potential relationship between immune-mediated effects of sabatolimab and response. Final results with additional follow-up will be reported at the time of presentation. Methods: Eligibility criteria and design of this multicenter, open-label study have been previously reported (Wei et al. EHA 2021). The primary objective was to evaluate safety and tolerability. Preliminary efficacy, a key secondary objective, was assessed with overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) endpoints. Safety and preliminary efficacy are reported for sabatolimab + HMA in pts with vHR/HR-MDS (per IPSS-R) or ND-AML. The proportion of pts who had a possible immune-mediated adverse event (imAE) was evaluated among pts who achieved remission (CR + PR + CRi/mCR) compared with pts that have not achieved remission. The outcomes of pts who received hematopoietic stem cell transplantation (HSCT) after coming off the study were assessed independent of the study by investigators. Results: As of the 15 Jun 2021 data cutoff, 53 pts with vHR/HR-MDS and 48 with ND-AML were treated with sabatolimab + HMA. The combination was safe and well tolerated, with the most common (≥15% in either vHR/HR-MDS or ND-AML) gr ≥3 AEs similar to HMA alone, consisting of thrombocytopenia (43.4%, 45.8%), neutropenia (47.2%, 50.0%), anemia (28.3%, 33.3%), and febrile neutropenia (35.8%, 29.2%), respectively. No pt with vHR/HR-MDS and only 3 with ND-AML discontinued treatment due to an AE regardless of relationship to treatment. In vHR/HR-MDS, 24.5% of pts had improvement allowing them to undergo HSCT. While on study, 6 pts with vHR/HR-MDS and 10 with ND-AML had possible imAEs regardless of relationship to study treatment. Few pts had clinically significant possible imAEs, with no gr ≥3 possible imAEs in pts with vHR/HR-MDS. In ND-AML, 5 pts had gr 3 and none had gr 4/5 possible imAEs. Among 51 pts with vHR/HR-MDS evaluable for response, ORR was 56.9%, with a median DOR (mDOR) of 16.1 mo (Table). The mDOR in pts with CR was 21.5 mo (95% CI, 12.1-NE). Estimated 12-mo PFS rate was 51.9% (95% CI, 30.6%-69.6%). In 40 evaluable pts with ND-AML, ORR was 40.0% and mDOR was 12.6 mo. The mDOR in pts with CR was 23.0 mo (95% CI, 1.3-NE). Estimated 12-mo PFS rate was 27.9% (95% CI, 14.9%-42.5%). Durable responses were also observed in pts with adverse-risk mutations, including TP53 mutations in pts with vHR/HR-MDS (ORR: 71.4% [10/14]; mDOR 21.5 mo [95%CI, 6.7-NE]) and at least 1 ELN adverse-risk mutation (TP53/RUNX1/ASXL1) in pts with ND-AML (ORR: 53.8% [7/13]; mDOR 12.6 mo [95%CI, 1.3-NE]). Although the majority (75%) of pts who went into remission did not experience an imAE, pts in the vHR/HR-MDS cohort who achieved remission more often had a possible imAE (6/24 [25%]) than pts without remission (n=27), none of whom had an imAE. Notably, all 6 pts with vHR/HR-MDS who had an imAE achieved remission. Among pts with ND-AML, the frequency of possible imAEs was similar regardless of remission status. Of the subset of pts who proceeded to HSCT, post-HSCT outcomes in pts with vHR/HR-MDS treated with sabatolimab + HMA were generally favorable without excess toxicities related to graft-versus-host disease. Conclusions: Sabatolimab + HMA was safe and well tolerated and demonstrated durable clinical responses in pts with vHR/HR-MDS and ND-AML. Responses were also durable in pts with adverse-risk mutations. The observed relationship between response and possible imAEs in vHR/HR-MDS would need further confirmation in ongoing studies, but suggests that an immunomodulatory mechanism of sabatolimab may be contributing to clinical responses. The STIMULUS clinical trial program is evaluating sabatolimab-based combination therapy in multiple Ph II and III studies in MDS and AML. Co-senior authors Uma Borate and Andrew H. Wei contributed equally. Figure 1 Figure 1. Disclosures Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Esteve: Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Knapper: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Traer: Schrodinger: Research Funding; ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier/Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Janssen: Uppsala County Council: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Speakers Bureau; Avillion: Research Funding; Ellipses Pharma: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Incyte Biosciences Benelux BV: Research Funding, Speakers Bureau; Glycomimetics: Research Funding. Narayan: Novartis: Research Funding; Sanofi Genzyme: Other: Spouse employment & equity interest; Takeda: Other: Spouse employment & equity interest; Genentech: Other: Spouse employment & equity interest. Kontro: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann: Celgene/BMS: Honoraria, Research Funding; Fusion: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Naidu: Novartis: Current Employment. Pelletier: Novartis: Current Employment. Han: Novartis: Current Employment, Current equity holder in publicly-traded company. Lewandowski: Novartis Institutes: Current Employment. Zhang: Novartis Institutes for BioMedical Research: Current Employment. Mohammed: Novartis: Current Employment. Rinne: Novartis: Current Employment; Qiagen: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Wei: Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Astellas: Honoraria. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.