Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with CO...

Background Unwanted weight gain affects some people living with HIV who are prescribed integrase strand transfer inhibitors (INSTI). Mechanisms and risk factors are incompletely understood. Methods We utilized two cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naïve participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142 and A5202 and did not receive INSTIs. Results In the observational cohort (N=61), CYP2B6 slow metabolizers had greater weight gain after switch (p=0.01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (N=462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (p=0.001) but not those receiving efavirenz with abacavir (p=0.65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Background and ObjectivesOveruse of symptomatic (i.e., acute) medications is common among those with chronic migraine. It is associated with developing frequent headaches, medication side effects, and reduced quality of life. The optimal treatment strategy for patients who have chronic migraine with medication overuse (CMMO) has long been debated. The study objective was to determine whether migraine preventive therapy without switching or limiting the frequency of the overused medication was noninferior to migraine preventive therapy with switching from the overused medication to an alternative medication that could be used on ≤2 d/wk.MethodsThe Medication Overuse Treatment Strategy (MOTS) trial was an open-label, pragmatic clinical trial, randomizing adult participants 1:1 to migraine preventive medication and (1) switching from the overused medication to an alternative used ≤2 d/wk or (2) continuation of the overused medication with no maximum limit. Participants were enrolled between February 2017 and December 2020 from 34 clinics in the United States, including headache specialty, general neurology, and primary care clinics. The primary outcome was moderate to severe headache day frequency during weeks 9 to 12 and subsequently during weeks 1 to 2 after randomization.ResultsSeven hundred twenty participants were randomized; average age was 44 (SD 13) years; and 87.5% were female. At baseline, participants averaged 22.5 (SD 5.1) headache days over 4 weeks, including 12.8 (SD 6.7) moderate to severe headache days and 21.4 (SD 5.8) days of symptomatic medication use. Migraine preventive medication without switching of the overused medication was not inferior to preventive medication with switching for moderate to severe headache day frequency during weeks 9 to 12 (switching 9.3 [SD 7.2] vs no switching 9.1 [SD 6.8]; p = 0.75, 95% CI −1.0 to 1.3). The treatment strategies also provided similar outcomes during the first 2 weeks (switching 6.6 [SD 3.7] moderate to severe headaches days vs no switching 6.4 [SD 3.6]; p = 0.57, 95% CI −0.4 to 0.7).DiscussionWhen reduction in moderate to severe headache days was used as the outcome of interest for the management of CMMO, migraine preventive medication without switching or limiting symptomatic medication is not inferior to migraine preventive medication with switching to a different symptomatic medication with a maximum limit of 2 treatment days per week.Trial Registration InformationClinicalTrials.gov identifier NCT02764320.Classification of EvidenceThis study provides Class III evidence that, for patients who have CMMO, migraine preventive medication without switching or limiting the overused medication is noninferior to migraine preventive medication with switching and limiting symptomatic medication.

Background Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. Methods Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the southeastern United States, and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping allowed adjustment for population stratification. Results Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 (95% C.I. 1.9 to 12.4; p = 0.001). This HR in Whites was 6.5 (95% CI: 2.3 to 18.8; p = 0.001), and in Blacks was 2.6 (95% C.I. 0.5 to 14.1; p = 0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9 to 11.0; p = 0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. Conclusions Slow metabolizer genotypes were significantly associated with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.

Summary and conclusionsIn a 10-year retrospective study of 25 921 consecutive deliveries in a neonatal unit in Newcastle upon Tyne 271 cases of congenital dislocation of the hips were identified. Of these, the outcome was unsatisfactory in 12: four diagnoses were missed at birth and eight children required further surgical treatment. Radiological abnormalities were detected in a further five children at long-term follow-up examination.From the results of this study and other published series it was concluded that lack of attention to detail was the main cause of inadequate diagnosis and management of congenital dislocation of the hips. More detailed instruction of junior staff, confirmation of the diagnosis by senior staff, the use of a non-removable splint early in treatment, and thorough follow-up by senior staff are all important.

Background: Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been associated with excess weight gain in some adults, which may be influenced by genetic factors. We assessed mitochondrial DNA (mtDNA) haplogroups and weight gain following switch to INSTI-based ART. Methods: All AIDS Clinical Trials Group A5001 and A5322 participants with mtDNA genotyping who switched to INSTI were included. mtDNA haplogroups were derived from prior genotyping algorithms. Race/ethnicity-stratified piecewise linear mixed effects models assessed the relationship between mtDNA haplogroup and weight change slope differences before and after switch to INSTI. Results: A total of 291 adults switched to INSTI: 78% male, 50% non-Hispanic White, 28% non-Hispanic Black, and 22% Hispanic. The most common European haplogroups were H [n = 66 (45%)] and UK [32 (22%)]. Non-H European haplogroups had a significant increase in weight slope after the switch. This difference was greatest among non-H clade UK on INSTI-based regimens that included tenofovir alafenamide (TAF) [3.67 (95% confidence interval 1.12, 6.21) kg/year; P = 0.005]. Although small sample size limited analyses among non-Hispanic Black and Hispanic persons, similarly significant weight gain was seen among the most common African haplogroup, L3 [n = 29 (39%); slope difference 4.93 (1.54, 8.32) kg/year, P = 0.005], after switching to TAF-containing INSTI-based ART. Conclusion: Those in European mtDNA haplogroup clade UK and African haplogroup L3 had significantly greater weight gain after switching to INSTI-based ART, especially those receiving TAF. Additional studies in large and diverse populations are needed to clarify the mechanisms and host risk factors for weight gain after switching to INSTI-based ART, with and without TAF.

BackgroundAtazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert’s polymorphism and bilirubin-related atazanavir discontinuation stratified by race/ethnicity.Patients and methodsPatients had initiated atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C→T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses.ResultsAmong 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7–31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6–78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05–12.7; P=0.87).ConclusionAmong patients who initiated atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.

Background Three-dose series of conventional alum-adjuvanted Hepatitis B surface antigen (HBsAg)-based vaccines achieve seroprotection rates (SPRs) of 35-70% in PLWH. HepB-CpG, a HBsAg vaccine adjuvanted with a TLR-9 agonist, achieves high SPR in immunocompetent adults with a 2-dose regimen, but limited data exist in PLWH. Methods A5379 is an ongoing prospective, open-label study to evaluate immunogenicity of the HBV vaccine HepB-CpG in PLWH. The HBV vaccine-naïve group consisted of PLWH without past HBV infection on antiretroviral therapy with CD4 ≥100 cells/mm3 and HIV-1 RNA < 1000 copies/mL. Participants received 0.5 mL of HepB-CpG intramuscularly (20 mcg recombinant HBsAg and 3000 mcg of CpG 1018® adjuvant) at Wks 0, 4, and 24. Primary objectives were to determine the proportion of participants who achieve seroprotection (HBsAb≥10 mIU/mL) at Wk 28 and to assess safety. This study was designed to conclude SPR >55%, with up to 10% loss to follow-up prior to 28 wks. Results Of the 74 eligible participants enrolled at 13 global sites: 46% were male, 66% Asian, 16% Black,15% White and median age was 47 years (range 23-68). 27% were enrolled in the US, 65% in Thailand. Median CD4 was 625 cells/mm3, 96% had HIV-1 RNA < 60 copies/mL, and 9% had diabetes. Primary analysis set per analysis plan consisted of 68 participants (excluded: 3 missed visit, 3 out of visit window). All 68 completed 3 doses and achieved seroprotection (100% [95% CI: 94.7%, 100%]). 88% had HBsAb >1000 mIU/mL (assay upper limit). The SPR was also 100% [CI: 94.2%,100%] in the per protocol analysis set of 62 participants. At 8 wks after the 2nd dose, the SPR was 94.4% followed by 98.5% at Wk 24, prior to the 3rd dose. The proportion of participants with HBsAb >1000 mIU/mL increased from 27.9% at Wk 24 to 83.8% at Wk 28. One or more AEs related to study treatment were experienced by 61% of participants (39% Grade 1, 20% Grade 2, Grade 3 malaise in one participant). Vaccination site pain (40%), malaise (26%), fatigue (23%), myalgia (22%) and headache (22%) were the most frequent AEs. Seroprotection achieved by study week. Percentage of participants achieving seroprotection over the first 28 study weeks. HepB-CpG vaccine was administered at Entry, Week 4, and Week 24. Conclusion In this study of PLWH with no history of HBV vaccination or evidence of prior HBV exposure, 100% seroprotection was achieved at 4 weeks after 3 doses of the HepB-CpG. No unexpected safety issues were observed. Disclosures Kristen Marks, MD, MS, Gilead Sciences: Grant/Research Support Andrea L. Cox, M.D. Ph.D., Janssen: Advisor/Consultant Jennifer C. Price, MD, PhD, AbbVie: Grant/Research Support|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Grant/Research Support|Theratechnologies: Advisor/Consultant Kelvin McKoy, M.D., M.B.A., Dynavax Technologies: Employee|Dynavax Technologies: Ownership Interest|Dynavax Technologies: Stocks/Bonds Kenneth E. Sherman, MD, PhD, AbbVie: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Helio: Grant/Research Support|Inovio: DSMB|Intercept: Grant/Research Support|MedPace: DSMB|Theratechnologies: Advisor/Consultant|Zydus: Grant/Research Support.