Infants Receiving a Single Dose of Nirsevimab to Prevent RSV Do Not Have Evidence of Enhanced Disease in Their Second RSV Season.

To characterize nirsevimab in the prevention of RSV, children from the Phase 3 MELODY trial were followed through their second RSV season. No increase in medically attended RSV lower respiratory tract infections or evidence of antibody-dependent enhancement of infection or disease severity was found for nirsevimab vs placebo recipients. Clinical Trial Registration: Clinicaltrials.gov, NCT03979313, https://clinicaltrials.gov/ct2/show/NCT03979313.

CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes.

Excessive inflammation by phagocytes during Aspergillus fumigatus infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce A. fumigatus colonization in vivo, however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen Aspergillus-induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon A. fumigatus infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with A. fumigatus following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction (p < 0.05) in Aspergillus-induced ROS. For CF PBMC, Aspergillus-induced ROS was significantly reduced when pre-treated with ivacaftor alone (p < 0.01) or in combination with lumacaftor (p < 0.01), with a comparable significant reduction in control subject PBMC (p < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat Aspergillus-induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action.

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.

BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING: ViiV Healthcare.

Effect of coadministration of metformin with mirogabalin: Results from a phase 1, randomized, open-label, drug-drug interaction study
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Mirogabalin, a selective voltage-dependent calcium channel α2δ ligand under development for treatment of neuropathic pain, may be coadministered with metformin in patients with type 2 diabetes mellitus who have diabetic peripheral neuropathic pain. A randomized, open-label, single-dose, 3-treatment, 3-period crossover study evaluated the pharmacokinetics (PK) and safety of mirogabalin and metformin upon coadministration. Eligible subjects received 3 treatments separated by a 7-day washout period: 1 oral dose of mirogabalin 15 mg; 1 oral dose of metformin 850 mg; and coadministration of mirogabalin 15 mg with metformin 850 mg. PK assessments included maximum observed plasma concentration (Cmax); time of maximum plasma concentration; area under the concentration-time curve from time 0 to the last quantifiable concentration, and from 0 to infinity (AUClast and AUC0-inf, respectively). Safety assessments included adverse event (AE) monitoring and physical and clinical laboratory evaluations. 21 healthy men with a mean age of 30.4 years were enrolled and completed the study. Geometric least square means ratios (coadministration vs. alone; 90% confidence interval) for metformin Cmax, AUClast, and AUC0-inf were 1.00 (0.95 - 1.05), 1.04 (1.00 - 1.07), and 1.03 (1.00 - 1.07), respectively; ratios for mirogabalin were 0.94 (0.87 - 1.02), 0.99 (0.95 - 1.04), and 1.00 (0.96 - 1.04), respectively. Three subjects reported treatment-emergent AEs: dyspepsia, headache, and increased hepatic enzymes (resolved upon follow-up without sequelae). There were no deaths, serious AEs, or discontinuations due to AEs. Coadministration of mirogabalin and metformin is well tolerated in healthy subjects with no evidence of a drug-drug interaction.
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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Mirogabalin When Coadministered With Lorazepam, Zolpidem, Tramadol, or Ethanol: Results From Drug-Drug Interaction Studies in Healthy Subjects.

Four randomized, double-blind, placebo-controlled, 4-period drug-drug interaction studies were conducted in healthy subjects to evaluate the pharmacokinetic and pharmacodynamic (PD) interactions between mirogabalin and commonly used central nervous system depressants. Mirogabalin or placebo was administered alone or with single-dose lorazepam, zolpidem, tramadol, ethanol, or interacting drug placebo. Safety was assessed and serial samples for pharmacokinetic parameters were collected for up to 48 hours postdose. PD assessments included body sway (except tramadol), digit symbol substitution test, vertigo symptom scale short form, brief ataxia rating scale, and the Bond and Lader visual analog scale. Coadministration of mirogabalin with any of the 4 drugs did not cause any clinically relevant pharmacokinetic interactions. Peak mirogabalin concentration decreased by 28% (least squares mean ratio, 0.72; 90% confidence interval, [CI] 0.67, 0.76) following tramadol coadministration, and increased by 20% (least squares mean ratio, 1.20; 90%CI, 1.12, 1.28) following ethanol coadministration. Mirogabalin alone had little to no effect on PD parameters, but coadministration of mirogabalin with either lorazepam or ethanol increased the PD effects in body sway and digit symbol substitution test assays. Mirogabalin/lorazepam and mirogabalin/zolpidem increased occurrence of somnolence. Increased incidence of nausea and headache was noted with mirogabalin/tramadol and mirogabalin/ethanol, respectively.

The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults.

BACKGROUND: Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance and type 2 diabetes mellitus, by inhibition of insulin-sensitive glucose transporters. Atazanavir (ATV) is a new PI with substantially less in vitro effect on glucose transport than observed with other PI, including lopinavir (LPV) or ritonavir (RTV). METHODS: Randomized, double-blind, crossover study of the effect of 5 days of administering ATV, lopinavir/ritonavir (LPV/r) or placebo on insulin-stimulated glucose disposal in 30 healthy HIV-negative subjects. Each subject was studied on two of three possible treatments with a wash-out period between treatments. RESULTS: The mean insulin-stimulated glucose disposal (mg/min per kg body weight) per unit insulin (microU/ml) (M/I) was 9.88, 9.80 and 7.52 for placebo, ATV and LPV/r, respectively (SEM, 0.84 for all). There was no significant difference between ATV and placebo. The M/I for LPV/r was 23% lower than that for ATV (P = 0.010) and 24% lower than that for placebo (P = 0.008). The mean glycogen storage rates were 3.85, 4.00 and 2.54 mg/min per kg for placebo, ATV and LPV/r, respectively (SEM, 0.39 for all). There was no significant difference between ATV and placebo. The glycogen storage rate for LPV/r was 36% lower than ATV (P = 0.003) and 34% lower than placebo (P = 0.006). CONCLUSIONS: ATV given to healthy subjects for 5 days did not affect insulin sensitivity, while LPV/r induced insulin resistance. This observation is consistent with differential in vitro effects of these PI on glucose transport. Further data are needed to assess clinical implications for body composition.