Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1. METHODS: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791. FINDINGS: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per µL) and total lymphocyte counts (mean change -0·20 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Characterization of cognitive symptoms in post COVID-19 patients.

Cognitive symptoms (CS) belong to the most common manifestations of the Post COVID-19 (PC) condition. We sought to objectify CS in PC patients using routine diagnostic assessments: neurocognitive testing (NCT) and brain imaging (BI). Further, we investigated possible associations of CS with patient reported outcomes (PROs), and risk factors for developing CS. Clinical data and PROs of 315 PC patients were assessed at a mean of 6 months after SARS-CoV-2 infection. 231 (73.3%) patients reported any sort of CS. Among them, 78 underwent NCT and 55 received BI. In NCT, the cognitive domains most affected were the working memory, attention, and concentration. Nonetheless, pathological thresholds were exceeded only in few cases. Neurocognitive performance did not differ significantly between patients complaining of severe (n = 26) versus non-severe (n = 52) CS. BI findings were abnormal in 8 (14.5%) cases with CS but were most likely not related to PC. Patients reporting high severity of CS scored worse in the PHQ-9, FSS, WHOQOL-BREF, were more likely to report impaired sleep, and had a higher prevalence of psychiatric diagnoses. Overall, NCT could confirm mild impairment in some but not all PC patients with CS, while BI studies were abnormal in only few cases. CS severity did not affect NCT results, but severe CS were associated with symptoms of depression (PHQ-9), fatigue (FSS), reduced quality of life (WHOQOL-BREF) and higher prevalence of psychiatric illnesses. These findings support the importance of NCT, BI, and neuro-psychological assessment in the work-up of PC patients reporting CS. TRIAL REGISTRATION: Trial registration number and date of registration: DRKS00030974, 22 Dec 2022, retrospectively registered.

Receptor transfer between immune cells by autoantibody-enhanced, CD32-driven trogocytosis is hijacked by HIV-1 to infect resting CD4 T cells.

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.

Mpox-specific immune responses elicited by vaccination or infection in people living with HIV.

In the recent mpox outbreak, people living with HIV (PLWH) were at high risk both for contracting infection and for suffering a more severe disease course. We studied cellular and humoral immune responses elicited by mpox infection (n = 5; n = 3 PLWH) or smallpox vaccination (n = 17; all PLWH) in a cohort of men who have sex with men. All PLWH were successfully treated, with stable CD4 counts and undetectable HIV viral loads. 11/17 vaccinated individuals had received childhood smallpox vaccination. In this group of individuals, both two-dose MVA-vaccination and natural infection evoked mpox-specific immune responses mediated by B cells as well as CD4 and CD8 T cells. This study improves our understanding of smallpox vaccination mediated cross-reactivity to other orthopox viruses, and the long-lasting durability of childhood smallpox vaccination mediated immune responses including in PLWH.

Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Substantial differences in perception of disease severity between post COVID-19 patients, internists, and psychiatrists or psychologists: the Health Perception Gap and its clinical implications.

Patient-reported outcome measures (PROMs) such as the Numeric Pain Rating Scale (NPRS) or Likert scales addressing various domains of health are important tools to assess disease severity in Post COVID-19 (PC) patients. By design, they are subjective in nature and prone to bias. Our findings reveal substantial differences in the perception of disease severity between patients (PAT), their attending internists (INT) and psychiatrists/psychologists (PSY). Patients rated almost all aspects of their health worse than INT or PSY. Most of the differences were statistically highly significant. The presence of fatigue and mood disorders correlated negatively with health perception. The physical health section of the WHO Quality of Life Assessment (WHOQoL-BREF) and Karnofsky index correlated positively with overall and mental health ratings by PAT and INT. Health ratings by neither PAT, PSY nor INT were associated with the number of abnormal findings in diagnostic procedures. This study highlights how strongly perceptions of disease severity diverge between PC patients and attending medical staff. Imprecise communication, different experiences regarding health and disease, and confounding psychological factors may explain these observations. Discrepancies in disease perception threaten patient-physician relationships and pose strong confounders in clinical studies. Established scores (e.g., WHOQoL-BREF, Karnofsky index) may represent an approach to overcome these discrepancies. Physicians and psychologists noting harsh differences between a patient's and their own perception of the patient's health should apply screening tools for mood disorders (i.e., PHQ-9, WHOQoL-BREF), psychosomatic symptom burden (SSD-12, FCV-19) and consider further psychological evaluation. An interdisciplinary approach to PC patients remains imperative. Trial Registration Number & Date of Registration: DRKS00030974, 22 Dec 2022, retrospectively registered.

Use of contraindicated antiretroviral drugs in people with HIV/HCV coinfections receiving HCV treatment with direct-acting antivirals-Results from the EuroSIDA study.

OBJECTIVES: Our objective was to determine whether antiretroviral drugs (ARVs) were used according to the European AIDS Clinical Society (EACS) guidelines for people with HIV/hepatitis C virus (HCV) coinfection treated with direct-acting antivirals (DAAs) between 30 November 2014 and 31 December 2019 in the pan-European EuroSIDA study. METHODS: At each publication date of the EACS guidelines, plus 3 and 6 months, we calculated the number of people receiving DAAs with potential and actual ARV contraindications ('red shading' in the EACS guidelines). We used logistic regression to investigate factors associated with using contraindicated ARVs. RESULTS: Among 1406 people starting DAAs, the median age was 51 years, 75% were male, 57% reported injected drug use as an HIV risk, and 76% were from western Europe. Of 1624 treatment episodes, 609 (37.5%) occurred while the patient was receiving ARVs with potential contraindications; among them, 38 (6.2%; 95% confidence interval [CI] 4.3-8.2) involved a contraindicated ARV (18 non-nucleoside reverse transcriptase inhibitors), 16 involved protease inhibitors, and four involved integrase strand transfer inhibitors. The adjusted odds of receiving a contraindicated ARV were higher (3.25; 95% CI 1.40-7.57) among participants from east/central east Europe (vs. south) and lower (0.22; 95% CI 0.08-0.65) for 2015-2018 guidelines (vs. 2014). In total, 29 of the 32 (90.6%) patients receiving a contraindicated ARV and 441 of the 461 (95.7%) with potential ARV contraindications experienced a sustained virological response ≥12 weeks after stopping treatment (SVR12; p = 0.55). CONCLUSION: In this large heterogenous European cohort, more than one-third of people with HIV/HCV coinfection received DAAs with potential ARV contraindications, but few received a contraindicated ARV. Use of contraindicated ARVs declined over time, corresponding to the increased availability of ARV therapy regimens without interactions with DAA across Europe. Participants who received a contraindicated DAA and ARV combination still had a high rate of SVR12.

Ecological effects of selective oral decontamination on multidrug-resistance bacteria acquired in the intensive care unit: a case-control study over 5 years.

PURPOSE: This case-control study investigated the long-term evolution of multidrug-resistant bacteria (MDRB) over a 5-year period associated with the use of selective oropharyngeal decontamination (SOD) in the intensive care unit (ICU). In addition, effects on health care-associated infections and ICU mortality were analysed. METHODS: We investigated patients undergoing mechanical ventilation > 48 h in 11 adult ICUs located at 3 campuses of a university hospital. Administrative, clinical, and microbiological data which were routinely recorded electronically served as the basis. We analysed differences in the rates and incidence densities (ID, cases per 1000 patient-days) of MDRB associated with SOD use in all patients and stratified by patient origin (outpatient or inpatient). After propensity score matching, health-care infections and ICU mortality were compared. RESULTS: 5034 patients were eligible for the study. 1694 patients were not given SOD. There were no differences in the incidence density of MDRB when SOD was used, except for more vancomycin-resistant Enterococcus faecium (0.72/1000 days vs. 0.31/1000 days, p < 0.01), and fewer ESBL-producing Klebsiella pneumoniae (0.22/1000 days vs. 0.56/1000 days, p < 0.01). After propensity score matching, SOD was associated with lower incidence rates of ventilator-associated pneumonia and death in the ICU but not with ICU-acquired bacteremia or urinary tract infection. CONCLUSIONS: Comparisons of the ICU-acquired MDRB over a 5-year period revealed no differences in incidence density, except for lower rate of ESBL-producing Klebsiella pneumoniae and higher rate of vancomycin-resistant Enterococcus faecium with SOD. Incidence rates of ventilator-associated pneumonia and death in the ICU were lower in patients receiving SOD.