Plasma concentrations of antiretroviral drugs in a successful 4-days-a-week maintenance treatment strategy in HIV-1 patients (ANRS 170-Quatuor trial).

OBJECTIVES: Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study. METHODS: Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the 'ON-treatment period' (Day 3 or 4 of the 4-day treatment block) and the 'OFF-treatment period' (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96. RESULTS: W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR) = 64-112) for 4/7 arm versus 130 ng/mL (82-160) for 7/7 arm, P < 0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73-135) for 4/7 arm versus 117 ng/mL (83-160) for 7/7 arm, P < 0.001; tenofovir alafenamide: 11 ng/mL (7-15) for 4/7 arm versus 14 ng/mL (11-18) for 7/7 arm, P = 0.001]. Median OFF concentrations were significantly lower (P < 0.001) at the 48 week analysis for all medications except for raltegravir (P = 0.493) and atazanavir (P = 0.105), for which the numbers of patients were very small. CONCLUSIONS: The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.

Intermittent doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains a high level of viral suppression in virologically suppressed people living with HIV.

INTRODUCTION: We aimed to determine whether doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) given 5 or 4 days a week was able to maintain viral suppression in people living with HIV (PLHIV). METHODS: In this observational, retrospective study, we included all PLHIVs who had received intermittent DOR/3TC/TDF between 10/01/2019 and 01/31/2021, in two French hospitals. RESULTS: Forty-three PLHIVs were included, median (IQR) age: 52 years (48-58), ART duration: 15 years (8-23), duration of virological suppression: 6 years (2-10). Median follow-up was 78 weeks (IQR 62-97). One virological failure (VF) occurred at W38 (HIV-RNA = 61 and 76 copies/mL), in a patient with no viral resistance at baseline or at time of VF, and during the study period five individuals discontinued DOR/3TC/TDF due to adverse events. There were no significant changes during follow-up in the CD4 count, CD4/CD8 ratio, body weight or residual viremia rate. CONCLUSION: These findings suggest the potential for intermittent DOR/3TC/TDF to maintain virological control.

Interest of Absolute Eosinopenia as a Marker of Influenza in Outpatients during the Fall-Winter Seasons 2016-2018 in the Greater Paris Area: The SUPERFLUOUS Study.

INTRODUCTION: Prior to the emergence of COVID-19, when influenza was the predominant cause of viral respiratory tract infections (VRTIs), this study aimed to analyze the distinct biological abnormalities associated with influenza in outpatient settings. METHODS: A multicenter retrospective study was conducted among outpatients, with the majority seeking consultation at the emergency department, who tested positive for VRTIs using RT-PCR between 2016 and 2018. Patient characteristics were compared between influenza (A and B types) and non-influenza viruses, and predictors of influenza were identified using two different models focusing on absolute eosinopenia (0/mm3) and lymphocyte count <800/mm3. RESULTS: Among 590 VRTIs, 116 (19.7%) were identified as outpatients, including 88 cases of influenza. Multivariable logistic regression analysis revealed the following predictors of influenza: in the first model, winter season (adjusted odds ratio [aOR] 7.1, 95% confidence interval [CI] 1.12-45.08) and absolute eosinopenia (aOR 6.16, 95% CI 1.14-33.24); in the second model, winter season (aOR 9.08, 95% CI 1.49-55.40) and lymphocyte count <800/mm3 (aOR 7.37, 95% CI 1.86-29.20). Absolute eosinopenia exhibited the highest specificity and positive predictive value (92% and 92.3%, respectively). CONCLUSION: During the winter season, specific biological abnormalities can aid physicians in identifying influenza cases and guide the appropriate use of antiviral therapy when rapid molecular tests are not readily available.

Four days/week antiretroviral maintenance strategy (ANRS 170 QUATUOR): substudies of reservoirs and ultrasensitive drug resistance.

BACKGROUND: In a 4 days/week (4/7 days) maintenance strategy (ANRS-170 QUATUOR trial), the virological impact of an intermittent strategy was assessed by ultrasensitive virological analyses of reservoirs and resistance. METHODS: HIV-1 total DNA, ultra-sensitive plasma viral load (USpVL) and semen VL were measured in the first 121 participants. Sanger and ultra-deep sequencing (UDS) were performed on the HIV-1 genome (Illumina technology) according to the ANRS consensus. A generalized estimation equation with a Poisson distribution was used to compare changes in the proportion of residual viraemia, detectable semen HIV RNA and HIV DNA within and between the two groups over time. RESULTS: The proportion of participants with residual viraemia at Day 0 (D0) and Week 48 (W48) was 16.7% and 25.0% in the 4/7 days group and 22.4% and 29.7% in the 7/7 days group, respectively (+8.3% versus +7.3%, P = 0.971). The proportion of detectable DNA (>40 copies/106 cells) at D0 and W48 was 53.7% and 57.4% in the 4/7 days group and 56.1% and 51.8% in the 7/7 days group, respectively (+3.7% versus -4.3%, P = 0.358). Semen HIV RNA was detectable (≥100 copies/mL) in 2.2% of participants at D0 and 4.5% at W48 in the 4/7 days group versus 6.1% and 9.1% in the 7/7 days group, respectively (+2.3% versus +3.0%, P = 0.743). Emerging resistance at failure was more frequent in the 4/7 days group detected by Sanger sequencing: 3/6 participants versus 1/4 in the 7/7 days group, and similar with the UDS assay: 5/6 versus 4/4, respectively. CONCLUSIONS: These findings support the potency of a 4/7 days maintenance strategy on virological suppression at the reservoirs and emergent resistance level, including minority variants.

Efficacy of ceftazidime/avibactam in various combinations for the treatment of experimental osteomyelitis in rabbits caused by OXA-48-/ESBL-producing Escherichia coli.

BACKGROUND: While the treatment of ESBL-producing Enterobacterales osteomyelitis relies on carbapenems, the optimal regimen for OXA48 types remains unclear. We evaluated the efficacy of ceftazidime/avibactam in different combinations in an experimental model of OXA-48-/ESBL-producing Escherichia coli osteomyelitis. METHODS: E. coli pACYC184 is a clinical strain harbouring blaOXA-48 and blaCTX-M-15 inserts, with 'increased exposure susceptibility' to imipenem (MIC, 2 mg/L), gentamicin (MIC, 0.5 mg/L), colistin (MIC, 0.25 mg/L), ceftazidime/avibactam (MIC, 0.094 mg/L) and fosfomycin (MIC, 1 mg/L), and resistance to ceftazidime (MIC, 16 mg/L). Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu of OXA-48/ESBL E. coli. Treatment started 14 days later for 7 days in six groups: (1) control, (2) colistin 150.000 IU/kg subcutaneously (SC) q8h, (3) ceftazidime/avibactam 100/25 mg/kg SC q8h, (4) ceftazidime/avibactam + colistin, (5) ceftazidime/avibactam + fosfomycin 150 mg/kg SC q12h, (6) ceftazidime/avibactam + gentamicin 15 mg/kg intramuscularly (IM) q24h. Treatment was evaluated at Day 24 according to bone cultures. RESULTS: In vitro, time-kill curves of ceftazidime/avibactam in combination showed a synergistic effect. In vivo, compared with controls, rabbits treated with colistin alone had similar bone bacterial density (P = 0.50), whereas ceftazidime/avibactam alone or in combinations significantly decreased bone bacterial densities (P = 0.004 and P < 0.0002, respectively). Bone sterilization was achieved using ceftazidime/avibactam in combination with colistin (91%) or fosfomycin (100%) or gentamicin (100%) (P < 0.0001), whereas single therapies were not different from controls. No ceftazidime/avibactam-resistant strains emerged in rabbits treated, regardless of the combination. CONCLUSIONS: In our model of E. coli OXA-48/ESBL osteomyelitis, ceftazidime/avibactam in combination was more effective than any single therapy, whatever the companion drug used (gentamicin or colistin or fosfomycin).

Striking differences in weight gain after cART initiation depending on early or advanced presentation: results from the ANRS CO4 FHDH cohort.

BACKGROUND: Many studies have reported weight gain in ART-naive people living with HIV (PWH) initiating an integrase strand-transfer inhibitor-based regimen. We studied the impact of early or advanced presentation and that of individual drugs in PWH initiating combined ART (cART) between 2012 and 2018. METHODS: From the French Hospital Database HIV cohort, we assessed factors associated with a weight gain  ≥10%, weight change after cART initiation or BMI increase  ≥5 kg/m2 up to 30 months. The analyses were conducted overall, and among PWH with early (primary infection or CD4 >350/mm3 and viral load  <100 000 copies/mL, without AIDS) and advanced presentation (AIDS or CD4 <200/mm3, not during primary infection). RESULTS: At 30 months, 34.5% (95% CI: 33.5-35.6) of the 12 773 PWH had a weight gain ≥10%, with 20.9% (95% CI: 19.6-22.2) among the 5794 with early presentation and 63.1% (95% CI: 60.9-65.3) among the 3106 with advanced presentation. Weight gain was 2.8 kg (95% CI: 2.0-3.7) for those with early presentation and 9.7 kg (95% CI: 8.4-11.1) for those with advanced presentation. Most weight gain occurred in the first 12 months. Underweight and obese PWH were at significantly higher risk of a BMI increase  ≥5 kg/m2 than normal-weight PWH. Results differed within classes and by outcome. Raltegravir and dolutegravir were consistently associated with greater weight gain than the other third agents. Tenofovir alafenamide was also associated with higher weight gain than tenofovir disoproxil or abacavir. CONCLUSIONS: After initiating cART, PWH with early presentation exhibited a small weight gain, whereas it was large among those with advanced presentation. The choice of ART should account for the risk of weight gain, especially for PWH who present with advanced disease and/or are obese.

Elevation of brain ADC (apparent diffusion coefficient) in HIV-associated neurocognitive disorders and evolution after treatment: A pilot study.

BACKGROUND: Thirty to 50% of HIV-infected patients develop HIV-Associated Neurocognitive Disorders (HAND) despite virological control. The previously published Neuro+3 study showed their neurocognitive status can be improved by intensifying antiviral therapy. Our study is a part of the Neuro3+ study and aims to study apparent diffusion coefficient (ADC) as a biomarker for neurological improvement. PATIENTS AND METHODS: We prospectively included 31 patients with HAND. They received therapy with better CNS Penetration Effectiveness (CPE) score with two-year follow-up. Cognitive status was assessed at day 0 (D0) and week 96 (W96) using Frascati 3-stage classification and Global Deficit Score (GDS). Brain MRI at D0 and W96 assessed morphological data (white matter hyperintensities, opportunistic infections, ischemic lesions, atrophy) and measured whole brain apparent diffusion coefficient (ADC). We compared their data with a control group of 20 healthy patients with similar ages and sex ratio. RESULTS: After ARV intensification, cognitive status was significantly improved: GDS (n = 1,4 vs 1,0 p = 0.01) and Frascati scale (2HAD/22MND/7ANI vs 1HAD/8MND/17ANI p = 0.001). Mean ADC was significantly higher in patients at inclusion than in controls (0.88 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.0001). ADC decreased after treatment (0.88 × 10-3 mm2/s ± 0.06 vs 0.85 × 10-3 mm2/s ± 0.06 (p = 0,04). In subgroup analysis, ADC significantly decreased in clinically improved patients (0.89 × 10-3 mm2/s ± 0.07 vs 0.85 × 10-3 mm2/s ± 0.07 (p = 0,03)) and did not significantly change in non-clinically improved patients (0.86 × 10-3 mm2/s ± 0.07 vs 0.84 × 10-3 mm2/s ± 0.07 (p = 0,31)). After treatment, there was no significant difference between patients and controls (0.85 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.17). CONCLUSION: Whole-brain ADC is a good biomarker of HIV-associated neurocognitive disorders. It is significantly increased in patients with HAND compared with controls and significantly decreases after treatment. It is all the more important to have a quantitative biomarker as conventional imaging does not contribute to the diagnosis.

A Restructured Hospital Into a One-Building Organization for COVID-19 Patients: A Resilient and Effective Response to the Pandemic.

The COVID-19 pandemic is a unique crisis challenging healthcare institutions as it rapidly overwhelmed hospitals due to a large influx of patients. This major event forced all the components of the healthcare systems to adapt and invent new workflows. Thus, our tertiary care hospital was reorganized entirely. During the cruising phase, additional staff was allocated to a one-building organization comprising an intensive care unit (ICU), an acute care unit, a physical medicine and rehabilitation unit, and a COVID-19 screening area. The transfer of patients from a ward to another was more efficient due to these organizations and pavilion structure. The observed mortality was low in the acute care ward, except in the palliative unit. No nosocomial infection with SARS-CoV-2 was reported in any other building of the hospital since this organization was set up. This type of one-building organization, integrating all the components for comprehensive patient care, seems to be the most appropriate response to pandemics.

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.

Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Superinfection is associated with short-term outcome and mortality in viral respiratory tract infections during the fall-winter seasons 2016-2018 in the Greater Paris area: the SUPERFLUOUS study: outcomes of viral infections.

BACKGROUND: Following a study of predictors of superinfection in viral respiratory tract infections (VRTIs), this study analyzes the predictors of the outcome. METHODS: Multicenter retrospective study conducted among adults who tested positive for VRTIs with reverse-transcription polymerase chain reaction. We compared characteristics between influenza virus, Paramyxoviridae, and Pneumoviridae and identified predictors of favorable short-term outcome, admission to the intensive care unit (ICU), and mortality. RESULTS: A total of 590 patients had VRTI, including 347 (59%) influenza infections. Mean (SD) patient age was 71.0 (18.3) years, with a sex ratio of 0.91. In multivariate analyses, predictors of favorable short-term outcome were age ≤75 years (adjusted odds ratio [aOR] 5.38 [95% confidence interval, 1.59-18.2]), absence of respiratory disease (4.94 [1.01-24.37]), and absence of superinfection (aOR 3.91 [1.37-11.13]). The predictors of ICU admission were age ≤75 years (aOR 3.28 [1.71-6.25]), chronic respiratory disease (aOR 2.49 [1.20-5.19]), and procalcitonin level >0.25 ng/mL (aOR 4.25 [1.55-11.67]). Predictors of mortality were use of inhaled corticosteroids (2.49 [1.10-5.63]), influenza infection (2.73 [1.27-5.85]), Charlson score ≥5 (5.35 [1.90-15.05]), superinfection (2.54 [1.05-6.18]), and eosinophil count <50/µL (4.39 [1.19-16.2]). Certainty of superinfection was significantly associated with mortality (2.23 [1.15-4.3]). CONCLUSION: Our study revealed that superinfection was significantly related to the outcome, and that virus species affects mortality. These findings emphasize the need for improving the tools used in daily practice to confirm certainty of superinfection and for broader implementation of vaccination of individuals at risk of VRTIs.

A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial.

BACKGROUND: Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen. METHODS: In a randomised, open-label, multicentre, parallel, non-inferiority trial, we randomly assigned (1:1) adults with HIV-1 infection with a plasma viral load (pVL) of less than 50 copies per mL for more than 12 months and no drug-resistance mutations to either the intermittent regimen or their existing continuous maintenance regimen, with stratification according to third therapeutic agent (protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase-strand transfer inhibitor). Participants were recruited from 59 hospitals throughout France. The main exclusion criteria were CD4 cell count lower than 250 cells per µL and chronic hepatitis B virus infection. The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population who started the study strategy presenting treatment success at week 48 (pVL <50 copies per mL without strategy modification), estimated using the US Federal Drug Administration snapshot approach, with a 5% non-inferiority margin. The study was registered with ClinicalTrials.gov (NCT03256422) and EudraCT (2017-000040-17). The trial is now closed. FINDINGS: From Sept 7, 2017, to Jan 22, 2018, 850 potential participants were screened for eligibility. 647 participants were enrolled and randomly assigned (1:1) to either the intermittent or the continuous treatment group. The mITT population included 636 participants (318 per group). At week 48, in the mITT population, treatment success was recorded in 304 (96%) of 318 participants in the intermittent treatment group and 308 (97%) of 318 in the continuous treatment group (adjusted difference -1·3%, 95% CI -4·2 to 1·7). Six (2%) participants in the intermittent treatment group and four (1%) participants in the continuous treatment group had virological failure. Grade 3-4 adverse events were reported in 29 (9%) participants in the intermittent treatment group and 39 (12%) participants in the continuous treatment group (p=0·320). Daily life satisfaction improved in 153 (59%) of 258 participants in the intermittent treatment group versus 19 (7%) of 255 in the continuous treatment group (p<0·0001). ART costs were 43% lower in the intermittent treatment group than in the continuous treatment group (p<0·0001). INTERPRETATION: These findings show the non-inferiority of the treatment strategy of 4-consecutive-days-on and 3-days-off strategy maintenance regimen relative to standard continuous ART triple therapy over 48 weeks. 4 days on and off treatment represents a workable, effective alternative strategy for patients with high adherence to ART, and using a drug combination with a high genetic barrier to resistance. FUNDING: Institut National de la Santé et de la Recherche Médicale Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes.

Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry.

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of ß-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control.

Predictors of Hospitalization and Superinfection in Viral Respiratory Tract Infections Between Influenza and Paramyxoviruses: The SUPERFLUOUS Study.

BACKGROUND: Viral respiratory tract infections (VRTIs) are among the most common diseases, but the risks of superinfection for different virus species have never been compared. METHODS: Multicenter retrospective study conducted among adults who tested positive for VRTIs with reverse-transcription polymerase chain reaction. We compared characteristics between influenza (A or B) and paramyxoviruses (respiratory syncytial virus, parainfluenza virus types 1 and 3, and human metapneumovirus) and identified predictors of superinfection and hospitalization.s. RESULTS: Five hundred ninety patients had VRTI, including 347 (59%) influenza and 243 paramyxovirus infections with comparable rates of superinfections (53% vs 60%). In multivariate analyses, the predictors of superinfections were age >75 years (adjusted odds ratio, 2.37 [95% confidence interval, 1.65-3.40]), chronic respiratory disease (1.79 [1.20-2.67]), and biological abnormalities, including neutrophil count >7000/µL (1.98 [1.34-2.91)], eosinophil count <50/µL (2.53 [1.61-3.98], and procalcitonin level >0.25ng/mL (2.8 [1.65-4.73]). The predictors of hospitalization were age >75 years old (adjusted odds ratio, 3.49 [95% confidence interval, 2.17-5.63]), paramyxovirus infection (2.28 [1.39-3.75]), long-term use of inhaled corticosteroids (2.49 [1.13-5.49]), and biological abnormalities, including neutrophil count >7000/µL (2.38 [1.37-4.12)] and procalcitonin level >0.25ng/mL (2.49 [1.23-5.02]). Kaplan-Meier survival curves showed that influenza-infected patients had a higher mortality rate than those with paramyxovirus infections (8.9% vs 4.5%, respectively; P = .02). CONCLUSIONS: Our study revealed a high rate of superinfection (56%), not related to viral species. However influenza virus was associated with a poorer prognosis than paramyxoviruses, pleading for a broader and large-scale vaccination of individual at risk of VRTIs.

The first wave of COVID-19 in hospital staff members of a tertiary care hospital in the greater Paris area: A surveillance and risk factors study.

INTRODUCTION: Understanding how hospital staff members (HSMs), including healthcare workers, acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first wave can guide the control measures in the current second wave in Europe. METHODS: From March 5 to May 10, 2020, the Raymond-Poincaré Hospital held a weekday consultation for HSMs for PCR testing. HSMs were requested to complete a questionnaire on their potential exposure to SARS-CoV-2. RESULTS: Of 200 HSMs screened, 70 tested positive for SARS-CoV-2. Ninety-nine HSMs completed the questionnaire of whom 28 tested positive for SARS-CoV-2. In the multivariable analysis, age of ≥44 years (aOR = 5.2, 95% CI [1.4-22.5]) and not systematically using a facemask when caring for a patient (aOR = 13.9, 95% CI [1.8-293.0]) were significantly associated with SARS-CoV-2 infection. Working in a COVID-19-dedicated ward (aOR = 0.7, 95% CI [0.2-3.2]) was not significantly associated with infection. Community-related exposure in and outside the hospital, hospital meetings without facemasks (aOR = 21.3, 95% CI [4.5-143.9]) and private gatherings (aOR = 10, 95% CI [1.3-91.0]) were significantly associated with infection. CONCLUSIONS: Our results support the effectiveness of barrier precautions and highlight in-hospital infections not related to patient care and infections related to exposure in the community. Protecting HSMs against COVID-19 is crucial in fighting the second wave of the epidemic.