Dolutegravir reshapes the genetic diversity of HIV-1 reservoirs.

Objectives: Better understanding of the dynamics of HIV reservoirs under ART is a critical step to achieve a functional HIV cure. Our objective was to assess the genetic diversity of archived HIV-1 DNA over 48 weeks in blood cells of individuals starting treatment with a dolutegravir-based regimen. Methods: Eighty blood samples were prospectively and longitudinally collected from 20 individuals (NCT02557997) including: acutely (n = 5) and chronically (n = 5) infected treatment-naive individuals, as well as treatment-experienced individuals who switched to a dolutegravir-based regimen and were either virologically suppressed (n = 5) or had experienced treatment failure (n = 5). The integrase and V3 loop regions of HIV-1 DNA isolated from PBMCs were analysed by pyrosequencing at baseline and weeks 4, 24 and 48. HIV-1 genetic diversity was calculated using Shannon entropy. Results: All individuals achieved or maintained viral suppression throughout the study. A low and stable genetic diversity of archived HIV quasispecies was observed in individuals starting treatment during acute infection. A dramatic reduction of the genetic diversity was observed at week 4 of treatment in the other individuals. In these patients and despite virological suppression, a recovery of the genetic diversity of the reservoirs was observed up to 48 weeks. Viral variants bearing dolutegravir resistance-associated substitutions at integrase position 50, 124, 230 or 263 were detected in five individuals (n = 5/20, 25%) from all groups except those who were ART-failing at baseline. None of these substitutions led to virological failure. Conclusions: These data demonstrate that the genetic diversity of the HIV-1 reservoir is reshaped following the initiation of a dolutegravir-based regimen and strongly suggest that HIV-1 can continue to replicate despite successful treatment.

Distribution and reduction magnitude of HIV-DNA burden in CD4+ T cell subsets depend on art initiation timing.

OBJECTIVE: The aim of our study was to analyze the dynamics of HIV-DNA levels in CD4 T-cell subsets in individuals starting successful dolutegravir-based regimens. DESIGN: Twenty-seven individuals with acute infection (AI, n = 8) or chronic infection (CI, n = 5) and patients in virological success (VS, n = 10) or virological failure (VF, n = 4) on antiretroviral therapy (ART) who initiated a dolutegravir-based regimen were enrolled (NCT02557997). METHODS: CD4 T-cells from baseline and week 48 of successful treatment were sorted into effector memory (TEM), transitional memory (TTM), central memory (TCM) and naïve (TN) cell groups for total HIV-DNA measurements by qPCR. Bayesian methods were used to estimate the posterior probability of a HIV-DNA decrease more than 0.25 log copies/10 cells at week 48. RESULTS: All patients achieved HIV-RNA suppression at 48 weeks. At baseline and week 48, the highest contributions to the HIV-DNA-infected pool from CD4 T cells were observed in TTM cells in the AI group (62.4 and 60.2%, respectively), but in TCM cells for the CI, VS and VF groups (54.6 and 59.4%, 58.2 and 62.9%, 62.4 and 67.2%), respectively. HIV-DNA burden declined in all subsets after 48 weeks of treatment in the AI (probability (Pr) > 91%), CI (Pr > 52%) and VF (Pr > 52%) groups, but only in TEM cells in the VS group (Pr = 95%). CONCLUSION: Our study showed that dolutegravir-based treatment reduced the HIV-DNA cellular burden in individuals from the AI, CI and VF groups, though the reduction levels differed between the patient subgroups. Early treated patients had the highest probability of HIV-DNA reduction. Interestingly, in the aviremic VS group, HIV-DNA reduction was limited to TEM cells.

Plethysmographic dynamic indices predict fluid responsiveness in septic ventilated patients.

OBJECTIVES: In septic patients, reliable non-invasive predictors of fluid responsiveness are needed. We hypothesised that the respiratory changes in the amplitude of the plethysmographic pulse wave (DeltaP(PLET)) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients. DESIGN: Prospective clinical investigation. SETTING: An 11-bed hospital medical intensive care unit. PATIENTS: Twenty-three deeply sedated septic patients mechanically ventilated with tidal volume >or=8 ml/kg and equipped with an arterial catheter and a pulse oximetry plethysmographic sensor. INTERVENTIONS: Respiratory changes in pulse pressure (DeltaPP), DeltaP(PLET) and cardiac index (transthoracic Doppler echocardiography) were determined before and after volume infusion of colloids (8 ml/kg). MEASUREMENTS AND MAIN RESULTS: Twenty-eight volume challenges were performed in 23 patients. Before volume expansion, DeltaPP correlated with DeltaP(PLET) (r2 = 0.71, p<0.001). Changes in cardiac index after volume expansion significantly (p<0.001) correlated with baseline DeltaPP (r2 = 0.76) and DeltaP(PLET) (r2 = 0.50). The patients were defined as responders to fluid challenge when cardiac index increased by at least 15% after the fluid challenge. Such an event occurred 18 times. Before volume challenge, a DeltaPP value of 12% and a DeltaP(PLET) value of 14% allowed discrimination between responders and non-responders with sensitivity of 100% and 94% respectively and specificity of 70% and 80% respectively. Comparison of areas under the receiver operator characteristic curves showed that DeltaPP and DeltaP(PLET) predicted similarly fluid responsiveness. CONCLUSION: The present study found DeltaP(PLET) to be as accurate as DeltaPP for predicting fluid responsiveness in mechanically ventilated septic patients.

The respiratory variation in inferior vena cava diameter as a guide to fluid therapy.

OBJECTIVE: To investigate whether the respiratory variation in inferior vena cava diameter (DeltaD(IVC)) could be related to fluid responsiveness in mechanically ventilated patients. DESIGN: Prospective clinical study. SETTING: Medical ICU of a non-university hospital. PATIENTS: Mechanically ventilated patients with septic shock (n=39). INTERVENTIONS: Volume loading with 8 mL/kg of 6% hydroxyethylstarch over 20 min. MEASUREMENTS AND RESULTS: Cardiac output and DeltaD(IVC) were assessed by echography before and immediately after the standardized volume load. Volume loading induced an increase in cardiac output from 5.7+/-2.0 to 6.4+/-1.9 L/min (P<0.001) and a decrease in DeltaD(IVC) from 13.8+/-13.6 vs 5.2+/-5.8% (P<0.001). Sixteen patients responded to volume loading by an increase in cardiac output > or =15% (responders). Before volume loading, the DeltaD(IVC) was greater in responders than in non-responders (25+/-15 vs 6+/-4%, P<0.001), closely correlated with the increase in cardiac output (r=0.82, P<0.001), and a 12% DeltaD(IVC) cut-off value allowed identification of responders with positive and negative predictive values of 93% and 92%, respectively. CONCLUSION: Analysis of DeltaD(IVC) is a simple and non-invasive method to detect fluid responsiveness in mechanically ventilated patients with septic shock.

Plethysmographic variation index predicts fluid responsiveness in ventilated patients in the early phase of septic shock in the emergency department: a pilot study.

PURPOSE: Feasibility study examining whether plethysmographic variability index (PVI) can predict fluid responsiveness in mechanically ventilated patients in the early phase of septic shock in the emergency department. MATERIALS AND METHODS: Monocentric, prospective, observational study that included 31 mechanically ventilated and sedated patients with septic shock in whom volume expansion was planned. The patients were equipped with a pulse oximeter that automatically calculated and displayed PVI. The intervention consisted in infusing 8 mL/kg of hydroxylethyl starch over a 20-minute period. Before and after intervention, we recorded PVI and measured the aortic velocity-time integral (VTIao) using transthoracic echocardiography. Responders were defined as patients who increased their VTIao by 15% or higher after fluid infusion. RESULTS: Sixteen patients were classified as responders, and 15 as nonresponders. Mean PVI values before intervention were significantly higher in responders vs nonresponders (30%±9% vs 8%±5%, P<.001). Plethysmographic variability index values before intervention were correlated with percent changes in VTIao induced by intervention (R2=0.67; P<.001). A PVI threshold value of 19% discriminates responders from nonresponders with a sensitivity of 94% and a specificity of 87% (area under the curve, 0.97; P<.001). CONCLUSION: Our study suggests that PVI is a feasible and interesting method to predict fluid responsiveness in early phase septic shock patients in the emergency department.

Procalcitonin levels to guide antibiotic therapy in adults with non-microbiologically proven apparent severe sepsis: a randomised controlled trial.

OBJECTIVE: Some patients with the phenotype of severe sepsis may have no overt source of infection or identified pathogen. We investigated whether a procalcitonin-based algorithm influenced antibiotic use in patients with non-microbiologically proven apparent severe sepsis. DESIGN: This multicentre, randomised, controlled, single-blind trial was performed in two parallel groups. SETTING: Eight intensive care units in France. PARTICIPANTS: Adults with the phenotype of severe sepsis and no overt source of infection, negative microbial cultures from multiple matrices and no antibiotic exposure shortly before intensive care unit admission. INTERVENTION: The initiation and duration of antibiotic therapy was based on procalcitonin levels in the experimental arm and on the intensive care unit physicians' clinical judgement without reference to procalcitonin values in the control arm. MAIN OUTCOME MEASURE: The primary outcome was the proportion of patients on antibiotics on day 5 postrandomisation. RESULTS: Over a 3-year period, 62/1250 screened patients were eligible for the study, of whom 31 were randomised to each arm; 4 later withdrew their consent. At day 5, 18/27 (67%) survivors were on antibiotics in the experimental arm, versus 21/26 (81%) controls (p=0.24; relative risk=0.83, 95% CI: 0.60 to 1.14). Only 8/58 patients (13%) had baseline procalcitonin <0.25 µg/l; in these patients, physician complied poorly with the algorithm. CONCLUSIONS: In intensive care unit patients with the phenotype of severe sepsis or septic shock and without an overt source of infection or a known pathogen, the current study was unable to confirm that a procalcitonin-based algorithm may influence antibiotic exposure. However, the premature termination of the trial may not allow definitive conclusions.

Impact of a region wide antimicrobial stewardship guideline on urinary tract infection prescription patterns.

BACKGROUND: Fluoroquinolones are frequently prescribed for non complicated urinary tract infection treatments and have a negative ecological impact. We aimed to substitute them by antibiotics with narrower activity spectrum in order to preserve fluoroquinolone activity in complicated hospital infections. OBJECTIVE: To assess the impact of a multi-modal approach that combines the dispatching of antibiotic prescription guidelines and voluntary attendance at educational sessions on general practitioners' (GP) antibiotic prescription habits. SETTING: This study was led in Franche-Comté, a French eastern region, where GPs were given a guideline recommending a restricted use of fluoroquinolones for urinary tract infections. METHOD: Segmented regression analysis of interrupted time series was used to assess changes in antibiotic prescription. MAIN OUTCOME MEASURE: The antibiotic prescription data of nitrofurantoin, fosfomycin-trometamol and fluoroquinolones for women aged 15-65 years were obtained from the regional agency of health insurance. RESULTS: Twenty months after intervention, the number of nitrofurantoin and fosfomycintrometamol prescriptions increased by 36.8% (95% CI: 30.6-42.2) and 28.5% (95% CI: 22.9-35.4), respectively, while that of norfloxacin decreased by 9.1% (95% CI: -15.3 to -3.5). CONCLUSION: This study suggests that the dispatch of the guideline on urinary tract infection had a moderate impact on antibiotic prescriptions.

Clinical relevance of echocardiography in acute severe dyspnea.

BACKGROUND: The aim of this study was to assess the most relevant echocardiographic parameter for the clinical diagnosis of acute dyspnea due to left-heart dysfunction. METHODS: Transthoracic echocardiography was performed in 88 patients in sinus rhythm admitted for respiratory distress. Two experts determined the cause of dyspnea as cardiogenic (26 patients) or noncardiogenic (62 patients). RESULTS: The feasibility was 100% for the E/A ratio and the E/E deceleration time (EDT) ratio but 97%, 89%, and 85% for the E/Ea ratio, left ventricular ejection fraction (LVEF), and the E/propagation velocity (Vp) ratio, respectively. The area under the receiver operating characteristic curve for E/EDT (0.947 +/- 0.035) was statistically significantly greater than that for E/A (0.753 +/- 0.068) (P = .004). The areas under the curves for all other parameters were not statistically significantly different. In the subpopulation of patients with LVEFs > 45%, the area under the curve for LVEF was significantly smaller than those for E/Ea, E/EDT, and E/Vp. CONCLUSION: E/EDT, E/Ea, and E/Vp appear equally useful to distinguish acute dyspnea due to left-heart dysfunction from that of pulmonary origin. However, E/EDT and E/Ea can be considered the best indices with regard to feasibility.

Pre-ejection period variations predict the fluid responsiveness of septic ventilated patients.

OBJECTIVES: In septic patients with acute circulatory failure, reliable predictors of fluid responsiveness are needed at the bedside. We hypothesized that the respiratory change in pre-ejection period (DeltaPEP) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients. DESIGN: Prospective clinical investigation. SETTING: A ten-bed hospital intensive care unit. PATIENTS: Patients admitted after septic shock equipped with an arterial catheter. INTERVENTIONS: Pre-ejection period (PEP)--defined as the time interval between the beginning of the R wave on the electrocardiogram and the upstroke of the radial arterial pressure curve (PEPKT) or the pulse plethysmographic waveforms (PEPPLET)--and cardiac index (transthoracic echocardiography-Doppler) were determined before and after volume infusion of colloid (8 mL x kg). DeltaPEP (%) was defined as the difference between expiratory and inspiratory PEP divided by the mean of expiratory and inspiratory values. Respiratory changes in pulse pressure (DeltaPP) was also measured. MEASUREMENTS AND MAIN RESULTS: : Twenty-two volume challenges were done in 20 deeply sedated patients. DeltaPEPKT, DeltaPEPPLET, and DeltaPP (measured in all patients) before volume expansion were correlated with cardiac index change after fluid challenge (r = .73, r = .67, and r = .70, respectively, p < .0001). Patients with a cardiac index increase induced by volume expansion > or = 15% and <15% were classified as responders and nonresponders, respectively. Receiver operating characteristic curves showed that the threshold DeltaPP value of 17% allowed discrimination between responder/nonresponder patients with a sensitivity of 85% and a specificity of 100%. For both DeltaPEPKT and DeltaPEPPLET, the best threshold value was 4% with a sensitivity-specificity of 92%-89% and 100%-67%, respectively. CONCLUSIONS: The present study found DeltaPEPKT and DeltaPEPPLET to be as accurate as DeltaPP in the prediction of fluid responsiveness in mechanically ventilated septic patients.