National Institutes of Health COVID-19 Treatment Guidelines Panel: Perspectives and Lessons Learned.

DESCRIPTION: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective. METHODS: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available. RECOMMENDATIONS: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area.

Improving Sepsis Outcomes in the Era of Pay-for-Performance and Electronic Quality Measures: A Joint IDSA/ACEP/PIDS/SHEA/SHM/SIDP Position Paper.

The Centers for Medicare & Medicaid Services (CMS) introduced the Severe Sepsis/Septic Shock Management Bundle (SEP-1) as a pay-for-reporting measure in 2015 and is now planning to make it a pay-for-performance measure by incorporating it into the Hospital Value-Based Purchasing Program. This joint IDSA/ACEP/PIDS/SHEA/SHM/SIPD position paper highlights concerns with this change. Multiple studies indicate that SEP-1 implementation was associated with increased broad-spectrum antibiotic use, lactate measurements, and aggressive fluid resuscitation for patients with suspected sepsis but not with decreased mortality rates. Increased focus on SEP-1 risks further diverting attention and resources from more effective measures and comprehensive sepsis care. We recommend retiring SEP-1 rather than using it in a payment model and shifting instead to new sepsis metrics that focus on patient outcomes. CMS is developing a community-onset sepsis 30-day mortality electronic clinical quality measure (eCQM) that is an important step in this direction. The eCQM preliminarily identifies sepsis using systemic inflammatory response syndrome (SIRS) criteria, antibiotic administrations or diagnosis codes for infection or sepsis, and clinical indicators of acute organ dysfunction. We support the eCQM but recommend removing SIRS criteria and diagnosis codes to streamline implementation, decrease variability between hospitals, maintain vigilance for patients with sepsis but without SIRS, and avoid promoting antibiotic use in uninfected patients with SIRS. We further advocate for CMS to harmonize the eCQM with the Centers for Disease Control and Prevention's (CDC) Adult Sepsis Event surveillance metric to promote unity in federal measures, decrease reporting burden for hospitals, and facilitate shared prevention initiatives. These steps will result in a more robust measure that will encourage hospitals to pay more attention to the full breadth of sepsis care, stimulate new innovations in diagnosis and treatment, and ultimately bring us closer to our shared goal of improving outcomes for patients.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Pneumocystis jirovecii Disease: Basis for the Revised EORTC/MSGERC Invasive Fungal Disease Definitions in Individuals Without Human Immunodeficiency Virus.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus definitions for Pneumocystis disease for the purpose of interventional clinical trials and epidemiological studies and evaluation of diagnostic tests. METHODS: Definitions were based on the triad of host factors, clinical-radiologic features, and mycologic tests with categorization into probable and proven Pneumocystis disease, and to be applicable to immunocompromised adults and children without human immunodeficiency virus (HIV). Definitions were formulated and their criteria debated and adjusted after public consultation. The definitions were published within the 2019 update of the EORTC/MSGERC Consensus Definitions of Invasive Fungal Disease. Here we detail the scientific rationale behind the disease definitions. RESULTS: The diagnosis of proven PCP is based on clinical and radiologic criteria plus demonstration of P. jirovecii by microscopy using conventional or immunofluorescence staining in tissue or respiratory tract specimens. Probable PCP is defined by the presence of appropriate host factors and clinical-radiologic criteria, plus amplification of P. jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in respiratory specimens and/or detection of ß-d-glucan in serum provided that another invasive fungal disease and a false-positive result can be ruled out. Extrapulmonary Pneumocystis disease requires demonstration of the organism in affected tissue by microscopy and, preferably, PCR. CONCLUSIONS: These updated definitions of Pneumocystis diseases should prove applicable in clinical, diagnostic, and epidemiologic research in a broad range of immunocompromised patients without HIV.

DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic Hepatitis B Virus or Hepatitis C Virus, with or without Human Immunodeficienct Virus Co-infection.

BACKGROUND: Several chronic diseases accelerate biological aging. We investigated age acceleration and the association between peripheral blood DNA methylation (DNAm) and immune cell markers in patients chronically infected with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) with and without human immunodeficiency virus (HIV) co-infection. METHODS: Age acceleration was measured as the difference between epigenetic age (Horvath clock) and chronological age. The immune marker model of age acceleration was developed using Elastic Net regression to select both the immune markers and their associated weights in the final linear model. RESULTS: Patients with chronic HBV (n = 51) had a significantly higher median epigenetic age compared to chronological age (age accelerated) (P < .001). In patients with chronic HCV infection (n = 63), age acceleration was associated with liver fibrosis as assessed by histology (P < .05), or presence of HIV co-infection (P < .05), but not HCV mono-infection. Age acceleration defined by immune markers was concordant with age acceleration by DNA methylation (correlation coefficient = .59 in HBV; P = .0025). One-year treatment of HBV patients with nucleoside therapy was associated with a modest reduction in age acceleration, as measured using the immune marker model (-.65 years, P = .018). CONCLUSION: Our findings suggest that patients with chronic viral hepatitis have accelerated epigenetic aging, that immune markers define biological age, and have the potential to assess the effects of therapeutic intervention on age acceleration.

Infectious Diseases Society of America Position Paper: Recommended Revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Sepsis Quality Measure.

The Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) measure has appropriately established sepsis as a national priority. However, the Infectious Diseases Society of America (IDSA and five additional endorsing societies) is concerned about SEP-1's potential to drive antibiotic overuse because it does not account for the high rate of sepsis overdiagnosis and encourages aggressive antibiotics for all patients with possible sepsis, regardless of the certainty of diagnosis or severity of illness. IDSA is also concerned that SEP-1's complex "time zero" definition is not evidence-based and is prone to inter-observer variation. In this position paper, IDSA outlines several recommendations aimed at reducing the risk of unintended consequences of SEP-1 while maintaining focus on its evidence-based elements. IDSA's core recommendation is to limit SEP-1 to septic shock, for which the evidence supporting the benefit of immediate antibiotics is greatest. Prompt empiric antibiotics are often appropriate for suspected sepsis without shock, but IDSA believes there is too much heterogeneity and difficulty defining this population, uncertainty about the presence of infection, and insufficient data on the necessity of immediate antibiotics to support a mandatory treatment standard for all patients in this category. IDSA believes guidance on managing possible sepsis without shock is more appropriate for guidelines that can delineate the strengths and limitations of supporting evidence and allow clinicians discretion in applying specific recommendations to individual patients. Removing sepsis without shock from SEP-1 will mitigate the risk of unnecessary antibiotic prescribing for noninfectious syndromes, simplify data abstraction, increase measure reliability, and focus attention on the population most likely to benefit from immediate empiric broad-spectrum antibiotics.

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre- or post-liver transplant.

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.

Hepatitis C virus treatment with direct-acting antivirals induces rapid changes in the hepatic proteome.

Treatment of chronic hepatitis C virus with direct-acting antivirals usually eradicates infection, but liver fibrosis does not resolve concurrently. In patients who develop cirrhosis prior to hepatitis C virus treatment, hepatic decompensation and hepatocellular carcinoma can still occur after viral elimination due to residual fibrosis. We hypothesized the liver proteome would exhibit meaningful changes in inflammatory and fibrinogenic pathways change upon hepatitis C virus eradication, which could impact subsequent fibrosis regression. We analysed the liver proteome and phosphoproteome of paired liver biopsies obtained from 8 hepatitis C virus-infected patients before or immediately after treatment with direct-acting antivirals. Proteins in interferon signalling and antiviral pathways decreased concurrent with hepatitis C virus treatment, consistent with prior transcriptomic analyses. Expression of extracellular matrix proteins associated with liver fibrosis did not change with treatment, but the phosphorylation pattern of proteins present within signalling pathways implicated in hepatic fibrinogenesis, including the ERK1/2 pathway, was altered concurrent with hepatitis C virus treatment. Hepatitis C virus treatment leads to reduced expression of hepatic proteins involved in interferon and antiviral signalling. Additionally, changes in fibrosis signalling pathways are detectable before alteration in extracellular matrix proteins, identifying a putative chronology for the dynamic processes involved in fibrosis reversal.

Considerations for Empiric Antimicrobial Therapy in Sepsis and Septic Shock in an Era of Antimicrobial Resistance.

Patients with sepsis present across a spectrum of infection sites and severity of illnesses requiring complex decision making at the bedside as to when prompt antibiotics are indicated and which regimen is warranted. Many hemodynamically stable patients with sepsis and low acuity of illness may benefit from further work up before initiating therapy, whereas patients with septic shock warrant emergent broad-spectrum antibiotics. The precise empiric regimen is determined by assessing patient and epidemiological risk factors, likely source of infection based on presenting signs and symptoms, and severity of illness. Hospitals should implement quality improvement measures to aid in the rapid and accurate diagnosis of septic patients and to ensure antibiotics are given to patients in an expedited fashion after antibiotic order.

Metabolic Changes in Chronic Hepatitis C Patients Who Carry IFNL4-ΔG and Achieve Sustained Virologic Response With Direct-Acting Antiviral Therapy.

BACKGROUND: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown. METHODS: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype. RESULTS: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status. CONCLUSIONS: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients.

Utilization of Direct Oral Anticoagulants in People Living with Human Immunodeficiency Virus: Observational Data from the District of Columbia Cohort.

BACKGROUND: Direct oral anticoagulants (DOACs) have become first-line treatment for venous thrombotic events. DOAC prescribing trends among people living with human immunodeficiency virus (PWH) are not well described. The coadministration of DOACs with the antiretroviral (ARV) pharmacokinetic boosters ritonavir (RTV) or cobicistat (COBI) may be complicated by pharmacokinetic interactions. METHODS: A longitudinal cohort study was conducted using the D.C. Cohort Database in Washington, D.C., from January 2011 to March 2017, to describe oral anticoagulant prescribing among PWH ≥ 18 years old and the prevalence of DOAC use with RTV or COBI. Data collection included demographic and clinical characteristics, ARV and anticoagulant prescriptions, and International Classification of Diseases Ninth and Tenth Edition diagnosis codes. RESULTS: Among 8315 PWH, there were 236 anticoagulant prescriptions (96 DOAC, 140 warfarin) for 206 persons. PWH prescribed anticoagulants were predominantly Black (82%) and male (82%), with a mean age at anticoagulant initiation of 56 years. DOAC use increased from 3% of total anticoagulant prescribing in 2011 to 43% in 2016, accounting for 64% of all newly recorded anticoagulant prescriptions by 2016. There were 19 bleeding events recorded among 16 individuals. Despite the Food and Drug Administration label recommendation to avoid rivaroxaban with boosted ARVs, 41% remained on boosted ARVs after rivaroxaban initiation. CONCLUSIONS: DOAC use increased substantially in PWH by 2016. Although rivaroxaban is not recommended with RTV or COBI, concomitant use was recorded in 41% of rivaroxaban recipients in this cohort. As DOAC usage increases, clinicians need to be aware of potential DOAC/ARV interactions in order to select the most appropriate oral anticoagulant and monitoring plan for PWH.

Concurrent Initiation of Hepatitis C and Opioid Use Disorder Treatment in People Who Inject Drugs.

BACKGROUND: People who inject drugs have a high prevalence of hepatitis C virus (HCV) and significant disease associated with drug use; however, HCV treatment often occurs in absence of interventions to address opioid use disorder and drug use-related harms. The impact of concurrent initiation of opioid agonist therapy (OAT) on HCV treatment and drug use outcomes is unknown. METHODS: In this prospective, open-label, observational trial at a harm reduction organization's drop-in center in Washington, DC, 100 patients with chronic HCV infection, opioid use disorder, and ongoing injection drug use were treated with sofosbuvir-velpatasvir for 12-weeks and offered buprenorphine initiation. The primary end point was sustained virologic response (SVR), and secondary end points included uptake of and retention in OAT, change in risk behavior, and determinants of SVR. RESULTS: Eighty-two patients (82%) achieved SVR, which was not associated with baseline OAT status (P = .33), on-treatment drug use (P >.99), or imperfect daily adherence (P = .35) but was significantly associated with completing 2 or more 28-pill bottles of sofosbuvir-velpatasvir (P < .001) and receiving OAT at week 24 (P = .01). Of 67 patients not already receiving OAT at baseline, 53 (79%) started OAT. At week 24, 68 (68%) patients were receiving OAT. Receipt of OAT was associated with fewer opiate-positive urine drug screens (P = .003), lower human immunodeficiency virus risk-taking behavior scores (P < .001), and lower rates of opioid overdose (P = .04). CONCLUSIONS: The Novel Model of Hepatitis C Treatment as an Anchor to Prevent HIV, Initiate Opioid Agonist Therapy, and Reduce Risky Behavior study demonstrates high uptake of buprenorphine collocated with HCV treatment, and it shows that concurrent initiation of OAT with HCV treatment can result in high rates of SVR while reducing risks associated with drug use. CLINICAL TRIALS REGISTRATION: NCT03221309.

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Peripheral blood correlates of virologic relapse after Sofosbuvir and Ribavirin treatment of Genotype-1 HCV infection.

BACKGROUND: Treatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. The duration of treatment required to achieve cure differs between individuals and relapse can occur. We asked whether cellular and transcriptional profiling of peripheral blood collected during treatment could identify biomarkers predictive of treatment outcome. METHODS: We analyzed peripheral blood collected during treatment of genotype 1 HCV with 24 weeks of sofosbuvir and weight-based or low dose ribavirin in a trial in which 29% of patients relapsed. Changes in host immunity during treatment were assessed by flow cytometry and whole blood gene expression profiling. Differences in expression of immune-relevant transcripts based on treatment outcome were analyzed using the Nanostring Human Immunology V2 panel. RESULTS: Multiple cellular populations changed during treatment, but pre-treatment neutrophil counts were lower and natural post-treatment killer cell counts were higher in patients who relapsed. Pre-treatment expression of genes associated with interferon-signaling, T-cell dysfunction, and T-cell co-stimulation differed by treatment outcome. We identified a pre- and post-treatment gene expression signature with high predictive capacity for distinguishing treatment outcome, but neither signature was sufficiently robust to suggest viability for clinical use. CONCLUSIONS: Patients who relapse after hepatitis C virus therapy differ immunologically from non-relapsers based on expression of transcripts related to interferon signaling and T-cell dysfunction, as well as by peripheral neutrophil and NK-cell concentrations. These data provide insight into the host immunologic basis of relapse after DAA therapy for HCV and suggests mechanisms which may be relevant for understanding outcomes with currently approved regimens.

Lack of Efficacy of High-Titered Immunoglobulin in Patients with West Nile Virus Central Nervous System Disease.

West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.

A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY).

BACKGROUND & AIMS: Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course. METHODS: The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs. RESULTS: In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1-95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases. CONCLUSION: Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course. LAY SUMMARY: Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.

Workforce, Workload, and Burnout Among Intensivists and Advanced Practice Providers: A Narrative Review.

OBJECTIVES: To assess-by literature review and expert consensus-workforce, workload, and burnout considerations among intensivists and advanced practice providers. DESIGN: Data were synthesized from monthly expert consensus and literature review. SETTING: Workforce and Workload section workgroup of the Academic Leaders in Critical Care Medicine Task Force. MEASUREMENTS AND MAIN RESULTS: Multidisciplinary care teams led by intensivists are an essential component of critical care delivery. Advanced practice providers (nurse practitioners and physician assistants) are progressively being integrated into ICU practice models. The ever-increasing number of patients with complex, life-threatening diseases, concentration of ICU beds in few centralized hospitals, expansion of specialty ICU services, and desire for 24/7 availability have contributed to growing intensivist staffing concerns. Such staffing challenges may negatively impact practitioner wellness, team perception of care quality, time available for teaching, and length of stay when the patient to intensivist ratio is greater than or equal to 15. Enhanced team communication and reduction of practice variation are important factors for improved patient outcomes. A diverse workforce adds value and enrichment to the overall work environment. Formal succession planning for ICU leaders is crucial to the success of critical care organizations. Implementation of a continuous 24/7 ICU coverage care model in high-acuity, high-volume centers should be based on patient-centered outcomes. High levels of burnout syndrome are common among intensivists. Prospective analyses of interventions to decrease burnout within the ICU setting are limited. However, organizational interventions are felt to be more effective than those directed at individuals. CONCLUSIONS: Critical care workforce and staffing models are myriad and based on several factors including local culture and resources, ICU organization, and strategies to reduce burden on the ICU provider workforce. Prospective studies to assess and avoid the burnout syndrome among intensivists and advanced practice providers are needed.

Characterization of changes in intrahepatic immune cell populations during HCV treatment with sofosbuvir and ribavirin.

Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) results in a sustained virologic response (SVR) in most patients. While highly efficacious, ~3%-5% of patients do not achieve SVR despite having virus that appears susceptible. It is unclear whether host factors contribute to treatment failures, although innate and adaptive immunity may play a role. Previous studies showed that after DAA treatment, the composition of intrahepatic immune cells does not normalize relative to healthy volunteers, even in cases where SVR is achieved. We used paired pre- and post-treatment liver biopsies from 13 patients treated with sofosbuvir and ribavirin, 4 of whom relapsed, to analyse intracellular immune changes during DAA treatment and explore correlations with inflammation and treatment outcome. We performed single marker immunohistochemistry followed by electronic image capture, manual annotation of parenchymal and non-parenchymal regions, and quantitative image analysis. The predominant cellular change during treatment was a decrease in CD8+ cellular density in both parenchymal and non-parenchymal regions. CD68+ Kupffer cell density correlated with hepatic inflammation (AST, ALT) pre-treatment, but did not change during treatment. CD4+ cellular density decreased in non-parenchymal regions and, intriguingly, was lower pre-treatment in subjects who eventually relapsed. Other cellular markers (CD56, CD20), as well as markers of apoptosis (TIA-1) and activated stellate cells, did not change significantly during treatment or differ by treatment outcome. The predominant intrahepatic cellular change during DAA treatment of chronic HCV infection is a reduction in CD8+ cellular density, but this did not correlate with treatment outcome.