Islatravir: evaluation of clinical development for HIV and HBV.

INTRODUCTION: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3'OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability. AREAS COVERED: The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed. EXPERT OPINION: Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.

New cardiovascular events in the convalescent period among survivors of SARS-CoV-2 infection.

BACKGROUND: Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have an increased risk of acute cardiovascular events in the convalescent period. AIMS: To determine whether patients with SARS-CoV-2 infection have an increased risk of cardiovascular events during the convalescent period. METHODS: We analyzed 10,691 hospitalized adult pneumonia patients with SARS-CoV-2 infection and contemporary matched controls of pneumonia patients without SARS-CoV-2 infection. The risk of new cardiovascular events following >30 days pneumonia admission (convalescent period) was ascertained using Cox proportional hazards regression analysis to adjust for potential confounders. RESULTS: Among 10,691 pneumonia patients with SARS-CoV-2 infection, 697 patients (5.8%; 95% CI, 5.4-6.2%) developed new cardiovascular events (median time interval of 218 days post pneumonia admission; interquartile range Q1 = 117 days, Q3 = 313 days). The risk of new cardiovascular events was not significantly higher among pneumonia patients with SARS-CoV-2 infection compared with those with pneumonia without SARS-CoV-2 infection (hazard ratio (HR), 0.90, 95% CI, 0.80-1.02) after adjustment for potential confounders. In addition, no significant difference in the rate of a new ischemic stroke (HR, 0.84; 95% CI, 0.70-1.02) or ischemic heart disease (HR, 1.00; 95% CI, 0.87-1.15) was observed between the pneumonia patients with and without SARS-CoV-2 infection. CONCLUSION: Our study suggests that new cardiovascular events rate in the convalescent period among pneumonia patients with SARS-CoV-2 infection was not significantly higher than the rate seen with other pneumonias.

New-Onset Dementia Among Survivors of Pneumonia Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Background: Case series without control groups suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in cognitive deficits and dementia in the postinfectious period. Methods: Adult pneumonia patients with SARS-CoV-2 infection (index hospitalization) and age-, gender-, and race/ethnicity-matched contemporary control pneumonia patients without SARS-CoV-2 infection were identified from 110 healthcare facilities in United States. The risk of new diagnosis of dementia following >30 days after the index hospitalization event without any previous history of dementia was identified using logistic regression analysis to adjust for potential confounders. Results: Among 10 403 patients with pneumonia associated with SARS-CoV-2 infection, 312 patients (3% [95% confidence interval {CI}, 2.7%-3.4%]) developed new-onset dementia over a median period of 182 days (quartile 1 = 113 days, quartile 3 = 277 days). After adjustment for age, gender, race/ethnicity, hypertension, diabetes mellitus, hyperlipidemia, nicotine dependence/tobacco use, alcohol use/abuse, atrial fibrillation, previous stroke, and congestive heart failure, the risk of new-onset dementia was significantly higher with pneumonia associated with SARS-CoV-2 infection compared with pneumonia unrelated to SARS-CoV-2 infection (odds ratio [OR], 1.3 [95% CI, 1.1-1.5]). The association remained significant after further adjustment for occurrence of stroke, septic shock, and intubation/mechanical ventilation during index hospitalization (OR, 1.3 [95% CI, 1.1-1.5]). Conclusions: Approximately 3% of patients with pneumonia associated with SARS-CoV-2 infection developed new-onset dementia, which was significantly higher than the rate seen with other pneumonias.

Utilization and Outcomes of Acute Revascularization Treatments in Ischemic Stroke Patients with SARS-CoV-2 Infection.

OBJECTIVES: Acute ischemic stroke patients with severe acute respiratory syndrome coronavirus maybe candidates for acute revascularization treatments (intravenous thrombolysis and/or mechanical thrombectomy). MATERIALS AND METHODS: We analyzed the data from 62 healthcare facilities to determine the odds of receiving acute revascularization treatments in severe acute respiratory syndrome coronavirus infected patients and determined the odds of composite of death and non-routine discharge with severe acute respiratory syndrome coronavirus infected and non-infected patients undergoing acute revascularization treatments after adjusting for potential confounders. RESULTS: Acute ischemic stroke patients with severe acute respiratory syndrome coronavirus infection were significantly less likely to receive acute revascularization treatments (odds ratio 0.6, 95% confidence interval 0.5-0.8, p = 0.0001). Among ischemic stroke patients who received acute revascularization treatments, severe acute respiratory syndrome coronavirus infection was associated with increased odds of death or non-routine discharge (odds ratio 3.0, 95% confidence interval 1.8-5.1). The higher odds death or non-routine discharge (odds ratio 2.1, 95% confidence interval 1.9-2.3) with severe acute respiratory syndrome coronavirus infection were observed in all ischemic stroke patients without any modifying effect of acute revascularization treatments (interaction term for death (p = 0.9) or death or non-routine discharge (p = 0.2). CONCLUSIONS: Patients with acute ischemic stroke with severe acute respiratory syndrome coronavirus infection were significantly less likely to receive acute revascularization treatments. Severe acute respiratory syndrome coronavirus infection was associated with a significantly higher rate of death or non-routine discharge among acute ischemic stroke patients receiving revascularization treatments.

Evolutionary analysis of the Delta and Delta Plus variants of the SARS-CoV-2 viruses.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been rapidly evolving in the form of new variants. At least eleven known variants have been reported. The objective of this study was to delineate the differences in the mutational profile of Delta and Delta Plus variants. High-quality sequences (n = 1756) of Delta (B.1.617.2) and Delta Plus (AY.1 or B.1.617.2.1) variants were used to determine the prevalence of mutations (≥20 %) in the entire SARS-CoV-2 genome, their co-existence, and change in prevalence over a period of time. Structural analysis was conducted to get insights into the impact of mutations on antibody binding. A Sankey diagram was generated using phylogenetic analysis coupled with sequence-acquisition dates to infer the migration of the Delta Plus variant and its presence in the United States. The Delta Plus variant had a significant number of high-prevalence mutations (≥20 %) than in the Delta variant. Signature mutations in Spike (G142D, A222V, and T95I) existed at a more significant percentage in the Delta Plus variant than the Delta variant. Three mutations in Spike (K417N, V70F, and W258L) were exclusively present in the Delta Plus variant. A new mutation was identified in ORF1a (A1146T), which was only present in the Delta Plus variant with ~58 % prevalence. Furthermore, five key mutations (T95I, A222V, G142D, R158G, and K417N) were significantly more prevalent in the Delta Plus than in the Delta variant. Structural analyses revealed that mutations alter the sidechain conformation to weaken the interactions with antibodies. Delta Plus, which first emerged in India, reached the United States through England and Japan, followed by its spread to more than 20 the United States. Based on the results presented here, it is clear that the Delta and Delta Plus variants have unique mutation profiles, and the Delta Plus variant is not just a simple addition of K417N to the Delta variant. Highly correlated mutations may have emerged to keep the structural integrity of the virus.

Effect of Race and Ethnicity on In-Hospital Mortality in Patients with COVID-19.

Objective: To identify differences in short-term outcomes of patients with coronavirus disease 2019 (COVID-19) according to various racial/ethnic groups. Design: Analysis of Cerner de-identified COVID-19 dataset. Setting: A total of 62 health care facilities. Participants: The cohort included 49,277 adult COVID-19 patients who were hospitalized from December 1, 2019 to November 13, 2020. Main Outcome Measures: The primary outcome of interest was in-hospital mortality. The secondary outcome was non-routine discharge (discharge to destinations other than home, such as short-term hospitals or other facilities including intermediate care and skilled nursing homes). Methods: We compared patients' age, gender, individual components of Charlson and Elixhauser comorbidities, medical complications, use of do-not-resuscitate, use of palliative care, and socioeconomic status between various racial and/or ethnic groups. We further compared the rates of in-hospital mortality and non-routine discharges between various racial and/or ethnic groups. Results: Compared with White patients, in-hospital mortality was significantly higher among African American (OR 1.5; 95%CI:1.3-1.6, P<.001), Hispanic (OR1.4; 95%CI:1.3-1.6, P<.001), and Asian or Pacific Islander (OR 1.5; 95%CI: 1.1-1.9, P=.002) patients after adjustment for age and gender, Elixhauser comorbidities, do-not-resuscitate status, palliative care use, and socioeconomic status. Conclusions: Our study found that, among hospitalized patients with COVID-2019, African American, Hispanic, and Asian or Pacific Islander patients had increased mortality compared with White patients after adjusting for sociodemographic factors, comorbidities, and do-not-resuscitate/palliative care status. Our findings add additional perspective to other recent studies.

Subarachnoid Hemorrhage and COVID-19: An Analysis of 282,718 Patients.

BACKGROUND: Intracranial hemorrhage (including subarachnoid hemorrhage [SAH]) has been reported in 0.3%-1.2% of patients with coronavirus disease 2019 (COVID-19). However, no study has evaluated the risk of SAH in patients with COVID-19. METHODS: We analyzed data from 62 health care facilities using the Cerner de-identified COVID-19 dataset. RESULTS: There were 86 (0.1%) and 376 (0.2%) patients with SAH among 85,645 patients with COVID-19 and 197,073 patients without COVID-19, respectively. In the multivariate model, there was a lower risk of SAH in patients with COVID-19 (odds ratio 0.5, 95% confidence interval 0.4-0.7, P < 0.0001) after adjusting for sex, age strata, race/ethnicity, hypertension, and nicotine dependence/tobacco use. The proportions of patients who developed pneumonia (58.1% vs. 21.3%, P < 0.0001), acute kidney injury (43% vs. 27.7%, P = 0.0005), septic shock (44.2% vs. 20.7%, P < 0.0001), and respiratory failure (64.0% vs. 39.1%, P < 0.0001) were significantly higher among patients with SAH and COVID-19 compared with patients without COVID-19. The in-hospital mortality among patients with SAH and COVID-19 was significantly higher compared with patients without COVID-19 (31.4% vs. 12.2%, P < 0.0001). CONCLUSIONS: The risk of SAH was not increased in patients with COVID-19. The higher mortality in patients with SAH and COVID-19 compared with patients without COVID-19 is likely mediated by higher frequency of systemic comorbidities.

Reassortant Cache Valley Virus Associated With Acute Febrile, Nonneurologic Illness, Missouri.

An adult male from Missouri sought care for fever, fatigue, and gastrointestinal symptoms. He had leukopenia and thrombocytopenia and was treated for a presumed tickborne illness. His condition deteriorated with respiratory and renal failure, lactic acidosis, and hypotension. Next-generation sequencing and phylogenetic analysis identified a reassortant Cache Valley virus.

Acute Ischemic Stroke and COVID-19: An Analysis of 27 676 Patients.

BACKGROUND AND PURPOSE: Acute ischemic stroke may occur in patients with coronavirus disease 2019 (COVID-19), but risk factors, in-hospital events, and outcomes are not well studied in large cohorts. We identified risk factors, comorbidities, and outcomes in patients with COVID-19 with or without acute ischemic stroke and compared with patients without COVID-19 and acute ischemic stroke. METHODS: We analyzed the data from 54 health care facilities using the Cerner deidentified COVID-19 dataset. The dataset included patients with an emergency department or inpatient encounter with discharge diagnoses codes that could be associated to suspicion of or exposure to COVID-19 or confirmed COVID-19. RESULTS: A total of 103 (1.3%) patients developed acute ischemic stroke among 8163 patients with COVID-19. Among all patients with COVID-19, the proportion of patients with hypertension, diabetes, hyperlipidemia, atrial fibrillation, and congestive heart failure was significantly higher among those with acute ischemic stroke. Acute ischemic stroke was associated with discharge to destination other than home or death (relative risk, 2.1 [95% CI, 1.6-2.4]; P<0.0001) after adjusting for potential confounders. A total of 199 (1.0%) patients developed acute ischemic stroke among 19 513 patients without COVID-19. Among all ischemic stroke patients, COVID-19 was associated with discharge to destination other than home or death (relative risk, 1.2 [95% CI, 1.0-1.3]; P=0.03) after adjusting for potential confounders. CONCLUSIONS: Acute ischemic stroke was infrequent in patients with COVID-19 and usually occurs in the presence of other cardiovascular risk factors. The risk of discharge to destination other than home or death increased 2-fold with occurrence of acute ischemic stroke in patients with COVID-19.

Hepatic Encephalopathy in the Hospitalized Patient: A Review for Hospitalists.

Hepatic encephalopathy is a well-recognized complication of decompensated cirrhosis. It is a reversible state of neurocognitive decline, the etiology of which is multifactorial. Diagnosis is predominantly clinical and usually a diagnosis of exclusion. The identification of precipitating factors and their correction is an essential part of the management along with medical therapies such as lactulose and rifaxmin.

Approach to Positive Blood Cultures in the Hospitalized Patient: A Review.

The use of blood cultures as a diagnostic tool has increased over the years along with improvements in techniques and results. The diagnostic dilemma arises when blood cultures are positive and there is possibility of contamination. Hence obtaining blood cultures in the appropriate setting and the interpretation of blood cultures by the hospitalist is imperative to the management of the hospitalized patient.