COVID-19 therapies for inpatients: a review and quality assessment of clinical guidelines.

Owing to condensed development processes, expanding evidence and differences in healthcare system characteristics, many COVID-19 guidelines differ in their quality and treatment recommendations, which has consequences for clinical practice. This review aimed to identify COVID-19 treatment guidelines, assess their quality and summarise their recommendations. Guidelines were identified for five therapies most commonly used among inpatients with COVID-19 (remdesivir, dexamethasone, tocilizumab, baricitinib and casirivimab/imdevimab) from 11 countries. Guideline quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool. Full details of recommendations and supporting evidence were analysed for high-quality guidelines, defined as those scoring ≥50% in Domain 3 (Rigour of Development) of AGREE-II. Overall, guidelines differed substantially in their quality and, even among high-quality guidelines using the same evidence, recommendations regarding specific therapeutics varied. Potential reasons for this heterogeneity, including the availability and consistency of clinical data, visibility of trial end-points and context-specific factors, are discussed.

Renal safety profile of STB in virologically suppressed subjects from two randomized phase 3b switch trials.

INTRODUCTION: Cobicistat, a component of stribild (STB), is known to inhibit renal creatinine secretion. A detailed analysis of the renal safety profile of STB in two Phase 3b switch studies of virologically-suppressed individuals on stable therapy: STRATEGY(S)-PI (STB vs a RTV-boosted protease inhibitor [PI] with emtricitabine and tenofovir DF [FTC/TDF]); and STRATEGY(S)-NNRTI (STB versus a non-nucleoside reverse transcriptase inhibitor [NNRTI] with FTC/TDF) is herein described. MATERIALS AND METHODS: Baseline eGFR ≥70 mL/min was an inclusion criterion. The renal safety profile of STB was examined by baseline eGFR through week 48 (i.e., changes in eGFR, renal tubular laboratory abnormalities, investigator-reported renal adverse events leading to discontinuation and unreported subclinical proximal renal tubulopathy [PRT]). Subclinical PRT was defined as a confirmed serum-creatinine increase ≥0.4 mg/dL and two or three markers of renal tubular dysfunction (hypophosphatemia, normoglycemic glycosuria, proteinuria) occurring at the same visit at least once and with no alternative etiologies. RESULTS: In S-PI, 433 subjects (STB 293; PI 140) and in S-NNRTI, 434 subjects (STB 291; NNRTI 143) were randomized and treated. Most (>85%) STB subjects had a baseline eGFR ≥90 mL/min. STB subjects with baseline eGFR <90 mL/min had smaller declines in eGFR compared to those with baseline eGFR ≥90 mL/min and similar occurrences of renal tubular laboratory abnormalities (Table 1). Rate of renal adverse events leading to study drug discontinuation were similar for the STB group (one PRT in a subject with baseline tubular laboratory abnormalities consistent with underlying PRT and one isolated increase in serum creatinine) and PI group (one isolated decrease in eGFR); none in the NNRTI group. The case of PRT improved after study drug discontinuation. There were no cases of unreported subclinical PRT in any group. CONCLUSIONS: In this virologically suppressed patient population, the renal safety of STB did not differ by baseline eGFR. The renal discontinuation rate was low in the STB group, similar to the RTV-boosted PI group, and consistent with published historical rates.

Histologic evidence of active liver injury in chronic hepatitis B patients with normal range or minimally elevated alanine aminotransferase levels.

GOALS: To evaluate the proportion of patients with histologic evidence of active liver disease (HEALD) who have chronic hepatitis B (CHB) and normal/minimally elevated serum alanine aminotransferase (ALT). Sub-analysis was performed to determine whether HEALD based upon liver biopsy better correlates with ALT using modified ALT (30 men/19 women) upper limit of normal (ULN) criteria compared with local conventional laboratory. BACKGROUND: There are limited data on CHB with normal range ALT (NRALT). We designed a study to evaluate histologic damage in this cohort of patients. STUDY: A retrospective, multicenter study evaluated CHB patients with normal/minimally elevated ALT [< or = 1.2 x ULN (hepatitis B e antigen positive) or < or = 1.5 x ULN (hepatitis B e antigen negative)]. Liver biopsy specimens were reviewed by an independent histopathologist. HEALD was defined as Knodell necroinflammatory score greater than 5 and Ishak fibrosis stage greater than 1. RESULTS: Forty-five patients met criteria: median age of 40 years; 51% males; 73% Asian; and 67% hepatitis B e antigen negative. Median hepatitis B virus DNA was 6.04 log10 copies/mL, aspartate aminotransferase (AST) 30 IU/L, and ALT 42 IU/L; and 40% of the patients had ALT greater than ULN. Overall, 20% had HEALD and among patients with NRALT, 4 of 27 (15%) and 0 of 5 (0%) had HEALD through conventional or modified ALT ULN, respectively. CONCLUSIONS: One fifth of patients with CHB and normal/minimally elevated ALT had HEALD. Among the subset of patients with NRALT, 15% (4 of 27) had HEALD when using conventional laboratory compared with 0% (0 of 5) patients by modified ALT ULN criteria. Use of the modified ALT ULN will likely improve accuracy in identifying patients who may have HEALD compared with conventional laboratory ULN.