Trends in characteristics and outcomes among US adults hospitalised with COVID-19 throughout 2020: an observational cohort study.

OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.

Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Patients chronically infected with the hepatitis B virus rarely achieve loss of serum hepatitis B surface antigen (HBsAg) with the standard of care. We evaluated HBsAg loss in patients receiving the combination of tenofovir disoproxil fumarate (TDF) and peginterferon α-2a (peginterferon) for a finite duration in a randomized trial. METHODS: In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus peginterferon for 48 weeks (group A), TDF plus peginterferon for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or peginterferon for 48 weeks (group D). The primary end point was the proportion of patients with serum HBsAg loss at week 72. RESULTS: At week seventy-two, 9.1% of subjects in group A had HBsAg loss compared with 2.8% of subjects in group B, none of the subjects in group C, and 2.8% of subjects in group D. A significantly higher proportion of subjects in group A had HBsAg loss than in group C (P < .001) or group D (P = .003). However, the proportions of subjects with HBsAg loss did not differ significantly between group B and group C (P = .466) or group D (P = .883). HBsAg loss in group A occurred in hepatitis B e antigen-positive and hepatitis B e antigen-negative patients with all major viral genotypes. The incidence of common adverse events (including headache, alopecia, and pyrexia) and treatment discontinuation due to adverse events was similar among groups. CONCLUSIONS: A significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone. ClinicalTrials.gov ID NCT01277601.

Association of baseline vitamin D levels with clinical parameters and treatment outcomes in chronic hepatitis B.

BACKGROUND & AIMS: The relationship between vitamin D levels and chronic hepatitis B (CHB) infection and treatment outcomes are poorly elucidated. We measured pre-treatment serum vitamin D (25-hydroxyvitamin D3; 25[OH]D3) levels and determined their association with clinical parameters and treatment outcomes in active CHB patients without advanced liver disease enrolled in a global clinical trial. METHODS: Patients were randomly assigned to either 48 weeks of tenofovir disoproxil fumarate (TDF) plus peginterferon alfa-2a (PegIFN), TDF plus PegIFN for 16 weeks followed by TDF for 32 weeks, PegIFN for 48 weeks, or TDF for 120 weeks. Univariate and multivariate analyses were conducted to determine associations between vitamin D, baseline factors, and week 48 clinical outcome. RESULTS: Of 737 patients, 35% had insufficient (⩾20 but <31 ng/ml) and 58% had deficient (<20 ng/ml) vitamin D levels. In univariate analysis, lower vitamin D levels were significantly associated with the following baseline parameters: younger age, lower uric acid levels, HBeAg-positive status, lower calcium levels, blood draw in winter or autumn, and HBV genotype D. On multivariate analysis, only HBV genotype, season of blood draw, calcium level, and age retained their association. High baseline level of vitamin D was associated with low HBV DNA, normal ALT and HBsAg at week 48 independent of treatment groups, but the association, with the exception of ALT, became statistically insignificant after adjusting for age, gender, HBeAg and HBV genotype. CONCLUSIONS: Abnormally low vitamin D levels are highly prevalent among untreated, active CHB patients. Baseline vitamin D levels are not associated with treatment outcomes, but were associated with normal ALT.

Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia-Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis. AIM: This study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment. METHODS: Post hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, open-label TDF for up to 240 weeks was evaluated. Patients with both baseline and week 240 liver biopsies were evaluated for histologic changes. RESULTS: At baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and non-Asian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-to-treat analysis, 74 % of Asian patients and 76 % of non-Asian patients had HBV DNA <400 copies/mL at the end of week 240 (P = 0.602). No differences were seen in HBeAg loss or seroconversion in Asian versus non-Asian patients. No Asian patient experienced hepatitis B surface antigen loss. Safety and tolerability of TDF through week 240, including changes in renal function and in hip/spine bone mineral density (from weeks 192 to 240), were comparable between Asian and non-Asian patients. CONCLUSIONS: Long-term virologic and histologic efficacy and safety of TDF are comparable in Asian and non-Asian CHB patients.

Baseline interpatient hepatitis B viral diversity differentiates HBsAg outcomes in patients treated with tenofovir disoproxil fumarate.

BACKGROUND AND AIMS: HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss. METHODS: This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity. RESULTS: Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region. CONCLUSION: In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements.

Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection.

BACKGROUND: Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks). AIM: We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients. METHODS: Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks). RESULTS: Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine ≥ 0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336). CONCLUSIONS: Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB.

Mechanisms of HCV survival in the host.

HCV infection is an important cause of liver disease worldwide-nearly 80% of infected patients develop chronic liver disease, which leads to the development of liver cirrhosis and hepatocellular carcinoma. The ability of HCV to persist within a host is believed to be related to the numerous mechanisms by which it evades the immune response of the host. These mechanisms can be divided into defensive and offensive strategies. Examples of defensive mechanisms include replication within enclosed structures, which provides protection from the host's antiviral defenses, genetic diversity created by inaccurate replication, which yields mutants resistant to the cell's antiviral strategies, and association of the virion with protective lipoproteins. Offensive mechanisms include virally encoded proteins and other factors that disrupt the ability of the host cells to detect the virus and downregulate its ability to respond to interferon, impair innate immune defense mechanisms and alter T-cell responses, and prevent the development of an effective B-cell-mediated humoral response. Greater understanding of these viral survival strategies will ultimately translate into more effective antiviral therapies and better prognosis for patients.

Diagnostic markers for hepatitis virus infection.

BACKGROUND: Accurate diagnosis and characterization of hepatitis viruses are essential from a public health perspective and for clinical management. OBJECTIVE: To review recent advances in the diagnosis of viral hepatitis A - D and their clinical utilities. METHODS: Review of the literature published up to 2007. RESULT/CONCLUSION: Recent advances in the sensitivity and ease of serologic and molecular diagnostics have improved our understanding of the natural history of viral hepatitis, are helpful in the pretreatment evaluation and provide guidance to antiviral therapy. As the technology improves, this will be reflected in an increased reliance and expanded role of these tests in clinical management and improved safety of the blood supply.