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BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Background Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding US National Institutes of Health.

Patient navigation interventions can improve health outcomes in underserved, low-income, and racial and ethnic minority groups, who often experience health disparities. We examined the effectiveness of patient navigation to improve linkage to hepatitis C virus (HCV) treatment receipt in a socioeconomically disadvantaged, racially diverse patient population.We performed a pre-post analysis evaluating the effectiveness of a patient navigation program among baby boomers who tested positive for HCV in a safety-net health system. The usual care group (June 2013 to May 2015) and patient navigation group (January 2016 to December 2017) were balanced using a stabilized inverse probability of treatment weighting approach. We used logistic regression analyses to evaluate associations between patient navigation and linkage to care for HCV treatment evaluation, treatment initiation, and sustained virologic response.Among 1353 patients (62% black, 61% uninsured, 16% homeless), 769 were in the usual care group, and 584 were in the patient navigation group. The patient navigation group had significantly higher odds of linkage to care (odds ratio [OR], 3.7; 95% confidence interval [CI], 2.9-4.8) and treatment initiation (OR, 3.2; 95% CI, 2.3-4.2) within 6 months. The patient navigation group continued to have increased linkage to care (OR, 3.4; 95% CI, 2.7-4.3) and treatment initiation (OR 2.3; 95% CI, 1.7-3.0) at 12 months. However, there was no significant difference in sustained virologic response between the groups (86.9% vs 86.1%; P = .78).Patient navigation was associated with significantly increased linkage to care and treatment initiation among patients with HCV infection. Patient navigation programs can be used to promote HCV elimination among traditionally difficult-to-reach patient populations.

BACKGROUND & AIMS: Although serological markers of disease severity improve after hepatitis C virus (HCV) treatment, it is unclear if all patients experience sustained improvement. We aim to evaluate longitudinal changes in aspartate (AST), alanine (ALT) aminotransferase, platelet count (PLT), and fibrosis-4 (FIB-4) after HCV treatment. METHODS: All adult chronic HCV patients who received antiviral therapy from January 2011 to February 2017 at four large urban hospital systems were evaluated to assess changes in AST, ALT, PLT, and FIB-4 from pre-treatment to post-treatment annually up to 4 years after HCV therapy. Comparisons used Student's t-test and analysis of variance, and were stratified by sex, race, ethnicity, age, body mass index (BMI), and diabetes mellitus. RESULTS: Among 2691 patients (62.2% men, 76.9% aged 45–65 years, 56.5% white), all markers of disease severity demonstrated sustained improvements from pre-treatment to 4 years post-treatment (AST 53 U/L to 27.5 U/L, ALT 53 U/L to 29 U/L, PLT 168 × 10(3) to 176 × 10(3), FIB-4 2.51 to 1.68). However, Hispanics and patients with BMI >30 kg/m(2) experienced rebound increases in AST, ALT, and FIB-4 at 4 years post-treatment after experiencing initial improvements in these serological markers in the first-year post-treatment. Sustained improvements in PLT were observed in all groups, including Hispanics and patients with BMI >30 kg/m(2). CONCLUSION: HCV treatment in a large community-based cohort demonstrated sustained improvements in AST, ALT, PLT, and FIB-4. Rebound increases in AST, ALT, and FIB-4 observed in Hispanics and those with BMI >30 kg/m(2) may reflect persisting nonalcoholic fatty liver disease.

Background & Aims Advanced liver disease, which includes fibrosis and cirrhosis, has been reported to be more prevalent in Hispanics patients at the time of diagnosis of chronic hepatitis C virus (HCV) infection than non-Hispanic black or non-Hispanic white patients. We performed a propensity score-matched analysis to determine whether metabolic risk factors contribute to this disparity. Methods We collected data from persons with 748 HCV infection (22% Hispanic, 53% non-Hispanic black, and 26% non-Hispanic white; 23% with advanced liver disease), born from 1945 through 1965, diagnosed at 6 health care systems in Texas. Advanced liver disease was defined as a FIB-4 index score above 3.25. We examined the association between advanced liver disease and race or ethnicity, metabolic risk (based on diabetes mellitus and body mass index [BMI]) and heavy alcohol use in propensity score-matched analyses. Results In propensity-score matched models, among those who were obese (BMI ≥30) with a diagnosis of diabetes, the adjusted odds ratio of advanced liver disease for Hispanics vs non-Hispanic black was 7.89 (95% CI, 3.66–17.01) and adjusted odds ratio = 12.49 (95% CI, 3.24–48.18) for Hispanic vs non-Hispanic white patients (both P Conclusions HCV-infected Hispanics with obesity and diabetes have a far higher risk for advanced liver disease than other racial or ethnic groups. These findings highlight the need for HCV treatment and management of probable concurrent fatty liver disease. Even after we accounted for metabolic risk factors, Hispanics were still at higher risk for advanced liver disease, indicating the potential involvement of other factors such as genetic variants.

BACKGROUND: Using data from a randomized trial, we evaluated the cost of HCV care facilitation that supports moving along the continuum of care for HIV/HCV co-infected individuals with substance use disorder. METHODS: Participants were HIV patients residing in the community, initially recruited from eight US hospital sites. They received HCV care facilitation (n=51) or treatment as usual (n=62) for up to six months. We used micro-costing methods to evaluate costs from the healthcare sector and patient perspectives in 2017 USD. We conducted sensitivity analyses varying care facilitator caseloads and examined offsetting savings using participant self-reported healthcare utilization. RESULTS: The average site start-up cost was $6,320 (site range: $4,320–$7,000), primarily consisting of training. The mean weekly cost per participant was $20 (site range: $4–$30) for care facilitation visits and contacts, $360 (site range: $130- $700) for supervision and client outreach, and $70 (site range: $20–$180) for overhead. In sensitivity analyses applying a weekly caseload of 10 participants per care facilitator (versus 1–6 observed in the trial), the total mean weekly care facilitation cost from the healthcare sector perspective decreased to $110. Weekly participant time and travel costs averaged $7. There were no significant differences in other healthcare service costs between participants in the intervention and control arms. CONCLUSION: Weekly HCV care facilitation costs were approximately $450 per participant, but approximately $110 at a real-world setting maximum caseload of 10 participants per week. No healthcare cost offsets were identified during the trial period, although future savings might result from successful HCV treatment.

Background: Despite treatment with licensed antiviral agents, high rates of influenza-related morbidity and mortality occur worldwide. Methods: Adults hospitalized with laboratory-confirmed influenza were randomized (1:1) to a single double-blind infusion of high-titer anti-influenza intravenous immunoglobulin (hIVIG) or saline placebo. The primary endpoint was an ordered categorical outcome, ranging in severity from death to post-discharge resumption of normal activities, assessed at Day 7. The odds ratio (OR) (hIVIG versus placebo) of a favorable outcome was estimated with a proportional odds model. Findings: Of 308 randomized patients, 73% and 27% had influenza A and B, respectively; antiviral use was 95%. As expected, hIVIG produced a robust rise in influenza A hemagglutination inhibition (HAI) titers, and smaller rises in influenza B titers. Viral load declined after 3 days by 1.99 (hIVIG) versus 2.32 log10 copies/mL (placebo) (p=0.49). The OR for favorable outcome was 1.25 (95% confidence interval [CI] 0.79-1.97, p=0.33). ORs for influenza A and B were 0.94 (95% CI: 0.55-1.59) and 3.19 (95% CI: 1.21-8.42), respectively (p=0.02 for difference). This difference between influenza A and B was mirrored for secondary clinical outcomes, changes in viral load, and in sensitivity analyses, overall and by strain. To investigate this outcome further, anti-HA antibody affinities were measured in the hIVIG lots administered, and much stronger antibody affinities for B strains were observed than for A in hIVIG used. Interpretation: Overall, hIVIG was not superior to placebo for adults hospitalized with influenza. In contrast to our pre-study subgroup hypothesis based upon conventional HAI titers in hIVIG, benefit was evident for those with influenza B but not A. Consistent with findings of a contemporaneous anti-influenza plasma trial (IRC005), adjunctive immunotherapy appears ineffective for severe influenza A. The beneficial effect of hIVIG for influenza B is supported by antibody affinity analyses, but confirmation of clinical benefit is warranted. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02287467. Funding: NIAID, NIH. Declaration of Interest: There are no competing interests to declare in regard to this manuscript submission. Ethical Approval: The trial was approved by the institutional review board or ethics committee for each clinical site. All patients provided written informed consent.

Background People living with HIV who report substance use (PLWH-SU) face many barriers to care, resulting in an increased risk for poor health outcomes and the potential for ongoing disease transmission. This study evaluates the mechanisms by which Patient Navigation (PN) and Contingency Management (CM) interventions may work to address barriers to care and improve HIV outcomes in this population. Methods Mediation analysis was conducted using data from a randomized, multi-site trial testing PN interventions to improve HIV care outcomes among 801 hospitalized PLHW-SU. Direct and indirect effects of PN and PN + CM were evaluated through five potential mediators—psychosocial conditions, healthcare avoidance, financial hardship, system barriers, and self-efficacy for HIV treatment adherence—on engagement in HIV care and viral suppression. Results The PN + CM intervention had an indirect effect on improving engagement in HIV care at 6 months by increasing self-efficacy for HIV treatment adherence (β = 0.042, 95% CI = 0.008, 0.086). PN + CM also led to increases in viral suppression at 6 months (β = 0.090, 95% CI = 0.023, 0.168) and 12 months (β = 0.069, 95% CI = 0.009, 0.129) via increases in self-efficacy, although the direct effects were not significant. No mediating effects were observed for PN alone. Conclusion PN + CM interventions for PLWH-SU can increase an individual’s self-efficacy for HIV treatment adherence, which in turn improves engagement in care at 6 months and may contribute to viral suppression over 12 months. Building self-efficacy may be a key factor in the success of such interventions and should be considered as a primary goal of PN + CM in practice.

Liver-related complications such as hepatocellular carcinoma (HCC) are a major cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), particularly among those also infected with hepatitis B or hepatitis C viruses. There is a lack of consensus regarding the clinical presentation, treatment options, and outcomes in HIV-infected patients with HCC. We compared the clinical presentation, treatment, and survival of patients with HCC, with and without HIV infection.We conducted a retrospective cohort study of cirrhotic patients diagnosed with HCC at a large safety-net hospital between January 2005 and December 2010. Patients without known HIV serologic status were excluded. Demographic features, tumor characteristics, treatment regimens, and survival were compared between patients (n = 26) with and without HIV infection (n = 164). Survival curves were generated by using Kaplan-Meier plots and compared by using the log-rank test.A higher percentage of HIV-infected patients presented with compensated liver disease (Child-Turcotte-Pugh stage A) than those without HIV infection (62% vs 32%, respectively; P = .01), as well as those with early-stage tumors (Barcelona Clinic Liver Cancer stage A, 39% vs 17%, respectively; P = .04 and Okuda stage I, 50% vs 21%, respectively; P.01). HIV-infected patients were more likely to be cured of HCC than uninfected patients (27% vs 4%, respectively; P = .01), but median overall survival times were similar between groups (9.6 vs 5.2 months, respectively; P = .85). The 1-year rates of survival for HIV-infected and uninfected patients were 40% and 38%, respectively.HIV-infected patients present with earlier-stage HCC and more preserved liver function than uninfected patients, resulting in more curative treatment options. Despite this difference, overall survival was similar between patients with HCC with and without HIV infection.

function. Daidzein increased BrdU incorporation to ~30% and prevented hyperbilirubinemia in mice subjected to IR+PHX. While all mice survived after PHX, survival decreased to ~13% after IR+PHX. Daidzein increased survival after IR+PHX to ~88%.Conclusion. Suppression of MB after IR+PHX plays an important role in inhibition of liver regeneration and function. MB is a novel therapeutic target to improve the outcome of MLR (NIDDK).