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BackgroundThe COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders.MethodsThe primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity.ResultsOf the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60–66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed.ConclusionsAn additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.Clinical Trials Registration. EUCTR2021-001054-57-N.

Background & Aims: Patients with chronic or resolved hepatitis B are at risk of hepatitis B reactivation (HBVr) when treated with high-risk immunosuppressive therapy such as rituximab. Therefore, international guidelines recommend HBV screening prior to rituximab treatment and subsequent antiviral prophylaxis among patients with a (resolved) infection. In this study, we evaluated the adherence to those recommendations. Methods: This is a retrospective multicentre study including patients treated with rituximab between 2000-2021. Performance of correct screening was assessed, defined as the measurement of hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc). Next, initiation of antiviral prophylaxis and HBVr rate among patients with a chronic or resolved HBV infection was studied. Results: We enrolled 3,176 patients of whom 1,448 (46%) were screened correctly. Screening rates differed significantly between academic and non-academic hospitals; respectively 65% vs 32% (p

Background: Invasive mechanical ventilation is the treatment of choice in COVID-19 patients when hypoxemia persists, despite maximum conventional oxygen administration. Some frail patients with severe hypoxemic respiratory failure are deemed not eligible for invasive mechanical ventilation. Objectives: To investigate whether High-flow nasal cannula (HFNC) in the wards could serve as a rescue therapy in these frail patients. Methods: This retrospective cohort study included frail COVID-19 patients admitted to the hospital between March 9th and May 1st 2020. HFNC therapy was started in the wards. The primary endpoint was the survival rate at hospital discharge. Results: Thirty-two patients with a median age of 79.0 years (74.5–83.0) and a Clinical Frailty Score of 4 out of 9 (3–6) were included. Only 6% reported HFNC tolerability issues. The overall survival rate was 25% at hospital discharge. Conclusions: This study suggests that, when preferred, HFNC in the wards could be a potential rescue therapy for respiratory failure in vulnerable COVID-19 patients.

BackgroundThe COVIH study is a prospective SARS-CoV-2 vaccination study in people living with HIV (PLWH). Of the 1154 PLWH enrolled, 14% showed a reduced or absent antibody response after a primary vaccination regimen. As the response to an additional vaccination in PLWH with hyporesponse is unknown, we evaluated whether an additional vaccination boosts immune responses in these hyporesponders.MethodsConsenting hyporesponders received an additional 100 µg of mRNA-1273. Hyporesponse was defined as ≤300 spike(S)-specific binding antibody units [BAU]/mL. The primary endpoint was the increase in antibodies 28 days after the additional vaccination. Secondary endpoints were the correlation between patient characteristics and antibody response, levels of neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity.ResultsOf the 75 PLWH enrolled, five were excluded as their antibody level had increased to >300 BAU/mL at baseline, two for a SARS-CoV-2 infection before the primary endpoint evaluation and two were lost to follow-up. Of the 66 remaining participants, 40 previously received ChAdOx1-S, 22 BNT162b2, and four Ad26.COV2.S. The median age was 63 [IQR:60-66], 86% were male, pre-vaccination and nadir CD4+ T-cell counts were 650/μL [IQR:423-941] and 230/μL [IQR:145-345] and 96% had HIV-RNA 300 BAU/mL in 64/66 (97%) with a mean increase of 4282 BAU/mL (95%CI:3241-5323). No patient characteristics correlated with the magnitude of the antibody response nor did the primary vaccination regimen. The additional vaccination significantly increased the proportion of participants with detectable ancestral S-specific B-cells (p=0.016) and CD4+ T-cells (p=0.037).ConclusionAn additional mRNA-1273 vaccination induced a robust serological response in 97% of the PLWH with a hyporesponse after a primary vaccination regimen. This response was observed regardless of the primary vaccination regimen or patient characteristics.

BackgroundVaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown.Methods and FindingsA prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S and Ad26.COV2.S vaccines in adult PLWH, without prior COVID-19, compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response and reactogenicity.Between February-September 2021, 1154 PLWH (median age 53 [IQR 44-60], 86% male) and 440 controls (median age 43 [IQR 33-53], 29% male) were included. 884 PLWH received BNT162b2, 100 mRNA-1273, 150 ChAdOx1-S, and 20 Ad26.COV2.S. 99% were on antiretroviral therapy, 98% virally suppressed, and the median CD4+T-cell count was 710 cells/µL [IQR 520-913]. 247 controls received mRNA-1273, 94 BNT162b2, 26 ChAdOx1-S and 73 Ad26.COV2.S. After mRNA vaccination, geometric mean concentration was 1418 BAU/mL in PLWH (95%CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV-status remained associated with a decreased response (0.607, 95%CI 0.508-0.725). In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+T-cell counts 250-500 cells/µL (2.845, 95%CI 1.876-4.314) or >500 cells/µL (2.936, 95%CI 1.961-4.394), whilst a viral load >50 copies/mL was associated with a reduced response (0.454, 95%CI 0.286-0.720). Increased IFN-γ, CD4+, and CD8+T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation induced marker assays, comparable to controls. Reactogenicity was generally mild without vaccine-related SAE.ConclusionAfter vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH. To reach and maintain the same serological responses and vaccine efficacy as HIV-negative controls, additional vaccinations are probably required.

To evaluate the implementation of home telemonitoring and oxygen therapy in COVID-19 patients. Primary outcomes were safety, patient satisfaction, reduction of hospital stay, and cost-effectiveness.Retrospective cohort study.All COVID-19 patients who were discharged with home telemonitoring and oxygen therapy between June 1st and November 1st 2020 were included. Eligible patients had a maximum oxygen requirement of 2 liters per minute during the 24 hours prior to discharge with a minimal peripheral oxygen saturation of 94%. A mobile application for telemonitoring was used, which patients or relatives had to be able to use independently. Patient demographics, clinical parameters, data on telemonitoring and readmissions were extracted from the electronic patient records. A survey for patient satisfaction and a cost-effectiveness analysis were performed.Out of 619 admissions, 49 patients were discharged with home telemonitoring and oxygen therapy. Median duration of home oxygen therapy was 11 days with a potential reduction in hospitalization of 616 days. Six patients were readmitted and were significantly more febrile on discharge (67% versus 14%, p=0.01) and had lower oxygenation (95%, (IQR 93-96) versus 96%, (IQR 95-97), p=0.02) with similar levels of oxygen administration. Patient satisfaction was high with a mean score of 5 to 6 on a scale measuring satisfaction from 1 to 7. Estimated total cost reduction was € 146.736.This study shows that home telemonitoring and oxygen administration can be safely applied in COVID-19 patients resulting in a high patient satisfaction and reduction in hospital stay and costs.

Background: In the midst of the COVID-19 crisis, many frail elderly adults were admitted to our hospital with COVID-19. Some faced severe respiratory failure but were not eligible for invasive mechanical ventilation, due to frailty, functional status, comorbidity or wish of the patient. Our main objective was to investigate whether High-flow nasal cannula (HFNC) treatment on the wards could be an effective alternative treatment for these patients.Methods: A retrospective cohort study amongst COVID-19 adult patients with respiratory failure defined as persisting hypoxemia despite maximum conventional oxygen administration requiring invasive mechanical ventilation in the Intensive Care Unit (ICU) but being treated with HFNC as they were non-eligible due to frailty or wish of the patient.Results: The study included 32 patients between March 9th and May 1st, 2020. The median age was 79.0 years (74.5-83.0) with a median of three comorbidities (3-4) and a median Clinical Frailty Score of 4 out of 9 (3-6). The median SpO2/FiO2 Ratio was 157.5 indicating moderate ARDS. Overall survival rate in the HFNC cohort was 25%. Age (80.5 (78.0-84.3) vs 69.5 (65.5-74.3) p=0.0040) and hypertension (92% vs 25%, p=0.0008) were correlated with mortality.Conclusion: This study suggests that HFNC could be an effective last resort respiratory management strategy for respiratory failure in vulnerable elderly COVID-19 patients who failed on conventional high dose oxygen supply and are not eligible for invasive mechanical ventilation.

Hypercoagulation is one of the most distinct prognostic factors of patients with COVID-19 and has been associated with arterial thrombosis and other venous thrombotic events (VTE). Bleeding complications are far less encountered. The International Society on Thrombosis and Haemostasis (ISTH) guidance advises giving prophylactic low-molecular-weight heparin (LMWH) to prevent these events, although there is evidence that the incidence remains high despite using prophylactic LMWH. We describe three cases of COVID-19 pneumonia that were admitted to our intensive care unit (ICU) and developed acute pulmonary embolisms (APE) despite high dosage prophylactic LMWH. These cases raise concerns about using prophylactic LMWH instead of therapeutic anticoagulation in severe and critically COVID-19 patients., Highlights • Hypercoagulation is one of the most distinct prognostic factors in COVID-19. • Despite prophylactic LMWH COVID-19 patients develop thrombotic complications. • Immune-thrombosis is a potential mechanism contributing to thrombotic complications.

Structured abstract for full paperBackgroundAfter recovery from COVID-19, most patients have anti-SARS-CoV-2 neutralizing antibodies. Their convalescent plasma could be an inexpensive and widely available treatment for COVID-19.MethodsThe Convalescent-plasma-for-COVID (ConCOVID) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands. Patients were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80. The primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.ResultsThe trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline. A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) patients tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40). These observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board, the study was discontinued. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care.ConclusionMost COVID-19 patients already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma. Clinicaltrials.gov:NCT04342182

Background: In the midst of the COVID-19 crisis, many frail elderly were admitted to our hospital with COVID-19. We sought a treatment for those who had severe respiratory failure but were not eligible for invasive mechanical ventilation, due to frailty, functional status, comorbidity or wish of the patient. We started with applying High-flow nasal cannula (HFNC) treatment on the wards.Methods: A retrospective cohort study amongst COVID-19 adult patients with respiratory failure defined as persisting hypoxemia despite maximum conventional oxygen administration requiring invasive mechanical ventilation at the Intensive Care Unit (ICU) but being treated with HFNC as they were non-eligible due to frailty or wish of the patient.Results: We included 32 patients between March 9 and May 1, 2020. The median age was 79.0 years (74.5-83.0) with a median of three comorbidities (3-4) and a median Clinical Frailty Score of 4 out of 9 (3-6). The median SPO2/FiO2 Ratio was 157.5 indicating moderate ARDS. Overall survival rate in the HFNC cohort was 25%. Age (80.5 (78.0-84.3) vs 69.5 (65.5-74.3) p=0.0040) and hypertension (92% vs 25%, p=0.0008) were associated with mortality.Conclusion: HFNC can be used as a last resort respiratory management strategy in vulnerable elderly COVID-19 patients in respiratory failure on the wards who failed on conventional high dose oxygen supply and are not eligible for invasive mechanical ventilation.

Background: In the Netherlands, access to direct-acting antivirals (DAA) against hepatitis C virus (HCV) infection has been unrestricted for chronic infection since 2015. We evaluated whether this changed the nationwide incidence of HCV primary and re-infection among HIV-positive individuals. Methods: Individuals participating in the national ATHENA HIV cohort between 2000-2018 were included. Incidence rates (IR) of HCV primary infection and re-infection were calculated per calendar year using piecewise exponential survival models. Findings: Among 22,775 individuals without prior HCV, 651 cases of HCV primary infection were documented (IR=2·9/1,000 person-years, 95%CI=2·7-3·1). The highest IR was observed in men who have sex with men (MSM) (4·5/1,000 person-years, 95%CI=4·1-4·8) and much lower among people who inject drugs (PWID) (0·8/1,000 person-years, 95%CI=0·4-1·6) and other transmission groups (0·2/1,000 person-years, 95%CI=0·1-0·4). In MSM, IR increased dramatically in 2007 (IR=8·3/1,000 person-years) and fluctuated between 4·6 and 8·6/1,000 person-years from 2008-2015. In 2016, IR declined to 2·6 cases/1,000 person-years and remained steady in 2017 and 2018 (IR=2·8 and 1·7/1,000 person-years, respectively). Among 1917 individuals with a previous HCV infection, 249 HCV re-infections were documented (IR=26·0/1,000 person-years, 95%CI=23·0-29·5). The highest IR was again observed in MSM (38·4/1,000 person-years, 95%CI=33·6-44·0) and was lower among PWID (5·5/1,000 person-years, 95%CI=2·1-14·6) and other transmission groups (9·5/1,000 person-years, 95%CI=6·7-13·5). In MSM, re-infection IRs fluctuated until 2015, reaching 51·4/1,000 person-years. In 2016, re-infection incidence declined to 37·0/1,000 person-years, followed by a further decrease in 2017 and 2018 (IR=25·1 and 15·1/1,000 person-years, respectively). Interpretation: The observed sharp decline in HCV incidence among HIV-positive MSM shortly after unrestricted DAA access suggests a “treatment-as-prevention” effect. HCV incidence was already low in PWID and other groups prior to unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but nonetheless high rate of reinfection, stressing the need for additional preventive measures. Funding: Dutch Ministry of Health, Welfare and Sport Conflict of Interest: BJAR reports grants from MSD and Gilead, all outside the submitted work; he hasparticipated in advisory boards organized by MSD, Gilead, Pfizer, ViiV Healthcare, Jansen Cilag, and Abbvie. EMM reports participating an advisory board of Gilead. WB reports other funds from GSK and non-financial support from Janssen, all outside the submitted work. KB reports participating in advisory boards of ViiV, Gilead, MSD and Janssen; he has received research grants form ViiV and Gilead. JS reports grants from Gilead Sciences, outside the submitted work. MP reports grants, personal fees and other funds from Gilead Sciences,Roche, MSD and Abbvie, all outside the submitted work. JA reports other funding fromGilead Sciences, Janssen-Cilag, Abbvie, BSM, and MSD, all outside the submitted work.MvdV reports grants and personal fees from Abbvie, Gilead, Johnson & Johnson, MSD, ViiV Healthcare, all outside the submitted work. All other authors report no conflicts of interest. PR reports grants from Gilead Sciences, ViiV Healthcare, and Merck & Co, and other funds from Gilead Sciences, ViiV Healthcare, Merck & Co, and Teva Pharmaceutical Industries, alloutside the submitted work. Ethical Approval: At its inception, the ATHENA cohort was approved by the institutional review boards of all participating centres. Individuals can opt out after being informed by their treating physician of the purpose of data and sample collection. Data are pseudonymized and made available to investigators in a coded form. Coded data may be used for scientific purposes without further consent. For the purpose of our analysis, only existing data have been used and therefore no additional review or consent was required.

Contains fulltext : 167321.PDF (Publisher’s version ) (Open Access) BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.