Clinical characteristics and outcome of hospitalized elderly patients with COVID- 19 after vaccine failure.

We described clinical characteristics and outcome of 160 patients over 65 years (01 September to 31 August 2021) who had a first positive SARS-CoV-2 PCR- test more than 14 days after full vaccination and were hospitalized with COVID-19. Median age of included patients was 84 years, 61.2% were over 80 years; 50.6% were male and most (82.5%) has at least one comorbidity. Up to 84% received specific treatment against COVID-19, including 76.9% low-flow oxygen therapy. We found that overall mortality was 25.6% and 30.6% in those older than 80 years. A higher mortality was significantly associated with older age and treatment with tocilizumab. Our data showed that although COVID-19 vaccines continue protecting elderly patients against hospitalization and death and might improve the prognosis after hospitalization in patients with breakthrough infections, mortality in this population -especially in those older than 80 years- remains very high.

TDF/FTC for HIGH-RISK PATIENTS with COVID-19: The PANCOVID RANDOMIZED CLINICAL TRIAL

Background: Some in vitro, animal, and epidemiological data suggest that tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) might be an efficacious treatment for COVID-19 Methods: In a multicenter open-label, pragmatic, randomized trial in 25 hospitals in Spain we included participants with symptomatic SARS-CoV-2 detected by PCR or antigenic test, with a creatinine clearance > 60 mL/min, > 60 years or younger if they had at least 2 comorbidities (hypertension, obesity, diabetes, cirrhosis, chronic neurologic disease, active cancer, heart failure, coronary heart disease or COPD). Participants were randomized to receive or not TDF/FTC. Randomization was stratified by age group, symptoms duration (< or ≥ 5 days) and health care setting (hospitalized, long-term care facility, ambulatory). Primary outcome was 28 days mortality. Secondary outcomes were disease progression (increased O2 requirements, need for mechanical ventilation or increase in medical therapy: steroid dose, need for tocilizumab). At any moment during the trial participants with room air O2 saturation < 95% and ≥ 1 increased inflammatory biomarker could be randomized to dexamethasone (D) or dexamethasone plus baricitinib (DB) Results: 355 participants included (TDF/FTC n=177, no TDF/FTC n=178), median age 67 years (IQR 62-73), male (64.5%), median days of symptoms 8 (IQR 5-10), 29% with < 5 days of symptoms, 96.9% hospitalized, 35.5% with 1 and 36.6 % with ≥ 2 comorbidities (62.8% hypertension, 9.3% diabetes, 1.7% obesity), median room air SaO2 95% (IQR 94-96), 63% receiving O2 and 11.8% Remdesivir. 74% of participants were simultaneously randomized to D or DB. There were not statistically significant differences in endpoints in participants not treated vs.treated with TDF/FTC: mortality 2.2%/4.0%, disease progression 23.6%/22.0%, deferred randomization to D or DB 6.7%/6.2%, mechanical ventilation (invasive or noninvasive) 22.5%/20.3%, days since randomization until discharge (median [IQR]) 7 [5,14]/6 [4,12], discharge before 28 days 91.9%/89.7%. By Cox regression Hazard Ratio (95% CI) of 28-day mortality was 1.96 (0.55-7.01) for participants treated with TDF/FTC. Serious adverse events occurred in 6.18%/5.65% of participants not treated/treated with TDF/FTC. Adverse events leading to TDF/FTC discontinuation occurred in 2.26%. Conclusion: In this clinical trial of high-risk patients with COVID-19 TDF/FTC did not improve disease outcomes. Overall mortality was unexpectedly low.

BARICITINIB for HIGH-RISK PATIENTS with COVID-19: The PANCOVID RANDOMIZED TRIAL

Background: Recent studies suggest that baricitinib added to dexamethasone may reduce mortality in hospitalized COVID-19 patients requiring supplemental oxygen Methods: In a multicenter open-label, pragmatic, randomized clinical trial in 25 hospitals in Spain we included symptomatic participants with SARS-CoV-2 detected by PCR or antigenic test, with a creatinine clearance >60 mL/min, > 60 years or younger if they had at least two comorbidities (hypertension, obesity, diabetes, cirrhosis, chronic neurologic disease, active cancer, heart failure, coronary heart disease or COPD). Participants were initially randomized to receive or not tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). At any moment during the trial participants with room air 02 saturation < 95% and at least one increased inflammatory biomarker could be randomized to dexamethasone (D) or dexamethasone plus baricitinib (DB). Primary outcome was 28 days mortality. Secondary outcomes were disease progression (increase of O2 requirements, mechanical ventilation or increase in medical therapy: steroid dose, need for starting tocilizumab) Results: Out of the 355 participants included in the trial 287 (80.8%) were randomized to D (n=142) or DB (n=145), 264 (91.9%) simultaneously with the TDF/FTC randomization and 23 (8.1%) later on. Median age 67 years (IQR 62, 73), male (65.5%), with median 8 days of symptoms (IQR 5-10), 28.6% with ≤ 5 days of symptoms, 100% hospitalized, 31.6% with one and 38.7% with ≥ 2 comorbidities (most common: 35.9% hypertension, 9.4% diabetes, 1.7 % obesity), 14.3% receiving remdesivir and 49.1% TDF/FTC. Endpoints in participants treated with D vs. those treated with DB favored DB without achieving statistical significance: mortality 4.9%/2.1%, disease progression 27.5%/24.8%, mechanical ventilation (invasive or noninvasive) 25.4%/23.4%, days since randomization until discharge (median [IQR]) 7 [5, 12]/7 [5, 13.5], discharge before 28 days 89%/94.2%. By Cox regression Hazard Ratio (95% CI) of 28-day mortality was 0.51 (0.13-2.06) for participants treated with DB. Serious adverse events occurred in 9.9%/9.7% of participants treated with D or DB respectively. Adverse events leading to B discontinuation occurred in 3.45% of participants. Conclusion: In this clinical trial of high-risk patients with COVID-19 all disease outcomes favored baricitinb added to dexamethasone but differences did not reach statistical significance. Overall mortality was unexpectedly low.

TENOFOVIR DISOPROXIL FUMARATE and SEVERITY of COVID-19 in PEOPLE with HIV INFECTION

Background: Effective, safe, and affordable antivirals are needed for COVID-19. Several lines of reseach suggest that tenofovir may be effective against COVID-19 but no large-scale human studies with appropriate adjustment for comorbidities have been conducted. We describe the incidence, clinical severity and mortality of laboratory-confirmed SARS-CoV-2 infection by antiretroviral therapy (ART) among HIV-positive individuals with virological control adjusting for key potential confounders including hypertension, diabetes, chronic renal disease, cardiovascular disease, and treatment with immunosuppressants or corticosteroids. Methods: We studied HIV-positive individuals on ART in 2020 at 69 HIV clinics in Spain from February 1 to December 31. These 69 clinics serve approximately 44% of all persons on ART with virological suppression in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared 48-week risks, relative risks, relative differences and 95% confidence intervals (CI) for individuals receiving tenofovir disoproxyl fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting. Results: Of 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals. Conclusion: Our findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older. Confirmatory randomized trials of TDF/FTC for the prophylaxis and early treatment of COVID-19 are warranted.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

COVID-19 in hospitalized HIV-positive and HIV-negative patients: A matched study

Background: We compared the characteristics and clinical outcomes of hospitalized patients with COVID-19 with and without HIV infection (HIV-pos and HIV-neg) in Spain during the first wave of the pandemic. Methods: HIV-pos were identified by reviewing clinical records and laboratory registries of 10,922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to June 30, 2020. Each HIV-pos was matched with 5 HIV-neg of the same age and sex randomly selected from COVID-19@Spain, a multicenter cohort of 4,035 patients hospitalized with PCR confirmed COVID-19 in Spain (Clin Microbiol Infect 2020;26:1525-36). Data were collected with the ISARIC-WHO Core case report form (https://isaric.org/document/COVID-19-crf/). The COVID-19 SEIMC score (predictive of 30-day mortality), based on age, sex, dyspnea, O2 saturation, neutrophil-to-lymphocyte ratio, and estimated glomerular filtration rate, was calculated at admission in all patients (ESCMID Conference on Coronavirus Disease, 2020, Abstract#00513). Outcomes included the need for mechanical ventilation and all-cause in-hospital mortality. Results: Forty-five patients with PCR confirmed COVID-19 were identified in CoRIS, 21 of which were hospitalized. A total of 105 age/sex-matched controls were selected from COVID-19@Spain. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In HIV-pos, 19.1% were IDUs, 95.2% were on ART, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4+ count was 595 (349-798) cells/mm3. No statistically significant differences were found between groups in number and type of comorbidities, presenting signs and symptoms, laboratory parameters, and radiology findings. The median (Q1-Q3) COVID-19 SEIMC score on admission was 4 (2-7) and 5 (3-7) in HIV-pos and HIV-neg, respectively;P=.890. Corticosteroids were administered to 33.3% and 27,4% HIV-pos and HIV-neg, respectively;P=.58. Remdesivir was administered to 0 and 2.9% of HIV-pos and HIV-neg, respectively;P=.426. During admission, 9.5% HIV-pos and 23.3% HIV-neg underwent mechanical ventilation;P=.158. In-hospital mortality was 9.5% in HIV-pos and 11.4% in HIV-neg;P=.800. Conclusion: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes in patients hospitalized with COVID-19. (Figure Presented).

Prevalence and factors associated with SARS-CoV-2 antibodies in a Spanish HIV cohort

Background: Within a prospective cohort of people with HIV (PWH) in Spain, we assessed the prevalence of SARS-CoV-2 antibodies (Ab), the proportion of asymptomatic COVID-19, and identified predictors of infection. Methods: We determined SARS-CoV-2 Ab in plasma samples collected from April 1st to September 30th, 2020, from enrollees in the Spanish HIV Research Network Cohort (CoRIS), a prospective national cohort of PWH, naive to ART at study entry, seen for the first time from January 1st, 2004. Samples were stored at-80°C in the Spanish HIV BioBank, and serology was performed using the Platelia SARS-CoV-2 Total Ab assays (BioRad, Hercules, CA, USA). Illness severity (NIH criteria) was assessed by medical records review and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes, non-AIDS related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, and N(t)RTI backbone. Results: During the study period, blood samples were collected and stored in the HIV BioBank from 1,076 consecutive PWH in CoRIS: 88.0% male at birth, median age 43 yr., 72.3% MSM, 97.7% on ART, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load. SARS-CoV-2 Ab were detected in 91 PWH, for a seroprevalence of 8.5% (95%CI: 6.9%-10.3%). A total of 41 PWH (45.0%) had asymptomatic infections;the disease was mild in 43 (47.3%), moderate in 4 (4.4%), severe in 3 (3.3%), and 0 critical. Seven PWH (7.7%) were hospitalized. COVID-19 was confirmed by RT-PCR in 22 (24.2%) PWH. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American (LA) Countries vs. Spain (adjusted odds ratio [aOR]: 2.34, 95%CI: 1.42-3.85;P=.001);arterial hypertension (aOR: 1.63, 95%CI: 1.00-2.67;P=.050);and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) vs tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR: 0.32, 95%CI: 0.12-0.84;P=.021). (Table). Conclusion: A large proportion of SARS-CoV-2 infections among PWH were asymptomatic. Birth in LA-countries and arterial hypertension were associated with increased risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggest that TDF/FTC may prevent SARS-CoV-2 infection among PWH. (Figure Presented).

Impact of concomitant hydroxychloroquine use on safety and efficacy of remdesivir in moderate COVID-19 patients

Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Hydroxychloroquine (HQN) is an experimental treatment for COVID-19. Effects of coadministration of HQN with RDV have not been studied and are relevant given the long half-life (∼22 days) of HQN. We report the impact of concomitant HQN and RDV use on clinical outcomes and safety in patients with moderate COVID-19. Methods: We enrolled hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation >94% on room air, and radiological evidence of pneumonia. Patients were randomized 1:1:1 to receive 5d or 10d of intravenous RDV once daily plus standard of care (SoC), or SoC only. We compared patients on concomitant HQN (HQNpos) vs not (HQNneg). Clinical recovery was evaluated using Cox proportional hazards. Covariate adjustment included age, sex, race, region, symptom duration, oxygen support status and obesity. Recovery and adverse events (AEs) were assessed through death, discharge, or d14. Results: Of 584 patients, 199 (34%) received HQN (5d RDV: n=57 [30%];10d RDV, n=49 [25%];SoC: n=93 [47%]). Through median follow-up of 13d (range 1-41d), HQNpos patients on 5d or 10d RDV had a lower recovery rate (adjusted HR [95% CI] 0.78 [0.59, 1.03], p=0.09) with longer median time to recovery (8 vs 6 days) compared to HQNneg. HQNpos compared to HQNneg patients in 5d RDV showed a trend of reduced recovery rate (HR: 0.69 [0.45,1.04], p=0.080);such an effect was not observed in 10d RDV or SoC (Table 1). More HQNpos than HQNneg patients had AEs in RDV (5/10d) or SoC arms evaluated separately, and all arms combined. This difference was significant for AEs and SAEs for all arms combined after covariate adjustment (Table 2). Conclusion: In moderate COVID-19 patients, concomitant HQN may delay recovery on RDV and showed no impact on recovery with SoC alone. The AE profile of HQNpos patients was worse than that observed for HQNneg patients, regardless of RDV treatment.

Geographical disparities in clinical outcomes of severe COVID-19 patients treated with remdesivir

Background: Remdesivir (RDV), a RNA polymerase inhibitor with potent in vitro activity against SARS-CoV-2, is the only treatment with demonstrated efficacy in shortening the duration of COVID-19. Here we report regional differences in clinical outcomes of severe COVID-19 patients treated with RDV, as part of an open-label, randomized phase-3 trial establishing RDV treatment duration. Methods: Hospitalized patients with oxygen saturation ≤94%, a positive SARS-CoV-2 PCR in the past 4 days and radiographic evidence of pneumonia were randomized 1:1 to receive 5d or 10d of intravenous RDV. We compared d14 clinical outcomes of patients from different geographical areas, as measured by mortality rates, change in clinical status from baseline (BL) on a 7-point ordinal scale and change in O2 requirements from BL. Based on previous analyses in compassionate use data showing region as an important predictor of outcome, Italy was examined separately from other regions. Results: 397 patients were treated with RDV, of which 229 (58%) were in the US, 77 (19%) Italy, 61 (15% in Spain), 12 (3%) Republic of Korea, 9 (2%) Singapore, 4 (1%) Germany, 4 (1%) Hong Kong and 1 (< 1%) Taiwan. BL clinical status was worse in Italy compared to other regions (72% vs 17% requiring high-flow oxygen delivery or higher), and Italian patients were more likely to be male than patients from other regions (69% vs 63%). Overall results showed 5d RDV was as effective as 10d. Mortality at d14 was higher in Italy (18%) compared to all other countries except Italy (7%). Similarly, clinical improvement at d14, measured as ≥2-point increase in the ordinal scale, was lower in Italian patients (39%) compared to all other countries combined (64%). (Fig.1). Conclusion: Overall, our results demonstrate significant geographical differences in the clinical course of severe COVID-19 patients treated with RDV. We observed worse outcomes, such as increased mortality and lower rate of clinical improvement, in patients from Italy compared to other regions. (Table Presented).