BASELINE AND TEMPORAL DIFFERENCES IN PROTEOMICS FOLLOWING SARS-CoV-2 INFECTION IN PWH

Background: COVID-19 may be more severe in persons with HIV (PWH). However, underlying biological mechanisms associated with the development of COVID-19 and its clinical severity among antiretroviral therapy (ART) treated PWH are largely unknown. Therefore, we wished to evaluate temporal changes in plasma proteins following SARS-CoV-2 infection and identify pre-infection proteomic markers associated with future COVID-19. Method(s): We analyzed the data of clinical, antibody-confirmed COVID-19 ARTtreated PWH from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Individuals were matched on geographic region, age, and sample timing to antibody-negative controls. For cases and controls, pre-COVID-19 pandemic specimens were obtained prior to January 2020 to assess temporal changes and baseline differences in protein expression in relationship to COVID-19 severity, using mixed effects models adjusted for false-discovery rate. Result(s): We compared 257 unique plasma proteins (Olink Proteomics) in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (median age 50 years, 73% male). 40% of cases were characterized as mild;60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months. Temporal changes in protein expression differed based on COVID-19 disease severity. Among moderate to severe cases vs. controls, NOS3 increased, whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased. Higher baseline circulating concentrations of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 in PWH and were related to immune function, including CD4, CD8 and the CD4/ CD8 ratio. Conclusion(s): We identified temporal changes in novel proteins in closely linked inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH. Further, we identified key granzyme proteins, serine proteases expressed by cytotoxic T lymphocytes and NK cells in response to foreign antigens, associated with future COVID-19 in PWH. Our results provide unique insights into the biological susceptibility and responses to COVID-19 infection in PWH. (Figure Presented).

Hospitalized patients with HIV and COVID-19 receiving convalescent plasma: A case series

The use of convalescent plasma in coronavirus disease 2019 (COVID-19) in the general population has not been shown to have a clear benefit. However, there are limited data available on its use in specific populations, such as in personswithhumanimmunodeficiencyvirus(HIV;PWH).The present case series study describes 12 hospitalized PWH who received convalescent plasma for severe COVID-19 between March 2020 and July 2020. Demographics, pre-existing comorbidities, HIV status, and COVID-19 management were reported and examined in a multivariate analysis. A high mortality rate of 58%, (7 out of 12 PWH) was observed in those receiving the convalescent plasma. By contrast, a brief review of 13 previously published cohorts of PWH hospitalized with COVID-19 revealed a cumulative mortality of 19% (85 of 439 PWH). In the present case series study, PWH had a significantly higher relative risk for in-hospital COVID-19-associated mortality compared with individuals without HIV (unadjusted range, 2.10-2.52;and adjusted range, 1.79-2.08;P<0.02 in all analyses). Covariate-adjustments were made for patient demographics, pre-existing co-morbidities, and mechanical ventilation needs. The high mortality rate of the present case series may be related to random sampling or an adverse effect of convalescent plasma in PWH and severe COVID-19. Additional research is thus required to investigate the risks and benefits of the use of COVID-19 convalescent plasma in PWH. © 2022 the Author(s).

ASYMPTOMATIC SARS-CoV-2 INFECTION IS EXTREMELY COMMON among PEOPLE with HIV

Background: Asymptomatic COVID-19 is common among the general population, but little has been reported on this phenomenon among people with HIV (PWH) globally. Here we present data on a representative subset of 2,464 REPRIEVE participants with blood collected for COVID-19 serology from May 2020 to February 2021. Methods: REPRIEVE is an international primary atherosclerotic cardiovascular disease (ASCVD) prevention RCT of pitavastatin calcium vs. placebo among 7,770 PWH ages 40-75 on antiretroviral therapy (ART). Beginning in April 2020, targeted data on COVID-19 diagnosis and symptoms were collected as part of routine trial visits every 4 months, and blood was collected annually to assess SARS-CoV-2 serology. SARS-CoV-2 infection was defined as either presence of SARS-CoV-2 IgG or IgA RBD protein (anti-spike) antibodies or reporting of confirmed COVID-19 disease prior to the date of antibody sampling in the absence of prior COVID-19 vaccine receipt. We distinguished symptomatic from asymptomatic disease based on completed COVID-19 symptom questionnaire. Demographic, cardiometabolic, and HIV-specific data are described among those with symptomatic versus asymptomatic COVID-19 disease. Results: Participant characteristics (n=2464) included median age 53 years, 35% female sex, 47% Black or African American race, median CD4 count 649 c/mm3, and 97% with HIV VL <400 cp/mL. SARS-CoV-2 infection occurred in 318 persons (13%): 58 with clinical disease diagnosis and 260 with reactive Abs but no reported clinical disease. Of these persons, 304 completed symptom questionnaires: 120 (39%) reported at least 1 symptom of COVID-19 disease, but 184 (61%) reported no symptoms. PWH with asymptomatic infection were more likely to be from non-High Income Regions, of Black or African American race, and to be non-obese (Table). Median ASCVD risk score was <5% (low risk) for the two groups. Potential differences in symptomatic disease based on ART-regimen were noted, but no clinical differences between the groups for CD4 counts or HIV viral suppression were observed. Conclusion: Asymptomatic SARS-CoV-2 infection is very common among ART-treated PWH globally. With Ab testing, we determined that 61% of COVID-19 infections were asymptomatic in the REPRIEVE cohort, similar to rates reported in the general population. HIV clinicians must remain vigilant about COVID-19 testing among PWH to assure that asymptomatic cases are identified.

COVID-19 VACCINATION RATES in A GLOBAL HIV COHORT

Background: Little is known regarding global COVID-19 vaccination rates in people with HIV (PWH), a population with significant morbidity from COVID-19. The Randomized Trial to Prevent Vascular Events (REPRIEVE) is a global primary cardiovascular prevention trial among PWH (N=7770) with representation from >100 sites across twelve countries (Brazil, Botswana, Canada, Haiti, India, Peru, Spain, South Africa, Thailand, Uganda, USA, Zimbabwe). Data collected on COVID-19 vaccination rates in REPRIEVE afford a unique opportunity to assess such rates among PWH across global regions. Methods: We assessed cumulative COVID-19 vaccination rates from January through July 2021 among 6952 active participants and compared rates to region-and country-specific vaccination data among the general population, determined from publicly available datasets (CDC, World Bank). Secondarily, within the REPRIEVE cohort, demographic, cardiovascular, and HIV-specific data were compared among those vaccinated vs not via Kaplan-Meier. Results: The cumulative probability of COVID-19 vaccination through the end of July 2021 was 47% among REPRIEVE participants, with rates varying substantially by global burden of disease (GBD) super-region and specific countries. Cumulative vaccination rates (Figure) were highest in the High-Income super-region (64%), followed by Latin America and the Caribbean (51%), Southeast/East Asia (36%), South Asia (16%) and Sub-Saharan Africa (12%). Country-specific rates varied dramatically, with vaccination rates highest in the United States, Peru, and Brazil, 67%, 60%, and 55%, and lowest in South Africa, Uganda, and Haiti with 11%, 3%, and 0%, respectively. Overall factors associated with COVID-19 vaccination among PWH included age, White race, natal male sex, BMI, and higher burden of cardiovascular risk factors, with important differences across GBD super-regions by log-rank test. Vaccination rates among PWH in REPRIEVE were largely comparable to the general population, in most GBD super-regions (Figure), though differences were observed in comparison to the general population in specific countries (data not shown). Conclusion: Global inequities in COVID-19 vaccine access among PWH are apparent, with highest vaccination rates observed among those residing in high-income regions. In addition to region, factors associated with vaccination among PWH included White race, natal male sex, and higher burden of CVD risk factors. Efforts are needed to increase global and regional vaccine rates for PWH.

IMPACT of the COVID-19 PANDEMIC on HIV OUTPATIENT CARE and VIRAL SUPPRESSION in NYC

Background: The COVID-19 pandemic has had significant impacts on the healthcare system, including HIV outpatient care. Lockdowns, infection concerns, and staffing and resource shortages had the potential to affect patient care and viral suppression. Methods: We conducted a retrospective analysis of patients at six HIV primary care clinics in New York City in the Mount Sinai Health system. We compared outcomes in a pre-COVID period [PC], Mar 2019-Feb 2020, to a COVID period [CP] of Mar 2020-Feb 2021. Demographics of interest included age, sex, race/ethnicity, and HIV risk factor. In the two time periods we compared viral load suppression (VLS;HIV RNA <200 copies/mL), primary care encounters, antiretroviral (ART) prescribing, and hospitalizations. We then evaluated predictors of loss of VLS or loss to follow-up in a logistic regression model. Results: Our cohort was comprised of 9,740 HIV primary care patients with ≥1 viral load measurement PC. Median age was 53 years and 79% were male;20% were white, 37% Black, and 30% Hispanic. 42% had an HIV risk factor of MSM, 22% heterosexual sex, and 4% injection drug use (IDU). 87.9% (8559/9740) of the PWH during PC had VLS. While 90.7% (7268/8013) of the population assessed during CP had VLS, 18% of the initial cohort had no VL testing during this period and 15% had neither testing nor a clinical visit during CP. In CP, 13% had at least one measured detectable HIV VL (≥200 copies/mL). Primary care encounters decreased from 93% to 79%. ART prescription rates were unchanged: 88% had active prescriptions for >80% of the year both PC and in CP. All-cause hospitalizations decreased from 766 (7.9%) to 633 (6.5%;p<.001). Male sex (OR 1.32,CI 1.17-1.49), identification as a transgender woman (OR 1.81,CI 1.22-2.69), age <35 years (OR 1.74,CI 1.53-1.97), Black race (OR 1.4,CI 1.23-1.59), and HIV risk factor of heterosexual sex (OR 1.54,CI 1.34-1.77) and IDU (OR 1.73,CI 1.35-2.22) were associated with loss of VLS or loss to follow-up. Conclusion: In this large cohort of PWH in a NYC medical system, viral suppression of those who remained in care remained stable-yet a substantial portion of patients were not engaged in care and monitored for VLS during the CP. Strategies to retain patients in care and ensure suppression (eg, with televisits and care coordination) may have helped mitigate effects of the pandemic. Clinics must continue targeted efforts to re-engage patients, facilitate access to testing, and prevent longstanding loss to follow-up in at-risk groups.

Acute kidney injury in patients with moderate COVID-19 treated with RDV versus SOC

Background: Remdesivir (RDV), an RNA-dependent RNA polymerase inhibitor of SARS-CoV-2, and its intravenous formulation excipient, cyclodextrin, are renally cleared. We sought to characterize whether RDV was associated with worsening renal function in hospitalized patients with moderate COVID-19. Methods: We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, oxygen saturation >94% on room air and eGFR ≥50 mL/ min/1.73m2. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone. Also included in this analysis were patients who enrolled in an extension phase of the trial, receiving 10d of RDV. RDV was dosed intravenously at 200 mg on d1 and 100 mg daily thereafter. Acute kidney injury (AKI) was defined as an increase in serum creatinine from baseline and classified as Stage 1 (increase > 0.3 and % change ≤25%, or % change >25% and ≤ 100%), Stage 2 (% change >100% and ≤200%), Stage 3 (% change >200%). For AKI development (ever/never for stage 1 or greater), age-adjusted risk ratios (RR) and 95% Wald confidence intervals (CI) were reported. Results: 1005 patients (822 [83%] RDV, 183 [17%] SoC) with creatinine values collected through d14 were evaluated. Baseline patient demographics, creatinine, and eGFR were mostly similar between RDV vs SoC arms. Worsening renal function was observed less frequently in patients receiving RDV vs SOC (7% vs 10%, p=0.03, Table). After adjustment for age, there was no significant association of RDV with risk of AKI relative to SoC (RR=0.66;95% CI 0.40, 1.09). Most AKI events were observed in patients with baseline eGFR >90 mL/min, with few events occurring in patients with a baseline eGFR 50-59 mL/min. In patients who developed Stage 3 AKI, those treated with RDV (n=2, 0.2%) returned to baseline creatinine values while those on SOC (n=4, 2%) remained elevated to d14. No difference in AKI between treatment arms was observed in patients with a history of chronic kidney disease (CKD;RDV: n=6 [12%] vs SOC: n=2 [40%] p=0.14). Older age, history of CKD, and eGFR status at baseline were independently associated with worsening renal function. Conclusion: AKI events were observed less frequently in patients with moderately severe COVID-19 patients treated with RDV compared to SoC.

Safety of remdesivir vs standard care in patients with moderate COVID-19

Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Here we report safety of RDV in patients with moderate COVID-19. Methods: We conducted an open-label, phase 3 trial (NCT04252664) in hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation >94% on room air. Patients were randomly assigned to receive RDV (5 or 10 days) or standard of care (SOC). RDV was dosed intravenously at 200 mg on day 1, 100 mg daily thereafter. Adverse events (AEs) and laboratory abnormalities were evaluated through the day 11 data cut;safety data through day 28 will be presented at the meeting. Results: 584 patients were randomized and treated (5d RDV: n=191;10d RDV, n=193;SOC: n=200). Baseline characteristics were balanced among groups;median (range) age was 57y (12-95y), 39% were female and 19% Black, 39% had arterial hypertension, 15% hyperlipidemia, 11% asthma. Briefly, across both the 5d and 10d arms, RDV was well tolerated with a similar rate of Grade 3 or 4 AEs and fewer SAEs compared to SOC (Table). AEs more common with RDV vs SOC included nausea, headache, and hypokalemia. Overall, across the 3 arms, incidence of AEs leading to discontinuation and death were low and no clinically relevant changes in laboratory parameters were observed. In addition, median changes in renal and liver function tests from baseline were not statistically significant between the RDV 5d and RDV 10d groups compared to the SOC only group at d14 (Table 1). Conclusion: RDV given for 5d or 10d was well tolerated in patients with moderate COVID-19. No clinically significant safety signals were observed with RDV vs SOC. (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.

Baseline characteristics associated with clinical improvement and mortality in hospitalized patients with moderate COVID-19

Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Here we report baseline characteristics associated with clinical improvement at day (d) 14. 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. For this analysis, patients were followed through discharge, d14, or death. Baseline demographic and disease characteristics associated with clinical improvement in oxygen support (≥2-point improvement on a 7-category ordinal scale ranging from discharge to death) were evaluated using multivariable logistic regression methods. Results: 584 patients were randomized and treated (5/10d RDV, n=384;SoC: n=200). 159 (27%) were ≥65y, 227 (39%) female, 328 (61%) white, 102 (19%) Asian, and 99 (19%) Black. 252 participants (43%) were enrolled in Europe, 260 (45%) North America (NA), and 72 (12%) in Asia. Most patients (483 [83%]) were not on supplemental oxygen but required medical care at baseline. In a multivariable model, 5/10d RDV was significantly positively associated with clinical improvement (adjusted odds ratio [OR] 1.69, 95% CI: 1.08, 2.65;p=0.0226). Significant covariables positively associated with clinical improvement included age < 65y (p< 0.0001) and region of treatment (Europe and NA vs Asia, p< 0.0001 each;Table);other examined factors were not significantly associated with clinical improvement, including gender, race, ethnicity, baseline oxygen support, duration of symptoms and hospitalization, obesity, and baseline transaminase levels. Conclusion: In moderate COVID-19 patients, after adjusting for treatment arm, age < 65y and region (NA vs Asia;Europe vs Asia) were associated with higher rates of clinical improvement. These observations recapitulate younger age as positive prognostic factor, and highlight the differences in the impact of the pandemic globally.

Elevated IL-1β level as a predictor of inflammation and death in COVID-19

Background: SARS-Cov-2 (severe acute respiratory disease coronavirus 2) causes Coronavirus Disease 2019 (COVID19) and is associated with respiratory failure and death in severe disease. This is associated with high levels of cytokines such as IL-6, IL-8 and TNF-alpha which are predictors of severe outcomes. SARSCoV- 2 leads to activation of the NLRP3 inflammasome which results in secretion of the cytokine IL-1ß. While high levels of IL-1ß are not observed in most patients with severe COVID-19, there is a subset of patients with high IL-1ß levels. Here we sought to characterize these patients and determine whether high IL-1ß levels are associated with adverse outcomes and death in COVID-19. Methods: We identified 90 patients with high IL-1ß levels (greater or equal to 2 pg/ml) and laboratory confirmed COVID-19 hospitalized in our hospital system in New York March 12 and May 8, 2020. We collected baseline clinical characteristics, laboratory values, COVID-19 treatment, and outcomes from this group and the group with IL-1ß levels below 2 pg/ml. Baseline clinical characteristics and outcomes were compared. Results: Comparing patients by IL-1ß level had similar demographics (age, sex, race/ethnicity, smoking status and comorbid disease prevalence). The group had comparable levels of adverse markers of disease severity but the patients with high IL-1ß had increased inflammatory biomarkers including IL-8 (629 vs. 68 pg/ml, p< 0.0001), TNF-alpha (30 vs. 51 pg/ml, p< 0.0001), IL-6 (173 vs. 5075 pg/ml, p< 0.0001), CRP (141 vs. 178, p=0.0007), d-dimer (2.6 vs. 4 p=0.0002), and increased rates of death (30% vs. 20%, p=0.008). Conclusion: Demographic and comorbid conditions are not effective at predicting high IL-1ß serum levels in COVID-19 patients, however those individuals with high levels are at risk for adverse outcomes of severe disease and death. Further investigation is required to probe the mechanism of NLRP3 inflammasome activation and IL-1ß signaling and the role of this cytokine in mediated inflammation and death in COVID-19.

Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARSCoV-2 across the Mount Sinai Health System in New York City

Background/Case Studies: To date, convalescent plasma for the treatment of SARS-CoV-2 has shown effectiveness in severely ill patients in reducing mortality. While studies have demonstrated a low risk of serious adverse events, the comprehensive incidence and nature of the spectrum of transfusion reactions to convalescent plasma is unknown. Here, we retrospectively examine 427 inpatient convalescent plasma transfusions to determine incidence and types of reactions, as well as clinical parameters and risk factors associated with transfusion reactions. Study Design/Methods: Retrospective analysis was performed for 427 transfusions to 215 COVID-19 patients within the Mount Sinai Health System (MSHS), through eIND and EAP approval pathways by the FDA. Transfusions were blindly evaluated by two reviewers and adjudicated by a third reviewer in discordant cases. Patient demographics, clinical, and laboratory parameters were compared and analyzed. Statistical analysis was performed determine the significance of these parameters and univariate logistic regression analysis was performed to assess which independent variables were correlated with a transfusion reaction. Results/Findings: Fifty-five reactions from 427 transfusion events were identified (12.9% incidence), thirteen of which were attributed to transfusion (3.1% incidence). Reactions were classified as underlying COVID-19 (76%), febrile non-hemolytic (10.9%), transfusion-associated circulatory overload (9.1%), allergic (1.8%), and hypotensive (1.8%) reactions. Statistical analysis identified increased transfusion reaction risk for ABO blood group B, Sequential Organ Failure Assessment scores of 12-13, or a cancer diagnosis. A decreased risk was identified for patients in the age group of 80-89 years. Conclusions: Our findings support the use of convalescent plasma as a safe therapeutic option from a transfusion reaction perspective, in the setting of COVID-19. Further studies are needed to confirm the clinical significance of ABO group B, cancer diagnosis, age, and predisposing disease severity in the incidence of transfusion reaction events.