key: cord-0808863-bcqei7tq
authors: Yendewa, George A; Perez, Jaime Abraham; Schlick, Kayla; Tribout, Heather; McComsey, Grace A
title: Clinical features and outcomes of COVID-19 among people living with HIV in the United States: A multicenter study from a large global health research network (TriNetX)
date: 2021-06-01
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab272
sha: e4686d81374a02053d912b1f34602ae453716912
doc_id: 808863
cord_uid: bcqei7tq

BACKGROUND: HIV infection is a presumed risk factor for severe COVID-19, yet little is known about COVID-19 outcomes in people with HIV (PLW). METHODS: We used the TriNetX database to compare COVID-19 outcomes of PWH and HIV negative controls aged ≥ 18 years who sought care in 44 healthcare centers in the US from January 1 to December 1, 2020. Outcomes of interest were rates of hospitalization (composite of inpatient non-intensive care (ICU) and ICU admissions), mechanical ventilation, severe disease (ICU admission or death) and 30-day mortality. RESULTS: Of 297,194 confirmed COVID-19 cases, 1638 (0.6%) were HIV-infected, with > 83% on antiretroviral therapy (ART) and 48% virally suppressed. Overall, PWH were more commonly younger, male, African American or Hispanic, had more comorbidities, were more symptomatic, and had elevated procalcitonin and interleukin 6. Mortality at 30 days was comparable between the two groups (2.9% vs 2.3%; p=0.123); however, PWH had higher rates hospitalization (16.5% vs 7.6%, p<0.001), ICU admissions (4.2% vs 2.3%, p<0.001) and mechanical ventilation (2.4% vs 1.6%, p<0.005). Among PWH, hospitalization was independently associated with male gender, being African American, integrase inhibitor use and low CD4 count; whereas severe disease was predicted by older age [adjusted odds ratio (aOR) 8.33, 95% confidence interval (CI) (1.06, 50.00); p=0.044] and CD4 <200 cells/mm (3) [aOR, 8.33, 95% CI (1.06, 50.00); p=0.044]. CONCLUSION: PWH had higher rates of poor COVID-19 outcomes but were not more at risk of death than non-HIV infected counterparts. Older age and low CD4 count predicted adverse outcomes.

A c c e p t e d M a n u s c r i p t BACKGROUND As of February 1, 2021, the COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an estimated 100 million confirmed infections and over 2 million deaths globally [1] . Black and other racial minority heritage, male gender, age > 65 years, obesity (body mass index [BMI] ≥ 30 kg/m 2 ), diabetes mellitus, hypertension, severe cardiopulmonary disease and other chronic conditions have been reported as contributing to poor COVID-19 outcomes, including increased risk of mortality [2] [3] [4] [5] .

Compared with the general population, PWH are presumed to be at greater risk of severe COVID-19 and adverse clinical outcomes [6, 7] . This has been attributed to the observation that PWH tend to have a higher burden of lifestyle-associated risk factors and underlying comorbidities, in addition to having an already heightened systemic inflammatory state at baseline that could potentially enhance or amplify the viral cytokine release syndrome-also referred to as the -cytokine storm‖-that has been described in the setting of COVID-19 [6] [7] [8] [9] [10] [11] .

Notwithstanding, emerging evidence from case report series, early observational studies and systematic reviews describing the clinical features of COVID-19 among PWH have yielded mixed findings thus far. Several studies from Europe and North America have observed no substantial differences in morbidity and mortality rates among HIV and non-HIV cohorts of patients hospitalized with COVID-19, with the majority of HIV-infected patients in these studies reported as stable on antiretroviral therapy (ART) and virally suppressed [12] [13] [14] [15] . On the other hand, recent data from two large population-based studies from South Africa and the United Kingdom found a 2-and 2.6-fold increase in the risk of COVID-19 death, respectively, among PWH compared with their non-HIV infected counterparts [16, 17] .

In the United Kingdom study by Bhaskaran et al [17] , Black ethnic minority status was associated with a 4.3-fold higher hazard of COVID-19 death among PWH compared with A c c e p t e d M a n u s c r i p t non-HIV infected controls. However, crucial questions around the associations (if any) between the degree of immunosuppression, level of virologic control or class of ART and COVID-19 outcomes in PWH have remained largely unanswered and are the focus of ongoing inquiry into the nature of the interactions between HIV and SARS-CoV-2.

In a multicenter study in the United States using TriNetX (a large global federated health research network), Hadi et al [15] had previously observed a higher crude COVID-19 mortality in 404 PWH, compared with their non-HIV infected counterparts; however, the study used an earlier time cut-off (July 2020) and importantly, did not examine the relationship between outcomes of interest and CD4 count, virologic control and class of ART. Herein, we used a higher time cut off in TriNetX (to include a larger number of patients) to characterize the clinical features and predictors of adverse COVID-19 among PWH in the United States.

We used the TriNetX database to conduct a retrospective study of adult patients aged ≥ 18 years with SARS-CoV-2 infection (confirmed by PCR or serology) who sought care across 44 health care organizations in the United States from January 1, 2020 to December 1, 2020. To safeguard protected health information, TriNetX does not include data on participating healthcare organizations (HCOs). Therefore, we are unable to provide geographic or institutional information. However, a participating HCO typically represents a large health center with main and satellite hospitals, specialty care services and outpatient clinics.

A c c e p t e d M a n u s c r i p t

We collected clinical data including patient demographics, comorbidities, lifestyleassociated risk factors (smoking, alcohol use and illicit drug use), vital signs and symptoms at presentation, laboratory findings, medication use, and healthcare services utilized-i.e., outpatient clinic, emergency room, inpatient non-intensive care setting (non-ICU) or intensive care unit (ICU) admission. We additionally collected the last CD4 count and viral load data (measured by HIV-1 RNA PCR) within the preceding 12 months. A full description of study definitions and variables used to query the TriNetX database and their corresponding ICD-10 codes are provided in the Supplementary Materials.

Our clinical outcomes of interest were the odds of outpatient visit (defined as utilizing ambulatory clinic or emergency department services only), hospitalization (defined as the composite outcome of inpatient non-ICU and ICU service utilization), mechanical ventilation use, severe COVID-19 (ICU admission or death), and mortality rate at 30 days after COVID-19 diagnosis.

We further analyzed COVID-19 severity in the PWH cohort based on hospital services utilized. Mild disease was defined as having required outpatient services only (i.e., ambulatory clinic or emergency department visit). Moderate disease was defined as having required inpatient non-ICU services, while severe disease was defined as having required ICU services or death within 30 days of COVID-19 diagnosis.

Summary statistics were generated for all variables at baseline. Continuous data were presented as means and standard deviations and were compared using independent ttests. Categorical data were presented as frequency and proportions and compared using Chi-square or Fishers exact test, as appropriate. To address possible confounders, we balanced cohorts using 1:1 greedy nearest-neighbor propensity score matching by demographics and key comorbidities associated with poor COVID-19 outcomes as outlined A c c e p t e d M a n u s c r i p t in Table 1 . Within the PWH cohort, we explored predictors of outcomes (moderate and severe COVID-19) using multinomial logistic regression models with the main effects of age, race, comorbidities, class of ART, CD4 count and viral load. For outcomes of interest, we calculated odds ratios (OR) and 95% confidence intervals (CI), with p < 0.05 considered statistically significant. All analyses were conducted in the statistical software R version 3.63 (R Core Team, 2020).

The study was approved by the Institution Board Review committee at Case Western Reserve University/University Hospitals Cleveland Medical Center. Written informed consent from patients was not required as data the TriNetX system safeguards patient's privacy by reporting de-identified data. M a n u s c r i p t and 3.5% of PWH required inpatient services directly upon presentation in the non-ICU and ICU settings, respectively, versus 4.1% and 1.5% of non-HIV infected patients (p < 0.001).

Compared with their non-HIV infected counterparts, PWH patients were more commonly younger ( 

Overall, PWH were more symptomatic at presentation compared with non-HIV infected patients ( Table 2 ). The most common symptoms were cough (16.9% vs 15.9%, p = 0.294), difficulty breathing (13.7% vs 8.6%, p < 0.001), and fever (11.4% vs 8.6%, p < 0.001), with a smaller proportion of patients exhibiting gastrointestinal and neurological symptoms.

On laboratory parameters, PWH were more commonly anemic (p < 0.001), thrombocytopenic (p < 0.001) and had elevated serum creatinine (p < 0.001), procalcitonin (p = 0.042) and interleukin-6 (p = 0.010) levels. Although C-reactive protein (CRP) (p < 0.0148) and erythrocyte sedimentation rate (ESR) (p < 0.001) were lower in PWH, serum levels of other markers of acute systemic inflammation, myocardial injury and coagulopathy were comparable between the two cohorts ( Table 2) .

A c c e p t e d M a n u s c r i p t Table 3 displays the differences in 30-day outcomes between PWH and non-HIV patients. PWH had higher rates of hospitalization (16.5% vs 7.6%, p < 0.001) and higher rates of severe illness requiring ICU admission (4.2% vs 2.3%, p < 0.001) and mechanical ventilation (2.4% vs 1.6%, p < 0.005). Mortality at 30 days was higher among PWH but did not attain statistical significance (2.9% vs 2.3%; p = 0.123). In propensity score-matched analysis based on demographics and key comorbidities, PWH remained at significantly higher odds of hospitalization [OR 1.26, 95% CI (1.04-1.53); p = 0.023]. A c c e p t e d M a n u s c r i p t

In this analysis of nearly 300,000 confirmed COVID-19 cases (0.6% PWH) from the United States, we found that almost half (47.6%) of PWH presented with mild disease (i.e., required outpatient care only), 38.3% with moderate disease (i.e., required inpatient non-ICU services) and 14.1% had severe disease (i.e., required ICU admission or died within 30 days of COVID-19 diagnosis). We found no significant difference in COVID-19 mortality rates between PWH and non-HIV infected patients. The crude death rates were low in both groups (2.9% vs 2.3%, respectively). Our findings are in broad agreement with population-based studies from other high resource settings with good healthcare infrastructure, where COVID-19 mortality rates have generally been reported at < 5% [6-9, [12] [13] [14] [15] [16] [17] [18] [19] [20] .

Furthermore, we observed that compared with non-HIV infected patients, PWH were more symptomatic at presentation, more likely to have severe disease and utilized more healthcare resources with higher rates of hospitalizations, mechanical ventilation use, and ICU admissions. The high risk for hospitalization of PWH persisted after propensity score matching by key variables. We hypothesize that the reasons for these findings may be related to the combined effects of the high prevalence of underlying comorbidities coupled with the possibility of a more vigorous manifestation of the cytokine release syndrome in PWH [6] [7] [8] [9] [10] [11] . Notably, the PWH in this study had a 2-to 2.5-fold higher serum levels of IL-6 and procalcitonin, respectively, compared with non-HIV infected patients. The role of IL-6 and other cytokines in COVID-19 pathogenesis has been well described. During the early phases of SARS-CoV-2 infection, activated T lymphocytes and macrophages release interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and other proinflammatory mediators of the so-called -cytokine storm‖ that is characterized by tissue damage, endothelial leakage and the activation of the complement and coagulation pathways [21, 22] . The centrality of IL-1β and IL-6 in particular in immune dysregulation has warranted the exploration of anti-cytokine antagonists as novel therapies for severe COVID-19 [22] [23] [24] [25] .

A c c e p t e d M a n u s c r i p t

Our study analyzed risk factors associated with poor COVID-19 outcomes in PWH.

Male gender and being Black or African American were associated with > 5-fold increase in the risk of hospitalization, while older age was associated with higher odds of ICU admission or death within 30 days of COVID-19 diagnosis. These findings are consistent with multiple previous reports from the United and elsewhere that have highlighted the gender, racial and ethnic disparities associated with the HIV and COVID-19 pandemics [26, 27] . African American, Hispanic and other minority populations in the United States continue to be disproportionately impacted by a synergy of persistent social and economic barriers that have limited their access to health services and placed them at heightened risk of poor disease outcomes [28, 29] . Importantly, in our study, even after adjusting for comorbidities and age, black race remained independently associated with worse outcomes. Public health efforts aiming to address inequities in HIV and COVID-19 outcomes would benefit from implementing policies and actions prioritizing minority and other vulnerable populations.

Similar to other studies, we did not detect any significant effects of HIV viremia on COVID-19 severity [12] [13] [14] [15] ; however, advanced HIV disease (CD4 count < 200 cells/mm 3 ) and INSTI use were associated with an 8-fold and 20-fold higher risk of poor outcomes, respectively. The association between low CD4 count and poor outcomes was anticipated, but the large effect demonstrated by INSTI use was unexpected. Although it has been widely speculated that some antiretrovirals may have a protective effect against SARS-CoV-2, their role in COVID-19 prevention and treatment remains in dispute. Several HIV-1 protease inhibitors (e.g., lopinavir, ritonavir, and saquinavir) had demonstrated potent activity against two earlier coronaviruses (SARS-CoV and MERS-CoV) and inhibited their replication in in vitro and animal studies [30] [31] [32] ; however, a randomized controlled trial of 199 critically-ill hospitalized patients failed to show benefit with lopinavir-ritonavir beyond standard of care [33] . Tenofovir and other nucleos(t)ide reverse transcriptase inhibitors (NRTIs) have been shown to inhibit SARS-CoV-2 in in vitro studies by attenuating the effects of interleukin-8 and interleukin-10, while promoting the production of interferon-gamma [34] [35] [36] . Two recent A c c e p t e d M a n u s c r i p t studies from Spain and South Africa found that compared with other therapies, tenofovirbased ART had a protective effect against COVID-19 death among PWH [16, 37] . In our study, however, NRTI-or PI-based ART did not show mortality benefit among PWH.

Integrase strand transfer inhibitors (INSTIs) are preferred first-line ART used in combination with two NRTIs and are particularly attractive due to their efficacy, good tolerability profile and high genetic barrier to resistance [38] [39] [40] Our study had several limitations. These included incomplete data on CD4 count, viral load, and other laboratory findings. In addition, we are unable to capture the start date of the symptoms, and as such we cannot exclude the possibility that PWH presented later in the course of COVID-19, which would explain the more frequent symptoms, hospitalizations, and ICU use among PWH with COVID-19. Nonetheless, to the best of our knowledge, this is one of the largest multicenter studies to date from the United States that was sufficiently powered to detect meaningful differences and statistically significant associations between patient characteristics and outcomes of interest. A c c e p t e d M a n u s c r i p t M a n u s c r i p t 

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