key: cord-313617-hh7lccet
authors: Sigel, Keith; Swartz, Talia; Golden, Eddye; Paranjpe, Ishan; Somani, Sulaiman; Richter, Felix; De Freitas, Jessica K; Miotto, Riccardo; Zhao, Shan; Polak, Paz; Mutetwa, Tinaye; Factor, Stephanie; Mehandru, Saurabh; Mullen, Michael; Cossarini, Francesca; Bottinger, Erwin; Fayad, Zahi; Merad, Miriam; Gnjatic, Sacha; Aberg, Judith; Charney, Alexander; Nadkarni, Girish; Glicksberg, Benjamin S
title: Covid-19 and People with HIV Infection: Outcomes for Hospitalized Patients in New York City
date: 2020-06-28
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa880
sha: 
doc_id: 313617
cord_uid: hh7lccet

BACKGROUND: There have been limited data regarding the clinical impact of COVID-19 disease on people with HIV (PWH). In this study we compared outcomes for PWH with COVID-19 disease to a matched comparison group. DESIGN: We identified 88 PWH hospitalized with laboratory confirmed COVID-19 in our hospital system in New York between March 12 and April 23, 2020. We collected data on baseline clinical characteristics, laboratory values, HIV infection status, COVID-19 treatment, and outcomes from this group and matched comparators (one PWH to up to five patients by age, sex, race/ethnicity and calendar week of infection). We compared baseline clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these two groups, as well as cumulative incidence of death by HIV status. RESULTS: Patients did not differ significantly by HIV status by age, sex or race/ethnicity due to the matching algorithm. PWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PWH had greater proportions of smoking (p<0.001) and comorbid illness than demographically similar uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (p=0.15). Poor outcomes for hospitalized PWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and ultimately 21% died during follow-up (compared with 23% and 20% respectively). There was similar cumulative incidence of death over time by HIV status (p=0.94). INTERPRETATION: We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared to a demographically similar patient group.

A c c e p t e d M a n u s c r i p t Background SARS-CoV-2, the causative agent of coronavirus disease-19 , has infected millions of people worldwide since its identification in December 2019, resulting in >400,000 deaths to-date. [1] Patients with immunocompromise have overall poorer outcomes from most serious infections, but this may vary based on the type of immune deficiency and the specific pathogens. HIV infection is one of the most common causes of immunocompromise globally, with over 1 million people with HIV (PWH) in the United States alone. [2] Despite the substantial reach of the COVID- 19 In this study we assessed the outcomes of COVID-19 disease in PWH, comparing a hospitalized cohort of PWH from our NYC health system and a demographically matched group of comparator patients. We then evaluated factors associated with mortality for PWH hospitalized with COVID-19.

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

We identified all hospitalized patients with laboratory confirmed SARS-CoV-2 infection at five hospitals in the Mount Sinai Health System admitted between March 12 and April 23, 2020. From this cohort we identified 88 patients with HIV-related diagnostic codes or those being treated with antiretroviral medications identified from inpatient or outpatient medication orders. We then selected an HIV uninfected comparator group (from the larger laboratory confirmed SARS-CoV-2 cohort) using a similar methodology to that used by the Veterans Aging Cohort Study for comparisons by HIV status. [5] We identified 405 HIV uninfected patients, matching one PWH to up to five patients by age (+/-2.5 years), sex, race/ethnicity, and calendar week of infection (to account for temporally associated changes in COVID-19 management and differences in follow-up time).

Electronic health record (EHR) data were then collected including demographics, all diagnostic codes and procedures, as well as clinical laboratory measurements and outcomes (death, mechanical ventilation, discharge). Smoking status was ascertained from a structured EHR element. Oxygen supplementation requirements on admission were collected, verified via chart review and used to categorize COVID-19 severity using published criteria. A c c e p t e d M a n u s c r i p t

We then compared baseline characteristics, treatments and outcomes, testing to assess significant differences between PWH and comparators using the Wilcoxon test for continuous variables and the chi-square test for categorical variables. We also stratified baseline laboratory measures by COVID-19 severity for PWH, testing for differences in measures by severity category using ordinal logistic regression. We then compared differences in time to death to assess disease trajectory for hospitalized patients by HIV status by fitting unadjusted cumulative incidence function curves with hospital discharge as a competing risk. Curves were compared using the test of Pepe and Mori. [7] To compare cumulative incidence of death by HIV status accounting for potential confounding factors we then fit a multivariable survival model using Fine-Grey competing risk methods, including demographics, COVID-19 severity, comorbid conditions and laboratory values that differed by HIV status. [8] Finally, we compared characteristics of PWH who died during hospitalization to those who were discharged or still alive at the end of follow-up. We explored the independent association of significant factors associated with death for PWH from COVID-19 by fitting separate multivariable competing risk models using demographic factors and significant univariate predictors (one model for each predictor). Based on our sample size, our primary analysis of proportion of hospital deaths by HIV status had 80% power to detect a 15% increase in the absolute risk of death for PWH compared to uninfected persons. All analyses were conducted using STATA Version 15. This study was approved by our Institutional Review Board.

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

Of the 4,402 patients hospitalized during the study period for COVID-19, 88 (2%) were PWH. The median age of PWH hospitalized with COVID-19 disease was 61 (Table 1; intraquartile range [IQR] 54-67) and most PWH were black (40%) or Hispanic/Latino (30%). Patients did not differ significantly by HIV status when comparing age, sex, or race/ethnicity due to the matching algorithm. Consistent with trends noted in HIV cohort studies, [9] PWH also had greater proportions of smoking (55% versus 23%; p<0.001) and comorbid illnesses than demographically-similar uninfected comparators, most notably chronic obstructive pulmonary disease (COPD; 10% vs. 3%; p<0.001), cirrhosis (6% vs. 2%; p=0.02) and a history of cancer diagnosis (17% vs. 6%; p=0.001). PWH and uninfected persons had similar COVID-19 severity on admission as measured by oxygen supplementation requirements (p=0.15).

All PWH admitted for COVID-19 were prescribed antiretroviral therapy and most (78%) were receiving integrase inhibitor-based regimens. The majority (58%) of patients with CD4 measurements on hospital admission had counts >200 cells/mm 3 (Table S2; p=0.005). The majority of PWH were treated with hydroxychloroquine and azithromycin; experimental or expanded-access agents were used less frequently.

Most hospitalized PWH were discharged from the hospital during the follow-up period (Figure 1 ).

There was no significant difference in intensive care use by HIV status in our cohort. Poor outcomes for hospitalized PWH were still frequent but similar to proportions in comparators; 18% required A c c e p t e d M a n u s c r i p t mechanical ventilation and 21% died during follow-up compared with 23% and 20%, respectively.

Competing risks analysis showed similar cumulative incidence of death over time by HIV status with no significant difference in the curves (p=0.94; Figure 2 ). HIV was not significantly associated with risk of death in multivariable competing risks analysis after adjusting for demographics, COPD, smoking, baseline ferritin level and baseline white blood cell count (Table S3) .

Comparisons of PWH who died to those who were still alive or discharged at the end of follow-up revealed few differences in patients who died compared to those who did not. We did find, however, differences in the proportions who were organ transplant recipients who died versus those who had not died ( 

Among patients from five hospitals in a large health system during the peak of the Spring 2020 NYC SARS-CoV-2 epidemic, we found that PWH hospitalized with COVID-19 had a substantial burden of comorbid illness and smoking but had good HIV disease control. Although mortality and other adverse outcomes were high among PWH in our cohort, these were not worse than a demographically and temporally matched group with similar COVID-19 severity at presentation and fewer comorbidities. Our study represents the largest and most diverse cohort of PWH with COVID-19 that has been described to date and adds to existing limited evidence that HIV might not be associated with more severe COVID-19 disease course.

Concern that COVID-19 disease might be more severe in persons with immunodeficiency or immune dysregulation has been raised since the emergence of the earliest cases. [10] Uncontrolled series of immunosuppressed persons such as kidney transplant recipients and cancer patients have shown A c c e p t e d M a n u s c r i p t high mortality rates. [11] Outcomes analyses for PWH during the COVID-19 pandemic have been limited however, consisting of small case reports or series. [12] A single center in Spain reported outcomes for five male PWH hospitalized with COVID-19. Four of the five men had been discharged and the fifth was in intensive care at the time of their report. [13] Larger uncontrolled series from New Jersey (13 hospitalized patients), New York City (31 hospitalized patients) and Madrid, Spain (28 hospitalized patients) also subsequently demonstrated COVID-19 outcomes for PWH similar to those described for the general population. [14] [15] [16] This is broadly consistent with our finding that respiratory failure requiring mechanical ventilation and death were not more frequent in PWH when compared to demographically similar persons with COVID-19. The lack of outcome differences is even more striking when noting that COPD, cancer and smoking, risk factors linked to worse COVID-19 outcomes in several previous studies, were far more prevalent in PWH in our cohort than in comparator patients. [17, 18] Immunomodulatory effects of SARS-CoV-2 have been associated with severe sequelae including a cytokine release syndrome. [4] Several factors have supported theoretical risks of worse COVID-19 disease in PWH including incomplete immune reconstitution and evidence of persistent immune activation in many patients prior to the pandemic. [19, 20] Furthermore, increased IL-6 and D-dimer measures have been independently associated with chronic HIV infection [21, 22] and have also been closely linked with COVID-19 severity in data from mostly HIV uninfected persons. [23, 24] Neither biomarker differed on presentation for patients by HIV status nor was either associated with COVID-19 severity at presentation for PWH. Among PWH, CD4 decline was noted in the majority of patients with available data, consistent with existing immunologic data on COVID-19 natural history, but the decrease in CD4 percentage was not large. [25] We did not find evidence of associations between immunologic measures (either decreases from pre-COVID-19 values or low values at the time of presentation) and adverse COVID-19 outcomes for PWH. Organ transplantation was associated with death for PWH in our study, however, suggesting that non-HIV causes of immunodeficiency may be more prominent risks for severe outcomes. Our study benefited from data collected from diverse patient groups from five hospitals within a NYC large health system that is one of the largest HIV care providers in the United States. Our sample size of PWH was limited but we were nonetheless able to identify a large, well-matched comparison group for comparison of outcomes. To maximize our comparison group size, we limited our matching strategy to demographic and temporal factors using a similar method to the largest American HIV cohort study although this yielded differences in comorbidity profiles for the two groups. [5, 29] This difference in comorbidity profiles may have also been influenced by more frequent medical care for PWH, leading to an imbalance in the ascertainment of comorbid diagnoses. However, the marked difference in smoking history for PWH versus HIV uninfected persons supports likely differences in the true prevalence of these comorbid diseases by HIV status in our cohort. In addition, some measures such as laboratory data were missing for substantial portions of the sample, in proportions too large for imputation. Nonetheless, our key exposures and outcomes were manually verified and provide important information for this vulnerable population.

In conclusion, we found no differences in adverse outcomes associated with HIV infection for 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 Anti-retroviral therapy (ART) 88 (100) --

Integrase 69 (78) --

COVID-19 Projections

The Time Is Now to End the HIV Epidemic

Do Biomarkers of Inflammation, Monocyte Activation, and Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People?

The trinity of COVID-19: immunity, inflammation and intervention

Veterans Aging Cohort Study (VACS): Overview and description

Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection

marginal or conditional probability curves in summarizing competing risks failure time data

Practical methods for competing risks data: a review

Excess Clinical Comorbidity Among HIV-Infected Patients Accessing Primary Care in US Community Health Centers

The Virus that Changed Spain: Impact of COVID-19 on People with HIV

Covid-19 and Kidney Transplantation

Co-infection of SARS-CoV-2 and HIV in a patient in Wuhan city

COVID-19 in patients with HIV: clinical case series

COVID-19 pneumonia in patients with HIV -A Case Series

Clinical characteristics and outcomes in people living with HIV hospitalized for COVID-19

Description of COVID-19 in HIVinfected individuals: a single-centre, prospective cohort

Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection

HIV-associated chronic immune activation

HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation

Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Dysregulation of immune response in patients with COVID-19 in Wuhan, China

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Compounds with Therapeutic Potential against Novel Respiratory

Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Aging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity?

Laboratory Values -median (IQR)

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t >50 copies/ul 1 (9) 11 (21) A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t