Factors Associated With Severity of COVID-19 Disease in a Multicenter Cohort of People With HIV in the United States, March–December 2020

Adrienne E. Shapiro, MD, PhD; Rachel A. Bender Ignacio, MD, MPH; Bridget M. Whitney, PhD; Joseph A. Delaney, PhD; Robin M. Nance, MS; Laura Bamford, MD, MSCE; Darcy Wooten, MD, MS; Jeanne C. Keruly, MS, CRNP; Greer Burkholder, MD, MSPH; Sonia Napravnik, PhD; Kenneth H. Mayer, MD; Allison R. Webel, RN, PhD; H. Nina Kim, MD, MSc; Stephen E. Van Rompaey, PhD; Katerina Christopoulos, MD, MPH; Jeffrey Jacobson, MD; Maile Karris, MD; Davey Smith, MD, MAS; Mallory O. Johnson, PhD; Amanda Willig, RD, PhD; Joseph J. Eron, MD, MPH; Peter Hunt, MD; Richard D. Moore, MD, MHS; Michael S. Saag, MD; W. Christopher Mathews, MD, MSPH; Heidi M. Crane, MD, MPH; Edward R. Cachay, MD, MAS; Mari M. Kitahata, MD, MPH


J Acquir Immune Defic Syndr. 2022;90(4):369-376. 

In This Article


We conducted this study in one of the largest and best-characterized multicenter cohorts of PWH and identified factors independently associated with severity of COVID-19 disease in PWH in the United States in the first calendar year of the pandemic. Our results demonstrate that both current CD4 count <350 and lowest CD4 count <200 cells/mm3 are important predictors of hospitalization among PWH with COVID-19. Although we did not find a statistically significant association between HIV VL suppression and disease severity, our ability to detect an association was limited by the very low numbers of PWH who were not receiving ART or who were virally unsuppressed. PWH with CKD and liver dysfunction had more than a 2-fold higher risk of more severe COVID-19 disease. In addition, PWH with COPD, diabetes, hypertension, and obesity were also at a higher risk of greater COVID-19 severity. Using clinically validated and easily measurable risk scores (ASCVD and FIB-4), we found that cardiovascular and liver comorbidities were highly predictive indicators of hospitalization for PWH with COVID-19. Our results confirm previously noted associations between comorbidities and COVID-19 severity but provide more specificity, especially in characterizing the contribution of chronic comorbid conditions and HIV immunologic history to the risk of hospitalization and severity of COVID-19 disease. Although most of the PWH in our cohort have reconstituted CD4 counts, previous immune destruction or persistent immune activation, as evidenced by low CD4/CD8 ratio, are also important predictors of COVID-19 severity.

Among 16,056 PWH, 106 (0.7%) were hospitalized with COVID-19 between March and December 2020. While identification of nonhospitalized cases was limited by COVID-19 test rationing early in the epidemic, hospitalization with severe disease is less subject to misclassification and bias. Testing for SARS-CoV-2 infection in US hospitals was widely and uniformly available throughout most of the study period, reducing potential for bias in identifying hospitalized patients. The proportions of PWH with COVID-19 requiring hospitalization (16%) and intensive care (5%) and who died (2%) were lower than proportions reported in a Spanish national cohort of PWH with COVID-19 early in the pandemic (64% hospitalized, 6% ICU, and 8% died)[36] and PWH in New York City with COVID-19 in March–June 2020 (42%, 5%, 13%, respectively),[37] which may be explained partly by overwhelmed health care capacity during the limited period of those early cohort studies. By contrast, PWH in a Spanish (PISCIS) registry through December 2020 and US national registry of COVID-19 patients (N3C cohort) through May 2021 had rates of severe outcomes (PISCIS: 13.8%, 0.9%, 1.7%; N3C: 32%, 4%, 2%, respectively) similar to our cohort.[38,39]

Cardiovascular, pulmonary, and metabolic comorbidities in PWH associated with increased COVID-19 disease severity were consistent with those seen in other cohorts of PWH and in people without HIV.[2,40–42] Comorbidities that are caused or exacerbated by smoking, including COPD, hypertension, and diabetes, were all associated with an increased risk of hospitalization. Notably, we found that CKD with even modest reductions in eGFR was among the strongest predictors of hospitalization for PWH with COVID-19, consistent with non-HIV cohorts and not previously well-recognized in PWH, despite the increased prevalence of CKD in PWH.[40,41,43]

Early studies of PWH with COVID-19 did not detect a strong association between CD4 count and severity of COVID-19 outcomes,[44,45] and initially, it was hypothesized that immune suppression may be protective of cytokine-mediated inflammatory responses in COVID-19.[46] Our results demonstrate consistent and significant increased risk of hospitalization in PWH with lower CD4 counts, an association that has been confirmed in multiple global settings.[39,47–49] While most marked in PWH with CD4 counts <200 cells/mm3, risk of hospitalization was significantly elevated in people with CD4 counts <350 cells/mm3 compared with those with CD4 counts ≥350 cells/mm3. In addition to current CD4 count, we also found that lowest CD4 count and lower current CD4/CD8 ratio were associated with an increased risk of hospitalization, suggesting an immune exhaustion effect persisting from the time of CD4 nadir despite subsequent CD4 reconstitution. Of importance, in this study, we excluded CD4 counts obtained at or after COVID-19 diagnosis because SARS-CoV-2 infection can cause profound CD4 and CD8 lymphocyte suppression, which if not carefully parameterized, may have contributed to confounding in other cohort studies. In addition to characterizing HIV-associated risks for hospitalization with greater precision, this study is the first, to our knowledge, in PWH or in the general population, to examine ASCVD and FIB-4, which are clinically available robust indicators of CVD risk and liver comorbidity, respectively, each being associated with severity of COVID-19. We recommend these scores be used by clinicians for risk estimation, encouragement of vaccination, and allocation of monoclonal antibodies and other early therapeutics to prevent disease progression.

Our study also confirmed that minoritized racial and ethnic groups had disproportionately severe COVID-19 outcomes, even within a population predominately representing minoritized groups. Black PWH diagnosed with COVID-19 were 50% more likely to be hospitalized than other PWH, a finding that persisted after controlling for multiple medical comorbidities. Racism, anti-LGBTQ bias, and other forms of discrimination and stigmatization also increase allostatic load, in addition to the structural barriers and health inequities faced by many PWH compounded by marginalized gender identities, sexual orientation, and substance use.[16,50–53]

The greatest strength of this analysis is the extensive and well-characterized multisite cohort, in which chronic comorbidities and HIV-specific factors have been previously validated. Our analysis has some limitations. The number of COVID-19 cases identified underestimates the true prevalence of SARS-CoV-2 infection and COVID-19 disease, especially for mild cases that may not have presented to clinical care. Thus, the proportion of cases who were hospitalized may be an overestimate, although absolute ascertainment of hospitalization and severe outcomes would not be affected. We were unable to make direct comparisons with the general population; such comparisons have been published, albeit without the rigorous case characterization and clinician hospitalization review as in CNICS.