key: cord-0831275-ridg1iyz
authors: Triant, Virginia A; Gandhi, Rajesh T
title: When Epidemics Collide: Why People with HIV May Have Worse COVID-19 Outcomes and Implications for Vaccination
date: 2021-01-04
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1946
sha: d32663b8cece24071ed50ce3bdd54302955d2c51
doc_id: 831275
cord_uid: ridg1iyz

nan

who are not receiving antiretroviral therapy (ART) or have low CD4 cell counts -that is, those who are immunodeficient -there has been concern that SARS-CoV-2 infection will cause severe disease, as is the case for influenza. 9 PWH who are receiving ART are typically not at high risk for other infections, but there are theoretical reasons why they may be more prone to severe COVID-19. PWH on ART continue to have excess inflammation, which has been linked to comorbidities, such as cardiovascular disease. 10, 11 Residual inflammation is most pronounced in PWH with low CD4 cell count nadirs, incomplete CD4 cell reconstitution, or persistently low CD4/CD8 ratios -an immune dysregulation "legacy effect". 12, 13 Because elevated inflammatory markers have been linked to severe COVID-19, 4 it is important to determine whether the HIV legacy effect "primes the pump" for worse outcomes after SARS-CoV-2 infection. If this is the case, one would predict worse COVID-19 outcomes in PWH, particularly among those with low CD4 cell count nadirs, incomplete CD4 cell count reconstitution or persistently low CD4/CD8 ratios.

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In addition to potential contributions of immune dysregulation, PWH may have worse COVID-19 outcomes because of comorbidities or social determinants of disease. Clinical and sociodemographic factors that are highly prevalent in people with HIV parallel risk factors for severe COVID-19. PWH are aging as a population, 14 are frequently Black or Hispanic, and have elevated rates of comorbidities including cardiometabolic risk factors (obesity, diabetes, hypertension) and cardiovascular disease; 11, 15 these factors closely mirror risk factors for development of severe COVID-19. [2] [3] [4] 16 Studies of PWH with COVID-19 find high rates of factors that increase severe COVID-19 risk.

In a study comparing COVID-19 outcomes in 404 PWH and 49,763 individuals without HIV, PWH had higher rates of obesity, hypertension, diabetes, and chronic kidney disease and were more likely to be African-American. 17 PWH with COVID-19 have higher body mass index (BMI) and a higher proportion with at least one comorbidity compared with PWH without COVID-19, 18 and have high rates of comorbidities in several case series, including 64% with at least one comorbidity in an Italian cohort, 19 83% with at least one comorbidity in a Boston cohort, 20 and half of patients with at least five comorbidities in an Atlanta case series. 21 With these potential contributors as background, what do we know about PWH who develop COVID-19? Several studies have failed to show an association of HIV with severe COVID-19 (Table) . A large US-based study using a multicenter research network and a propensity-matched cohort of COVID-19 patients without HIV showed no difference in mortality after matching for demographics and comorbidities. 17 Several studies in which COVID-19 patients without HIV were compared with PWH with COVID-19 failed to show associations of HIV status with intensive care unit (ICU) admission, 22,23 mechanical ventilation, [22] [23] [24] [25] or mortality, [22] [23] [24] [25] although matching factors differed.

An as-yet unpublished abstract from the Veterans Aging Cohort Study found that PWH had no increased risk of severe COVID-19 outcomes. 26 By contrast, several large population-based studies have found that PWH are at increased risk of severe COVID-19 (Table) . Data from a large cohort in South Africa showed HIV to be A c c e p t e d M a n u s c r i p t associated with increased COVID-19 mortality (adjusted hazard ratio 2.14), adjusting for some comorbidities but not for BMI, smoking, or socioeconomic status. 27 A United Kingdom (UK) population-based study encompassing 1,728,905 patients, including 27,480 with HIV, showed that HIV conferred a more than 2-fold increased risk of COVID-19 mortality (adjusted hazard ratio 2.59 adjusting for deprivation, ethnicity, smoking and obesity). 28 A prospective study of patients hospitalized with COVID-19 showed increased 28-day mortality in PWH after adjusting for age (adjusted hazard ratio 1.47); in patients under age 60, mortality rates were higher for PWH compared with non-HIV COVID-19 patients (21.3% vs. 9.6%). 29 A New York City study that did not

show an overall effect of HIV on severe COVID-19 showed a significant association of HIV with intubation and mortality among patients ≤50 years. 23 A separate New York State study in preprint form demonstrated a standardized mortality ratio for HIV of 1.23 for in-hospital mortality, but did not adjust for comorbidities. 30 Several factors merit consideration in interpreting studies investigating the impact of HIV on COVID-19 outcomes. First, the ability to adjust for comorbidities may profoundly impact results.

Comorbidities are highly prevalent in PWH, typically at higher rates than in non-HIV comparator groups, and increase risk for severe COVID-19. A finding of increased risk of severe COVID-19 conferred by HIV may be attenuated or lose significance after adjustment for relevant comorbidities.

Second, findings may reflect the selection of the study population. Studies limited to hospitalized patients may fail to detect a mortality signal if the at-risk group in question is hospitalized at higher In terms of the impact of HIV disease stage or virologic suppression on COVID-19, data from several recent studies are beginning to shed light on this critical question. A study from the University of Missouri showed CD4 cell count <200/mm 3 to increase risk of a composite outcome of ICU admission, mechanical ventilation, or death more than 3-fold; 32 a South African populationbased study showed CD4 cell count <200/mm 3 in hospitalized patients to be associated with COVID-19 death; 27 a New York State study showed CD4 cell count <200/mm 3 to be associated with increased risk of hospitalization; 30 and an Italian series showed nadir CD4 cell count to be lower in hospitalized patients in unadjusted analyses. 33 The New York State study also showed HIV viremia to be associated with increased risk of hospitalization. 30 The current study by Braunstein et al. Despite these uncertainties, based on the currently available data, there is growing concern that PWH may be at increased risk for severe COVID-19; indeed, several large studies (but not all) point to a signal of increased COVID-19 mortality in individuals with HIV (Table) . Exactly why PWH A c c e p t e d M a n u s c r i p t While awaiting these necessary and critical studies to sort out exactly why PWH may have worse COVID-19 outcomes, we must make decisions today about how to apportion vaccines and how best to counsel and manage PWH. Even if increased risk of COVID-19 mortality in HIV is largely limited to individuals with lower CD4 cell counts or active viremia, we do not yet have the data to precisely identify which individuals in this population are at highest risk. Even if risk of severe COVID-19 is mostly driven by comorbidities, these are often under-diagnosed and under-recognized in PWH -particularly as they can manifest at younger ages in this group -and might not be adequately factored into COVID-19 risk stratification. Even if structural inequities long endured by many PWH influence COVID-19 outcomes (and they almost certainly do), this makes vaccination even more pressing because COVID-19 prevention -such as staying home and social distancing -is likely to be more challenging for many PWH due to employment, family obligations, or other unavoidable constraints. For all these reasons, we call for prioritization of people with HIV for COVID-19 vaccination into the same tier as people with other comorbidities that confer increased risk of severe COVID-19, such as those with cardiovascular or chronic pulmonary disease. 

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Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

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VAT reports grants from National Institutes of Health. RTG reports grants from National Institutes of Health and has previously served on Scientific Advisory Boards for Gilead and Merck.

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