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Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK): a prospective observational study
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A High Percentage of People with HIV on Antiretroviral Therapy Experience Detectable Low-Level Plasma HIV-1 RNA Following COVID-19 - (11/28/20)
Elevated COVID-19 outcomes among persons living with diagnosed HIV infection in New York State: Results from a population-level match of HIV, COVID-19, and hospitalization databases - (11/12/20)
Clinical Infectious Diseases, 23 October 2020
Anna Maria Geretti*1,2, Alexander J. Stockdale*1,2, Sophie H. Kelly*1,2, Muge Cevik3, Simon Collins4, Laura Waters5,6, Giovanni Villa7, Annemarie Docherty8,9, Ewen M Harrison8, Lance Turtle1,2, Peter JM Openshaw10, J Kenneth Baillie9,11, Caroline A. Sabin12,13*, Malcolm G Semple1,14*.
Summary: HIV-positive people hospitalized with COVID-19 had an age-adjusted 47% higher risk of day-28 mortality compared with a large population of HIV-negative people within the same dataset. The effect persisted after adjusting for sex, ethnicity, and major comorbidities.
Abstract
Background
Evidence is conflicting about how HIV modulates COVID-19. We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the ISARIC WHO CCP study.
Methods
We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, ten individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy).
Results
Among 47,592 patients, 122 (0.26%) had confirmed HIV infection and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 versus 74 years; p<0.001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive vs. HIV-negative groups (26.7% vs. 32.1%; p=0.16), but in those under 60 years of age HIV-positive status was associated with increased mortality (21.3% vs. 9.6%; p<0.001 [log-rank test]). Mortality was higher among people with HIV after adjusting for age (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.01-2.14; p=0.05), and the association persisted after adjusting for the other variables (aHR 1.69; 95% CI 1.15-2.48; p=0.008) and when restricting the analysis to people aged <60 years (aHR 2.87; 95% CI 1.70-4.84; p<0.001).
Conclusions
HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19.
Conclusions
Our data are limited by the relatively small number of people with HIV included in the study and the findings should be interpreted with caution. Nonetheless, after careful considerations, our analysis of the outcomes of patients hospitalized with COVID-19 in the UK shows an increased risk of day-28 mortality due to HIV-positive status. As the pandemic continues to spread, including in areas of increased HIV prevalence, it is important to record the HIV status of people hospitalized with COVID-19 and gather further data to corroborate our findings and confirm the population-specific determinants of outcomes. Meanwhile, emphasis for PWH should be placed on early HIV diagnosis, prompt ART initiation, and optimized screening for and control of comorbidities including obesity and diabetes.
Principal findings
This study found evidence suggesting an age-adjusted 47% increased risk of day-28 mortality among PWH hospitalized with COVID-19 compared to HIV-negative individuals in the same dataset. Among people aged <60 years, HIV-positive status more than doubled the risk of mortality after adjusting for sex, ethnicity, age, baseline date, ten separate comorbidities, and disease severity at presentation (as indicated by a record of hypoxia or receiving oxygen therapy). The latter adjustment considered that doctors may be more likely to admit HIV- positive adults with COVID-19 despite less severe symptoms. …….the increased risk of COVID-19 related mortality in PWH was not merely due to the presence of promoting comorbidities. It should be highlighted that we did not take into consideration differences in the control of comorbidities between the two groups.
Introduction
Older age and presence of comorbidities including immunosuppression are recognized to increase the severity of COVID-19 [1-5]. However, existing evidence for an association between HIV infection and COVID-19 related outcomes is mixed. Despite effective antiretroviral therapy (ART), people with HIV (PWH) may continue to experience persistent immunodysfunction [6, 7] which might promote COVID-19 severity, or conversely, attenuate its pathological immune responses [8]. Although some antiretroviral drugs have been proposed to protect against COVID-19, the data remain uncertain [9,10]. Importantly, the common occurrence of co-factors such as diabetes and chronic renal and pulmonary disease [11], alongside disadvantageous socioeconomic variables [12], may increase the risk of adverse outcomes among PWH who acquire SARS-CoV-2.
Several case series and observational cohort studies have described the outcomes of COVID-19 in PWH across Europe [9,13-19], Asia [18,19], and the United States [8,18-22]. These studies have often been limited by small sample sizes, lack of direct comparative data from people without HIV, or inability to adjust for comorbidities. Some reports indicated that PWH did not experience higher rates of COVID-19 related hospitalization or mortality than people without HIV [14,21], whereas others suggested increased disease severity [9,20]. Importantly, preliminary data from South Africa indicated that despite effective ART, HIV infection more than doubled the risk of COVID-19 related mortality [23].
To characterize the presenting characteristics and outcomes of COVID-19 related hospitalization in PWH relative to those without HIV in the United Kingdom (UK), we analyzed data collected within the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterization Protocol (CCP), the largest prospective observational study of patients admitted to hospital with COVID-19 worldwide [24].
Results Participants
ISARIC CCP-UK recorded 53,993 people with COVID-19 between 17th January and 18th June 2020. After excluding non-eligible participants (Figure 1), we included 47,592 patients, of whom 122 (0.26%) had confirmed HIV infection. A positive SARS-CoV-2 RNA PCR test was recorded for 43,062/47,592 (90.5%) individuals. Patients excluded from the analysis did not differ by sex, ethnicity or age; in particular, the characteristics of those excluded due to missing HIV status closely resembled those reported to be HIV-negative (Supplementary Table 1). Among PWH, one person was diagnosed with HIV during the admission and 112 (91.8%) had an ART record. The regional distribution of study participants was similar to the UK population of PWH receiving care (Supplementary Table 2).
Characteristics at presentation
PWH were younger than HIV-negative people (median 56 vs. 74 years, p<0.001) (Table 1, Figure 2) and comprised a greater proportion of males and people of black ethnicity. PWH had fewer comorbidities overall, and a lower prevalence of cardiac, pulmonary and rheumatological disease, dementia, and malignancy, but higher rates of moderate/severe liver disease; proportions with chronic renal disease, diabetes and hematological disease were similar. The duration of symptoms was longer in PWH (median 5 vs. 3 days, p=0.002) (Table 2). PWH were more likely to present with fever, headache, myalgia and tachycardia, and to have cough and chest pain. Respiratory rate, occurrence of tachypnoea and hypoxia, and radiological evidence of chest infiltrates did not differ significantly between the two groups. PWH presented with lower total white blood cell and platelet count, but higher lymphocyte count and C-reactive protein (CRP) (Table 3).
COVID-19 outcomes
After adjustment for sex, ethnicity, age, baseline date, indeterminate/probable hospital acquisition of COVID-19, and ten comorbidities, the odds of admission to critical care were similar regardless of HIV status (odds ratio 1.22; 95% confidence interval [CI] 0.80-1.87; p=0.35) (Supplementary Table 3). By day 28 (Supplementary Table 4), 30 (24.6%) PWH were known to have died compared with 13,969 (29.4%) of the HIV-negative group; the cumulative incidence of day-28 mortality was 26.7% vs. 32.1%, respectively (p=0.16 Figure 3 A). Whilst findings were similar in men and women (Figure 3 B, C), univariate stratification for age revealed higher mortality among PWH in the younger age group (Figure 3 D-F). Among participants under 60 years of age, mortality was 21.3% in HIV-positive patients versus 9.6% in HIV-negative patients (p<0.001).
In the unadjusted analysis (Table 4), the cumulative hazard of day-28 mortality was lower in PWH (HR 0.77, 95% CI 0.54-1.11; p=0.17). Results did not change after adjusting for sex or ethnicity. In contrast, adjustment for age resulted in a change in the direction of the association (adjusted HR 1.47, 95% CI 1.01-2.14; p=0.05). Results were similar after adjustment for sex, ethnicity, age, baseline date, indeterminate/probable hospital acquisition of COVID-19 and ten comorbidities and following additional adjustment for disease severity at presentation. When restricted to people <60 years, the analysis yielded an adjusted HR of 2.87 (95% CI 1.70-4.86; p<0.001). Sensitivity analyses showed consistent results (Supplementary Table 5). In particular, censoring follow-up on the day of discharge, including definite hospital-acquired COVID-19, using symptom onset as baseline and excluding PWH lacking an ART record did not significantly alter the model. A separate logistic regression model with a binary variable of day-14 mortality and a competing risk regression model with discharge as a competing risk for mortality also showed increased odds of mortality in the HIV-positive group.
Among PWH, relative to patients who survived by day 28, patients who died were older and had a higher prevalence of diabetes and obesity and were less likely to have a record of ART (Table 5 and Supplementary Tables 6 and 7).
Discussion
Principal findings
This study found evidence suggesting an age-adjusted 47% increased risk of day-28 mortality among PWH hospitalized with COVID-19 compared to HIV-negative individuals in the same dataset. Among people aged <60 years, HIV-positive status more than doubled the risk of mortality after adjusting for sex, ethnicity, age, baseline date, ten separate comorbidities, and disease severity at presentation (as indicated by a record of hypoxia or receiving oxygen therapy). The latter adjustment considered that doctors may be more likely to admit HIV- positive adults with COVID-19 despite less severe symptoms.
The influence of age, sex and ethnicity on COVID-19 outcomes is currently debated [1,2,25]. PWH in our study were significantly younger than the HIV-negative group and adjusting for age changed the direction of the association between HIV status and day-28 mortality, indicating that age was a significant confounder in our analyses. Men were more prevalent in the HIV- positive group, which is consistent with the epidemiology of HIV infection in the UK, where men represent just over two thirds of the whole population with HIV [26]. People of black ethnicity comprised 42% of the HIV-positive group in this analysis relative to ~26% among PWH in the UK population [26]. Adjustment for sex or ethnicity alone did not impact our relative hazard estimates.
Whilst there is a recognized interplay between HIV and comorbidities, neither omitting the adjustment for comorbidities nor adjusting for separate comorbidities modified the association.
PWH had fewer comorbidities, notably lower prevalence of chronic pulmonary disease and malignancies, and this is largely a function of their younger age. HIV-positive people who died were older and were more likely to suffer from obesity and diabetes with complications than those who survived to discharge. Similar trends have been seen in the general population [1,25]. While these observations highlight the importance of obesity and diabetes as cofactors, the increased risk of COVID-19 related mortality in PWH was not merely due to the presence of promoting comorbidities. It should be highlighted that we did not take into consideration differences in the control of comorbidities between the two groups.
Comparison with other studies
Evidence about the interplay between HIV and COVID-19 is not entirely consistent [8,9,13-23]. A case-control study from New York compared 88 PWH, all of whom were receiving ART, and 405 HIV-negative controls matched by age, gender, ethnicity, and calendar week of infection [21]. The study found no difference in the outcomes of COVID-19 related hospitalization after adjusting for demographics, chronic obstructive pulmonary disease, smoking, and baseline ferritin and white blood cell count. There are important differences in the two study populations. Participants in the New York study had a median age of 61 years (IQR 54-67), whereas we found excess mortality in HIV-positive people aged <60 years. Whereas malignancies were recorded less commonly in our cohort (3% vs. 10%), prevalence of obesity was higher (17% vs. 11%). It is also noteworthy that mortality in the overall ISARIC CCP-UK population was higher than that reported in the New York study [21] and other countries [1]. Consistent with our findings, there are preliminary data that HIV-positive status was associated with increased hazard of mortality (adjusted HR 2.75) in South Africa [23]. Although the analysis did not account for history of tuberculosis, obesity and socioeconomic status, it is noteworthy that HIV suppression on ART did not alter the mortality risk.
Strengths and limitations of this study
A key strength of this study was the ability to perform a direct comparison of people with and without HIV in the same dataset, and to account for age, gender, ethnicity and key comorbidities.
The data for this study were collected during the first peak of the UK COVID-19 epidemic and there are missing data, including 2,742 patients with missing HIV status, who were excluded from the analysis. We also excluded 10 people initially recorded as having HIV but whose HIV status could not be confirmed; this group was similar to the HIV-negative group, with a median age of 81, suggesting that their initial HIV record was incorrect. Thus, these missing data are unlikely to affect the results.
Our focus was on the effect of HIV-positive status on day-28 mortality among people hospitalized with COVID-19. We did not address risk factors for a COVID-19 diagnosis or hospitalization among PWH, or the suggested modulating role of certain antiretroviral agents [9,10]. We also lacked data to adjust for deprivation or socioeconomic status. Our analysis cannot provide evidence of the role of HIV-related parameters on outcomes of COVID-19 related hospitalization, as we did not have details of the ART history, plasma HIV-1 RNA load, CD4 cell count, and history of HIV-related disease. HIV-positive people who died were less likely to have ART recorded than those who survived at day 28. This raises the possibility that some of the patients who died were not receiving ART, although this cannot be stated with certainty. In the UK, 93% of the 103,000 people estimated to have HIV infection have been diagnosed; of these, 97% receive ART with excellent virological suppression and only a small subset (~3%) is either not engaged with care or experiences problems with virological control despite ART [26]. Only a few PWH in our cohort had Pneumocystis jirovecii prophylaxis recorded in their admission medications, suggesting that the likelihood of PWH in our study being severely immunosuppressed was overall low.
Despite effective ART and normalized CD4 cell counts, a subset of PWH continue to experience immune activation, inflammation and a pro-coagulatory state [7] which may modulate the risk of COVID-19 related morbidity and mortality [28,29]. Persistent immune dysfunction may be the consequence of advanced immunocompromise prior to the start of ART, as defined by a low nadir CD4 cell count and inverted CD4:CD8 ratio. In the UK, 43% of people newly diagnosed with HIV in 2018 had a CD4 count <350 cells/mm3, a threshold indicative of significant immunosuppression [26,30]. Furthermore, current guidelines about starting ART at the time to diagnosis were implemented relatively recently, whereas in the past ART initiation in the UK was deferred until the CD4 count had declined below thresholds of initially 200, then 350 and subsequently 500 cells/mm3 [6,30]. Thus, many older PWH in the UK (and worldwide) will have experienced years of uncontrolled HIV replication prior to commencing treatment and may also have received earlier regimens of suboptimal efficacy, with potentially lasting effects on immune function [30,31]. Immunological studies will be required to confirm these hypotheses.
Conclusions
Our data are limited by the relatively small number of people with HIV included in the study and the findings should be interpreted with caution. Nonetheless, after careful considerations, our analysis of the outcomes of patients hospitalized with COVID-19 in the UK shows an increased risk of day-28 mortality due to HIV-positive status. As the pandemic continues to spread, including in areas of increased HIV prevalence, it is important to record the HIV status of people hospitalized with COVID-19 and gather further data to corroborate our findings and confirm the population-specific determinants of outcomes. Meanwhile, emphasis for PWH should be placed on early HIV diagnosis, prompt ART initiation, and optimized screening for and control of comorbidities including obesity and diabetes.
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