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EDITORIAL REVIEW

SARS-CoV-2 infection and coronavirus disease 2019 severity in persons with HIV on antiretroviral treatment

del Amo, Juliaa; Polo, Rosaa; Moreno, Santiagob,c; Jarrín, Inmac,d; Hernán, Miguel A.e

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doi: 10.1097/QAD.0000000000003132
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Abstract

Introduction

Since early in the COVID-19 pandemic, the susceptibility of people with HIV (PWH) to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been debated. On the one hand, residual immunodeficiency and a higher prevalence of comorbidities and immune senescence in persons with HIV could be associated with a greater risk of acquiring the infection and with greater severity [1–3]. On the other hand, precisely because of their immune dysfunction, PWH could be less likely to develop the hyper inflammatory response that leads to the most severe outcomes [4,5]. Further, some antiretroviral drugs used by PWH could impair SARS-CoV-2 replication, and thus reduce the severity of the infection [6–8].

Numerous studies have reported apparently contradictory findings. However, comparisons across studies is difficult as the studies differ in terms of their populations (e.g. different age distribution, sociodemographic factors, prevalence of comorbidities), comparison groups of persons with HIV (e.g. HIV-negative individuals from the same population, other COVID-19 hospitalized patients, general population), and ability to adjust for important confounders.

In this article, we review the evidence regarding the frequency of SARS-CoV-2 testing, the risk of SARS-CoV-2 infection, and the severity of COVID-19 in PWH compared with people without HIV infection. We examine the implications of the choice of the comparison group, the role of unmeasured confounding, and the consequences of adjustment for risk factors of COVID-19 severity, which are affected by HIV infection.

Study designs and data sources

Various data sources and study designs have been used to estimate the frequency of SARS-CoV-2 testing, SARS-CoV-2 infection, and COVID-19 clinical severity in PWH compared with people without HIV. Most of the early publications were based on clinical surveys and cohorts of hospitalized patients with COVID-19, with HIV infection as one of the many exposures of interest. The outcomes of interest were admission to the ICU and death. The studies on hospitalized patients with COVID-19 quickly identified risk factors for severity but could not provide information on persons not admitted to the hospital. Also, the urgency to generate evidence precluded detailed collection of data on potential confounders and opened the possibility of selection bias [9].

Case reports of PHW with COVID-19 range from the initial single case report in China [10] to several case series [11–15]. Case series, however, provide only limited information. Cohorts of PWH are more informative as they include both people with and without COVID-19. These cohorts have been used to study the incidence of SARS-CoV-2-related outcomes and its relation with HIV-related variables, such as CD4+ cell count, HIV viral load, and antiretroviral drugs. Yet these cohorts include only PWH and thus do not allow to study differences between persons with and without HIV.

The choice of a comparison group of individuals without HIV is a long-standing challenge in HIV research. Ideally, PWH would be compared with people without HIV from the same population but assembling such comparison cohorts is logistically difficult. Some examples of studies that have used this approach to investigate outcomes in PWH are the Veteran Aging Cohort studies (VACS) [16], the Amsterdam Cohort Studies (ACS) [17], the Multicenter AIDS Cohort Study (MACS) [18], the Women's Interagency HIV Study (WIHS) [19], the AGEhIV cohort [20], and the COBRA cohort [21] which is a collaboration with POPPY (Pharmacokinetic and clinical Observations in PeoPle over fiftY Study) [22]. In practice, most PWH cohorts are compared with cohorts of people without HIV from the general population using routine data registries (primary healthcare records, hospital records, vital statistics) with a likely different prevalence of risk factors, such as smoking and illicit drug use.

We now review how these studies have been used to answer four key questions in HIV and COVID-19 research.

Are people with HIV at higher risk of SARS-CoV-2 testing than people without HIV?

Among United States veterans during the first wave of the pandemic, Park et al.[23] reported that 2346 PWH had a higher probability of being tested for SARS-CoV-2 than 4473 HIV-negative individual of comparable characteristics [odds ratio (OR) 1.36; 95% confidence interval (CI): 1.29–1.43). A similar finding was reported by the Corona-Infectious-Virus Epidemiology Team (CIVET) when comparing PWH (from five clinical cohorts within health systems and one interval cohort) with HIV-negative individuals from several United States populations [24].

Are people with HIV at higher risk of SARS-CoV-2 infection than people without HIV?

In New York City, Braunstein et al.[25] estimated an age-adjusted HIV prevalence of 1.1% among all 204 583 COVID-19 cases diagnosed through June 2020, compared with 1.5% in the New York City general population. PWH may be at a higher risk of SARS-CoV-2 infection because of socioeconomic factors, which include a greater proportion of racial/ethnic minorities and migrants living in crowded residences in neighborhoods with intense SARS-CoV-2 transmission [26–28], and working in occupations which preclude working from home and require the use of public transportation. In New York City, PWH (with and without COVID-19) were more likely to be men and black or Hispanic, and to live in areas with high poverty levels than HIV-negative people with COVID-19 [25]. Behavioral factors include multiple sex partners, sex work, and drug use, which may also favor the transmission of SARS-CoV-2. Therefore, determining whether HIV affects the risk of SARS-CoV-2 infection may require adjustment for the above confounders. Depending on the relative distribution of the confounders in each population, the unadjusted associations between HIV infection and SARS-CoV-2 infection may differ between populations with different confounding structure.

In some populations, PWH have a higher incidence of SARS-CoV-2 infection than persons without HIV in unadjusted analyses but not after adjustment for available confounders [25,28]. For example, Tesoriero et al.[28] estimated that the unadjusted incidence of laboratory-confirmed COVID-19 in New York State was 43% higher in PWH than in the general population (rate ratio 1.43; 95% CI 1.38–1.48) but it was 6% lower after adjustment for age, sex, and location (rate ratio 0.94; 95% CI 0.91–0.97). In other populations, PWH do not have a higher incidence of SARS-CoV-2 infection in unadjusted analyses. Among SARS-CoV-2-tested United States veterans, Park et al.[23] found no increased risk of SARS-CoV-2 infection (OR 1.05 95% CI 0.89–1.24) in PWH compared with persons without HIV, though this comparison needs to be interpreted with caution because of the conditioning on testing. Similar findings were reported by CIVET in the US [24].

During the first pandemic wave in Spain, the risk of PCR-confirmed COVID-19 (largely symptomatic) was 30 per 10,000 among 77,590 PWH on antiretroviral therapy. This risk was lower than that in the general population (41.7 per 10 000) but the difference largely disappeared after excluding healthcare workers (HCW) (33.9 per 10 000) who had been heavily tested [29,30].

In summary, the available evidence suggests that PWH do not have a greater risk of SARS-CoV-2 infection than persons without HIV through mechanisms other than increased exposure to both infections because of socioeconomic vulnerability and risky behaviors. It was hypothesized early into the COVID-19 pandemic that some antiretroviral drugs may impair the replication of SARS-CoV-2 [6,7,31,32], and thus decrease the susceptibility to SARS-CoV-2 infection. Although randomized trials have discarded any relevant benefit of some protease inhibitors in the HIV-negative population [8], the role of nucleos(t)ide analogs reverse (NRTI) transcriptase inhibitors is under active investigation.

Are people with HIV at higher risk of severe coronavirus disease 2019 outcomes than people without HIV?

Severe COVID-19 outcomes include hospitalization, ICU admission, and death. Findings about the risk of severe COVID-19 outcomes in PWH compared with people without HIV are conflicting. We review the available evidence by study design.

Surveys of hospitalized patients with coronavirus disease 2019

Three studies of hospitalized patients with COVID-19 during the first pandemic wave found lower than expected HIV prevalences: 0.6% among 2226 individuals in New York City [33], 0.8% among 5700 individuals in Madrid, Spain [34], and 0.7% among 4035 individuals in Spain [35].

Cohorts of hospitalized patients with coronavirus disease 2019

Hadi et al.[36] studied 50 167 hospitalized COVID-19 patients in the United States, including 404 PWH who were more likely to be black and had more comorbidities than people without HIV. After matching on race and comorbidities, the mortality rate ratio was 1.55 (95% CI 1.01–2.39) for HIV infection vs. no HIV infection. After further adjustment for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney disease, race, history of nicotine dependence and sex, the rate ratio was 1.33 (95% CI 0.69–2.57) [36].

Geretti et al.[37] studied 47 592 hospitalized COVID-19 patients in the UK, including 122 PWH who were younger on average than people without HIV. The unadjusted mortality hazard ratio for HIV infection versus no HIV infection was 0.77 (95% CI 0.54–1.11) and 1.45 (95% CI 1.00–2.12) after adjusting for age and sex. Additional adjustments for ethnicity, hospital acquisition of COVID-19, 10 comorbidities and hypoxia/receiving oxygen at presentation among individuals under 60 years increased the hazard ratio to 2.87 (95% CI 1.70–4.86) [37]. No viral load data were available [37].

Smaller studies have reported more imprecise estimates [38–42]. For example, Patel et al.[38] studied 4613 hospitalized COVID-19 patients in the Bronx, New York, including 100 PWH who had an increased risk of intubation but no longer duration of hospitalization and in-hospital mortality.

The WHO Global Clinical Platform for COVID-19 [43] studied 168 449 hospitalized individuals with suspected or confirmed COVID-19 from 37 countries, including 15 522 PWH of whom 92% were on ART (no viral load data were available) and 96% originated from the WHO African region (most from South Africa). The risk of in-hospital mortality for HIV vs. no HIV varied by region: the hazard ratio adjusted for age, sex, disease severity, and comorbidities was 1.29 (95% CI 1.23–1.34) in the African region, 0.59 (95% CI 0.29–1.20) in the European region, and 0.92 (95% CI 0.37–2.31) in the Americas [43].

Cohorts of people with HIV compared with people without HIV

Among United States Veterans, Parks et al.[23] reported a similar risk of hospital admission (OR 1.09, 95% CI 0.85–1.41), ICU admission (OR 1.08, 95% CI 0.72–1.62), intubation (OR 0.89, 95% CI 0.49–1.59), and death (OR 1.08, 95% CI 0.66–1.75) in PWH compared with persons without HIV.

In Spain, we reported [29] a risk of COVID-19 death of 2.6 per 10 000 persons among 77 790 PWH on ART, which increased to 3.7 per 10 000 persons after standardization to the age and sex distribution of the Spanish population. This risk was 1.8 times higher than the risk of COVID-19 death of the general population in Spain, which was 2.1 per 10 000 persons for the same period. No data on comorbidities and viral load were available.

In New York state, Tesoriero et al.[28] reported higher risks of severe COVID-19 outcomes in PWH compared with the general population. The unadjusted rate ratio for HIV vs. no HIV was 2.61 (95% CI 2.45–2.79) for COVID-19 hospitalization and 2.55 (95% CI 2.22–2.93) for in-hospital death. After adjustment for sex, age and location, these rate ratios were 1.38 (95% CI 1.29–1.47) and 1.23 (95% CI 1.07–1.40), respectively. COVID-19 hospitalization and mortality in PWH increased with age, like in the general population [28].

In England, Bhaskaran et al.[44] cross-matched records from primary healthcare and the Office for National Statistics. Of 27 480 PWH registered, 60% were 40–59 years old, 15.6% above 60 years, and 26% were black. These proportions were 34.1, 31.7, and 1.9% among 17 255 425 people without HIV. Except for a larger proportion of chronic liver disease in PWH (3.4 vs. 0.6%), there were no differences for any other comorbidities compared with people without HIV. The unadjusted hazard ratio COVID-19 related death was 1.03 (95% CI 0.70–1.52) for HIV vs. no HIV and increased to 2.90 (95% CI 1.96–4.30) after adjusting for age and sex. This hazard ratio was higher among people of black ethnicity (hazard ratio 4.31; 95% CI 2.42–7.65) than among those of other ethnicities (hazard ratio 1.84; 95% CI 1.03–3.26). No differences in COVID-19 related death were seen between HIV-positive and HIV-negative people with no comorbidities (hazard ratio 1.01; 95% CI 0.26–4.10) but a higher mortality was observed among PWH with one or more comorbidities, (hazard ratio 2.57; 95% CI 1.71–3.88) [44]. As people without comorbidities may be less likely to be registered as HIV-positive in their general practitioner records, PWH in this study may not be representative of the population of PWH in England [45].

In Cape Town, South Africa, Boulle et al.[46] studied healthcare records of 3 460 932 persons, of whom 536 574 were PWH and 22 308 had a prior COVID-19 diagnosis. The unadjusted hazard ratio of COVID-19 death was 1.07 (95% CI 0.88–1.32) for HIV vs. no HIV, and 2.14 (95% CI 1.70–2.20) after adjustment for age, sex, and other comorbidities. Analyses within the subset of hospitalized patients with COVID-19 also identified an increased risk of death associated with HIV infection (hazard ratio 1.45, 95% CI 1.14–1.84) among hospitalized patients with COVID-19 [46].

In summary, the available evidence is compatible with a higher COVID-19 severity in PWH compared with people without HIV. However, a firm conclusion is not possible because of the difficulties in merging different study designs with different comparison groups of HIV-negative populations and varying degrees of potential confounding and selection bias. Meta-analyses by Mellor et al.[47] and Ssentongo et al.[48] acknowledged these difficulties. In addition, as pointed out above, studies restricted to hospitalized patients may yield biased estimates because of collider stratification [9]. Notably, the only study that compared PWH with individuals from the same population with extensive adjustment for potential confounders did not find a higher COVID-19 disease severity among PWH compared with HIV-negative individuals [23].

What factors are associated with severe coronavirus disease 2019 outcomes in people with HIV?

Cohorts of PWH have compared COVID-19 incidence and COVID-19 outcomes by sociodemographic and clinical characteristics as well as by HIV-specific markers, such as disease stage, CD4+ cell counts and viral loads, and antiretroviral drugs.

In New York state, Tesoriero et al.[28] described that hospitalization and mortality rates in PWH with COVID-19 increased with age. Compared with HIV disease stage 1 (CD4+ cell counts >500 cells/μl), hospitalization rates were 29% higher for stages 2 (CD4+ cell counts 200–499 cells/μl) and 69% higher for stage 3 (CD4+ cell counts <200 cells/μl). The corresponding increases for mortality were 11% and 26% [28].

In Madrid, Spain, Vizcarra et al.[29] reported that values of CD4+ cell counts did not differ between 51 HIV-positive patients with COVID-19 and 1288 HIV-positive persons without COVID-19 but the prevalence of comorbidities, such as diabetes, hypertension, chronic liver, and renal disease was higher in PWH and COVID-19 (63%) than in PWH without COVID-19 (38%) [49].

In Barcelona, Spain, Inciarte et al.[50] did not find any HIV-related factor clearly associated with COVID-19 severity among 5683 PWH. Median CD4+ cell count (interquartile range) was 624 cells/ml (462–838) in the 53 individuals with PWH and COVID-19 and 662 cells/ml (484–880) in PWH without COVID-19. Overall, 43% of COVID-19 cases had at least one comorbidity and 40% at least two [50].

In two case series of PWH and COVID-19, lower CD4+ cell count was associated with increased mortality. Hoffman et al.[13] reported an mortality odds ratio of 2.85 (95% CI 1.26–6.44) for CD4+ cell count under 350 cells/ml compared with higher values. Dandachi et at [14] identified higher mortality for CD4+ cell count under 200 cells/ml.

In summary, the available evidence indicates that COVID-19 severity for PWH varies by age and comorbidities, similarly to people without HIV. The evidence for CD4+ cell count and HIV viral load is less clear but it is important to highlight it originates largely from settings with high ART coverage, and therefore, with small numbers of people with low CD4+ cell count and high HIV viral load. If HIV were to have a direct effect on COVID-19 susceptibility and severity, clearer associations with HIV-specific disease markers were to be expected.

What is the role of antiretrovirals for coronavirus disease 2019 outcomes?

Intriguing associations have been reported for tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and COVID-19 outcomes in PWH. Three observational studies among PWH, two in Spain and one in South-Africa, have reported associations between TDF/FTC and lower risk of SARS-CoV-2 seroprevalence [51], COVID-19 diagnosis [29,30], hospitalizations [29,30], and mortality [29,30,46]. In Spain, the risk of PCR-confirmed COVID-19 was lower among PWH on TDF/FTC (16.9 per 10 000) than in PWH with other drug regimens [29,30]. This difference was maintained in age-adjusted analyses using TAF/FTC as a reference category (rate ratio 0.44; 95% CI 0.27–0.70) and could not be entirely explained by selective prescription of TDF/FTC to healthier people [30]. The risk of COVID-19 hospitalization was 47% lower in persons on TDF/FTC (rate ratio 0.53, 95% CI 0.27–0.97) compared with PWH on TAF/FTC [29,30]. In South Africa, the hazard ratio of COVID-19 death for TDF/FTC compared with abacavir or zidovudine was 0.41 (95% CI 0.21–0.78) in analyses adjusted for baseline renal function [46].

Associations suggesting a protective effect of TDF/FTC on COVID-19 related outcomes have been also reported in some studies of HIV pre-exposure prophylaxis (PrEP) users in Spain [52] and Brazil [53]. In one cohort of 4736 people treated for chronic hepatitis B infection in Spain, better COVID-19 outcomes were reported among TDF/FTC users than in entecavir users [54]. A recent randomized trial from Colombia (not yet peer-reviewed) reports a lower risk of invasive mechanical ventilation in patients on TDF/FTC with colchicine and rosuvastatin compared with interventions without TDF/FTC [55].

The data from these observational studies [29–30,46,51,54] supports a potential protective role of TDF/FTC against SARS-CoV-2 infection and outcomes. The biological plausibility of a protective effect for TDF/FTC is supported by molecular docking studies showing that NRTIs inhibit the RNAdRNAp and drug pharmacokinetics) [6,31,32,56,57], as well as animal models [7] and in-vivo studies [56]. A small randomized trial in France by Parienti et al.[58] found an increased clearance of SARS-CoV-2 virus in the TD/FTC group compared with standard of care. Three randomized trials of TDF/FTC are ongoing; one evaluates preexposure prophylaxis among healthcare workers (EPICOS) [59] in Spain and Latin America and the others evaluate treatment of nonsevere cases (PANCOVID) in Spain [60] and in Brazil (ARTAN-C19) [61].

Confounders and other variables on the causal pathway

PWH are often different from people without HIV used as comparison groups. For example, HIV-positive people are usually younger than the comparison groups of people without COVID-19. As a result, unadjusted associations between HIV infection and COVID-19 outcomes may be misleading as they may be confounded by age, that is, the association reflects the effect of age differences rather than the effect of HIV infection. People with and without HIV also differ in the prevalence of comorbidities. Specifically, some of the risk factors for COVID-19 severity – hypertension, diabetes mellitus, renal disease, and cancer – may be more common in PWH than in populations without HIV of similar age and sex. However, adjustment for these comorbidities needs to be approached with caution as their pathogenesis is multifactorial and some may be partially the result of chronic HIV infection, and thus, on the causal pathway between HIV and COVID-19 severity. Therefore, each comorbidity needs to be considered separately.

If we wanted to answer the question ‘What is the causal effect of HIV infection on COVID-19 severity?’ then adjusting for diabetes diagnosed after HIV infection is incorrect: the effect of HIV infection on severity may be partly mediated through diabetes. That is, diabetes is not a confounder. In addition, if there are shared causes of diabetes and COVID-19 severity other than HIV infection (i.e. obesity), diabetes would be a collider and adjustment could introduce bias. However, if we want to answer the question ‘What is the causal effect of HIV infection on COVID-19 severity through mechanisms other that diabetes?’, then adjusting for diabetes might be defensible if we could also adjust for all shared causes of diabetes and COVID-19 severity. As these shared causes may be unknown or unmeasured, estimates adjusted for post-HIV comorbidities should be regarded with caution.

In summary, evidence from the United States suggests that PWH with access to healthcare had a higher frequency of SARS-CoV-2 testing than people without HIV during the first wave of the pandemic. Despite this higher testing intensity, it is unclear that PWH on ART have a higher risk of SARS-CoV-2 infection after socioeconomic factors are adjusted for. PWH in many locations may have a higher incidence of SARS-CoV-2 infection because of shared risk factors for both conditions, including socioeconomic vulnerability and different lifestyles.

Many studies found increased COVID-19 severity in PWH compared with people without HIV, though the conclusion that HIV infection increases the risk of hospitalization and mortality is not straightforward. If HIV were to have a direct effect on COVID-19 severity, strong associations with HIV-specific markers would be expected. As most studies include PWH on ART, thus with high CD4+ cell counts and low viral loads, these associations cannot be appropriately evaluated. In addition, the ability of many studies to account for differences between PWH and HIV-negative individuals was limited. The study with arguably better comparability between PWH And HIV-negative individuals did not find differences in COVID-19 disease severity [23].

Compared with the general population, COVID-19 mortality in PWH was higher in New York, South-Africa, and Spain after adjusting for age and sex. These findings are consistent with the higher mortality that PWH, previous to the COVID-19 pandemic, still had compared with the general population of the same age and sex [62–65]. In Spain, this excess risk has been reported for all-cause mortality as well for cause-specific causes, and is higher in PWH with lower CD4+ cell counts, hepatitis C virus (HCV) coinfection, and low socioeconomic level [64]. Analyses from 10 cohorts from different parts of the world have identified that although the life expectancy of PWH on ART has improved greatly and worldwide over the last decade, gaps remain compared with the general population [65].

All the publications consistently identify that COVID-19 severity in PWH is not homogeneous and increases with age and with the presence of certain comorbidities. As PWH may have a higher prevalence of comorbidities than people without HIV, examining their respective contribution to the development of poor health outcomes is not straightforward as they could mediate some or all the effect HIV may have on COVID-19 outcomes. Additional analyses framing the research questions with these caveats in mind are needed.

Acknowledgements

We thank Marta Cobos, Javier Gómez, and Susana Martínez for their assistance in the literature review.

This article is supported by research grants COV20/01112; PROYECTOS DE INVESTIGACIÓN SOBRE EL SARS-COV-2 Y LA ENFERMEDAD COVID19; Institute of Health Carlos III, Spain and U.S. National Institutes of Health grant R37 AI102634.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

HIV; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); coronavirus disease 2019; mortality; bias; tenofovir disoproxil fumarate/emtricitabine

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