HIV and COVID-19: review of clinical course and outcomes

Abstract

Background:Understanding the relationship between HIV and SARS-CoV-2 has important public health implications.

Objective:To summarize current research on COVID-19 among people with HIV (PWH) as published through 15 July 2021.

Methods: We conducted a search of PubMed, Scopus, preprint databases (medRxiv, bioRxiv), and the references of publications found using key terms relevant to COVID-19 (‘COVID-19’ OR ‘SARS-CoV-2’ OR ‘coronavirus’) AND to HIV (‘HIV’ OR ‘Human Immunodeficiency Virus’ OR ‘AIDS’ OR ‘Acquired Immunodeficiency Syndrome’). We summarized all articles that reported data or opinions on SARS-CoV-2 and HIV coinfection.

Conclusions: Although many initial case series and cohort studies found no increased risk for SARS-CoV-2 infection or severe COVID-19 outcomes among PWH, recent studies have signaled an increased risk for severe COVID-19 disease progression even in the setting of well-controlled HIV. Whether this is due to the increased prevalence of comorbidities in PWH and other social determinants of health is unknown. These conflicting findings highlight the continued need for COVID-19 related research among PWH that addresses COVID-19 disease course as well as exacerbation of existing comorbidities already disproportionately represented among PWH.

Keywords:

• Human immunodeficiency virus
• SARS-CoV-2
• COVID-19
• coinfection

Introduction

When COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, began to surface in late 2019 and early 2020, healthcare officials and providers assumed that individuals with Human Immunodeficiency Virus (HIV) infection and other immunocompromising conditions would be at particularly high risk of both acquisition and severe disease.¹ Without effective antiretroviral therapy (ART), HIV leads to depletion of CD4 T-lymphocytes, resulting in a weakened adaptive immune response.² In the presence of effective ART, the cellular immune response recovers to variable degrees; however, individuals with HIV appear to remain at greater risk for many infections, including pneumococcal pneumonia, influenza, meningococcal disease, herpes virus infections, and tuberculosis.^2–7

As COVID-19 precipitated widespread closures of businesses, schools, and community gatherings, healthcare agencies, and other critical operations scrambled to determine how to provide essential services to patients while protecting their employees. In an attempt to limit potential spread to patients and employees, many clinics converted to virtual or telephone-based visits.⁸ However, as businesses, schools, and healthcare facilities have gradually resumed in-person services, the ongoing risk for acquiring SARS-CoV-2 infection, or developing severe disease, remain somewhat elusive.

While increasing age, obesity, diabetes, and Black or Hispanic race/ethnicity have consistently been linked to acquisition and severe disease in U.S. populations, the role of other factors, such as HIV, in contributing to risk of COVID-19 acquisition and disease severity have been less certain.^9–14 Furthermore, people with HIV (PWH) frequently have overlapping risk factors for COVID-19, often at rates higher than the general population. These risks include being male, Black or Hispanic, smoking, older age, and medical comorbidities.^15–23 Lastly, despite effective ART, PWH have higher levels of inflammation, one of the key factors driving the development of severe respiratory disease, thromboembolic disease, and other poor outcomes with COVID-19.^24,25 Parsing out the added risk of HIV with or without ART in the setting of these other epidemiologic and physiologic risks is therefore challenging.

Methods

To better understand what is currently known about the relationship between HIV and COVID-19 acquisition and disease severity, we conducted a search of PubMed, Scopus, preprint databases (medRxiv, bioRxiv), and the references of publications found using key terms relevant to COVID-19 (‘COVID-19’ OR ‘SARS-CoV-2’ OR ‘coronavirus’) AND to HIV (‘HIV’ OR ‘Human Immunodeficiency Virus’ OR ‘AIDS’ OR ‘Acquired Immunodeficiency Syndrome’) between 1 March 2020 and 15 July 2021. Of 2210 initial results we considered each study that reported data or opinions on COVID-19 among PWH, applying extra filters to access articles related to ‘symptoms’, ‘severity’, ‘hospitalization’, ‘mental health’, ‘access to care’, and ‘ART’. This resulted in the 212 articles presented in this review. We then summarized the risk for acquiring COVID-19, presenting symptoms of COVID-19, severity of COVID-19 illness, and impacts on mental health and access to care during the COVID-19 pandemic. We also report findings on the effects of antiretroviral therapy on COVID-19 risk and outcomes for PWH.

Discussion

Are people living with HIV more likely to contract SARS-CoV-2?

Many experts initially considered individuals living with HIV as a vulnerable group with regards to SARS-CoV-2 infection due to a greater burden of some comorbidities, higher systemic inflammation despite effective ART, and some degree of immune alteration even among those on effective ART with immune reconstitution.^26–32 Whether this is true remains unclear. PWH account for approximately 0.7% of the general population of adults in the world, and roughly 0.5–1.5% of COVID-19 cases in various COVID-19 case series and cohort studies.^28,33–36

One prospective cohort study of 5683 PWH observed a lower incidence of COVID-19 among PWH compared to the general population, suggesting a possible protective effect of HIV, ART, or less exposure through physical isolation and consistent use of personal protective equipment.³⁷ However, this study was limited in that it did not control for ART use. Multiple other prospective cohort studies, limited by their study sizes, have found similar rates of SARS-CoV-2 among PWH and the general population.^38–41 A study from San Francisco of 4252 PWH suggested that PWH were more susceptible to SARS-CoV-2 infection than those without HIV.⁴² Numerous other confounders, however, may have explained these differences: for example, 8% of PWH in San Francisco experience unstable housing as compared to the 1% of the San Francisco general population.⁴² As of 28 July 2020, the Centers for Disease Control and Prevention concluded that based on the limited data available, PWH on effective ART appear to have a similar risk for acquisition of SARS-CoV-2 as people who do not have HIV.⁴³

It is important to note that multiple studies have attempted to distinguish the difference between test positivity and disease incidence. In a recent analysis of over 30,000 PWH in the USA, PWH were more likely to be tested for SARS-CoV-2 but did not have an increased percentage of COVID-19 positivity compared to individuals without HIV.⁴⁴ However, the authors note that testing shortages and the potential for differential adherence to stay-at-home guidance by immunosuppression status could have influenced the outcome of the study. In contrast, researchers in Southern Italy found that PWH were more reluctant to obtain SARS-CoV-2 testing and thus were likely underdiagnosed with COVID-19, though this was an opinion piece and the conclusion was not backed by data.⁴⁵

Do the presenting symptoms of COVID-19 differ among people with or without HIV?

In the general population, the most common presenting symptoms of COVID-19 include fever, cough, or shortness of breath (70%) and less commonly muscle aches (36%), headaches (34%), and loss of smell or taste (8%).⁹ A cohort of 286 PWH showed similar symptoms: cough (76.2%), fever (70.7%), and fatigue (66.0%).²⁰ This study was especially strong as it took data from multiple states and countries. These results have been supported by numerous other studies.^46–53 Besides one review, these studies are limited in their small sample size. Of note, other individual case studies have found that PWH may present with COVID-19 and opportunistic infections such as Pneumocystis jirovecii pneumonia and AIDS-related disseminated histoplasmosis, perhaps exacerbated by or contributing to presenting symptoms of COVID-19.^54–60

Are people living with HIV more likely to present with severe disease and/or be hospitalized for COVID-19?

Similar to the general population, age and co-morbidities appear to be the strongest predictors of severe disease and mortality in PWH.^{22,46,61–73} Most PWH who develop symptomatic COVID-19 have at least one co-morbidity, most commonly hypertension, dyslipidemia, or type 2 diabetes mellitus.^{28,38,46,51,61,64,74–78} Per Dandachi et al. (n = 286), 81% of PWH had at least one co-morbidity which impacted their COVID-19 clinical course.²⁰

Data describing the likelihood of hospitalization due to COVID-19 among PWH is limited and mixed: rates of hospital admission among people living with HIV range from 0.8% to 1.8%.^33,38,74,79 Notably, these rates derive from cohorts in numerous countries including Spain, China, and the United States, which may differ demographically with varying rates of comorbidities and clinical threshold for hospitalization. A retrospective, matched cohort study at a New York health system indicated PWH (n = 21) had a significantly higher rate of hospital admission but not intensive care unit admission, mechanical ventilation, or mortality, compared to people without HIV (n = 42).⁸⁰ All PWH in this cohort were on ART, the majority had an undetectable viral load, and only six of 19 had a CD4 count < 200 cells/uL, thus limiting the ability to determine the effect of HIV severity of COVID-19 outcomes. A separate small analysis of 31 PWH hospitalized at a New York, NY hospital also found similar rates of hospitalization among those with or without HIV.³⁵ In a much larger Veteran cohort of 107,636 patients with COVID-19, risk of hospital admission among PWH did not differ from those without HIV, although these results have not yet been published in a peer-reviewed paper.⁴⁴

In a retrospective study in New York comparing 21 PWH with 42 matched-uninfected controls admitted with COVID-19, a similar burden of comorbidities and similar admission laboratory values were seen between PWH and uninfected controls.⁸⁰ In addition, no statistically significant differences were seen between PWH and the uninfected controls when comparing consolidation, infiltrate, or opacity on chest imaging.⁸⁰ Although the study was small, findings are strengthened by matching PWH and controls by admission date, age, body mass index, gender, tobacco history, and a history of chronic kidney disease, hypertension, asthma, chronic obstructive pulmonary disease, and heart failure. In summary, among PWH, risk factors for hospitalization and clinical presentation at the time of hospitalization appear to be influenced more by comorbidities or demographic risk factors seen in the general population (race/ethnicity, socio-economic status), and less by HIV-specific factors.

Are people with HIV more likely to have severe outcomes?

A number of studies on HIV and SARS-CoV-2 coinfection have addressed the question whether PWH have more severe outcomes than the general population (as defined by more ICU admissions, greater need for mechanical ventilation, and higher mortality rates). As summarized in Table 1, many large studies and smaller case reports have found greater likelihood of ICU admission and higher mortality rates among PWH than the general population.^76,81–91 Indeed, of 3,460,932 patients in the public sector in South Africa, 16% were PWH and 22,308 (0.6%) were diagnosed with COVID-19. In this large study, HIV infection was associated with a doubling of COVID-19 mortality risk, independent of CD4 count or HIV viral load (though >90% were virologically suppressed).⁹¹. In a study of 17,282,905 adults (including 27,480 PWH) in the United Kingdom, a substantially higher risk of mortality was seen with COVID-19 in PWH than in the general population, although the actual number of deaths among PWH was only 25, thus limiting some of the conclusions.¹⁹ Furthermore, data were available on some comorbidities and demographics but not HIV-related characteristics (ART, CD4 count, or viral load). A landmark report by the World Health Organization (WHO) included 15,522 PWH and 168,649 adults without known HIV hospitalized with suspected or confirmed SARS-CoV-2 from 24 countries (96% from the WHO African Region).⁹² HIV was associated with an increased risk of severe or critical disease at admission compared to uninfected controls, after adjusting for age, sex, and underlying comorbidities. HIV was also independently associated with higher mortality risk. The majority of persons included were from South Africa, and no data were presented on ART, CD4 count, or virologic suppression.⁹² Two systematic reviews/meta-analyses also concluded that PWH had a higher risk of mortality, though only in studies of PWH from Africa and the United States.^93,94 A smaller study of PWH in Brazil (n = 255) found that being Black/Mixed race and having lower education were associated with greater mortality in adjusted models, while age, sex, CD4 count, viral load, and comorbidities were not.⁶³ To the best of our knowledge, thus far only one study has investigated the risk of post-acute symptoms following COVID-19 and found that moderate to severe disease was associated with an increased risk of persistent symptoms in PWH.⁹⁵

Table 1. Summary of 2020–2021 publications (through 15 July 2021) related to HIV and COVID-19.

First author	Population	Location	Publication date	Journal	Description or findings
Zhu, F.^26	1 PWH	China	11-Mar-20	J Med Virol	Described how PWH should be regarded as a vulnerable population in regard to COVID-19
Chen, J.^199	1 PWH	China	14-Apr-20	J Med Virol	Described a coinfected PWH with atypical CT imaging of the chest
Blanco, J.L.^33	5 PWH	Spain	15-Apr-20	Lancet HIV	Described clinical course of patients (<50 years old)
Wang, M.^82	1 PWH	China	23-Apr-20	Int J Infect Dis	COVID-19 and HIV (low CD4 count) led to a longer disease course
Aydin, O.A.^23	4 PWH	Turkey	29-Apr-20	J Med Virol	Comorbidities are an important factor in mortality for coinfected PWH
Ridgway, J.P.^41	8 PWH/1061 HIV negative controls	USA	7-May-20	AIDS Behav	PWH did not test positive for COVID-19 at a different rate than the general population
Hӓrter, G.^47	33 PWH	Germany	11-May-20	Infection	PWH did not have more severe morbidity or mortality than the general population
Gervasoni, C.^105	47 PWH	Italy	14-May-20	Clin Infect Dis	PWH coinfected with COVID-19 had favorable outcomes as compared to the general population
Patel, R.H.^106	1 PWH	USA	22-May-20	J Med Virol	Coinfected patient under treatment with ART had a less severe clinical presentation than the general hospitalized population
Iordanou, S.^81	1 PWH	Republic of Cyprus	25-May-20	J Med Virol	Coinfected (PWH/COVID-19) patient had a prolonged need for mechanical ventilation and increased risk for thrombotic complications
Childs, K.^49	18 PWH	United Kingdom	27-May-20	Clin Infect Dis	Black PWH were at higher risk of severe disease; ARTs did not appear to provide protection against COVID-19 severity
Vizcarra, P.^38	51 PWH and COVID-19 positive/1288 PWH	Spain	28-May-20	Lancet HIV	Clinical presentation in PWH was similar to the general population, however, lower CD4 counts affected disease severity; PWH had a higher prevalence of comorbidities
Okoh, A.K.^142	27 PWH	USA	28-May-20	J Acquir Immune Defic Syndr	Coinfected PWH presented similarly to the general population
Ridgway, J.P.^50	5 PWH	USA	29-May-20	AIDS Patient Care STDS	A similar COVID-19 clinical course was seen in PWH as in the general population
Shalev, N.^35	31 PWH	USA	30-May-20	Clin Infect Dis	HIV coinfection did not lead to increased rates of hospitalization; outcomes for PWH were similar to the general population
Suwanwongse, K.^27	9 PWH	USA	9-Jun-20	J Med Virol	PWH did not have more favorable COVID-19 outcomes especially when their CD4 counts were low
Coleman, H.^55	1 PWH	United Kingdom	10-Jun-20	AIDS	Pneumocystis jirovecii pneumonia and COVID-19 infection were observed in a PWH
Karmen-Tuohy, S.^80	21 PWH/42 HIV negative controls	USA	12-Jun-20	J Acquir Immune Defic Syndr	PWH had a higher admission rate for COVID-19 but did not show significant differences in ICU admissions, mechanical ventilator use, or mortality
Benkovic, S.^113	4 PWH	USA	16-Jun-20	J Med Virol	Clinical severity was not different in uncomplicated cases of COVID-19 and HIV coinfection as compared to the general population
Byrd, K.M.^115	27 PWH	USA	19-Jun-20	J Int AIDS Soc	Clinical course and severity appeared similar in PWH as the general public
Meyerowitz, E.A.^75	47 PWH	USA	25-Jun-20	AIDS	Coinfected PWH were on average 53.4 years old and a substantial proportion had comorbidities, were non-Hispanic Black, and lived or worked in a congregate setting
Del Amo, J.^202	236 PWH and COVID-19 positive/77,590 PWH receiving ART	Spain	26-Jun-20	Ann Intern Med	The risk for COVID-19 hospitalization was 20.3 among patients receiving TAF/FTC, 10.5 among those receiving TDF/FTC, 23.4 among those receiving ABC/3TC, and 20.0 for those receiving other regimens
Sigel, K.^74	88 PWH/405 HIV negative controls	USA	28-Jun-20	Clin Infect Dis	There was no difference in COVID-19 severity on admission by HIV status and PWH did not have more severe COVID-19 outcomes than the general population
Toombs, J.M.^129	3 PWH	United Kingdom	29-Jun-20	J Med Virol	PWH may be protected from severe COVID-19 if they are on ART
Ho, H.^84	72 PWH	USA	30-Jun-20	J Infect Dis	PWH were at higher risk for severe COVID-19 outcomes, especially those with increased markers of inflammation and immune dysfunction
Guo, W.^76	14 PWH	China	1-Jul-20	J Int AIDS Soc	HIV and COVID-19 coinfection led to a higher mortality rate and higher proportion of severe cases than the general population
Park, L.S.^44	30,891 PWH/76,745 HIV negative controls	USA	6-Jul-20	AIDS 2020 Conference	PWH had higher COVID-19 testing rates but no evidence to support increased positivity or more severe outcomes
Ruan, L.^102	4 PWH	China	6-Jul-20	J Med Virol	PWH in the stage of AIDS had a more complicated clinical course than those not in AIDS
Gudipati, S.^112	14 PWH	USA	15-Jul-20	J Acquir Immune Defic Syndr	PWH were not at a higher risk for severe COVID-19 outcomes
Mahmood, K.^196	1 PWH	USA	15-Jul-20	JACC Case Rep	Coinfected PWH on a LVAD
Cooper, T.J.^140	70 PWH	United Kingdom	15-Jul-20	HIV Med	PWH with well-controlled disease are not at risk of poorer COVID-19 outcomes than the general population
Adachi, E.^141	2 PWH	Japan	15-Jul-20	AIDS	Transgender PWH have similar clinical course of COVID-19 as compared to the general population
Charre, C.^39	77 PWH/27 PrEP users/19009 other patients	France	17-Jul-20	AIDS	The positivity rate appeared similar in HIV-infected patients, in PrEP users, and in other patients
Maggiolo, F.^61	55 PWH and COVID-19 postive/69 PWH	Italy	24-Jul-20	J Med Virol	HIV coinfection did not protect from COVID-19 coinfection or from severe disease
Su, J.^52	1 PWH	China	1-Aug-20	AIDS	Described COVID-19 in a patient with AIDS; speculated that protease inhibitors might have a protective effect for COVID-19
Stoeckle, K.^116	30 PWH/90 HIV-negative controls	USA	1-Aug-20	Open Forum Infect Dis	A similar COVID-19 clinical course was seen in PWH as in negative controls
Sun, L.J.^111	1 PWH	Singapore	1-Aug-20	J Acquir Immune Defic Syndr	He recovered from a mild and uncomplicated clinical course of COVID-19 without treatment
Calza, L.^48	26 PWH	Italy	3-Aug-20	Infection	PWH had a similar COVID-19 clinical presentation to the general population
Bhaskaran, K.^19	27480 PWH/17.3 million adults	United Kingdom	7-Aug-20	Lancet	PWH had nearly three-fold higher risk of COVID-19 death than those without HIV after adjusting for age and sex
Tian, C.^108	1 PWH	China	10-Aug-20	Ann Palliat Med	Described favorable outcome in coinfected PWH
Guo, W.^138	11 PWH	China	10-Aug-20	Res Sq	PWH have comparable COVID-19 morbidity rates as the general population,
Marbaniang, I.^158	167 PWH	India	13-Aug-20	Res Sq	¼ of PWH had anxiety during the COVID-19 pandemic
Huang, J.^34	35 PWH	China	17-Aug-20	Clin Infect Dis	PWH had similar severity and fatality from COVID-19 as the general population
Parker, A.^136	24 PWH/92 HIV negative controls	South Africa	21-Aug-20	S Afr Med J	Coinfected PWH had similar presentations and outcomes as those without HIV
Boulle, A.^91	553,749 PWH	South Africa	29-Aug-20	Clin Infect Dis	HIV was independently associated with increased COVID-19 mortality
Larzábal, F.J.^7	1 PWH	Argentina	31-Aug-20	Medicina	Described a PWH hospitalized with Pneumocysti jiroveccii and COVID-19 coinfection
Molina-Iturritza, E.^139	8 PWH	Spain	1-Sep-20	AIDS	The rate of COVID-19 in PWH is similar to the rate in the general population
Sasset, L.^70	2 PWH	Italy	1-Sep-20	AIDS	PWH had similar demographic and clinical characteristics to the general population
Hu, Y.^197	12 PWH	China	1-Sep-20	J Acquir Immune Defic Syndr	The value of ART for mitigation of COVID-19 infection is discussed
Shekhar, R.^110	5 PWH	USA	1-Sep-20	J Acquir Immune Defic Syndr	PWH may have a milder course of COVID-19 than the general population
Madge, S.^117	18 PWH	United Kingdom	2-Sep-20	Sex Transm Infect	PWH did not have prolonged hospital courses or worse outcomes compared to the general population
Etienne, N.^64	54 PWH and COVID-19 positive/4000 PWH	France	3-Sep-20	AIDS	PWH had worse COVID-19 outcomes when they were older age, male, had comorbidities, higher BMI, sub-Saharan Africa origins, had lower CD4 counts
Inciarte, A.^37	53 PWH and COVID-19 positive/5683 PWH	Spain	3-Sep-20	AIDS	Incidence rate of COVID-19 was lower in PWH compared to general population; clinical course of COVID-19 was not dependent on any HIV- or ART-related factor
Winston, A.^77	699 PWH/304 HIV negative controls	United Kingdom and Ireland	3-Sep-20	AIDS	PWH tended to have more comorbidities which was associated with poorer COVID-19 outcomes
d’Ettore, G.^31	1 PWH	Italy	4-Sep-20	Medicine	Coinfection of HIV and COVID-19 showed increased levels of IFNα/β and T-cell activation as compared to healthy individuals with COVID-19
Bertolini, M.^54	1 PWH	Argentina	9-Sep-20	Int J STD AIDS	Described a male patient with AIDS-related disseminated histoplasmosis associated with COVID-19
Dandachi, D.^20	286 PWH	USA	9-Sep-20	Clin Infect Dis	PWH were at higher risk for severe COVID-19 outcomes, especially those with comorbidities and lower CD cell counts
Akyala, A.I.^198	4 PWH	Nigeria	10-Sep-20	Pan Afr Med J	PWH experienced a mild COVID-19 clinical course
Nagarakanti, S.R.^114	23 PWH/23 HIV negative controls	USA	19-Sep-20	J Med Virol	Among, PWH, there was not higher mortality, ICU admissions, or mechanical ventilation in PWH than in the general population
Chiappe Gonzalez, A.J.^83	1 PWH	Peru	21-Sep-20	Int J STD AIDS	HIV/COVID-19 coinfection led to a fatal outcome
Mondi, A.^120	5 PWH	Italy	25-Sep-20	J Med Virol	PWH did not have more severe COVID-19 outcomes than the general population
Isernia, V.^78	30 PWH	France	26-Sep-20	Int J Infect Dis	HIV was not a risk factor for COVID-19
Sun, S.^150	703 PWH	China	Oct-20	AIDS Behav	PWH reported high rates of anxiety, depression, and insomnia
Collins, L.F.^46	20 PWH	USA	1-Oct-20	AIDS	PWH with more than 5 comorbidities, who are non-Hispanic Black, are male had more severe COVID-19 outcomes
Di Biagio, A.^206	4 PWH	Italy	1-Oct-20	AIDS	Protease inhibitor-based regimens were not protective against contracting COVID-19 in PWH
Yamamoto, S.^200	5 PWH	Japan	2-Oct-20	J Microbiol Immunol Infect	PWH coinfected with COVID-19 have a similar clinical course as patients without HIV
Kim, J.Y.^118	1 PWH	Korea	12-Oct-20	Korean Med Sci	PWH had a favorable clinical outcome with COVID-19
Gamboa, E.^123	1 PWH	USA	17-Oct-20	Cureus	Noted that CD4+ lymphocytes declined over the course of COVID-19 hospitalization in a PWH
Zhang, J.C.^32	2 PWH	China	19-Oct-20	BMC Infect Dis	Described the importance of accurate diagnosis for PWH with COVID-19 coinfection
Geretti, A.M.^85	115 PWH/47,424 HIV negative controls	United Kingdom	23-Oct-20	Clinical Infectious Diseases	Following additional adjustment for disease severity at presentation, mortality was higher in PWH
Yang, R.^97	3 PWH/53 HIV negative controls	China	27-Oct-20	Expert Review of Respiratory Medicine	Low CD4 count was a risk factor for severe COVID-19 outcomes
Cabello, A.^137	63 PWH	Spain	27-Oct-20	Int J Infect Dis	Coinfected PWH do not have different outcomes based on severity of HIV or type of ARV treatment
Di Biagio, A.^96	69 PWH	Italy	1-Nov-20	AIDS	Lower CD4 counts were associated with higher rates of COVID-19 hospital admission and more severe outcomes
Hadi, Y.B.^28	404 PWH/49,763 HIV negative controls	USA	1-Nov-20	AIDS	Propensity-matched analysis showed no difference in outcomes for PWH compared to the non-HIV controls; higher mortality was related to comorbidities
Siewe Fodjo, J.N.^157	317 PWH	Belgium, Brazil	1-Nov-20	J Acquir Immun Defic Syndr	23.3% of PWH screened positive for depression and 22.7% screened positive for anxiety during the COVID-19 pandemic
Morani, Z.^69	43 PWH	Belize, USA	2-Nov-20	SN Compr Clin Med	Comorbidities and advanced age make PWH more prone to worse COVID-19 outcomes
Tesoriero, J.M.^90	2988 PWH	USA	6-Nov-20	MedRxiv	PWH experienced poorer COVID-19 related outcomes than those without HIV
Jones, D.L.^163	1554 PWH	Argentina, USA	18-Nov-20	Res Sq	PWH who had higher levels of social support reported less depression during the COVID-19 pandemic
D'Souza, G.^53	2078 PWH/1333 HIV negative controls	USA	19-Nov-20	HIV Res Clin Pract	PWH had similar prevalence and type of COVID-19 symptoms as the general population
Sachdev, D.^42	193 PWH and COVID-19 positive/4252 PWH	USA	20-Nov-20	J Acquir Immune Defic Syndr	PWH were more susceptible to COVID-19 than those without HIV
Turken, M.^98	4 PWH	Turkey	30-Nov-20	Curr HIV Res	Two patients with normal CD4+ count had mild coinfections, a patient with low CD4+ count died
Braunstein, S.L.^103	2410 PWH	USA	30-Nov-20	Clin Infect Dis	More PWH had adverse COVID-19 outcomes than the general population, perhaps due to comorbidities and other social determinants of health
Swaminathan, N.^145	6 PWH	USA	1-Dec-20	J Med Virol	PWH had similar mortality when compared to other studies
Hardy, Y.O.^127	3 PWH	Ghana	Dec-20	Ghana Med J	PWH with advanced immunosuppression may not have an unfavorable COVID-19 disease outcome
Kowalska, J.D.^122	34 PWH	Central and Eastern Europe	13-Dec-20	Int J Infect Dis	HIV serostatus was not associated with more severe disease
Kuman Tuncel, O.^159	307 PWH	Turkey	17-Dec-20	Turk J Med Sci	A significant proportion of PWH had anxiety during the COVID-19 pandemic
Hoffmann, C.^209	175 PWH	Germany, Spain, Italy	27-Dec-20	HIV Med	Virological suppression was possibly related to severe COVID-19 outcomes; no evidence of protective effect by ARTs
Noe, S.^135	500 PWH	Germany	2-Jan-21	Infection	There were no marked differences for PWH with and without SARS-CoV-2 co-infection
Cooley, S.A.^156	54 PWH/133 HIV negative controls	USA	6-Jan-21	J Neurovirol	PWH had increased symptoms of anxiety and depression during the COVID-19 pandemic
Laracy, J.^132	68 PWH/272 HIV negative controls	USA	28-Jan-21	Open Forum Infect Dis	PWH did not did not differ from HIV-uninfected controls by rate of mechanical ventilation or death
Tesoriero, J.M.^89	2988 PWH/2409 HIV negative controls	USA	1-Feb-21	JAMA Netw Open	PWH experienced poorer COVID-19 outcomes than the general population
Patel, V.V.^134	100 PWH/4513 HIV negative controls	USA	1-Feb-21	Acquir Immune Defic Syndr	PWH had increased risk of intubation but similarly frequent rates of AKI and in-hospital death as those without HIV
Ceballos, M.E.^133	36 PWH	Chile	3-Feb-21	Int J STD AIDS	No differences were found between PWH and the general population in the need for mechanical ventilation and death
Nasreddine, R.^65	101 PWH	Belgium	9-Feb-21	J Med Virol	HIV patients with COVID-19 experienced a high degree of hospitalization
Delle Donne, V.^162	98 PWH	Italy	1-Mar-21	Infez Med	Almost half of PWH experienced significant distress due to the COVID-19 pandemic
Eybpoosh, S.^124	90 PWH	Iran	10-Mar-21	Med J Islam Repub Iran	HIV infection was not a risk factor for increased COVID-19 severity and death
Sorbera, M.^183	211 PWH	USA	16-Mar-21	J Am Coll Clin Pharm	Telehealth for pharmacy services did not jeopardize patient outcomes
Weerasuria, M.^149	153 PWH	Australia	17-Mar-21	AIDS Res Hum Retroviruses	Telehealth was widely used; many PWH experienced negative mental health in the COVID-19 pandemic
Farinacci, D.^59	1 PWH	Italy	31-Mar-21	AIDS Res Hum Retroviruses	PWH coinfected with Pneumocystis jirovecii
Durstenfeld, M.S.^128	220 PWH	USA	7-Apr-21	MedRxiv	HIV was not associated with adverse outcomes of COVID-19
Mohindra, R.^130	1 PWH/1 HIV negative control	India	7-Apr-21	Virus disease	PWH had a similar clinical course to HIV negative persons
Liu, W.^146	1 PWH	Taiwan	21-Apr-21	J Formos Med Assoc	The clinical presentation of coinfected PWH were similar to other COVID-19 patients without HIV infection
Diaz, M.M.^153	156 PWH	Peru	26-Apr-21	MedRxiv	PWH reported increased anxiety and stress during the COVID-19 pandemic
Mang, S.^60	1 PWH	Germany	26-Apr-21	Clin Infect Dis	PWH coinfected with COVID-19 and Pneumocystis jirovecii
Siewe Fodjo, J.N.^154	247 PWH	Brazil	27-Apr-21	Int J Environ Res Public Health	27.1% of PWH screened positive for anxiety, 27.9% screened positive for depression during the COVID-19 pandemic
Spinelli, M.A.^87	955 PWH/1062 HIV negative controls	USA	29-Apr-21	Lancet HIV	PWH had more cases of severe COVID-19
Liang, M.^104	7718 PWH/196,043 HIV negative controls	China	3-May-21	Infect Dis Ther	Coinfected PWH were not associated with higher COVID-19 mortality
Merchant, E.A.^58	1 PWH	USA	7-May-21	ID Cases	Coinfection PWH had PJP
Charifi, Y.^57	1 PWH	Morocco	15-May-21	Clin Case Rep	Coinfected PWH had pneumocystis with typical lesions
Massarvva, T.^126	730 PWH	Cyprus	17-May-21	Epidemiol Health	Coinfected PWH had comparable clinical outcomes with the general population
Kumar, S.^151	167 PWH	India	19-May-21	New Microbes New Infect	Many PWH experience fear, anxiety and depression in the COVID-19 pandemic
Venturas, J.^125	108 PWH/276 HIV negative controls	South Africa	26-May-21	J Infect	HIV is not a risk factor for severe COVID-19 disease or mortality
Ader, F.^210	583 patients	France	26-May-21	Clin Microbiol Infect	COVID-19 clearance and clinical status were not improved but lopinavir/ritonavir
Pujari, S.^67	86 PWH	India	31-May-21	AIDS Res Hum Retroviruses	Coinfected PWH had similar clinical outcomes as the general population; comorbidities are associated with more severe outcomes
Pujari, S.^95	94 PWH	India	2-Jun-21	Immun Inflamm Dis	Long-COVID is common among PWH with moderate-severe acute COVID-19
Rocha, S.Q.^63	255 PWH	Brazil	4-Jun-21	AIDS Care	Skin color/race, and schooling remained significantly associated with higher COVID-19 mortality in PWH
Chanda, D.^101	122 PWH	Zambia	4-Jun-21	MMWR	Severe HIV is associated with increased risk of COVID-19 death
Di Castelnuovo, A.^213	3,451 patients	Italy	9-Jun-21	Front med	DRV/c was associated with increased mortality
Wu, M.^56	68 PWH/980 HIV negative controls	China	9-Jun-21	Res Sq	Older age was considered a driving force for coinfection in PWH
Wion, R.K.^152	154 PWH	USA	15-Jun-21	AIDS Behav	PWH experienced an increase in social isolation, depression, and stress
Flannery, S.^99	99 PWH	USA	22-Jun-21	Int J STD AIDS	Hospitalized coinfected PWH did not have worse outcomes than the general population; PWH who had CD4% <14 or not on treatment for HIV had higher mortality rates
Berenguer, J.^203	91 PWH	Spain	26-Jun-21	Clin Microbiol Infect	TDF/FTC may prevent SARS-CoV-2 infection among PWH
Dong, Y.^93	41,113 PWH/ 18,081,257 HIV negative controls	China	2-Jul-21	Medicine (Baltimore)	PWH had a higher risk of mortality from COVID-19 than those without HIV infection
Bertagnolio, S.^92	15,522 PWH/168,649 negative controls	24 countries	15-Jul-21	WHO	PWH were at increased risk for severe or critical COVID-19

Abbreviations: PWH, person(s) living with HIV; ART, antiretroviral therapy; USA: United States of America.

Dandachi et al. (n = 286) noted that patients with lower CD4 counts (<200 cells/mm³) may be at risk for more severe outcomes despite viral suppression and this was supported by other smaller studies.^{20,72,84,96–103} The results of Dandachi et al. are strong and generalizable as they pull data from 36 institutions across 21 states and three countries. However, the study did not collect data on social determinants of health or COVID-19 therapies, which may have differed and confounded the results. Greater co-morbidity burden in PWH has also been associated with more severe COVID-19 outcomes.^{20,28,46,64,76,77,104}

Other studies suggest that PWH have fewer COVID-19 complications, fewer admissions to the ICU, and lower mortality rates (as seen in Table 1).^105–111 Larger cohorts from Spain, Italy, and the USA as well as many smaller studies have found no association or an unclear association between severity of outcomes such as ICU admission, need for mechanical ventilation, or mortality rates and HIV serostatus.^{34,38,44,61,74,80,99,112–147}

In general, PWH appear to be at higher risk for severe COVID-19 outcomes even after considering demographic factors and comorbidities associated with severe disease. However, it is important to note that due to the quickly changing testing procedures and requirements for hospitalization throughout the pandemic, as well as the reliance on public health surveillance data and/or medical record review, the ability to truly distinguish severity of outcomes in PWH is difficult and often confounded.¹⁴⁸ Regardless, preventive measures for PWH should be strongly encouraged (particularly vaccination) to limit disease severity.

How does COVID-19 impact the mental health of PWH?

The social distancing and quarantine strategies required to reduce the spread of SARS-CoV-2 have left many feeling isolated and lonely. This is especially impactful to PWH as they have increased worry about physical health (68%), mental health (66%), finances (50%), and accommodation (25%) during the COVID-19 pandemic.¹⁴⁹ One study found that of 703 PWH, 61% of PWH reported depressive symptoms, 50% noted anxiety symptoms, and 39% experienced recent insomnia.¹⁵⁰ Other smaller studies have also found increased rates of depression, anxiety, insomnia, and substance abuse in relation to the COVID-19 pandemic.^151–162 Importantly, these rates are lower amongst people who report strong levels of social support in a large study from two countries.¹⁶³

How does COVID-19 impact access to care for PWH?

The COVID-19 pandemic has restricted access to care for much of the population by restricting public transportation, suspending routine appointments, and adding financial hardships. PWH specifically are at high risk of treatment interruption due to reduced access to HIV clinics, reduction in primary care or specialty referrals, and difficulties refilling ART prescriptions.^{150,156,157,164–176} Telemedicine has proven to be very effective in many countries as it provides flexibility in scheduling appointments, reduces the need for transportation, and provides privacy for patients not wanting to be seen attending an HIV clinic.^{149,177–184} However, telemedicine also presents barriers including technological challenges, client/provider experiences, digital literacy, low socio-economic status of client population, and reimbursement issues.^185–187 Many countries have identified this imbalance in access to care both with HIV diagnosis and ongoing care and have provided at-home testing kits, distributed condoms with COVID-19 testing services, and mailed ART to ensure continuity of care.^188–193

How does ART influence acquisition of SARS-CoV-2 or severity of COVID-19?

In the USA, an estimated 61.5% of the 1.2 million persons living with HIV are virologically suppressed using ART.¹⁹⁴ Consequently, most PWH who develop COVID-19 will be on suppressive ART. While maintaining suppressed viral load and a normal CD4 T-lymphocyte count likely decreases the risk of severe COVID-19, there is yet to be clear evidence that ART itself prevents the acquisition of SARS-CoV-2 infection or alters the rate of progression to severe disease.^{51,144,195–201} Three observational studies have suggested a potential protective role of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) among PWH.^91,202,203 The last of these adjusted for comorbidities, demographics, country of birth, and education level. As TDF/FTC tends to be avoided due to toxicity among older patients with more comorbid conditions, this finding may be due to confounders of younger age and fewer comorbidities, rather than a protective effect of the drug.^91,202 Similarly, the HIV protease inhibitor lopinavir-ritonavir has in vitro activity against SARS-CoV-2 and some speculate that it may be protective against COVID-19.²⁰⁴ However, a randomized control trial of this medication in 199 HIV-negative persons with COVID-19 have failed to demonstrate a clinical benefit and other studies, including systemic reviews and meta-analyses, support the conclusion that ART does not serve a protective role against SARS-CoV-2 infection.^49,205–212 A study of darunavir/cobicistat actually showed an increased mortality rate.²¹³ However, this was an observational study that may have been affected by confounders.

General management of COVID-19 among PWH

The guidelines for management of care for PWH and COVID-19 does not differ from those without HIV, although the likelihood of severe disease and poor outcomes may be heightened. Thus, we suggest that the following principles of HIV management are important in persons who present with COVID-19²¹⁴:

• Public health precautions including hand hygiene, mask wearing, and physical distancing should be strictly adhered to.

• Compliance with routine vaccinations, including influenza, should be emphasized.

• COVID-19 vaccination should be given.

• Consideration could be given to telehealth visits in place of in-person visits to ensure continuity of care, particularly in areas of high COVID-19 rates and when there are no acute health concerns.

• For persons who are on HIV treatment, ART and opportunistic infection prophylaxis (if applicable) should be continued, if feasible based on the patient’s clinical condition.

• ART should not be adjusted in an attempt to treat COVID-19.

• With regards to COVID-19 treatment, there are no significant drug–drug interactions between remdesivir and ART. Dexamethasone is an inducer of hepatic metabolism of drugs and could decrease the levels of some co-administered ART.²¹⁵ As the course of dexamethasone is typically limited to 10 days or less, it is unlikely that this interaction will be significant in most circumstances.

• If there is a need to adjust or change ART, consultation with an HIV specialist is recommended. For critically ill patients who require enteral feeding, some ART are available in liquid formulations and some pills may be crushed. Clinicians should consult an HIV specialist and/or pharmacist to assess the best way for a patient with a feeding tube to continue an effective regimen.

• Regarding prophylaxis for opportunistic infections, whether the lymphopenia associated with COVID-19 places PWH at higher risk for opportunistic infections is not currently known. As this lymphopenia is limited, the risk of acquiring infections is not expected to alter prophylactic therapy.

• As COVID-19 may occur more commonly in people with limited prior access or engagement to the healthcare system, the hospitalization is an opportunity to screen for HIV and other infections (hepatitis C, tuberculosis), as indicated. For persons who present with COVID-19 and a new diagnosis of HIV infection, the timing of starting ART is currently unknown. Currently, the Department of Health and Human Services guidelines recommend immediate initiation of ART in persons with newly diagnosed HIV infection.²¹⁴ Immune reconstitution could help in the management of SARS-CoV-2 infection. In contrast, immune reconstitution could also exacerbate the inflammatory response and worsen respiratory failure or contribute to a hypercoagulable state in others. Other characteristics such as renal failure, thrombosis, or mechanical ventilation might suggest a delay in ART initiation to avoid further exacerbating inflammation. Consultation with an HIV specialist is advised.

Conclusion

Although initial case studies and small cohorts found similar rates of infection and severity in PWH, the growing literature in diverse settings throughout the course of the pandemic now suggests that PWH are at greater risk for severe disease, even with well-controlled HIV. As the pandemic continues, PWH should be counseled regarding the heightened risk from HIV, in addition to other demographic or comorbid factors. Precautions to limit unnecessary exposure and decrease risk for acquisition (i.e. handwashing, physical distancing, mask wearing) should be encouraged particularly during surges in infection rates. While the general care of PWH who also acquire SARS-CoV-2 infection does not differ from people without HIV, certain considerations regarding drug–drug interactions can be guided through consultation with an HIV specialist. Lastly, while separate from the direct complications of COVID-19, the isolation and loneliness experienced during this pandemic, potential interruptions of medication therapy, and reduced access to care may have an even more profound effect on those experiencing the stigma of HIV. Ensuring that PWH are able to stay connected to local resources and monitoring for the impact on mental health and well-being will have important long-term implications.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported in part by the National Institutes of Health, National Institute on Aging [R01AG054366-05S] and the GEMS-Health Professionals Program [R25HL103286]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. KME has received grant funding from Gilead Sciences (paid to the University of Colorado).

Notes on contributors

Lauren K. Barbera

Lauren K. Barbera is an MD candidate at the University of Colorado School of Medicine in Aurora, CO.

Kevin F. Kamis

Kevin F. Kamis, MPH, is a Researcher at Denver Public Health, a department within Denver Health and Hospital Authority, Denver, CO, USA.

Sarah E. Rowan

Sarah E. Rowan, MD, is an Associate Professor in the Division of Infectious Diseases at the University of Colorado Denver and the Associate Director of HIV and Viral Hepatitis Prevention at Denver Public Health, a division of Denver Health and Hospital Authority.

Amelia J. Davis

Amelia J. Davis is a MD/MPH candidate at the University of Colorado School of Medicine and the Colorado School of Public Health in Aurora, CO.

Soraya Shehata

Soraya Shehata is a MD/PhD candidate at the University of Colorado School of Medicine, currently completing her thesis work in the Molecular, Cellular, and Developmental Biology Department of CU Boulder.

Jesse J. Carlson

Jesse J. Carlson is a Research Associate at Denver Public Health and an MPH candidate at the Colorado School of Public Health in Aurora, CO.

Steven C. Johnson

Steven C. Johnson, MD, is a Professor of Medicine and the Associate Division Head for Clinical Affairs in the Division of Infectious Diseases, Department of Medicine, at the University of Colorado School of Medicine in Aurora, Colorado.

Kristine M. Erlandson

Kristine M. Erlandson, MD, MS is an Associate Professor of Medicine and Epidemiology at the University of Colorado in Aurora, CO.