key: cord-0998910-90168tzh authors: Eisinger, Robert W; Lerner, Andrea M; Fauci, Anthony S title: HIV/AIDS in the Era of COVID-19: A Juxtaposition of Two Pandemics date: 2021-04-07 journal: J Infect Dis DOI: 10.1093/infdis/jiab114 sha: 1ac7cf790301209cefe5926387837c56c68e6c53 doc_id: 998910 cord_uid: 90168tzh The COVID-19 pandemic has significantly impacted persons with HIV interfering with critical health services for HIV prevention, treatment, and care. While there are multiple profiles of persons living with HIV and the impact of COVID-19 may differ for each, the severity of COVID-19 disease in persons with HIV is related strongly to the presence of comorbidities that increase the risk of severe disease in COVID-19 patients in the absence of HIV. An effective response to the juxtaposition of the HIV and COVID-19 pandemics requires a novel coordinated and collaborative global effort of scientists, industry, and community partners to accelerate basic and clinical research, as well as implementation science to operationalize evidence-based interventions expeditiously in real-world settings. The accelerated development and clinical evaluation of prevention and treatment countermeasures is urgently needed to mitigate the juxtaposition of the HIV and COVID-19 pandemics. A c c e p t e d M a n u s c r i p t clinical outcomes, e.g., hospitalizations, admissions to intensive care units (ICUs), and mortality, compared to white individuals. Factors contributing include long-standing systemic health disparities, socio-economic inequalities, as well as multigenerational households and frontline jobs not permitting social distancing and remote work conditions that may make exposure to SARS-CoV-2 more likely [10, 11] . These also are the same populations in the United States who have limited access to HIV treatment and achieving viral suppression [5, 12] . These populations also have a higher burden of comorbidities that place them at increased risk of severe COVID-19 disease [13] . Mascolo et al [14] propose a possible correlation between HIV-associated immune impairment with susceptibility to SARS-CoV-2 infection and the clinical manifestations and severity of COVID-19. They speculate that individuals with HIV who are not receiving ART develop lymphopenia that may protect them from severe COVID-19 disease, although they remain susceptible to SARS-CoV-2 infection. Others have proposed that individuals with HIV who are not receiving ART or virally suppressed may be at increased risk of contracting SARS-CoV-2 due to a compromised immune system and these individuals are then at increased risk of serious COVID-19 and death [12] . Initial reports of HIV and SARS-CoV-2 coinfection came from Wuhan, China during the early days of the COVID- 19 pandemic. An initial report [15] of coinfection described a 61year old male, with diabetes and a history of heavy smoking, who presented in January 2020 with the now-recognized symptoms of COVID-19 disease confirmed with chest computed tomography results that indicated multiple ground-glass opacities in both lungs. The patient was newly diagnosed with HIV during admission for COVID-19, subsequently recovered and returned home. Based on this case, the authors proposed that immunocompromised patients, including those individuals with HIV, should be considered a vulnerable population group at increased risk of COVID-19 [15] . A c c e p t e d M a n u s c r i p t While additional single-case reports of HIV and SARS-CoV-2 coinfection emerged from Wuhan, information was limited until a large cohort survey of 1,174 individuals with HIV in two districts of Wuhan China was conducted in late February to determine the risk of SARS-CoV-2 in this population and the potential role of ART in the prevention or treatment of COVID-19 disease [16] . The data showed that the rate of SARS-CoV-2 infection in persons with HIV was 0.68%, slightly higher than among the general population (~0.5%) in Wuhan at the end of February 2020. In contrast, a systematic review of 25 published studies recently showed no increased risk for incident SARS-CoV-2 infection or disease progression for individuals with HIV receiving ART and virally suppressed as compared to individuals without HIV [17] . The findings indicated that the percent of individuals with HIV and SARS-CoV-2 coinfection was similar to that of the general population with SARS-CoV-2 mono-infection. Disease. Many questions remain as to whether persons with HIV are more at risk for severe COVID-19 and death as reports are in some cases contradictory. Mounting evidence indicates that the presence of comorbidities in persons with HIV is the predominant determining factor as to the severity of COVID-19 disease. In this regard, a meta-analysis [18] showed a high prevalence of comorbidities in individuals with HIV who developed severe COVID-19. The findings underscore the critical role of comorbidities as a key factor in morbidity and death for individuals with HIV and SARS-CoV-2 coinfection as they are for COVID-19 patients who are not infected with HIV [18] . Similar findings were reported from an analysis of the multicenter TriNETX research network that included data on 50,167 patients with COVID-19 in the United States, including 404 persons with HIV [19] . A c c e p t e d M a n u s c r i p t However, when co-morbidities are removed from the calculation, HIV infection itself does not appear to be a risk factor for severe COVID-19 disease. A systematic review involving an analyses of 8 studies, totaling 70 persons with HIV, including 13 with AIDS and 57 individuals who were on ART and virally suppressed, showed persons with controlled HIV infection do not appear to be at increased risk of poorer outcomes of COVID-19 disease than the population at large [20] . Similarly, Calza et al [21] reported that COVID-19 in A c c e p t e d M a n u s c r i p t In contrast to the above reports, several studies have shown that individuals with HIV are at increased risk for severe COVID-19 disease and death. A population retrospective study using the OpenSAFELY database in the U.K. involving 17.3 million adults including >27,000 who had HIV, showed persons with HIV were at 2.9 times the risk of COVID-19 death compared to people without HIV after accounting for age and sex [24] . This risk decreased slightly to 2.3 times for individuals with HIV when adjusting for comorbidities. The findings also showed that HIV infection was associated with a 4.3-fold higher risk of COVID-19 death among black ethnic individuals [24] . Two additional analyses of large cohorts showed increased risk of severe COVID-19 disease and mortality among SARS-CoV-2 and HIV coinfected individuals. An analysis of the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) database of more than 47,000 hospitalized COVID-19 patients, 0.26% with confirmed HIV status and >90% receiving ART found an age-adjusted 47% increased risk of 28-day mortality from COVID-19 among persons with HIV compared to the general population with COVID-19 [25] . Among hospitalized COVID-19 patients <60 years of age, the risk of mortality doubled for those patients with HIV compared to patients without HIV [25] . Another multicenter analysis involving 286 patients coinfected with HIV and SARS-CoV-2 showed severe clinical outcomes were common, with decreased survival rates associated with age, lung disease, and hypertension [26] . Lower CD4+ T cell counts (<200 cell/mm 3 ), despite HIV viral suppression due to ART, was associated with higher rates of hospitalizations, lower rates of ICU-free survival, and overall survival [26] . In a large population cohort study of >3.4 million adults [27] , an analysis in the Western Cape Province of South Africa showed HIV was associated with an approximate doubling of COVID-19 mortality risk. The authors suggested that individuals with HIV should be A c c e p t e d M a n u s c r i p t considered a high-risk population for COVID-19, regardless of viral suppression when they have other comorbidities [27] . Sax [28] suggested the negative outcomes in individuals with HIV and SARS-CoV-2 coinfection may be due to their comorbidities, including CVD or renal disease, which are common high-risk factors associated with severe COVID-19 disease [10] . patients without HIV infection. Coinfected patients <50 years of age had higher relative risks of intubation (2.97) and death (4.36). However, the study found there were no significant differences between COVID-19 patients with/without HIV among the older age groups or for the relative risk for admission to the ICU [30] . A c c e p t e d M a n u s c r i p t Persons with HIV may experience various comorbidities, many of which also have emerged as risk factors for severe COVID-19 illness. The etiology for development of many HIVassociated comorbidities is multifactorial and is in certain cases not clearly established. The following comorbidities have emerged as risk factors for severe COVID-19 illness (defined as hospitalization, admission to the ICU, intubation or mechanical ventilation or death) [10] and represent a significant burden in persons with HIV. There is an increased incidence of certain cancers in persons with HIV, including several non-AIDS-defining cancers [31] . A large prospective cohort study among United States military veterans with HIV demonstrated that individuals with viral suppression still had excess cancer risk [32] . Cancer also is associated with an increased risk of severe COVID-19 illness [10] . The aspects of various types of cancers and their treatments that confer a risk for severe COVID-19 illness, as well as the underlying pathophysiology, will require further study [33, 34] . In the United States, the prevalence of HIV-associated kidney diseases, such as HIVassociated nephropathy and thrombotic microangiopathy, associated with high viral loads and low CD4 T-cell counts, has decreased. In contrast, among people with HIV who are effectively treated with ART, kidney disease associated with diabetes, hypertension, nephrotoxic effects of medication, and aging is becoming more prominent [35] . Chronic kidney disease (CKD) is associated with severe COVID-19 illness [10] . The mechanisms A c c e p t e d M a n u s c r i p t underlying the association of CKD with severe COVID-19 are not fully understood and may be heterogeneous depending on the nature of the underlying illness leading to CKD. Chronic obstructive pulmonary disease (COPD) is prevalent in people with HIV. HIV is increasingly recognized, apart from smoking, as an independent risk factor for COPD, with HIV-related immune activation possibly involved in the pathogenesis of this condition [36, 37] . COPD also is recognized as a risk factor for development of severe disease in COVID-19 [10] . Certain aspects of COPD, such as host immune responses, structural damage of the lung, microbiome imbalance, and mucous production, may predispose the individual to development of pneumonia from a variety of causes [38] . Factors unique to SARS-CoV-2, such as differential expression of ACE2 also may potentially play a role [39] . Persons with HIV, including those receiving ART, have an increased risk of developing ischemic heart disease and certain other cardiovascular conditions. While the underlying etiology of this excess risk is likely to be multifactorial, chronic immune activation due to HIV may play a role [40] . Pre-existing cardiovascular disease (CVD) is linked to an increased risk of severe illness and poor outcomes in patients with COVID-19 [10, 41] . In addition, COVID-19 can cause various acute presentations of CVD, including acute coronary syndrome, arrythmia, myocarditis, and thromboembolic disease. Myocardial injury during acute COVID-19 is associated with increased mortality [41] . A c c e p t e d M a n u s c r i p t The strong tendency towards obesity in the United States, the effects of certain ARVs, as well as an aging population are all potential contributing factors to the growing problem of obesity among persons with HIV [42] . One study utilizing cross-sectional data from two United States surveys estimates that obesity affects 2 in 5 women and 1 in 5 men with HIV [43] . Obesity (BMI>/ 30kg/m2) and severe obesity ((BMI>/ 40kg/m2) are underlying conditions that increase risk of severe disease from COVID-19 [10] . A recent meta-analysis [44] showed that obese individuals with COVID-19 had a higher risk of hospitalization (OR = 2.13; 95% CI, 1.74-2.60; p < 0.0001); ICU admission, (OR = 1.74; 95% CI, 1.46-2.08; p < 0.0001) and death (OR = 1.48; 95% CI, 1.22-1.80; p < 0.001). Mechanisms to explain this increased risk are not fully understood, but may include metabolic and immune alterations, chronic inflammation and physical features of obese individuals that impact respiratory function [44] . In addition to traditional risk factors for development of type 2 diabetes mellitus (T2DM), persons with HIV may also face metabolic effects of certain ARVs, lipodystrophy, and hepatitis C co-infection [45] . In the general population, T2DM is associated with severe COVID-19 disease [10] . The etiology of this poorer prognosis is likely multifactorial and complex, with hypothesized contributing factors being concomitant comorbidities, and a proinflammatory and pro-coagulative state [46] . A c c e p t e d M a n u s c r i p t Several studies have noted that persons with HIV and COVID-19 co-infection have a median age about 10 years younger than COVID-19 patients without HIV infection [47] . This may reflect that persons with HIV have an advanced biological age compared to the general population. Early onset or "premature" aging has been described in individuals with HIV, even those who are virally suppressed. This phenomenon is associated with the biological age of the individual compared to their chronological age and may be characterized by appearance of comorbidities that occur in individuals without HIV at a chronological age of 10-13 years older. Persistent inflammation, immune-senescence and innate immune activation characteristic of chronic HIV infection causes pre-mature aging of the immune system despite the beneficial effects of ART suppression on HIV replication [48, 49] . These immunologic abnormalities have been causally associated with premature onset of non-AIDS complications including heart disease, cancer, and end-stage liver and renal diseases among other end organ diseases [48] . Guaraldi et al [50] reported the occurrence of non-infectious comorbidities and multiple comorbidities occurring in persons with HIV approximately 10 years earlier that in the general population, at 41 to 50 years of age compared to 51-60 years of age. They noted certain risk factors associated with the occurrence of these comorbidities, including low nadir CD4+ T cell counts and prolonged ART exposure [50] . Cross-sectional analysis of the Co-morBidity in Relation to AIDS (COBRA) cohort study demonstrated that persons with HIV and undetectable HIV RNA may experience accelerated aging by 13.2 years compared to individuals without HIV based on a series of validated biomarkers of aging [51] . They reported the factors associated with advanced aging in persons with HIV include historic severe immunosuppression, certain ARVs, as well as potential viral coinfections with chronic hepatitis B virus and cytomegalovirus [51] . A c c e p t e d M a n u s c r i p t Although the totality of the data is somewhat contradictory, it is nonetheless clear that the COVID-19 pandemic has had a negative impact on persons with HIV. The most consistent finding is that the severity of COVID-19 disease in persons with HIV is related strongly to the presence of comorbidities that increase the risk of severe disease in COVID-19 patients in the absence of HIV. There are multiple profiles of persons living with HIV and the impact of COVID-19 may differ for each; although the data are somewhat contradictory certain general patterns emerge (Table 1) . With COVID-19 pandemic engulfing the globe, there is an even higher priority and urgency An effective response to these dual pandemics requires an unprecedented coordinated and collaborative global effort of scientists, industry, and community partners to accelerate basic and clinical research, as well as implementation science to operationalize evidence-based interventions expeditiously in real-world settings. Clearly, the most definitive approach to these two pandemics is the development of safe and effective vaccines. It is highly likely that the effective implementation of efficacious vaccines for COVID-19 will end this global pandemic within a reasonable period of time. While individuals with HIV were initially excluded from participating in Phase 3 COVID-19 vaccine trials, this was later changed to allow those with stable disease to enroll in these critical studies. The development of a vaccine for HIV has been much more challenging [52] . Apart from vaccines, additional A c c e p t e d M a n u s c r i p t M a n u s c r i p t On ART, virologically suppressed, immune competent without comorbidities + *Given the somewhat conflicting data regarding each of these situations, the assignment of a risk from + to ++++ is based on a broad interpretation of the weight of the data. Prevailing Against Pandemics by Putting People at the Centre -World AIDS Day Report Potential effects of disruption to HIV programmes in sub-Saharan Africa caused by COVID-19: results from multiple mathematical models Perceived interruptions to HIV prevention and treatment services associated with COVID-19 for gay, bisexual, and other men who have sex with men in 20 countries The Potential Impact of the COVID-19 Epidemic on HIV, TB and Malaria in Low-and Middle-Income Countries; A Modelling Study The Lancet Global Heath Mental Health, HIV Prevention and HIV Treatment Impacts of COVID-19 and the COVID-19 Response on a Global Sample of Cisgender Gay Men and Other Men Who Have Sex with Men Changing the Use of HIV Pre-exposure Prophylaxis Among Men Who Have Sex With Men During the COVID-19 Pandemic in PrEP retention and prescriptions for pregnant women during COVID-19 lockdown in South Africa HIV postexposure prophylaxis during COVID-19 Postexposure prophylaxis during COVID-19 lockdown in People Who Are at Higher Risk for Severe Illness The impact of ethnicity on clinical outcomes in COVID-19: A systematic review The Impact of COVID-19 on HIV Treatment and Research: A Call to Action HIV/SARS-CoV-2 coinfected patients in Istanbul, Turkey Could HIV infection alter the clinical course of SARS-CoV-2 infection? When less is better Co-infection of SARS-CoV-2 and HIV in a patient in Wuhan city A Survey for COVID-19 Among HIV/AIDS Patients in Two Districts of Wuhan, China COVID-19 Among People Living with HIV: A Systematic Review When Epidemics Collide: Why People with HIV May Have Worse COVID-19 Outcomes and Implications for Vaccination Characteristics and outcomes of COVID-19 in patients with HIV: a multi-center research network study Coronavirus disease 2019 (COVID-19) outcomes in HIV/AIDS patients: a systematic review COVID-19 in patients with HIV-1 infection: a singlecentre experience in northern Italy COVID-19 in the largest US HIV cohort HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK): a prospective observational study Characteristics, Comorbidities, and Outcomes in a Multicenter Registry of Patients with HIV and Coronavirus Disease-19 Risk factors for COVID-19 death in a population cohort study from the Western Cape Province Is COVID-19 Different in People with HIV? Available at COVID-19 infection among people with HIV in New York City: A population-level analysis of linked surveillance data Prognosis of coronavirus disease 2019 (COVID-19) in patients with HIV infection Comorbidities Among US Patients With Prevalent HIV Infection-A Trend Analysis Association of Viral Suppression With Lower AIDS-Defining and Non-AIDS-Defining Cancer Incidence in HIV-Infected Veterans: A Prospective Cohort Study Determinants of COVID-19 disease severity in patients with cancer COVID-19 in Immunocompromised Hosts: What We Know So Far Kidney Diseases Associated with Human Immunodeficiency Virus Infection Obstructive Lung Disease in HIV-Phenotypes and Pathogenesis Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis Pneumonia in Patients with Chronic Obstructive Pulmonary Disease ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19 Immunologic basis of cardiovascular disease in HIVinfected adults COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives Obesity and Weight Gain in Persons with HIV Obesity Among HIV-Infected Adults Receiving Medical Care in the United States: Data From the Cross-Sectional Medical Monitoring Project and National Health and Nutrition Examination Survey Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships Diabetes in People Living with HIV COVID-19 in people with diabetes: understanding the reasons for worse outcomes Impact of COVID-19 on people living with HIV: A review HIV infection, inflammation, immunosenescence, and aging Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers Premature age-related comorbidities among HIVinfected persons compared with the general population Do people living with HIV experience greater age advancement than their HIV-negative counterparts? Ending the Human Immunodeficiency Virus Pandemic: Optimizing the Prevention and Treatment Toolkits A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t