key: cord-0729936-5a4lij48
authors: Squillace, Nicola; Ricci, Elena; Colella, Elisa; Bonfanti, Paolo
title: HIV and SARS-CoV-2 Co-Infection: What are the Risks?
date: 2021-09-28
journal: Infect Drug Resist
DOI: 10.2147/idr.s277899
sha: ee32ac7fd6aca239055ed05f5dd93c7e0e6f0642
doc_id: 729936
cord_uid: 5a4lij48

The dramatic increase of the global pandemic of SARS-CoV-2 infection represents a critical issue that needs to be investigated to evaluate the associated risk factors for acquisition and worse outcome. The interplay between immune activation and immune depression during SARS-CoV-2 infection is an intriguing topic that still needs to be clarified. The role of HIV in SARS-CoV-2 infection is not well defined. Chronic inflammation linked to HIV infection could be a driver for a worse prognosis in people living with HIV (PLWH). We explored the role of HIV as a risk factor for SARS-CoV-2 infection and severity and which factors contributed to a worse prognosis when HIV infection was present. PubMed/MEDLINE was searched for “COVID-19” or “SARS-CoV2” and “HIV” or “AIDS” and (“hospitalization” or “intensive care” or “mechanical ventilation” or “death” OR “mortality”), both in MeSH and as free text in all fields. Our review focused on 21 studies that enrolled at least 40 PLWH. In most studies, HIV infection did not represent a risk factor for SARS-CoV-2 infection. On the contrary, the risk of severe COVID-19 and hospitalization was higher in PLWH. Low CD4 cell count consistently emerged as a risk factor for severe COVID-19. Comorbidities, either in people with or without HIV diagnosis, played a key role, especially because of their early development in PLWH.

As of early June 2021, more than 170 million cases of SARS-CoV-2 disease (COVID-19) were diagnosed, with over 3.7 million deaths worldwide (https:// covid19.who.int/).

High mortality rates are associated with progressive respiratory failure and acute kidney injury 1 and are linked to systemic microvascular thrombosis and generalized coagulopathy, both related to high inflammatory response and continuing complement activation.

Previous health conditions have been consistently identified as risk factors for severe COVID-19 outcomes, mainly obesity, hypertension, diabetes, and chronic pulmonary disease. Due to the accelerated aging linked to persistent inflammation, cardiovascular comorbidities are more frequent among people living with HIV (PLWH) than in the general population. 2 Given this disproportionate burden, a larger number of severe cases and deaths are expected among PLWH.

HIV-1 and SARS-CoV-2 infection share CD4+T cells (CD4) loss in association with disease outcome and immunodeficiency. In both diseases, immune activation, direct attacks on CD4, and redistribution of CD4 contribute, in quite different proportions, to CD4 lymphopenia. Like for HIV, lymphopenia and marked CD4 count reduction in COVID-19 patients have been linked with poor clinical outcomes. However, when HIV and COVID-19 meet, no additional decrease of CD4 count has been observed. 3 PLWH could even experience protection from the most serious sequelae of COVID-19, because of their history of immune response or the hypothesized activity of Anti-Retroviral Treatment (ART) against SARS-CoV-2. 4, 5 The interplay between SARS-CoV-2 and HIV is affected by several conflicting aspects. The residual chronic inflammation, present even in suppressed PLWH, and the immune deficiency due to HIV may exert opposite effects. The age might also affect the outcomes in coinfected COVID-19-HIV patients, who may be younger and monitored for comorbidities at an earlier age than their HIV-negative counterparts. The conflicting evidence about their interaction may be due to the relative weight of these factors. 6 However, evidence regarding the clinical outcome of SARS-CoV-2 in PLWH is still inconsistent.

For example, in a single-center cohort study, PLWH diagnosed with COVID-19 was not different from the COVID-19 patients without known HIV diagnosis. 7 Clinical presentation, severity of the disease, and mortality did not depend on HIVrelated or ART-related factors. The standardized incidence rate of COVID-19 was lower in PLWH than in the Barcelona general population, although no comparison of mortality rate was performed between the two groups. Similarly, a propensity matched analysis revealed no difference between HIV+ and HIV-subjects, suggesting that higher mortality was likely driven by a higher number of comorbidities. 8 On the contrary, a comparison between HIV-negative and positive patients, admitted in 207 hospitals across the United Kingdom, showed higher day-28 mortality in PLWH, after considering potential risk factors such as age, sex, comorbidities and need for oxygen at presentation. In particular, in people aged less than 60 years the adjusted hazard ratio (aHR) was 2.87 (95% confidence interval, CI, 1.70-4.86), increased risk due to HIV status. 9 The objective of this review was to explore the role of HIV infection as risk factor for COVID-19 diagnosis, hospitalization, and death, and to investigate the risk factors for COVID-19 severity in PLWH.

PubMed/MEDLINE was searched for "COVID-19" or "SARS-CoV-2" and "HIV" or "AIDS" and ("hospitalization" or "intensive care" or "mechanical ventilation" or "death" OR "mortality"), both in MeSH and as free text in all fields (limits: Human, English). The search was limited to articles published in English until 15 May 2021, retrieving 552 results in PubMed/MEDLINE.

We excluded papers that reported protocols, no information about HIV status, laboratory studies, case reports, and editorials.

Among 47 studies reporting on COVID-19 outcomes in PLWH, we evaluated 21 studies with at least 40 PLWH enrolled and analyzed HIV infection as risk factor for the different considered outcomes.

Bibliography from the retrieved articles was manually searched to identify further relevant literature about the relationship between SARS-CoV-2 and HIV.

The main characteristics of selected studies are reported in Tables 1 and 2 .

Most cohort studies did not show a higher incidence of COVID-19 in PLWH than in the general population (Table 1) . 7, [10] [11] [12] [13] In a large cohort study 10 that involved 2988 COVID-19 positive PLWH, similar diagnosis rates for COVID-19 were observed in PLWH and in people not living with known HIV diagnosis (PNLWH) after standardization (standardized rate ratio, sRR, 0.94, 95% CI, 0.91-0.97). In an adjusted model, PLWH of older age, not white non-Hispanic race/ethnicity, and living in the regions of metropolitan New York City (NYC) were significantly more likely to receive a diagnosis of COVID- 19 On the contrary, in the analysis from Inciarte et al, 7 the incidence of confirmed COVID-19 cases in a cohort of 5683 PLWH was 62% lower than in the Barcelona population.

On the other hand, Sachdev et al 13 found a significantly higher diagnosis rate in 4252 PLWH compared to PNLWH (4.5% vs 3.5%, p=0.00004).

Finally, we considered the prevalence of comorbidities in PLWH with or without COVID-19. Boulle et al 15 described a slightly lower prevalence of diabetes (4% vs 11%) and hypertension (12% vs 19%) in PLWH without COVID-19 vs PLWH with COVID-19. Vizcarra et al 14 confirmed the lower prevalence of diabetes and hypertension in PLWH without COVID-19, also finding a lower percentage of patients with chronic kidney disease and liver disease in this subset of patients.

Many studies demonstrated a higher rate of hospitalization in PLWH than in PNLWH (Table 1) . 8, 10, 12, 14 Tesoriero et al 10 observed population-level rates of COVID-19 hospitalization significantly higher among PLWH (8.28 per 1000) than among PNLWH (3.15 per 1000; sRR 1.38, 95% CI, 1.29-1.47). In the adjusted analysis, older age and region were associated with hospitalization. This study observed an increasing hospitalization risk across stage 1, 2 and 3 of HIV infection: more in detail, a per-person hospitalization standardized rate analysis was conducted by stage of HIV disease. Compared to people living without HIV infection, hospitalization risk was progressively higher by HIV stage 1 infection: sRR was 1. 19 

In the first three months of the SARS-CoV-2 infection outbreak in NYC, Braunstein et al 12 showed a rate of ICU admission of 5% in 2410 PLWH vs 3% in 202,012 PNLWH with confirmed COVID-19.

Patel et al 16 conducted a retrospective cohort study on 4613 COVID-19 positive patients; 100 were PLWH. In an analysis adjusted for age, sex, race/ethnicity, BMI, history of chronic lower respiratory diseases and calendar time, PLWH had an increased risk of intubation compared to PNLWH (aHR 1.73, 95% CI 1.12-2.67; p= 0.01).

Miyashita et al 17 also carried out a retrospective study on 8912 patients with COVID-19; 161 had also HIV infection. The author observed a higher risk of intubation in the age group under 50 years (relative risk 2.97, 95% CI, 1.29-6.84), whilst no differences were observed in the other age groups.

On the contrary, Geretti et al 9 reported no differences between HIV-negative patients and PLWH in the risk of admission to ICU, after adjustment for sex, ethnicity, age, baseline date, indeterminate/probable hospital acquisition of COVID-19 and comorbidities, regardless of HIV status (odds ratio, OR 1.22, 95% CI, 0.80-1.87; p=0.35).

A very large retrospective cohort study, reported by Bhaskaran et al 18 compared the risk of COVID-19 death among PLWH and PNLWH: crude mortality risk was similar between the two groups (HR 1.03, 95% CI 0.7-1.52); after adjusting for age and sex, HIV infection was associated with a higher risk of COVID-19 death (HR 2.90, 95% CI 1.96-4.30; p < 0.0001), with a slight attenuation after further adjustment for index of multiple deprivation, ethnicity, obesity and smoking (HR 2.59, 95% CI, 1.74-3.84; p < 0.0001).

The Western Cape Department of Health (South Africa) performed a study on 223,080 COVID-19 positive patients 15 , 625 of them died. A greater proportion of COVID-19 death was observed in PLWH younger than 50 years compared with same age PNLWH (39% vs 13%). After adjusting for age, sex, and other comorbidities, HIV was associated with increased COVID-19 mortality (aHR 2.14, 95% CI 1.70-2.70), irrespectively of viremia or immunosuppression prior to the COVID-19 infection.

In the large Tesoriero cohort study 10 (2988 patients), no differences were observed in in-hospital death between people living with diagnosed HIV infection, and people without diagnosed HIV infection (adjusted rate ratio 0.98, 95% CI 0.85-1.12). Anyway, a significantly higher mortality rate per person and per diagnosis was observed in PLWH (case fatality rate, 69.28 per 1000 vs 38.70 per 1000: sRR 1.30, 95% CI, 1.13-1.43).

Hadi et al 8 performed an analysis on all patients diagnosed with COVID-19 (total 50,167), who were divided into two cohorts, based on the presence or absence of HIV infection: 49,763 patients without concurrent HIV infection and 404 with preexisting HIV diagnosis. In the unmatched analysis, PLWH had higher mortality at 30 days from COVID-19 diagnosis (4.95% vs 3.2%, risk ratio 1.55, 95% CI, 1.01-2.39), while after matching for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney diseases, race, nicotine dependence and sex, no difference in mortality was found between the two groups (5.0% vs 3.7%, risk ratio 1.33, 95% CI, 0.69-2.57%). These observations are probably due to the demographic characteristics of PLWH (greater proportion of men, African American race, obesity, and the other listed comorbidities). No differences in mortality were found even in two subgroup analyses, including only (1) patients with HIV-associated diseases (risk ratio 1.12, 95% CI 0.59-2.12) or (2) 

Considering studies that enrolled less than 200 PLWH, most did not report higher mortality in the overall PLWH population (Table 1) , 9, 16, 17, 19 whereas some differences were observed in patients aged less than 60 years in the study of Geretti et al 9 and in patients aged less than 50 years in the study of Miyashita et al. 17 Risk Factors for COVID-19 Severity in PLWH Risk Factors for Severe COVID-19 In PLWH, rates of severe COVID-19 ranged from 11% to 28% (Table 2) . 7, 14, [19] [20] [21] [22] Severe SARS-CoV-2 Infection was associated mostly with age and presence of comorbidities (see Table 3 ).

In In most studies, patients had high CD4 (usually >500 cells/µL) and suppressed HIV-viral load (VL).

The reported hospitalization rates ranged from 27% to 63% (Table 2) . 10, [23] [24] [25] [26] Age, low CD4 nadir and low current CD4 were the most frequent risk factors.

In Italy, Gervasoni et al 24 15 .1%) in South Africa, with a higher risk in patients with low CD4. These significant differences could be due to different socioeconomic status and to significantly lower age in Boulle's study. However, lower CD4 were consistently reported as a risk factor for hospitalization in PLWH.

Rates of ICU admission ranged from 5% to 28.7% ( On the other hand, Braunstein et al 12 described a 5% rate of ICU admission, with a higher risk in patients with CD4 less than 200 cells/µL. Vizcarra et al 14 described an ICU admission rate of 12% (6/51) in a cohort of PLWH with a mean age of 53.3 (±9.5) years, with 63% of patients affected from at least one comorbidity, median CD4 nadir 224 (IQR 101-437), recent CD4 565 (IQR 296-782) and HIV-VL <50 copies in 98% of patients.

The reported mortality rates are extremely variable, depending on sample characteristics, region of origin and socio-economic factors ( Smaller studies usually reported a mortality rate ≤10%, 14, 22, 24, 26 showing older age and comorbidities as risk factors. In these studies, most patients were on ART, had CD4>500 cells/µL and undetectable HIV-VL.

In most studies, HIV infection did not represent a risk factor for SARS-CoV-2 infection.

Evidence from larger studies 7,10-12 did not support a higher risk of SARS-CoV-2 infection in PLWH.

Only Sachdev et al 13 described a higher risk of SARS-CoV-2 in PLWH than in PNLWH, but 45% of PLWH in their sample experienced unstable housing, a factor that could have influenced the rate of infection. In the study by Tesoriero et al, 10 The protective role of tenofovir is a matter of debate, with conflicting evidence about its possible effect on COVID-19 prevention and treatment. 4 Protease inhibitors, which had a role in treating the MERS-CoV infection, did not seem effective in preventing or treating SARS-CoV-2. 29 Once SARS-CoV-2 infection is acquired, risk of severe COVID-19 and hospitalization is higher in PLWH. Low CD4 are consistently reported as a risk factor for severe COVID-19. Tesoriero et al 10 demonstrated an increasing risk of hospitalization across the three stages of HIV infection (CD4 ≥500 vs 200-499 vs <200 cells/µL). Age older than 50 years and the presence of comorbidities are other strong risk factors for the disease severity. Uncontrolled HIV-VL was not reported as a risk factor for COVID-19 severity in three studies, 15, 16, 23 although PLWH with uncontrolled VL represented less than 15% of enrolled patients.

Few data are available on PLWH younger than 50 years, which are underrepresented in the studies on COVID-19 severity.

Inciarte et al 7 described a low prevalence of severe SARS-CoV-2 infection in a population mostly younger than 50 years.

Many studies 14, 19, 21, 22 reporting a prevalence of severe cases higher than 20% showed a median age between 52 and 61.

From the published evidence, PLWH aged 50 or more years appear more at risk of severe COVID-19, especially in the presence of severe immune suppression (CD4<200 cells/micrL). This could be due both to the higher burden and early development of comorbidities in this group of PLWH 2,30 and to the immune dysfunction occurring in PLWH with CD4<200 cells/µL. Low CD4 have been also associated with poor outcomes in the general population. 31 We can hypothesize that CD4 at diagnosis of SARS-CoV-2 infection were extremely low as a consequence of SARS-CoV-2 infection. However, in most studies, CD4 during the course of COVID-19 were not available. "Current CD4" were usually defined as retrospectively collected, from three years to four weeks before SARS-COV-2 infection diagnosis. Only Patel et al 16 stated that they included CD4 during hospitalization only when a previous measure was unavailable; nonetheless, they did not stratify their results according to time of CD4 measurement. Thus, we were unable to evaluate the possible role of fast CD4 loss during SARS-CoV-2 infection.

However, there are several reasons for inappropriate immune response in HIV infection.

A prompt and hard CD4 response has been reported to be necessary for IgG and IgA response to SARS-CoV-2. 32 Immune activation has been demonstrated to persist in HIV chronic infection with alteration in kynureninetryptophan ratio, a marker of defective adaptive immunity, even in patients treated early for HIV infection. 33, 34 On the other hand, HIV and SARS-CoV-2 share a common evasion of innate immunity, 35 that could explain a deficient response to Interferon.

Inflammation and immune-activation related to severe HIV infection (CD4 <200) could explain the worse prognosis of SARS-CoV-2 infection in this subset of patients.

The risk of ICU admission was reported as higher than in people not living with HIV in most studies. 12, 16, 17 CD4 <200 were a risk factor for ICU admission in the study of Dandachi et al 23 while the increase in current CD4 (per 100 cells/µL) was a risk factor for Patel et al. 16 The two studies included a slightly different number of intubated patients with significantly different ages: Dandachi et al enrolled 47 intubated patients (twice as much than Patel et al) with significantly younger age. This difference could partially explain the inconsistency of their findings. The immune reconstitution as a risk factor could be an interesting hypothesis in the development of cytokine storm in COVID−19, but high CD4 were not frequently associated with severity of disease, even if most patients enrolled in these studies had CD4 >500 cells/µL and suppressed HIV-VL. However, as previously discussed, low and dysfunctional CD4 are not the only immune dysfunction in HIV infection.

PLWH with high CD4 (>500) did not show a higher risk of cytokine storm in most studies, suggesting that, in this group of patients, the role of comorbidities could be stronger than that of CD4.

In PLWH, higher mortality rates were reported in two large studies. 12, 15 It is interesting that in the study of Tesoriero et al 10 they did not find a significantly higher mortality rate in https://doi.org/10.2147/IDR.S277899

Infection and Drug Resistance 2021:14

PLWH per hospitalization, but when they analyzed per population and per diagnosis, HIV infection represented a risk factor for death. These results were likely due to the higher percentage of PLWH with severe disease.

On the other hand, Hadi et al 8 demonstrated a higher mortality in PLWH but adjusting for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney diseases, race, nicotine dependence and sex, no differences were found between PLWH vs PNLWH. CD4<200 cells/µL, age and comorbidities were the most documented risk factors for mortality in PLWH.

The role of comorbidities has been demonstrated to be crucial. In particular, in Miyashita's study 17 most PLWH who deceased younger than 50 years old were male, with hypertension and other comorbidities. In the study by Geretti et al, 9 a higher risk of mortality was also reported in PLWH aged <60 years, especially if associated with obesity and diabetes.

Besides median age and number of comorbidities that are increasing in cohorts of PLWH, especially in Europe, 36 another concern is that chronic airway abnormalities and pulmonary inflammation are highly prevalent in HIV infection, even in non-smokers. 37, 38 This review has some limitations. First, we did not perform a meta-analysis and we cannot evaluate the impact of statistical power in the selected studies. Secondly, we did not evaluate all the studies on HIV and SARS-CoV-2 but only those including more than 40 PLWH.

In conclusion, HIV infection did not seem a risk factor for SARS-CoV-2 infection, but when PLWH acquire COVID-19 a worse outcome was more frequent than in PNLWH, especially in case of severe immune deficiency (CD4<200) and in presence of multiple comorbidities.

Dr Nicola Squillace reports personal fees from ViiV Healthcare, outside the submitted work. The authors report no other conflicts of interest in this work.

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Infection and Drug Resistance is an international, peer-reviewed openaccess journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventive strategies to minimize the development and spread of resistance. The journal is specifically concerned with the epidemiology of antibiotic resistance and the mechanisms of resistance development and diffusion in both hospitals and the community. The manuscript management system is completely online and includes a very quick and fair peerreview system, which is all easy to use. Visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors.