Impact of nonalcoholic fatty liver disease on clinical outcomes in patients with COVID-19 among persons living with HIV: A multicenter research network study

Abstract

Background

People living with human immunodeficiency virus (PLWH) are at an increased risk of nonalcoholic fatty liver disease (NAFLD) but how these patients react to COVID-19 infection is unclear. We examined the clinical characteristics and outcomes of patients with and without nonalcoholic fatty liver disease (NAFLD) among people living with human immunodeficiency virus (PLWH) diagnosed with COVID-19.

Methods

A multicenter, retrospective cohort study was conducted using TriNetX. Participants diagnosed with COVID-19 between January 20, 2020, and October 31, 2021, in PLWH were identified and divided into cohorts based on preexisting NAFLD. The primary outcome was all-cause mortality, and secondary outcomes were hospitalization, severe disease, critical care, need for mechanical ventilation, and acute kidney injury(AKI). Propensity score matching (PSM) mitigated the imbalance among group covariates. Risk ratios (RR) with 95 % confidence intervals (CI) were calculated.

Results

Of the 5012 PLWH identified with confirmed COVID-19 during the study period, 563 had a diagnosis of NAFLD. After PSM, both groups were well-matched with 561 patients. The primary outcome did not differ between the cohorts at 30-days, even after a fully adjusted analysis, and the risk of all-cause mortality did not differ at 60 and 90 days. NAFLD had a significantly higher risk for hospitalization rates (RR 1.32; 95 % CI, 1.06–1.63) and AKI (RR 2.55; 95 % CI 1.42–4.57) than the non-NAFLD group at 30 days. No other differences were detected in other secondary outcome measures.

Conclusions

Preexisting NAFLD is associated with an increased risk for hospitalization and AKI among PLWH infected with COVID-19. The potential role of NAFLD in developing severe COVID-19 among PLWH remains to be elucidated in future studies. Still, this study indicates the need for careful monitoring of this at-risk population.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a devastating infectious disease globally, with a rapid surge in cases and deaths since its first reporting [1]. Older age, male gender, obesity, and underlying comorbidities such as hypertension, diabetes mellitus, cancer, lung disease, chronic kidney disease, cardiovascular disease, and chronic liver disease are known risk factors associated with poor outcomes in COVID-19 patients [2], [3]. Studies have also shown that conditions linked with immunosuppression, such as solid organ transplantation or malignancies, are risk factors for worse COVID-19-related outcomes [4]. However, there is insufficient evidence on the impact of COVID-19 in patients with other types of immunocompromising conditions, including persons living with the human immunodeficiency virus (PLWH). A large registry study suggests that PLWH has 1.29 increased odds of death and 1.20 increased odds for hospitalization from COVID-19 infection [5], with a higher prevalence of many underlying comorbidities associated with COVID-19 disease severity. PLWH are particularly vulnerable during COVID-19 due to immunodepression by depleted CD4 cells [6], thus predisposing patients to further infections.

Similarly, patients with nonalcoholic fatty liver disease (NAFLD), fat accumulation in the liver in the absence of excessive alcohol use, have a high predisposition or vulnerability to synergistic infections. A few examples include the hepatitis B virus (HBV), hepatitis C virus (HCV), Helicobacter pylori (H. pylori), pneumonia, and, most relative to the topic at hand, HIV and COVID-19 [7], [8], [9], [10]. In addition, studies have shown that 2–11 % of patients with COVID-19 have underlying pre-existing liver disease, while liver injuries such as elevated transaminase occurred in 14–53 % of patients without underlying liver disease [11], [12]. Notably, NAFLD is the most common chronic liver disease in the United States and worldwide [13]; NAFLD is quite prevalent among PLWH [14], and it is a growing public health concern among PLWH [15]. From published studies, prevalence estimates of NAFLD among PLWH range between 48 % and 65 % across studies depending on the studies’ diagnostic modality (48 % based on imaging or transient elastography or up to 65 % on biopsy) [16], [17], and prevalence estimates of NAFLD are higher among PLWH than in the general population (25 %) [18]. Notably, HIV exacerbates fibrosis progression in NAFLD [19], and it is likely due to altered immune functions adversely impacting the hepatic microenvironment 30[20]. Other cofactors include antiretroviral therapy (ART), higher prevalence of dysmetabolic conditions, HIV-related inflammation, and persistent immune activation [21], [22]. Equally important, PLWH with NAFLD has an increased risk for cardiovascular disease and associated complications and mortality [23], [24].

Regarding COVID-19, available studies indicate an interwoven relationship between NAFLD and COVID-19. A large body of literature, inclusive of multiple meta-analyses, have demonstrated that NAFLD is independently associated with COVID-19 progression and disease severity [25], [26], [27]. Furthermore, compared to COVID-19 patients without NAFLD, COVID-19 patients with NAFLD are sicker on hospital admission (e.g., more respiratory symptoms, higher body temperature, and heart rate, and higher levels of alanine aminotransferase and aspartate aminotransferase) and have a greater risk for longer hospital stays, intensive care unit use, and mechanical ventilation [28].

Though not widely published, it is plausible that the intersection of NAFLD along with HIV and COVID-19 may be more synergistic than HIV and COVID-19 without NAFLD, particularly in terms of more severe COVID-19 outcomes. It is currently unknown whether PLWH and NAFLD have a greater susceptibility to worse COVID-19 outcomes, and resultant data would be informative and advantageous for clinicians aiming to avert severe outcomes in clinical management and treatment of COVID-19. Accordingly, data from studies would facilitate clinicians’ ability to readily identify patients at risk of severe outcomes and those in need of critical care to help improve healthcare delivery, optimize resource allocation, and prioritize critical therapies and targeted interventions. We hypothesize that compared to PLWH without NAFLD, PLWH with NAFLD would have less favorable COVID-19-related outcomes, even after controlling for traditional COVID-19 risk factors. Here, we aimed to examine the clinical characteristics and outcomes of patients with and without NAFLD among PLWH diagnosed with COVID-19.

Methods

Study design

This population-based, multicenter, retrospective cohort study was conducted using TriNetX (Cambridge, MA, USA), a federated health research network data set. TriNetX is a multi-institutional health research network that provides de-identified electronic medical records systems (EHRs) from the included healthcare organizations. TriNetX received a waiver from Western IRB as a federated network as it only provides aggregate patient counts and statistical summaries to ensure de-identification at all levels of retrieval and dissemination of patient data. Details of the data source and quality checks are described in the supplementary.

Study participants

All adult patients (age ≥18 years) diagnosed with HIV and confirmed COVID-19 infection between January 20, 2020, and October 31, 2021, were included in the analysis. The search criteria for potential patients with COVID-19 were based on specific COVID-19 diagnosis codes or positive laboratory confirmation of COVID-19. Identified patients with COVID-19 and HIV were then stratified into two groups based on the presence (NAFLD, main group) or absence of preexisting NAFLD (non-NAFLD, control group). Patients with diagnoses of HIV and NAFLD for at least 6 months prior to COVID-19 infection were a minimal requirement to be included. Patients were excluded if they met any of the following criteria: 1) chronic liver disease other than NAFLD, 2) history of excessive alcohol use/abuse or history of alcohol-related disorders, 3) patients with the diagnoses of HIV and NAFLD for<6 months prior to the COVID-19 diagnosis, 4) NAFLD with other coexisting liver diseases. Details of the diagnosis codes used for patient selection are described in the supplementary.

Matching process

Each patient in the NAFLD group was matched to a non-NAFLD control group using 1:1 propensity score matching (PSM) to reduce confounding effects. Covariates in the propensity score model were adjusted for a priori–identified potential confounders: age, sex, race/ethnicity (Hispanic, non-Hispanic white, non-Hispanic black, or non-Hispanic other), body mass index (BMI), nicotine dependence, CD4 + cell count, use of antiretroviral therapy and comorbidities that listed in Table 1. Logistic regression on these input matrices was used to obtain propensity scores for each patient in both cohorts. Logistic regression was performed in Python 3.6.5 (Python Software Foundation) using standard libraries NumPy and Sklearn. The same analyses were also performed in R 3.4.4 software (R Foundation for Statistical Computing, Vienna, Austria) to ensure outputs match. After calculating propensity scores, matching was performed using a greedy nearest-neighbor matching algorithm with a caliper of 0.1 pooled standard deviations. The order of the rows in the covariate matrix can affect the nearest neighbor matching; therefore, the order of the rows in the matrix was randomized to eliminate this bias.

Table 1.

Comparison of baseline and clinical characteristics of patients with NAFLD and without NAFLD among PLWH with COVID-19.

Variables	Before propensity score matching			After propensity score matching
	NAFLD (N = 563)	Non-NAFLD (N = 4449)	P-value	NAFLD (N = 561)	Non-NAFLD (N = 561)	P-value
Age in years, mean±SD	51.3 ± 11.9	46.7 ± 13.9	< 0.001	51.3 ± 11.9	51.5 ± 13.4	0.41
Sex, n(%) Male	374(66.4)	2979(66.9)	0.93	372(66.3)	368(65.6)	0.89
Ethnicity, n (%) Hispanic or Latino	126(22.4)	533(11.9)	< 0.001	126(22.4)	86(15.3)	<0.001
Race, n (%) White Black or African Americans Others	291(51.6) 210(37.3) 60(10.6)	1716(38.6) 2250(50.6) 512(11.5)	< 0.001 < 0.001 0.32	289(51.5) 210(37.4) 60(10.7)	292(52.0) 209(37.2) 63(11.2)	0.49 0.65 0.68
Nicotine dependence, n(%)	152(27.0)	776(17.4)	< 0.001	152(27.1)	157(27.9)	1.00
BMI (kg/m2), mean±SD	32.6 ± 8.1	29.6 ± 7.25	< 0.001	32.6 ± 8.1	30.3 ± 7.31	0.04
Comorbidities, n (%)
Cardiovascular disease Hypertension Congestive heart failure Ischemic heart disease	387(68.7) 100(17.8) 138(24.5)	1908(42.9) 353(7.9) 542(12.2)	< 0.001 < 0.001 < 0.001	385(68.6) 98(17.5) 136(24.2)	391(69.7) 90(16.0) 135(24.1)	0.78 0.31 0.88
Type 2 diabetes mellitus	222(39.4)	931(20.9)	< 0.001	220(39.2)	217(38.7)	0.79
Chronic lower respiratory diseases	255(45.3)	1238(27.8)	< 0.001	253(45.1)	262(46.7)	0.75
Chronic neurological disease	87(15.4)	333(7.5)	< 0.001	87(15.5)	65(11.6)	0.85
Asthma	149(26.5)	750(16.8)	< 0.001	147(26.2)	157(27.9)	0.41
Chronic kidney disease	138(24.5)	641(14.4)	< 0.001	137(24.4)	139(24.8)	0.82
Malignancies	331(58.8)	1459(32.8)	< 0.001	329(58.6)	321(57.2)	0.89
Antiretroviral therapy, n %)
Protease inhibitors	351(62.3)	2042(45.9)	< 0.001	351(62.6)	350(62.3)	0.12
Integrase inhibitors	457(81.2)	3058(68.7)	0.01	457(81.5)	454(80.9)	0.14
NNRTIs	230(40.8)	1481(33.3)	0.01	230(41.0)	228(40.6)	0.25
NRTIs	360(63.9)	2901(65.2)	0.78	360(64.2)	352(62.7)	0.16
HIV-related profile, n (%)
CD4 count < 200 cells/mm3	184(33.0)	1512 (35.9)	0.18	181(32.7)	206(37.2)	0.11
CD4 count > 200 cells/mm3	83(14.9)	654(15.5)	0.69	82(14.8)	84(15.2)	0.87
HIV-1 RNA > 20 copies/mL	35(6.0)	309(6.7)	0.53	35(6.1)	44 (7.6)	0.29
HIV-1 RNA < 20 copies/mL	113(19.5)	975(21.2)	0.35	112(19.4)	124 (21.4)	0.38

Abbreviations: SD, standardized deviation; COVID-19, coronavirus disease 2019; NAFLD, nonalcoholic fatty liver disease; PLWH, people living with human immunodeficiency virus; BMI, body mass index; NNRTIs, non-nucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; HIV, human immunodeficiency virus; CD, cluster of differentiation; RNA, ribonucleic acid.

Study outcomes

The primary outcome was all-cause mortality from the index event within 30 days. The index event was defined as either the time of COVID-19 diagnosis or the COVID-19 positive test result date, whichever occurred first. Secondary outcomes were risk of hospitalization, severe disease, ICU requirement (requiring extracorporeal membrane oxygenation or mechanical ventilation), and acute kidney injury (AKI) 30 days from COVID-19 diagnosis. Severe disease was operationalized and defined as a composite outcome requiring ICU or death within 30 days of COVID-19 diagnosis. We performed a sensitivity analysis to assess the mortality within 60 and 90 days from the COVID-19 diagnosis.

Statistical analysis

All statistical analyses were performed in real-time using the TriNetX platform. Continuous variables are expressed as means± standard deviation (SD). Categorical variables were defined as frequency and percentage. For each outcome, the risk ratio (RR) and confidence intervals (CI) were calculated to compare the association of NAFLD with the outcome. Numbers were then validated by comparing them with the output from SAS version 9.4. A priori-defined two-sided alpha of less than ≤ 0.05 was used for statistical significance, and all statistical data analyses were performed utilizing the limitation in real-time.

Results

A total of 535,731 patients were identified with confirmed COVID-19 diagnosis during the study period; of those, 5012 were PLWH. Among these patients, 563 had a diagnosis of NAFLD and were included in the main cohort, and 4449 patients who did not have NAFLD were included in the control group ( Fig. 1). After PSM, NAFLD and non-NAFLD (561 each) groups were well matched (Supplementary Fig. 1). Among the patients in the PSM analysis, the mean age was 51 years, a majority of participants were male, and 27 % were smokers in both groups. NAFLD patients had a higher mean BMI than the controls. After PSM, most comorbidities had no significant differences between the NAFLD and non-NAFLD groups. Patients with and without NAFLD did not differ in HIV-related characteristics (use of antivirals, CD4 count, or viral suppression) (Table 1).

Fig. 1.

Flow chart showing patient selection for study cohorts. COVID-19, coronavirus disease-2019; HIV, human immunodeficiency virus; NAFLD, nonalcoholic fatty liver disease.

Clinical characteristics

Overall, patients with NAFLD were more symptomatic at presentation than those without NAFLD (Supplementary Table 1). A higher proportion of patients with NAFLD presented with throat and chest pain, difficulty breathing, cough, nausea and vomiting, headache, heartbeat abnormalities, malaise and fatigue, diarrhea, and fever. Patients with NAFLD also had higher mean aminotransferases and triglycerides. Patients without NAFLD had higher mean values of platelets, blood urea nitrogen, potassium, erythrocyte sedimentation rate, and lower serum creatinine and glomerular filtration rate.

Study outcomes

Primary outcome

Mortality as the primary outcome did not differ between the NAFLD cohort vs. the non-NAFLD cohort (RR 1.51; 95 % CI 0.79–2.87) within 30 days of infection in the unadjusted models. Even after a fully adjusted analysis, the mortality rate at 30 days from COVID-19 diagnosis was 2.0 % for NAFLD patients and 2.1 % for non-NAFLD patients. The risk of all-cause mortality did not differ (RR 0.91; 95 % CI 0.40–2.06) statistically among patients with NAFLD compared to the matched non-NAFLD patients ( Fig. 2).

Fig. 2.

Risk of mortality at 30, 60, and 90 days from COVID-19 diagnosis between patients with NAFLD and patients without NAFLD among PLWH. The numbers inside the bars represent the number of patients who developed outcomes related to the study. COVID-19, coronavirus disease-2019; PLWH, a person living with human immunodeficiency virus; NAFLD, nonalcoholic fatty liver disease; RR, risk ratio; CI, confidence interval.

Sensitivity analysis

Results of the sensitivity analyses are provided in Table 2. In an unadjusted model, the NAFLD cohort had significantly higher incidences of mortality within 60 (3.4 % vs. 1.7, RR 1.9; 95 % CI 1.17–3.14) and 90 (3.5 vs.2.0 RR 1.73; 95 % CI 1.07–2.78) days. However, fully adjusted analyses within 60 and 90 days from COVID-19 diagnosis were similar to the results from the primary outcome (Fig. 2).

Secondary outcomes

In the unadjusted cause-specific models, the NAFLD cohort had significantly higher incidences of all secondary outcomes. In the fully adjusted analysis, patients with and without NAFLD did not differ statistically in risk for severe disease (4.1 % vs. 2.8 %, RR 1.42; 95 % CI 0.75–2.66), ICU requirement (2.3 % vs. 2.1 %; RR 1.42, 95 % CI 0.75–2.66) at 30 days from COVID-19 diagnosis. However, patients with NAFLD had a significantly higher risk for rates of hospitalization (29.0 % vs. 20.5 %, RR 1.32; 95 % CI, 1.06–1.63) and AKI (7.1 % vs. 2.7 %, RR 2.55; 95 % CI 1.42–4.57) than the non-NAFLD control group ( Fig. 3).

Fig. 3.

Risk of hospitalization, severe diseases, ICU requirement, and acute kidney injury at 30 days from COVID-19 diagnosis between patients with NAFLD and patients without NAFLD among PLWH. The numbers inside the bars represent the number of patients who developed outcomes related to the study. COVID-19, coronavirus disease-2019; PLWH, a person living with human immunodeficiency virus; NAFLD, nonalcoholic fatty liver disease; RR, risk ratio; CI, confidence interval.

Discussion

In this population-based, large multicenter retrospective study analysis with its large sample size using the nationally representative database and statistical adjustments with a priori–identified potential confounders to balance the critical variables at the baseline by PSM, the present study presents evidence that the presence of NAFLD is not associated with an increased risk of mortality, but a greater risk for hospitalization (1.3 times higher) and AKI (2.5 times increased) than patients without NAFLD among PLWH. Our findings add novel data to the current literature, and clinicians are encouraged to be mindful of the need to monitor these associated risk factors in this at-risk population.

We observed that patients with NAFLD had no difference in mortality after meticulously adjusted risk factors and comorbidities, implying an increase in COVID-19-related mortality (1.9 times) among PLWH. The role of NAFLD among HIV–SARS-CoV-2 co-infected individuals and other underlying factors remain unclear. Several mechanisms associated with NAFLD that alter lipid synthesis, sterol regulatory element-binding protein-2 activation, and liver X-receptor activation may increase the inflammatory immune response, leading to the SARS-CoV-2 infection-induced cytokine storm [29]. The pathophysiology of NAFLD among PWLH is likely due to the exposure of hepatocytes and hepatic stellate cells to HIV-promoted oxidative stress. Also, HIV infects T lymphocytes and macrophages, altering the hepatic microenvironment [30]. In addition to these immune responses, the polarization of Kupffer cells could shift anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages, and the pro-inflammatory state of NAFLD could exacerbate the SARS-CoV-2 induced cytokine storm allowing for uncontrolled viral replication and cellular damage of organs [31], [32]. This distinctive polarization of Kupffer cells is caused by free fatty acids, which leads to ectopic lipid accumulation and chronic low-grade inflammation [33]. Though we did not find any impact of COVID-19 on mortality outcomes in PLWH with NAFLD, clinicians are advised not to overlook the potential for mortality outcomes until other studies are able to replicate our study findings.

Our results indicate a potential increased risk of hospitalization for COVID-19 in PLWH with NAFLD. Immune depression or dysregulation and the chronic inflammation related to HIV can be suggested to elevate the risk of severe COVID-19 disease in PLWH [34]. Similarly, chronic inflammation has been reported to be associated with the development of NAFLD. In addition, there is a strong link between NAFLD and the features of obesity and metabolic syndrome (MetS) in PLWH [35]. The presence of inflammation in PLWH, even under effective ART, is considered to cause renal, neurological, and cardiovascular diseases (CVD). Likewise, NAFLD is found to be a well-established risk factor for T2DM, HT, CKD, and CVD [36]. These comorbidities are strongly associated with poor outcomes of COVID-19[1], [3]. Thus, we hypothesize that this immunological and metabolic dysregulation could exacerbate the effects of SARS-CoV-2 infection that leads to adverse outcomes associated with COVID-19. In our analysis, NAFLD patients were more likely to need hospitalization even after robustly controlling these risk factors directly related to poor outcomes in propensity-matched analysis.

Our results also show that the presence of NAFLD does not increase the risk of presenting severe disease and ICU requirements. Declining CD4 cell counts are generally associated with COVID-19 severity; low CD4 cell counts may increase the risk for severe COVID-19 among PLWH [37], [38]. Nevertheless, after controlling for other metabolic factors, we observed that the percentage of patients with CD4 cell counts< 200 cells/mm³ was similar between the two groups in our study. ART among PLWH may confer some protection against SARS-COV-2, as a result reducing the severe disease [39], [40]. In addition, it has been hypothesized that some antivirals (e.g., ritonavir and remdesivir) may have a protective effect against COVID-19 [41]. Future studies are needed to elucidate the potential protective effects of antivirals in HIV patients with COVID-19.

Our study observed higher population-level AKI in patients with NAFLD than in those without NAFLD. AKI can further complicate clinical management and treatment because the kidney and liver share similar pathological pathways that are linked to one another (e.g., kidney-liver crosstalk) [42]. As such, clinicians may consider the utility and benefits of multispecialty assessment and management to prevent or minimize the progression to and severity of AKI. The pathophysiology of AKI in COVID-19 is thought to involve systemic inflammation, endothelial injury, activation of coagulation pathways, and the renin-angiotensin system [43]. Another potential mechanism of AKI involves SARS-CoV-2-related dysregulation of the immune response and cytokine storm [44]. Furthermore, the angiotensin-converting enzyme receptor is widely distributed in the lung, hepatobiliary cells, renal tubular epithelium, and podocytes. Additionally, it is known that the expression of the angiotensin-converting enzyme receptor increases, especially after COVID-19 infection [45]. Therefore, hyperactivation of the receptor of the angiotensin-converting enzyme-mediated immune system elicited by pulmonary infarction can cause collateral damage to hepatocytes and renal tubular epithelium [46], [47]. Our data did not include details of insulin resistance (IR), such as the homeostatic model assessment index; however, NAFLD is closely related to IR.

Furthermore, IR is closely related to various comorbidities and the inflammatory cascade associated with the cytokine storm, hyper-activation of the systemic inflammation caused by COVID-19 infection that may be triggered by IR, and may lead to AKI as a severe complication. In addition, we speculate that perhaps there is an interaction between chronic inflammation from NAFLD or HIV patients' co-infection with COVID-19, suggesting a synergistic influence on AKI. However, further studies are needed to confirm these findings, and future mechanistic studies are also required to better understand the link between NAFLD and the risk of AKI associated with COVID-19. Renal function should be carefully monitored in HIV-infected patients to detect actual changes compatible with renal impairment.

Strengths and limitations

Our study has several strengths. Firstly, we included robust control and adjustment for baseline and potential confounders. Secondly, the large sample in the propensity-matched analyses resulted in narrow confidence intervals. It allowed us to capture a significant number of outcomes, which lends strength to the conclusions that we have derived. Thirdly, we excluded the patients with alcohol-related disorders and alcohol use/abuse, which gives some accuracy in excluding alcohol-related fatty liver disease. Finally, our results remained consistent across sensitivity analyses for mortality.

The study had some notable limitations. First, the data derived from an EHRs-based database is susceptible to errors in coding or data entry when patient information is translated into the diagnosis and procedure codes. However, care was taken to use standardized measures to identify cases to minimize documentation errors. Second, even though we adjusted our analyses, it is still possible that there is some residual confounding we did not account for. Third, our data did not include imaging modalities(i.e., conventional imaging techniques, elastography) to confirm the diagnosis of NAFLD. Severe and progressive forms of NAFLD (nonalcoholic steatohepatitis, or NASH-cirrhosis) or surrogate serum markers for fibrosis (NAFLD fibrosis score, Fibrosis-4 Index, and ALT/AST ratio) were not evaluated. In addition, the inclusion criteria were not based on histologic diagnosis and are thus susceptible to misdiagnosis. Furthermore, we recognize that future studies are needed to link nonalcoholic steatohepatitis (NASH)-cirrhosis separately to the disease severity and mortality alone. Patients who were asymptomatic throughout infection and did not undergo COVID-19 testing remained uncaptured in the study. Fourth, the inclusion criteria were not based on histologic diagnosis, and misdiagnosis can result in some pollution in the data. We did not grade the severity of comorbid conditions at baseline, which can also result in some selection bias in the cohorts. Fifth, our data did not include imaging modalities to confirm the diagnosis of NAFLD. Finally, The COVID-19 vaccine was unavailable in the U.S. until mid-way into the study's observation period, and vaccination status was not included in the analysis. Our data were not able to include COVID-19 vaccines nor SARS-CoV-2 variants to assess the impact in accuracy in patients with NAFLD. Further studies should explore the impact of NAFLD on long-term morbidity and mortality and elucidate the pathogenic mechanisms.

Conclusions

In conclusion, preexisting NAFLD is associated with an increased risk for hospitalization and AKI among PLWH infected with COVID-19. Still, it does not appear to be associated with an increased risk of 30, 60, and 90-day mortality. The potential role of NAFLD in the development of severe COVID-19 among PLWH remains to be elucidated by large prospective future studies. Findings suggest clinicians may want to prioritize PLWH and NAFLD when they are diagnosed with COVID-19, develop and employ research-informed clinical measures to prevent hospitalization and AKI, and emphasize the need for these patients to follow recommended preventive measures against SARS-CoV-2 exposure. Otherwise, non-prevention of synergistic effects of NAFLD, HIV, and COVID-19 could potentially lead to long-term morbidity and mortality complications that not only have not been elucidated but that may further complicate clinical management and treatment of these respective intersecting multisystemic chronic and infectious diseases.

Financial Support

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

CRediT authorship contribution statement

Krishnan A conceptualized and designed the research. Alqahtani SA supervised the project; Krishnan A performed the formal analysis; Krishnan A performed interpretation of the data, and Krishnan A, Sims OT wrote the original draft; Krishnan A, Sims OT, and Alqahtani SA performed the review and editing of the draft; Krishnan A and Alqahtani SA performed a critical revision of the manuscript for important intellectual content. All authors revised the manuscript for important intellectual content; All authors approved the article's final version, including the authorship list.

Conflict of Interest

The authors have no relevant financial or non-financial interests to disclose.

Appendix A. Supplementary material

Supplementary material

.