TYPE Original Research PUBLISHED 21 June 2023 DOI 10.3389/fmed.2023.1182359 Cardiovascular events in delayed OPEN ACCESS presentation of HIV: the prospective PISCIS cohort study EDITED BY Guido Poli, Vita-Salute San Raffaele University, Italy REVIEWED BY Lishomwa (Lish) Ndhlovu, Raquel Martín-Iguacel1,2*† Mari Carmen Vazquez-Friol3† , Cornell University, United States Silvia Nozza, Joaquin Burgos4 , Andreu Bruguera1,5,6 , Juliana Reyes-Urueña1 , San Raffaele Hospital (IRCCS), Italy Sergio Moreno-Fornés1,5 , Jordi Aceitón1 , Yesika Díaz1 , *CORRESPONDENCE Raquel Martín-Iguacel Pere Domingo7 , Maria Saumoy8 , Hernando Knobel9 , raquel@bisaurin.org Josep M. Llibre David Dalmau10 , Beatriz Borjabad11 , Isik Somuncu Johansen2 , jmllibre@flsida.org Jose M. Miro12,13 , Jordi Casabona1,5,6,14 and Josep M. Llibre15,16* on † These authors have contributed equally to this behalf of the PISCIS study group work 1 Centre of Epidemiological Studies of HIV/AIDS and STI of Catalonia (CEEISCAT), Health Department, RECEIVED 08 March 2023 Generalitat de Catalunya, Badalona, Spain, 2 Department of Infectious Diseases, Odense University ACCEPTED 22 May 2023 Hospital, Odense, Denmark, 3 Infectious Diseases Unit, University Hospital of Ferrol, A Coruña, Spain, PUBLISHED 21 June 2023 4 Department of Infectious Diseases, Hospital Universitari de la Vall d’Hebron, Barcelona, Spain, 5 CIBER CITATION Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain, 6 Department of Paediatrics, Obstetrics and Martín-Iguacel R, Vazquez-Friol MC, Burgos J, Gynecology and Preventive Medicine, Universitat Autònoma de Barcelona, Badalona, Spain, 7 Infectious Bruguera A, Reyes-Urueña J, Moreno-Fornés S, Diseases Unit, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain, 8 Department of Internal Aceitón J, Díaz Y, Domingo P, Saumoy M, Medicine and Infectious Diseases, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Knobel H, Dalmau D, Borjabad B, Johansen IS, Spain, 9 Department of Infectious Diseases, Hospital del Mar- Parc de Salut MAR, Barcelona, Spain, 10 Miro JM, Casabona J and Llibre JM (2023) Department of Internal Medicine, Hospital Universitari Mútua Terrassa, Barcelona, Spain, 11 Department Cardiovascular events in delayed presentation of Internal Medicine, Consorci Sanitari Integral, Hospitalet del Llobregat, Barcelona, Spain, 12 Hospital of HIV: the prospective PISCIS cohort study. Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Front. Med. 10:1182359. Spain, 13 Centro de Investigación Biomédica en Red Enfermedades Infecciosas (CIBERINFEC), Instituto de doi: 10.3389/fmed.2023.1182359 Salud Carlos III, Madrid, Spain, 14 Fundació Institut D’investigació en Ciències de la Salut Germans Trias I Pujol (IGTP), Badalona, Spain, 15 Infectious Diseases Department, University Hospital Germans Trias i COPYRIGHT Pujol, Barcelona, Spain, 16 Fight Infections Foundation, Barcelona, Spain © 2023 Martín-Iguacel, Vazquez-Friol, Burgos, Bruguera, Reyes-Urueña, Moreno-Fornés, Aceitón, Díaz, Domingo, Saumoy, Knobel, Dalmau, Borjabad, Johansen, Miro, Casabona Objectives: People with HIV (PWH) have a higher cardiovascular risk than the and Llibre. This is an open-access article general population. It remains unclear, however, whether the risk of cardiovascular distributed under the terms of the Creative disease (CVD) is higher in late HIV presenters (LP; CD4 ≤350 cells/µL at HIV Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is diagnosis) compared to PWH diagnosed early. We aimed to assess the rates of permitted, provided the original author(s) and incident cardiovascular events (CVEs) following ART initiation among LP compared the copyright owner(s) are credited and that to non-LP. the original publication in this journal is cited, in accordance with accepted academic practice. Methods: From the prospective, multicentre PISCIS cohort, we included all No use, distribution or reproduction is adult people with HIV (PWH) initiating antiretroviral therapy (ART) between 2005 permitted which does not comply with these terms. and 2019 without prior CVE. Additional data were extracted from public health registries. The primary outcome was the incidence of first CVE (ischemic heart disease, congestive heart failure, cerebrovascular, or peripheral vascular disease). The secondary outcome was all-cause mortality after the first CVE. We used Poisson regression. Results: We included 3,317 PWH [26 589.1 person/years (PY)]: 1761 LP and 1556 non-LP. Overall, 163 (4.9%) experienced a CVE [IR 6.1/1000PY (95%CI: 5.3–7.1)]: 105 (6.0%) LP vs. 58 (3.7%) non-LP. No differences were observed in the multivariate analysis adjusting for age, transmission mode, comorbidities, and calendar time, regardless of CD4 at ART initiation [aIRR 0.92 (0.62–1.36) and 0.84 (0.56–1.26) in LP with CD4 count <200 and 200–≤350 cells/µL, respectively, compared to non-LP]. Overall mortality was 8.5% in LP versus 2.3% in non-LP (p < 0.001). Mortality after the CVE was 31/163 (19.0%), with no differences between groups [aMRR 1.24 (0.45–3.44)]. Women vs. MSM and individuals with chronic lung and liver disease Frontiers in Medicine 01 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 experienced particularly high mortality after the CVE [aMRR 5.89 (1.35–25.60), 5.06 (1.61–15.91), and 3.49 (1.08–11.26), respectively]. Sensitivity analyses including only PWH surviving the first 2 years yielded similar results. Conclusion: CVD remains a common cause of morbidity and mortality among PWH. LP without prior CVD did not exhibit an increased long-term risk of CVE compared with non-LP. Identifying traditional cardiovascular risk factors is essential for CVD risk reduction in this population. KEYWORDS late HIV presentation, cardiovascular disease, myocardial infarction, cerebrovascular disease, HIV Introduction individuals who were diagnosed early. We aimed to assess the rates of incident CV events following ART initiation among LP in a Despite absolute rates of cardiovascular disease (CVD) prospective cohort. declining significantly over time, people with HIV (PWH) continue to have an ∼50% higher relative risk compared with HIV-negative individuals (1). The American Heart Association recommends Methods adjusting the calculated risk estimate upward by 1.5–2 times for PWH on the basis that most risk calculators tend to underestimate Study design and data sources their cardiovascular risk (2). Late HIV diagnosis, defined as CD4 count <350 cells/µL or This is a cohort study conducted in Catalonia, Spain. On AIDS at diagnosis regardless of CD4 count, still represents an January 2021, Catalonia had a population of 7.7 million citizens unmet need, with half of PWH being diagnosed late. Individuals not and an estimated adult prevalence of HIV infection of 0.4%. belonging to the traditional HIV risk groups, such as heterosexual The Catalan healthcare system provides universal, tax-funded men, females, older individuals, and migrants, are at a higher risk healthcare, and ART to all citizens. of late HIV diagnosis (3). Older people are at increased risk of both Data were retrieved from the PISCIS cohort (Catalonian late HIV diagnosis and CVD, and their proportional rates among and Balearic Islands HIV cohort) and PADRIS (Public Data PWH are increasing (4). Analysis for Health Research and Innovation Program). Briefly, Late HIV diagnosis has been associated with increased risks PISCIS is an ongoing, prospective, multicentre, population-based of death, AIDS, and non-AIDS comorbidities (5, 6). The risk cohort that includes all PWH aged ≥16 years followed in one for AIDS and death is highest in the first year, mainly due to of the 16 collaborating hospitals, representing 84% of all PWH AIDS-related conditions, often present at baseline (3). Factors in Catalonia, from 1998 to 2022 (21). Data are updated yearly such as unremitting inflammation potentially related to higher and include demographics, date of HIV diagnosis, AIDS-defining HIV reservoirs and persistent immune activation due to late ART events, ART, and measurement of CD4 count and plasma HIV- initiation (7), have been associated with premature aging and may RNA over time. PADRIS is a central research-oriented database that predispose to non-AIDS comorbidities (8). However, their link with gathers and cross-matches real-world health data generated by the CVD in this scenario has not been proven, and the understanding different public health systems (SISCAT), provided by the Catalan of the subsequent CV risk in late presenters (LPs) is incomplete. Agency for Health Quality and Evaluation (AQuAS). The database Furthermore, additional factors other than low CD4 cell count and includes comorbidity data from hospital discharge diagnoses and chronic inflammation may also contribute to the disparity in long- primary healthcare from 2005 according to the International term morbidity and mortality in LP such as differences in access Classification of Disease 10th revision (ICD-10) (22). We used and adherence to care (9, 10), behavioral factors such as smoking ICD-10 codes to define comorbidities according to the Swedish (11), the burden of comorbidities, and socio-economic factors. National Study of Aging and Care in Kungsholmen (SNAC-K) In addition, lower CD4 count led to more conservative surgical cohort (www.snac-k.se). Mortality data were obtained by cross- approaches to CV complications (12). matching the information from PISCIS, PADRIS, and the national While some studies have not found a greater risk of CVD in LP mortality registry. (13–15), others have reported that CD4 count depletion along the The study complies with the STROBE reporting guidelines. course of the HIV disease is associated with a higher risk of CVD. The latter, however, has been mainly described in immunological non-responders after the initiation of ART or in individuals with Ethics approval unsuppressed viremia (16–20). It is thus uncertain whether the long-term cardiovascular The PISCIS cohort has received ethical approval from risk in LP who initiate effective ART is higher than in those Germans Trias i Pujol University Hospital’s Clinical Research Frontiers in Medicine 02 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 Ethics Committee, reference number EO-11-108, and patient data whichever came first. The cumulative mortality was compared extraction is allowed by the 203/2015 Decree from the Catalan using the log-rank test. We used a Poisson regression analysis to Health Department. All data are pseudo-anonymized in accordance assess the risk of late HIV presentation and mortality adjusting for with Regulation 2016/679 of the European Parliament. the above-mentioned potential confounders. We provide mortality rates (MRs) and MR ratios (MRRs) and a 95%CI. We conducted a sensitivity analysis including only PWH who Study population initiated ART and survived 2 years, in order to remove the bias of the increased risk of severe AIDS-related comorbidities and We included all treatment naïve PWH aged ≥18 years, who complications in the initial period and to assess the effect of early initiated ART between 1 January 2005 and 30 June 2019. PWH with immune recovery on CVD (3, 24). PWH were stratified according prior CV events were excluded from the analysis. to their 2-year CD4 count (<200, 200–500, and >500 cells/µL in Individuals were classified according to their CD4 count at ART LP and ≤500 cells/µL and >500 cells/µL in non-LP). initiation into LP (i.e., CD4 count <200 and 200–350 cells/µ) and All analyses were conducted with STATA software (v.16; Stata non-LP (i.e., CD4 count >350 cells/µL). Non-LP contributed as the Corp, College Station, TX, USA). reference population. Results Outcomes Study participants The primary outcome was the first CV event after ART initiation, defined as the first event of ischemic heart disease, We identified 4036 adult PWH who initiated ART between congestive heart failure, cerebrovascular disease, or peripheral 2005 and 2019. Of them, 3317 met the inclusion criteria, 1556 vascular disease during the study period. (46.9%) non-LP, and 1,761 (53.1%) LP (Figure 1). The median The secondary outcome was all-cause mortality among PWH follow-up was 8.0 years (IQR: 5.0–11.2), giving rise to 26 589.1 experiencing a CV event. persons/years (PY) at risk. Table 1 summarizes baseline characteristics. LP were more likely heterosexual men, women, IDU, older, treated with protease Statistical analysis inhibitors or non-nucleoside reverse transcriptase inhibitors, having higher plasma HIV-RNA, and having lower educational Continuous variables were described as the median and levels. LP had higher rates of AIDS-defining events, liver disease, interquartile range (IQR), whereas categorical variables were dementia, and less arterial hypertension. presented as the frequency and percentage over available data. At 2 years, 112 (8.1%) LP remained with a CD4 count of <200 We used Pearson’s chi-squared test, t-test, and Mann–Whitney cells/µL, 286 (20.6%) had 200–350 cells/µL, 661 (26.0%) had 351– U-test to compare these variables between LP and non-LP. For 500 cells/µL, and 627 (45.2%) had >500 cells/µL. LP with a 2-year polychotomous categorical variables with a statistically significant CD4 count of <200 cells/µL after ART initiation had higher rates chi-square test of homogeneity, we further provided a significance of detectable HIV-RNA (p < 0.0001) (Table 1). test of the difference between proportions across categories of the variable between LP and non-LP. Individuals were followed from ART initiation to the first CVD outcomes CV event, loss-to-follow-up, death, or end of the observation period (30 June 2021), whichever occurred first. The cumulative Overall, 163 (4.9%) PWH experienced a first CV event during incidence of the first CV event in LP vs. non-LP was compared the study period [IR 6.1/1000 PY (95%CI: 5.3–7.1)]: 105 (6.0%) LP using the log-rank test. We used Poisson regression to assess vs. 58 (3.7%) non-LP (p = 0.003). Forty-eight (29.4%) experienced a the association between CD4 count at ART initiation (<200, heart failure event, 42 (25.8%) experienced an ischemic heart event, 200–350, and >350 cells/µL) and the risk of a subsequent CV 53 (32.5%) experienced a cerebrovascular event, and 20 (12.3%) event. We adjusted for the following potential confounders at experienced a peripheral artery event (Supplementary Table 3). baseline: age (time-updated), gender, mode of HIV transmission, Most PWH experienced 1 CV event (n = 136, 83.4%), 24 (14.7%) region of birth, time-updated calendar period [2005–2009, 2010– experienced 2 CV events, and 3 (1.8%) experienced 3 different 2014, 2015–2019, according to pre-integrase strand transfer events. The rates of CV events did not change along the calendar inhibitor (INSTI)-available period, INSTI-available period, and time analyzed (Table 2). universal ART implementation, respectively] (23), HIV-1 viral load, Kaplan–Meier curves for incident CV events stratified by CD4 AIDS-defining disease, comorbidities (diabetes mellitus, arterial count at ART initiation (LP vs. non-LP) or by their 2-year CD4 hypertension, dyslipidemia, chronic kidney, lung, or liver disease, recovery (non-LP with CD4 count >500 cells/µL vs. LP with CD4 malignancy, or depression), and educational level. We provide count >500, >350–500, 200–350, and <200 cells/µL) showed no incidence rates (IRs) and IR ratios (IRRs) and their corresponding significant differences between groups (log-rank test, p = 0.07 and 95% confidence interval (CI). p = 0.22, respectively) (Figures 2A, B). For mortality after the first CV event, individuals were followed In the univariate regression analysis, only LP with a baseline from the CV event to death, loss-to-follow-up, or 30 June 2021, CD4 count of <200 cells/µL had an increased risk of CV events Frontiers in Medicine 03 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 FIGURE 1 Flowchart of cohort construction. compared to non-LP [IRR 1.71 (95%CI: 1.19–2.44)]. However, were small. Women and individuals with chronic lung and/or this association was no longer shown in the multivariate analysis liver disease had an increased mortality after a CV event adjusted for age, HIV transmission mode, calendar time, and [aMRR 5.89 (95%CI:1.35–25.60), 5.06 (95%CI:1.61–15.91) and 3.49 comorbidities [aIRR 0.92 (95%CI: 0.62–1.36) and 0.84 (95%CI: (95%CI:1.08–11.26), respectively] (Table 3). 0.56–1.26) for LP with baseline CD4 count <200 and 200– 350 cells/µL, respectively] (Table 2). The risk of CV events increased significantly paralleling the age of PWH with no Sensitivity analysis evidence of effect modification for LP (Supplementary Table 4). Other variables associated with increased risk were heterosexual Given the known high morbidity and mortality due to AIDS- males compared to MSM [aIRR 2.43 (95%CI: 1.62–3.67)], chronic related conditions in LP during the first 2 years, we specifically liver disease [aIRR 2.38 (1.48–3.82)], and malignancy [aIRR 2.27 analyzed the subset surviving the first 2 years after ART initiation (1.20–4.30)]. Diabetes, arterial hypertension, dyslipidemia, chronic (n = 2625 PWH) (Supplementary Figure 1). In this analysis, with kidney or lung disease, and depression were not associated 103 persons experiencing a CV event, we found similar results with an increased risk for CV events in the multivariate with no increased risk of CV events in LP compared to non-LP analysis. with 2-year CD4 count >500 cells/µL (reference population) after adjusting for age (time-updated), calendar time (time-updated), HIV transmission mode, and comorbidities, regardless of the 2- Mortality outcomes year CD4 count [aIRR 0.99 (0.43–2.26) and 0.82 (0.48–1.39), in LP with a 2-year CD4 count of <200 cells/µL and 200–500 cells/µL, Overall, 185 (5.6%) patients died during the study period respectively] (Supplementary Tables 7, 8; Supplementary Figure 3). (Supplementary Tables 5, 6). Among the 163 PWH experiencing a CV event, 31 died [26 LP and 5 non-LP, MR 40.4/1000PY (95%CI: 28.4–57.4)]. One-third of these deaths (n = 12, 38.7%) Discussion occurred within 3 months and 18 (58%) within the first year (Supplementary Figure 2). LP exhibited higher cumulative In this multicenter, population-based, prospective cohort mortality (log-rank, P = 0.038) (Supplementary Figure 2); however, analysis, we observed that LP with no previous CV events at mortality was no longer higher in the multivariate analysis after ART initiation did not have an increased long-term risk of CV adjusting for age, HIV transmission mode, and comorbidities events compared to non-LP. The definition included a composite [aMRR 1.24 (95%CI: 0.45–3.44)], although the absolute numbers endpoint of congestive heart failure, ischemic heart disease, Frontiers in Medicine 04 frontiersin.org Frontiers in Medicine Martín-Iguacel et al. TABLE 1 Baseline characteristics of the study participants. Study population according to initial CD4 cell count at ART Study population according to immune recovery 2 years after ART initiation Non-LP n = LP n = 1,761 P-value LP n = 1,386 Non-LP CD4 1,556 (46.9%) (53.1%) >500 cells/µL n = 1,114 (89.9%) CD4 cell count (cells/µ) >500 n = >350-500 n ≥200-350 n <200 n = 627 (45.2%) = 361 (26.0%) = 286 (20.6%) 112 (8.1%) Male, n (%) 1,360 (87.4) 1,468 (83.4) 0.003 539 (86.0) 305 (84.5) 226 (79.0) 94 (83.9) 995 (89.3) Age (years), median (IQR) 34 (29–41) 38 (31–45) <0.001 36 (30–42) 38 (32–45) 40 (34–47) 39 (34–47) 35 (29–41) Birth area, n (%) 0.010 Spain 702 (57.1) 867 (59.3) 0.018 326 (60.5) 174 (57.1) 149 (63.7) 62 (67.4) 514 (57.9) Europe 157 (12.8) 130 (8.9) 0.006 47 (8.7) 30 (9.8) 15 (6.4) 2 (2.2) 109 (12.3) Africa 54 (4.4) 86 (5.9) 0.043 17 (3.2) 19 (6.2) 22 (9.4) 10 (10.9) 36 (4.1) America 297 (24.2) 360 (24.6) 0.33 139 (25.8) 79 (25.9) 48 (20.5) 16 (17.4) 215 (24.2) 05 Asia 19 (1.6) 19 (1.3) 0.70 10 (1.9) 3 (1.0) 0 2 (2.2) 14 (1.6) Route of HIV transmission, n (%) <0.001 MSM 1,088 (69.9) 890 (50.5) <0.001 410 (65.4) 194 (53.7) 93 (32.5) 34 (30.4) 823 (73.9) Heterosexual men 150 (9.6) 322 (18.3) <0.001 82 (13.1) 61 (16.9) 78 (27.3) 28 (25.0) 103 (9.3) Women 157 (10.1) 233 (13.2) 0.005 74 (11.8) 48 (13.3) 51 (17.8) 12 (10.7) 99 (8.9) IDU 78 (5.0) 180 (10.2) <0.001 26 (4.2) 37 (10.3) 32 (11.2) 28 (25.0) 43 (3.9) Unknown 83 (5.3) 136 (7.7) 0.006 35 (5.6) 21 (5.8) 32 (11.2) 10 (8.9) 46 (4.1) First ART- regimen in the first 2 years, n (%) NNRTI-based regimen 597 (38.4) 786 (44.6) <0.001 329 (52.5) 181 (50.1) 127 (44.4) 45 (40.2) 475 (42.6) PI-based regimen 370 (23.8) 698 (39.6) <0.001 226 (36.0) 149 (41.3) 130 (45.5) 66 (58.9) 273 (24.5) 10.3389/fmed.2023.1182359 INSTI-based regimen 680 (43.7) 562 (31.9) <0.001 193 (30.8) 102 (28.3) 76 (26.6) 36 (32.1) 492 (44.2) CD4 count at ART initiation (cells/µL), n (%) <100 cells/µL - 472 (26.8) 65 (18.2) 89 (24.9) 125 (34.9) 79 (22.1) - frontiersin.org (Continued) Frontiers in Medicine Martín-Iguacel et al. TABLE 1 (Continued) Study population according to initial CD4 cell count at ART Study population according to immune recovery 2 years after ART initiation Non-LP n = LP n = 1,761 P-value LP n = 1,386 Non-LP CD4 1,556 (46.9%) (53.1%) >500 cells/µL n = 1,114 (89.9%) CD4 cell count (cells/µ) >500 n = >350-500 n ≥200-350 n <200 n = 627 (45.2%) = 361 (26.0%) = 286 (20.6%) 112 (8.1%) 100–199 cells/µL - 391 (22.2) 106 (35.3) 94 (31.3) 82 (27.3) 18 (6.0) - 200–350 cells/µL - 898 (51.0) 456 (62.6) 178 (24.5) 79 (10.9) 15 (2.1) - >350–500 cells/µL 725 (46.6) - - - - - 497 (44.6) >500 cells/µL 831 (53.4) - - - - 617 (55.4) 10 Viral load at ART initiation (log 4.4 (3.6–4.9) 4.9 (4.0–5.5) <0.001 4.9 (4.3–5.3) 4.8 (3.9–5.5) 4.9 (4.0–5.7) 4.9 (4.0–5.7) 4.4 (3.7–4.9) copies/mL), median (IQR) CD4 cell count 2 years after ART 804 (633–999) 477 (329–630) <0.001 - - - - - initiation (cells/µL), median (IQR) 06 Detectable viral load 2 years after ART 59 (5.2) 89 (6.8) 0.11 25 (4.2) 14 (4.1) 23 (8.6) 27 (25.0) 35 (3.5) initiation (>200 copies/mL), n (%) History of AIDS-defining events at ART 25 (1.6) 227 (12.9) <0.001 52 (8.3) 44 (12.2) 54 (18.9) 37 (33.0) 14 (1.3) initiation, n (%) Comorbidity at ART initiation, n (%) Chronic kidney disease 9 (0.6) 8 (0.5) 0.62 3 (0.5) 5 (1.4) 2 (0.7) 0 11 (1.0) Chronic liver disease 64 (4.1) 114 (6.5) 0.003 42 (6.7) 36 (1.0) 36 (12.6) 24 (21.4) 63 (5.7) Chronic lung diseasea 14 (0.9) 23 (1.3) 0.26 10 (1.6) 4 (1.1) 9 (3.2) 1 (0.9) 17 (1.5) Diabetes 13 (0.8) 15 (0.9) 0.96 9 (1.4) 7 (1.9) 6 (2.1) 3 (2.7) 14 (1.3) Arterial hypertension 123 (9.9) 102 (7.4) 0.019 44 (7.0) 30 (8.3) 24 (8.4) 4 (3.6) 115 (10.3) Dyslipidaemia 63 (4.1) 56 (3.2) 0.18 26 (4.1) 9 (2.5) 11 (3.8) 4 (3.3) 58 (4.1) 10.3389/fmed.2023.1182359 Hematological neoplasm 5 (0.3) 11 (0.6) 0.21 4 (0.6) 6 (1.7) 4 (1.4) 5 (4.5) 8 (0.7) Solid neoplasm 24 (1.5) 56 (3.2) 0.002 25 (4.0) 19 (5.3) 28 (9.8) 16 (14.3) 39 (3.5) Dementia 1 (0.08) 5 (0.3) 0.14 2 (0.3) 1 (0.3) 3 (1.1) 3 (2.7) 1 (0.09) frontiersin.org Depression 102 (6.6) 94 (5.3) 0.14 53 (8.5) 25 (6.9) 33 (11.5) 11 (9.8) 115 (10.3) (Continued) Frontiers in Medicine Martín-Iguacel et al. TABLE 1 (Continued) Study population according to initial CD4 cell count at ART Study population according to immune recovery 2 years after ART initiation Non-LP n = LP n = 1,761 P-value LP n = 1,386 Non-LP CD4 1,556 (46.9%) (53.1%) >500 cells/µL n = 1,114 (89.9%) CD4 cell count (cells/µ) >500 n = >350-500 n ≥200-350 n <200 n = 627 (45.2%) = 361 (26.0%) = 286 (20.6%) 112 (8.1%) Modified Charlson Comorbidity Score 0.004 at ART initiationb , n (%) 0 1,442 (92.7) 1,569 (89.1) <0.001 583 (92.3) 329 (89.7) 256 (88.0) 95 (78.5) 1,325 (92.9) 1 76 (4.9) 118 (6.7) 0.026 28 (4.4) 21 (5.7) 24 (8.3) 17 (14.1) 68 (4.8) 2–3 32 (2.1) 62 (3.5) 0.011 19 (3.0) 14 (3.8) 10 (3.4) 8 (6.6) 28 (2.0) 07 ≥4 6 (0.4) 12 (0.7) 0.25 2 (0.3) 3 (0.8) 1 (0.3) 1 (0.8) 5 (0.4) Calendar time of ART initiation, n (%) <0.001 2005–2009 216 (24.1) 680 (75.9) <0.001 229 (36.6) 147 (41.0) 144 (51.1) 58 (51.8) 138 (12.5) 2010–2014 691 (53.4) 517 (46.6) 0.001 261 (41.8) 138 (38.4) 83 (29.4) 35 (31.3) 562(52.1) 2015–2019 649 (57.5) 479 (42.5) <0.001 135 (21.6) 74 (20.6) 55 (19.5) 19 (17.0) 404 (36.6) Educational level, n (%) <0.001 None or primary education only 274 (23.6) 434 (35.7) <0.001 132 (28.2) 86 (33.0) 84 (43.8) 29 (44.6) 179 (21.0) Secondary education 467 (40.2) 444 (36.5) 0.063 185 (39.5) 104 (39.9) 60 (31.3) 20 (30.8) 353 (41.3) University 420 (36.2) 338 (27.8) <0.001 151 (32.3) 66 (25.3) 42 (21.9) 15 (23.1) 316 (37.0) ART, antiretroviral therapy; CVD, cardiovascular disease (includes ischemic heart disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease); IDU, Injection drug use; INSTI, integrase strand transfer inhibitor; IQR, interquartile range 10.3389/fmed.2023.1182359 (percentiles 25th and 75th); LP, late presenters; non-LP, non-late presenters; MSM, men who have sex with men; NNRTI, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitor. a Chronic lung disease included chronic obstructive pulmonary disease, lung emphysema, unspecified chronic bronchitis, and bronchiectasis. b Described in Supplementary Table 9. frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 TABLE 2 Incidence rate of a first CV event in the overall cohort, including all LP and non-LP. CV Events (n) IR per 1,000 PY IRR (95% CI) aIRR (95%CI)a Total 163 6.1 (5.3–7.1) Gender Female 26 6.3 (4.3–9.3) Ref (1) Male 137 6.1 (5.2–7.2) 0.97 (0.64–1.47) Age (time-updated) (years) <40 29 2.4 (1.7–3.4) Ref (1) Ref (1) 40–49 55 6.1 (4.7–8.0) 2.58 (1.64–4.04) 2.11 (1.33–3.33) 50–59 54 13.1 (1.0–17.1) 5.49 (3.50–8.62) 3.87 (2.42–6.20) ≥60 25 19.1 (12.9–28.3) 8.04 (4.71–13.72) 4.56 (2.53–8.20) Country of birth Spain 108 8.3 (6.8–1.0) Ref (1) Europe 14 6.6 (3.9–11.2) 0.80 (0.46–1.40) Africa 8 6.6 (3.3–13.3) 0.80 (0.39–1.65) America 16 2.8 (1.7–4.6) 0.34 (0.20–0.58) Asia 1 3.6 (0.5–25.5) 0.43 (0.06–3.12) Transmission mode MSM 57 3.6 (2.8–4.7) Ref (1) Ref (1) Heterosexual men 47 12.5 (9.4–16.6) 3.48 (2.37–5.12) 2.43 (1.62–3.67) Women 16 4.7 (2.9–7.7) 1.32 (0.76–2.30) 1.14 (0.65–1.99) IDU 28 13.7 (9.5–19.9) 3.82 (2.43–6.01) 2.23 (1.35–3.71) Unknown/other 15 9.9 (5.9–16.4) 2.75 (1.56–4.85) 1.98 (1.11–3.55) CD4 cell count at ART initiation Late presenters, CD4 ≤350 cells/µL 105 6.9 (5.7–8.3) 1.35 (0.98–1.86) Non-late presenters, Cd4 >350 cells/µL 58 5.1 (3.9–6.6) Ref (1) CD4 cell count at ART initiation Late presenters, CD4 <200 cells/µL 63 8.7 (6.8–11.2) 1.71 (1.19–2.44) 0.92 (0.62–1.36) Late presenters, CD4 200–≤350 cells/µL 42 5.3 (3.9–7.1) 1.03 (0.69–1.53) 0.84 (0.56–1.26) Non-late presenters, Cd4 >350 cells/µL 58 5.1 (3.9–6.6) Ref (1) Ref (1) HIV viral load at ART initiation >100,000 copies/ml 43 5.5 (4.1–7.4) 0.87 (0.61–1.23) ≤100,000 copies/ml 120 6.4 (5.3–7.6) Ref (1) Calendar time (time-updated) 2005–2009 8 4.5 (2.2–9.0) 0.72 (0.35–1.48) 0.81 (0.39–1.69) 2010–2014 47 6.3 (4.8–8.4) 1.02 (0.72–1.44) 1.16 (0.82–1.64) 2015–2021 108 6.2 (5.1–7.5) Ref (1) Ref (1) AIDS-defining event at ART initiation Yes 29 13.8 (9.6–19.9) 2.52 (1.69–3.77) 1.49 (0.95–2.34) No 134 5.5 (4.6–6.5) Ref (1) Ref (1) Educational levelb None or primary education only 55 9.5 (7.3–12.3) Ref (1) Secondary education 33 4.5 (3.2–6.3) 0.47 (0.31–0.73) University 19 3.3 (2.1–5.1) 0.35 (0.21–0.58) (Continued) Frontiers in Medicine 08 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 TABLE 2 (Continued) CV Events (n) IR per 1,000 PY IRR (95% CI) aIRR (95%CI)a Comorbidities at ART initiation Diabetes Yes 6 32.0 (14.4–71.3) 5.38 (2.38–12.17) 1.32 (0.51–3.39) No 157 5.9 (5.1–7.0) Ref (1) Ref (1) Arterial hypertension Yes 16 5.8 (4.9–6.8) 2.48 (1.48–4.15) 1.83 (1.07–3.11) No 147 14.3 (8.8–23.3) Ref (1) Ref (1) Dyslipidaemia Yes 13 16.5 (9.6–28.5) 2.84 (1.61–5.01) 1.34 (0.71–2.55) No 150 5.8 (5.0–6.8) Ref (1) Ref (1) Chronic kidney disease Yes 3 31.0 (1.0–96.1) 5.13 (1.64–16.08) 1.98 (0.58–6.76) No 160 6.0 (5.2–7.1) Ref (1) Ref (1) Chronic lung disease Yes 6 26.5 (11.9–59.0) 4.45 (1.97–1.06) 1.67 (0.71–3.90) No 157 6.0 (5.1–7.0) Ref (1) Ref (1) Chronic liver disease Yes 25 20.3 (13.7–30.1) 3.74 (2.44–5.72) 2.38 (1.48–3.82) No 138 5.4 (4.6–6.2) Ref (1) Ref (1) Malignancyc Yes 11 22.4 (12.4–40.5) 3.85 (2.09–7.10) 2.27 (1.20–4.30) No 152 5.8 (5.0–6.8) Ref (1) Ref (1) Depression Yes 14 9.9 (5.9–16.8) 1.68 (0.97–2.90) 1.08 (0.61–1.91) No 149 5.9 (5.0–6.9) Ref (1) aIRR, adjusted incidence rate ratio; CVD, cardiovascular disease (includes ischemic heart disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease); IR, incidence rate; IRR, incidence rate ratio; IDU, Injection drug use; MSM, men who have sex with men; PY, person-years. a The aIRR was adjusted for age, transmission mode, CD4 cell count, calendar time and AIDS-defining event, and comorbidities (diabetes mellitus, arterial hypertension, dyslipidemia, chronic kidney disease, chronic lung disease, chronic liver disease, malignancy, and depression). b Not included in the final multivariate analysis because of the lack of statistical significance. c Hematological or solid organ malignancy. cerebrovascular, and peripheral vascular disease. Mortality rates However, our results do not confirm an increased risk of CV after CV events were high with ∼40% of them occurring within the events in LP compared to the rest of PWH. Although no first 3 months after the event. Women and individuals with chronic differences were observed in the adjusted analysis, PWH with lung and liver disease experienced particularly elevated mortality a CD4 count of <200 cells/µL at ART initiation or after 2 rates after CV events. Additional adjusted analyses including only years had an approximately unadjusted 2-fold increased risk of PWH surviving the first 2 years after ART initiation yielded similar CV events compared to non-LP. This association is likely due results, regardless of 2-year CD4 cell recovery, reinforcing the main to the confounding effect of age, calendar time, and various findings of the study. comorbidities, which themselves are independent risk factors Several studies have shown that unremitting immune for CVD. Not unexpectedly, an increased risk for CV events activation, persistent inflammation, and vascular dysfunction was seen in older PWH. Older people are at increased risk of could be common in PWH and potentially associated with both LP and CVD and in fact, the proportion of PWH older earlier atherosclerosis and premature CVD (25). LP have than 50 years is increasing, and about half of them have delayed increased chronic inflammation due to persistent immune presentation (4). On the other side, multimorbidity is common damage established before ART initiation (7), and higher levels in LP, and a recent cross-sectional Italian study showed that of immune activation could theoretically play an additional multimorbidity was more common in LP compared to non-LP role in the development of early CVD in this subpopulation. across all age distributions (26). All this suggests that data Frontiers in Medicine 09 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 A Incident CVD by CD4 cell count at ART initiation B Incident CVD by CD4 cell count recovery 2 years after ART initiation 0.90 0.90 Log rank, p=.22 0.70 Log rank, p=.07 0.70 0.50 0 2 4 6 8 10 12 14 Years from 2 years after ART initiation Number at risk LP, CD4<200 112 89 76 60 45 26 6 1 LP, CD4 200−350 286 238 206 174 141 92 48 3 0.50 LP, CD4>350−500 361 312 255 190 145 79 26 1 0 2 4 6 8 10 12 14 LP, CD4>500 627 563 449 340 230 125 44 7 Years from after ART initiation Non−LP, CD4>500 1114 930 661 418 200 82 30 1 Number at risk LP, CD4 <200cells/µL LP, CD4 200−350cells/µL Late presenters 1761 1604 1441 1234 1006 776 487 201 Non−late presenters 1556 1436 1267 968 640 369 161 52 LP, CD4 >350−500cells/µL LP, CD4 >500cells/µ L Late presenters Non−late presenters Non−LP, CD4 >500cells/µL FIGURE 2 Kaplan–Meier curves of time to cardiovascular events. (A) Incident cardiovascular events by CD4 cell count at ART initiation. (B) Incident cardiovascular events by CD4 cell count 2 years after ART initiation. suggesting increased rates of CV events in LP could be biased by ART with a CD4 count of <200 cells/µL compared to those ≥200 unadjusted confounders. cells/µL (15). In a Dutch Athena Cohort study including patients Calendar time could theoretically play a role as well, with lower between 1998 and 2009, no association was found between LP with CV risk in recent years, paralleling with improved cardiovascular a 2-year CD4 count of <200 cells/µL and risk of CVD in the risk management in PWH and increased safety and efficacy of adjusted analysis, although individuals with previous CVD were ART, although this trend was not confirmed in our cohort. Recent not excluded (13). investigations on the risk of CVD using INSTI-based regimens, the In contrast, other studies have described an association currently recommended first-line choices, have yielded inconsistent between CD4 cell count below 200 cells/µL and a higher risk of results. A study from the RESPOND cohort consortium, which CVD. Two cohort studies from the US (Veterans Aging Cohort included 29340 individuals, 14000 of whom were given an INSTI, and North American AIDS Cohort Collaboration on Research have reported an increased risk of CVD in the first 2 years and Design [NA-ACCORD]) and two metanalyses, all including after INSTI initiation compared to initiating other regimens (27). participants before the year 2013, have shown that CD4 counts However, another recent study in the Swiss HIV Cohort, which <200 cells/µL were associated with increased CV risk, including included 5362 individuals initiating ART after May 2008, 1837 incident myocardial infarction (aHR 2.02; 95% CI, 1.42–2.88), individuals initiated an INSTI-based regimen, found no such risk ischemic stroke (aHR 1.66; 95% CI, 1.30–2.12), and peripheral (28). In the following years, it will be important to determine artery disease (HR, 1.91; 95% CI, 1.71–2.13) (16–20). However, whether the link between INSTI usage and CVD is due to INSTI most of these studies included immunological non-responders, use or to unmeasured confounding. On the other side, the use of who fail to reconstitute their CD4 cell count despite virological INSTI has been recently been associated with several studies with a suppression on ART, who are known to have increased long- more favorable immune recovery (29, 30). term morbidity and mortality risk (31). Furthermore, a significant Our results are in concordance with the results from the proportion of individuals in these studies had unsuppressed Spanish CoRIS cohort including patients initiating ART between viremia at the moment of the event, either because they were 2004 and 2018, where they found no evidence of an increment of not on ART at the time or because they belonged to an HIV CV events in LP compared to non-LP. However, the analysis was subpopulation that was heavily treated or had poor treatment not adjusted for previous comorbidities that could play a major adherence. HIV unsuppressed viremia is strongly correlated with role in the development of CVD (14). Similarly, in a study from chronic inflammation, ongoing immune activation, and accelerated the Veterans Aging Cohort including individuals from 1996 to atherosclerosis and could have confounded the finding. Our study 2012, no increased risk of CVD was seen with individuals initiating included very few immunological non-responders with a 2-year Frontiers in Medicine 10 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 TABLE 3 All-cause mortality in 163 people with HIV developing a first CV event. Death (n) MR per 1,000 PY MRR (95% CI) aMRR (95% CI) Total 31 40.4 (28.4–57.4) Gender Male 23 36.0 (23.9–54.2) Ref (1) Female 8 62.1 (31.0–124.1) 1.72 (0.77–3.85) Age at baseline 1.06 (1.03–1.10) 1.07 (1.03–1.11) Route of HIV transmission MSM 3 11.6 (3.7–35.9) Ref (1) Ref (1) Heterosexual men 11 49.4 (27.4–89.2) 4.26 (1.19–15.28) 2.90 (0.76–11.03) Women 5 74.5 (31.0–179.0) 6.43 (1.54–26.91) 5.89 (1.35–25.60) IDU 8 57.3 (28.7–114.6) 4.95 (1.31–18.6) 2.58 (0.52–12.72) Unknown 4 50.5 (19.0–134.5) 4.36 (0.98–19.48) 1.67 (0.30–9.19) Cardiovascular disease Heart failure 9 42.0 (21.8–80.6) 2.13 (0.66–6.92) Ischemic heart disease 4 19.7 (7.4–52.4) Ref (1) Cerebrovascular disease 14 56.2 (33.3–94.8) 2.85 (0.94–8.67) Peripheral vascular disease 4 39.8 (14.9–105.9) 2.02 (0.50–8.08) Calendar time 2005–2009 1 120.8 (17.0–857.7) 3.45 (0.46–25.58) 2010–2014 8 60.9 (30.4–121.7) 1.74 (0.77–3.90) 2015–2021 22 35.0 (23.1–53.2) Ref (1) AIDS at baseline Yes 11 89.5 (49.6–161.6) 2.88 (1.38–6.02) No 20 31.0 (2.0–48.1) Ref (1) CD4 cell count at ART initiation Late presenters, CD4 ≤350 cells/µL 26 5.0 (34.0–73.4) 2.48 (0.95–6.45) 1.24 (0.45–3.44) Non-late presenters, >350 cells/µL 5 20.2 (8.4–48.5) Ref (1) Ref (1) Comorbidity at ART initiation Diabetes mellitus Yes 2 88.5 (22.1–354.0) 2.27 (0.54–9.53) No 29 38.9 (27.1–56.0) Ref (1) Dyslipidaemia Yes 3 60.2 (19.4–186.8) 1.54 (0.47–5.08) No 28 39.0 (26.9–56.5) Ref (1) Arterial hypertension Yes 3 41.5 (13.4–128.7) 1.03 (0.31–3.39) No 28 40.3 (27.8–58.3) Ref (1) Chronic kidney disease Yes 1 107.9 (15.2–756.8) 2.73 (0.37–2.00) No 30 39.6 (27.7–56.6) Ref (1) Chronic lung disease Yes 4 215.8 (81.0–575.0) 5.99 (2.10–17.11) 5.06 (1.61–15.91) No 27 36.0 (24.7–52.6) Ref (1) Ref (1) (Continued) Frontiers in Medicine 11 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 TABLE 3 (Continued) Death (n) MR per 1,000 PY MRR (95% CI) aMRR (95% CI) Chronic liver disease Yes 8 78.7 (39.3–157.3) 2.28 (1.02–5.09) 3.49 (1.08–11.26) No 23 34.5 (23.0–52.0) Ref (1) Ref (1) Malignancy Yes 3 77.4 (24.9–239.8) 2.01 (0.61–6.62) No 28 38.4 (26.5–55.6) Ref (1) Depression Yes 2 40.4 (28.1–58.2) 0.99 (0.24–4.14) No 29 39.9 (1.0–159.7) Ref (1) aMRR, adjusted mortality rate ratio; ART, antiretroviral therapy; IDU, injection drug use; MR, mortality rate; MRR, mortality rate ratio; MSM, men who have sex with men; PY, person-years. CD4 count of <200 cells/µL and CV events to draw reliable cells/µL after 2 years of ART initiation was low (only 8%) and it is conclusions in this subpopulation. These patients had higher therefore not possible to draw definitive conclusions to establish a rates of detectable viremia, comorbidities (AIDS-defining events, relationship between immunological non-response and CVD. We chronic liver disease, and malignancies), and lower educational had no information on current smoking, alcohol consumption, or levels, which could also influence their CV risk. However, in the substance abuse other than injectable drug usage, all of which are whole cohort, only 6.4% of LP had detectable viremia 2 years after known independent risk factors for CVD. We included chronic ART initiation. lung and liver disease in the model, which could be interpreted as a We also identified an increased risk of CV events in patients surrogate marker, especially for the first two risk factors. Finally, the with chronic liver disease and malignancies. This association number of events was low, and type II errors in this analysis cannot must be interpreted with caution given that other risk factors, be ruled out. such as tobacco and alcohol abuse, could be possible underlying In conclusion, CVD remains a common cause of morbidity confounders in these groups. A higher frequency of smoking, and mortality among PWH. LP with no prior CV events at ART alcohol, and recreational drug abuse has been, indeed, associated initiation did not have an increased long-term risk of CV events with higher rates of CVD (32). compared with non-LP. Our results call for risk stratification and Mortality after a CV event was very high. However, we identification of PWH at increased risk of future CVD based did not observe mortality differences between LP and non-LP. on traditional risk factors and comorbidities linked to increased Nevertheless, the absolute numbers were low and do not allow for CV risk, to focus risk-reducing strategies in these subjects. When an in-depth analysis to establish robust conclusions. initiating successful ART, late HIV presentation does not increase To our knowledge, this is the first assessment of CV event rates by itself the risk for CVD. in LP starting ART in a more recent calendar period (2005–2019), including integrase inhibitor use, with information on important comorbidities related to CVD enabling the performance of an Data availability statement accurate adjusted analysis. We adjusted for calendar time because The data analyzed in this study is subject to the following both the management and prognosis of CVD and ART initiation licenses/restrictions: The data collected for this study are guidelines have varied over time. Other strengths of this study available from the Centre for Epidemiological Studies of Sexually include the prospective, population-based, multicenter HIV-cohort Transmitted Diseases and HIV/AIDS in Catalonia (CEEISCAT), design, including 84% of all PWH followed in Catalonia and the the coordinating center of the PISCIS Cohort Study and from long observation period. We had access to high-quality, real-world each of the collaborating hospitals upon request. Requests can be health data generated by the public health system of Catalonia, made via https://pisciscohort.org/contacte/. The study protocol, the including all hospital and primary care diagnoses, thus including statistical codebook and codes for the analysis can be requested accurate information on CV events, comorbidities, and mortality. from RM-I (raquel@bisaurin.org). We assessed the risk of CVD in PWH initiating ART and in PWH surviving the first 2 years, to avoid the vulnerable first 2-year period after HIV diagnosis with high risk for severe comorbidities Ethics statement and complications. In terms of limitations, we did not have access to causes of The studies involving human participants were reviewed death, neither overall nor in CV event-related deaths, and a low and approved by Germans Trias i Pujol University Hospital’s prevalence of the latter limits a more thorough interpretation. Clinical Research Ethics Committee, Reference Number EO-11- Furthermore, the percentage of subjects with a CD4 count of <200 108. Written informed consent for participation was not required Frontiers in Medicine 12 frontiersin.org Martín-Iguacel et al. 10.3389/fmed.2023.1182359 for this study in accordance with the national legislation and the Acknowledgments institutional requirements. The authors are grateful to the patients who participated in this cohort and our colleagues in the clinical departments for their Author contributions continued contribution and dedication. The authors are grateful to PADRIS and the Programme for the Prevention, Control, and RM-I conducted the research and analyzed the data. RM-I, Care for HIV, Sexually Transmitted Diseases and Viral Hepatitis MV-F, and JL wrote the first draft of the manuscript. All authors of the Ministry of Health of the Government of Catalonia for contributed to the interpretation of the results and revision of the their support and the Danish AIDS Foundation, the University manuscript and gave their final approval to the manuscript. of Southern Denmark, the Region of Southern Denmark, Odense University Hospital, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for financial PISCIS study group support. The PISCIS study group includes: Jordi Casabona, A. Esteve, Andreu Bruguera, Sergio Moreno-Fornés (CEEISCAT), Jose M. Miró, J. Mallolas, E. Martínez, JL Blanco, M. Laguno, M. Martínez- Conflict of interest Rebollar, B. Torres, A. Gonzalez-Cordon (Hospital Clínic-Idibaps, JM has received consulting honoraria and/or research grants Universitat de Barcelona), Elisa De Lazzari (Hospital Clínic- from AbbVie, Angelini, Contrafect, Cubist, Genentech, Gilead Idibaps), Arkaitz Imaz (Unitat de VIH i ITS, Servei de Malalties Sciences, Jansen, Lysovant, Medtronic, MSD, Novartis, Pfizer, and Infeccioses, Hospital Universitari de Bellvitge, IDIBELL), Pere ViiV Healthcare, outside the submitted study. JL has received Domingo (Unitat de VIH/SIDA Hospital de la Santa Creu honoraria and/or research grants from ViiV Healthcare, Gilead i Sant Pau), Josep María Llibre (Fundació Lluita contra la Sciences, and Janssen-Cilag. Sida-Hospital Universitari Germans Trias i Pujol-Universitat The remaining authors declare that the research was conducted Autònoma de Barcelona), Francisco Fanjul (Servei Medicina in the absence of any commercial or financial relationships that Interna, Hospital Universitari Son Espases), Gemma Navarro could be construed as a potential conflict of interest. (Unitat de VIH/SIDA, Parc Tauli Hospital Universitari-Universitat Autònoma de Barcelona), Vicenç Falcó Ferrer [Servei de Malalties Infeccioses, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR)], and Hernando Knobel (Servei de Publisher’s note Malalties Infeccioses, Hospital del Mar). All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Funding organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or This work was supported by scholarships from the University claim that may be made by its manufacturer, is not guaranteed or of Southern Denmark, the Danish AIDS-foundation, and Public endorsed by the publisher. Regional Funds. JM received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–23. The study was Supplementary material investigator-driven and thus independent of any pharmaceutical company. The funding sources were not involved in study design, The Supplementary Material for this article can be found data collection, analyses, report writing, or the decision to submit online at: https://www.frontiersin.org/articles/10.3389/fmed.2023. the paper. 1182359/full#supplementary-material References 1. Gooden TE, Gardner M, Wang J, Jolly K, Lane DA, Benjamin LA, et al. Incidence 4. 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