Late presentation for HIV remains a major health issue in Spain: results from a multicenter cohort study, 2004–2018

RESEARCH ARTICLE Late presentation for HIV remains a major health issue in Spain: Results from a multicenter cohort study, 2004–2018 Marta RavaID 1☯ *, Lourdes Domı ´nguez-Domı ´nguez 2☯ , Otilia Bisbal 2 , Luis Fernando Lo ´pez- Corte ´s 3 , Carmen Busca 4 , Antonio Antela 5 , Patricia Gonza ´lez-Ruano 6 , Cristina Herna ´ndez 7 , Josè-Antonio IribarrenID 8 , Rafael Rubio 2 , Santiago Moreno 9‡ , Inmaculada Jarrı ´n 1‡ , Cohort of the Spanish HIV/AIDS Research Network (CoRIS) ¶ 1Unit AIDS Research Network Cohort (CoRIS), National Center of Epidemiology (CNE), Health Institute Carlos III (ISCIII), Madrid, Spain, 212 de Octubre University Hospital, Madrid, Spain, 3Virgen del Rocı´o University Hospital, Sevilla, Spain, 4La Paz University Hospital, Madrid, Spain, 5University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, 6Infanta Sofı ´a University Hospital, Madrid, Spain, 7Prı ´ncipe de Asturias University Hospital, Alcala ´de Henares, Madrid, Spain, 8Department of Infectious Diseases, University Hospital, IIS Biodonostia, San Sebastia ´n, Spain, 9Ramo ´n y Cajal University Hospital, Madrid, Spain ☯These authors contributed equally to this work. ‡ These authors also contributed equally to this work. ¶ Membership of the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) is listed in the Acknowledgments. *[email protected] Abstract Objectives With the purpose of reducing the well-known negative impact of late presentation (LP) on people living with HIV (PLWH), guidelines on early HIV diagnosis were published in 2014 in Spain, but since then no data on LP prevalence have been published. To estimate prevalence and risk factors of LP and to evaluate their impact on the development of clinical outcomes in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) during 2004– 2018. Methods CoRIS is an open prospective multicenter cohort of PLWH, adults, naive to ART at entry. LP was defined as HIV diagnosis with CD4 count �350 cells/μL or an AIDS defining event (ADE). Multivariable Poisson regression models were used to estimate both prevalence ratios (PR) for the association of potential risk factors with LP and Incidence rate ratios (IRRs) for its impact on the development of the composite endpoint (first ADE, first serious non-AIDS event [SNAE] or overall mortality). Results 14,876 individuals were included. Overall, LP prevalence in 2004–2018 was 44.6%. Risk factors for LP included older age, having been infected through injection drug use or heterosexual intercourse, low educational level and originating from non-European countries. LP PLOS ONE PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 1 / 19 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Rava M, Domı´nguez-Domı´nguez L, Bisbal O, Lo ´pez-Corte ´s LF, Busca C, Antela A, et al. (2021) Late presentation for HIV remains a major health issue in Spain: Results from a multicenter cohort study, 2004–2018. PLoS ONE 16(4): e0249864. https://doi.org/10.1371/journal.pone.0249864 Editor: Graciela Andrei, Katholieke Universiteit Leuven Rega Institute for Medical Research, BELGIUM Received: January 12, 2021 Accepted: March 26, 2021 Published: April 21, 2021 Copyright: ©2021 Rava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data file are available from figshare: https://figshare.com/s/ 3bae8fa2db3354d66ebb. Funding: RR received funds from Gilead for this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: We acknowledge that the project has been financed by Gilead Science, being Rafael Rubio and Santiago Moreno the PIs of the was associated with an increased risk of the composite endpoint (IRR: 1.34; 95%CI 1.20, 1.50), ADE (1.39; 1.18, 1.64), SNAE (1.22; 1.01, 1.47) and mortality (1.71; 1.41, 2.08). Conclusions LP remains a health problem in Spain, mainly among certain populations, and is associated with greater morbidity and mortality. Public policies should be implemented to expand screening and early diagnosis of HIV infection, for a focus on those at greatest risk of LP. Introduction Late presentation (LP) of HIV infection represents an important barrier in achieving the UNAIDS goals to end AIDS epidemic by 2030. Despite multiple efforts to establish strategies to improve the early diagnosis of HIV infection, the prevalence of LP remains high (between 40–60% in developed countries [1–3] and higher in developing countries [4]) and has not decreased during the last years. In Spain, results from the most recent study within the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) showed an overall LP prevalence of 46.9% from 2004 to 2013 [5]. According to the last treatment cascade estimates [6], 13% of people living with HIV in Spain are unaware of it. Of those diagnosed, 97.3% were on ART, of whom 90.4% had an undetectable viral load. In 2014 the Spanish Ministry of Health published national guidelines for promoting early HIV diagnosis [7]. They recommended offering HIV testing when there is an in case of indication or clinical suspicion of HIV infection or AIDS but also recommended routine offer of HIV screening. So far, there is no information on whether the implementation of these guidelines have had an impact on LP prevalence. The implications of LP are widespread: increased risk of morbidity and mortality [8,9], suboptimal virologic and immunologic effectiveness of antiretroviral therapy [10], increased risk of transmission due to lack of awareness of HIV serostatus [11,12] as well as higher negative impact on healthcare costs [13]. However, while it is clear that LP carries a risk for the development of AIDS-related diseases and death, [5] its relationship with the development of non-AIDS diseases is less clear, based only on studies that relate poor immunologic status to its development. To the best of our knowledge, there are very few studies that directly evaluate LP as a risk factor for the development of non-AIDS events. Therefore, the aims of this study are (i) to estimate the prevalence and associated risk factors of LP and late presentation with advanced disease (LPAD) and their changes over time in the period 2004–2018, and (ii) to estimate the impact of LP and LPAD on the development of clinical outcomes including AIDS-defining events (ADE), serious non-AIDS events (SNAE) and mortality in participants from the CoRIS cohort. Materials and methods Study population CoRIS is an open, prospective, multicenter cohort of subjects with confirmed HIV infection, naïve to ART at study entry. Participants are recruited in 46 centers from 13 of the 17 autonomous regions in Spain from 2004-onwards. Administrative censoring date for these analyses was 30 November 2018. A complete description of CoRIS has been published in 2007 [14]. The study was approved by the Research Ethic Committee of the Instituto de Salud Carlos III PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 2 / 19 project. This does not alter our adherence to PLOS ONE policies on sharing data and materials. and was conducted in accordance with the Declaration of Helsinki. All patients gave their written informed consent. Briefly, CoRIS collects a minimum dataset which includes baseline and follow-up sociodemographic, immunologic and clinical data, including ART medication. Data are highly standardized and are submitted for periodic quality control procedures. Patients are followed-up periodically in accordance with routine clinical practice. All patients undergo blood collection for immunologic analysis, including CD4+ and CD8+ T lymphocyte quantification. Furthermore, all centers are invited to provide data on incident ADE and non-AIDS events, including non-AIDS–defining malignancies and cardiovascular, renal, liver, psychiatric, bone, and metabolic events. The study population includes all CoRIS participants, aged �18 years recruited from 1 January 2004 to 30 November 2018 who had available information on CD4 count or ADE between 4 weeks before and 24 weeks after enrolment. For analyses on association of LP and LPAD with first occurrence of clinical events, individuals followed-up for less than six months were excluded from the relevant analysis. Individuals monitored in centers not providing data on NAEs were excluded for the relevant analyses. Definitions of late presentation and late presentation with advanced disease Using the consensus definition [15], LP was defined as an HIV-diagnosis at a CD4 count below 350 cells/μL between 4 weeks before and 24 weeks after enrolment or with an AIDS- defining event within the first 24 weeks after enrolment, both conditions met before ART initiation. Participants with LPAD were a subgroup of those with LP, with an HIV diagnosis at a CD4 count <200 cells/μL between 4 weeks before and 24 weeks after enrolment. Health outcomes The primary composite endpoint was first ADE, first SNAE or death from any cause occurred from 6 months after enrolment. SNAE consisted of the following conditions: cardiovascular disease (myocardial infarction, angina, heart disease, transient ischemic attack, reversible ischemic deficit, stroke and peripheral arteriopathy) or death from cardiovascular disease, renal disease (end-stage renal disease, initiation of dialysis or renal transplantation) or death from renal disease, liver disease (ascites, gastrointestinal hemorrhage due to esophageal varices, hepatic encephalopathy, liver transplantation) or death from liver disease, non-AIDS-defining cancer or death from non-AIDS- defining cancer, and infectious-related deaths. Statistical methods Variables were summarized as medians and interquartile ranges (IQR) when continuous, and as percentages when categorical. Multivariable Poisson regression models with robust standard errors estimates [16] were used to estimate prevalence ratios (PRs) and 95% confidence intervals (CI) for the association of potential risk factors for LP and LPAD: in all these models we compared participants with LP vs those without LP (non-LP, CD4 count �350 cells/μL and no AIDS-defining event) and participants with LPAD with those without LPAD (non-LPAD, CD4 count �200 cells/μL and no AIDS-defining event). Variables included were: a combined variable of gender and HIV transmission category (men who have sex with men [MSM], injection drug users [IDU], heterosexual men, heterosexual women and other/unknown), age at enrolment (<30, 30–49, �50 years), educational level (none or primary education only, secondary education, university, other/unknown) and region of origin (Europe, Sub-Saharan PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 3 / 19 Africa [SSA], Latin America [LA], other/unknown). To assess whether risk factors for LP and LPAD had changed over time, interaction terms between each risk factor and the time-period (2004–2008, 2009–2012 and 2013–2018) were included in the multivariable models. The same model was used to obtain prevalence of LP and LPAD adjusted for a combined variable of gender and HIV transmission category, age at enrolment, educational level and region of origin. Incidence rates for the composite endpoint, the first ADE, the first SNAE and death from any cause were calculated as the number of new cases occurred after six months from enrolment divided by the total person-years at risk from six months after enrolment until the first event, last follow-up visit or death, whichever came first. Incidence rate ratios (IRRs) and 95% CI for the association between LP and LPAD and the development of the composite endpoint and its components were estimated with multivariable Poisson regression models with persontime at risk as the offset variable and robust standard error estimates accounting for clusters between centers. All models were adjusted for the combined variable of gender and HIV transmission category, educational level, region of origin and age, presence of hepatitis C virus (HCV) antibodies (no, yes or unknown), presence of hepatitis B virus surface antigen (HBsAg, no, yes or unknown) and viral load (<10,000, 10,000–100,000, �100,000 copies/mL or unknown) at enrolment. All statistical analyses were performed using R version 4.0 [17]. Sensitivity analyses We performed sensitivity analyses using different definitions of LP and LPAD as HIV-diagno- sis at a CD4 <350 cells/μL (for LP) or <200 cells/μL (for LPAD) or with an ADE in the first 4, 12 or 48 weeks after enrolment. Results Of the 15,509 antiretroviral naïve individuals enrolled in CoRIS until the 30th November 2018, 14,876 individuals were included (S1 Fig) of whom 12,652 (85.0%) were men, 9,182 (61.7%) were MSM, 3,742 (25.2%) had a university degree and 10,800 (72.6%) were from Europe, mostly from Spain (8,725, 58.7%). At enrolment, median age was 35.2 years (1st-3rd quartile: 28.9, 42.9), median CD4 count was 397 cells/μL (215, 592), 1,961 (13.2%) individuals had an AIDS diagnosis and 5,102 (34.3%) had a viral load �100,000 copies/mL (Table 1). Late presentation and late presentation with advanced disease: Magnitude, trends and risk factors Total number of late presenters was 6,636 (prevalence 44.6%; 95%CI 43.8, 45.4) and of late presenters with advanced disease was 3,931 (26.4%; 95%CI 25.7, 27.1). Annual prevalence of LP and LPAD is shown in Fig 1. In 2004–2008 the prevalence of LP was 51.8% (95%CI 50.4, 53.3); it decreased to 40.9% (95%CI 39.4, 42.4) in 2009–2012 and remained stable at 42.0% (95%CI 40.8, 43.2) during 2013–2018 (p-value for trend <0.001). Likewise, the prevalence of LPAD decreased from 33.9% (95%CI 32.5, 35.3) in 2004–2008 to 22.7% (95%CI 21.5, 24.0) in 2009– 2012 and remained stable with a modest increase up to 23.6% (95%CI 22.6, 24.7) during 2013– 2018 (p-value for trend<0.001). Among individuals older than 50 years, prevalence of LP was 63.8% and of LPAD was 46.5% (Table 1). Around 60% of IDU and of heterosexual men had LP and more than 40% had LPAD. Among persons originating from SSA, prevalence of LP was almost 60% and prevalence of LPAD was around 35%. Around 60% and of persons with primary or less educational level had LP and around 39% had LPAD. PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 4 / 19 Table 1. Sociodemographic and clinical characteristics of the participants included, and prevalence of late presentation and late presentation with advanced disease according to their characteristics at enrolment, Spain, 2004–2018 (n = 14,876). Overall, Late presentation, Late presentation with advanced disease, N = 14,876 N = 6,636 (44.6%) N = 3,931 (26.4%) [N (%)] [N (row %)] [N (row %)] Sex Females 2,224 (15.0%) 1,176 (52.9%) 761 (34.2%) Males 12,652 (85.0%) 5,460 (43.2%) 3,170 (25.1%) Age (year) Median [1 st , 3 rd quartile] 35.2 (28.9, 42.9) <30 3,720 (25.0%) 1,199 (32.2%) 507 (13.6%) 30–49 9,326 (62.7%) 4,269 (45.8%) 2,573 (27.6%) �50 1,830 (12.3%) 1,168 (63.8%) 851 (46.5%) Transmission group MSM 9,182 (61.7%) 3,344 (36.4%) 1,685 (18.4%) IDU 1,090 (7.3%) 658 (60.4%) 449 (41.2%) Heterosexual women 1,894 (12.7%) 999 (52.7%) 643 (33.9%) Heterosexual men 2,177 (14.6%) 1,297 (59.6%) 906 (41.6%) Other/unknown 533 (3.6%) 64 (60.4%) 248 (46.5%) Educational level None or primary education only 1,864 (12.5%) 1,103 (59.2%) 730 (39.2%) Secondary education 6,801 (45.7%) 2,923 (43.0%) 1,758 (25.8%) University 3,742 (25.2%) 1,349 (36.1%) 650 (17.4%) Other/unknown 2,469 (16.6%) 1,261 (51.1%) 793 (32.1%) Region of origin Europe 10,800 (72.6%) 4,609 (42.7%) 2,749 (25.5%) Sub-Saharan Africa 685 (4.6%) 407 (59.4%) 251 (36.6%) Latin America 3,083 (20.7%) 1,465 (47.5%) 822 (26.7%) Other/unknown 308 (2.1%) 155 (50.3%) 109 (35.4%) CD4 count, cells/μL Median [1st; 3rd quartile] 397 [215, 592] AIDS-defining event No 12,915 (86.8%) 4,675 (36.2%) 1,970 (15.3%) Yes 1,961 (13.2%) 1,961 (100.0%) 1,961 (100.0%) Viral load, copies/mL <10,000 3,076 (20.7%) 668 (21.7%) 259 (8.4%) 10,000–100,000 6,238 (41.9%) 2,320 (37.2%) 1,031 (16.5%) �100,000 5,102 (34.3%) 3,295 (64.6%) 2,348 (46.0%) Unknown 460 (3.1%) 353 (76.7%) 293 (63.7%) HCV antibodies No 11,676 (78.5%) 5,013 (42.9%) 2,868 (24.6%) Yes 1,468 (9.9%) 845 (57.6%) 564 (38.4%) Unknown 1,732 (11.6%) 778 (44.9%) 499 (28.8%) HBsAg No 9,169 (61.6%) 3,856 (42.1%) 2,189 (23.9%) Yes 3,955 (26.6%) 1,997 (50.5%) 1,236 (31.3%) Unknown 1,752 (11.8%) 783 (44.7%) 506 (28.9%) Year 2004–2008 4,434 (29.8%) 2,296 (51.8%) 1,502 (33.9%) (Continued) PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 5 / 19 Independent risk factors for LP compared to non-LP (Table 2) included older age (adjusted PR 1.36; 95%CI 1.30, 1.43 for 30–49 years and 1.77; 95%CI 1.65, 1.89 for �50 years vs <30 years) and transmission category, with IDU (aPR 1.49; 95%CI 1.33, 1.68), heterosexual men (aPR 1.41; 95%CI 1.27, 1.57) and heterosexual women (aPR 1.27; 95%CI 1.15, 1.41) having higher risks of LP compared to MSM. Other risk factors for LP were low educational level (aPR 1.31; 95%CI 1.20, 1.43 for primary education and 1.09; 95%CI 1.04, 1.14 for secondary education vs university) and region of origin with individuals originating from SSA (aPR 1.17; 95%CI 1.10, 1.25) and LA (aPR 1.23; 95%CI 1.16, 1.30) showing a higher risk of LP than Europeans. Similar risk factors were observed when we compared participants with LPAD with those without (Table 2). Overall risk factors for LP and LPAD were confirmed during the three time periods considered (S1 Table). Nevertheless, adjusted LP prevalence were not homogeneous across transmission categories, as shown in Fig 2. Specifically, the adjusted prevalence of LP decreased from 28.4% in 2004–2008 to 22.6% in 2009–2012 in MSM and from 37.6% in 2004–2008 to 32.3% in 2009–2012 in heterosexual men, while adjusted LP prevalence in heterosexual women remained stable around 30%-33% during the whole 15-years period. Furthermore, while adjusted LP prevalence in MSM and heterosexual men, after an initial decrease from 2004– Table 1. (Continued) Overall, Late presentation, Late presentation with advanced disease, N = 14,876 N = 6,636 (44.6%) N = 3,931 (26.4%) [N (%)] [N (row %)] [N (row %)] 2009–2012 4,168 (28.0%) 1,705 (40.9%) 947 (22.7%) 2013–2018 6,274 (42.2%) 2,635 (42.0%) 1,482 (23.6%) MSM: men who have sex with men, IDU: injection drug users, HCV: hepatitis C virus, HBsAg: hepatitis B surface antigen. https://doi.org/10.1371/journal.pone.0249864.t001 Fig 1. Annual prevalence of LP and LPAD, 2004–2018. https://doi.org/10.1371/journal.pone.0249864.g001 PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 6 / 19 2008 to 2009–2012, remained stable during 2013–2018, adjusted LP prevalence in IDU continued to decrease from 39.4% in 2004–2008 to 34.3% in 2009–2012 to 30.1% in 2013–2018. Impact of late presentation and late presentation with advanced disease on morbidity and mortality Of 14,876 participants, 13,031 (87.6%) had available follow-up data: 5,790 (87.3%) had LP and 3,412 (86.8%) had LPAD, with a total of 69,142 person-years (PY) of follow-up. Table 3 shows the number of participants experiencing each outcome, incidence rates (IR) per 100 PY of follow-up and incidence rate ratios for LP and LPAD. Overall, 435 non-late presenters and 726 late presenters experienced any of the events defined by the composite endpoint, with an IR of 1.21 (95%CI 1.10, 1.33) x100 PY in non-late presenters and of 2.34 (95%CI 2.17, 2.52) in late presenters, with an adjusted incidence rate ratio (aIRR) of 1.34 (95%CI 1.20, 1.50). IR for first ADE was almost double in participants with LP (IR: 0.99; 95%CI 0.88, 1.12) than in participants who were diagnosed early (IR: 0.51; 95%CI 0.44, 0.59), with an aIRR of 1.39 (95%CI 1.18, 1.64). 406 participants with LP experienced an SNAE with a rate of 1.32 (95%CI 1.19, 1.45) as did 262 participants non-late Table 2. Independent risk factors associated with late presentation and late presentation with advanced disease, Spain, 2004–2018 (N = 14,876). Late presentation vs non-late presentation Late presentation with advanced disease vs non-late presentation with advance disease Adjusted PR (95% CI) a, b Adjusted PR (95% CI) a, b Age (years): <30 1.00 1.00 30–49 1.36 (1.30, 1.43) 1.87 (1.71, 2.05) �50 1.77 (1.65, 1.89) 2.77 (2.52, 3.05) Transmission category: MSM 1.00 1.00 IDU 1.49 (1.33, 1.68) 1.82 (1.53, 2.16) Heterosexual women 1.27 (1.15, 1.41) 1.53 (1.31, 1.79) Heterosexual men 1.41 (1.27, 1.57) 1.79 (1.53, 2.10) Other/Unknown 1.50 (1.35, 1.67) 1.98 (1.68, 2.33) Educational level: None or primary education only 1.31 (1.20, 1.43) 1.57 (1.39, 1.77) Secondary education 1.09 (1.04, 1.14) 1.28 (1.18, 1.39) Other/Unknown 1.21 (1.10, 1.33) 1.43 (1.24, 1.65) University 1.00 1.00 Region of origin: Europe 1.00 1.00 Sub-Saharan Africa 1.17 (1.10, 1.25) 1.10 (0.97, 1.26) Latin America 1.23 (1.16, 1.30) 1.23 (1.15, 1.32) Other/Unknown 1.08 (0.97, 1.21) 1.21 (1.05, 1.40) CI: confidence interval; MSM: men who have sex with men, IDU: injection drug users, PR: prevalence ratio. a Global p-values for each variable included in the model was <0.001. b Adjusted PR (95%CI): adjusted prevalence ratio and 95% CI obtained with multivariable Poisson regression models with robust standard error estimates adjusted for a combined variable of gender and HIV transmission category (MSM, IDU, heterosexual men, heterosexual women and other/unknown), age at enrolment (<30, 30–49, �50 years), educational level (None or primary education only, secondary education, university, other/unknown) and region of origin (Europe, Sub-Saharan Africa, Latin America, other/unknown). https://doi.org/10.1371/journal.pone.0249864.t002 PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 7 / 19 Fig 2. Adjusted prevalence of late presentation by transmission category and time-period. https://doi.org/10.1371/journal.pone.0249864.g002 PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 8 / 19 presenters with an IR of 0.73 (95%CI 0.65, 0.83), giving an aIRR of 1.22 (95%CI 1.01, 1.47). LP was associated with an increased risk of liver events (aIRR 1.74; 95%CI 1.12, 2.71), and neoplasms (aIRR 1.32; 95%CI 1.08, 1.63). Higher mortality rates were observed in late presenters (IR: 1.00; 95%CI 0.89, 1.11) than in non-late presenters (IR: 0.36; 95%CI 0.30, 0.42), with an aIRR of 1.71 (95%CI 1.41, 2.08). Table 3. Impact of late presentation and late presentation with advanced disease on the composite endpoint, first ADE, first SNAE and overall mortality, Spain, 2004–2018, (N = 13,031 and 69,142 persons-year of follow-up). N of events Follow-up (PYs) Rate (95% CI) (per 100 PYs) N of events Follow-up (PYs) Rate (95% CI) (per 100 PYs) Unadjusted IRR (95% CI) a, b pvalue Adjusted IRR (95% CI) a, b pvalue Non-late presenters Late presenters LP vs non-LP LP vs non-LP Composite endpoint c 435 36,046 1.21 (1.10, 1.33) 726 31,006 2.34 (2.17, 2.52) 1.95 (1.71, 2.22) < 0.001 1.34 (1.20, 1.50) < 0.001 ADE 177 34,840 0.51 (0.44, 0.59) 295 29,653 0.99 (0.88, 1.12) 1.95 (1.58, 2.42) < 0.001 1.39 (1.18, 1.64) < 0.001 SNAE c, d 262 35,519 0.73 (0.65, 0.83) 406 30,769 1.32 (1.19, 1.45) 1.80 (1.53, 2.11) < 0.001 1.22 (1.01, 1.47) 0.039 Cardiovascular event 85 35,752 0.24 (0.19, 0.29) 112 31,070 0.36 (0.30, 0.43) 1.52 (1.08, 2.13) 0.016 0.89 (0.63, 1.27) 0.534 Liver event 26 35,778 0.07 (0.05, 0.11) 58 31,178 0.19 (0.14, 0.24) 2.56 (1.73, 3.78) < 0.001 1.74 (1.12, 2.71) 0.014 Kidney event 6 35,333 0.02 (0.01, 0.04) 9 30,561 0.03 (0.01, 0.06) 1.73 (0.55, 5.45) 0.346 0.84 (0.24, 2.92) 0.787 Neoplasm 150 34,367 0.44 (0.37, 0.51) 228 29,094 0.78 (0.69, 0.89) 1.80 (1.49, 2.17) < 0.001 1.32 (1.08, 1.63) 0.007 Overall mortality 132 36,886 0.36 (0.30, 0.42) 321 32,253 1.00 (0.89, 1.11) 2.78 (2.27, 3.41) < 0.001 1.71 (1.41, 2.08) < 0.001 Non-late presenters with advanced disease Late presenters with advanced disease LPAD vs non-LPAD LPAD vs non- LPAD Composite endpoint c 600 48,361 1.24 (1.14, 1.34) 561 18,691 3.00 (2.76, 3.26) 2.42 (2.08, 2.80) < 0.001 1.66 (1.46, 1.89) < 0.001 ADE 236 46,528 0.51 (0.44, 0.58) 236 17,966 1.31 (1.15, 1.49) 2.57 (2.06, 3.20) < 0.001 1.89 (1.61, 2.23) < 0.001 SNAE c, d 360 47,473 0.76 (0.68, 0.84) 307 18,815 1.63 (1.45, 1.82) 2.15 (1.81, 2.56) < 0.001 1.45 (1.18, 1.78) < 0.001 Cardiovascular event 117 47,838 0.24 (0.20, 0.29) 80 18,983 0.42 (0.33, 0.52) 1.72 (1.29, 2.30) < 0.001 0.93 (0.71, 1.21) 0.577 Liver event 38 47,873 0.08 (0.06, 0.11) 46 19,084 0.24 (0.18, 0.32) 3.04 (2.08, 4.43) < 0.001 2.13 (1.30, 3.50) 0.003 Kidney event 8 47,271 0.02 (0.01, 0.03) 7 18,622 0.04 (0.02, 0.08) 2.22 (0.80, 6.16) 0.125 1.06 (0.32, 3.50) 0.918 Neoplasm 203 45,992 0.44 (0.38, 0.51) 175 17,469 1.00 (0.86, 1.16) 2.27 (1.87, 2.76) < 0.001 1.70 (1.32, 2.19) < 0.001 Overall mortality 197 49,456 0.40 (0.34, 0.46) 256 19,683 1.30 (1.15, 1.47) 3.27 (2.63, 4.06) < 0.001 2.04 (1.64, 2.54) < 0.001 ADE: AIDS defining event; CI: confidence interval; IRR: incidence rate ratio; LP: late presenters; LPAD: late presenters with advanced disease; PY: person-years; SNAE: serious non-AIDS event. a IRR (CI 95%) were estimated with Poisson regression models with person-years at risk as the offset variable and robust standard error estimates. b IRR estimates obtained after adjustment for a combined variable of gender and HIV transmission category (MSM, IDU, heterosexual men, heterosexual women and other/unknown), educational level (None or primary education only, secondary education, university, other/unknown), region of origin (Europe, Sub-Saharan Africa, Latin America, other/unknown), and age (<30, 30–49, �50 years), presence of HCV antibodies (no, yes or unknown), presence of HBsAg (no, yes or unknown) and viral load (<10,000, 10,000–100,000, �100,000 copies/mL or unknown) at enrolment. c Individuals who were monitored in centers not providing data on non-AIDS events were excluded. d The number of specific SNAE do not sum up because one individual can have multiple SNAE. https://doi.org/10.1371/journal.pone.0249864.t003 PLOS ONE Late presentation for HIV: A major health issue in Spain PLOS ONE | https://doi.org/10.1371/journal.pone.0249864 April 21, 2021 9 / 19 Hospital Universitario Fundacio ´n Jime ´nez Dı ´az (Madrid) Miguel Go ´rgolas, Alfonso Cabello, Beatriz A ´lvarez, Laura Prieto. Hospital Universitario Prı ´ncipe de Asturias (Alcala ´de Henares) Jose ´Sanz Moreno, Alberto Arranz Caso, Cristina Herna ´ndez Gutie ´rrez, Marı ´a Novella Mena. Hospital Clı ´nico Universitario de Valencia (València) Marı ´a Jose ´Galindo Puerto, Ramo ´n Fernando Vilalta, Ana Ferrer Ribera. Hospital Reina Sofı ´a (Co ´rdoba) Antonio Rivero Roma ´n, Antonio Rivero Jua ´rez, Pedro Lo ´pez Lo ´pez, Isabel Machuca Sa ´nchez, Mario Frias Casas, Angela Camacho Espejo. Hospital Universitario Severo Ochoa (Legane ´s) Miguel Cervero Jime ´nez, Rafael Torres Perea. Nuestra Señora de Valme (Sevilla) Juan A Pineda, Pilar Rinco ´n Mayo, Juan Macı ´as Sanchez, Nicola ´s Merchante Gutierrez, Luis Miguel Real, Anais Corma Gomez, Marta Ferna ´ndez Fuertes, Alejandro Gonzalez-Serna. Hospital A ´lvaro Cunqueiro (Vigo) Eva Poveda, Alexandre Pe ´rez, Manuel Crespo, Luis Morano, Celia Miralles, Antonio Ocampo, Guillermo Pousada Author Contributions Conceptualization: Lourdes Domı ´nguez-Domı ´nguez, Otilia Bisbal, Josè-Antonio Iribarren, Rafael Rubio, Santiago Moreno, Inmaculada Jarrı ´n. Data curation: Marta Rava. Formal analysis: Marta Rava. Funding acquisition: Josè-Antonio Iribarren, Rafael Rubio. Methodology: Marta Rava, Inmaculada Jarrı ´n. Resources: Santiago Moreno. Supervision: Inmaculada Jarrı ´n. Writing – original draft: Marta Rava, Lourdes Domı ´nguez-Domı ´nguez, Otilia Bisbal. Writing – review & editing: Marta Rava, Lourdes Domı ´nguez-Domı ´nguez, Otilia Bisbal, Luis Fernando Lo ´pez-Corte ´s, Carmen Busca, Antonio Antela, Patricia Gonza ´lez-Ruano, Cristina Herna ´ndez, Josè-Antonio Iribarren, Rafael Rubio, Santiago Moreno, Inmaculada Jarrı ´n. References 1. Wilson KDA, Dray-Spira R, Aubrière C, Hamelin C, Spire B, Lert F. 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