RESEARCH ARTICLE Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors Belén Alejos1☯*, Inés Suárez-Garcı́a ID2,3☯*, Otilia Bisbal4, José Antonio Iribarren5, Vı́ctor Asensi6, Miguel Górgolas7, Roberto Muga8, Santiago Moreno9, Inma Jarrı́n1, CoRIS cohort¶ 1 Centro Nacional de Epidemiologı́a, Instituto de Salud Carlos III, Madrid, Spain, 2 Infectious Diseases Unit, Department of Internal Medicine, Hospital Universitario Infanta Sofia, Madrid, Spain, 3 Universidad Europea, a1111111111 Madrid, Spain, 4 Hospital Universitario Doce de Octubre, Madrid, Spain, 5 Hospital Universitario de a1111111111 Donostia, Donostia, Spain, 6 Hospital Universitario Central de Asturias, Oviedo, Spain, 7 Hospital Universitario Fundación Jiménez Dı́az, Madrid, Spain, 8 Hospital Universitari Germans Trias i Pujol, a1111111111 Badalona, Spain, 9 Hospital Universitario Ramón y Cajal-IRYCIS, Madrid, Spain a1111111111 a1111111111 ☯ These authors contributed equally to this work. ¶ The complete membership of the author group can be found in the Acknowledgments. * balejos@isciii.es(BA); inessuarez@hotmail.com (ISG) OPEN ACCESS Abstract Citation: Alejos B, Suárez-Garcı́a I, Bisbal O, Iribarren JA, Asensi V, Górgolas M, et al. (2019) Choice of the initial antiretroviral treatment for HIV- Background positive individuals in the era of integrase inhibitors. PLoS ONE 14(8): e0221598. https://doi. We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regi- org/10.1371/journal.pone.0221598 mens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Editor: Robert Güerri-Fernández, Institut Hospital Research Network (CoRIS) and to investigate factors associated with the choice of each del Mar d’Investigacions Mediques, SPAIN regimen. Received: June 14, 2019 Accepted: August 10, 2019 Methods Published: August 26, 2019 We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable Copyright: © 2019 Alejos et al. This is an open access article distributed under the terms of the multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between Creative Commons Attribution License, which sociodemographic and clinical characteristics and the choice of the initial regimen. permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Results Data Availability Statement: The authors confirm Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most that, for approved reasons, some access frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/ restrictions apply to the data underlying the emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) findings. Data cannot be made publicly available because they are owned by a third party, the AIDs (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), Research Network (RIS), and because participants TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegra- agreed that data would only be used for research vir (RAL) (5.6%). projects by RIS or those projects approved by its Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with Executive and Scientific Committee. Interested readers may send requests for the data to CD4<200 cells/μL and HIV-RNA>100.000 copies/mL. TDF/FTC+DTG was more frequent in proyectoscoris@gmail.com. Requests will be those with CD4<200 cells/μL and HIV-RNA>100.000 copies/mL. TDF/FTC+RAL and TDF/ PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 1 / 12 Initial antiretroviral treatment choice assessed by the Executive and Scientific FTC+bDRV were also more frequent among patients with CD4<200 cells//μL and with trans- Committee. mission categories other than men who have sex with men. Compared with ABC/3TC/DTG, Funding: The RIS cohort (CoRIS) is supported by the prescription of other initial ART regimens decreased from 2014–2015 to 2016–2017 with the Instituto de Salud Carlos III through the Red the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/ observed by hospitals’ location. 0006) as part of the Plan Nacional I+D+i and cofinanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Conclusions Regional (FEDER). This study was funded by ViiV Healthcare. ViiV Healthcare was given the The choice of initial ART regimens is consistent with Spanish guidelines’ recommendations, opportunity to review a preliminary version of this but is also clearly influenced by physician’s perception based on patient’s clinical and socio- manuscript for factual accuracy. The funders had demographic variables and by the prescribing hospital location. no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are solely responsible for final content and interpretation of the results. Competing interests: IJ has received teaching fees from ViiV Healthcare and has been an external evaluator of scientific projects for GILEAD. ISG has Introduction received conference grants or speaker fees from Bristol-Myers Squibb, ViiV Healthcare, Merck International and local guidelines for the treatment of HIV-infection provide recommenda- Sharp & Dohme and Gilead. SM has been involved tions on the preferred drug combinations for initial antiretroviral therapy (ART) of treatment- in speaking activities and has received grants for naïve patients [1,2]. Although there is a wide range of highly effective and well tolerated thera- research from Abbott, Boehringer & Ingelheim, pies, most recent guidelines in Spain and the United States have limited preferred options to Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, integrase inhibitor-based regimens based on the results of clinical trials as well as on the Janssen Cilag, Merck Sharp & Dohme, Pfizer, advantages of individual drugs [3,4]. Other guidelines such as the ones from the European Roche, and Schering Plough. All other authors declare no conflict of interest. This does not alter AIDS Clinical Society also include regimens based on rilpivirine and boosted darunavir as pre- our adherence to PLOS ONE policies on sharing ferred [2]. Some experts and clinicians feel that current recommendations might be too restric- data and materials. tive and regimens other than those based on integrase inhibitors would be at least as good choices to initiate therapy in most patients. Previous studies have shown that the decision on what specific ART regimen is prescribed to each patient can be influenced by a variety of factors, not only dependent on the patient (such as comorbidities, HIV stage, concerns about toxicity or drug interactions, risk of nonad- herence, patient’s preference) but also on the prescribing physician (such as HIV treatment experience, budget limitations, hospital’s characteristics, physician’s preference) [5,6]. The few studies that have investigated the factors influencing the choice of initial ART were published before newer drugs such as rilpivirine and integrase inhibitors were widely used [5,7–9], and there is no evidence on the factors that could influence the choice of ART with the more recent treatment regimens, and specifically with those including an integrase inhibitor. In this study, we aimed to describe the most frequently prescribed initial ART regimens in recent years in HIV-positive patients in the Cohort of the Spanish HIV/AIDS Research Net- work (CoRIS) and to investigate factors associated with the choice of initial ART. Methods Study design CoRIS is an open, multicentre, prospective cohort of ART-naïve HIV-positive adults recruited in 45 centres from 13 of the 17 Autonomous Regions of Spain. Patients are followed periodi- cally in accordance with routine clinical practice. Data are subject to internal quality control. A complete description of the cohort has been published elsewhere [10,11]. PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 2 / 12 Initial antiretroviral treatment choice Study population Patients included were antiretroviral-naïve, aged � 18 years, and had started ART between 1st September 2014 (when DTG became available in Spain) and 30th November 2017 with the most commonly used first-line antiretroviral regimens. In order to facilitate the analyses, only regimens prescribed in >5% of individuals were considered. Patients with no follow-up after initiation of ART were excluded. Definition of variables The primary endpoint was the choice of the initial ART according to the most frequently pre- scribed regimens: abacavir (ABC) /lamivudine (3TC) /dolutegavir (DTG) was the most fre- quently prescribed ART, followed by tenofovir disoproxil fumarate (TDF) /emtricitabine (FTC)/ elvitegravir (EVG)/ cobicistat (COBI), TDF/FTC/rilpivirine (RPV), tenofovir alafena- mide(TAF)/FTC/EVG/COBI, TDF/FTC+DTG, TDF/FTC+darunavir/ritonavir or darunavir/ cobicistat (bDRV) and TDF/FTC+raltegravir (RAL). Possible explanatory variables included sex (male, female), age at ART initiation (<30, 30– 49, �50 years), transmission category (men who have sex with men [MSM], heterosexual, injecting drug use, other, unknown), educational level (no education or compulsory education, upper secondary or university education, unknown), origin (Spain, immigrants, unknown), CD4 T-cell count (<200, �200 cells/μL, unknown) and viral load (�100,000, >100,000 cop- ies/mL, unknown), presence of hepatitis C virus antibodies (no, yes, unknown), presence of hepatitis B virus surface antigen (HBVSA) (no, yes, unknown), triglycerides (�150, >150 mg/ dL, unknown), HDL (�40, >40 mg/dL, unknown) and total cholesterol (�200, >200 mg/dL, unknown) within 6 months previous to ART initiation, AIDS diagnosis at ART initiation (no, yes), presence of comorbidities (cardiovascular, nephrology, neurologic [no, yes]), period of ART initiation (2014–2015,2016–2017) and hospital characteristics (number of beds [<500, �500] and hospital’s location [Autonomous region]). Statistical analysis Descriptive analysis of patients’ characteristics was carried out using frequency tables for cate- gorical variables and median and interquartile range for continuous variables. Differences in socio-demographic and clinical characteristics according to initial regimen were assessed with the non-parametric Kruskal-Wallis test for continuous variables and the chi-squared test for independence for categorical variables. We used multivariable multinomial regression to esti- mate Relative Risk Ratios (RRRs) for the association between explanatory variables and the choice of the initial regimen. All variables that retained a significant independent association (p <0.05) were included in the final model. Heterogeneity introduced by different hospitals was accounted for by including the study hospital as a fixed effect in the model and by using robust methods to estimate standard errors and, thus, to calculate 95% confidence intervals and p-values. All statistical analyses were performed using Stata software (version 15.0; Stata Corporation, College Station, Texas, USA). Ethics Ethics approval was obtained from all hospitals’ Ethics’ Committees and every patient pro- vided written informed consent to participate in the cohort. This study was approved by the Ethics Committee of Instituto de Salud Carlos III (CEI PI 63_2017-v2). PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 3 / 12 Initial antiretroviral treatment choice Results Between September 1, 2014 and November 30, 2017, 3,575 patients aged �18 years initiated treatment; among these, 147 (4.1%) with no follow-up after ART initiation and 554 (15.5%) who initiated a treatment prescribed in <5% of patients were excluded. The final analysis included 2,874 (80.4%) subjects who initiated ART during the period of study. They were pre- dominantly male (88.5%) and 59.7% were from Spain. Transmission route was heterosexual contact in 23.5% and MSM in 68.9%. At treatment initiation, median age was 36 years (inter- quartile range [IQR]: 30–44), median CD4+ T-cell count was 416 cells/μL (IQR: 243–591), 8.5% of patients had a history of AIDS diagnosis, 34.5% had a viral load >100,000 copies/mL and 89.2% were attending hospitals with more than 500 beds. The most frequently prescribed initial regimens in the study period and the differences in sociodemographic and clinical characteristics of patients according to their initial ART regi- men are shown in Table 1. TDF/FTC+bDRV and TDF/FTC+RAL were significantly less often used in participants with upper education and among MSM. TAF/FTC/EVG/COBI was more likely prescribed among immigrants and TDF/FTC+RAL among those aged 50 years or older. As expected, rilpivirine was rarely used in patients with high baseline viral load >100,000 copies/mL (2.5%) or CD4 counts <200 cells/μL (4.0%). A higher proportion of the patients starting TDF/FTC+DTG, TDF/FTC+bDRV and TDF/FTC+RAL had a CD4 cell count below 200 cells/μL and an AIDS diagnosis at start of treatment. TDF/FTC+DTG and TDF/FTC +RAL were more frequent in participants with triglycerides >150 mg/dL and cholesterol- HDL �40 mg/dL. Large differences in the prescription of initial regimen were noted by hospi- tal location but not by hospital size. There were also differences in the use of initial regimen in relation to HBVSA and previous cardiovascular event; nevertheless they must be interpreted with caution as the number of events was small. We also observed changes over time in the distribution of the most frequent initial ART regimens (Fig 1). In the period 2014–2015, TDF/FTC/RPV (25.3%) and TDF/FTC/EVG/ COBI (25.2%) were the most frequently prescribed initial ART, followed by ABC/3TC/DTG (21.6%). However, in the period 2016–2017, the most frequent regimen was ABC/3TC/DTG (40.0%), followed by TAF/FTC/EVG/COBI (23.8%). When grouping the regimens by their third agent, the only regimens whose prescription increased over time were the ones based in DTG (including ABC/3TC/DTG and TDF/FTC+DTG) and EVG (including TDF/FTC/EVG/ COBI and TAF/FTC/EVG/COBI), while the prescription of all other regimens decreased. Reg- imens based in DTG increased from being prescribed in 29.1% of the patients in 2014–2015 to 51.8% in 2016–2017, and those based in EVG increased from 25.2% to 30.9%, respectively (Fig 1). Results from multivariable analysis are shown in Table 2. Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4 counts <200 cells/μL (RRR, 95% CI: 0.41, 0.25–0.67) and with HIV-RNA >100.000 copies/mL (RRR, 95% CI: 0.05, 0.03–0.10); inversely TDF/FTC+DTG was more frequent in those with CD4 counts <200 cells/μL (RRR, 95% CI: 3.35, 2.34–4.80) and with HIV-RNA >100.000 copies/mL (RRR, 95% CI: 1.74, 1.21– 2.52). TDF/FTC+RAL and TDF/FTC+bDRV were also more likely to be prescribed among patients with CD4 counts <200 cells/μL (RRR, 95% CI: 3.76, 2.39–5.92 and RRR, 95% CI: 2.61, 1.51–4.49, respectively) and those with transmission categories other than MSM (RRR, 95% CI: 2.00, 1.29–3.10 and RRR, 95% CI: 1.73, 1.14–2.61, respectively). Compared with ABC/ 3TC/DTG, the prescription of other initial ART regimens decreased over time (p<0.001), with the exception of TDF/FTC+DTG (p = 0.173). Valid conclusions regarding changes over time in the prescription of TAF/FTC/EVG/COBI could not be drawn because it was widely avail- able only after 2016. Overall differences in the choice of the initial ART regimen were observed PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 4 / 12 Initial antiretroviral treatment choice Table 1. Baseline characteristics of 2,874 study participants according to the initial antiretroviral regimen. ABC/3TC/ TDF/FTC/EVG/ TDF/FTC/ TAF/FTC/EVG/ TDF/FTC TDF/FTC TDF/FTC P DTG COBI RPV COBI +DTG +bDRV +RAL 923 (32.1%) 427 (14.9%) 401 (14.0%) 394 (13.7%) 287 (10.0%) 282 (9.8%) 160 (5.6%) Male sex 815 (88.3%) 393 (92.0%) 365 (91.0%) 345 (87.6%) 253 (88.2%) 248 (87.9%) 125 (78.1%) <0.001 Upper education 518 (56.1%) 242 (56.7%) 215 (53.6%) 232 (58.9%) 155 (54.0%) 125 (44.3%) 70 (43.8%) 0.033 Immigrants 339 (36.7%) 172 (40.3%) 151 (37.7%) 191 (48.5%) 109 (38.0%) 101 (35.8%) 61 (38.1%) 0.003 Men who have sex with men 659 (71.4%) 324 (75.9%) 289 (72.1%) 278 (70.6%) 191 (66.6%) 154 (54.6%) 84 (52.5%) <0.001 Age �50 years-old 117 (12.7%) 33 (7.7%) 40 (10.0%) 41 (10.4%) 45 (15.7%) 45 (16.0%) 31 (19.4%) <0.001 AIDS 53 (5.7%) 28 (6.6%) 3 (0.7%) 19 (4.8%) 54 (18.8%) 41 (14.5%) 47 (29.4%) <0.001 Median CD4 (IQR) 443 (283–609) 445 (274–590) 506 (378–719) 430 (265–591) 286 (94–473) 296 (111–492) 230 (72–449) <0.001 CD4 count <200 cells/μL 120 (13.0%) 71 (16.6%) 16 (4.0%) 65 (16.5%) 107 (37.3%) 94 (33.3%) 68 (42.5%) <0.001 Viral load >100,000 copies/ 317 (34.3%) 147 (34.4%) 10 (2.5%) 154 (39.1%) 155 (54.0%) 131 (46.5%) 77 (48.1%) <0.001 mL Triglycerides >150 mg/dL 154 (16.7%) 65 (15.2%) 54 (13.5%) 62 (15.7%) 69 (24.0%) 48 (17.0%) 39 (24.4%) <0.001 HDL cholesterol �40 mg/dL 419 (45.4%) 147 (34.4%) 128 (31.9%) 168 (42.6%) 139 (48.4%) 129 (45.7%) 74 (46.3%) <0.001 Total cholesterol >200 mg/ 113 (12.2%) 49 (11.5%) 47 (11.7%) 49 (12.4%) 27 (9.4%) 32 (11.3%) 21 (13.1%) 0.941 dL HCV + antibody 46 (5.0%) 21 (4.9%) 23 (5.7%) 19 (4.8%) 16 (5.6%) 19 (6.7%) 14 (8.8%) 0.073 HBV S + antigen 3 (0.3%) 11 (2.6%) 13 (3.2%) 6 (1.5%) 12 (4.2%) 5 (1.8%) 5 (3.1%) 0.551 Cardiovascular event 14 (1.5%) 9 (2.1%) 5 (1.2%) 6 (1.5%) 9 (3.1%) 5 (1.8%) 11 (6.9%) <0.001 Renal event 17 (1.8%) 10 (2.3%) 5 (1.2%) 8 (2.0%) 7 (2.4%) 3 (1.1%) 7 (4.4%) 0.258 Neurologic event 33 (3.6%) 14 (3.3%) 12 (3.0%) 8 (2.0%) 15 (5.2%) 8 (2.8%) 10 (6.3%) 0.151 Hospital size < = 500 beds 834 (90.4%) 377 (88.3%) 352 (87.8%) 340 (86.3%) 268 (93.4%) 250 (88.7%) 143 (89.4%) 0.081 Hospitals’ location� <0.001 A 123 (13.3%) 118 (27.6%) 67 (16.7%) 124 (31.5%) 22 (7.7%) 26 (9.2%) 17 (10.6%) B 2 (0.2%) 1 (0.2%) 3 (0.7%) 2 (0.5%) 0 (0.0%) 2 (0.7%) 0 (0.0%) C 11 (1.2%) 0 (0.0%) 5 (1.2%) 1 (0.3%) 6 (2.1%) 17 (6.0%) 0 (0.0%) D 9 (1.0%) 1 (0.2%) 2 (0.5%) 0 (0.0%) 4 (1.4%) 4 (1.4%) 0 (0.0%) E 87 (9.4%) 62 (14.5%) 36 (9.0%) 36 (9.1%) 16 (5.6%) 27 (9.6%) 18 (11.3%) F 22 (2.4%) 12 (2.8%) 19 (4.7%) 5 (1.3%) 5 (1.7%) 2 (0.7%) 6 (3.8%) G 104 (11.3%) 19 (4.4%) 21 (5.2%) 26 (6.6%) 9 (3.1%) 9 (3.2%) 0 (0.0%) H 22 (2.4%) 0 (0.0%) 7 (1.7%) 0 (0.0%) 20 (7.0%) 3 (1.1%) 1 (0.6%) I 407 (44.1%) 159 (37.2%) 131 (32.7%) 146 (37.1%) 138 (48.1%) 56 (19.9%) 49 (30.6%) J 40 (4.3%) 19 (4.4%) 6 (1.5%) 17 (4.3%) 26 (9.1%) 15 (5.3%) 6 (3.8%) K 25 (2.7%) 0 (0.0%) 12 (3.0%) 3 (0.8%) 0 (0.0%) 23 (8.2%) 21 (13.1%) L 5 (0.5%) 0 (0.0%) 56 (14.0%) 0 (0.0%) 0 (0.0%) 67 (23.8%) 32 (20.0%) M 66 (7.2%) 36 (8.4%) 36 (9.0%) 34 (8.6%) 41 (14.3%) 31 (11.0%) 10 (6.3%) Period of ART initiation- 657 (71.2%) 116 (27.2%) 89 (22.2%) 391 (99.2%) 194 (67.6%) 128 (45.4%) 67 (41.9%) <0.001 2016–17 � Each capital letter identifies one of the Autonomous Regions. The names of the Autonomous Regions cannot be disclosed due to confidentiality reasons https://doi.org/10.1371/journal.pone.0221598.t001 by hospital’s location. No other significant factors were found for the choice of TDF/FTC/ EVG/COBI and TAF/FTC/EVG/COBI, compared to ABC/3TC/DTG. Discussion This is, to our knowledge, the first study assessing the factors influencing the choice of initial ART in a reasonable large cohort in recent years, when newer treatment regimens have PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 5 / 12 Initial antiretroviral treatment choice Fig 1. Distribution of the initial antiretroviral treatment by period of ART initiation. https://doi.org/10.1371/journal.pone.0221598.g001 become widely available. All the regimens analyzed were considered preferred or alternative by the Spanish treatment guidelines during the study period [1,12–14], but our results suggest that the choice between different regimens could be influenced by certain characteristics of the patient or the hospitals where the treatment is initiated, in addition to the efficacy and toxicity results shown in clinical trials. Overall, ABC/3TC/DTG was the most frequently prescribed regimen. Interestingly, the pre- scription of initial regimens changed over the calendar period. Over time, the prescription of regimens based in DTG and EVG increased. TDF/FTC/EVG/COBI prescription decreased but this was probably partly due to the introduction of TAF/FTC/EVG/COBI, which became available in Spain in 2016. The prescription of the other regimens (TDF/FTC/RPV, TDF/FTC +bDRV and TDF/FTC+RAL) decreased over time. These changes reflect those introduced in the Spanish HIV treatment guidelines. In 2014, all the regimens included in this study were considered preferred treatments [12]. However, since 2015 the guidelines became much more restrictive and have only recommended regimens based on integrase inhibitors as preferred, and have classified all the other regimens analyzed as alternative [1,13,14]. Despite being a pre- ferred regimen, TDF/FTC+RAL was prescribed much less than the regimens based in DTG or EVG. This is probably due to the availability of these latter drugs as part of single tablet regimens. Different regimens were preferentially prescribed to certain groups. The use of integrase inhibitors was more frequent among MSM. This could be in part due to patients’ preference, as MSM frequently have more access to information about HIV [8] and could be more informed about new treatments (and request them to their physicians) than other risk groups. TDF/FTC+RAL, TDF/FTC+bDRV and TDF/FTC+DTG were more likely to be prescribed to patients with low CD4 counts. The use of TDF/FTC is probably due to the need to initiate PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 6 / 12 Initial antiretroviral treatment choice Table 2. Multivariable relative risk ratios for predictors of the choice of the initial ART regimen relative to ABC/3TC/DTG. TDF/FTC/EVG/ TDF/FTC/RPV TAF/FTC/EVG/ TDF/FTC+DTG TDF/FTC+bDRV TDF/FTC+RAL COBI COBI RRR (IC P RRR (IC 95%) P RRR (IC P RRR (IC P RRR (IC 95%) P RRR (IC 95%) P 95%) 95%) 95%) HIV transmission category MSM 1 1 1 1 1 1 Non-MSM 0.96 (0.67– 0.833 1.10 (0.79– 0.575 1.10 (0.78– 0.598 0.98 (0.69– 0.892 1.73 (1.14– 0.009 2.00 (1.29– 0.002 1.39) 1.54) 1.54) 1.38) 2.61) 3.10) CD4 T-cell count > = 200 cells/μL 1 1 1 1 1 1 <200 cells/μL 1.28 (0.97– 0.085 0.41 (0.25– <0.001 1.18 (0.84– 0.331 3.35 (2.34– <0.001 2.61 (1.51– 0.001 3.76 (2.39– <0.001 1.70) 0.67) 1.66) 4.80) 4.49) 5.92) Viral Load < = 100,000 cop/ 1 1 1 1 1 1 mL >100,000 cop/mL 1.03 (0.72– 0.869 0.05 (0.03– <0.001 1.15 (0.87– 0.330 1.74 (1.21– 0.003 1.21 (0.84– 0.300 1.16 (0.70– 0.566 1.48) 0.10) 1.52) 2.52) 1.75) 1.91) Period of ART initiation 2014–2015 1 1 1 1 1 1 2016–2017 0.17 (0.12– <0.001 0.09 (0.05– <0.001 NA 0.79 (0.57– 0.173 0.22 (0.12– <0.001 0.23 (0.12– <0.001 0.22) 0.15) 1.11) 0.42) 0.42) Hospitals’ location� <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 A 1 1 1 1 1 1 B 1.17 (0.84– 7.02 (4.87– 0.57 (0.39– NA 9.25 (4.43– NA 1.63) 10.12) 0.85) 19.32) C NA 2.06 (0.71– 0.05 (0.02– 3.96 (1.30– 10.54 (3.34– NA 5.95) 0.12) 12.03) 33.30) D 0.22 (0.15– 0.98 (0.73– NA 3.38 (1.85– 4.34 (2.14– NA 0.31) 1.31) 6.18) 8.79) E 1.08 (0.57– 1.37 (0.35– 0.28 (0.16– 1.00 (0.39– 1.60 (0.45– 1.53 (0.69– 2.04) 5.42) 0.51) 2.55) 5.64) 3.40) F 0.70 (0.21– 2.12 (1.31– 0.18 (0.07– 1.28 (0.66– 0.43 (0.03– 1.78 (0.89– 2.34) 3.43) 0.44) 2.51) 6.69) 3.56) G 0.28 (0.21– 0.71 (0.55– 0.18 (0.12– 0.54 (0.31– 0.50 (0.27– NA 0.39) 0.93) 0.27) 0.93) 0.92) H NA 1.10 (0.83– NA 5.87 (3.38– 0.75 (0.39– 0.38 (0.18– 1.46) 10.17) 1.42) 0.78) I 0.60 (0.30– 1.08 (0.73– 0.26 (0.13– 2.01 (0.93– 0.85 (0.39– 1.15 (0.47– 1.20) 1.61) 0.51) 4.36) 1.87) 2.84) J 0.80 (0.39– 0.63 (0.32– 0.30 (0.12– 3.59 (1.45– 2.15 (1.06– 1.38 (0.42– 1.66) 1.21) 0.74) 8.86) 4.35) 4.53) K NA 2.23 (1.61– 0.08 (0.05– NA 5.12 (2.67– 6.97 (3.32– 3.08) 0.12) 9.82) 14.65) L NA 78.87 (28.19– NA NA 101.92 (17.62– 71.74 (26.53– 220.65) 589.58) 194.01) M 0.77 (0.25– 1.60 (0.60– 0.39 (0.15– 3.73 (1.49– 2.66 (0.73– 1.25 (0.32– 2.43) 4.27) 1.01) 9.33) 9.74) 4.88) � Each capital letter identifies one of the Autonomous Regions. The names of the Autonomous Regions cannot be disclosed due to confidentiality reasons https://doi.org/10.1371/journal.pone.0221598.t002 PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 7 / 12 Initial antiretroviral treatment choice treatment promptly when results from HLA B5701 are not yet available, and RAL and DTG could probably be used to minimize interactions in patients that might be being treated for other opportunistic diseases. Also, prevalence of resistance to integrase inhibitors is low in Spain [15,16] and these agents are frequently prescribed when resistance tests are still pending. The prescription of TDF/FTC+bDRV for patients with low CD4 counts reached borderline statistical significance, probably due to the high genetic barrier of protease inhibitors that allows their use in severely immunosuppressed patients while waiting for resistance test results, as described in earlier studies[5]. The choice of regimens varied significantly by hospital location. This is not explained by local variations in clinical characteristics of the patients, as these differences were still large after adjusting for all other factors. Possible explanations include regional variations on the physicians’ perceptions of efficacy and safety of different regimens[17], different experience on HIV treatment among the treating physicians, and institutional constraints. Although we could not assess limitations to ART prescription in all the participating hospitals for the study period, we have recently described the limitations for the prescription of antiretrovirals in the CoRIS cohort for the period 2010–2015: 54.1% of the centres had a cost limitation for the pre- scription of ART and 29.7% had restricted access to at least one antiretroviral or single-tablet regimen (mainly some of the newest integrase inhibitors)[18,19]. Although we could not ana- lyze the influence of institutional constraints in the results of this study, it is possible that they could have an influence in the choice of the initial ART: our previous study demonstrated that hospitals with restricted access to at least one antiretroviral were more likely to prescribe ART regimens that were not recommended by the Spanish clinical guidelines[19]. Our study is limited by the lack of information on individual physician’s characteristics, and some clinical variables that could influence the choice of ART such as pregnancy, resis- tance testing or other drugs that could interact with ART. However, our strengths include the analysis of a reasonably large number of patients from a multicenter well established cohort, and the recent time period which allow us to analyze the newer treatment regimens. Our results suggest that initial ART prescriptions are influenced by clinical and demographic patient variables, and also by the prescribing hospital location. In conclusion, in this multicenter Spanish cohort the prescription of initial ART regimens varied not only with patients’ clinical and demographic characteristics, but also with other var- iables such as the period of ART initiation and hospital location. Over time, regimens based on integrase inhibitors have become the most frequent choice as initial ART. Acknowledgments This study would not have been possible without the collaboration of all patients, medical and nursery staff and data mangers who have taken part in the project. Centers and investigators involved in CoRIS Executive committee: Santiago Moreno, Inma Jarrı́n, David Dalmau, Maria Luisa Navarro, Maria Isabel González, Jose Luis Blanco, Federico Garcia, Rafael Rubio, Jose Antonio Iribar- ren, Félix Gutiérrez, Francesc Vidal, Juan Berenguer, Juan González. Fieldwork, data management and analysis: Belén Alejos, Victoria Hernando, Cristina Moreno, Carlos Iniesta, Luis Miguel Garcia Sousa, Nieves Sanz Perez BioBanK HIV: Hospital General Universitario Gregorio Marañón: M Ángeles Muñoz-Fer- nández, Isabel Marı́a Garcı́a-Merino, Irene Consuegra Fernández, Coral Gómez Rico, Jorge Gallego de la Fuente, Paula Palau Concejo. Participating centres: PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 8 / 12 Initial antiretroviral treatment choice Hospital General Universitario de Alicante (Alicante): Joaquı́n Portilla, Esperanza Merino, Sergio Reus, Vicente Boix, Livia Giner, Carmen Gadea, Irene Portilla, Marı́a Pam- pliega, Marcos Dı́ez, Juan Carlos Rodrı́guez, José Sánchez-Payá. Hospital Universitario de Canarias (San Cristobal de la Laguna): Juan Luis Gómez, Jeho- vana Hernández, Marı́a Remedios Alemán, Marı́a del Mar Alonso, Marı́a Inmaculada Hernán- dez, Felicitas Dı́az-Flores, Dácil Garcı́a, Ricardo Pelazas., Ana López Lirola Hospital Universitario Central de Asturias (Oviedo): José Sanz Moreno, Alberto Arranz Caso, Cristina Hernández Gutiérrez, Marı́a Novella Mena Hospital Universitario 12 de Octubre (Madrid): Rafael Rubio, Federico Pulido, Otilia Bis- bal, Asunción Hernando, Lourdes Domı́nguez, David Rial Crestelo, Laura Bermejo, Mireia Santacreu. Hospital Universitario de Donostia (Donostia-San Sebastián): José Antonio Iribarren, Julio Arrizabalaga, Marı́a José Aramburu, Xabier Camino, Francisco Rodrı́guez-Arrondo, Miguel Ángel von Wichmann, Lidia Pascual Tomé, Miguel Ángel Goenaga, Mª Jesús Bustin- duy, Harkaitz Azkune, Maialen Ibarguren, Aitziber Lizardi, Xabier Kortajarena. Hospital General Universitario De Elche (Elche): Félix Gutiérrez, Mar Masiá, Sergio Padi- lla, Andrés Navarro, Fernando Montolio, Catalina Robledano, Joan Gregori Colomé, Araceli Adsuar, Rafael Pascual, Marta Fernández, Elena Garcı́a., José Alberto Garcı́a, Xavier Barber. Hospital Universitari Germans Trias i Pujol (Can Ruti) (Badalona): Roberto Muga, Ara- ntza Sanvisens, Daniel Fuster. Hospital General Universitario Gregorio Marañón (Madrid): Juan Berenguer, Juan Car- los López Bernaldo de Quirós, Isabel Gutiérrez, Margarita Ramı́rez, Belén Padilla, Paloma Gijón, Teresa Aldamiz-Echevarrı́a, Francisco Tejerina, Francisco José Parras, Pascual Balsalo- bre, Cristina Diez, Leire Pérez Latorre. Hospital Universitari de Tarragona Joan XXIII (Tarragona): Francesc Vidal, Joaquı́n Peraire, Consuelo Viladés, Sergio Veloso, Montserrat Vargas, Miguel López-Dupla, Montser- rat Olona, Anna Rull, Esther Rodrı́guez-Gallego, Verónica Alba. Hospital Universitario y Politécnico de La Fe (Valencia): Marta Montero Alonso, José López Aldeguer, Marino Blanes Juliá, Marı́a Tasias Pitarch, Iván Castro Hernández, Eva Cala- buig Muñoz, Sandra Cuéllar Tovar, Miguel Salavert Lletı́, Juan Fernández Navarro. Hospital Universitario La Paz/IdiPAZ: Juan González-garcia, Francisco Arnalich, José Ramón Arribas, Jose Ignacio Bernardino de la Serna, Juan Miguel Castro, Luis Escosa, Pedro Herranz, Victor Hontañón, Silvia Garcı́a-Bujalance, Milagros Garcı́a López-Hortelano, Alicia González-Baeza, Maria Luz Martı́n-Carbonero, Mario Mayoral, Maria Jose Mellado, Rafael Esteban Micán, Rocio Montejano, Marı́a Luisa Montes, Victoria Moreno, Ignacio Pérez- Valero, Berta Rodés, Talia Sainz, Elena Sendagorta, Natalia Stella Alcáriz, Eulalia Valencia. Hospital San Pedro Centro de Investigación Biomédica de La Rioja (CIBIR) (Logroño): José Ramón Blanco, José Antonio Oteo, Valvanera Ibarra, Luis Metola, Mercedes Sanz, Laura Pérez-Martı́nez. Hospital Universitario Miguel Servet (Zaragoza): Piedad Arazo, Gloria Sampériz. Hospital Universitari MutuaTerrassa (Terrasa): David Dalmau, Angels Jaén, Montse Sanmartı́, Mireia Cairó, Javier Martinez-Lacasa, Pablo Velli, Roser Font, Mariona Xercavins, Noemı́ Alonso. Complejo Hospitalario de Navarra (Pamplona) Marı́a Rivero, Jesús Repáraz, Marı́a Gra- cia Ruiz de Alda, Marı́a Teresa de León Cano, Beatriz Pierola Ruiz de Galarreta. Corporació Sanitària Parc Taulı́ (Sabadell): Ferrán Segura, Marı́a José Amengual, Gemma Navarro, Montserrat Sala, Manuel Cervantes, Valentı́n Pineda, Sonia Calzado, Marta Navarro. PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 9 / 12 Initial antiretroviral treatment choice Hospital Universitario de La Princesa (Madrid): Ignacio de los Santos, Jesús Sanz Sanz, Ana Salas Aparicio, Cristina Sarriá Cepeda, Lucio Garcia-Fraile Fraile, Enrique Martı́n Gayo. Hospital Universitario Ramón y Cajal (Madrid): Santiago Moreno, José Luis Casado, Fer- nando Dronda, Ana Moreno, Marı́a Jesús Pérez Elı́as, Cristina Gómez Ayerbe, Carolina Gutiérrez, Nadia Madrid, Santos del Campo Terrón, Paloma Martı́, Uxua Ansa, Sergio Ser- rano, Marı́a Jesús Vivancos. Hospital General Universitario Reina Sofı́a (Murcia) Enrique Bernal, Alfredo Cano, Antonia Alcaraz Garcı́a, Joaquı́n Bravo Urbieta, Ángeles Muñoz, Maria Jose Alcaraz, Maria del Carmen Villalba. Hospital Nuevo San Cecilio (Granada): Federico Garcı́a, José Hernández, Alejandro Peña, Leopoldo Muñoz, Paz Casas, Marta Alvarez, Natalia Chueca, David Vinuesa, Clara Martinez- Montes. Centro Sanitario Sandoval (Madrid): Jorge Del Romero, Carmen Rodrı́guez, Teresa Puerta, Juan Carlos Carrió, Mar Vera, Juan Ballesteros, Oskar Ayerdi. Hospital Clı́nico Universitario de Santiago (Santiago de Compostela): Antonio Antela, Elena Losada. Hospital Universitario Son Espases (Palma de Mallorca): Melchor Riera, Marı́a Peñar- anda, Marı́a Leyes, Mª Angels Ribas, Antoni A Campins, Carmen Vidal, Francisco Fanjul, Javier Murillas, Francisco Homar. Hospital Universitario Virgen de la Victoria (Málaga): Jesús Santos, Crisitina Gómez Ayerbe, Isabel Viciana, Rosario Palacios, Carmen Marı́a González. Hospital Universitario Virgen del Rocı́o (Sevilla): Pompeyo Viciana, Nuria Espinosa, Luis Fernando López-Cortés. Hospital Universitario de Bellvitge (Hospitalet de Llobregat): Daniel Podzamczer, Elena Ferrer, Arkaitz Imaz, Juan Tiraboschi, Ana Silva, Marı́a Saumoy. Hospital Universitario Valle de Hebrón (Barcelona): Esteban Ribera, Adrian Curran. Hospital Costa del Sol (Marbella): Julián Olalla, Alfonso del Arco, Javier de la torre, José Luis Prada, José Marı́a Garcı́a de Lomas Guerrero, Javier Pérez Stachowski. Hospital General Universitario Santa Lucı́a (Cartagena): Onofre Juan Martı́nez, Fran- cisco Jesús Vera, Lorena Martı́nez, Josefina Garcı́a, Begoña Alcaraz, Amaya Jimeno. Complejo Hospitalario Universitario a Coruña (Chuac) (A Coruña): Angeles Castro Iglesias, Berta Pernas Souto, Alvaro Mena de Cea. Hospital Universitario Basurto (Bilbao): Josefa Muñoz, Miren Zuriñe Zubero, Josu Mir- ena Baraia-Etxaburu, Sofı́a Ibarra Ugarte, Oscar Luis Ferrero Beneitez, Josefina López de Munain, Mª Mar Cámara López, Mireia de la Peña, Miriam Lopez. Hospital Universitario Virgen de la Arrixaca (El Palmar): Carlos Galera, Helena Alben- din, Aurora Pérez, Asunción Iborra, Antonio Moreno, Maria Angustias Merlos, Asunción Vidal. Hospital de la Marina Baixa (La Vila Joiosa): Concha Amador, Francisco Pasquau, Javier Ena, Concha Benito, Vicenta Fenoll., Concepcion Gil Anguita, Jose Tomas Algado Rabasa. Hospital Universitario Infanta Sofia (San Sebastian de los Reyes): Inés Suárez-Garcı́a, Eduardo Malmierca, Patricia González-Ruano, Dolores Martı́n Rodrigo, Mª Pilar Ruiz Seco. Complejo Hospitalario de Jaén (Jaén) Mohamed Omar Mohamed-Balghata, Marı́a Amparo Gómez Vidal. Hospital San Agustı́n (Avilés): Miguel Alberto de Zarraga. Hospital Clı́nico San Carlos (Madrid): Vicente Estrada Pérez, Maria Jesus Téllez Molina, Jorge Vergas Garcı́a, Juncal Pérez-Somarriba Moreno. Hospital Universitario Fundación Jiménez Dı́az (Madrid): Miguel Górgolas., Alfonso Cabello., Beatriz Álvarez., Laura Prieto. PLOS ONE | https://doi.org/10.1371/journal.pone.0221598 August 26, 2019 10 / 12 Initial antiretroviral treatment choice Hospital Universitario Prı́ncipe de Asturias (Alcalá de Henares): José Sanz Moreno, Alberto Arranz Caso, Cristina Hernández Gutiérrez, Marı́a Novella Mena. Hospital Clı́nico Universitario de Valencia (València): Marı́a José Galindo Puerto, Ramón Fernando Vilalta, Ana Ferrer Ribera. Hospital Reina Sofı́a (Córdoba): Antonio Rivero Román, Maria Teresa Brieva Herrero, Antonio Rivero Juárez, Pedro López López, Isabel Machuca Sánchez, José Peña Martı́nez. Hospital Universitario Severo Ochoa (Leganés): Miguel Cervero Jiménez, Rafael Torres Perea, Juan José Jusdado Ruiz-Capillas. Nuestra Señora de Valme: Juan A Pineda. Author Contributions Conceptualization: Santiago Moreno, Inma Jarrı́n. Data curation: Belén Alejos, Inés Suárez-Garcı́a, Otilia Bisbal, José Antonio Iribarren, Vı́ctor Asensi, Miguel Górgolas, Roberto Muga. Formal analysis: Belén Alejos. Funding acquisition: Santiago Moreno, Inma Jarrı́n. Investigation: Belén Alejos, Inés Suárez-Garcı́a, Otilia Bisbal, José Antonio Iribarren, Vı́ctor Asensi, Miguel Górgolas, Roberto Muga. Methodology: Belén Alejos, Santiago Moreno, Inma Jarrı́n. Project administration: Inma Jarrı́n. 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