AIDS Research and Therapy Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 https://doi.org/10.1186/s12981-022-00457-0 RESEARCH Open Access Observational cohort study of rilpivirine (RPV) utilization in Europe Alessandro Cozzi‑Lepri1*, Lars Peters2, Annegret Pelchen‑Matthews1, Bastian Neesgaard2, Stephane De Wit3, Isik Somuncu Johansen4, Simon Edwards5, Christoph Stephan6, Georgios Adamis7, Therese Staub8, Alexandra Zagalo9, Pere Domingo10, Daniel Elbirt11, Katharina Kusejko12, Johanna Brännström13, Dzmitry Paduta14, Tatyana Trofimova15, Janos Szlavik16, Kai Zilmer17, Marcello Losso18, Veerle Van Eygen19, Helen Pai20, Jens Lundgren2, Amanda Mocroft1,2 and for the EuroSIDA Study Group Abstract Introduction: Data on safety and effectiveness of RPV from the real-world setting as well as comparisons with other NNRTIs such as efavirenz (EFV) remain scarce. Methods: Participants of EuroSIDA were included if they had started a RPV- or an EFV-containing regimen over November 2011-December 2017. Statistical testing was conducted using non-parametric Mann–Whitney U test and Chi-square test. A logistic regression model was used to compare participants’ characteristics by treatment group. Kaplan–Meier analysis was used to estimate the cumulative risk of virological failure (VF, two consecutive values > 50 copies/mL). Results: 1,355 PLWH who started a RPV-based regimen (11% ART-naïve), as well as 333 initiating an EFV-containing regimen were included. Participants who started RPV differed from those starting EFV for demographics (age, geo‑ graphical region) and immune-virological profiles (CD4 count, HIV RNA). The cumulative risk of VF for the RPV-based group was 4.5% (95% CI 3.3–5.7%) by 2 years from starting treatment (71 total VF events). Five out of 15 (33%) with resistance data available in the RPV group showed resistance-associated mutations vs. 3/13 (23%) among those in the EFV group. Discontinuations due to intolerance/toxicity were reported for 73 (15%) of RPV- vs. 45 (30%) of EFV-treated participants (p = 0.0001). The main difference was for toxicity of central nervous system (CNS, 3% vs. 22%, p < 0.001). Conclusion: Our estimates of VF > 50 copies/mL and resistance in participants treated with RPV were similar to those reported by other studies. RPV safety profile was favourable with less frequent discontinuation due to toxicity than EFV (especially for CNS). Keywords: Cohort Study, Europe, Edurant™, Eviplera™, Efavirenz, Real-world effectiveness Introduction Rilpivirine (RPV) is a non-nucleoside reverse tran- Edurant™ by the European Commission on 28 Novem- scriptase inhibitor (NNRTI) which was approved as ber 2011 for the treatment of human immunodeficiency *Correspondence: a.cozzi-lepri@ucl.ac.uk virus type 1 (HIV-1) infection in antiretroviral treatment 1 Centre for Clinical Research, Epidemiology, Modelling and Evaluation (ART)-naïve adult persons living with HIV (PLWH) with (CREME), Institute for Global Health, University College London, Rowland Hill a baseline viral load (VL) ≤ 100,000 HIV-RNA copies/ St, London NW3 2PF, UK Full list of author information is available at the end of the article ml. RPV has been made available over the years as the © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 2 of 12 active ingredient in several marketed fixed dose com- EuroSIDA was initiated. Monitoring previously included bination (FDC) tablets [1]. Although RPV in the FDC on-site visits to all participating centers. However, as the tenofovir disoproxil fumarate (TDF) (Eviplera™) was ini- tablet formulation including emtricitabine (FTC) and study has evolved, new processes have been formulated including centralized monitoring, building on the risk- tially approved for ART-naïve adult PLWH with a base- based monitoring used in clinical trials. In autumn 2014, line VL ≤ 100,000 copies/ml only, the indication was EuroSIDA also transitioned from collecting data on paper extended in October 2013 for ART-experienced adults forms to using the electronic case report system Research who are virologically suppressed with no history of viro- Electronic Data Capture [16]. More details together with logical failure (VF). the full ist of collect variables are provided here [13, 17]. Several randomized studies [2–9] have compared the efficacy of RPV-based regimens with that of EFV-based Study population regimens in both the ART-naïve and ART-experienced Participants were included if they were at least 16 years populations. Overall, these studies have shown relatively of age and they had started a RPV-containing or EFV- low rates of VF at 1 year (never above 15%) with no evi- containing regimen over the period November 2011 to dence for a difference in rate of VF. However, long-term end of December 2017. November 2011 is the earliest of ucts (Edurant™, the single agent tablet, or Eviplera™, a virological outcomes of these regimens have been rarely the dates of market availability of RPV-containing prod- examined in real-world clinical practice across Europe [10–12]. single tablet regimen containing RPV/TDF/FTC) within The aim of this analysis was to describe the use of RPV- the 28 countries where RPV-containing regimens were containing regimens in routine clinical practice among approved and marketed for use in participants with base- adult PLWH followed in the EuroSIDA study. Specifically, line VL ≤ 100,000 copies/ml (see full list of these coun- In October 2013, Eviplera™ was approved and mar- key objectives were: (i) to evaluate factors associated tries in Additional file 1). with the probability of initiation of RPV- instead of EFV- containing regimens and (ii) to describe the safety and keted for use in ART-experienced adults who are viro- people starting Eviplera™ from ART-naive or switching effectiveness of RPV, including evaluation of virological logically suppressed with no history of VF, and therefore to Eviplera™ were also included. The last follow-up date response and treatment-emergent resistance-associated mutations (RAMs). recorded for a person in this analysis is December 31, Methods name Odefsey™) was approved in the European Union in 2017. Although FTC/RPV/tenofovir alafenamide (brand Study design The EuroSIDA study cohort is a prospective, observa- June 2016, there was no use of this formulation in par- tional cohort of HIV-1 infected participants from 117 ticipants of this analysis. Thus, RPV mentioned through- the single agent Edurant™ or the FDC (FTC/RPV/TDF), clinical centers across Europe, Israel and Argentina [13]. out this work refers to RPV-containing regimens, either Eviplera™, while EFV refers to EFV-containing regimens, Details regarding study design and data collection are either the single agent (SUSTIVA/STOCRIN™) or the described elsewhere [https://​chip.​dk/​Resea​rch/​Studi​es/​ FDC ATRIPLA™. EuroS​IDA]. Information about adverse events are col- lected in the EuroSIDA cohort according to the Data Col- lection on Adverse events of Anti-HIV Drugs (D:A:D) All PLWH who started EFV-based regimens regardless definitions starting from 1998 [14], and detailed informa- of the level of VL were included, as a comparator group, tion about the cause of death is collected using the Cod- to provide a contemporary context of utilization and out- ing of Death (CoDe) algorithm [15]. comes (i.e. rates of VF and resistance patterns). Unfortu- Up to March 2017, source documents from the labo- nately, the use of EFV has waned in the clinics over time ratories performing resistance testing were sent to the and the a priori target for the minimum number of VF EuroSIDA coordination center and recorded RAMs were events in this group required for a formal comparison keyed into a central database. The keyed results were was never reached over the duration of the study. subsequently double checked for correctness by a second person. After March 2017 resistance test results were no Statistical analysis longer reported to EuroSIDA because VF was infrequent Continuous variables were summarised using medi- and resistance testing was very rarely perfomed. ans, minimums, maximums, and interquartile ranges as appropriate. Characteristics of participants who initiated Data quality assurance RPV- or EFV-based regimens were described. Statistical To ensure verification of collected data, an extensive testing was conducted to compare population medians quality assurance programme has been in place since (non-parametric Mann–Whitney U test) and chi-square Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 3 of 12 test for proportions by treatment group. A logistic Additional information regarding participants included regression model was used to identify factors indepen- in the RPV treatment group alone are shown in Addi- dently associated with the probability of starting RPV- vs. tional file 1: Table AF2. Of the 333 included partici- EFV- based regimens. Age, gender, weight, or body mass pants who started an EFV-containing regimen, 178 index (BMI), ethnicity, CD4 cell count, pre-treatment VL, (55%) were ART-naïve (Fig. 1). mode of HIV transmission, co-infection with hepatitis Table 1 shows the main characteristics of participants B/C, HIV treatment status (naïve/experienced) were all who started RPV or EFV at time of treatment initia- identified as potential determinants of treatment initia- tion. Participants treated with RPV were older (median tion either with RPV or EFV. See Additional file 1: Table ages 48 vs. 39 years; p < 0.0001), had higher CD4 cell AF1 for a detailed codebook of variables included. Unad- counts (median 566 vs. 306 cells/mm3; p < 0.0001), justed and adjusted odds ratios (ORs) of starting RPV vs. lower HIV-RNA VL (median 1.59 vs. 4.05 ­log10 cop- EFV were tabulated with 95% confidence intervals (CI). ies/ml; p < 0.0001), and had been enrolled in EuroSIDA Characteristics showing an association with the outcome for a longer period (140.8 vs. 21.4 months; p < 0.0001). of starting RPV with a p-value < 0.1 were considered A higher proportion of participants who received RPV for inclusion in the multivariable model; for categorical resided in Southern and West Central Europe (32.8% variables the global (type III) p-value was used to detect vs. 21.0% and 29.5% vs. 17.4%, respectively), with a overall associations. similar proportion residing in the North (19.9% RPV, The main reason for discontinuing RPV and EFV, as 20.4% EFV), while a far lower proportion of partici- reported by the treating physicians from a pre-specified pants resided in Eastern Europe (2.1% vs. 23.1%; region list of options, were summarized and frequency com- global p = 0.0001). Other baseline characteristics and pared by treatment group. Average levels of selected more detailed information are shown in Additional laboratory parameters (most recent value before stopping file 1: Table AF3. These differences detected by univari- RPV/ EFV) were also calculated and compared. able analysis were confirmed in a multivariable logis- Time to confirmed VF > 50 copies/mL in participants tic regression analysis. Adjusted Odds Ratio [aOR] for who started RPV-based regimens and had at least two starting RPV-based vs. EFV-based regimens are shown VL measurements after starting therapy was estimated. in Table 2. Regarding the geographical distribution, The date of VF was defined at the time of the first of two after controlling for the other variables included in the consecutive values > 50 copies/mL after >6 months from model, participants treated with RPV were confimerd starting the RPV- or EFV-based regimen. Due to the to be less likely to reside in East Europe (adjusted Odds small number of VF events, especially in the EFV-treated Ratio [aOR]: 0.11 (95% confidence interval [CI]. 0.04– group, VF and resistance accumulation analyses are only 0.28; p < 0.001)) compared with West Central Europe. descriptive. Kaplan–Meier analysis was used to estimate the cumulative probability of VF > 50 copies/mL by 1 and 2 years with 95% CI in the RPV group alone. There were missing data for some of the variables col- lected. For categorical factors, under the assumption of data missing at random, a separate group for missing val- ues was allowed so that no participants were excluded from the analysis (the missing- indicator method). If a variable was analysed as continuous and there were miss- ing values for this variable, participants with the missing value were instead excluded. All data were analysed using SAS version 9.4 (Cary, NC, USA). Results Study population Overall, as of December 31st, 2017, the number of par- ticipants within the labelled indication in EU for RPV (i.e. participants with a baseline VL of ≤ 100,000 cop- ies/ml) newly initiating a RPV-containing regimen Fig. 1 Overview of EuroSIDA participants included in the analysis. was 1,355, and the number of participants initiating VF: first two consecutive VL > 50 copies/mL after >6 months from an EFV-containing regimen was 333. A total of 144 initiation of RPV/RFV-based regimens. *≥2 Viral load measures after baseline (11%) of the RPV-based treated group were ART-naïve. Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 4 of 12 Table 1 Demographic characteristics, comorbidities and medical conditions of participants initiating RPV or EFV-containing regimens Characteristic RPV N = 1355 EFV N = 333 p-value1 Age Median (IQR) 48.0 (40.0–54.0) 39.0 (32.5–47.0) < 0.0001 Weight (kg)2 Median (IQR) 73.8 (65.0–82.4) 70.2 (64.0–80.0) 0.1628 Gender Female 294 (21.7%) 53 (15.9%) 0.0193 Male 1061 (78.3%) 280 (84.1%) Ethnicity Non-white 214 (15.8%) 52 (15.6%) 0.9364 White 1141 (84.2%) 281 (84.4%) Geographical Distribution4 0.0001 South 445 (32.8%) 70 (21.0%) West Central 399 (29.4%) 58 (17.4%) North 269 (19.9%) 68 (20.4%) East Central 214 (15.8%) 60 (18.0%) East 28 (2.1%) 77 (23.1%) Mode of HIV transmission 0.0001 MSM 628 (46.3%) 116 (34.8%) PWID 318 (23.5%) 114 (34.2%) Heterosexual 316 (23.3%) 81 (24.3%) Other 93 (6.9%) 22 (6.6%) Prior AIDS diagnoses No 1036 (76.5%) 266 (79.9%) 0.1828 Yes 319 (23.5%) 67 (20.1%) Prior non-AIDS diagnoses Cardiovascular disease 59 (4.4%) 4 (1.2%) 0.0065 Non-AIDS defining malignancies 60 (4.4%) 6 (1.8%) 0.0267 End stage renal disease 5 (0.4%) 0 (0.0%) 0.2669 Pancreatitis 3 (0.2%) 0 (0.0%) 0.3901 HCV antibody status Negative 736 (54.3%) 127 (38.1%) < 0.0001 Positive 541 (39.9%) 161 (48.3%) Unknown 78 (5.8%) 45 (13.5%) HBsAg status Negative 1133 (83.6%) 235 (70.6%) < 0.0001 Positive 58 (4.3%) 19 (5.7%) Unknown 164 (12.1%) 79 (23.7%) Diabetes No 638 (47.1%) 124 (37.2%) < 0.0001 Yes 91 (6.7%) 6 (1.8%) Unknown 626 (46.2%) 203 (61.0%) Hypertension No 768 (56.7%) 113 (33.9%) < .0001 Yes 348 (25.7%) 48 (14.4%) Unknown 239 (17.6%) 172 (51.7%) eGFR (mL/1.73m2) Median (IQR) 99.2 (84.2–108.3) 106.9 (96.0–115.1) < 0.0001 CD4 cell count (/mm3) Median (IQR) 566.0 (388.0–770.0) 305.5 (151.5–486.0) < 0.0001 Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 5 of 12 Table 1 (continued) Characteristic RPV N = 1355 EFV N = 333 p-value1 CD4 cell count nadir (/mm3) Median (IQR) 169.0 (35.0–283.0) 224.0 (76.0–330.0) < 0.0001 HIV viral load (log10 copies/ml) Median (IQR) 1.59 (1.28–1.69) 4.05 (1.60–5.11) < 0.0001 Time enrolled in EuroSIDA (months) Median (IQR) 140.8 (69.4–209.7) 21.4 (1.3–89.2) < 0.0001 IQR: Interquartile Range; BMI: Body Mass Index; MSM: Men who have sex with men; PWID: Injecting Drug User; HBsAg: Hepatitis B surface antigen; eGFR: estimated glomerular filtration rate; N/A: Not enough data to compute 1 P-value for comparison of population distributions using the Kruskal–Wallis test or comparison of proportions using the chi-square test 2 Baseline weight and eGFR are the closest measurements up to 1 year prior to baseline 3 Participants can be included in EuroSIDA from the age of 16 years 4 See Additional file 1: Fig. S5 for map of countries inclused in each geographical region ARV treatment status months from study entry are shown as box-plots strati- Overall, in the RPV group, 144 (10.6%) participants were fied by treatment group in Additional file 1: Fig. AF2. ART-naive and 172 (12.7%) were naïve to cART (i.e. they In the subset of 1,302/1,355 (96.1%) RPV and 323/333 had never previously received a regimen including ≥ 3 (97.0%) EFV participants who had at least two VL val- ARVs); overall 1,211 individuals (89.4%) had previously ues during follow-up, the proportion of those who taken at least one ARV drug. experienced VF (two consecutive HIV-RNA > 50 cop- Additional file 1: Fig. AF1(a) shows the breakdown of ies/mL) was 5.5% (71/1,302, 95% CI 4.3–6.8%) and 7.4% the ARV treatment status of participants prior to initiat- (24/323, 95% CI 7.4–10.9%) for RPV- and EFV-based ing RPV- or EFV- containing regimens. A higher propor- ART, respectively. The Kaplan–Meier estimates of the tion of participants treated with RPV vs. EFV had been cumulative probability of VF for the RPV-based group previously exposed to ARVs (i.e., exposure to at least 1 were 1.5% (95% CI 0.7–2.2%) by 1 year and 4.5% (95% CI ARV from any class) (89.4% vs. 46.5%; p < 0.0001) and 3.3–5.7%) by 2 years from starting the RPV-based regi- cART (i.e. exposure to ≥ 3 ARVs from any class) (87.3% men (Fig. 2). Of note, this rate was mainly driven by the vs. 42.6%; p < 0.0001) as compared to those who started treatment-experienced group in whom the overall risk EFV. of VF was 66/1211 (5.5%). Due to the small number of In the newly initiated RPV/EFV-based regimen, the events in the EFV group, the Kaplan–Meier estimates for most frequently used NRTI pair was TDF/FTC (61%) participants who started the EFV-based regimens were followed by ABC/3TC (33%) and ZDV/3TC (2%) with not performed. no evidence for a difference in distribution by treat- Pre-treatment screening for ARV RAMs was available ment group. Approximately 5% of the RPV group also for only 103/1,355 (8.3%) RPV-treated and 55/320 (17.2%) received an INSTI (i.e. RAL or DTG) (Additional file 1: EFV-treated participants. Of the 103 RPV-treated par- Fig. AF1(b)). ticipants with documented pre-treatment screening for ARV RAMs, 76 (73.8%) were treatment-experienced and Viral load and HIV drug resistance monitoring 27 (26.2%) were treatment-naïve. The proportion of RPV- Of the 1,355 participants who started an RPV-containing and EFV-treated participants with prior resistance test- regimen, 1,184 (87.4%) had a VL measurement available ing who had at least 1 NNRTI RAM was 18/103 (17.5%) in the 6 months prior to baseline. Of these, 938 (79.1%) vs. 11/55 (20.0%), respectively. Among the 71 RPV- had a VL ≤ 50 copies/ml, 235 (19.8%) had a VL between treated participants with VF, 15 (21.1%) had data avail- 51 and 100,000 copies/mL and 11 individuals (0.9%) had able on treatment-emergent RAMs and 5 (33.3%) showed a VL > 100,000 copies/mL. both NRTI and NNRTI RAMs, while 1 participant (6.7%) The median duration of virological follow-up for par- showed NNRTI RAMs but no NRTI RAMs. Thirteen ticipants initiating RPV was 29.0 months (IQR: 15.6– out of 24 (54.2%) of the EFV-treated participants with 41.6; range: 0–65.5) and 38.4 months (IQR: 17.2–52.7 VF had data available on treatment-emergent RAMs, range: 0–70.5) for those starting EFV. Median and IQR and 3 of these (23.1%) showed both NRTI and NNRTI HIV-1 RNA at various follow-up times and up to 36 RAMs (Additional file 1: Tables AF4(a) an AF4(b) ). The Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 6 of 12 Table 2 Odds ratios of starting a RPV- vs. EFV-based regimen from fitting a logistic regression model Factor Logistic regression estimates of factors associated with initiating RPV vs EFV Based on 1355 initiations of RPV and 333 initiations of EFV Univariable estimates Multivariable estimates Type III p-value Odds ratio (95% CI) p-value Adjusted Odds p-value ratio (95% CI) Age/Sex/Race/Weigh Age per 5 years older 1.42 (1.33, 1.52) < 0.001 Male vs. Female 0.68 (0.50, 0.94) 0.020 0.63 (0.34, 1.16) 0.137 White vs. Non-white 0.99 (0.71, 1.37) 0.936 1.68 (0.87, 3.22) 0.119 Underweight (BMI < 19) vs. (19 <  = BMI < 25) 0.85 (0.48, 1.51) 0.588 Overweight (25 <  = BMI < 30) vs. (19 <  = BMI < 25) 1.36 (0.82, 2.26) 0.240 Obese (BMI >  = 30) vs. (19 <  = BMI < 25) 1.27 (0.55, 2.92) 0.572 BMI unknown vs. (19 <  = BMI < 25) 0.46 (0.34, 0.63) < 0.001 Geographical region < 0.001 South vs. West Central 0.92 (0.64, 1.34) 0.679 0.64 (0.33, 1.24) 0.189 North vs. West Central 0.58 (0.39, 0.84) 0.005 0.45 (0.23, 0.91) 0.025 East Central vs. West Central 0.52 (0.35, 0.77) 0.001 0.43 (0.21, 0.91) 0.026 East vs. West Central 0.05 (0.03, 0.09) < 0.001 0.11 (0.04, 0.28) < 0.001 HIV Parameters CD4 Cell count per doubling 1.19 (1.13, 1.25) < 0.001 1.37 (1.15, 1.63) < 0.001 CD4 Cell count nadir per doubling 0.96 (0.91, 1.01) 0.119 0.79 (0.67, 0.92) 0.003 HIV viral load per log10 higher 0.46 (0.42, 0.51) < 0.001 0.72 (0.61, 0.84) < 0.001 HIV Transmission Route < 0.001 PWID vs. MSM 0.52 (0.38, 0.69) < 0.001 0.79 (0.43, 1.46) 0.458 Heterosexuals vs. MSM 0.72 (0.53, 0.99) 0.041 0.46 (0.26, 0.81) 0.007 Other vs. MSM 0.78 (0.47, 1.29) 0.337 0.56 (0.24, 1.29) 0.173 Hepatitis virus coinfection < 0.001 HBsAg positive vs. Negative 0.63 (0.37, 1.08) 0.095 0.84 (0.27, 2.59) 0.766 HBsAg unknown vs. Negative 0.43 (0.32, 0.58) < 0.001 1.49 (0.79, 2.78) 0.214 HCVAb positive vs. Negative 0.58 (0.45, 0.75) < 0.001 HCVAb unknown vs. Negative 0.30 (0.20, 0.45) < 0.001 Hypertension/Diabetes/eGFR Previous hypertension vs. None 1.07 (0.74, 1.53) 0.726 1.19 (0.70, 2.03) 0.519 < 0.001 Unknown hypertension vs. None 0.20 (0.15, 0.27) < 0.001 0.59 (0.31, 1.11) 0.100 Previous diabetes vs. None 2.95 (1.26, 6.88) 0.012 1.04 (0.33, 3.27) 0.942 < 0.001 Unknown diabetes vs. None 0.60 (0.47, 0.77) < 0.001 1.40 (0.88, 2.23) 0.155 eGFR per 5 mL/1.73m2 0.85 (0.81, 0.89) < 0.001 0.94 (0.88, 1.00) 0.046 Prior AIDS diagnoses Previous AIDS 1.22 (0.91, 1.64) 0.183 0.62 (0.34, 1.14) 0.125 Prior non-AIDS diagnoses Cardiovascular disease 3.74 (1.35, 10.38) 0.011 Non-AIDS defining malignancies 2.53 (1.08, 5.90) 0.032 Smoking Status < 0.001 Never smoked vs. Curr smoker 1.26 (0.88, 1.81) 0.216 1.30 (0.78, 2.17) 0.322 Former smoker vs. Curr smoker 1.82 (1.02, 3.27) 0.044 0.87 (0.40, 1.93) 0.739 Unknown smoking status vs. Curr smoker 0.27 (0.20, 0.36) < 0.001 1.24 (0.61, 2.50) 0.551 Time Controllers Time Enrolled in EuroSIDA per year longer 1.18 (1.15, 1.21) < 0.001 1.17 (1.12, 1.23) < 0.001 ART-status ART-naïve vs. ART-experienced 0.10 (0.08, 0.14) < 0.001 0.86 (0.46–1.61) 0.634 Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 7 of 12 Table 2 (continued) BMI Body mass index; MSM Men who have sex with men; PWID Injecting Drug User; HBsAgHepatitis B surface antigen; HCVAb Hepatitis C antibody; eGFR estimated glomerular filtration rate Multivariable model includes all variables selected by backward selection that were retained with a p-value less than 0.3 level Outcome: Two consecutive VL>50 copies/mL 0.50 0.45 Cumulative Probability of Virolgical Failure 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from the date of starting RPV 95% Confidence Limits Month 0 3 6 9 12 15 18 21 24 27 30 33 36 No. 1302 1262 1227 1166 1094 1035 957 882 813 726 654 567 491 at risk Fig. 2 Kaplan Meier estimates of the risk of virological failure > 50 copies/mL in the RPV-recipient group breakdown of the individual treatment emergent NNRTI 73 (14.7%) of RPV-treated participants compared with RAMs is also reported in these supplementary Tables. 45 (30.4%) of EFV-treated participants (p = 0.0001). Unfortunately, none of the participants who experienced Of note, toxicity of central nervous system (CNS) was VF with resistance, had resistance test results available at significantly higher in participants who started EFV vs. baseline. RPV (22% vs. 3%, p < 0.001). Treatment failure (viro- logical, immunological, and/or clinical) was the rea- Adverse events son for discontinuation for 29 (5.8%) and 14 (9.5%) in In total, 498 (36.8%) of 1,355 participants initiating a the RPV and EFV groups, respectively (p = 0.03). In RPV-containing regimen discontinued treatment dur- the RPV-treated group, 167 (33.5%) discontinued due ing follow-up compared to 148 (44.4%) of 333 partici- to physician’s decision compared to 23 of 148 (15.5%) pants initiating a EFV-containing regimen. EFV-treated participants (p = 0.005). The proportion of Table 3 summarizes the reasons for discontinuing discontinuations due to participants’ choice was 7.6% treatment. Discontinuations due to toxicity (combining in the RPV-treated group compared to 12.2% in the all intolerance and toxicities reasons) were reported for EFV-treated group (p = 0.09). For 445/1,111 (40.1%) Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 8 of 12 Table 3 Reasons for discontinuing RPV or EFV RPV1 N (%) EFV2 N (%) Median (IQR) duration of treatment at discontinuation (Months) 18.2 (6.7–34.2) 9.8 (3.4–23.1) Treatment failure (virological, immunological, and/or clinical) 29 (5.8) 14 (9.5) Toxicity 73 (14.7) 45 (30.4) Predominantly from central nervous system (CNS) 13 (2.6) 33 (22.3) Predominantly from kidneys 20 (4.0) 4 (2.7) Liver 6 (1.2) 3 (2.0) Hypersensitivity reaction (skin eruption etc.) 3 (0.6) 2 (1.4) Predominantly from abdomen/GI tract 13 (2.6) 1 (0.7) Abnormal fat redistribution 2 (0.4) 0 (0.0) Cardiovascular disease 2 (0.4) 0 (0.0) Dyslipidaemia 0 (0.0) 1 (0.7) Other side effects–not specified 14 (2.8) 1 (0.7) Other Physician’s decision, not specified 167 (33.5) 23 (15.5) Participant’s wish/decision, not specified 38 (7.6) 18 (12.2) Availability of more effective treatment (not specifically failure or side effect related) 15 (3.0) 5 (3.4) Structured Treatment Interruption (STI) 3 (0.6) 0 (0.0) Enrolled in RCTs 2 (0.4) 0 (0.0) Other causes, not specified 91 (18.3) 23 (15.5) Unknown 80 (16.1) 20 (13.5) Reasons listed are those for stopping either RPV or EFV 1 Denominator is the number of participants who have discontinued RPV (n = 498) 2 Denominator is the number of participants who have discontinued EFV (n = 148) Reasons for discontinuation can be found at https://​hicdep.​org/​Wiki/v/​9/​pt/4/​Table/​36/​Field​ID/​439 RPV-treated participants and 89/183 (48.6%) EFV- There were some key differences in the case-mix of treated participants, ALT was reported to be above the participants who started RPV-based regimens vs. EFV- normal range; and for 401/997 (40.2%) RPV-treated based regimens in the study. First, there were signifi- participants and 71/156 (45.5%) EFV-treated partici- cant regional differences with participants treated with pants, AST was reported to be above the normal range RPV less likely to reside in East Europe compared with (Table 4). There was no statistical evidence for a differ- West Central Europe. Participants starting RPV-based ence in AST between treatment groups (p>0.21). regimens also typically had lower HIV-1 RNA levels and higher CD4 counts. Interestingly, there was no evidence Discussion for a difference in the prevalence of ART-naïve partici- We have assessed clinical characteristics, virologi- pants by treatment group after controlling for other key cal outcomes, emergence of RAMs and adverse events predictors. during follow up, for individuals who initiated a RPV- Protocol targets for the number of VF required to or EFV-containing regimen. Over the period Novem- perform a formal comparison could not be achieved ber 2011-December 2017, the majority (99%) of because the number of participants who started EFV individuals initiating a RPV-containing regimen, did so and recruited in the study decreased over time, most with a HIV-RNA ≤ 100,000 copies/ml, in accordance with likely because the European treatment guidelines start- the approved EU labelled indication. Overall, although ing from 2015 ceased to recommend its use. However, a formal comparison with EFV was not perfomed as by some conclusions might be drawn by comparing the the pre-specified protocol, we found that rate of VF and VF estimates in the RPV group with those of historical development of RAMs by 2 years was low in the RPV data [2–9, 14, 15]. In the majority of the previously con- group (23%) and rates were comparable to those expe- ducted randomized comparisons, EFV was the control rienced by PLWH who started EFV (33%). Of note, the group and, in these settings, no difference in rate of VF frequency of discontinuation due to toxicity was lower in was found between RPV and EFV overall or in subsets RPV vs. EFV (15% versus 30%). of individuals (e.g. people with HBV co-infection). Even Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 9 of 12 Table 4 Frequency of laboratory abnormalities during the note, most of these clinical trials were conducted in course of RPV or EFV treatment ART-naïve participants, while our analysis uses the Parameter Adverse event RPV N (%) EFV N (%) p-value* data of participants who started RPV when they were ART-experienced, comprising a selected population at Haemoglobina (N with data: RPV = 691; EFV = 108) reduced risk of VF. A summary of the rates of RPV VFs Below normal range 149 (21.6%) 41 (38.0%) 0.001 by 1 year in EuroSIDA as well as in the mentioned ran- Normal range 488 (70.6%) 63 (58.3%) domized clinical trials [2–9] is shown in a Additional Above normal range 54 (7.8%) 4 (3.7%) file 1: Table AF5 which also includes other estimates ALTb (N with data: RPV = 1111; EFV = 183) from real-world studies in Europe [10–12]. Normal range 666 94 Resistance test results were available for a small subset Above normal range 445 (40.1%) 89 (48.6%) 0.03 (21%) of RPV participants who experienced VF. Detec- Above 3 times the normal range 85 (11.3%) 18 (16.1%) 0.15 tion of genotypic resistance in this subset was infrequent ASTc (N with data: RPV = 997; EFV = 156) and the profile of individual treatment-emergent NRTI Normal range 596 85 and NNRTI RAMs among participants on RPV-based Above normal range 401 (40.2%) 71 (45.5%) 0.21 regimens was that expected in those failing these combi- Above 3 times the normal range 69 (10.4%) 13 (13.3%) 0.39 nations. Participants in whom resistance mutations were ALPd (N with data: RPV = 718; EFV = 127) detected at time of failure did not have a baseline resist- Normal range 603 79 ance test available. However, the prevalence of baseline Above normal range 115 (16.0%) 48 (37.8%) < 0.0001 NNRTI-associated resistance estimated from those with Above 3 times the normal range 2 (0.3%) 4 (4.8%) 0.003 available data was lower than 20%; thus, we can specu- Bilirubine (N with data: RPV = 1014; EFV = 156) late that for the majority of participants, the mutations Normal range 913 150 detected at VF have been newly acquired rather than pre- Above normal range 101 (10.0%) 6 (3.9%) 0.01 exist, which is consistent with the results of previously Above 2 times the normal range 29 (3.1%) 3 (2.0%) 0.61 published reports [2–9]. Nevertheless, in Study GS-US- Plateletsf (N with data: RPV = 880; EFV = 127) 264-0110 (STaR), 6% of participants starting RPV in FDC Normal range 731 112 developed HIV-drug resistance by 96 weeks of follow-up, Below normal range 149 (17.0%) 15 (11.8%) 0.16 which was mainly seen within the first 48 weeks [5–7]; of Below 100 ­109/L 58 (7.4%) 3 (2.6%) 0.07 note, this rate was significantly higher than that seen for a Haemoglobin normal range: (Men: 14.0 < g/dl < 18.0; Women: 12.0 < g/dl < 16.0) EFV (2.3%), but our data did not confirm this finding. b ALT normal range: (Men: U/L < 50; Women: U/L < 40) Overall 37% of participants initiating RPV discontin- c AST normal range: (Men: U/L < 40; Women: U/L < 34) ued the drug compared to 44% in those initiating EFV. d ALP normal range: (Men: U/L < 128; Women: U/L < 98) RPV led to less discontinuation due to toxicity (14.7% e Bilirubin normal range: (mg/dL < 1.4; μmol/L < 25.0) vs. 30.4%), especially for CNS toxicity, which is a recog- f Platelets normal range: (140 < ­109/L < 400) nized side effect for EFV [18]. There was a higher prob- & Considering all values after baseline and while the person was still receiving ability of stopping RPV due to physician’s choice (33.5% the drug * vs. 15.5%), possibly indicating modifications due to pro- Chi-square p-value or Fisher exact test when < 5 events in the EFV group * active switches, risk of drug to drug interactions, prob- When two p-values are shown, they refer to separate 2 × 2 tables with the ‘Normal range’ category used as common comparator lems associated with food intake, planning of pregnancy or possibly reported poor adherence. Although misclas- sification of the reason for stopping is always possible, when considering the upper limit of confidence interval treatment toxicity and VF are specifically listed as one of 6% VF by 2 years for RPV recipients, this estimated of the reasons in EuroSIDA RedCap, so it is unlikely rate is lower than that observed in participants enrolled that those were recorded as ‘physician’s choice’. Moreo- in randomized studies [2–9]. The slight discrepancy in ver, only adverse events leading to drug discontinua- the rate of RPV VF in our cohort vs. that observed in tions are recorded in EuroSIDA and a number of low the ECHO/THRIVE trials (5.4% failure by 1 year) might grade adverse events are not routinely recorded. Of note, be due to the fact that the trial participants used sin- because EFV has a more recognized toxicity profile, it gle compound combination therapy while in our anal- is possible that for a given symptom severity EFV had a Eviplera™. Indeed, Study GS-US-264-0106 (SPIRIT), ysis a large proportion of participants used the FDC greater risk of being discontinued than RPV. However, it could be equally argued that because RPV was a newer conducted in participants with VL ≤ 50 copies/mL drug, monitoring of toxicity might have been stricter for who were switched to RPV- based FDC, showed a participants receiving RPV. The frequency of discontnua- more comparable rate of VF of 11% by 1 year [9]. Of tions due to VF were higher in the RPV group but this Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 10 of 12 was not analysed by means of the more reliable analysis mutations was low in the few participants who experi- looking at the actual viral load values. Drug formula- enced VF in both treatment groups. Importantly, this tion are known to also have an effect on adherence and data also confirm the safety profile of RPV, with less fre- hence effectiveness/outcomes. Nevertheless, cases in quent discontinuation due to toxicity than EFV (espe- which drugs were used as FDC vs. combinations of sin- cially for CNS toxicity) and no evidence for a difference gle compounds have been treated equally in this analy- in liver toxicity, consistent with what was observed in sis. In addition, no difference in laboratory abnormalities randomized trials. The potential low cost and dose of between RPV and EFV when comparing the proportion the drug means that rilpivirine can potentially be manu- of participants with a value below/above normal values factured at a low price. Moreover, its long half-life sug- for ALT and AST were found. These data confirm the gests the potential for monthly dosing via nonoral routes, safety profile of RPV observed in the trials [2–9]. with promising early results from studies of a long-acting This study has several limitations. First, since allocation injectable formulation. These characteristics still cur- of treatment in observational studies is not randomised, rently make rilpivirine an attractive drug for resource- treatment decisions may be influenced by prognostic fac- limited settings. tors and the resulting imbalance in the underlying risk profile between groups can generate biased results. Some Supplementary Information of these unmeasured confounders may include adherence The online version contains supplementary material available at https://​doi.​ to treatment, minor symptoms and socio-demographic org/​10.​1186/​s12981-​022-​00457-0. factors. Importantly, most comparisons were conducted Additional file 1. Key defintions and additional results mentioned in the in unadjusted analysis or, like for the virological end- text which are not included in the main Tables and Figures. point, using historical data so measured confounding cannot be excluded either. The slow recruitment of new Acknowledgements participants starting EFV could not be predicted and ulti- EUROSIDA STUDY GROUP The multi-centre study group, EuroSIDA (national mately limited the ability to perform a formal compari- coordinators in parenthesis). Albania: (A Harxhi), University Hospital Center of Tirana, Tirana. Argentina: (M Losso), M Kundro, Hospital JM Ramos Mejia, son between the two groups. Moreover, resistance data Buenos Aires. Austria: (B Schmied), Klinik Penzing, Vienna; R Zangerle, Medical collection stopped in EuroSIDA in March 2017 so cumu- University Innsbruck, Innsbruck. Belarus: (I Karpov), A Vassilenko, Belarusian lative estimates of resistance detection are likely to be State Medical University, Minsk; VM Mitsura, Gomel State Medical University, Gomel; D Paduto, Regional AIDS Centre, Svetlogorsk. Belgium: (N Clumeck), underestimated. Finally, the analysis includes EuroSIDA S De Wit, M Delforge, Saint-Pierre Hospital, Brussels; E Florence, Institute of data collected up to 2018 and this is the reason why more Tropical Medicine, Antwerp; L Vandekerckhove, University Ziekenhuis Gent, contemporary RPV regimens such as those based on TAF Gent. Bosnia-Herzegovina: (V Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo. Croatia: (J Begovac), University Hospital of Infectious Dis‑ have not been included. eases, Zagreb. Czech Republic: (L Machala), D Jilich, Faculty Hospital Bulovka, Key strengths of the study are the real-world setting, Prague; D Sedlacek, Charles University Hospital, Plzen. Denmark: G Kronborg, its large sample size (larger than any other cohort study T Benfield, Hvidovre Hospital, Copenhagen; J Gerstoft, O Kirk, Rigshospitalet, Copenhagen; C Pedersen, IS Johansen, Odense University Hospital, Odense; published to date for the ART-experienced popula- L Ostergaard, Skejby Hospital, Aarhus, L Wiese, Sjællands Universitetshospital, tion treated with RPV-based regimens) and the average Roskilde; L N Nielsen, Hillerod Hospital, Hillerod. Estonia: (K Zilmer), West- two years of virological follow-up. Another strength is Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla- Järve. Finland: (I Aho), Helsinki University Hospital, Helsinki. France: (J-P Viard), the prospective nature of the EuroSIDA cohort so that Hôtel-Dieu, Paris; K Lacombe, Hospital Saint-Antoine, Paris; C Pradier, E Fontas, reverse causality is unlikely to have occurred for the main Hôpital de l’Archet, Nice; C Duvivier, Hôpital Necker-Enfants Malades, Paris. endpoint of VF/development of resistance as this tem- Germany: (J Rockstroh), Universitäts Klinik Bonn; O Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; C Hoffmann, porarily occured after the initiation of RPV or EFV. Of HJ Stellbrink, IPM Study Center, Hamburg; C Stefan, JW Goethe University note, the results and conclusions from this analysis are Hospital, Frankfurt; J Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, not directly generalizable outside of the subset of Euro- Universität Köln, Cologne. Georgia: (N Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Greece: (H Sambatakou), SIDA participants satisfying the inclusion criteria for Ippokration General Hospital, Athens; G Adamis, N Paissios, Athens General this analysis. Hospital "G Gennimatas", Athens. Hungary: (J Szlávik), South-Pest Hospital Cen‑ In conclusion, RPV was used in accordance with the tre – National Institute for Infectology and Haematology, Budapest. Iceland: (M Gottfredsson), Landspitali University Hospital, Reykjavik. Ireland: (E Devitt), approved indication for RPV-containing regimen in St. James’s Hospital, Dublin. Israel: (L Tau), D Turner, M Burke, Ichilov Hospital, Europe. Even in the worst-case scenario (upper limit of Tel Aviv; E Shahar, LM Wattad, Rambam Health Care Campus, Haifa; H Elinav, M confidence interval) our real-world estimate of the rate of Haouzi, Hadassah University Hospital, Jerusalem; D Elbirt, AIDS Center (Neve Or), Rehovot. Italy: (A D’Arminio Monforte), Istituto Di Clinica Malattie Infettive VF > 50 copies/mL in participants treated with RPV were e Tropicale, Milan; G Guaraldi, R Esposito, I Mazeu, C Mussini, Università Mod‑ similar to those reported by other European cohorts and ena, Modena; F Mazzotta, A Gabbuti, Ospedale S Maria Annunziata, Firenze; even lower than the rates observed in randomized clini- A Lazzarin, A Castagna, N Gianotti, Ospedale San Raffaele, Milan; M Galli, A Ridolfo, Osp. L. Sacco, Milan. Lithuania: (V Uzdaviniene) Vilnius University cal studies. Based on available data, the proportion of Hospital Santaros Klinikos, Vilnius; R Matulionyte, Vilnius University, Faculty of participants who acquired NNRTI resistance-associated Medicine, Department of Infectious Diseases and Dermatovenerology, Vilnius. Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 11 of 12 Luxembourg: (T Staub), R Hemmer, Centre Hospitalier, Luxembourg. Nether‑ EuroCoord grant agreement n˚ 260694. The participation of centres from Swit‑ lands: (Marc vd Valk), Academisch Medisch Centrum bij de Universiteit van zerland has been supported by The Swiss National Science Foundation (Grant Amsterdam, Amsterdam. North Macedonia (J Trajanovska), University Clinic 148522).The study is also supported by a grant [grant number DNRF126] from for Infectious Diseases & Febrile Conditions, Mother Teresa 17, Skopje. Norway: the Danish National Research Foundation and by the International Cohort (DH Reikvam), A Maeland, J Bruun, Oslo University Hospital, Ullevaal. Poland: (B Consortium of Infectious Disease (RESPOND). Knysz), B Szetela , M Inglot, Medical University, Wroclaw; E Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; R Flisiak, A Grzeszczuk, Medical University, Availability of data and materials Bialystok; M Parczewski, K Maciejewska, B Aksak-Was, Medical Univesity, Szc‑ Access to the EuroSIDA Data: The EuroSIDA Steering Committee encour‑ zecin; M Beniowski, E Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; ages the submission of concepts for research proposals. Concepts can be E Jablonowska, J Kamerys, K Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; submitted for review using an online research concept, please see our website I Mozer-Lisewska, B Rozplochowski,Poznan University of Medical Sciences, (https://​www.​chip.​dk). The concept is evaluated by the Steering Committee Poznan. Portugal: (A Zagalo), Hospital Santa Maria, Lisbon; K Mansinho, Hospi‑ for scientific relevance, relevance to the EuroSIDA study, design, feasibility and tal de Egas Moniz, Lisbon; F Maltez, Hospital Curry Cabral, Lisbon. Romania: (R overlap with already approved projects. All proposers will receive feedback Radoi), C Oprea, Carol Davila University of Medicine and Pharmacy Bucharest, and revision of the concept may be requested. If approved, a writing group Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest. will be established consisting of proposers, members of the Steering Commit‑ Russia: D Gusev, Medical Academy Botkin Hospital, St Petersburg; T Trofimova, tee and staff at the coordinating center and the statistical center. Novgorod Centre for AIDS, Novgorod, I Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E Kuzovatova, Academician I.N.Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiol‑ Declarations ogy, Nizhny Novgorod; E Borodulina, E Vdoushkina, Samara State Medical University, Samara. Serbia: (J Ranin), The Institute for Infectious and Tropical Ethics approval and consent to participate Diseases, Belgrade. Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Patient Informed Consent was obtained according to local and/or national Ljubljana. Spain: (JM Miro), JM Miró, M. Laguno, E. Martinez, F. Garcia, JL Blanco, Ethics Committees requirements, this was obtained from each participant M. Martinez-Rebollar, J. Mallolas, P Callau, J Rojas, A Inciarta, Hospital Clinic – before any study related procedure was performed and in accordance with IDIBAPS University of Barcelona, Barcelona; S Moreno, S. del Campo, Hospital the International Conference on Harmonisation of Technical Requirements for Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, J Puig, JM Llibre, JR Santos, Registration of Pharmaceuticals for Human Use (ICH)–Good Clinical Practice Infectious Diseases Unit & IrsiCaixa AIDS Research Institute, Hospital Germans Guidelines. Further information is available at https://​www.​chip.​dk/​Porta​ Trias I Pujol, Badalona; P Domingo, M Gutierrez, G Mateo, MA Sambeat, Hos‑ ls/0/​files/​Euros​ida/​EuroS​IDA/​EuroS​IDA_​Proto​col_​v4_​2019J​ULI05.​pdf?​ver=​ pital Sant Pau, Barcelona; JM Laporte, Hospital Universitario de Alava, Vitoria- 2019-​10-​02-​145631-​730. Gasteiz. Sweden: (P Novak), A Thalme, A Sönnerborg, Karolinska University Hospital, Stockholm; J Brännström, Venhälsan-Sodersjukhuset, Stockholm; L Consent for publication Flamholc, Malmö University Hospital, Malmö. Switzerland: (K Kusejko), D Braun, All authors have give consent to publication. University Hospital Zurich; M Cavassini, University Hospital Lausanne; A Calmy, University Hospital Geneva; H Furrer, University Hospital Bern; M Battegay, Competing interests University Hospital Basel; P Schmid, Cantonal Hospital St. Gallen. Ukraine: A This analysis was funded by Janssen Research and Development, who did Kuznetsova, Kharkov State Medical University, Kharkov; J Mikhalik, Crimean not influence the analyses presented or the decision to publish study find‑ Republican AIDS centre, Simferopol; M Sluzhynska, Lviv Regional HIV/AIDS ings. Amanda Mocroft received honoraria, travel support, lecture fees and Prevention and Control CTR, Lviv. United Kingdom: A Milinkovic, St. Stephen’s consultancy for ViiV, Gilead, Eiland and Bonnin, all outside the submitted work. Clinic, Chelsea and Westminster Hospital, London; AM Johnson, S Edwards, Mortimer Market Centre, London; A Phillips, MA Johnson, A Mocroft, Royal Author details 1 Free and University College Medical School, London (Royal Free Campus); C Centre for Clinical Research, Epidemiology, Modelling and Evaluation Orkin, Royal London Hospital, London; A Winston, Imperial College School (CREME), Institute for Global Health, University College London, Rowland Hill of Medicine at St. Mary’s, London; A Clarke, Royal Sussex County Hospital, St, London NW3 2PF, UK. 2 CHIP, Rigshospitalet, University of Copenhagen, Brighton; C Leen, Western General Hospital, Edinburgh. The following centers Copenhagen, Denmark. 3 Department of Infectious Diseases, CHU Saint-Pierre, have previously contributed data to EuroSIDA: Medical University, Gdansk, Université Libre de Bruxelles, Brussels, Belgium. 4 Department of Infectious Poland Infectious Diseases Hospital, Sofia, Bulgaria Hôpital de la Croix Rousse, Diseases, Odense University Hospital, Odense, Denmark. 5 Mortimer Market Lyon, France Hôpital de la Pitié-Salpétière, Paris, France Unité INSERM, Bor‑ Centre, Department of HIV, London, UK. 6 Infectious Diseases Unit, Goethe- deaux, France Hôpital Edouard Herriot, Lyon, France Bernhard Nocht Institut University Hospital, Frankfurt, Germany. 7 1St Department of Internal Medicine für Tropenmedizin, Hamburg, Germany 1st I.K.A Hospital of Athens, Athens, and Infectious Diseases Unit, General Hospital of Athens G. Gennimatas, Ath‑ Greece Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy Ospedale ens, Greece. 8 Centre Hospitalier de Luxembourg, Service des Maladies Infec‑ di Bolzano, Divisione Malattie Infettive, Bolzano, Italy Ospedale Cotugno,III tieuses, Luxembourg City, Luxembourg. 9 Department of Infectious Diseases, Divisione Malattie Infettive, Napoli, Italy Dérer Hospital, Bratislava, Slovakia Santa Maria University Hospital, Lisbon, Portugal. 10 Hospital de La Santa Creu I Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain Sant Pau, Barcelona, Spain. 11 Allergy, Immunology and HIV Unit | Kaplan, Medi‑ Kiev Centre for AIDS, Kiev, Ukraine Luhansk State Medical University, Luhansk, cal Center, Rehovot, Israel. 12 Division of Infectious Diseases, University Hospital Ukraine Odessa Region AIDS Center, Odessa, Ukraine St Petersburg AIDS Cen‑ Zürich, Zurich, Switzerland. 13 Department of Infectious Diseases, Venhälsan tre, St Petersburg, Russia Infectology Centre of Latvia, Riga, Latvia University Södersjukhuset, Stockholm, Sweden. 14 Gomel Regional Centre for Hygiene, di Roma la Sapienza, Rome, Italy Istituto Nazionale Malattie Infettive Lazzaro Gomel, Belarus. 15 Novgorod Centre for AIDS Prevention and Control, Spallanzani, Rome, Italy. Novgorod the Great, Russia. 16 South-Pest Hospital Centre–National Institute for Infectiology and Haematology, Budapest, Hungary. 17 West-Tallinn Central Author contributions Hospital, Infectious Diseases Clinic, Talinn, Estonia. 18 Hospital J.M. Ramos Mejia, AC-L performed the statistical analysis and wrote the main manuscript and Buenos Aires, Argentina. 19 Janssen Research & Development, Beerse, Belgium. 20 text. LP, AP-M, BN, SDW, JB, VVE, HPJL and AM critically commented and Janssen Research & Development, Raritan, NJ, USA. reviewed the text. ISJ, SE, CS, GA, TS, AZ, PD, DE, KK, JB, DP, TT, JS, KZ and ML have contributed data and reviewed the manuscript. All authors read and Received: 10 January 2022 Accepted: 16 June 2022 approved the final manuscript. Funding EuroSIDA has received funding from ViiV Healthcare LLC, Janssen Scientific Affairs, Janssen R&D, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp, Gilead Sciences and the European Union’s Seventh Framework Pro‑ gramme for research, technological development and demonstration under Cozzi‑Lepri et al. AIDS Research and Therapy (2022) 19:38 Page 12 of 12 References Causes of Death in HIV (CoDe) Project: initial results and evaluation of 1. EACS European Guidelines for treatment of HIV-positive adults in Europe. methodology. Epidemiology. 2011 Jul;22(4):516–23. https://​doi.​org/​10.​ http://​www.​eacso​ciety.​org/​guide​lines/​eacs-​guide​lines/​eacs-​guide​lines.​ 1097/​EDE.​0b013​e3182​1b5332. PMID: 21522013. html 16. Research Electronic Data Capture. https://​chip-​crf.​info/​redcap/​HIV. 2. Pozniak AL, Morales-Ramirez J, Katabira E, Steyn D, Lupo SH, Santoscoy M, Cohorts Data Exchange Protocol. http://​hicdep.​org/. 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Laut K, Kirk O, Rockstroh J, Phillips A, Ledergerber B, Gatell J, Gazzard B, Horban A, Karpov I, Losso M, d’Arminio Monforte A, Pedersen C, Ristola M, Ready to submit your research ? Choose BMC and benefit from: Reiss P, Scherrer AU, de Wit S, Aho I, Rasmussen LD, Svedhem V, Wandeler G, Pradier C, Chkhartishvili N, Matulionyte R, Oprea C, Kowalska JD, • fast, convenient online submission Begovac J, Miró JM, Guaraldi G, Paredes R, Raben D, Podlekareva D, Peters L, Lundgren JD, Mocroft A. The EuroSIDA study: 25 years of scientific • thorough peer review by experienced researchers in your field achievements. HIV Med. 2020;21(2):71–83. • rapid publication on acceptance 14. Friis-Møller N, Weber R, Reiss P, Thiébaut R, Kirk O, d’Arminio Monforte • support for research data, including large and complex data types A, Pradier C, Morfeldt L, Mateu S, Law M, El-Sadr W, De Wit S, Sabin CA, Phillips AN, Lundgren JD; DAD study group. Cardiovascular disease risk • gold Open Access which fosters wider collaboration and increased citations factors in HIV patients--association with antiretroviral therapy. Results • maximum visibility for your research: over 100M website views per year from the DAD study. AIDS. 2003 May 23;17(8):1179–93. https://​doi.​org/​10.​ 1097/​01.​aids.​00000​60358.​78202.​c1. PMID: 12819520. At BMC, research is always in progress. 15. Kowalska JD, Friis-Møller N, Kirk O, Bannister W, Mocroft A, Sabin C, Reiss P, Gill J, Lewden C, Phillips A, D’Arminio Monforte A, Law M, Sterne J, De Wit Learn more biomedcentral.com/submissions S, Lundgren JD; CoDe Working Group; D:A:D Study Group. The Coding