Durability of first-line antiretroviral regimens in the era of integrase inhibitors: a cohort of HIV-positive individuals in Spain, 2014–2015

Inmaculada Jarrin, Ines Suarez-Garcia, Cristina Moreno, Maria Tasias, Jorge Del Romero, Rosario Palacios, Joaquim Peraire, Miguel Gorgolas, Santiago Moreno,

Background: We compared time to treatment change (TC), viral suppression (VS) and change in CD4+ T-cell counts of first-line antiretroviral regimens (ART).

Methods: We analyzed HIV treatment-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) initiating the most commonly used ART regimens from September 2014 to November 2015. We used proportional hazards models on the sub-distribution hazard to estimate sub- distribution hazard ratios (sHR) for time to TC, logistic regression to estimate odds ratios (ORs) for VS (viral load<50 copies/ml), and linear regression to assess mean differences in CD4 changes from ART initiation. Results: Among 960 individuals, tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) was the most frequently prescribed regimen (24.2%), followed by elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC (22.8%), abacavir (ABC)/lamivudine (3TC)/dolutegavir (DTG) (17.4%), TDF/FTC+darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c) (12.1%), TDF/FTC/efavirenz (EFV) (8.8%), TDF/FTC+raltegravir (RAL) (7.7%) and TDF/FTC+DTG (7.0%). Initiating ART with TDF/FTC+DRV/r or DRV/c (adjusted sHR: 2.96; 95% CI: 1.44 – 6.08), TDF/FTC/EFV (2.18; 0.98 – 4.82), TDF/FTC+RAL (2.37; 1.08 – 5.22) and TDF/FTC+DTG (6.34; 3.18 – 12.64) was associated with a higher risk of TC compared to ABC/3TC/DTG. At 24 weeks, VS was lower in TDF/FTC+DRV/r or DRV/c (adjusted OR: 0.37, 95% CI: 0.18; 0.74) compared to ABC/3TC/DTG, and CD4increase was lower in patients initiating with TDF/FTC/RPV (adjusted mean difference: -75.9, 95% CI: -130.6; -21.2) compared to those who did with ABC/3TC/DTG. Conclusions: Time to TC, VS and change in CD4+ T-cell counts varies by initial regimen. These differences may be useful for making decision when initiating ART. Accepted 23 January 2019, published online 12 February 2019 Running head: Durability of initial antiretroviral regimens in integrase inhibitors’ era Introduction Medication persistence is defined as “the duration of time from initiation to discontinuation of therapy”. In the literature, the terms persistence and durability are often used to describe the continuation of the initial regimen [1]. Persistence of antiretroviral therapy (ART) is linked to clinical outcomes, as decreased persistence on ART has been associated with lower probability of achieving virological suppression [2]. Among HIV-infected patients, decreased treatment persistence is associated with patient-dependent factors (such as high viral load, low CD4 cell count, female gender, younger age, mental diseases, etc) and medication-dependent factors. Regarding medication-dependent factors, in an extensive review [2], Bae et al identified adverse effects and treatment failure as the two most frequent reasons for treatment discontinuation in Western countries; other factors associated with the antiretroviral regimen, such as more frequent dosing and higher pill burden have also been linked to decreased persistence [2]. Several research works have investigated the influence of individual antiretroviral medications, or antiretroviral classes, on treatment persistence or durability. Many of these studies, however, lack information on the reasons for treatment discontinuation [1,3,4]. Moreover, most of them were done before the widespread use of newer treatments such as rilpivirine or integrase inhibitors. Studies evaluating the durability of treatments based in integrase inhibitors are very scarce, and the evidence is particularly lacking on newer integrase inhibitors such as elvitegravir and dolutegravir [1,3,5–9]. The efficacy of different antiretroviral treatments has been well studied in clinical trials. However, these trials include selected patients with characteristics that are different from those of the population who will receive those treatments (such as lower number of patients with severe immunosuppression, elderly patients, or those with co-morbidities), limiting the generalizability of their findings. Therefore, it is necessary to contrast the findings from clinical trials with “real life” data, such as those obtained from cohort studies [10,11]. Clinical guidelines provide recommendations for ART in naïve patients. However, along with the information from clinical trials, clinicians might find other information from “real world” situations useful in order to make the decision on which treatment to prescribe. The questions asked when prescribing an initial ART can include, among other things, how long can the initial treatment be maintained without having to change it due to lack of effectiveness, adverse side effects, or for the need of more convenient regimens. In this study, we aimed to assess the time to treatment change (TC) and reasons for and patterns of TC, viral suppression and change in CD4+ T-cell counts of the most frequently prescribed regimens in recent years (2014 and 2015) in HIV-positive patients in the Cohort of the Spanish AIDS Research Network (CoRIS). Methods Study design CoRIS is an open, multicenter and prospective cohort of HIV-positive adults, naive to ART at study entry, seen for the first time from January 2004 in any of the 42 centers from 13 of 17 Regions in Spain, and followed-up until 30 November 2015, the administrative censoring date for these analyses. Subjects agree to participate in the study by signing an informed consent form. Ethical approval for CoRIS was granted. Briefly, CoRIS collects a minimum dataset as provided for in the cohort protocol which includes baseline and follow-up socio-demographic, immunological and clinical data including ART medication, with start and stop dates, as well as reasons for drug discontinuation practice. Study population Patients considered for inclusion were antiretroviral-naïve patients, aged  18 years, who started ART between 1st September 2014 (when DTG became available in Spain) and 30th November 2015 with the most commonly used first-line antiretroviral regimens. In order to facilitate the analyses, only regimens accounting for >5% of individuals were considered. Patients with no follow-up after initiation of ART were excluded.


The primary outcome was time from ART initiation to treatment change during the first 48 weeks after ART initiation, and the reason for treatment change. Discontinuation of treatment was not classified as treatment change if patients resumed the initial regimen. Reasons for treatment change were classified as simplification, adverse side effect, treatment failure, drug interaction, patient’s decision, pregnancy, enrolment in a clinical trial, other and unknown. In turn, adverse side effects were classified as neuropsychiatric (headache, dizziness, fatigue, insomnia, sleep disturbance, anxiety/depression, emotional instability), renal, gastrointestinal (nauseas/vomiting, diarrhea, abdominal pain), skin, liver, other, and unknown. The secondary outcomes were viral suppression, defined as achieving a viral load  50 copies/ml at week 24 (±12) after ART initiation, and the change in CD4+ T-cell counts at week 24 (±12) after treatment initiation. Both responses were analyzed by initial regimen, independently of later treatment changes and reasons for those.

Statistical analysis

Descriptive analysis of patients’ characteristics was carried out using frequency tables for categorical 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. For the analyses on time to treatment change during the first 48 weeks after ART initiation, an individual’s follow-up started at ART initiation and ended at date of treatment change, death, last study contact or after 48 weeks, whichever arose first.
We used the multiple decrement method to calculate the cumulative incidence of treatment change and proportional hazards models on the sub-distribution hazard to estimate sub-distribution Hazard Ratios (sHR) for treatment change, treating deaths before any treatment change as competing events. Assessment of the proportional sub-hazards assumption was tested for by adding a time-by-treatment interaction term to the models. Logistic regression models were used to estimate Odds Ratios (ORs) of association between initial regimen and viral suppression at week 24 (±12). Linear regression models were used to assess differences by initial regimen in mean changes in CD4+ T-cell counts at week 24 (±12).

All models were adjusted for the following potential confounders: sex (male, female), age at ART initiation (<30, 30-49, 50 years), transmission category (homo/bisexual, heterosexual, other/unknown), educational level (no education or compulsory education, upper secondary or university education, other/unknown), country of origin (Spain, foreign born, unknown), CD4 T-cell count (<200, 200-499, 500 cells/microl, unknown) and viral load (<100000, 100000 copies/ml, unknown) within 6 months previous to ART initiation, presence of hepatitis C virus antibodies (no, yes, unknown), presence of hepatitis B virus surface antigen (no, yes, unknown) and AIDS diagnosis at initiation of ART (no, yes). To adjust for clustering of patients within centers, robust methods were used to estimate standard errors and, thus, to calculate 95% confidence intervals and p-values. Wald tests were used to derive p-values. All statistical analyses were performed using Stata software (version 14.0; Stata Corporation, College Station, Texas, USA) Of 12,239 patients included in CoRIS by 30 November 2015, 11,279 were excluded from analyses as follows: 2,754 who never initiated ART, 13 aged < 18 years at ART initiation, 8,192 who did not start .ART between 1 September 2014 and 30 November 2015, 149 with no follow-up after ART initiation and 171 who initiated a treatment prescribed in < 5% of patients. Finally, 960 patients were included in the analyses, of which 870 (90.6%) were men, 661 (72.3%) had been infected through homo/bisexual contact and 684 (72.2%) were Spanish. At ART initiation, median age was 37 years (IR: 30 – 45), median CD4+ T-cell count was 412 cells/microl (247 – 590), 91 (9.5%) patients had an AIDS diagnosis and 308 (33.8%) had a viral load>100000 copies/ml.
Median follow-up time was 168 days (IR: 91-272).

The most frequently prescribed initial regimen was tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) (n = 232, 24.2%), followed by elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC (n = 219, 22.8%), abacavir (ABC)/lamivudine (3TC)/dolutegavir (DTG) (n = 167, 17.4%), TDF/FTC+darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c) (n = 116, 12.1%), TDF/FTC/efavirenz (EFV) (n = 85, 8.8%), TDF/FTC+raltegravir (RAL) (n = 74, 7.7%) and TDF/FTC+DTG (n = 67, 7.0%). There were differences in the sociodemographic and clinical characteristics of patients according to their initial ART regimen (Figure 1). A higher proportion of men infected through homo/bisexual contact had initiated treatment with ABC/3TC/DTG, EVG/COBI/TDF/FTC and TDF/FTC+DTG. The proportion of migrants was considerably higher among those initiating with TDF/FTC/EFV. The highest proportions of patients with less than 200 CD4 cells/microl at ART initiation were found among those starting with TDF/FTC+DTG and TDF/FTC+RAL, and the higher proportions of patients with viral load 100000 copies/ml were found among those starting with TDF/FTC+DTG, TDF/FTC+RAL, TDF/FTC/EFV, and TDF/FTC+DRV/r or DRV/c.

At 24 weeks from ART initiation, 15.3% of individuals had changed their initial regimen; this proportion ranged from between 8% and 9% in patients initiating with ABC/3TC/DTG, TDF/FTC/RPV and EVG/COBI/TDF/FTC to 46.9%, 25.6% and 23.3% for those who initiated with TDF/FTC+DTG, TDF/FTC+DRV/r or DRV/c and TDF/FTC+RAL, respectively (Figure 2). In multivariable analyses, initiating ART with TDF/FTC+DRV/r or DRV/c (adjusted sHR: 2.96; 95% CI: 1.44 – 6.08), TDF/FTC/EFV (adjusted sHR: 2.18; 0.98 – 4.82), TDF/FTC+RAL (adjusted sHR: 2.37; 1.08 – 5.22)
and TDF/FTC+DTG (adjusted sHR: 6.34; 3.18 – 12.64) was associated with a higher risk of treatment change during the first 48 weeks after ART initiation compared to ABC/3TC/DTG. However, no significant differences in the risk of treatment change were found between initiating with ABC/3TC/DTG and initiating with TDF/FTC/RPV (adjusted sHR: 1.09; 0.50 – 2.37) or EVG/COBI/TDF/FTC (adjusted sHR: 1.22; 0.59 – 2.48) (Table 1). Median time to treatment change ranged from 53 days (IR: 28 – 113) among patients initiating TDF/FTC+DTG to 123 days (IR: 48 – 168) for those initiating TDF/FTC+DRV/r o DRV/c however, we think this has not been a strong limitation given the low number of treatment changes due to virological failure. cohort in Spain, and we have found that durability of antiretroviral treatment varied with the regimen chosen. Overall, simplification was the main reason for treatment modification, followed by adverse side effects; the latter was the main reason for treatment modification for certain regimens, mainly TDF/FTC/EFV. Although viral suppression and the change in CD4+ T-cell counts differed between different treatment regimens, lack of durability due to treatment failure was very infrequent for all the regimens studied. Our study shows that when prescribing initial ART, we can be more confident on the durability of our regimen if we choose a simpler treatment, specially ABC/3TC/DTG, EVG/COBI/TDF/FTC or TDF/FTC/RPV (all available as single tablet regimens). With the newer, more effective and better tolerated regimens analyzed, we can also be confident that virological failure or adverse side effects will not influence the continuation of the treatment no matter what regimen we choose, with the exception of TDF/FTC/EFV. This regimen, which is no longer recommended in the guidelines [14,22], had a higher rate of discontinuation due to adverse side effects. These findings might be considered when starting the treatment of naïve HIV-infected patients.

Role of each author
SM and IJ initiated this project. All authors and CoRIS contributors in the Acknowledgments section were involved in data collection and exchange. IJ did the analyses. IJ and ISG drafted the manuscript, which was first reviewed by SM. All authors were involved in the study design, revised the manuscript for important intellectual content, and contributed to the final version of the manuscript.

Funding for this study was provided by (i) the Instituto de Salud Carlos III through the Red Tematica de Investigacion Cooperativa en SIDA (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional R+D+I and cofinanced by ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER) and (ii) ViiV Healthcare. ViiV Healthcare was given the opportunity to review a preliminary version of this manuscript for factual accuracy. The authors are solely responsible for final content and interpretation of the results.

IJ has received teaching fees from ViiV Healthcare. ISG has received conference grants or speaker fees from BMS, ViiV Healthcare and Gilead. SM has been involved in speaking activities and has received grants for research from Abbott, Boehringer&Ingelheim, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen Cilag, Merck Sharp&Dohme, Pfizer, Roche, and Schering Plough.

Meetings at which parts of the data were presented:
VIII Congreso Nacional de GESIDA 2016, 29th November – 2nd December 2016, San Sebastian, Spain
This study would not have been possible without the collaboration of all the patients, medial and nursery staff, and data managers who have taken part in the project.

Annex: Centers and investigators involved in CoRIS

Executive committee: Santiago Moreno, Julia del Amo, David Dalmau, Maria Luisa Navarro, Maria Isabel González, Jose Luis Blanco, Federico Garcia, Rafael Rubio, Jose Antonio Iribarren, Félix Gutiérrez, Francesc Vidal, Juan Berenguer, Juan González.
Fieldwork, data management and analysis: Paz Sobrino, Victoria Hernando, Belén Alejos, Débora Álvarez, Inma Jarrín, Nieves Sanz, Cristina Moreno.
BioBanK HIV: M Ángeles Muñoz-Fernández, Isabel García-Merino, Coral Gómez Rico, Jorge Gallego de la Fuente y Almudena García Torre.
Participating centres: Hospital General Universitario de Alicante (Alicante): Joaquín Portilla, Esperanza Merino, Sergio Reus, Vicente Boix, Livia Giner, Carmen Gadea, Irene Portilla, Maria Pampliega, Marcos Díez, Juan Carlos Rodríguez, Jose Sánchez-Payá. Hospital Universitario de Canarias (San Cristobal de la Laguna): Juan Luis Gómez, Jehovana Hernández, María Remedios Alemán, María del Mar Alonso, María Inmaculada Hernández, Felicitas Díaz-Flores, Dácil García, Ricardo Pelazas., Ana López Lirola. Hospital Universitario Central de Asturias (Oviedo): Victor Asensi, Eulalia Valle, José Antonio Cartón., Maria Eugenia Rivas Carmenado. Hospital Universitario
12 de Octubre (Madrid): Rafael Rubio, Federico Pulido, Otilia Bisbal, Asunción Hernando, Maria Lagarde, Mariano Matarranz, Lourdes Dominguez, Laura Bermejo, Mireia Santacreu. Hospital Universitario de Donostia (Donostia-San Sebastián): José Antonio Iribarren, Julio Arrizabalaga, María José Aramburu, Xabier Camino, Francisco Rodríguez-Arrondo, Miguel Ángel von Wichmann, Lidia Pascual Tomé, Miguel Ángel Goenaga, Mª Jesús Bustinduy, Harkaitz Azkune Galparsoro., Maialen Ibarguren, Maitane Umerez. Hospital General Universitario De Elche (Elche): Félix Gutiérrez, Mar Masiá, Sergio Padilla, Andrés Navarro, Fernando Montolio, Catalina Robledano, Joan Gregori Colomé, Araceli Adsuar, Rafael Pascual, Marta Fernández, Elena García., Jose Alberto García, Xavier Barber. Hospital Universitari Germans Trias i Pujol (Can Ruti) (Badalona): Roberto Muga, Jordi Tor, Arantza Sanvisens. Hospital General Universitario Gregorio Marañón (Madrid): Juan Berenguer, Juan Carlos López Bernaldo de Quirós, Pilar Miralles, Isabel Gutiérrez, Margarita Ramírez, Belén Padilla, Paloma Gijón, Ana Carrero, Teresa Aldamiz-Echevarría, Francisco Tejerina, Francisco Jose Parras, Pascual Balsalobre, Cristina Diez. Hospital Universitari de Tarragona Joan XXIII (Tarragona): Francesc Vidal, Joaquín Peraire, Consuelo Viladés, Sergio Veloso, Montserrat Vargas, Miguel López- Dupla, Montserrat Olona, Anna Rull, Esther Rodriguez-Gallego, Verónica Alba. Hospital Universitario y Politécnico de La Fe (Valencia): Marta Montero Alonso, José López Aldeguer, Marino Blanes Juliá, Mariona Tasias Pitarch, Iván Castro Hernández, Eva Calabuig Muñoz, Sandra Cuéllar Tovar, Miguel Salavert Lletí, Juan Fernández Navarro. Hospital Universitario La Paz-CarlosIII-Cantoblanco: Juan González-García, F Arnalich, José Ramón Arribas, José Ignacio Bernardino, Juan Miguel Castro, Luis Escosa, Pedro Herranz, Víctor Hontañón, Silvia García-Bujalance, Milagros García López- Hortelano, Alicia González-Baeza, María Luz Martín-Carbonero, Mario Mayoral, María José Mellado, Rafael Micán, Rocío Montejano, María Luisa Montes, Victoria Moreno, Ignacio Pérez-Valero, Berta Rodés, Talia Sainz, Elena Sendagorta, Natalia C Stella y 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-Martínez. Hospital Universitario Miguel Servet (Zaragoza): Ascensión Pascual, Carlos Ramos, Piedad Arazo, Desiré Gil. Hospital Universitari MutuaTerrassa (Terrasa): David Dalmau, Angels Jaén, Montse Sanmartí, Mireia Cairó, Javier Martinez-Lacasa, Pablo Velli, Roser Font, Mariona Xercavins, Noemí Alonso. Complejo Hospitalario de Navarra (Pamplona): María Rivero, Jesús Repáraz, María Gracia Ruiz de Alda, Carmen Irigoyen, María Jesús Arraiza. Corporació Sanitària Parc Taulí (Sabadell): Ferrán Segura, María José Amengual, Gemma Navarro, Montserrat Sala, Manuel Cervantes, Valentín Pineda, Victor Segura, Marta Navarro, Esperanza Antón, Mª Merce Nogueras. Hospital Universitario de La Princesa (Madrid): Ignacio de los Santos, Jesús Sanz Sanz, Ana Salas Aparicio, Cristina Sarriá Cepeda, Lucio Garcia-Fraile Fraile. Hospital Universitario Ramón y Cajal (Madrid): Santiago Moreno, José Luis Casado, Fernando Dronda, Ana Moreno, María Jesús Pérez Elías, Cristina Gómez Ayerbe, Carolina Gutiérrez, Nadia Madrid, Santos del Campo Terrón, Paloma Martí, Uxua Ansa, Sergio Serrrano, Maria Jesús Vivancos. Hospital General Universitario Reina Sofía (Murcia): Alfredo Cano, Enrique Bernal, Ángeles Muñoz. Hospital Nuevo San Cecilio (Granada): Federico García, José Hernández, Alejandro Peña, Leopoldo Muñoz, Ana Belén Pérez, Marta Alvarez, Natalia Chueca, David Vinuesa, Jose Angel Fernández. Centro Sanitario Sandoval (Madrid): Jorge Del Romero, Carmen Rodríguez, Teresa Puerta, Juan Carlos Carrió, Mar Vera, Juan Ballesteros. Hospital Clínico Universitario de Santiago (Santiago de Compostela): Antonio Antela, Elena Losada. Hospital Universitario Son Espases (Palma de Mallorca): Melchor Riera, Maria Peñaranda, Maria Leyes, Mª Angels Ribas, Antoni A Campins, Carmen Vidal, Francisco Fanjul, Javier Murillas, Francisco Homar. Hospital Universitario Virgen de la Victoria (Málaga): Jesús Santos, Manuel Márquez, Isabel Viciana, Rosario Palacios, Isabel Pérez, Carmen Maria González. Hospital Universitario Virgen del Rocío (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, Maria Saumoy. Hospital Universitario Valle de Hebrón (Barcelona): Esteban Ribera. Hospital Costa del Sol (Marbella): Julián Olalla, Alfonso del Arco, Javier de la torre, José Luis Prada, José María García de Lomas Guerrero. Hospital General Universitario Santa Lucía (Cartagena): Onofre Juan Martínez, Francisco Jesús Vera, Lorena Martínez, Josefina García, Begoña Alcaraz, Amaya Jimeno. Complejo Hospitalario Universitario a Coruña (Chuac) (A Coruña): Eva Poveda, Berta Pernas, Álvaro Mena, Marta Grandal, Ángeles Castro, José D. Pedreira. Hospital Universitario Basurto (Bilbao): Josefa Muñoz, Miren Zuriñe Zubero, Josu Mirena Baraia-Etxaburu, Sofía Ibarra, Oscar Ferrero, Josefina López de Munain, Mª Mar Cámara. Iñigo López, Mireia de la Peña. Hospital Universitario Virgen de la Arrixaca (El Palmar): Carlos Galera, Helena Albendin, Aurora Pérez, Asunción Iborra, Antonio Moreno, Maria Ángeles Campillo, Asunción Vidal. Hospital de la Marina Baixa (La Vila Joiosa): Concha Amador, Francisco Pasquau, Javier Ena, Concha Benito, Vicenta Fenoll. Hospital Universitario Infanta Sofia (San Sebastian de los Reyes): Inés Suárez-García, Eduardo Malmierca, Patricia González-Ruano, Dolores Martín Rodrigo. Complejo Hospitalario de Jaén (Jaen): Mohamed Omar Mohamed-Balghata, Maria Amparo Gómez Vidal. Hospital San Agustín (Avilés): Miguel Alberto de Zarraga. Hospital Clínico San Carlos (Madrid): Vicente Estrada Pérez, Maria Jesus Téllez Molina, Jorge Vergas García, Elisa Pérez-Cecila Carrera. Hospital Universitario Fundación Jiménez Díaz
(Madrid): Miguel Górgolas., Alfonso Cabello., Beatriz Álvarez., Laura Prieto. Hospital Universitario Príncipe de Asturias (Alcalá de Henares): Jose Sanz Moreno, Alberto Arranz Caso, Julio de Miguel Prieto, Esperanza Casas García. Hospital Universitario Fundación Alcorcón (Alcorcón): Juan Emilio Losa, Maria Velasco Arribas, Leonor Moreno Núñez, Rafael Hervás Gómez. Hospital Clínico Universitario de Valencia (València): Maria Jose Galindo Puerto, Ramón Fernando Vilalta, Ana Ferrer Ribera.


1. Davy-Mendez T, Eron JJ, Zakharova O, Wohl DA, Napravnik S. Increased Persistence of Initial Treatment for HIV Infection With Modern Antiretroviral Therapy. J Acquir Immune Defic Syndr 2017; 76:111–115.
2. Bae JW, Guyer W, Grimm K, Altice FL. Medication persistence in the treatment of HIV infection: a review of the literature and implications for future clinical care and research. AIDS 2011; 25:279–290.
3. Haggblom A, Lindback S, Gisslen M, et al. HIV drug therapy duration; a Swedish real world nationwide cohort study on InfCareHIV 2009-2014. PLoS One 2017; 12:e0171227.
4. Sheth AN, Ofotokun I, Buchacz K, et al. Antiretroviral regimen durability and success in treatment-naïve and treatment-experienced patients by year of treatment initiation, United States, 1996-2011. J Acquir Immune Defic Syndr 2016; 71:47–56.
5. Elzi L, Erb S, Furrer H, et al. Adverse events of raltegravir and dolutegravir. AIDS 2017;
6. Bonfanti P, Madeddu G, Gulminetti R, et al. Discontinuation of treatment and adverse events in an Italian cohort of patients on dolutegravir. AIDS 2017; 31:455–457.
7. de Boer MG, van den Berk GE, van Holten N, et al. Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS 2016; 30:2831–2834.
8. Trottier B, Machouf N, Huchet E, et al. Tolerability is more important than simplicity for treatment durability. J Int AIDS Soc 2014; 17:19765.
9. Sweet D, Song J, Zhong Y, Signorovitch J. Real-world medication persistence with single versus multiple tablet regimens for HIV-1 treatment. J Int AIDS Soc 2014; 17:19537.
10. Moore DA, Goodall RL, Ives NJ, Hooker M, Gazzard BG, Easterbrook PJ. How generalizable are the results of large randomized controlled trials of antiretroviral therapy? HIV Med 2000; 1:149– 154.
11. Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials 2015; 16:495.
12. Berenguer J, Rivero A, Blasco AJ, et al. Costs and cost-effectiveness analysis of 2015 GESIDA/Spanish AIDS National Plan recommended guidelines for initial antiretroviral therapy in HIV- infected adults. Enferm Infecc Microbiol Clin 2016; 34:361–371.
13. Jarrin I, Hernandez-Novoa B, Alejos B, et al. Persistence of novel first-line antiretroviral regimes in a cohort of HIV-positive subjects, CoRIS 2008-2010. Antivir Ther 2013; 18:161–170.
14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents living with HIV. (Updated 25 Cotober 2018. Accessed 7 December 2018). Available from https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
15. Eaton EF, Tamhane A, Davy-Mendez T, et al. Trends in antiretroviral therapy prescription, durability and modification: new drugs, more changes, but less failure. AIDS 2018; 32:347–355.
16. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63:77–85.
17. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med 2014; 161:461–471.
18. O’Brien ME, Clark RA, Besch CL, Myers L, Kissinger P. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003; 34:407–414.
19. d’Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS 2000; 14:499– 507.
20. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS 2015; 29:1723–1725.
21. Clotet B, Feinberg J, van Lunzen J, et al. Raltegravir Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383:2222–2231.
22. Documento de consenso de GeSIDA/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana. (Updated January 2018. Accessed 7 December 2018). Available from http://gesida-seimc.org/wp- content/uploads/2018/01/gesida_TAR_adultos_v3-1.pdf