The algorithm used for the interpretation of doravirine transmitted drug resistance strongly influences clinical practice and guideline recommendations

Abstract

Objectives

We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance.

Methods

We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms.

Results

NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients.

Conclusions

The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype–phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

Introduction

Transmitted drug resistance (TDR) can lead to virological failure as a consequence of resistance to one or more drugs in the antiretroviral regimen.¹ Thus, testing for TDR mutations in reverse transcriptase (RT) and protease (PR) is recommended in clinical guidelines for newly HIV-diagnosed patients.^2–5 In recent years, there has been an increase in TDR, which has been driven by resistance to NNRTIs. The increase in the prevalence of acquired NNRTI TDR has promoted an intensive scale-up of new drugs that fulfil clinical requirements,⁴ including having higher genetic barriers.

Figure 1.

Prevalence of mutations associated with NNRTI, NRTI and PI resistance in CoRIS cohort patients in 2018, according to the WHO-List and additional mutations. (a) Prevalence of NNRTI-associated mutations observed in our cohort. Doravirine-associated mutations are depicted in grey. The V106I mutation is shown in a different pattern due to its clinical relevance for doravirine use (Stanford version 8.7 algorithm). (b) NRTI mutation prevalence and (c) PI mutations.

Figure 2.

Clinically relevant resistance to doravirine determined by different algorithms.

Doravirine is a recently developed NNRTI drug approved by the US FDA in 2018. The in vitro resistance profile suggests that, in the presence of doravirine, most viruses present mutations at positions 106, 108, 227 and 234.⁶ V106A, Y188L and M230L single mutations were associated with resistance to doravirine, as well as other double and triple mutants.⁶ In Phase 3 randomized clinical trials, doravirine has demonstrated non-inferior efficacy as well as a favourable safety and tolerability profile compared with efavirenz⁷ and ritonavir-boosted darunavir⁸ in treatment-naive HIV-1-infected adults. Many clinical trials with doravirine are currently ongoing and preliminary results suggest the high potential of doravirine to fulfil the requirements for a next-generation NNRTI treatment.⁹

Data on the prevalence of mutations associated with doravirine resistance in naive patients are scarce. Most reports come from clinical trials and there is only one European (Greece, France and Italy)¹⁰ report addressing TDR to doravirine so far. As doravirine is a new drug, there is no unique list of mutations for resistance interpretation and there may be important differences with different interpretation algorithms. Here, we report the prevalence of doravirine resistance-associated mutations and the interpretation of doravirine resistance by four different algorithms: Stanford University Genotypic Resistance Interpretation Algorithm v 8.7, https://hivdb.stanford.edu/hivdb/by-sequences/; the algorithm from the Spanish Network of AIDS Research (RIS) 2019 update, https://www.redris.es/documents/20143/151217/AntiretroviralResistanceGuidelines_RIS_01172019.pdf/72106e34-1ea6-f96e-2605-164d01d1f7a5? version=1.0; the algorithm from the French National Agency for AIDS Research (ANRS) 2018 update, http://www.hivfrenchresistance.org/2018b/Algo-nov2018-HIV1.pdf; and the 2019 update of the IAS-USA drug resistance mutation list.¹¹

Patients and methods

The Cohort of the Spanish AIDS Research Network (CoRIS) is an open, multicentre, prospective cohort of HIV-positive, antiretroviral-naive subjects >13 years of age, including both seroprevalent (patients with no evidence of seroconversion) and seroconverter (patients with a documented prior HIV-negative sample) patients. Subjects are recruited and followed up in 46 HIV units from 13 of the 17 Autonomous Communities of Spain.^12,13 Annually, each centre provides FASTA sequences including HIV RT and PR. More detailed data and description of the CoRIS cohort has been previously published.^12,14 Patient-related data such as country of origin, sex, age, CD4 count, viral load and educational level were available through the CoRIS database. In this study we present data from 2018, the last year that has been updated.

The RT and PR regions from HIV were sequenced at the time of inclusion by the routine resistance testing in use at each participating centre. We used the Stanford University HIV database (v 8.7, available at https://hivdb.stanford.edu/hivdb/by-sequences/) for sequence alignment, quality assessment, resistance interpretation and subtyping. The ANRS and RIS algorithms and the IAS-USA 2019 mutation list were also used to describe clinically relevant TDR to doravirine. The Stanford Algorithm scores individual mutations from 5 to 60, considering viruses as resistant when the mutational score is ≥15. The ANRS and RIS algorithms score resistance when a specific set of individual or combined mutations are found. The IAS-USA considers as resistant those viruses that harbour any of the major mutations listed in the 2019 update.

The WHO 2009 list, with the additional mutations in RT of E138A/G/K/Q/R, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F, were used to describe relevant NNRTI/NRTI and PI mutations.¹⁵ With regard to doravirine TDR mutations, we evaluated the following: V106A/M, V108I, Y188L, V190S, H221Y, F227C/L/V, M230I/L, L234I, P236L, Y318F and K103N/Y181C, as described by Soulie et al., 2019.¹⁰

Ethics

Ethics approval was obtained from each of the participating sites and the written informed consent was obtained from the patients included in this study before entering CoRIS.

Results

A total of 22 centres from CoRIS contributed FASTA sequences in 2018. After quality control we were able to include 606 RT sequences (RT cohort) and 614 PR sequences (PR cohort), with a total number of 602 patients with both an RT and a PR sequence available. All patients were antiretroviral-naive with a resistance test performed before HIV treatment. Virological, demographic and clinical characteristics of patients enrolled in both cohorts are shown in Table 1. Most of the patients (>90%) were male; the main transmission route (70%) was MSM. Our cohort included a high proportion of newly diagnosed patients coming to Spain from abroad (35% from South/Central America) and also a high representation of non-B subtypes (17%).

Table 1.

Clinical, demographical and virological characteristics of the study population

		Cohort
Characteristic	Class	RT (n = 606)	PR (n = 614)	P
Gender (%)	male	91.9	91.2	NS
	female	8.1	8.8
Age, years (%)	<30	30.6	30.8	NS
	30–50	55.4	55.2
	>50	14.0	14.0
Education (%)	no education	1.1	1.1	NS
	primary school	6.1	6.5
	secondary school	12.0	11.7
	high school	29.9	29.9
	university	27.1	27.0
	other/unknown	23.8	23.8
Origin (%)	Spain	49.7	48.7	NS
	Europe	9.7	9.9
	Africa	2.6	3.6
	Asia/Oceania	1.3	2.0
	America (South/Central)	34.8	34.2
	other/unknown	1.9	1.6
Transmission route (%)	PWID	1.5	1.5	NS
	MSM	72.1	71.5
	MSW	20.6	21.2
	other/unknown	5.8	5.8
CD4 count (cells/mm3) (%)	<200	15.1	15.0	NS
	200–350	14.7	14.6
	350–1000	43.2	43.3
	>1000	2.4	2.4
	unknown	24.6	24.7
Viral load (copies/mL) (%)	<500 000	32.8	32.9	NS
	50 000–100 000	10.6	10.6
	100 000–1 000 000	25.7	25.7
	>100 000	7.4	7.2
	unknown	23.5	23.6
Viral subtype (%)	B	83.3	82.6	NS
	A	1.7	1.3
	B + G	1.7	1.1
	C	2.1	2.3
	CRF02_AG	3.6	5.2
	F	2.6	2.4
	others	5.0	5.1

PWID, people who inject drugs; MSW, men who have sex with women; NS, not significant.

TDR in Spain, 2018

The overall prevalence of NNRTI resistance-associated mutations was 13.5% (n = 82/606, according to the WHO list and additional doravirine resistance mutations). According to the Stanford HIV database v 8.7 algorithm, the WHO list and the additional mutations in the RT region affecting doravirine, the prevalence of individual mutations, as shown in Figure 1(a), was: K101E 0.3% (n = 2), K101P 0.2% (n = 1), K103N 3.1% (n = 19), K103S 0.2% (n = 1), V106I 3.8% (n = 23), V106M 0.2% (n = 1), V108I 1.2% (n = 7), E138A 3.8% (n = 23), E138G 0.7% (n = 4), E138K 0.3% (n = 2), Y188C 0.2% (n = 1), Y188L 0.3% (n = 2), G190A 0.3% (n = 2), H221Y 0.2% (n = 1), P225H 0.2% (n = 1) and Y318F 0.2% (n = 1).

The prevalence of NRTI resistance-associated mutations was 3.0% (n = 18/606). Those mutations were: M41L 0.3% (n = 2), K65R 0.3% (n = 2), D67E 0.2% (n = 1), M184V 0.5% (n = 3), L210W 0.5% (n = 3), T215 revertant 2.5% (n = 15), T215D 0.5% (n = 3), T215E 0.2% (n = 1), T215I 0.3% (n = 2), T215S 0.7% (n = 4), T215V 0.2% (n = 1), K219Q 0.5% (n = 3) and K219R 0.2% (n = 1). These data are represented in Figure 1(b).

With regard to individual PI mutations according to the WHO list, only five patients harboured relevant mutations, resulting in a prevalence of 0.8% (n = 5/614). As described in Figure 1(c), the frequency of mutations was as follows: M46I 0.2% (n = 1), M46L 0.2% (n = 1), F53L 0.2% (n = 1) and L90M 0.3% (n = 2).

Doravirine TDR

We observed 11 patients harbouring doravirine resistance-associated mutations, according to the list by Soulie et al.,¹⁰ which represent a prevalence of 1.8% (n = 11/606). As shown in Figure 1(a), V108I was the most prevalent mutation [V108I 1.2% (n = 7)]; the other doravirine resistance-associated mutations were very infrequent, with a prevalence lower than 0.4% [V106M 0.2% (n = 1), Y188L 0.3% (n = 2), H221Y 0.2% (n = 1) and Y318F 0.2% (n = 1)].

However, when we interpreted the clinically relevant resistance to doravirine with the ANRS, RIS, IAS-USA and Stanford version 8.7 algorithms we observed differences between them. According to the ANRS and RIS algorithms, the prevalence of resistance to doravirine was 0.7% (n = 4) and for IAS-USA major mutations it was 0.5% (n = 3), while Stanford v 8.7 revealed a prevalence of resistance of 5.0% (Figure 2). These discrepancies were driven mainly by the V106I mutation, present in 23 patients (3.8%), which only Stanford v 8.7 considers relevant for doravirine resistance (scored as low-level resistance). The detection of the V106I mutation was not significantly related to either the viral subtype or to gender, age, viral load, origin or transmission route.

Discussion

Surveillance of TDR is highly relevant for clinical practice, due to the possible emergence of new resistance events that may reduce the efficacy of ART. Both the wide use of first-line regimens and the continuous development of drugs that fulfil the clinical requirements need observational programmes to assess their trends over the years. Here, we present the latest update (2018) of RT/PR HIV TDR in Spain, with a special focus on doravirine, a new NNRTI recently approved by the FDA. As for the other periods we have previously analysed, covering 2007 to 2017, the prevalence of NNRTI TDR was much higher than for NRTIs and was very low for PIs.^16,17 Our main finding was the presence of a previously unreported high prevalence of V106I in RT (n = 23/602; 3.8%), which was responsible for a high prevalence of clinically relevant TDR to doravirine when the Stanford v 8.7 algorithm was used for interpretation. This finding might hamper the use of doravirine within first-line regimens as part of the rapid initiation strategies, with no baseline resistance tests available.

Doravirine has in vitro activity against K103N, Y181C, K103N/Y181C and G190A mutant viruses.¹⁸ Moreover, some highly prevalent transmitted NNRTI mutations, such as E138A, do not have any impact on doravirine activity.¹⁰ This unique resistance profile makes it an excellent candidate for first-line treatment. In Spain, due to the low prevalence of TDR to PIs and integrase strand transfer inhibitors (INSTIs), GESIDA guidelines³ consider that first-line ART including these drugs may be started even if the resistance test results are still pending. Achieving undetectability rapidly after diagnosis^19,20 is now one of the main goals of ART, as it has been proven to have many benefits, especially in preventing transmission events. If TDR to doravirine is as low as for INSTIs and PIs, use of this drug may also benefit from the possibility of starting treatment even if the results of the baseline drug resistance test are not yet available.

Many studies have evaluated TDR in Europe^21–24 since the prevalence changes substantially over years and by country. In Spain, our group has characterized the TDR and clinically relevant resistance to first-line drugs from 2007,^16,17,25 including INSTIs.¹³ Those studies revealed that resistance to first-line PIs and INSTIs is lower than 1%. Moreover, the resistance to first-line NRTIs is residual, suggesting that baseline resistance testing could be unnecessary from a cost-effectiveness point of view. However, none of our Spanish studies have evaluated TDR to the recently FDA-approved NNRTI, doravirine. A recent European report including patients from France, Greece and Italy describes the rare occurrence of doravirine-associated resistance mutations in HIV-1-infected treatment-naive HIV patients.¹⁰ That study evaluated samples from 9764 antiretroviral-naive patients from the period 2010–16, with very similar findings to our study in Spain in 2018: an overall prevalence of doravirine resistance-associated mutation of 1.4% (1.8% in our study), with V108I (0.6%) being the most prevalent mutation (1.2% in our study), and a similar frequency of doravirine resistance-associated mutations between B and non-B subtypes. However, in that study the presence of V106I was not reported.

Here, we have analysed not only the prevalence of mutations responsible for TDR, but also clinically relevant resistance. For doravirine, the Stanford v 8.7 algorithm reports much higher clinical resistance, up to 5%, than the ANRS and RIS algorithms (both 0.7% resistance) and the IAS-USA list (0.5%). The Stanford v 8.7 algorithm scores HIV isolates carrying V106I mutations as ‘low-level resistance’ to doravirine, with a score of 15. As indicated on the Stanford website, V106I is an NNRTI-selected mutation that occurs in 1% to 2% of viruses from untreated persons.²⁶ Alone it appears to have little, if any, effect on NNRTI susceptibility^27,28 although available data for doravirine are preliminary. A recent update of the Stanford version 8.9-1 (November 2019) has lowered the V106I score to 10, with a ‘potential low-level resistance’ call for doravirine. V106I is considered a minor mutation for doravirine in the IAS-USA 2019 list; for IAS-USA, a minor mutation on its own may not raise concern that a drug is at least partially compromised, but it should add concern in the presence of other mutations.¹¹ In our study, V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients.

Our study has several limitations. First, our results come from CoRIS, a cohort that is representative of the Spanish HIV epidemic; therefore, further studies are needed to determine the prevalence of V106I in isolates from other European countries, as well as from other parts of the world. Second, we did not perform a phylogenetic analysis to find out if patients carrying V106I clustered together; as there was no case accumulation with the same geographical origin this seems highly improbable.

In summary, we present the latest data on RT and PR TDR resistance in Spain. As for the previous updates, we found that the prevalence of TDR to NRTIs and PIs is low in our setting. However, TDR to NNRTIs continues to remain the major concern and is still a limitation to including these drugs in first-line regimens. Regarding the new NNRTI, doravirine, we report important differences in the prevalence of clinically relevant TDR when RIS/ANRS/IAS-USA or Stanford algorithms are used. Discrepancies are mainly driven by the presence of the V106I mutation. Further genotype–phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

Acknowledgements

This study would not have been possible without the collaboration of all patients, medical and nursing staff, data managers and collaborating centres for the generous gifts of clinical samples used in this work.

Members of CoRIS

Centres and investigators involved in CoRIS. Executive committee: Santiago Moreno, Inma Jarrín, David Dalmau, Maria Luisa Navarro, Maria Isabel González, Federico Garcia, Eva Poveda, Jose Antonio Iribarren, Félix Gutiérrez, Rafael Rubio, Francesc Vidal, Juan Berenguer, Juan González, M Ángeles Muñoz-Fernández. Fieldwork, data management and analysis: Inmaculada Jarrin, Belén Alejos, Cristina Moreno, Carlos Iniesta, Luis Miguel Garcia Sousa, Nieves Sanz Perez, Marta Rava. BioBanK HIV: Hospital General Universitario Gregorio Marañón: M Ángeles Muñoz-Fernández, Irene Consuegra Fernández.

Participating centres. Hospital General Universitario de Alicante (Alicante): Esperanza Merino, Gema García, Irene Portilla, Iván Agea, Joaquín Portilla, José Sánchez-Payá, Juan Carlos Rodríguez, Lina Gimeno, Livia Giner, Marcos Díez, Melissa Carreres, Sergio Reus, Vicente Boix, Diego Torrús. Hospital Universitario de Canarias (San Cristóbal de la Laguna): Ana López Lirola, Dácil García, Felicitas Díaz-Flores, Juan Luis Gómez, María del Mar Alonso, Ricardo Pelazas, Jehovana Hernández, María Remedios Alemán, María Inmaculada Hernández. Hospital Universitario Central de Asturias (Oviedo): Víctor Asensi, Eulalia Valle, María Eugenia Rivas Carmenado, Tomás Suárez-Zarracina Secades, Laura Pérez Is. Hospital Universitario 12 de Octubre (Madrid): Rafael Rubio, Federico Pulido, Rafael Delgado, Otilia Bisbal, Asunción Hernando, Lourdes Domínguez, David Rial Crestelo, 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, M^a Jesús Bustinduy, Harkaitz Azkune, Maialen Ibarguren, Aitziber Lizardi, Xabier Kortajarena, M^a Pilar Carmona Oyaga, Maitane Umerez Igartua. Hospital General Universitario De Elche (Elche): Félix Gutiérrez, Mar Masiá, Sergio Padilla, Catalina Robledano, Joan Gregori Colomé, Araceli Adsuar, Rafael Pascual, Marta Fernández, José Alberto García, Xavier Barber, Vanessa Agullo Re, Javier Garcia Abellán, Reyes Pascual Pérez, María Roca. Hospital Universitari Germans Trias i Pujol (Can Ruti) (Badalona): Roberto Muga, Arantza Sanvisens, Daniel Fuster. Hospital General Universitario Gregorio Marañón (Madrid): Juan Berenguer, Juan Carlos López Bernaldo de Quirós, Isabel Gutiérrez, Margarita Ramírez, Belén Padilla, Paloma Gijón, Teresa Aldamiz-Echevarría, Francisco Tejerina, Francisco José Parras, Pascual Balsalobre, Cristina Diez, Leire Pérez Latorre, Chiara Fanciulli. Hospital Universitari de Tarragona Joan XXIII (Tarragona): Francesc Vidal, Joaquín Peraire, Consuelo Viladés, Sergio Veloso, Montserrat Vargas, Montserrat Olona, Anna Rull, Esther Rodríguez-Gallego, Verónica Alba, Alfonso Javier Castellanos, Miguel López-Dupla. Hospital Universitario y Politécnico de La Fe (Valencia): Marta Montero Alonso, José López Aldeguer, Marino Blanes Juliá, María Tasias Pitarch, Iván Castro Hernández, Eva Calabuig Muñoz, Sandra Cuéllar Tovar, Miguel Salavert Lletí, 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, Ana Delgado Hierro, Luis Escosa, Pedro Herranz, Víctor Hontañón, Silvia García-Bujalance, Milagros García López-Hortelano, Alicia González-Baeza, Maria Luz Martín-Carbonero, Mario Mayoral, Maria Jose Mellado, Rafael Esteban Micán, Rocio Montejano, María Luisa Montes, Victoria Moreno, Ignacio Pérez-Valero, Guadalupe Rúa Cebrián, 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-Martínez. Hospital Universitario Miguel Servet (Zaragoza): Piedad Arazo, Gloria Sampériz. Hospital Universitari Mutua Terrassa (Terrasa): David Dalmau, Angels Jaén, Montse Sanmartí, Mireia Cairó, Javier Martinez-Lacasa, Pablo Velli, Roser Font, Marina Martinez, Francesco Aiello. Complejo Hospitalario de Navarra (Pamplona): Maria Rivero Marcotegui, Jesús Repáraz, María Gracia Ruiz de Alda, María Teresa de León Cano, Beatriz Pierola Ruiz de Galarreta. Corporació Sanitària Parc Taulí (Sabadell): María José Amengual, Gemma Navarro, Manel Cervantes Garcia, Sonia Calzado Isbert, Marta Navarro Vilasaro. Hospital Universitario de La Princesa (Madrid): Ignacio de los Santos, Jesús Sanz Sanz, Ana Salas Aparicio, Cristina Sarria Cepeda, Lucio J. Garcia-Fraile, Enrique Martín Gayo. Hospital Universitario Ramón y Cajal (Madrid): Santiago Moreno, José Luis Casado Osorio, Fernando Dronda Nuñez, Ana Moreno Zamora, Maria Jesús Pérez Elías, Carolina Gutiérrez, Nadia Madrid, Santos del Campo Terrón, Sergio Serrano Villar, Maria Jesús Vivancos Gallego, Javier Martínez Sanz, Usua Anxa Urroz, Tamara Velasco. Hospital General Universitario Reina Sofía (Murcia): Enrique Bernal, Alfredo Cano Sanchez, Antonia Alcaraz García, Joaquín Bravo Urbieta, Ángeles Muñoz Perez, Maria Jose Alcaraz, Maria del Carmen Villalba. Hospital Universitario Clínico San Cecilio (Granada): Federico García, José Hernández Quero, Leopoldo Muñoz Medina, Marta Alvarez, Natalia Chueca, David Vinuesa García, Clara Martinez-Montes, Carlos Guerrero Beltrán, Adolfo de Salazar Gonzalez, Ana Fuentes Lopez, Fernando Garcia, Esther Serrano-Conde. Centro Sanitario Sandoval (Madrid): Jorge Del Romero, Montserrat Raposo Utrilla, Carmen Rodríguez, Teresa Puerta, Juan Carlos Carrió, Mar Vera, Juan Ballesteros, Oskar Ayerdi. Hospital Clínico Universitario de Santiago (Santiago de Compostela): Antonio Antela, Elena Losada. Hospital Universitario Son Espases (Palma de Mallorca): Melchor Riera, María Peñaranda, M^a Angels Ribas, Antoni A. Campins, Carmen Vidal, Francisco Fanjul, Javier Murillas, Francisco Homar, Helem H. Vilchez, Maria Luisa Martin, Antoni Payeras. Hospital Universitario Virgen de la Victoria (Málaga): Jesús Santos, Cristina Gómez Ayerbe, Isabel Viciana, Rosario Palacios, Carmen Pérez López, Carmen Maria Gonzalez-Domenec. Hospital Universitario Virgen del Rocío (Sevilla): Pompeyo Viciana, Nuria Espinosa, Luis Fernando López-Cortés. Hospital Universitario de Bellvitge (Hospitalet de Llobregat): Daniel Podzamczer, Arkaitz Imaz, Juan Tiraboschi, Ana Silva, María Saumoy, Paula Prieto. Hospital Universitario Valle de Hebrón (Barcelona): Esteban Ribera, Adrian Curran. Hospital Costa del Sol (Marbella): Julián Olalla Sierra, Javier Pérez Stachowski, 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): Ángeles Castro Iglesias, Berta Pernas Souto, Álvaro Mena de Cea. Hospital Universitario Basurto (Bilbao): Josefa Muñoz, Miren Zuriñe Zubero, Josu Mirena Baraia-Etxaburu, Sofía Ibarra Ugarte, Oscar Luis Ferrero Beneitez, Josefina López de Munain, M^a Mar Cámara López, Mireia de la Peña, Miriam Lopez, Iñigo Lopez Azkarreta. Hospital Universitario Virgen de la Arrixaca (El Palmar): Carlos Galera, Helena Albendin, Aurora Pérez, Asunción Iborra, Antonio Moreno, Maria Angustias Merlos, Asunción Vidal, Marisa Meca. Hospital de la Marina Baixa (La Vila Joiosa): Concha Amador, Francisco Pasquau, Javier Ena, Concha Benito, Vicenta Fenoll, Concepción Gil Anguita, José Tomás Algado Rabasa. Hospital Universitario Infanta Sofía (San Sebastián de los Reyes): Inés Suárez-García, Eduardo Malmierca, Patricia González-Ruano, Dolores Martín Rodrigo, M^a Pilar Ruiz Seco. Hospital Universitario de Jaén (Jaén): Mohamed Omar Mohamed-Balghata, María Amparo Gómez Vidal. Hospital San Agustín (Avilés): Miguel Alberto de Zarraga. Hospital Clínico San Carlos (Madrid): Vicente Estrada Pérez, Maria Jesús Téllez Molina, Jorge Vergas García, Juncal Pérez-Somarriba Moreno. Hospital Universitario Fundación Jiménez Díaz (Madrid): Miguel Górgolas, Alfonso Cabello, Beatriz Álvarez, Laura Prieto. Hospital Universitario Príncipe de Asturias (Alcalá de Henares): José Sanz Moreno, Alberto Arranz Caso, Cristina Hernández Gutiérrez, María Novella Mena. Hospital Clínico Universitario de Valencia (València): María José Galindo Puerto, Ramón Fernando Vilalta, Ana Ferrer Ribera. Hospital Reina Sofía (Córdoba): Antonio Rivero Román, Antonio Rivero Juárez, Pedro López López, Isabel Machuca Sánchez, Mario Frias Casas, Angela Camacho Espejo. Hospital Universitario Severo Ochoa (Leganés): Miguel Cervero Jiménez, Rafael Torres Perea. Nuestra Señora de Valme (Sevilla): Juan A Pineda, Pilar Rincón Mayo, Juan Macías Sanchez, Nicolás Merchante Gutierrez, Luis Miguel Real, Anais Corma Gomez, Marta Fernández Fuertes, Alejandro Gonzalez-Serna. Hospital Álvaro Cunqueiro (Vigo): Eva Poveda, Alexandre Pérez, Manuel Crespo, Luis Morano, Celia Miralles, Antonio Ocampo, Guillermo Pousada.

Funding

The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación 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-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). This work was supported in part by grants from Plan Nacional de I + D+I, Fondo Europeo de Desarrollo Regional-FEDER (https://www.isciii.es/QuienesSomos/Organizacion/SGRCIC/Paginas/default.aspx) (RD16/0025/0040; RD16/0025/0026), and Fundacion Progreso y salud, Junta de Andalucia (http://www. juntadeandalucia.es/fundacionprogresoysalud/es) (PI-0550–2017).

Transparency declarations

A.I. has received financial compensation for lectures, consultancy work and educational activities, and funds for research from Abbvie, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare. C.G.-B. has received payments or collaborations for conferences and grants to organize courses by Gilead Sciences, Merck Sharp & Dohme, Janssen-Cilag and ViiV Healthcare. A.A has done consulting work for the Gilead Sciences laboratories and has received fees for participation in meetings as a speaker by Gilead Sciences, Abbvie, Merck Sharp & Dohme and Abbott Laboratories. F.G. has received grants to attend congresses and scientific meetings, financial compensation for talks, and grants for the development of research projects and biomedical education activities of Gilead Sciences, Merck Sharp & Dohme, ViiV Healthcare, Abbvie, Abbott, Roche, Qiagen, Werfen and Hologic. All other authors: none to declare.

Author notes

Carlos Guerrero-Beltrán, Javier Martínez-Sanz, Federico García and Santiago Moreno made an equal contribution.

Members are listed in the Acknowledgements section.