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

Carlos Guerrero-Beltra´n1†, Javier Mart´ınez-Sanz2†, Marta A´ lvarez1, Julia´n Olalla3, Mo´nica Garc´ıa-A´ lvarez4, Jose Antonio Iribarren5, Mar Masia´ 6, Marta Montero7, Silvia Garc´ıa-Bujalance8, Jose´ Ramo´n Blanco 9, Mar´ıa Rivero10, Lucio Jesu´s Garc´ıa-Fraile11, Nu´ria Espinosa12, Carmen Rodr´ıguez13, Antonio Aguilera14, Mar´ıa Carmen Vidal-Ampurdanes15, Marina Mart´ınez16, Asuncio´n Iborra17, Arkaitz Imaz18,
Juan Luis Go´mez-Sirvent19, Joaquim Peraire20, Joaqu´ın Portilla21, Estrella Caballero22, Bele´n Alejos23, Federico Garc´ıa 1*† and Santiago Moreno2† on behalf of CoRIS‡

1Hospital Universitario San Cecilio, Instituto de Investigacio´n Biosanitaria Ibs, Granada, Spain; 2Hospital Ramo´n y Cajal, Madrid, Spain; 3Hospital Costa del Sol, Marbella (Ma´laga), Spain; 4Hospital Doce de Octubre, Madrid, Spain; 5Hospital Universitario Donostia, San Sebastian, Spain; 6Hospital General Universitario de Elche, Universidad Miguel Herna´ndez, Elche, Spain; 7Hospital Universitario La Fe, Valencia, Spain; 8Hospital Universitario La Paz/IdiPAZ, Madrid, Spain; 9Hospital San Pedro, Logron~o, Spain; 10Hospital de Navarra, Pamplona, Spain; 11Hospital La Princesa, Madrid, Spain; 12Hospital Virgen del Roc´ıo, Sevilla, Spain; 13Centro Sanitario Sandoval, Madrid, Spain; 14Complexo Hospitalario Santiago Compostela, Universidad de Santiago de Compostela, Santiago de Compostela, Spain; 15Hospital Son Espases, Mallorca, Spain; 16Hospital Universitari Mutua Terrassa, Terrasa, Spain; 17Hospital Virgen Arrixaca, Murcia, Spain; 18Hospital Universitario de Bellvitge, Barcelona, Spain; 19Hospital Universitario de Canarias, Las Palmas de Gran Canaria, Spain; 20Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain; 21Hospital Alicante, Alicante, Spain; 22Hospital Vall D’Hebron, Barcelona, Spain; 23Instituto de Salud Carlos III, Madrid, Spain
*Corresponding author. E-mail: [email protected]
†These authors made an equal contribution.
‡Members are listed in the Acknowledgements section.

Received 3 October 2019; returned 24 December 2019; revised 31 December 2019; accepted 5 January 2020

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 rele- vant 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 de- tection 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–pheno- type studies are necessary to elucidate the role of V106I in doravirine resistance.

VC The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].
Introduction
Transmitted drug resistance (TDR) can lead to virological failure as a consequence of resistance to one or more drugs in the antiretro- viral regimen.1 Thus, testing for TDR mutations in reverse tran- scriptase (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 resist- ance 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.
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 muta- tions 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 dora- virine 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 inter- pretation and there may be important differences with different interpretation algorithms. Here, we report the prevalence of dora- virine 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/AntiretroviralRe sistanceGuidelines_RIS_01172019.pdf/72106e34-1ea6-f96e-260 5-164d01d1f7a5? 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, multi- centre, 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 individ- ual mutations from 5 to 60, considering viruses as resistant when the muta-
tional 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 muta-
tions 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 re- gard 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 sequen- ces (RT cohort) and 614 PR sequences (PR cohort), with a total number of 602 patients with both an RT and a PR sequence avail- able. 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 repre- sentation of non-B subtypes (17%).

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 muta- tions in the RT region affecting doravirine, the prevalence of indi- vidual 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

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.

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 infre- quent, 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 dora- virine 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 resist- ance 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.

Kfi0fiP Kfi03N Kfi03S Vfi06I Vfi06M Vfi08I Efi38A Efi38G Efi38K Yfi88C Yfi88(n = 2) (n = fi) (n = fi9) (n = fi) (n = 23) (n = fi) (n = 7) (n = 23) (n = 4) (n = 2) (n = fi) (n = 2) (n = 2) (n = fi) (n = fi) (n = f(n = 2) (n = 2) (n = fi) (n = 3) (n = 3) (n = 3) (n = fi5) (n = 3) (n = fi) (n = 2) (n = 4) (n = fi) (n = 3) (n = fi)

M46I M46L F53L L90M

(n = fi) (n = fi) (n = fi) (n = 2)

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.
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 require- ments 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 re- cently approved by the FDA. As for the other periods we have previ- ously 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 respon- sible 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 preva- lent 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 trans- fer 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 diagnosis19,20 is now one of the main goals of ART, as it has been proven to have many benefits, especially in preventing transmis- sion 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

ANRS RIS IAS-USA Stanford (n = 4) (n = 4) (n = 3) (n = 30)

Figure 2. Clinically relevant resistance to doravirine determined by dif- ferent algorithms.

treatment even if the results of the baseline drug resistance test are not yet available.
Many studies have evaluated TDR in Europe21–24 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 re- sidual, suggesting that baseline resistance testing could be un- necessary 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 preva- lence 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 dora- virine, the Stanford v 8.7 algorithm reports much higher clinical re- sistance, 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 algo- rithm 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 susceptibility27,28 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 compro- mised, but it should add concern in the presence of other muta- tions.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 phylogenet- ic 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 re- sistance 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 Jarr´ın, David Dalmau, Maria Luisa Navarro, Maria Isabel Gonza´lez, Federico Garcia, Eva Poveda, Jose Antonio Iribarren,
Fe´lix Gutie´rrez, Rafael Rubio, Francesc Vidal, Juan Berenguer, Juan Gonza´lez, M A´ ngeles Mun~oz-Ferna´ndez. Fieldwork, data management and analysis: Inmaculada Jarrin, Bele´n Alejos, Cristina Moreno, Carlos
Iniesta, Luis Miguel Garcia Sousa, Nieves Sanz Perez, Marta Rava. BioBanK HIV: Hospital General Universitario Gregorio Maran~o´n: M A´ ngeles Mun~oz-Ferna´ndez, Irene Consuegra Ferna´ndez.
Participating centres. Hospital General Universitario de Alicante (Alicante): Esperanza Merino, Gema Garc´ıa, Irene Portilla, Iva´n Agea, Joaqu´ın Portilla, Jose´ Sa´nchez-Paya´, Juan Carlos Rodr´ıguez, Lina Gimeno, Livia Giner, Marcos D´ıez, Melissa Carreres, Sergio Reus, Vicente Boix, Diego Torru´s. Hospital Universitario de Canarias (San Cristo´bal de la Laguna): Ana Lo´pez Lirola, Da´cil Garc´ıa, Felicitas D´ıaz-Flores, Juan Luis Go´mez, Mar´ıa del Mar Alonso, Ricardo Pelazas, Jehovana Herna´ndez, Mar´ıa Remedios Alema´n, Mar´ıa Inmaculada Herna´ndez. Hospital Universitario Central de Asturias (Oviedo): V´ıctor Asensi, Eulalia Valle, Mar´ıa Eugenia Rivas Carmenado, Toma´s Sua´rez-Zarracina Secades, Laura Pe´rez Is. Hospital Universitario 12 de Octubre (Madrid): Rafael Rubio, Federico Pulido, Rafael Delgado, Otilia Bisbal, Asuncio´n Hernando, Lourdes Dom´ınguez, David Rial Crestelo, Laura Bermejo, Mireia Santacreu. Hospital Universitario de Donostia (Donostia-San Sebastia´n): Jose´ Antonio Iribarren, Julio Arrizabalaga, Mar´ıa Jose´
Aramburu, Xabier Camino, Francisco Rodr´ıguez-Arrondo, Miguel A´ ngel von Wichmann, Lidia Pascual Tome´, Miguel A´ ngel Goenaga, Ma Jesu´s Bustinduy, Harkaitz Azkune, Maialen Ibarguren, Aitziber Lizardi, Xabier
Kortajarena, Ma Pilar Carmona Oyaga, Maitane Umerez Igartua. Hospital General Universitario De Elche (Elche): Fe´lix Gutie´rrez, Mar Masia´, Sergio Padilla, Catalina Robledano, Joan Gregori Colome´, Araceli Adsuar, Rafael Pascual, Marta Ferna´ndez, Jose´ Alberto Garc´ıa, Xavier Barber, Vanessa Agullo Re, Javier Garcia Abella´n, Reyes Pascual Pe´rez, Mar´ıa Roca. Hospital Universitari Germans Trias i Pujol (Can Ruti) (Badalona): Roberto Muga, Arantza Sanvisens, Daniel Fuster. Hospital
General Universitario Gregorio Maran~o´n (Madrid): Juan Berenguer, Juan Carlos Lo´pez Bernaldo de Quiro´s, Isabel Gutie´rrez, Margarita Ram´ırez, Bele´n Padilla, Paloma Gijo´n, Teresa Aldamiz-Echevarr´ıa, Francisco Tejerina, Francisco Jose´ Parras, Pascual Balsalobre, Cristina Diez, Leire Pe´rez Latorre, Chiara Fanciulli. Hospital Universitari de Tarragona Joan XXIII (Tarragona): Francesc Vidal, Joaqu´ın Peraire, Consuelo Vilade´s, Sergio Veloso, Montserrat Vargas, Montserrat Olona, Anna Rull, Esther Rodr´ıguez-Gallego, Vero´nica Alba, Alfonso Javier Castellanos, Miguel Lo´pez-Dupla. Hospital Universitario y Polite´cnico de La Fe (Valencia): Marta Montero Alonso, Jose´ Lo´pez Aldeguer, Marino Blanes Julia´, Mar´ıa Tasias Pitarch, Iva´n Castro Herna´ndez, Eva Calabuig Mun~oz, Sandra Cue´llar Tovar, Miguel Salavert Llet´ı, Juan Ferna´ndez Navarro. Hospital Universitario La Paz/IdiPAZ: Juan Gonza´lez-Garcia, Francisco Arnalich, Jose´ Ramo´n Arribas, Jose Ignacio Bernardino de la Serna, Juan Miguel Castro, Ana Delgado Hierro, Luis Escosa, Pedro Herranz, V´ıctor Hontan~o´n, Silvia Garc´ıa-Bujalance, Milagros Garc´ıa Lo´pez- Hortelano, Alicia Gonza´lez-Baeza, Maria Luz Mart´ın-Carbonero, Mario Mayoral, Maria Jose Mellado, Rafael Esteban Mica´n, Rocio Montejano, Mar´ıa Luisa Montes, Victoria Moreno, Ignacio Pe´rez-Valero, Guadalupe Ru´a Cebria´n, Berta Rode´s, Talia Sainz, Elena Sendagorta, Natalia Stella Alca´riz, Eulalia Valencia. Hospital San Pedro Centro de Investigacio´n Biome´dica de La Rioja (CIBIR) (Logron~o): Jose´ Ramo´n Blanco, Jose´ Antonio Oteo, Valvanera Ibarra, Luis Metola, Mercedes Sanz, Laura Pe´rez-Mart´ınez. Hospital Universitario Miguel Servet (Zaragoza): Piedad Arazo, Gloria Sampe´riz. Hospital Universitari Mutua Terrassa (Terrasa): David Dalmau, Angels Jae´n, Montse Sanmart´ı, Mireia Cairo´, Javier Martinez-Lacasa, Pablo Velli, Roser Font, Marina Martinez, Francesco Aiello. Complejo Hospitalario de Navarra (Pamplona): Maria Rivero Marcotegui, Jesu´s Repa´raz, Mar´ıa Gracia Ruiz de Alda, Mar´ıa Teresa de Leo´n Cano, Beatriz Pierola Ruiz de Galarreta. Corporacio´ Sanita`ria Parc Taul´ı (Sabadell): Mar´ıa Jose´ Amengual, Gemma Navarro, Manel Cervantes Garcia, Sonia Calzado Isbert, Marta Navarro Vilasaro. Hospital Universitario de La Princesa (Madrid): Ignacio de los Santos, Jesu´s Sanz Sanz, Ana Salas Aparicio, Cristina Sarria Cepeda, Lucio J. Garcia-Fraile, Enrique Mart´ın Gayo. Hospital Universitario Ramo´n y Cajal (Madrid): Santiago Moreno, Jose´ Luis Casado Osorio, Fernando Dronda Nun~ez, Ana Moreno Zamora, Maria Jesu´s Pe´rez El´ıas, Carolina

Guerrero. Hospital General Universitario Santa Luc´ıa (Cartagena): Onofre Juan Mart´ınez, Francisco Jesu´s Vera, Lorena Mart´ınez, Josefina Garc´ıa, Begon~a Alcaraz, Amaya Jimeno. Complejo Hospitalario
Universitario a Corun~a (Chuac) (A Corun~a): A´ ngeles Castro Iglesias, Berta Pernas Souto, A´ lvaro Mena de Cea. Hospital Universitario Basurto
(Bilbao): Josefa Mun~oz, Miren Zurin~e Zubero, Josu Mirena Baraia- Etxaburu, Sof´ıa Ibarra Ugarte, Oscar Luis Ferrero Beneitez, Josefina Lo´pez de Munain, Ma Mar Ca´mara Lo´pez, Mireia de la Pen~a, Miriam Lopez, In~igo Lopez Azkarreta. Hospital Universitario Virgen de la Arrixaca (El Palmar): Carlos Galera, Helena Albendin, Aurora Pe´rez, Asuncio´n Iborra, Antonio Moreno, Maria Angustias Merlos, Asuncio´n Vidal, Marisa Meca. Hospital de la Marina Baixa (La Vila Joiosa): Concha Amador, Francisco Pasquau, Javier Ena, Concha Benito, Vicenta Fenoll, Concepcio´n Gil Anguita, Jose´ Toma´s Algado Rabasa. Hospital Universitario Infanta Sof´ıa (San Sebastia´n de los Reyes): Ine´s Sua´rez-Garc´ıa, Eduardo Malmierca, Patricia Gonza´lez-Ruano, Dolores Mart´ın Rodrigo, Ma Pilar Ruiz Seco. Hospital Universitario de Jae´n (Jae´n): Mohamed Omar Mohamed-Balghata, Mar´ıa Amparo Go´mez Vidal. Hospital San Agust´ın (Avile´s): Miguel Alberto de Zarraga. Hospital Cl´ınico San Carlos (Madrid): Vicente Estrada Pe´rez, Maria Jesu´s Te´llez Molina, Jorge Vergas Garc´ıa, Juncal Pe´rez-Somarriba Moreno. Hospital Universitario
Fundacio´n Jime´nez D´ıaz (Madrid): Miguel Go´rgolas, Alfonso Cabello, Beatriz A´ lvarez, Laura Prieto. Hospital Universitario Pr´ıncipe de Asturias (Alcala´ de Henares): Jose´ Sanz Moreno, Alberto Arranz Caso,
Cristina Herna´ndez Gutie´rrez, Mar´ıa Novella Mena. Hospital Cl´ınico Universitario de Valencia (Vale`ncia): Mar´ıa Jose´ Galindo Puerto, Ramo´n Fernando Vilalta, Ana Ferrer Ribera. Hospital Reina Sof´ıa (Co´rdoba): Antonio Rivero Roma´n, Antonio Rivero Jua´rez, Pedro Lo´pez Lo´pez, Isabel Machuca Sa´nchez, Mario Frias Casas, Angela Camacho Espejo. Hospital Universitario Severo Ochoa (Legane´s): Miguel Cervero Jime´nez, Rafael Torres Perea. Nuestra Sen~ora de Valme (Sevilla): Juan A Pineda, Pilar Rinco´n Mayo, Juan Mac´ıas Sanchez, Nicola´s Merchante Gutierrez, Luis Miguel Real, Anais Corma Gomez, Marta Ferna´ndez Fuertes, Alejandro Gonzalez-Serna. Hospital A´ lvaro Cunqueiro (Vigo): Eva Poveda, Alexandre Pe´rez, Manuel Crespo, Luis Morano, Celia Miralles, Antonio Ocampo, Guillermo Pousada.

Gutie´rrez, Nadia Madrid, Santos del Campo Terro´n, Sergio Serrano Villar, Maria Jesu´s Vivancos Gallego, Javier Mart´ınez Sanz, Usua Anxa Urroz,

Tamara Velasco. Hospital General Universitario Reina Sof´ıa (Murcia): Enrique Bernal, Alfredo Cano Sanchez, Antonia Alcaraz Garc´ıa, Joaqu´ın Bravo Urbieta, A´ ngeles Mun~oz Perez, Maria Jose Alcaraz, Maria del
Carmen Villalba. Hospital Universitario Cl´ınico San Cecilio (Granada): Federico Garc´ıa, Jose´ Herna´ndez Quero, Leopoldo Mun~oz Medina, Marta Alvarez, Natalia Chueca, David Vinuesa Garc´ıa, Clara Martinez-Montes, Carlos Guerrero Beltra´n, Adolfo de Salazar Gonzalez, Ana Fuentes Lopez, Fernando Garcia, Esther Serrano-Conde. Centro Sanitario Sandoval (Madrid): Jorge Del Romero, Montserrat Raposo Utrilla, Carmen Rodr´ıguez, Teresa Puerta, Juan Carlos Carrio´, Mar Vera, Juan Ballesteros, Oskar Ayerdi. Hospital Cl´ınico Universitario de Santiago (Santiago de Compostela): Antonio Antela, Elena Losada. Hospital Universitario Son Espases (Palma de Mallorca): Melchor Riera, Mar´ıa Pen~aranda, Ma

Funding
The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Tema´tica de Investigacio´n 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-Subdireccio´n General de Evaluacio´n y el Fondo Europeo de Desarrollo Regional (FEDER). This work was sup- ported 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).

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 (Ma´laga): Jesu´s Santos, Cristina Go´mez Ayerbe, Isabel Viciana, Rosario Palacios, Carmen Pe´rez Lo´pez, Carmen Maria Gonzalez-Domenec. Hospital Universitario Virgen del Roc´ıo (Sevilla): Pompeyo Viciana, Nuria Espinosa, Luis Fernando Lo´pez-Corte´s. Hospital Universitario de Bellvitge (Hospitalet de Llobregat): Daniel Podzamczer, Arkaitz Imaz, Juan Tiraboschi, Ana Silva, Mar´ıa Saumoy, Paula Prieto. Hospital Universitario Valle de Hebro´n (Barcelona): Esteban Ribera, Adrian Curran. Hospital Costa del Sol (Marbella): Julia´n Olalla Sierra, Javier Pe´rez Stachowski, Alfonso del Arco, Javier de la torre, Jose´ Luis Prada, Jose´ Mar´ıa Garc´ıa de Lomas

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.

References
1 Gupta RK, Hill A, Sawyer AW et al. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect Dis 2009; 9: 409–17.
2 Gunthard HF, Calvez V, Paredes R et al. Human immunodeficiency virus drug resistance: 2018 recommendations of the International Antiviral Society-USA panel. Clin Infect Dis 2019; 68: 177–87.
3 AIDS Study Group (GESIDA) of the Spanish Society of Infectious Diseases and Clinical Microbiology and the National AIDS Plan. Executive Summary of the GESIDA/National AIDS Plan Consensus Document on Antiretroviral Therapy in Adults Infected by the Human Immunodeficiency Virus (Updated January 2018). http://gesida-seimc.org/wp-content/uploads/2018/01/ gesida_TAR_adultos_v3-1.pdf.
4 Saag MS, Benson CA, Gandhi RT et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA panel. JAMA 2018; 320: 379–96.
5 European AIDS Clinical Society. Guidelines, Version 9.1, 2018. http://www. eacsociety.org/files/2018_guidelines-9.1-english.pdf.
6 Feng M, Wang D, Grobler JA et al. In vitro resistance selection with doravir- ine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with dis- tinct mutation development pathways. Antimicrob Agents Chemother 2015; 59: 590–8.
7 Orkin C, Squires KE, Molina JM et al. Doravirine/lamivudine/tenofovir diso- proxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis 2019; 68: 535–44.
8 Molina JM, Squires K, Sax PE et al. Doravirine versus ritonavir-boosted daru- navir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 2018; 5: e211–20.
9 Gatell JM, Morales-Ramirez JO, Hagins DP et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc 2014; 17: 19532.
10 Soulie C, Santoro MM, Charpentier C et al. Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients. J Antimicrob Chemother 2019; 74: 614–7.
11 Wensing AM, Calvez V, Checcerini-Silberstein F et al. 2019 update of the drug resistance mutations in HIV-1. Top Antivir Med 2019; 27: 111–21.
12 Caro-Murillo AM, Castilla J, Perez-Hoyos S et al. Spanish cohort of naive HIV-infected patients (CoRIS): rationale, organization and initial results. Enferm Infecc Microbiol Clin 2007; 25: 23–31.

13 Alvarez M, Casas P, de Salazar A et al. Surveillance of transmitted drug re- sistance to integrase inhibitors in Spain: implications for clinical practice. J Antimicrob Chemother 2019; 74: 1693–700.
14 Sobrino-Vegas P, Gutierrez F, Berenguer J et al. The Cohort of the Spanish HIV Research Network (CoRIS) and its associated biobank; organizational issues, main findings and losses to follow-up. Enferm Infecc Microbiol Clin 2011; 29: 645–53.
15 Bennett DE, Camacho RJ, Otelea D et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS One 2009; 4: e4724.
16 Monge S, Diez M, Alvarez M et al. Use of cohort data to estimate national prevalence of transmitted drug resistance to antiretroviral drugs in Spain (2007-2012). Clin Microbiol Infect 2015; 21: 105.e1–5.
17 Monge S, Guillot V, Alvarez M et al. Clinically relevant transmitted drug re- sistance to first line antiretroviral drugs and implications for recommenda- tions. PLoS One 2014; 9: e90710.
18 Feng M, Sachs NA, Xu M et al. Doravirine suppresses common nonnucleo- side reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrob Agents Chemother 2016; 60: 2241–7.
19 Van Der Elst EM, Kombo B, Mugo P et al. Adjustment to acute or early HIV-1 infection diagnosis to prompt linkage to care and ART initiation: qualita- tive insights from coastal Kenya. Psychol Health Med 2019; 24: 631–41.
20 Mbonye M, Seeley J, Nalugya R et al. Test and treat: the early experiences in a clinic serving women at high risk of HIV infection in Kampala. AIDS Care 2016; 28 Suppl 3: 33–8.
21 Karlsson A, Bjorkman P, Bratt G et al. Low prevalence of transmitted drug resistance in patients newly diagnosed with HIV-1 infection in Sweden 2003- 2010. PLoS One 2012; 7: e33484.
22 Balode D, Westman M, Kolupajeva T et al. Low prevalence of transmitted drug resistance among newly diagnosed HIV-1 patients in Latvia. J Med Virol 2010; 82: 2013–8.
23 Bracciale L, Colafigli M, Zazzi M et al. Prevalence of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy: evolution over 12 years and predictors. J Antimicrob Chemother 2009; 64: 607–15.
24 Assoumou L, Bocket L, Pallier C et al. Stable prevalence of transmitted drug resistance mutations and increased circulation of non-B subtypes in antiretroviral-naive chronically HIV-infected patients in 2015/2016 in France. J Antimicrob Chemother 2019; 74: 1417–24.
25 Monge S, Guillot V, Alvarez M et al. Analysis of transmitted drug resistance in Spain in the years 2007-2010 documents a decline in mutations to the non-nucleoside drug class. Clin Microbiol Infect 2012; 18: E485–90.
26 Rhee SY, Gonzales MJ, Kantor R et al. Human immunodeficiency virus re- verse transcriptase and protease sequence database. Nucleic Acid Res 2003; 31: 298–303.
27 Vingerhoets J, Rimsky L, Van Eygen V et al. Pre-existing mutations in the rilpivirine Phase III trials ECHO and THRIVE: prevalence and impact on viro- logical response. Antivir Ther 2013; 18: 253–6.
28 Lai MT, Feng M, Falgueyret JP et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrobial MK-1439 Agents Chemother 2014; 58: 1652–63.