Decline in clinically relevant resistance to first line ARV regimens in Spain

PATIENTS&METHODS RESULTS

ConclusionTDR remained stable in Spain through 2007-2017 when individual mutations were evaluated. However, clinically relevant TDR to approved first line regimens showed a slow decline from 2007 to 2017. Resistance to INSTIs remains at very low levels in 2017 in Spain. These findings, together with the very low prevalence of resistance to first line NRTIs in 2015-2017 may question the need for baseline resistance prior to starting an INSTI based first line regimen.

OBJECTIVE

To present data on clinically relevant transmitted drug resistance to ARVs recommended for first line treatment in Spain during the period 2007-2017.

Marta Alvarez , José Ángel Fernández-Caballero , Ana B. Perez , Nuria Espinosa , Silvia García-Bujalance , Maria Jesus J. Perez-Elías , Rafael Delgado , Jose A. Iribarren , Isabel Viciana , David Dalmau , Antonio Aguilera , Mar Masia , Victoria Hernando& Federico García , for the CoRIS Resistance Study Group. Hospital Universitario San Cecilio, Granada, Spain; Hospital Universitario Virgen del Rocio, Sevilla, Spain; La Paz University Hospital, Madrid, Spain; Hospital Ramon y Cajal, Madrid, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Donostia, San Sebastián, Spain, Hospital Virgen de la Victoria,

Málaga, Spain; Hospital Universitari Mútua de Terrassa, Terrassa, Spain; Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain; Hospital General Universitario de Elche, Elche, Spain; Instituto de Salud Carlos III, Majadahonda, Spain.

We acknowledge help and funding fromFEDER&ISCIII,allparticipantsinCoRISandtheresistanceWorkPackage&alsototheRIS Biobank ( RD 16/0025/0019 ) for theirgenerosity in providing samples for theintegrasestudy

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!  28 centers from across Spain are contributing fasta sequences (RT & Pro) to CoRIS resistance Workpackage. CoRIS is the HIV ARV naïve cohort of the Spanish AIDS Research Network; contributing centers by autonomous communities are shown in figure 1.

Transmitted Drug Resistance (TDR) 2007-2017

0

2

4

6

8

10

12

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

TOTAL NRTI NNRTI PI INIs481 574 594 767 538 555 565 672 405 490 324

p = 0.552

p = 0.125

p = 0.488

p = 0.670

Resistance to First Line Drugs 2007-2017

!  We analysed 5484 RT & Pro Fasta sequences, obtained as part of baseline routine evaluation at the participating centers. !  As Integrase resistance is not part of routine testing in naïve patients in Spain, we run a surveillance programme (2012-2017) and tested 902 patients with samples available at the RIS Biobank. !  We evaluated the prevalence of TDR mutations using the WHO list 2009 update (Bennet et al) and the 2017 IAS list (Wensing et al) for Integrase mutations. !  Clinically relevant TDR was investigated using Stanford v 8.4 Algorithm, and potential low-level resistance was pooled into the susceptible category. ! First line regimens for each study period were those recommended by the Spanish treatment guidelines (GESIDA), which are summarized in figure 2.

AZT TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

TDF ABC

3TC/FTC

2007 2008 2009

2010 2011 2014 2013 2012 2015

2017

EFV

LPV FOS

ATZ DRV LOP

LPV FOS SQV ATZ DRV

ATZ DRV LOP

ATZ DRV

EFV

LPV FOS SQV ATZ DRV

EFV NVP

EFV NVP

EFV NVP RPV

EFV RPV

RAL RAL RAL EVG DTG

RAL DTG EVG

RAL

TDR mutations using the WHO list was 7.9% (3.6% NRTIs, 3.7% NNRTIs, 2.0% Pis), and 2,7 % INSTIs (IAS list) with no significant change during the study period. Trends during the study period is shown in Figure 3.

Clinically relevant resistance to recommended 1st line regimens showed a slow decline from 2007-2012, and peaked in 2013-2014 due to the inclusion of Rilpivirine for 1st line in the Spanish recommendations. As shown below, when integrase regimens were recommended as first line by the Spanish GESIDA guidelines, a sharp decline in resistance to first line drugs is observed. These data are presented in Figure 5.

The only major IAS mutation in the integrase detected during the study period was T66I. The prevalence of IAS-USA mutations (n = 902) in the integrase is shown in Figure 4.

0,1 0,2

2,3

0

0,5

1

1,5

2

2,5

T66I L74M T97A

0

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8

9

2007 2008-2009 2010-2011 2012 2013 2014 2015-2017

TOTAL NRTI NNRTI PI INIs

Period Overall % (IQR)

NRTIs (%) NNRTIs (%) PIs (%)

INsTIs (%)

2007 (n=482) 8,5 [6.2-11.4] 3,3 [1.9-5.3] 5,6 [3.7-8.0] 1,4 [0.5-2.9] * 2008-2009 (n= 1169) 6,8 [5.4-8.4] 3,5 [2.5-4.7] 4,3 [3.2-5.6] 0,6 [0.2-1.2] * 2010-2011 (n=1298) 6,2 [4.9-7.6] 1,6 [1.0-2.4] 4,5 [3.4-5.8] 0,6 [0.3-1.2] * 2012 (n=555) 6,7 [4.8-9.1] 2,5 [1.4-4.2] 4,7 [3.1-6.8] 1,1 [0.4-2.4] 0,7 [0.01-4.0]

(n=134) 2013 (n=577) 9,5 [7.2-12.2] 1,2 [0.5-2.5] 8,1 [6.0-10.6] 0,9 [0.3-2.1] 0 (n=60) 2014 (n=582) 11,8 [9.3-14.7] 1,7 [0.8-3.1] 10,1 [7.8-12.8] 1,4 [0.6-2.7] 0 (n=103) 2015-2017 (n=821) 2,2 [1.3-3.4] 2,1 [1.2-3..3] * * 0,7 [0.1-2.5] (n=279)

Figure 1

Figure 2

Figure 3

1" 2"

5"

21"

9"

1"0"

5"

10"

15"

20"

25"

T66I$ L74M$ Q95K$ T97A$ E157Q$ G163K$

DTG S S S S S S

EVG R S PLL PLL PLL LLR

RAL I S PLL PLL PLL LLR

Figure 4

TDR to NRTIs was significantly lower for patients infected by a non-B subtype, and significantly higher if patients were PWID. TDR to NNRTIs was significantly higher for patients whose origin was Africa. These data are shown in Table 1.

Figure 5

Table 2 shows the prevalence of Clinically relevant resistance according to the different periods in which GESIDA guidelines have updated first line treatment recommendations

Figure 6 shows the number of patients (n=902) that showed mutations integrase mutations and their impact on integrase inhibitors activity according to Stanford v 8.4 algorithm.

Table 2

Figure 6

Annex:CentersandinvestigatorsinvolvedinCoRIS:Executivecommittee:SantiagoMoreno,JuliadelAmo,DavidDalmau,MariaLuisaNavarro,MariaIsabelGonzález,EvaPoveda,FedericoGarcía,RafaelRubio,JoseAntonioIribarren,FélixGutiérrez,FrancescVidal,JuanBerenguer,JuanGonzález.Fieldwork,datamanagementandanalysis:PazSobrino,VictoriaHernando,BelénAlejos,DéboraÁlvarez,InmaJarrín,CristinaMoreno.BioBanKHIV:MÁngelesMuñoz-Fernández,IsabelGarcía-Merino,CoralGómezRico,JorgeGallegodelaFuenteyAlmudenaGarcíaTorre.Participatingcentres:HospitalGeneralUniversitariodeAlicante(Alicante):JoaquínPortilla,EsperanzaMerino,SergioReus,VicenteBoix,LiviaGiner,CarmenGadea,IrenePortilla,MariaPampliega,MarcosDíez,JuanCarlosRodríguez,JoseSánchez-Payá.HospitalUniversitarideBellvitge(HospitaletdeLlobregat):DanielPodzamczer,ElenaFerrermArkaitzImaz,EvanVanDenEyncle,SilvanaDiYacovo,MariaSumoy.HospitalUniversitariodeCanarias(SantaCruzdeTenerife):JuanLuisGómez,JehovanaHernández,MaríaRemediosAlemán,MaríadelMarAlonso,MaríaInmaculadaHernández,FelicitasDíaz-Flores,DácilGarcía,RicardoPelazas.HospitalUniversitarioCentraldeAsturias(Oviedo):VictorAsensi,EulaliaValle,JoséAntonioCartón.HospitalClínicoSanCarlos(Madrid):VicenteEstradaPérez,MariaJesusTéllezMolina,JorgeVergasGarcía,ElisaPérez-CecilaCarrera.HospitalDocedeOctubre(Madrid):RafaelRubio,FedericoPulido,OtiliaBisbal,MarianoMatarranz,MariaLagarde,RafaelRubio-Martín,AsunciónHernando,LauraBermejoyLourdesDominguez.HospitalUniversitarioDonostia(SanSebastián):JoséAntonioIribarren,JulioArrizabalaga,MaríaJoséAramburu,XabierCamino,FranciscoRodríguez-Arrondo,MiguelÁngelvonWichmann,LidiaPascualTomé,MiguelÁngelGoenaga,MªJesúsBustinduy,HarkaitzAzkuneGalparsoro.MaialenIbarguren,MirianAguado,MaitaneUmerez.HospitalGeneralUniversitariodeElche(Elche):FélixGutiérrez,MarMasiá,CristinaLópez,SergioPadilla,AndrésNavarro,FernandoMontolio,CatalinaRobledano,JoanGregoriColomé,AraceliAdsuar,RafaelPascual,FedericoCarlos,MaravillasMartinez,JaraLlenasGarcía,MartaFernández,ElenaGarcía.HospitalGermansTríasiPujol(Badalona):RobertoMuga,JordiTor,ArantzaSanvisensHospitalGeneralUniversitarioGregorioMarañón(Madrid):JuanBerenguer,JuanCarlosLópezBernaldodeQuirós,PilarMiralles,IsabelGutiérrez,MargaritaRamírez,BelénPadilla,PalomaGijón,AnaCarrero,TeresaAldamiz-Echevarría,FranciscoTejerina,FranciscoJoseParras,PascualBalsalobre,CristinaDiez.HospitalUniversitarideTarragonaJoanXXIII,IISPV,UniversitatRoviraiVirgili(Tarragona):FrancescVidal,JoaquínPeraire,ConsueloViladés,SergioVeloso,MontserratVargas,MiguelLópez-Dupla,MontserratOlona,AlbaAguilar,JoanJosepSirvent,VerónicaAlba,OlgaCalavia.HospitalUniversitarioLaFe(Valencia):MartaMontero,JoséLacruz,MarinoBlanes,EvaCalabuig,SandraCuellar,JoséLópez,MiguelSalavert.HospitalUniversitarioLaPaz/IdiPaz(Madrid):JuanGonzález,IgnacioBernardinodelaSerna,JoséRamónArribas,MaríaLuisaMontes,JoseMªPeña,BlancaArribas,JuanMiguelCastro,FcoJavierZamora,IgnacioPérez,MiriamEstébanez,SilviaGarcía,MartaDíaz,NataliaStellaAlcáriz,JesúsMingorance,DoloresMontero,AliciaGonzález,MariaIsabeldeJosé.HospitaldelaPrincesa(Madrid):IgnaciodelosSantos,JesúsSanz,AnaSalas,CristinaSarriá,AnaGómezBerrocal,LucioGarcia-Fraile.HospitalSanPedro-CIBIR(Logroño):JoséAntonioOteo,JoséRamónBlanco,ValvaneraIbarra,LuisMetola,MercedesSanz,LauraPérez-MartínezHospitalUniversitarioMiguelServet(Zaragoza):AscensiónPascual,CarlosRamos,PiedadArazo,DesiréGil.HospitalUniversitariMutuadeTerrassa(Terrassa):DavidDalmau,AngelsJaén,MireiaCairó,DanielIrigoyen,QueraltJordano,MarionaXercavins,JavierMartinez-Lacasa,PabloVelli,RoserFont,MontseSanmartí,LauraIbáñez.ComplejoHospitalariodeNavarra(Pamplona):MaríaRivero,MarinaItziarCasado,JorgeAlbertoDíaz,JavierUriz,JesúsRepáraz,CarmenIrigoyen,MaríaJesúsArraiza.HospitalParcTaulí(Sabadell):FerránSegura,MaríaJoséAmengual,GemmaNavarro,MontserratSala,ManuelCervantes,ValentínPineda,VictorSegura,MartaNavarro,EsperanzaAntón,MªMerceNogueras.HospitalRamónyCajal(Madrid):SantiagoMoreno,JoséLuisCasado,FernandoDronda,AnaMoreno,MaríaJesúsPérezElías,DoloresLópez,CarolinaGutiérrez,NadiaMadrid,AngelLamas,PalomaMartí,AlbertodeDiaz,SergioSerrrano,LucasDonat.HospitalReinaSofía(Murcia):AlfredoCano,EnriqueBernal,ÁngelesMuñoz.HospitalSanCecilio(Granada):FedericoGarcía,JoséHernández,AlejandroPeña,LeopoldoMuñoz,JorgeParra,MartaAlvarez,NataliaChueca,VicenteGuillot,DavidVinuesa,JoseAngelFernández.CentroSanitarioSandoval(Madrid):JorgeDelRomero,CarmenRodríguez,TeresaPuerta,JuanCarlosCarrió,MarVera,JuanBallesteros.HospitaldelaSantaCreuiSantPau(Barcelona):PereDomingo,MªAntoniaSambeat,KarunaLamarca,GraciaMateo,MarGutiérrez,IreneFernández.HospitalUniversitarioSantiagodeCompostela(SantiagodeCompostela):AntonioAntela,ElenaLosada.HospitalSonEspases(PalmadeMallorca):MelchorRiera,MariaPeñaranda,MariaLeyes,MªAngelsRibas,AntoniACampins,CarmenVidal,LeireGil,FranciscoFanjul,CarmenMarinescu.HospitalUniversitariValld´Hebron(Barcelona):EstebanRibera.HospitalVirgendelaVictoria(Málaga):JesúsSantos,ManuelMárquez,IsabelViciana,RosarioPalacios,IsabelPérez,CarmenMariaGonzález.HospitalUniversitarioVirgendelRocío(Sevilla):PompeyoViciana,ManuelLeal,LuisFernandoLópez-Cortés,NuriaEspinosa.HospitalUniversitariodeBasurto(Bilbao):JosefaMuñoz,MirenZuriñeZubero,JosuMirenaBaraia-Etxaburu,SofíaIbarra,OscarFerrero,JosefinaLópezdeMunain,MªMarCámara.IñigoLópez,MireiadelaPeña.HospitalUniversitarioInfantaSofía(SanSebastiándelosReyes):InésSuárez-García,EduardoMalmierca.HospitalUniversitarioCostadelSol(Marbella):JuliánOlalla,AlfonsodelArco,Javierdelatorre,JoséLuisPrada,ZairaCaracuel.HospitaldelPoniente(ElEjido):AnaMariaLopez-Lirola,AnaBelénLozano,ElisaFernández,InésPérez,JuanManuelFernández.HospitalUniversitarioSantaLucia(Cartagena):OnofreJuanMartínez,FranciscoJesúsVera,LorenaMartínez,JosefinaGarcía,BegoñaAlcaraz,AmayaJimeno.INIBIC-ComplejoHospitalarioUniversitariodeACoruña(ACoruña):EvaPoveda,BertaPernas,ÁlvaroMena,MartaGrandal,ÁngelesCastro,JoséD.Pedreira.HospitalClínicoUniversitarioVirgendelaArrixaca(Murcia):CarlosGalera,HelenaAlbendin,AsunciónIborra,AntonioMoreno,MariaAngelesCampillo,Asunciónvidal.HospitalMarinaBaixa(Villajoyosa):ConchaAmador,FranciscoPasquau,JavierEna,ConchaBenito,VicentaFenoll.ComplejoHospitalariodeJaén(Jaén):MohamedOmarMohamed-Balghata,MariaAmparoGómez.HospitalSanAgustíndeAviles(Avilés):MiguelAlbertodeZarraga,MariaEugeniaRivas.FundaciónJiménezDiaz(Madrid):MiguelGórgolas