G E S I D A Análogos de Nucleósidos, todavía necesarios? Mesa Debate. Santiago Moreno Hospital U. Ramón y Cajal Madrid

Transcripción

1 Mesa Debate Análogos de Nucleósidos, todavía necesarios? Santiago Moreno Hospital U. Ramón y Cajal Madrid 1

2 2

3 Análogos de nucleósidos, todavía útiles? Eficacia Tolerancia/Toxicidad Resistencia Conveniencia, interacciones, calidad de vida Situaciones especiales

4 Análogos de Nucleósidos, todavía necesarios? Eficacia (1) Pacientes sin Tratamiento Previo 4

5 Con qué empezar? Recomendaciones DHHS, 2017 Recommended Regimens INSTI based DTG/ABC/3TC* DTG + TDF/FTC or TAF/FTC EVG/COBI/TAF/FTC or EVG/COBI/TDF/FTC RAL + TDF/FTC or TAF/FTC DHHS Guidelines

6 Con qué empezar? Recomendaciones GESIDA, 2017 Preferred Regimens that have shown superior efficacy to their comparators in randomized clinical trials or that, having show non-inferiority, present advantages of good tolerability, low toxicity and low risk of pharmacological interactions. They can be given to most patients. ABC/3TC + DTG TFV/FTC + DTG TFV/FTC + RAL TFV/FTC/EVGc GeSIDA Guidelines

7 Con qué empezar? IAS-USA Guidelines, 2016 IAS USA Guidelines JAMA. 2016;31:

8 PI/r-based dual therapy NVP EFV MVC RAL 3TC ETV Study N Study N Study N Study N Study N Study N TOTAL NEKA 16 A VEMAN 30 CCTG 26 LOREDA 40 MULTINEKA 34 BIKS 86 KALMAR 20 PROGRESS 106 GARDEL 205 LPV/r DRV + RTV ATV + RTV PALM 25 KITE 40 OLE 125 EARNEST 400 SECOND LINE 280 A MIDAS 25 PK 14 MODERN 402 A GUSTA 165 RADAR 80 PK 15 NEAT A PK 78 ATLAS 40 SPARTAN 60 SALT 160 SWITCH 60 NCT NCT

9 PI/r + EFV as Initial TAR Study PI/r + EFV arm PI component Comparator arm First line DMP 006 IDV IDV + 3TC + AZT EFV + 3TC + AZT A5142 LPV/r LPV/r+ 3TC + 2NRTI EFV + 3TC + 2NRTI

10 Tashima K, Staszewski S, NelsonM, et al. 15th International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4547. PI/r + EFV as Initial TAR DMP 006 Study

11 Probability of no VF (%) Riddler SA et al. N Engl J Med 2008; 358: PI/r + EFV as Initial TAR ACTG EFV + 2 NRTIs LPV/r + 2 NRTIs LPV/r + EFV EFV + 2 NRTIs LPV/r + 2 NRTIs LPV/r + EFV EFV + 2 NRTIs vs. LPV/r + 2 NRTIs: p = LPV/r + EFV vs. EFV + 2 NRTIs: p = 0.49 (NS) LPV/r + EFV vs. LPV/r + 2 NRTIs: p = 0.13 (NS) (threshold for significance p < 0.014) Time after randomisation (weeks)

12 Riddler SA et al. N Engl J Med 2008; 358: ACTG 5142: Qué pasa en CV altas PI/r + EFV as Initial TAR ACTG 5142 P=0,02 P=0,01

13 PI/r + EFV as Initial TAR Study PI/r + EFV arm PI component Comparator arm First line DMP 006 IDV IDV + 3TC + AZT EFV + 3TC + AZT A5142 LPV/r LPV/r+ 3TC + 2NRTI EFV + 3TC + 2NRTi

14 PI/r + MVC as Initial TAR Study PI/r + MVC arm Comparator arm PI component First line VEMAN LPV/r LPV/r + TDF/FTC A ATV+RTV ATV+RTV + TDF/FTC MIDAS DRV+RTV - MODERN DRV+RTV DRV+RTV + TDF/FTC

15 PI/r + RAL as Initial TAR Study PI/r + BID RAL Comparator arm arm PI component First line PROGRESS LPV/r LPV/r + TDF/FTC SPARTAN ATV ATV+RTV + TDF/FTC RADAR DRV+RTV DRV+RTV + TDF/FTC A5262 DRV+RTV - NEAT 001 DRV+RTV DRV+RTV + TDF/FTC

16 PI/r + 3TC as Initial TAR Study PI/r + 3TC arm Comparator arm PI component First line GARDEL LPV/r LPV/r + 3TC + NRTI LOREDA LPV/r - ANDES DRV/r DRV/r +FTC+TDF

17 LPV/r + 3TC as Initial TAR GARDEL: Viral load <50 copies/ml at week 48 (ITTe) (p= 0.171, difference +4.6% [CI 95% :-2.2% to +11.8%]) Cahn P, et al. EACS, Brussels, Belgium.

18 Proporción (%) DRV/r + 3TC as Initial TAR Triple terapia Doble terapia TT:(97%) DT(95%) Diferencia (95% CI): -2.5% (-7.9; 2.9) Semana Similar aumento medio de CD4+ en ambos brazos (TD=206 cel/mm 3 ; TT=204 cel/mm 3 ). Sued O, et al. IAS Abstract MOAB0106LB

19 PI/r + 3TC as Initial TAR Study PI/r + 3TC arm Comparator arm PI component First line GARDEL LPV/r LPV/r + 3TC + NRTI LOREDA LPV/r - ANDES DRV/r DRV/r +FTC+TDF

20 DTG + 3TC as Initial TAR The Paddle Study (96 weeks) Figueroa MI et al. IAS Abstract MOPEB

21 DTG + 3TC as Initial TAR ACTG A5353 (24 semanas) Carga viral basal > 100,000 N=37 100,000 N=83 Total N=120 Supresión virológica 3 3 (89%) 75 (90%) 108 (90%) HIV-1 RNA < 50 c/m [95% CI] [75%,97%] [82%,96%] [83%,95%] No supresión 3 (8%) 2 (2%) 5 (4%) HIV-1 RNA 50 c/m Discontinuación con CV > 50* No datos virológicos 1 (3%) 6 (7%) 7 (6%) Discontinuación por otras razones # En estudio pero sin datos * Mala adherencia; # Pérdida de seguimiento, embarazo. Taiwo BO, et al. IAS Abstract MOAB0107LB.

22 Non-Nukes in Naive Patients Monotherapy with any available drug cannot be considered for initial therapy PI/r based, NUC sparing dual regimens do not seem to be suitable alternatives for initiation of ART, especially in patients with high viral loads Only dual regimens consisting of IP/r + 3TC (and possibly DTG+3TC) have shown non inferiority when compared to IP/r + 2NUCs, regardless CD4 counts and viral loads.

23 Análogos de Nucleósidos, todavía necesarios? Eficacia (2) Pacientes con CV indetectable 23

24 SWORD Studies: Switching to DTG + RPV Virologic outcomes Adjusted treatment difference (95% CI) a CAR DTG + RPV < Percentage-point difference DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 Llibre et al. CROI 2017; Seattle, WA. Abstract 44LB

25 The Ramón y Cajal Study: Switching to DTG + RPV in heavily pretreated patients Díaz A. IAC 2016, Durban, South Africa

26 Withdrawing inactive NRTIs in HIV-1 subjects with suppressed viraemia A randomized trial (NUKE-Out Study) The baseline regimen for 46 (51%) subjects contained 4 drugs and the baseline regimen for 37 (41%) subjects contained 3 drugs. Seventy-four subjects (82%) harboured the mutation M184V/I and the median number of thymidine- associated mutations was 3 (IQR: 0 4), T215X and D67X being the most frequent. In the experimental arm, thirty-two (71%) subjects removed 1 NRTI and 13 (29%) removed 2 NRTIs. Overall, 29 of 45 (64%) discontinued emtricitabine or lamivudine, and 22 of 45 (49%) discontinued tenofovir disoproxil fumarate (tenofovir DF) Llibre JM. J Antimicrob Chemother

27 3TC + PI/r in Switching Study (n) DT group TT group ATLAS-M 1 (266) ATV/r+3TC ATV/r+2N(t)RTIs SALT 2 (286) ATV/r+3TC ATV/r+2N(t)RTIs OLE 3 (250) LPV/r+3TC LPV/r+2N(t)RTIs DUAL 4 (249) DRV/r+3TC DRV/r+2N(t)RTIs Source: 1 Di Giambenedetto S. et al. Journal of Antimicrobial Chemotherapy. 2017;72: Perez-Molina JA. et al. The Lancet Infectious Diseases. 2015;15: Arribas JR. et al. The Lancet Infectious Diseases. 2015;15: Pulido F. et al. Clinical Infectious Diseases 2017; Aug 17. doi: /cid/cix734 Perez Molilna JA, et al. EASC 2017; Milan, Italia 27

28 3TC + PI/r in Switching At 48w, 4% of patients on DT vs. 3.04% on TT had HIV-RNA 50 cop/ml Difference 0.9% (95%CI, -1.3% to 3.2%) HIV-RNA 50 cop/ml at week 48 Dual therapy triple therapy (%) Absolute risk difference, (95% CI) Non-inferiority margin: 4% SALT ATLAS DUAL OLE POOLED Favours DT 4% 1.40 (-2.80, 5.60) (-5.90, 4.40) 1.50 (-2.20, 5.30) 1.70 (-2.60, 6.00) 0.90 (-1.30, 3.20) Treatment difference (DT vs. TT) was not affected by Sex, HCV infection status or type of PI 0% Perez Molilna JA, et al. EASC 2017; Milan, Italia 28

29 3TC + DTG in Switching ASPIRE (week 48) N On Study Taiwo BO, et al. EACS Abstract PE 8/5. 29

30 LA Cabotegravir + RPV in Switching Oral CAB induction period (ITT-ME population) LATTE-2 (Week 96) Maintenance period BL, baseline; CAB, cabotegravir; ITT-ME, intent-to-treat maintenance exposed; Q4W, every 4 weeks; Q8W, every 8 weeks. Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

31 Non-Nukes in Suppressed Patients Monotherapy with available drugs cannot longer be recommended NUC sparing dual regimens are a potential alternative in maintenance therapy PI/r + 3TC and DTG + 3TC have been shown to be a good switching strategy in suppressed patients and offer advantages over other regimens

32 Análogos de Nucleósidos, todavía necesarios? Eficacia (3) Pacientes en Fracaso 32

33 Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa EARNEST: Trial design HIV positive adolescents / adults (n=1200) 1 st line NNRTI-based regimen >12m; > 90% adherence last 1m Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria RANDOMIZE PI NRTIs (NRTIs according to local standard of care) PI + RAL PI + RAL (12 wk induction) PI (Monotherapy) FOLLOW-UP FOR 144 WEEKS Primary outcome at week 96: Good HIV disease control defined as all of: Alive and no new WHO4 events from 0-96 weeks AND CD4 cell count > 250 cells/mm 3 at 96 weeks AND VL<10,000 c/ml OR >10,000 c/ml without PI res. mutations at 96 weeks Paton NI. N Engl J Med 2014;371:

34 Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa VL suppression at 96 weeks PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88 PImono+ vs PI/NRTI P=0.002 P< P< P< Paton NI. N Engl J Med 2014;371:

35 MOBIDIP Study: bpi + 3TC for Maintenance of Virological Suppression in Patients on Second Line Therapy in Africa Randomized, open-label, superiority trial Multicenter Central and military Hospital -Yaoundé, Cameroon; CRCF and CTA H. Fann - Dakar Senegal; Day Hospital CHU - Bobo-Dioulasso, Burkina Faso Do = Randomization W 96 ANRS LADY >48 weeks ANRS MOBIPID N= 264 (Expected) N = 454 FTC + TDF + LPV/r Arm A LPV/r N = 82 N = 152 ABC + DDI + LPV/r N = 147 Arm B LPV/r + 3TC N = 82 Arm A DRV/r N = 50 FTC + TDF + DRV/r N = 155 Arm B DRV/r + 3TC N = 50 Ciaffi L, et al. HIV Glasgow; October 2016; Glasgow, UK; Abst. O122; Lancet HIV

36 MOBIDIP Study: Baseline Characteristics bpi n=133 bpi +3TC n=132 Total n=265 Site, n (%) Bobo Dioulasso 26 (20%) 27 (20%) 53 (20%) Dakar 16 (12%) 16 (12%) 32 (12%) Yaoundé 91 (68%) 89 (67%) 180 (16%) Women, n (%) 101 (76%) 93 (70%) 194 (73%) Age, median (IQR) 41 (36-49) 43 (37-50) 42 (36-50) VL <50 copies/ml, n (%) 107 (80%) 110 (83%) 217 (82%) CD4, median (IQR) n= ( ) 472 ( ) 475 ( ) CD4 <200/mm 3, n (%) n=259 3 (2%) 4 (3%) 7 (3%) bpi = DRV/r, 56 (42%) 44 (33%) 100 (38%) Nadir CD4 < 100, n (%) n= (56%) 65 (52%) 138 (54%) Time on first line (months), median (IQR) 50 (33-69) 50 (34-68) 50 (33-68) Time on second line (months), median (IQR) 37 (30-47) 38 (30-47) 37 (30-47) M184V at inclusion, n (%) n= (95%) 127 (97%) 252 (96%) Resistance to one 2 nd line drug, n (%) n= (61%) 78 (60%) 159 (60%) Resistance to two 2 nd line drugs, n (%) n= (15%) 14 (11%) 34 (13%) Ciaffi L, et al. HIV Glasgow; October 2016; Glasgow, UK; Abst. O122; Lancet HIV

37 MOBIDIP Study: Results Number at risk bpi bpi=3tc HR: 0.11 (95% CI ; P=0.001) bpi bpi+3tc Follow-up (Weeks) Neither adherence, nadir CD4 count, or PI drug were associated with failure Ciaffi L, et al. HIV Glasgow; October 2016; Glasgow, UK; Abst. O122; Lancet HIV

38 Análogos de Nucleósidos, todavía necesarios? Tolerabilidad Toxicidad 38

39 Neat 001: Safety and tolerability RAL + DRV/r TDF/FTC + DRV/r p value (log rank) SAE, n 89 (73 patients) 75 (61 patients) Fatal, n 4 1 Type Life-threatening, n 8 4 Hospitalisation, n Other medical condition, n Incidence rate (/100 py) Incidence rate (/100 py) Grade 4 AEs Grade 3 or 4 AEs Grade 3 or 4 treatment-modifying AEs Any Grade treatment-modifying AEs st CROI, Boston, March 3-6,2014, 84LB. Lancet 2014; 384:

40 SWORD Studies: Adverse Events (Week 52) Llibre et al. CROI 2017; Seattle, WA. Abstract Early switch phase DTG + RPV (n=513) n (%) CAR (n=511) n (%) Any AE 395 (77) 364 (71) AEs occurring in 5% of subjects in either group Nasopharyngitis Headache Upper respiratory tract infection Diarrhea Back pain 49 (10) 41 (8) 24 (5) 32 (6) 15 (3) 50 (10) 23 (5) 37 (7) 27 (5) 31 (6) Any Serious AEs 1 27 (5) 21 (4) Drug-related AEs Grades 1-2 Grades 3-4 AEs leading to withdrawal from the study CNS AEs leading to withdrawal 89 (17) 8 (2) 21 (4) 9 (2) 1 Two deaths in the study, both unrelated to study drug. DTG+RPV Kaposi s Sarcoma (N=1), CAR Lung cancer (N=1). 8 (2) 1 (<1) 3 (<1) 1 (<1)

41 Neat 001: Laboratory results W96 Proportion with graded toxicity Mean changes in fasting lipids at W96 from baseline (mmol/l) 10 % RAL (n = 401) TDF/FTC (n = 404) 8 Grade 3-4 CK elevation Grade 3-4 ALT elevation 2 Total cholesterol LDL-c HDL-c Triglycerides Total chol: HDL-c ratio p < p = 0.02 p < p = 0.49 p = st CROI, Boston, March 3-6,2014, 84LB. Lancet 2014; 384:

42 Earnest Trial: Adverse Events Paton NI. N Engl J Med 2014;371:

43 La monoterapia con IP/r tiene ventajas de toxicidad? Efectos adversos en el estudio MONET a 96 semanas DRV/r + 2NRTI N=129 DRV/r N=127 At least one SAE 13 (10%) 13 (10%) Deaths 0 (0%) 0 (0%) Grade 1-4 AE 109 (85%) 112 (88%) Grade 1-4 psychiatric AE, all cause 20 (16%) 15 (12%) Grade 1-4 nervous system AE, all cause 25 (19%) 27 (21%) Grade 2-4 psychiatric AE, drug related 0 (0%) 2 (1.6%) Grade 2-4 nervous system AE, drug related 4 (3.1) 3 (2.4%) Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]

44 Estudio PROTEA. Treatment-emergent adverse events to Week 48 Treatment arm DRV/r arm DRV/r+2NRTIs n=137 n=136 Serious Adverse Events 9 (6.6%) 5 (3.7%) Deaths* 1 (0.7%) 0 Grade 1-4 AEs 96 (70.1%) 83 (61.0%) Grade 3-4 AEs 7 (5.1%) 3 (3.7%) Grade 1-4 Psychiatric AEs 10 (7.3%) 9 (6.6%) Grade 1-4 Nervous System 13 (9.5%) 14 (10.3%) AEs** *1 myocardial infarction, judged to be unrelated to randomised treatment ** 1 patient in the PI monotherapy arm was hospitalised with HIV encephalomyelitis Antinori A. HIV Drug Therapy Conference, Glasgow, UK, November 2014 [oral presentation: O423A] 44

45 Neat 001: Renal Safety Creatinine clearance (egfr, ml/min [Cockroft-Gault formula] Mean (95% CI) change from baseline p= Weeks RAL + DRV/r TDF/FTC + DRV/r No grade 2-4 creatinine elevation in either arm 21st CROI, Boston, March 3-6,2014, 84LB. Lancet 2014; 384:

46 54 TH ICAAC, Washington DC, H NEAT 001: Mean % Change in Lumbar spine BMD 21st CROI, Boston, March 3-6,2014, 84LB. Lancet 2014; 384:

47 Mean adjusted percentage change SWORD studies: Change in BMD and Bone Markers at Week 48 Adjusted Change From Baseline in Total Hip and Lumbar Spine BMD (g/cm 2 ) at Week 48* Adjusted Week 48 to Baseline Ratio in Bone Markers DTG + RPV, n=46 CAR, n=35 DTG + RPV CAR P=0.014 P=0.039 Baseline 48 weeks Baseline 48 weeks n=48 n=45 n=49 n=44 n=49 n=45 BSAP P<0.001 P1NP P<0.001 CTx P=0.019 Changes in total hip and lumbar spine BMD were consistent across subgroups (ie, age, sex, BMI, baseline third-agent class) BSAP, bone-specific alkaline phosphatase; CTx, type-1 collagen cross-linked C-telopeptide; P1NP, procollagen type 1 N-propeptide No differences in inflammatory markers McComsey G, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUPDB0205LB. 47

48 Adverse Effects of ARVs and Drug Classes EACS Guidelines versión 9.0,

49 Study 109: Suppressed Adults Switched from a TDF-containing regimen to E/C/F/TAF Changes in Quantitative Proteinuria Through Week 48 and 96 UPCR UACR Tubular Proteinuria RBP:Cr RBP:Cr β-2-μg:cr Week 48* Week 96* Week 48* Week 96* *Each difference between treatment arms was statistically significant (p <0.001) FTC/TDF+3 rd Agent E/C/F/TAF Week 48* 1. DeJesus E, et al. ASM Boston MA. #087LB; 2. Mills A, et al. IAS 2015, Vancouver, Canada. Oral # TUAB

50 Median % Change (Q1, Q3) from Baseline Study 109: Suppressed Adults Switched from a TDF-containing regimen to E/C/F/TAF Changes in Spine and Hip BMD through Week 96 E/C/F/TAF FTC/TDF+3 rd Agent Spine (N=1,369) Hip (N=1,354) Weeks 2.3 p < p < Weeks Switching to E/C/F/TAF from a regimen containing FTC/TDF + 3 rd agent resulted in progressive increase in spine and hip BMD over 96 weeks DeJesus E, et al. ASM Boston MA. #087LB 50

51 Estudio MONET Monoterapia y longitud de los telómeros Changes in Telomere Length (-0.04 vs /year, p= 0.58) and Telomerese Activity (-0.07 vs +0.01, p=0.28) was not different in the two treatment arms Solomon A. PLoS One

52 Tolerability / Toxicity No clinical trial in naive or treated patients has shown a better tolerability of NUC-sparing regimen compared to NUC-based regimens The toxicity of TDF can be easily resolved by substitution with TAF or ABC Three of the currently used NRTIs are the only drugs with no recognizable toxicity

53 Análogos de Nucleósidos, todavía necesarios? Resistencia 53

54 21st CROI, Boston, March 3-6,2014, 84LB. Lancet 2014; 384: NEAT 001: Virological failure and resistance data RAL + DRV/r n=401 TDF/FTC + DRV/r n=404 Protocol-defined virological failure (PDVF), n Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32) Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing) * 1 additional patient with T97A Genotype done, n 28/36 13/15 Major resistance mutations, n 5 0 NRTI 1 (K65R) 0 PI 0 0 INI 5 (N155H)* - Protocol-defined VF, change of any component of the initial randomised regimen before W32 because of confirmed insufficient virological response, defined as HIV-1 RNA reduction< 1 log 10 c/ml by W18 or HIV-1 RNA 400 copies/ml at W24 ;failure to achieve virological response by W32 (confirmed HIV-1 RNA 50 c/ml at W32); confirmed HIV-1 RNA 50 c/ml at any time after W32. Genotypic testing was carried out by local labs when patients had a single VL > 500 copies/ml at or after W32.

55 Estudio EARNEST: Los fracasos con monoterapia con IP/r provocan un mayor desarrollo de resistencias a IP que el tratamiento con IP/r + 2 ITIAN X * X Paton NI. N Engl J Med 2014;371:

56 Estudio DOLUMONO: resultados Supresión viral en la semana 24 OT Supresión viral: toda la población de estudio en DOLUMONO* vs controles simultáneos Cuando 77/96 llegaron a semana 48 FV en 8. Genotipados 6/8 mutaciones en integrasa en 3/6. Estudio suspendido. TAR reiniciado en FV todos CVP < 50 a las 12 semanas del reinicio. Wijting IEA et al. CROI Seattle, Febrero Abstract 451LB

57 FV y Resistencias con DTG-mono Número de pacientes controlados en las 3 cohortes: DTG-bi-triterapia: (10%) DTG-monoterapia: 122 (1,17%) Fracaso virológico 64 (6%; IC 95%: 5-7%) Valor exacto de Fisher p=0,17 Razón de VF mono: 1,58 (IC 95%: 0,73-3,13) Fracaso virológico: 11 (9%; IC 95%: 6-18%) No MR 64 Si MR 0 No MR: 2 Si MR 9 82% Blanco JL et al. CROI Seattle, Febrero Abstract 42

58 ACTG A5353: FV definidos por protocolo y aparición de resistencias >100k HIV-1 RNA less than limit of detection. No DTG drug level detected. <100 k Off DTG/3TC <100 k Off DTG/3TC Taiwo BO, et al. IAS Abstract MOAB0107LB.

59 DOLAM: Dolutegravir-based simplification strategies Open-label Randomisation 1 : 1 : 1 Stratifying by 3 rd agent W24 W48 HIV+ 18 years On triple cart HIV RNA < 50 c/ml > 12 months No prior VF to 3TC/FTC or INSTI Nadir CD4 >200 cells/mm 3 HBsAg negative Continue on the same cart (CONTROL) Switch to DTG + 3TC dual therapy Switch to DTG monotherapy Blanco JL, et al. EACS Abstract PE.

60 DOLAM: VF and Resistance (24 weeks) Three patients (none previously exposed to INSTI) prematurely discontinued due to viral failure: Patient Arm Week HUGTiP 1 DTG + 3TC 12 weeks HUGTiP 2 DTG 24 weeks HCB DTG 24 weeks The two patients on DTG monotherapy developed resistance to INI Blanco JL, et al. EACS Abstract PE.

61 SWORD Studies: Confirmed Virologic Withdrawals and Development of Resistance Early switch phase a DTG + RPV n=513 n (%) CAR n=511 n (%) Confirmed Virologic Withdrawal 2 (<1) 2 (<1) (CVW) b One subject on DTG + RPV meeting virologic withdrawal criteria had identified an NNRTI resistance associated mutation (K101K/E) No INI resistance associated mutations were identified a Data pooled across SWORD-1 and SWORD-2. b CVW Current retest HIV-1 RNA 200 c/ml, prior 50 c/ml. Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.

62 3/100 1/100 4/100 2/55 7/100 1/21 2/49 Porcentaje de pacientes 11/100 3/21 11/49 4/14 3/11 4/15 5/15 21/55 46/100 Porcentaje de pacientes con resistencia en el momento del fallo virológico, según las clases de ARV y el régimen de terapia triple o doble TAR triple TAR doble ITIAN ITINN IP/r INI Calvez V, et al. 16 th EACS. Milan, October 25-27, PS1/4.

63 Porcentaje de pacientes con resistencia en el momento del fallo virológico, según las clases de ARV y el régimen de terapia triple o doble En TAR triple: Gran protección de los IP/r a los ITIAN No desarrollo de resistencia a DTG En TAR doble: DTG no siempre protege a RPV o 3TC DRV/r o ATV/r no siempre protegen a 3TC en términos generales, en los pacientes con fallo virológico, el TAR doble genera mayor número de mutaciones de resistencia que el TAR triple. Calvez V, et al. 16 th EACS. Milan, October 25-27, PS1/4.

64 Análogos de Nucleósidos, todavía necesarios? Conveniencia Interacciones Calidad de Vida Situaciones Especiales 64

65 Current Nukes Are highly convenient Can be administered in fixed dose combinations (Kivexa, Truvada, Descovy ) or as a single tablet regimen (Atripla, Eviplera, Stribild, Triumeq, Genvoya, Odefsey ) At any time of the day With no food or fluid requirements With long half-lives and high permisiveness Have no significant interactions

66 Ensayo Clínico QoLKAMON Calidad de vida en los pacientes VIH+ que inician monoterapia con LPV/r frente a los que continúan un régimen en triple terapia con un inhibidor de proteasa potenciado. Ensayo Clínico QolKamon Juan Pasquau 1, Carmen Hidalgo 1, Antonio Vergara 2, Marisa Montes 3, Jorge Vergas 4, Isabel Sanjoaquín 5, José Hernández-Quero 6, Koldo Aguirrebengoa 7, Francisco Orihuela 8, Jesús Rodríguez-Baño 9, Arkaitz Imaz 10, Carmen Fariñas 11, Juan Flores 12, Pilar Vázquez 13, Mª José Galindo 14, Isabel García-Mercé 15, Fernando Lozano 16, Ignacio de los Santos 17, Julio C. Blázquez 18 y Coral García-Vallecillos 1, en representación del Equipo de Investigadores del Estudio QolKamon. 1) Hospital Virgen de las Nieves, Granada; 2) Hospital Puerto Real, Cádiz; 3) Hospital La Paz, Madrid; 4) Hospital Clínico San Carlos, Madrid; 5) Hospital Lozano Blesa, Zaragoza; 6) Hospital Clínico San Cecilio, Granada; 7) Hospital Cruces, Bilbao; 8) Hospital Carlos Haya, Málaga; 9) Hospital Virgen Macarena, Sevilla; 10) Hospital de Bellvitge, Barcelona; 11) Hospital Marqués de Valdecilla, Santander; 12) Hospital Arnáu de Vilanova, Valencia; 13) Hospital Juan Canalejo, La Coruña; 14) Hospital Clínico, Valencia; 15) Hospital de l Hospitalet, L Hospitalet de Llobregat. Pasquau J. SAEI 2012

67 Ensayo Clínico QoLKAMON 100 EQ-5D, CALIDAD DE VIDA, Punt. en EVA) ADHERENCIA, Punt. en EVA SMAQ-GEEMA, (% Pac. Adherentes) 81,3 83, MOS-HIV, CALIDAD DE VIDA (Punt. Total, Estado Físico y Salud Mental) CESTA, SATISFACCIÓN GENERAL y CON EL TAR LPV/r en MONOTERAPIA IP/r en TRIPLE TERAPIA Pasquau J. SAEI 2012

68 Situaciones Especiales Tuberculosis asociada a la infección por VIH Todos los regímenes, de elección y alternativos, incluyen nucleósidos No hay régimen sin nucleósidos Coinfección con el Virus de la Hepatitis B Precisa la administración de dos nucleósidos, incluidos en el régimen antirretroviral Embarazo Piedra angular del tratamiento

69 Análogos de Nucleósidos, todavía necesarios? Eficacia Unica opción en el conjunto de pacientes en tratamiento de inicio Mejor opción en el mantenimiento Altamente convenientes en el rescate Toxicidad Los AN actuales son seguramente los fármacos antirretrovirales con mejor tolerabilidad y menor toxicidad Resistencia Su presencia disminuye la aparición de resistencias a otros fármacos en el régimen Otros Cómodos, convenientes, sin interacciones Utiles en el tratamiento de condiciones asociadas

70 Análogos de Nucleósidos, todavía necesarios? Por todo lo dicho, los análogos de nucleósidos inhibidores de la transcriptasa inversa no solo siguen siendo necesarios, sino que son in-dis-pen-sa-bles

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73 Gracias 73