“Top-Ten” Novedades en el Tratamiento Antirretroviral.

Presentación del tema: "“Top-Ten” Novedades en el Tratamiento Antirretroviral."— Transcripción de la presentación:

1 “Top-Ten” Novedades en el Tratamiento Antirretroviral.
Dr. MIGUEL GARCÍA DELTORO Hospital General Universitario Valencia Unidad Enfermedades Infecciosas

2 Top Ten Tenis

3 25 Fármacos antirretrovirales
DLV NVP ddC ABC TFV d4T ETR ZDV ddI EFV 3TC FTC ’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 Speaking Notes: Once again you see all the ARVs currently approved for use in the US market, this time mapped by their year of release. Note that from 1987 to 1995, the first 5 ARV drugs developed were all nucleoside analogues. Thus, when the idea of combining drugs together arose, the first combinations utilized drugs that were then available, i.e., a pair of nucleosides: either zidovudine (Retrovir) and zalcitabine (Hivid), didanosine (Videx), or lamivudine (Epivir), or the combination of lamivudine (Epivir) and stavudine (Zerit). NRTI SQV NFV LPV ATV NNRTI FPV DRV PI APV RTV TPV Inhibidor entrada T-20 MVC IDV Ø INTEGRASA 25 antirretrovirales aprobados por la FDA

4 DRV MVC RAL ETR

5 Preferred Regimens for Treatment-Naive Pts: DHHS (12/09)
3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BID, twice daily; ddI, didanosine; DHHS, US Department of Health and Human Services; DRV, darunavir; EFV, efavirenz; FPV, fosamprenavir; FTC, emtricitabine; LPV, lopinavir; NVP, nevirapine; QD, once daily; RTV, ritonavir; SQV, saquinavir; TDF, tenofovir; ZDV, zidovudine. The next slide lists recommended regimens for treatment‑naive patients according to the DHHS November 2008 guidelines. The NNRTI of choice is efavirenz. The PIs from which one may choose include atazanavir, darunavir, fosamprenavir, or lopinavir, all boosted with ritonavir. The preferred NRTI pair is tenofovir/emtricitabine. The alternative choices are also listed for all 3 drug classes: NNRTI, PI, and NRTI. DHHS guidelines. Available at: 1

6 Evitar añadir ptes al “carro” de la Multirresistencia y Lipodistrofia ....
Y entre todos lo estamos consiguiendo, pero sobre todo por los nuevos fármacos y los “combos”....

7 Top Ten Novedades Tto ARV….
1.- DARUNAVIR (DRV). 2.- MARAVIROC (MVC). 3.- RALTEGRAVIR (RAL). 4.- ETRAVIRINA (ETR), Rilpivirina (RPV), Nevirapina (NVP) XR. 5.-MISCELÁNEA (DHHS 2011). . Algunas matizaciones. . Inicio ARV y tto TBC. . Algunas interacciones relevantes.

8 DRV/r: el último de los IPs y ya casi el más recetado….

9 DRV. IP/r casi perfecto: el más eficaz, como el más tolerable y benévolo metabólicamente, el que menos falla y cuando lo hace con menos mutaciones. Ahora ya datos a medio plazo de ptes naive. Ya no necesidad de nevera para el rtv. Si no mutaciones de su score se puede dar qd (ODIN). Monoterapia no demuestra la no inferioridad a 96 semanas, se debería de concretar adecuadamente al pte candidato a ella.

10 La excusa de la nevera se acabó…
La excusa de la nevera se acabó…. ( : RTV Meltrex aprobado en España y dispobible desde Enero/2011)

11 ARTEMIS: Viral load <50 copies/mL to Week 96 (ITT-TLOVR)a
Mills A, et al H-1250c Estimated difference in response vs LPV/r for non-inferiority: PP = 8.4% (95% CI: ) p<0.001 Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI: ) p=0.012 Time (weeks) 79% 71% LPV/r QD or BID (N=346) DRV/r QD (N=343) 100 80 60 40 20 Patients with VL <50 copies/mL (% [±SE]) aEstimated from a logistic regression model including treatment and stratification factors (baseline log10 viral load and baseline CD4+ cell count)

12

13 Treatment phase (up to 48 weeks)
ODIN: study design ODIN (TMC114-C229) is a Phase IIIb, randomized, open-label study compares efficacy, safety and tolerability at Week 48 in treatment-experienced adults with no DRV RAMs Treatment phase (up to 48 weeks) ARV-experienced patients, aged 18 years HIV-1 RNA >1000 copies/mL CD4 cell count >50 cells/mm3 No DRV RAMs at screening* Stable HAART for 12 weeks 590 patients randomized DRV/r 800/100mg qd + OBR (2 NRTIs)‡ (N=294) DRV/r 600/100mg bid + OBR (2 NRTIs)‡ (N=296) Patients stratified by screening HIV-1 RNA (50,000, >50,000 copies/mL) *DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V; ‡Individualized OBR included 2 N(t)RTIs based on ARV history and resistance testing

14 ODIN: viral load <50 copies/mL to Week 48 (ITT-TLOVR)
100 80 72.1% 70.9% 60 DRV/r 800/100mg qd Patients with HIV-1 RNA <50 copies/mL (% [95% CI]) DRV/r 600/100mg bid 40 Difference in response qd vs bid: ITT: 72.1–70.9 = 1.2% (95% CI = –6.1%, 8.5%) PP: 73.4–72.5 = 0.9% (95% CI = –6.7%, 8.4%) 20 4 8 12 24 36 48 CI = confidence interval; PP = per protocol Time (weeks)

15 ODIN: laboratory abnormalities
Treatment-emergent grade 2–4 lipid and liver-related laboratory abnormalities (≥2% incidence), n (%)* Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) P value Triglycerides 15 (5.2) 31 (11.0) <0.014 Total cholesterol* 29 (10.1) 58 (20.6) <0.0007 LDLc cholesterol* 28 (9.8) 47 (16.7) <0.019 ALT 5 (1.7) 10 (3.5) 0.20 AST 6 (2.1) 0.32 Non-graded lipid-related laboratory abnormalities, n (%) HDL below the lower normal limit 57 (19.9) 52 (18.4) 0.67 *Based on the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events 2004, which does not have a grade 1 classification for triglycerides and grade 4 for total cholesterol and LDL 15 15

16 + 2 NRTI (re-optimised at baseline)
MONET - Trial Design BRU_J&J953_ _Medical Knowledge Management_v6 Inclusion: Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified) HIV RNA <50 copies/mL for at least 6 months, no prior use of darunavir (DRV) No history of virological failure DRV/r 800/100 mg OD + 2 NRTI (re-optimised at baseline) n = 129 256 subjects DRV/r 800/100 mg OD n = 127 144 weeks Primary Endpoint: failure at week 48 (TLOVR). Per Protocol, Switch = Failure The Week 96 analysis was a secondary endpoint. Rieger et al. Int AIDS Conf July 2010, Vienna [abstr TBLBB209] 16

17 MONET: HIV RNA <50 copies/mL at Week 96, TLOVR, Switch=failure (ITT population)
Switch=failure analysis (TLOVR) Switch included analysis Difference = -5.8% (-16.0%, +4.4%)* Difference = +1.4% (-5.5%, +8.3%)* 100 92.1% 90.7% 90 80.6% 74.8% 80 HIV RNA <50 by Week 96 (%) 70 60 50 40 30 20 10 DRV/r + 2NRTI DRV/r mono DRV/r + 2NRTI DRV/r mono n=129 n=127 n=129 n=127 * 95% confidence intervals from univariate analysis

18 CONCLUSIONES La monoterapia con IPs es ligeramente inferior a la triple terapia, pero es semejante si se reintroducen los NRTI. Darunavir/r en monoterapia es no inferior a su triple terapia a las 48 semanas, y es ligeramente inferior a su triple terapia a las 96 semanas. En pacientes seleccionados, como los pacientes con toxicidad a NRTI puede ser una alternativa razonable (GESIDA, EACS, etc…). Crea escasas mutaciones. La monoterapia es coste-efectiva, suponiendo un ahorro del 40%.

19 Annual Spanish Costs of ARV’s
cost per person €11283 €11326 €8515 €5471

20 MVC: Nuevos datos y posibilidad de utilización qd….

21 MVC. Mejora parcialmente marcadores de inmunoactivación en ptes suprimidos. Disponibilidad de tropismo genotípico rápida y para todos los centros y en breve posibilidad de tropismo en PBMC para ptes indetectables. Datos QD PK (ATV // DRV) y clínicos con ATV disponibles. Precio QD muy competitivo. Datos QD con DRV “ongoing”. Inclusión de QD en ficha técnica por EMEA prevista para Sept-Oct/2011.

22 Effect of Adding and Removing MVC on Immune Activation in HIV+ Patients on Suppressive ART: Results from ACTG A5256. Timothy Wilkin et al. CROI 2011 abstract 574.

23 Mi pequeña contribución al Documento de Consenso Español de Tropismo….

24 Estamos en tiempos de crisis…. Coste tratamiento/día
Tratamiento diario (PVL) Fármaco Dosificación Coste Coste RTV Isentress® 400 mg Bid 21,00 € (19,00€) - QD 10,88 € Celsentri® 150 mg 300 mg Bid 21,76 € Fuzeon® 90 mg/ml Bid 50,85 € - Intelence® 200 mg 400 mg Bid QD 13,00 € - Viramune® 400 mg Bid/QD 8,51 € Atripla® 600/200/245 mg QD 23,33 € - Kaletra® 400/100 mg 800/200 mg Bid QD 13,33 € - Reyataz® 300/100 mg QD 14,55 € 0,75 € Prezista® 600/100 mg 800/100 mg Bid QD 21,36 € 14,24 € 1,50 € 0,75 €

25 MVC 150 MG QD (+ ATV/R) All Patients Had Plasma MVC Concentrations Above the in vivo IC50 Across the Dosing Interval 1 10,000 * 1000 MVC Concentration (ng/mL) 100 10 This slide shows the maraviroc concentration plots from all 15 individuals in the intensive PK substudy confirming that maraviroc exposures exceeded by several fold the target in vivo IC50 throughout the dosing interval. These data were presented earlier this year (2010) in full . 7.65 ng/mL (in vivo IC50)2 1 4 8 12 16 20 24 Hours * One patient accidentally dosed with MVC prior to the 24-hour sample draw 1. Vourvahis et al ICWPHIV Rosario MC, et al. J Acquir Immune Defic Syndr. 2006;42:

26 Maraviroc 300mg Once Daily + Darunavir/Ritonavir 800/100mg Once Daily Provides Maraviroc Trough Concentrations Comparable to Trough Concentrations in HIV1 Patients Taking Maraviroc 300mg Twice Daily + Truvada: Implications for Phase 3 Studies. Stephen Taylor et al. CROI 2011 POSTER 636

27 Estudio PK de MVC. Conclusiones relevantes.
300mg MVC OD with DRV/r 800/100 OD achieved comparable MVC Cpeak and higher Ctrough compared to 300 mg BD dosed with NRTIs (no bPIs) • Limited data on MVC 150mg OD with DRV/r 800/100 OD achieved comparable Ctrough compared to 300 mg BD dosed with NRTIs (no bPIs) • All regimens were well tolerated with no cases of symptomatic postural hypotension identified • The planned phase 3 study (A ) is using a dose of 150 mg of MVC OD with DRV/r 800/100 • Higher [MVC]s in Black subjects was observed and needs to be investigated further Stephen Taylor et al. CROI 2011 POSTER 636

28 MOTIVATE 1 y 2 Gulick R, et al. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia, 22–25 July Poster WEPEB116LB

29 A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC—Wk 24 Interim Analysis
ATV/RTV + MVC (n=60) HIV-1 RNA < 50 copies/mL Overall and by BL VL ATV/RTV + TDF/FTC (n=61) 100 95 89 80 80 81 80 77 60 Patients (%) 40 20 n = 60 61 44 39 16 22 Overall HIV-1 RNA < 100K HIV-1 RNA  100K CD4 + cell count increases similar ATV/RTV + MVC: 195 cells/mm³ ATV/RTV + TDF/FTC: 173 cells/mm³ Grade 3/4 hyperbilirubinemia ATV/RTV + MVC: 59.3% ATV/RTV + TDF/FTC: 49.2% 5 patients in MVC arm, 1 patient in TDF/FTC arm switched to DRV/RTV per protocol for jaundice or scleral icterus Mills A, et al. Int AIDS Conf Abstract THLBB203.

30 RAL y otros inhibidores de la integrasa….

31 RAL. Eficacia y Tolerancia perfectas ya con datos a medio plazo de pacientes naive. RAL/LPV posible como tto libre de NRTI. Esperanza en 1 comp en combo QD con elvitegravir. Esperanza en rescate con dolutegravir. Dosis QD es inferior a la BID.

32 Raltegravir (RAL): 156 Week (Wk) Results from STARTMRK
J.K. Rockstroh, et al. CROI 2010 Abstract # K-135 Design Multicenter, double-blind, randomized (1:1), active-controlled study RAL 400mg BID vs. EFV 600mg qhs. Both given with co-formulated tenofovir (TDF) / emtricitabine (FTC) Main Objectives RAL + TDF/FTC will have non-inferior efficacy compared to EFV + TDF/FTC Primary hypothesis time point: 48 weeks Secondary hypothesis time point: 96 weeks Long term follow-up planned through 5 years Primary outcome: vRNA <50 c/mL Secondary outcomes: vRNA <400 c/mL, CD4 change from baseline

33 Patient Disposition at Week 156
Enrolled Patients Randomized 1:1 To RAL:EFV Arms 281 Patients Treated with RAL 282 Patients Treated with EFV 54 Patients (19.2%) Discontinued 5 – lack of efficacy 12 – AEs 8 – lost to follow-up 29 – miscellaneous* 71 Patients (25.2%) Discontinued 7 – lack of efficacy 22 – AEs 14 – lost to follow-up 28 – miscellaneous* 227 Patients (80.8%) Completed 156 Weeks 211 Patients (74.8%) Completed 156 Weeks *Miscellaneous includes consent withdrawn, protocol deviation, and patients who completed the base protocol but who did not enter the extension as well as other

34 Proportion (%) of Patients (95% CI) with HIV RNA <50 c/mL through 156 Weeks (NC = F)
Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7] Non-Inferiority p-Value <0.001

35 Mean Change from Baseline in Metabolic Parameters at Week 144
T CHOL HDL-C LDL-C TG Glucose 10 20 30 40 50 Mean Change (mg/dL) Raltegravir Efavirenz ‡ ‡ ‡ p<0.001 * p=0.137 ‡ ‡ ‡ * The change from baseline in the T CHOL:HDL-C ratio was for the RAL group and 0.04 for EFV group (p=0.061) 35

36 Lipoatrophy Due to attrition in Patients participating in the DEXA substudy it is difficult to interpret the data in a comparative fashion The majority of patients in both groups experienced modest fat gain “Return to health” phenomenon 1/25 patients on RAL and 2/32 patients on EFV had at least 20% appendicular fat loss (lipoatrophy) at Week 156 There was no discordance between appendicular and trunk fat loss among these few patients None of the patients with lipoatrophy identified by DEXA scanning had investigator-reported lipodystrophy as an adverse event

37 QDMRK (P071) Study Design Multicenter, double-blind, randomized, active-controlled study Non-inferiority design (10% margin) Primary endpoint Week 48 Secondary endpoint Week 96 Raltegravir 800 mg QD + TDF/FTC FDC n=382 HIV-1-infected Treatment naive HIV-1 RNA >5000 copies/mL No CD4 cell cut-off No documented resistance to tenofovir or emtricitabine 1:1 Raltegravir 400 mg BID + TDF/FTC FDC n=388 J Eron et al. CROI 2011, 150 LB. 37

38 QDMRK % of Patients with HIV RNA < 50 copies/mL (NC=F†)
BID 88.9% 100 80 QD 83.2% 60 Percent of Patients with HIV RNA <50 Copies/mL 40 Δ (QD-BID) [95% CI] = -5.7 [-10.7, -0.83] 20 4 8 12 16 24 36 48 Study Week Number of Contributing Patients RAL 800 mg QD 382 382 377 381 379 380 381 382 RAL 400 mg BID 388 388 386 387 386 387 386 386 *All patients received TDF/FTC FDC † Non-completer equals failure (NC=F) approach treats all discontinuations as failures 38

39 QDMRK Time to Loss of Virologic Response (TLOVR)
TLOVR (OF) Patients With BL vRNA >100,000 cp/mL TLOVR (OF) Patients With BL vRNA <=100,000 cp/mL 8 16 24 36 48 60 72 84 96 Week 20 40 80 100 Percent of Event Free Number of Patients at Risk 152 138 137 135 132 122 88 39 23 10 126 125 112 79 31 17 5 RAL 800 mg QD RAL 400 mg BID 8 16 24 36 48 60 72 84 96 Week 20 40 80 100 Percent of Event Free Number of Patients at Risk 236 231 230 229 226 212 147 71 32 15 224 219 216 215 199 144 65 34 13 RAL 800 mg QD RAL 400 mg BID. HR (0.250,1.308) p-value HR (0.276, 0.867) P-value Hazard Ratio shows the risk of developing VF For all pts, more chance to having VF Risk is consistent from beginning of study to end of study in pts with available data Risk is not over yet at Wk 48 Hazard Ratio (95% CI) p-value TLOVR (OF) All patients: (0.322, 0.823) TLOVR (OF) >100K: (0.276, 0.867) TLOVR (OF) <=100K: (0.250,1.308) 39

40 QDMRK - 48 Week Summary of Virologic Failures & Resistance Data
Raltegravir QD Raltegravir BID Virologic Failures 53/382 (13.9%) 35/388 (9.0%) VF >400 c/mL, (data available) 30 (27 with IN data) 16 (12 with IN data) No Evidence of Resistance 7 Integrase Resistance and FTC Resistance 9 2 FTC Resistance Alone 11 4 Number of VF by Baseline HIV RNA Raltegravir QD BID BL VL (cp/mL) ≤ 100,000 16 8 > 100,000 37 27 Definition Of Virologic Failure 1. HIV RNA >50 copies/mL at Week 24 (confirmed at least 1 week apart), OR 2. virologic relapse after initial response: HIV RNA>50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response with HIV RNA <50 copies/mL Characteristics of pts with FTC resistance only: All 15 had baseline VL > 100,000 What is the VL at time of failure? QD (N=11) BID ( N=4) VL <400 at Failure VL >=400 at Failure The ANs of those pts with VL <400 are 40929,41067 in QD and in BID in case you want to check their vRNA history in the VF listing table. - Time of VF: Most Pts failed with 2 or more mutations known to be associated with RAL resistance.  Signature mutations included N155H (4 pts in QD), Y143C/R (3 pts in QD, 1 pt in BID) NOTE: No Patient in Either Arm Failed with Evidence of TDF Resistance 40

41 QDMRK - Summary of Intense and Sparse PK Parameters
RAL QD RAL BID Ratio RAL QD / PK Parameter N LS Mean† (% CV‡) GMR (90% CI) AUC || (µM·hr) 22 30.87 (70) 20 13.14 (99) 1.17 (0.80, 1.72) Cmax (µM) 13.46 (69) 3.38 (135) 3.98 (2.58, 6.16) Ctrough§ (nM) 40 (111) 257 (167) 0.15 (0.09, 0.26) GM Ctrough* (nM)  245 83 (140) 304 380 (126) 0.22 (0.19, 0.25) † Back-transformed from log scale; LS Mean = Geometric Least-Squares Mean. ‡ %CV = 100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-scale. ||AUC0-12hr for BID arm and AUC0-24hr for QD arm. Ratio is for 24-hour exposure: (AUC0-24hr QD / 2*AUC0-12hr BID) §Ctrough = C12hr for BID and C24hr for QD *GM Ctrough = Ctrough calculated from sparse PK samples; for each patient, GM Ctrough represents the geometric mean of all concentration values measured between 11 and 13 hours postdose (for BID arm) or 22 and 26 hours postdose (for QD arm)

42 QDMRK Histograms for GM Ctrough and % with HIV RNA <50 copies/mL (Observed Failure)
GM C12hr (nM) GM C24hr (nM) Range Range Median Median Overall Responses: 400 mg BID – 92% 800 mg QD – 87% In 800 mg QD dataset, there is a drop-off in efficacy for patients in lowest Ctrough quartile

43 PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients
Randomized, open-label, multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mL LPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vs LPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105) Relatively low mean baseline HIV-1 RNA 4.25 log10 copies/mL 20 40 60 80 100 Wks HIV-1 RNA < 40 copies/mL (ITT-TLOVR) 8 16 24 32 48 83.2% 84.8% Difference: -1.6% (95% CI: -12.0% to 8.8%) *Statistically significant difference between arms: Wks 2, 4, 8 P < .002 Wk 16 P = .038 * Patients (%) LPV/RTV + RAL Similar CD4+ cell count gain at Wk 48 LPV/RTV + RAL: 215 cells/mm³ LPV/RTV + NRTIs: 245 cells/mm³ Reynes J, et al. Int AIDS Conf Abstract MOAB0101. Graphic used with permission.

44

45 VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients
International, multicenter, single-arm, phase II study in 27 patients with RAL resistance S/GSK mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapy Day 11-Wk 24: S/GSK mg QD continued and regimen optimized Median fold-change in RAL susceptibility at BL: 161 (range: > 166) Median S/GSK572 FC at BL: 1.5 (range: ) Stratified by BL integrase genotype Group 1: Q148 + ≥ 1 secondary resistance mutations (n = 9) Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18) HIV-1 RNA Response at Day 11 Group 1 (n = 9) Group 2 (n = 18) < 400 c/mL or ≥ 0.7 log10 c/mL decline, % 33 100 Change from baseline, log10 c/mL -0.72 -1.82 Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P < .001) Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutations In 17 subjects, < 2 FC in susceptibility In 1 subject, ~ 6 FC in susceptibility Eron J, et al. Int AIDS Conf Abstract MOAB0105.

46 Dolutegravir (DTG). (50 mg qd para naive y vía 155 y 50 mg bid para vía 148).
CROI Paper 151LB.

47 ETR: Utilización QD. NVP XR. RPV, un nuevo combo para el 2012.

48 ETR. Vida media “casi infinita” (41 horas).
Primeros datos SENSE QD a 12 S, en este año los de 48 S (IAS). Algún estudio piloto QD pequeño en simplificación. NVP XR, más de lo mismo (?). Esperanza con RPV de nuevo combo de 1 comp (TRU + RPV), pendiente dictamen FDA en Mayo/2011. Formulación mejorable (aunque “bebible”), posible para Sept-Oct/2011 comps 200 mg (aprovados por FDA en Dic/2010).

49 SENSE: EFV vs ETR in Treatment-Naive Patients
Randomized, double-blind trial of treatment-naive patients with HIV-1 RNA > 5000 copies/mL EFV 600 mg QD (n = 78) vs ETR 400 mg QD (n = 79) Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC) Primary endpoint: % of patients with grade 1-4 drug-related treatment- emergent neuropsychiatric AEs at Wk 12 Mean change in HIV-1 RNA at Wk 12 similar between arms (-2.9 log10 copies/mL) More drug-related neuropsychiatric AEs in EFV arm vs ETR arm Drug-Related Neuropsychiatric AEs 100 Grade 1-4 Grade 2-4 80 P < .001 P = .02 60 Patients (%) 46 40 20 17 17 5 ETR EFV ETR EFV 10 patients discontinued in ETR and 8 in EFV arm by Wk 12 Gazzard B, et al. Int AIDS Conf Abstract LBPE19. Nelson M, et al. AIDS 2011 Jan 28; 25 (3):

50 Switching to dual therapy with rtv/DRV/ETR (qd)
Estudio retrospectivo. N 21 ptes. Cambio por simplificación de 2 IPS (N=13), toxicidad NRTI (N=7), fallo CBV/NVP (N=1) Al cambio 19 de 21 ptes (90%) CV< 50 cop/ml. A 24 S todos CV < 50 cop/ml. A 48S (9 ptes) CV< 50 cop/ml. Marshall NJ, et al. HIV10 Conference, Glasgow, November 2010; P51.

51 HIV-1 RNA < 50 copies/mL (TLOVR)
VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48 Multicenter, randomized, double- blind, noninferiority study in treatment-naive patients NVP XR 400 mg QD (n = 508) vs NVP IR 200 mg BID (n = 505) Both combined with TDF/FTC Inclusion criteria HIV-1 RNA > 1000 copies/mL CD4+ cell count < 400 cells/mm3 if male or < 250 cells/mm3 if female HIV-1 RNA < 50 copies/mL (TLOVR) Adjusted difference 4.92% (95% CI: to 9.96) 100 Patients (%) 81.0 80 75.9 60 40 20 NVP IR NVP XR Similar safety and tolerability for both arms AEs included Stevens-Johnson (n = 5) Hepatitis (n = 14) Rash (n = 21) Gathe J, et al. Int AIDS Conf Abstract THLBB202.

52 ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
Randomized, double-blind phase III trials Stratification by BL HIV-1 RNA < 100,000 vs ≥ 100,000 copies/mL, NRTI use* Wk 48 primary analysis Wk 96 final analysis Rilpivirine 25 mg QD + TDF/FTC 300/200 mg QD (n = 346) ECHO (N = 690) EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 344) Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL no NNRTI RAMs, susceptible to NRTIs THRIVE (N = 678) Rilpivirine 25 mg QD + 2 NRTIs† (n = 340) EFV 600 mg QD + 2 NRTIs† (n = 338) *THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC. Cohen C, et al. Int AIDS Conf Abstract THLBB206.

53 ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL 6.6 ( ) HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48 100 90 90 91 84 83 84 80 100 60 85.6 84.3 82.3 Patients (%) 82.9 82.8 81.7 40 80 20 332/ 368 276/ 330 162/ 181 136/ 163 170/ 187 140/ 167 60 Patients (%) Pooled ECHO THRIVE 40 ≤100,000 copies/mL -3.6 (-9.8 to +2.5) 20 100 81 82 79 80 n = 686 682 346 344 340 338 80 77 76 Pooled ECHO THRIVE 60 Patients (%) 40 20 *P < for noninferiority at -12% margin. 246/ 318 285/ 352 125/ 165 149/ 181 121/ 153 136/ 171 Cohen C, et al. Int AIDS Conf Abstract THLBB206. Graphics used with permission. Pooled ECHO THRIVE > 100,000 copies/mL

54 ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events
Treatment Failure in ECHO and THRIVE 15 Rilpivirine Adverse Events and Discontinuation 12 EFV 9.0 Wk 48 Outcome, % Rilpivirine (n = 686) Efavirenz (n = 682) P Value DC for AE 3 8 .0005 Most Common AEs of Interest, % Any neurologic AE 17 38 < .0001 Any psychiatric AE 15 23 .0002 Any rash 14 9 6.7 Patients (%) 6 4.8 2.0 3 n = 346 686 682 686 682 VF AE Resistance at Virologic Failure Wk 48 Outcome Rilpivirine (n = 686) Efavirenz (n = 682) VF with resistance data, n 62 28 No NNRTI or NRTI RAMs,% 29 43  1 Emergent NNRTI RAM,% 63 54 Most frequent NNRTI RAM E138K K103N  1 Emergent NRTI RAMs, % 68 32 Most frequent NRTI RAM M184I M184V Cohen C, et al. Int AIDS Conf Abstract THLBB206.

55 Miscelánea (DHHS 2011).

56 Recuento de céls CD4

57 Fallo virológico: > 200 cop/ml. (en práctica clínica diaria)

58 PR/QT e IP/r

59 PR/QT e IP/r y metadona

60 ARV con potenciales ventajas en interacciones prácticas: FPV ó DRV/rtv; ETR; RAL; MVC.
Y cuidado que hay interacciones que matan….

61 TBC/VIH e inicio tto ARV.

62 CAMELIA: Survival With Early (2 S) vs Late (8 S) Therapy (D4T + 3TC + EFV) in TB-Coinfected Patients
Survival Probability, Early vs Late Therapy Log rank P = .0042 Wks From TB Treatment Initiation Probability of Survival 1.00 0.90 0.80 0.70 0.60 Early arm Late arm 50 100 150 200 250 Factors Independently Associated With Mortality Factor Multivariate Adjusted HR (95% CI) P Late therapy 1.52 ( ) .007 BMI ≤ 16 1.68 ( ) .01 Karnofsky score ≤ 40 4.96 ( ) < .001` Pulmonary + extrapulmonary TB 2.26 ( ) < .001 NTM 2.84 ( ) MDR-TB 8.02 ( ) Wk Survival Probability, % (95% CI) P Early Arm Late Arm 50 ( ) ( ) .07 100 ( ) ( ) .006 150 ( ) ( ) .002 Significantly higher incidence of IRIS with early vs late HAART 4.03 vs 1.44 per 100 person-mos, respectively (P < .0001) Blanc FX, et al. AIDS Abstract THLBB206. 62

63 Interacciones tto ARV.

64 Interacciones tto ARV.

65 125 mg/12 horas, ahora 62,5 mg QOD= AHORRO ANUAL DE 120. 000 €
Interacciones tto ARV. Bosentan (tracleer®) Dosis: Inicial 62.5 mg 1 comp/12 horas 4 semanas y después 125 mg 1 comp/12 horas. Comps de 62.5 y 125 mg (ambos PVL 2230 € envase 56 comps). Nuestra Cohorte: 6 PTES todos con LPV/ATV y Bosentan estables, antes llevaban 125 mg/12 horas, ahora 62,5 mg QOD= AHORRO ANUAL DE €

66 Conclusiones….

67 La ficha (técnica) , el ficha y los fichajes….