HIGH VIRAL LOAD AND TREATMENT RESPONSE

Transcription

1 16 th Annual Resistance and Antiviral Dr Bonaventura Clotet Hospital Germans Trias i Pujol, Barcelona, Spain Thursday 20 September 2012, Wellcome Collection Conference Centre, London HIGH VIRAL LOAD AND TREATMENT RESPONSE Bonaventura Clotet Irsicaixa Foundation HIV Clinical Unit Hospital Universitari Germans Trias i Pujol Badalona, Catalonia Dr Bonaventura Clotet 1

2 CONSIDERATIONS High VL (>100,000 c/ml) and/or low CD4 (< 100/mm3) count are associated with higher risk of treatment failure Will a quick control of VL help to reduce the risk of emergence of resistance? Rapid selection of drug-resistant HIV-1 during the first weeks of suppressive ART in naïve patients. Role for intensification during initial treatment? Is there something at a PK level that causes insufficient drug delivery into cells when HIV VL is very high? CONSIDERATIONS High VL (>100,000 c/ml) and/or low CD4 (< 100/mm3) count are associated with higher risk of treatment failure Will a quick control of VL help to reduce the risk of emergence of resistance? Rapid selection of drug-resistant HIV-1 during the first weeks of suppressive ART in naïve patients. Role for intensification during initial treatment? Is there something at a PK level that causes insufficient drug delivery into cells when HIV VL is very high? Dr Bonaventura Clotet 2

3 Low BL VL 2 new NRTIs Avoid nonboosted PIs 2000;16: Time to VL< 500 predicts virological failure Dr Bonaventura Clotet 3

4 NRTIs A5202: Kivexa vs Truvada CROI 2010 A5202: Study Design CROI 2010 HIV-1 RNA 1000 c/ml Any CD4+ count > 16 years of age ART-naïve 1857 N=1858 enrolled Randomized 1:1:1:1 Stratified by screening HIV-1 RNA (< or 100,000 c/ml) Arm A B C TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD TDF/FTC QD ABC/3TC Placebo QD EFV QD EFV QD ATV/r QD Enrolled Followed through Sept 2009, 96 wks after last pt enrolled D ABC/3TC QD TDF/FTC Placebo QD ATV/r QD Dr Bonaventura Clotet 4

5 ABC/3TC vs. TDF/FTC Primary Virologic and Safety Endpoints (High Viral Load Stratum at DSMB Action) N=797; median (25 th, 75th) follow-up = 60 weeks (28, 84) Time to Virologic Failure TDF/FTC (26 events) ABC/3TC (57 events) Time to Safety Endpoint TDF/FTC (78 events) ABC/3TC (130 events) Log rank test p-value= HR (95% CI) 2.33 (1.46,3.72) Log rank test p-value< HR (95% CI) 1.89 (1.43,2.50) Sax PE, et al. NEJM 2009; 361: NNRTIs RIILPIVIRINE (ECHO & THRIVE) Dr Bonaventura Clotet 5

6 Pooled ECHO & THRIVE: Response by Baseline CD4 and HIV RNA Randomized, double-blind, double-dummy, multicenter, 96-week study Objective: virologic outcomes; univariate =N =N Cohen C, et al. 19th CROI; Seattle, WA; March 5-8, Abst Cohen C, et al. 6th IAS 2011; Abstract TULBPE032 Pooled ECHO & THRIVE: Response by Baseline CD4 and HIV RNA Randomized, double-blind, double-dummy, multicenter, 96-week study Objective: virologic outcomes; univariate =N =N Cohen C, et al. 19th CROI; Seattle, WA; March 5-8, Abst Cohen C, et al. 6th IAS 2011; Abstract TULBPE032 Dr Bonaventura Clotet 6

7 PIs DARUNAVIR (ODIN TRIAL) Dr Bonaventura Clotet 7

8 ODIN: viral load <50 copies/ml to Week 48 (ITT-TLOVR) Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) Time (weeks) DRV/r 800/100mg qd DRV/r 600/100mg bid Difference in response qd vs bid: ITT: = 1.2% (95% CI = 6.1%, 8.5%) PP: = 0.9% (95% CI = 6.7%, 8.4%) 72.1% 70.9% CI = confidence interval; PP = per protocol Cahn P, et al. 17th CROI Abstract 57 ODIN: median change in absolute CD4 cell count to Week 48 (LOCF) 120 Median change in CD4 cell count from baseline (cells/mm 3 ) Time (weeks) 100 cells/mm 3 94 cells/mm 3 DRV/r 800/100mg qd DRV/r 600/100mg bid LOCF = last observation carried forward Cahn P, et al. 17th CROI Abstract 57 Dr Bonaventura Clotet 8

9 ODIN: confirmed virologic response by screening HIV-1 RNA Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) DRV/r 800/100mg qd DRV/r 600/100mg bid N= ,000 >50,000 Screening HIV-1 RNA (copies/ml) Cahn P, et al. 17th CROI Abstract 57 INTEGRASE INHIBITORS BASED APPROACHES Dr Bonaventura Clotet 9

10 CROI LB QDMRK, A Phase III Study of the Safety & Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV- Infected Patients (Pts) J. Eron 1, J. Rockstroh 2, J. Reynes 3, J. Andrade 4, J. Madruga 5, J. Zhao 6, P. Sklar 6, B-Y. Nguyen 6 for the QDMRK Study Team 1 Univ. of North Carolina, Chapel Hill, NC, USA; 2 Univ. of Bonn, Bonn- Venusberg, Germany; 3 Montpellier Univ. Hospital, Montpellier, France; 4 Universidad de Guadalajara, Mexico; 5 Centro de Referência DST/AIDS, São Paulo, Brazil and 6 Merck Research Laboratories, North Wales, PA, USA 19 CROI LB QDMRK % of Patients with HIV RNA < 50 copies/ml (NC=F ) 100 BID 88.9% RAL 400mg Percent of Patients with HIV RNA <50 Copies/mL QD 83.2% (QD-BID) [95% CI] = -5.7 [-10.7, -0.83] Number of Contributing Patients Non-inferiority design (10% margin) Study Week RAL 800 mg RAL 800 mg QD RAL 400 mg BID *All patients received TDF/FTC FDC Non-completer equals failure (NC=F) approach treats all discontinuations as failures Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 20 Dr Bonaventura Clotet 10

11 CROI LB QDMRK HIV RNA < 50 copies/ml at Week 48 by Subgroup (NC=F) Response Difference RAL QD n/n % RAL BID n/n % % (95% CI) Baseline HIV RNA (copies/ml) > 100,000 copies/ml 113/ / (-19.0, -0.8) 100,000 copies/ml 205/ / (-8.3, 2.7) Baseline CD4 (cells/mm 3 ) 200 cells/mm 3 63/ / (-22.3, 2.2) > 200 cells/mm 3 254/ / (-9.8, 0.4) Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 21 CROI LB QDMRK HIV RNA < 50 copies/ml at Week 48 by Subgroup (NC=F) Response Difference RAL QD n/n % RAL BID n/n % % (95% CI) Baseline HIV RNA (copies/ml) > 100,000 copies/ml 113/ / (-19.0, -0.8) 100,000 copies/ml 205/ / (-8.3, 2.7) Baseline CD4 (cells/mm 3 ) 200 cells/mm 3 63/ / (-22.3, 2.2) > 200 cells/mm 3 254/ / (-9.8, 0.4) Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 22 Dr Bonaventura Clotet 11

12 Dr Bonaventura Clotet 12

13 Virologic response in QUAD Studies <100K QUAD Atripla K >400K 3-D Column 4 < >351 3-D Column 8 <95% adh >95% adh Dr Bonaventura Clotet 13

14 Dr Bonaventura Clotet 14

15 Virologic response in QUAD Studies QUAD ATV <100K K >400K 3-D Column 4 < >350 Dr Bonaventura Clotet 15

16 CROI 2011#551 Results from a Single Arm Study of Darunavir/Ritonavir plus Raltegravir in treatment-naïve HIV-1 infected patients (ACTG A5262) Patients with high viral load (>100K) and or low CD4 do worse in most trials. Dr Bonaventura Clotet 16

17 BUT WHAT HAPPENS IN REAL LIFE? Carlo F Perno Dr Bonaventura Clotet 17

18 Dr Bonaventura Clotet 18

19 Success achieved in patients with BL VL >100K ( ) HIV Unit. irsicaixa Foundation Hospital Universitari Germans Trias i Pujol. Badalona. Barcelona.Catalonia Dr Bonaventura Clotet 19

20 Methods Inclusion criteria: All naïve patients (>18y/o) from our HIV-Unit starting HAART from with BL VL > 100K VL measurements available every 12 wks (or at least 2 VL values during all follow-up) Patients changing therapy were also included (OT) Survival analysis: Time-to undetectability (first VL <50) was assessed by Kaplan-Meier. Groups comparison by Breslow test. NAIVE PATIENTS INITIATING TREATMENT IN CV <100K 79% (n:711) CV >100 21% (n:189) Dr Bonaventura Clotet 20

21 Patients >100k characteristics ( ) Drug Administered NRTIs ABV 3TC 6% TDF 3TC AZT 3TC 2% OTHERS 1% 3% PATIENTS CHARACTERISTICS VARIABLE N=189 Male, n(%) 169, (89%) FTC TDF 88% Age, years 41 Pre HAART plasma HIV- RNA median 5,65 Pre HAART CD4 (cels/mm) Median 73.5 NNRTI 31% MRV 5% THIRD DRUG RAL 8% IP/r 56% Patients >100k characteristics ( ) Drug Administered NNRTI PATIENTS CHARACTERISTICS VARIABLE N=189 EFV 79% NVP 21% Male, n(%) 169, (89%) Age, years 41 IP Pre HAART plasma HIV- RNA median 5,65 Pre HAART CD4 (cels/mm) Median 73.5 DRV 55% ATV 16% FOSAPV 4% LPV 25% Dr Bonaventura Clotet 21

22 Pre-Haart Viremia >500 28% (n:52) % (n:100) % (n:37) Time to achive virological undetectability and the rate of succes at 48 weeks (in patients with VL > 100K) On treatment analysis Kaplan Meier survival curves (Event viremia<50 copies/ml) Success 83,6% Success <100K: 98% MTU: 14 wks (IQR: 11-20) Median (IQR) time to undetectability (MTU): 25wks (18;38) Dr Bonaventura Clotet 22

23 Efficacy according to the initial HAART approach (48 wks) ABC/3TC+LPV/r TDF/FTC+NVP ABC/3TC+EFV TDF/FTC+LPV/r TDF/FTC+ATV/r TDF/FTC+EFV TDF/FTC+DRV/r TDF/FTC+RAL PIs based % responding NNRTI based Success 83,6% Time to achive virological undetectability and the rate of succes at 48 weeks are pre-haart viremia dependent Median 25% Percentile 75% Percentile Rate of succes > >48 73, , ,7 Global ,6 Kaplan Meier survival curves by pre-haart viremia (Event viremia<50 copies/ml) Breslow p-value=0.012 Dr Bonaventura Clotet 23

24 Pre-HAART viremia 100K-300K Success 83,7% Median (IQR) time to undetectability: 23 wks (16;31) Pre-HAART viremia 300K-500K Success 89,2% Median (IQR) time to undetectability: 24 wks (17;35) Dr Bonaventura Clotet 24

25 Time to achive virological undetectability and the rate of success at 48 weeks are pre-haart viremia dependent Pre-HAART viremia >500K Success 73,1% Median (IQR) time to undetectability: 30 wks (22;>48) CONSIDERATIONS High VL (>100,000 c/ml) and/or low CD4 (< 100/mm3) count are associated with higher risk of treatment failure Will a quick control of VL help to reduce the risk of emergence of resistance? Rapid selection of drug-resistant HIV-1 during the first weeks of suppressive ART in naïve patients. Role for intensification during initial treatment? Is there something at a PK level that causes insufficient drug delivery into cells when HIV VL is very high? Dr Bonaventura Clotet 25

26 CONSIDERATIONS High VL (>100,000 c/ml) and/or low CD4 (< 100/mm3) count are associated with higher risk of treatment failure Will a quick control of VL help to reduce the risk of emergence of resistance? Rapid selection of drug-resistant HIV-1 during the first weeks of suppressive ART in naïve patients. Role for intensification during initial treatment? Is there something at a PK level that causes insufficient drug delivery into cells when HIV VL is very high? Dr Bonaventura Clotet 26

27 Antiviral Therapy 2006;11(1): Control Group Enfuvirtide Group log10 HIV-1 RNA log10 HIV-1 RNA Time (days) Time (days) 6.00 log CV Mean day 1-6 slope HIV-1 RNA decay p: Control Gl ENF G Dr Bonaventura Clotet 27

28 Changes in viral kinetics or increased potency? Dr Bonaventura Clotet 28

29 A Randomized, Open-Label Trial of 5-Drug versus Standard 3-Drug PI-based cart Initiated During Acute and Early Infection: 48-Week Results M. Markowitz, T. Evering, M. Caskey, D. Garmon, A. Figueroa, K. Rodriguez, B. Davis, L. St. Bernard, M. LaMar, S. Palmer, V. Sahi, N. Prada, and H. Mohri Treatment regimen 3-drugs Fixed dose combination TDF/FTC Once daily ritonavir boosted protease inhibitor Atazanavir (N=17) Darunavir (N=23) 5-drugs Above plus Maraviroc 150 mg twice daily Raltegravir 400 mg twice daily Dr Bonaventura Clotet 29

30 Immunology: Mean change in absolute CD4+ T cell levels Changes in Absolute CD4+ T cells (cells/mm 3 ) Weeks 3-drugs 5-drugs Plasma HIV-1 RNA by standard assay % of subjects below detection p=0.06 p= /11 20/23 3-drugs 5-drugs Weeks of treatment Dr Bonaventura Clotet 30

31 Single copy assay: week 48 Plasma viremia (copies/ml) # below detection 3/11 (p=0.21) 9/18 3/11 (p=0.46) 9/21 3-drugs 5-drugs Treatment groups Proviral DNA levels Copies of HIV-1 DNA/10 6 CD4+ T cells Weeks of therapy 3-drugs 5-drugs Dr Bonaventura Clotet 31

32 Efficacy of Treatment Intensification with Maraviroc on HIV-1 Viral Latency in Recently Infected HIV-1 Naïve Patients Starting Raltegravir plus Tenofovir/Emtricitabine. A 48 week randomized, proof-of-concept pilot clinical trial. The MaraviBoost Trial. Coordinating investigator: Dr. Josep M Llibre, Lluita contra la SIDA Foundation Participating centers: Hospital Universitari Germans Trias i Pujol, Badalona, Spain (Dr Josep M Llibre; Dr Bonaventura Clotet) Hospital Clínic i Provincial de Barcelona, Spain (Dr Josep M Miró, Dr Josep M Gatell) Chelsea and Westminster Hospital NHS Foundation Trust, HIV/GUM (Dr Anton Pozniak) Intensification MVC Naïves: Phase 3 Trial Design Randomization 1:1 n=20 n=10 n=10 RAL (400 mg BID) + Truvada (TDF+FTC) RAL (400 mg BID) + Truvada (TDF+FTC) + MVC (300 mg BID) Screening (6 weeks) 0 24 wk 48 wk First patient visit Primary subanalysis Patient eligibility criteria: 18 years of age No evidence of resistance to NRTI Treatment naive HIV-1 primary infection documented in the past 6 months (acute ARV R5 HIV-1 infection syndrome or ELISA conversion) Dr Bonaventura Clotet 32

33 VIRAL LOAD VL (copies/ml) RAL+TVD RAL+TVD +MVC 0 BL W1 W2 W4 W8 W12 W24 W36 W48 VIRAL LOAD <100,000 copies/ml VL (copies/ml) BL W1 W2 W4 W8 W12 W24 W36 W48 RAL+TVD RAL+TVD+ MVC VIRAL LOAD >100,000 copies/ml VL (copies/ml) BL W1 W2 W4 W8 W12 W24 W36 W48 RAL+TVD RAL+TVD+ MVC Dr Bonaventura Clotet 33

34 ABSOLUT CD4 COUNT CD4 Lymphocites (cel/microl) BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD +MVC ABSOLUT CD4 COUNT <100,000 copies/ml CD4 Lymphocites (cel/microl) BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD+MVC ABSOLUT CD4 COUNT >100,000 copies/ml 1000 CD4 Lymphocites (cel/microl) BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD+MVC Dr Bonaventura Clotet 34

35 Poster 351; CROI 2012 MC Puertas et al Increased potency apparently not possible. Increase drug delivery to lymphoid tissue? Dr Bonaventura Clotet 35

36 CONSIDERATIONS High VL (>100,000 c/ml) and/or low CD4 (< 100/mm3) count are associated with higher risk of treatment failure Will a quick control of VL help to reduce the risk of emergence of resistance? Rapid selection of drug-resistant HIV-1 during the first weeks of suppressive ART in naïve patients. Role for intensification during initial treatment? Is there something at a PK level that causes insufficient drug delivery into cells when HIV VL is very high? PK issues The major target of most antiretrovirals (ARVs) is within cells infected with HIV and the clinical outcome of ARV therapy is related to intracellular (IC) drug concentrations. IC concentrations are likely to be influenced by different pharmacological aspects: drug oral bioavailability, plasma protein binding, drug physiochemical characteristics (i.e. lipophilicity or ionization), involvement of multidrug transport proteins responsible for drug cellular influx/efflux Penetration in lymphatic tissue Methods to assay IC concentrations are still a major challenge and have not been standardized. Dr Bonaventura Clotet 36

37 Viral replication in pharmacologic sanctuaries Quantitation of intracellular ARV concentrations, including NRTI-triphosphates in PMBC, LN and GALT. Pharmacokinetic data suggest drug-specific compartmentalization EFV (ng/ml) ATV (ng/ml) PBMC LN Ileal Rectal 1 PBMC LN Ileal Rectal Barcelona, 13/03/12 Fletcher #108 Poster 590; CROI 2012 Dr Bonaventura Clotet 37

38 Ongoing II Overview of putative raltegravir (RAL) transporters in T cells Chapter I Ongoing II Conclusions P-gp efficiently effluxes RAL both in a T-lymphoblastic cell model and in primary CD4+ T cells with high transporter activity. HIV Protease Inhibitors and NNRTIs are inhibiting P-gp function whereas RAL is not. CD4+ P-gp high cells show a higher percentage of early activation markers and a phenotype of transitional (T TM ) and effector memory (T EM ) cells. Intracellular/sanctuaries penetration of ARV drugs could be different also at different VL values which could explain the lower efficacy in patients with high viral load values Dr Bonaventura Clotet 38

39 SUMMARY Patients with BL VL > 100 K To prevent VF: Avoid Abacavir and Rilpivirine as initial treatments (role for switching?) QD is enough for DRV/r (> 50 K) ATV/r Atripla Quad /DTG BID is needed for RAL Intensified ART (>3 drugs): no evidence (> 500,000 c/ml?) Benefits of rapid VL decline (INIs) Treatment as prevention Reduction of resist emergence Need to design clinical trials (Intensification with a 4th drug vs 3 drugs) in very high VL (> K)???. How to increase drug penetration in Sanctuaries? (Inflammation, fibrosis, ARVs reach not equally LN, GALT) ACKNOWLEDGEMENTS To all those from whom I borrowed or stollen slides for this presentation: From my team: JM Llibre Roger Paredes Javier Martínez-Picado Gerard Minuesa Cristina Miranda Nuria Perez From other teams: Carlo F Perno Martin Markowitz Dr Bonaventura Clotet 39