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
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
Low BL VL 2 new NRTIs Avoid nonboosted PIs 2000;16:1123-1132 Time to VL< 500 predicts virological failure Dr Bonaventura Clotet 3
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 2005-2007 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
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= 0.0003 HR (95% CI) 2.33 (1.46,3.72) Log rank test p-value< 0.0001 HR (95% CI) 1.89 (1.43,2.50) Sax PE, et al. NEJM 2009; 361:2230-2240 NNRTIs RIILPIVIRINE (ECHO & THRIVE) Dr Bonaventura Clotet 5
Pooled ECHO & THRIVE: Response by Baseline CD4 and HIV RNA Randomized, double-blind, double-dummy, multicenter, 96-week study Objective: virologic outcomes; univariate 6 5 78 54 194 176 90 94 =N 28 31 116 121 119 131 54 70 =N Cohen C, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 626. 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 6 5 78 54 194 176 90 94 =N 28 31 116 121 119 131 54 70 =N Cohen C, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 626. Cohen C, et al. 6th IAS 2011; Abstract TULBPE032 Dr Bonaventura Clotet 6
PIs DARUNAVIR (ODIN TRIAL) Dr Bonaventura Clotet 7
ODIN: viral load <50 copies/ml to Week 48 (ITT-TLOVR) Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) 100 80 60 40 20 0 0 4 8 12 24 36 48 Time (weeks) DRV/r 800/100mg qd DRV/r 600/100mg bid 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%) 72.1% 70.9% CI = confidence interval; PP = per protocol Cahn P, et al. 17th CROI 2010. 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 ) 100 80 60 40 20 0 0 4 8 12 24 36 48 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 2010. Abstract 57 Dr Bonaventura Clotet 8
ODIN: confirmed virologic response by screening HIV-1 RNA Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) 100 80 60 40 20 0 DRV/r 800/100mg qd DRV/r 600/100mg bid 78.4 76.8 52.8 52.8 N= 222 224 72 72 50,000 >50,000 Screening HIV-1 RNA (copies/ml) Cahn P, et al. 17th CROI 2010. Abstract 57 INTEGRASE INHIBITORS BASED APPROACHES Dr Bonaventura Clotet 9
CROI 2011 150LB 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 2011 150LB 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 80 60 40 20 0 QD 83.2% (QD-BID) [95% CI] = -5.7 [-10.7, -0.83] 0 4 8 12 16 24 36 48 Number of Contributing Patients Non-inferiority design (10% margin) Study Week RAL 800 mg RAL 800 mg QD RAL 400 mg BID 382 382 377 381 379 380 381 382 388 388 386 387 386 387 386 386 *All patients received TDF/FTC FDC Non-completer equals failure (NC=F) approach treats all discontinuations as failures Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 20 Dr Bonaventura Clotet 10
CROI 2011 150LB 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 113/152 74.3 128/152 84.2-9.9 (-19.0, -0.8) 100,000 copies/ml 205/230 89.1 215/234 91.9-2.7 (-8.3, 2.7) Baseline CD4 (cells/mm 3 ) 200 cells/mm 3 63/89 70.8 80/99 80.8-10.0 (-22.3, 2.2) > 200 cells/mm 3 254/292 87.0 262/286 91.6-4.6 (-9.8, 0.4) Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 21 CROI 2011 150LB 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 113/152 74.3 128/152 84.2-9.9 (-19.0, -0.8) 100,000 copies/ml 205/230 89.1 215/234 91.9-2.7 (-8.3, 2.7) Baseline CD4 (cells/mm 3 ) 200 cells/mm 3 63/89 70.8 80/99 80.8-10.0 (-22.3, 2.2) > 200 cells/mm 3 254/292 87.0 262/286 91.6-4.6 (-9.8, 0.4) Copyright 2011 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All rights Reserved 22 Dr Bonaventura Clotet 11
Dr Bonaventura Clotet 12
Virologic response in QUAD Studies 100 90 80 <100K 70 60 50 40 30 20 10 0 QUAD Atripla 100-400K >400K 3-D Column 4 <200 200-350 >351 3-D Column 8 <95% adh >95% adh Dr Bonaventura Clotet 13
Dr Bonaventura Clotet 14
Virologic response in QUAD Studies 100 90 80 70 60 50 40 30 20 10 0 QUAD ATV <100K 100-400K >400K 3-D Column 4 <200 200-350 >350 Dr Bonaventura Clotet 15
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
BUT WHAT HAPPENS IN REAL LIFE? Carlo F Perno Dr Bonaventura Clotet 17
Dr Bonaventura Clotet 18
Success achieved in patients with BL VL >100K (2008-2011) HIV Unit. irsicaixa Foundation Hospital Universitari Germans Trias i Pujol. Badalona. Barcelona.Catalonia Dr Bonaventura Clotet 19
Methods Inclusion criteria: All naïve patients (>18y/o) from our HIV-Unit starting HAART from 2008-2011 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 2008-2011 CV <100K 79% (n:711) CV >100 21% (n:189) Dr Bonaventura Clotet 20
Patients >100k characteristics (2008-2011) 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 (2008-2011) 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
Pre-Haart Viremia >500 28% (n:52) 100-300 53% (n:100) 300-500 19% (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
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 66.2 67.3 69.8 74.0 78.4 80.6 84.0 85.8 PIs based 0 25 50 75 100 % 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 >500 30 22 >48 73,1 300-500 24 17 35 89,2 100-300 23 16 31 83,7 Global 25 18 38 83,6 Kaplan Meier survival curves by pre-haart viremia (Event viremia<50 copies/ml) Breslow p-value=0.012 Dr Bonaventura Clotet 23
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
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
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
Antiviral Therapy 2006;11(1):47-51. Control Group Enfuvirtide Group log10 HIV-1 RNA 3.0 4.0 5.0 6.0 log10 HIV-1 RNA 3.0 4.0 5.0 6.0 0 1 2 3 4 5 6 Time (days) 0 1 2 3 4 5 6 Time (days) 6.00 log CV 5.00 4.00 3.00 2.00 Mean day 1-6 slope HIV-1 RNA decay p:0.025 1.00 0.00 1 2 Control Gl ENF G Dr Bonaventura Clotet 27
Changes in viral kinetics or increased potency? Dr Bonaventura Clotet 28
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
Immunology: Mean change in absolute CD4+ T cell levels Changes in Absolute CD4+ T cells (cells/mm 3 ) 400 300 200 100 0 0 10 20 30 40 50 Weeks 3-drugs 5-drugs Plasma HIV-1 RNA by standard assay % of subjects below detection 100 80 60 40 20 0 p=0.06 p=0.045 11/11 20/23 3-drugs 5-drugs 0 12 24 36 48 60 Weeks of treatment Dr Bonaventura Clotet 30
Single copy assay: week 48 Plasma viremia (copies/ml) 15 10 5 0 # 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 10 5 10 4 10 3 10 2 0 10 20 30 40 50 Weeks of therapy 3-drugs 5-drugs Dr Bonaventura Clotet 31
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
VIRAL LOAD VL (copies/ml) 140000 120000 100000 80000 60000 40000 20000 RAL+TVD RAL+TVD +MVC 0 BL W1 W2 W4 W8 W12 W24 W36 W48 VIRAL LOAD <100,000 copies/ml VL (copies/ml) 30000 25000 20000 15000 10000 5000 0 BL W1 W2 W4 W8 W12 W24 W36 W48 RAL+TVD RAL+TVD+ MVC VIRAL LOAD >100,000 copies/ml VL (copies/ml) 350000 300000 250000 200000 150000 100000 50000 0 BL W1 W2 W4 W8 W12 W24 W36 W48 RAL+TVD RAL+TVD+ MVC Dr Bonaventura Clotet 33
ABSOLUT CD4 COUNT CD4 Lymphocites (cel/microl) 800 700 600 500 400 300 200 100 0 BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD +MVC ABSOLUT CD4 COUNT <100,000 copies/ml CD4 Lymphocites (cel/microl) 800 700 600 500 400 300 200 100 0 BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD+MVC ABSOLUT CD4 COUNT >100,000 copies/ml 1000 CD4 Lymphocites (cel/microl) 800 600 400 200 0 BL W4 W12 W24 W36 W48 RAL+TVD RAL+TVD+MVC Dr Bonaventura Clotet 34
Poster 351; CROI 2012 MC Puertas et al Increased potency apparently not possible. Increase drug delivery to lymphoid tissue? Dr Bonaventura Clotet 35
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
Viral replication in pharmacologic sanctuaries Quantitation of intracellular ARV concentrations, including NRTI-triphosphates in PMBC, LN and GALT. Pharmacokinetic data suggest drug-specific compartmentalization 10 5 10 4 10 4 10 3 EFV (ng/ml) 10 3 10 2 10 1 ATV (ng/ml) 10 2 10 1 1 PBMC LN Ileal Rectal 1 PBMC LN Ileal Rectal Barcelona, 13/03/12 Fletcher #108 Poster 590; CROI 2012 Dr Bonaventura Clotet 37
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
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 (> 300-500K)???. 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