Kiat Ruxrungtham Professor of Medicine Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre
www.iasusa.org; www.aidsinfo.nih.gov; www.clinicaloptions.com;
www.clinicaloptions.com/hiv Faculty panel* convened in February 2010 to review data supporting different options for managing contemporary initial failure scenarios Addressing causes of failure Initial NNRTI failure Initial boosted PI failure Initial integrase inhibitor failure *Faculty: Joseph J. Eron, Jr., MD (chair); Eric S. Daar, MD; Daniel R. Kuritzkes, MD; Kimberly Y. Smith, MD, MPH
Prevention HAART failure Early detection Rational to select the next regimen Key factors to the success for viral resupression Practical managment Patients with few or no options Ongoing randomized trials for second-line
How to detect failure and DR? Time-course of HAART Failure Resistance CD4 drop Non- Adherence Viral load 1 2 3 4 5 Clinical Started HAART Time (months years)
ADHERENCE: The key factor for the success of long-term antiretroviral therapy Proper ART of choice Proper monitor and early detect t nonadherence and VF Early switching if DR detected Prevent ent resistance transmission
Ongoing patient education Support and reinforcement Simplified dosing strategies Reminders, alarms, timers, and pillboxes Trust in primary care provider December 2009 www.aidsetc.org
Virus Transmitted resistance Superinfection with DR Doctor Experience Attitude Continuing patient motivation Drug Suboptimal potency wrong dose Risk of toxicity it Drug-drug interaction Single vs multiple dosing Patient Adherence Genetics : Toxicogenomic Socioeconomic Life-style Multi-comorbidity Psychiatric disorder
Possible Clinical Scenario of HIV Drug Resistance At Baseline prior to ART ART with incomplete viral suppression continuing the same ART 1 2 Recent infection Wild type only Chronic infection Wild type plus pre-existing existing mutants t Early failure with more of the same mutants or new resistant mutants Late failure with accumulation of mutants Further compromise future ARV options 3 Transmitted mutants Primary resistance Treatment failure More mutants
the Risk of HIV DR found in the Risk of HIV DR found in Controlled Trials
Pts With Mutation, % ABC/3TC with Any Major Mutation* NNRTI NRTI PI ATV/RTV (n = 76) 10-20 < 10 10-20 < 10 EFV (n = 63) 60-70 60-70 40-50 < 10 P, ATV vs EFV <.0001.0003 TDF/FTC with ATV/RTV (n = 54) < 10 0 < 10 0 EFV (n = 48) 50-60 50-60 20-30 0 P, ATV vs EFV <.0001. 046 *Major mutations defined by IAS-USA (2008) list plus T69D, L741, G190C/E/Q/T/V for RT and L241, F53L, 154V/A/T/S and G73C/S/T/A for PR. Virologic failures; no baseline resistance. Daar E, et al. CROI 2010. Abstract 59LB. From Joseph Eron, CCO 2010
Likely (> 30%) Less likely (10% to 30%) Rare (< 10%) or none DHHS Preferred Regimens HIV-1 RNA < 50 copies/ml at Wk 48, % EFV, TDF, FTC 80 % (n = 244) [1] 82 % (n = 230) [2] 90 % (n = 464) [3] EFV, TDF, 3TC 76 % (n = 299) [4] Detectable Resistance at VF* NRTI NNRTI M184V/I Other *For patients with available baseline and postfailure genotypes. 96 wks. From Joseph Eron, CCO 2010 1. Gallant JE, et al. N Engl J Med. 2006;354:251-260. 2. Lennox J, et al. Lancet. 2009; 5;374:796-806. 3. Daar E, et al. CROI 2010. Abstract 59LB. 4. Gallant JE, et al. JAMA. 2004;292:191-201.
Characteristic ATV/RTV + TDF/FTC (n = 440) CASTLE [1] ARTEMIS [2] LPV/RTV + TDF/FTC (n = 443) DRV/RTV + TDF/FTC (n = 343) LPV/RTV + TDF/FTC (n = 346) Virologic failures, n 28 29 41 74 Genotypic assays, n 26 26 31 46 Major PI mutation, n 1 0 0 0 NRTI mutations, n 7 10 2 4 Major PI RAM is uncommon in early first PI-based failure 1. Molina JM, et al. J Acquir Immun Defic Syndr. 2010;53:323-332. 2. Mills A, et al. AIDS. 2009, 23:1679-1688. From Joseph Eron, CCO 2010
Likely (> 30%) Less likely (10% to30%) Rare (< 10%) or none DHHS Preferred and/or IAS- USA Recommended Regimens HIV-1 RNA < 50 copies/ml at Wk 48, % ATV/RTV, TDF/FTC 78 (n = 440) [1] 89 (n = 465) [2] DRV/RTV, TDF/FTC 84 (n = 340) [3] 76 (n = 443) [1] 78 (n = 346) [3] LPV/RTV, TDF/FTC 67 (n = 345) [4] 64 (n = 170) [5] 77 (n = 664) [6] SQV/RTV, TDF/FTC 65 (n = 167) [5] Detectable Resistance at VF* NRTI PI M184V/I Other *For patients with available baseline and postfailure genotypes. 96 weeks From J Eron CCO 2010 1. Molina JM, et al. Lancet. 2008;372:646-655 2. Daar E, et al. CROI 2010 59 LB. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Smith K, et al. AIDS. 2009;23:1547-1556. 5. Walmsley SL, et al. J Acquir Immune Defic Syndr. 2009;50:367-374. 6. Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50:474-481.
Likely (> 30%) Less likely (10% to 30%) Rare (< 10%) or none HIV-1 RNA DHHS Preferred < 50 copies/ml Regimens at twk48 48, % RAL, TDF/FTC* 78 (n = 440) [1] Detectable Resistance at VF* NRTI M184V IN Other /I *For patients with available baseline and postfailure genotypes. 1. Lennox J, et al. Lancet. 2009; 374:796-806. From Joseph Eron, CCO 2010
NNRTI-RAMs: K103N, Y181C/I, Y188L, G190G/A, V106M. L10I, K101E 0 >2 1 2 RAMs RAM RAMs Number of RAMs Number of susceptible NNRTI Time on failing ART NVP EFV ETV ETV 0
TAMs =Thymidine analog-associated mutations Number of RAMs 0 3TC-R M184V 1-3 TAMs >3 TAMs Time on failing ART 3TC, FTC AZT, d4t, ddi, ABC, TDF AZT, d4t ddi, ABC, TDF d4t, ddi ABC, TDF TDF 0 Number of susceptible NRTIs
Number of RAMs 0 1-5 PRAMS >5-10 PRAMs >10 PRAMs LPV/r, ATV/r, SQV/r, IDV/r FPV/r,DRV/r LPV/r, ATV/r, SQV/r, IDV/r FPV/r,DRV/r DRV/r 0 Time on failing ART Number of susceptible bpis
There is no a randomized controlled study to support the changing options
Pretreated patients Baseline naive patients <40% DR Saeng-aroon et al. Antiviral Res 2010
N=120, NNRTI-based failure 100 80 60 40 20 0 NRTI-RAMRAM 85 100 80 60 23 40 12 4.5 20 0 M184V 4 TAMs Q151M K65R cpx NNRTI-RAMRAM 98 48 1 RAMs ETV GT-WS 4 Independent predictor associated with NRTI-MDR ( 4 TAMs, Q151Mcpx) Baseline CD4 <15% : OR 5.5; 95% CI 2.0-14.9] Baseline VL>5 log 10 copies/ml : OR 2.5; 95% CI 1.0-5.8 Puthanakit T, et al. HIV Med. 2010 Mar 25.
New Drugs Approval by U.S. FDA ARV Class Year Darunavir PI 2006 Maraviroc CCR5 inh 2007 Raltegravir Integrase inh 2007 Etravirine NNRTI 2008
Class Thailand U.S., Europe Dosage PI Darunavir 300 (Prezista) NNRTI Etraverine 200 (Intelence) Darunavir (Prezista) Etraverine 200 (Intelence) DRV/r 600/100 bid 800/100 od ETV 400 bid Integrase Raltegravir 400 Raltegravir 400 Ral 400 bid inhibitor (Isentress) (Isentress) CCR5 inhibitor - Maraviroc 150,300 (Selzentry) MVC 300 bid 150 bid (if + CYP3A inhibitors)
Virus Number of RAMs Number class-resistance Doctor Experience Attitude Continuing patient motivation Drug Patient Adherence Baseline VL Baseline CD4 Efficacy studies 3 active drugs Tl Tolerable Available Simple dose schedule, low pill burden
Number of active ARV in the regimen Adherence Tolerability Baseline VL level Baseline CD4 count Potency against virus with more RAMs
Subgroup Analysis: Phase 3 BENCHMRK-1 and BENCHMRK-2 % wit th VL<50 c/ml 100 Raltegravir Placebo (Both + OBT) 80 60 40 20 51 61 29 71 71 39 61 Summary Raltegravir when combined with at least 2 active ARVs provided highest % of undetectable VL 0 Cooper DA et al. NEJM 2008 2 0 1 2 3 Phenotypic Sensitivity Score or PSS
Baseline VL determined the success rates Subgroup Analysis: BENCHMRK-1 & BENCHMRK-2 100 Raltegravir Placebo ith VL< 50 c/ml 80 60 40 64 34 74 47 55 73 43 48 % w 20 20 16 0 Total 50,000 50,000 100,000 100,000 Baseline viral load Cooper DA et al. NEJM 2008
Baseline CD4 determined the success rates Subgroup Analysis: BENCHMRK-1 & BENCHMRK-2 100 Raltegravir Placebo 50 c/ml % with VL< 80 60 40 20 64 34 50 20 67 39 76 44 0 Total 50 49-200 >200 Baseline CD4 cell count (cells/mm3) Cooper DA et al. NEJM 2008
Darunavir fold change 10 and HIV-1 RNA 100,000 copies/ml at baseline significantly associated with HIV-1 RNA < 50 copies/ml at Week 24 copies/m L (%) HIV-1 RNA < 50 100 80 60 40 20 0 n = P <.0001 P <.0001 P =.0036 55 54 50 48 27 22 17 18 9 170 88 33 35 178 68 74 37 49 82 Darunavir Fold Change g g 10 HIV-1 RNA, log 10 copies/ml CD4+ Cell Count, cells/mm 3 Molina JM, et al. J Acquir Immune Defic Syndr. 2007;46:24-31. CCO 2008
100 80 N = 2,202 PI-resistant, recombinant isolates from 5,601 patients 98% of PI-resistant clinical isolates were susceptible to TMC114 at <100nM DRV susceptibility EC 50 <10nM EC 50 10 100nM EC 50 >100nM Clin nical isolates s (%) 60 40 20 0 IDV RTV NFV SQV APV LPV ATV TMC114 PI-Resistance isolates De Meyer S, et al. Antimicrob Agents Chemother 2005;49:2314 21
es/ml < 50 copi Wk 96 (%) IV-1 RNA at W H 100 DRV/RTV observed 90 LPV/RTV observed 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 Major IAS-USA PI Mutations* *D30N, V321, L33F, M461, I47V, G48V, I50V/L, I54V/L/M, L76V, V82A/F/S/T, I84V, N88S, and L90M. Identification of new genotypic cut-off levels to predict the efficacy of lopinavir/ritonavir and darunavir/ritonavir in the TITAN trial., Hill A, et al HIV Med. Copyright 2009. Vol 10: pp. 620-626.. Reproduced with permission of John Wiley & Sons, Inc. Modified from Eron J CCO 2010
V11I, V32I, L33F, I47V, I50V, I54M/L, T74P, L76V, I84V, and L89V >3 DRV-RAMs are associated with a reduced virological responses de Meyer S, et al. AIDS Res Hum Retroviruses. 2008;24:379-388.
showed associated with high rates for failure when used with less number of active OBRs
TMC125-C227: Virologic Response to ETR vs PI in NNRTI-Experienced Patients From Joseph Eron, CCO 2010 V-1 RNA ]) lasma HIV s/ml [± SE ange in Pl g 10 copies Mean Cha (log ETR, n Control, n -1.0-2.0-3.0 0 ETR 800 mg BID Control -4.0 0 4 8 12 16 20 24 Wk 59 55 47 40 28 17 8 57 55 56 53 52 41 52 Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naıve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. Ruxrungtham K, et al. HIV Med. Vol ;9:883-896.Copyright 2009. Reproduced with permission of John Wiley & Sons, Inc..
SWITCHMRK -1 and -2: Switch From Stable LPV/RTV- to RAL-Based HAART Stratified by duration of previous LPV/RTV therapy ( vs > 1 yr) Mean change in lipids at Wk 12 HIV-1 RNA < 50 copies/ml at Wk 24 HIV-infected patients with undetectable HIV-1 RNA for 3 mos on LPV/RTVbased regimen (Protocol 032: N = 348; Protocol 033: N = 354) Switch to RAL* (Protocol 032: n = 174; Protocol 033: n = 176) Continue LPV/RTV* (Protocol 032: n = 174; Protocol 033: n = 178) *All patients continued treatment with background regimen including at least 2 NRTIs. No exclusion for number of previous regimens or history of previous virologic failure. Eron J, et al. Lancet. 2010;375:396-407. CCO 2010
Virologic Suppression in SWITCHMRK in Patients t With and Without t Previous VF RAL LPV/RTV es/ml (%) = F) < 50 copie k 24 (NC = V-1 RNA at Wk 100 80 60 40 20 77 92 89 90 This finding suggests that if there was NRTI resistance present, raltegravir might not have been as effective as remaining on the boosted PI based regimen. Eron CCO 2010 HI 0 Prev VF No VF n= 111 123 228 221 Eron J, et al. Lancet. 2010;375:396-407. CCO 2010
2 NRTIs + ETR TMC125-C227 C227 study demonstrated ETR inferior to PI in patients with first-line NRTI + NNRTI failure and resistance [1] 2 NRTIs + RAL SWITCHMRK suggests previous virologic failure (NRTI resistance) associated with increased risk of rebound on 2 NRTIs + RAL [2] 1. Ruxrungtham K, et al. HIV Med. 2008;9:883-896. 2. Eron J, et al. Lancet. 2010;375:396-407. From Joseph Eron, CCO 2010
Randomized, controlled trial of LPVnaive pts on stable therapy, HIV-1 RNA 1000 copies/ml LPV/RTV 800/200 mg QD (n = 300) vs 400/100 mg BID (n = 299), both R (%) HIV-1 RNA < 50 c/ml, ITT-TLOV 100 with 2 optimized NRTIs 60 55.3 51.8 QD noninferior to BID at Wk 48 Response rates comparable btwn arms for pts with < 3 PI RAMs at BL QD inferior to BID in pts with 3 BL PI mutations Emergence of new PI RAMs similar btwn arms CD4: +135 (QD) vs +122 (BID) Zadjenverg R, et al. J Acquir Immune Defic Syndr. 2010; 80 40 20 0 P =.413 65 62 LPV/RTV QD LPV/RTV BID 31 57 n = 300 299 255 250 13 14 Overall < 3 PI RAMs 3 PI RAMs No differences in safety, AEs at Wk 48 except nausea greater with BID vs QD (7.4% vs 2.7%; P =.009) From Joseph Eron, CCO 2010
maintain the failing regimen should avoid NNRTIs, Ral, to preserve future option in the same class should include 3TC or FTC to minimize viral fitness May combined with TDF, AZT to generate reversal sensitivity
TDF AZT anged type lds cha om wild Fo fro 3 2 1 2.8 1.1 0 K65R K65R / M184V Parikh et al. J. Virol May 2006
Fold changed fro m WT 50 40 30 20 10 0 48 1 1.3 6.3 Bazmi et al. Antimicrobial Agents and Chemotherapy. 2000; 44:1783-88
HAART Failure Poor adherence NNRTI-based Cause? Adherence Intolerance Blips Drug interaction Suboptimal ART Dr transmission VL>1000 on ARV Solved Genotypic Assay VL <50 VL still high Number of active drugs available 2 < 2 Rx for VL<50 Defer switch Review Hx, previous ART, DR tests, etc. 0 Partial STI Keep 3TC
Initial Regimen Failure (First-line Failure) 1-2 Classes DR 1. 2 active NRTIs + bpi 2. 2 new classes : Ral+bPI? 2 NRTIs + NNRTI Failure 1. 2 active NRTIs + bpi 2. 3TC + active NRTI + bpi 3. Ral + bpi 2 NRTIs + bpi Failure 2 NRTIs + Ral Failure 1. 2 active NRTIs + DNV/r 2. 1NRTIs + NNRTI + DRV/r 3. NNRTI+ Ral +DRV/r 1. 2 active NRTIs + bpi 2. 1 active NRTI + NNRTI+ new bpi 3. NNRTI+ MVC + new bpi
NHSO SSO Reimbursement 2 active NRTIs + LPV/r TDF+3TC + LPV/r TDF+3TC + ATV/r Pi Private Individual Self Support Avoid to Use Similar options: May more prefer ATV/r 2 active NRTIs + DRV/r OD Ral + ATV/r? 2 active NRTIs + Ral 2 active NRTIs + ETV
Although all are retrospective they Although all are retrospective, they provide interesting information
N=40, median age 37, median BL CD4 123, median VL 55800 at 48 wk : VL< 50% =60%, VL<400 = 75% Manosuthi W et al. AIDS Res Ther. 2009 Dec 23;6:30.
100 bpi ± OBR d-bpis n=140 n=64 80 (82% 1 active OBR) 66 59 60 56 42 40 Remarks bpi±obr 87% IDV/r 6 % LPV/r 3% ATV/r d-bpis ATV/SQV/r 31% SQV/IDV/r 23% LPV/SQV/r 20% LPV/IDV/r 16% 20 0 ITT OT Siripassorn, et al. AIDS Res Hum Retroviruses. 2010 Feb;26(2):139-48. d-bpis were associated with a 2- folds higher rates of dyslipidemia (20-30% vs 11-15%, respectively)
HIV DR minority: a Thai study Pyrosquencing assay to detect Y181C and M184V sensitivity cut-off at >1% of RAMS Recent HIV infection N=105 M184V + : 3 % (% of RAM =2.8-4.2%) Y181C + : 0.5 % (% of RAM 2.9%) NNRTIs-based failure with no RAMs detection by the standard genotypic resistance test, N=38 M184V + : 1 case or 3 % (% of RAM 8.4%) Y181C +:1 case or 3 %(%ofram2 2.4%) Both cases respond well to TDF or AZT/3TC/LPV/r, recent VL<50 Hai Nguyen, et al. Preliminary report
N=200: TDF/3TC +LPV/r vs LPV/r alone HIVNAT initiated, sponsor: NSHO and Swiss Cohort Expecting the complete analyses by Nov 2010
A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and Raltegravir in Participants Virologically Failing First-line NNRTI/2N(t)RTI Therapy N = 550 NNRTI-based failure Raltegravir + LPV/r 2-3 NRTIs + LPV/r
When initiating HAART, be responsible to aim for a long-term success Persistent low-level viremia (e.g., VL 50 200 c/ml) does not necessarily indicate virologic failure but required a close monitoring The goal of treatment for previous HAART failing patients is to re-establish establish VL suppression <50 copies/ml
The new regimen should include ideally 3 active ARVs If not possible, should maintain an appropriate p regimen which includes 3TC, but should avoid using NNRTIs, raltegravir (to prevent within class cross resistance with future agents) Patients with low baseline CD4 and high VL are at risk of virologic failure, more attention is thus needed.