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ESCMID Online Lecture Library © by Author Optimal management of the antiretroviral- naive HIV-infected patient: Possible strategies for a correct sequencing of cART Anton Pozniak MD FRCP Director of HIV Services© by author Chelsea and Westminster Foundation Trust Hospital London UKESCMID Online Lecture Library Available ARVs: 2012 NRTI/NtRTI NNRTI Protease Fusion Tenofovir4 Efavirenz6 Darunavir Enfuvirtide 3TC2 Nevirapine Atazanavir FTC5 Etravirine Lopinavir/r Integrase Abacavir3 Rilpivirine Saquinavir Raltegravir ZDV1 Fosamprenavir ddI© by Nelfinavir author CCR5 Indinavir Maraviroc Tipranavir ESCMID Online Lecture Library Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 An evolving landscape TDF? ABC? DRV NVP EFV RTV LPV/r 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 LPV/RTV ABC/3TC EVG/COBI/FTC/TDF5 TDF/FTC ABC/3TC/AZT DTG/ABC/3TC3 1 EFV/TDF/FTC RPV/TDF/FTC 4 Fixed-dose combination LPV/RTV/3TC 2 Single-tablet regimen © by author DRV/COBI New drugs EU patent expiration (approx.) Dolutegravir Fosdevirine Cobicistat Lersivirine DRV/FTC/GS-7340/COBI ESCMID Online Lecture Library(2017?) 2 www.clinicaltrials.gov and Considerations for Selecting first-line therapy “Sequencing not a factor?” Patient factors Antiretroviral drug factors Readiness EFFICACY Baseline drug susceptibility/resistance Baseline CD4+ cell count/HIV-1 RNA Tolerability Age Long-term toxicity, metabolic Sex Drug interactions Occupation (night shifts) Dosing frequency Comorbidity Pill burden Plans for pregnancy© by Pharmacokinetics author Access to care Cost Co-medications (methadone, PPI) AdherenceESCMID Online Genetic:Lecture HLA B5701 Library The Guidelines Initial Regimen: Recommended/Preferred Agents EFV ATV/RTV TDF/FTC + DRV/RTV © by authorRAL . ESCMID Online Lecture Library Efavirenz primary end points Not beaten Study Comparator Comparator Result .ECHO, THRIVE .Rilpivirine (TMC- .Non inferiority 278) .STARTMRK .Raltegravir .Non inferiority .MERIT .Not-Non inferiority. Non- .Maraviroc inferiority .ACTG 5202 .Atazanavir/ritonavir .Equivalence not shown .ACTG 5142 .Lopinavir/ritonavir .Inferioritiy .2NN .Nevirapine© by author.Not-Non inferiority .CLASS .Amprenavir/ritonavi .Inferiority r .FOCUSESCMID.Saquinavir/ritonavir Online Lecture.Inferiority Library .ACTG 5095 .Abacavir .Inferiority PI/r Which has best efficacy in ARV-naïve patients? Virological suppression at 96 weeks KLEAN1 ARTEMIS2 CASTLE3 (ITT-E, TLOVR) (ITT, TLOVR) (ITT, TLOVR) Noninferiority Noninferiority Noninferiority 100 100 100 Extension phase N=196 90 90 90 HIV RNA <50 copies/mL (%) copies/mL <50 HIV RNA 85 (%) copies/mL <50 HIV RNA (%) copies/mL <50 HIV RNA 79 80 75 80 80 71 70 70 70 70 63 60 60 60 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 n=105 n=91 n=346 n=343 n=443 n=440 0 © 0by author 0 LPV/r FPV/r LPV/r DRV/r LPV/r ATV/r mg 400/100 700/100 800/200 QD 800/100 400/100 300/100 BID BID 400/100 BID QD BID QD Data in figures are from different studies and cannot be compared directly ITT, intent-to-treat; ITT-E, intent-to-treat exposed; M=NR, missing = non-response; NC=F, non-completer = failure; TLOVR, time to loss of virological response Adapted from:ESCMID 1. Pulido F, et al. 47th ICAAC Chicago,Online 17–20 Sept, 2007; LectureAbstract H-361; 2. Mills A, et al.Library 48th ICAAC. Washington DC, Oct 25–28, 2008. Abstract H-1250c; 3. Molina JM, et al. 48th ICAAC. Washington, DC, Oct 25–28, 2008. Abstract H-1250d STARTMRK: Raltegravir vs Efavirenz 96 week Patients with HIV RNA < 50 copies/mL through 96 weeks (Noncompleter = Failure) 100 86% HIV RNA Levels < 50copies/mL HIV RNA 81% 80 RAL + TDF/FTC EFV + TDF/FTC % Patients With 82% 79% 60 40 Noninferiority P-Value < 0.001 20 Immunologic:© by 240 vsauthor 225 cells/mm 3 (95% CI –13 to +42) 0 0 8 16 24 32 40 48 60 72 84 96 Study Week Lennox J, et al. PresentedESCMID at: 49th Annual ICAAC; September Online 12-15, 2009; San Francisco, Lecture CA. Abstract H- Library 924b. Causes of ARV Treatment Failure Few patients fail with resistant mutations Social/personal issues Poor potency Regimen issues Wrong dose Toxicities Host genetics Poor absorption Poor adherence Drug pharmacokinetics Transmitted resistance Insufficient drug level Drug interactions Viral© replicationby author in the presence of drug Resistant virus ESCMID Online Lecture Library ACTG 5202: ATV/r or EFV in Combination with ABC/3TC or TDF/FTC in Antiretroviral Naïve Patients Total (n=1857) BACKBONE 100 ABC/3TC TDF/FTC 90 p=0.046 p=0.0003 80 ANY p-values: p<0.0001 p<0.0001 ATV/r vs EFV MAJOR 70 NNRTI (amongst failures) ANY 60 MAJOR NNRTI 50 Percent NRTI 40 30 ANY NRTI 20 MAJOR NRTI ANY MAJOR NRTI 10 NNRTI PI/r PI/r NNRTI PI/r PI/r 0 © by author ATV/rEFV ATV/R EFV Viral failures No baseline resistance n= 76 63 54 48 *Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR Daar E et al. 17thESCMIDCROI 2010, San Francisco, Online California, USA. OralLecture presentation 59LB Library 10 Resistance Consequences of Initial PI-Based Regimen Failure Likely (> 30%) Less likely (10% to 30%) Rare (< 10%) or none Detectable Resistance at VF* HIV-1 RNA DHHS “Preferred” and/or IAS-USA < 50 copies/mL at NRTI “Recommended” Regimens Wk 48, % PI M184V/I Other ATV/RTV, TDF/FTC 78 (n = 440)[1] 89 (n = 465)[2]† DRV/RTV, TDF/FTC ©84 (nby = 340) author[3] *For patients with available baseline and postfailure genotypes. †96 weeks 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.ESCMID Online Lecture Library Resistance After Virologic Failure in the STARTMRK Trial at 96 Wks Resistance in Patients With RAL + TDF/FTC EFV + TDF/FTC Virologic Failure (n = 281) (n = 282) Virologic failure confirmed, n 39 45 Genotype obtained, n 16 11 4 (Q148H + G140S; RAL RAMs, n Q148R + G140S; 0 Y143H + L74L/M + E92Q + T97A; Y143R) EFV RAMs, n© by author 0 6 Resistance to FTC, n 2 2 Lennox J, et al.ESCMID ICAAC 2009. Abstract Online H924b. Lecture Library Should we sequence based on resistance ? . Very few patients fail with resistant mutations . All first line recommended combinations might fail with the 184V/I mutation +/- K65R losing the utility of FTC ,3TC +/- tenofovir . Fail with efavirenz might stay with NNRTI class eg etravirine . Fail with boosted PI then ©can by continue author ESCMID Online Lecture Library Resistance to FTC/3TC what can you use? NRTI/NtRTI NNRTI Protease Tenofovir Efavirenz Darunavir ZDV Nevirapine Atazanavir ddI Etravirine Integrase Rilpivirine Raltegravir © by author CCR5 ESCMID Online Lecture LibraryMaraviroc Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 Resistance to Tenofovir and FTC/3TC what can you use? NRTI/NtRTI NNRTI Protease ZDV Efavirenz Darunavir Nevirapine Atazanavir Etravirine Integrase Rilpivirine Raltegravir © by author CCR5 Maraviroc ESCMID Online Lecture Library Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 Resistance to Tenofovir and FTC/3TC +Resistance to efavirenz -what can you use? NNRTI Protease Darunavir Atazanavir Etravirine Integrase Rilpivirine? Raltegravir © by author CCR5 Maraviroc ESCMID Online Lecture Library Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 Resistance to Tenofovir and FTC/3TC +Resistance to PI/r -what can you use? NNRTI Protease Efavirenz Darunavir Atazanavir Etravirine Integrase Rilpivirine? Raltegravir © by author CCR5 Maraviroc ESCMID Online Lecture Library Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 Resistance to Tenofovir and FTC/3TC +Resistance to Integrase -what can you use? NNRTI Protease Efavirenz Darunavir Atazanavir Etravirine Rilpivirine? © by author CCR5 Maraviroc ESCMID Online Lecture Library Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6 After first failure what should we do? . Very few patients fail with resistant mutations-perhaps deep sequencing will find more . But if they do and have mutations to the nucleoside backbone … . No one really wants to use ZDV or DDI . So if no tenofovir resistance© by re authoruse tenofovir with a boosted PI . Use a combination of other drugs ESCMID Online Lecture Library Don’t sequence to continue nucleosides and a drug with low genetic barrier to resistance TMC125-C227: ETR vs PI in Patients With First-line NNRTI Failure, Resistance . Exploratory phase II, randomized, controlled, open-label trial Stratified by tx status Wk 24 unplanned and geographic region interim analysis Wk 48 ETR 800 mg BID + 2 NRTIs† PI-naive patients with first-line NNRTI failure, (n = 59) ≥ 1 NNRTI resistance mutation, HIV RNA > 1000 copies/mL Investigator-selected PI (N = 116)* + 2 NRTIs† © by author(n = 57) *Majority of study population from resource-limited nations. Major centers: South Africa (41%), Brazil (23%), Thailand (16%), Mexico (2%); other patients from Spain, Russia, UK, Mexico. †NRTIs selected using resistance testing. Most common: ZDV/ddI (17%), ZDV/TDF (16%), ZDV/3TC (12%). Ruxrungtham K,ESCMID et al. HIV Med. 2008;9:883-896. Online Lecture Library TMC125-C227: Virologic Response to ETR vs PI/r in NNRTI-Experienced Patients 0 ETR 800 mg BID Control -1.0 -2.0 copies/mL [±copies/mL SE]) 10 -3.0 RNA (log RNA Mean Change in Plasma HIV-1 in Plasma HIV-1 Mean Change -4.0 0 4© 8 by author 12 16 20 24 Wk ETR, n 59 55 47 40 28 17 8 Control, n 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.
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