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 (%) 85 HIV RNA <50 copies/mL (%) HIV RNA <50 copies/mL (%) 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 81% 80 RAL + TDF/FTC EFV + TDF/FTC % Patients With% Patients 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 MAJOR ATV/r vs EFV 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

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

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?

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 HIV-1 in Plasma 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. Ruxrungtham K, ESCMIDet al. HIV Med. Vol ;9:883-896 Online .Copyright © 2009. Lecture Reproduced with permission Library of John Wiley & Sons, Inc.. Second-Line Regimens: How Many Drugs? Which Drugs? . At least 2, and preferably 3, active drugs should be in new regimen based on resistance testing . To date, virtually all data/clinical experience reflect NRTI-containing second-line regimens . Availability of 5 approved classes of antiretrovirals potentially allows use of 2 entirely new classes in second regimen – However, very few data on© such by regimensauthor

ESCMID Online Lecture Library Second Line for nuke resistance

Nuke sparing/limiting regimens PI/r with raltegravir PI/r with maraviroc PI/r© with by single author nucleoside But all being tried in Naives!!

ESCMID Online Lecture Library Darunavir/r + Raltegravir: NRTI Sparing Regimen for ARV-naïve Patients-ACTG A5262

Single arm study of DRV/r (800/100 mg) QD + RAL (400 mg BID) (N=112) Age (years) Median (Q1,Q3) 36 (27, 45) Sex Male 98 (88%) Race White 49 (44%) CD4 cell count (cells/mm3) <200 40 (36%) 200<350 32 (29%) ≥350 40 (36%) HIV-1 RNA (copies/mL) ≤100,000 63 (56%) ≥100,000 49 (44%)

Proportion Of Subjects With HIV-1 RNA <200 and <50 copies/mL (ITT analysis, missing/off study= ignored

ESCMID Online Lecture Library Taiwo B, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 551. RADAR: Darunavir/RTV + Raltegravir vs Darunavir/RTV+TDF/FTC

Proportion of patients with HIV RNA < 48 c/mL through week 24 (NC=M)*

VL < 48 at wk24: RAL: 86.2%: TDF/FTC: 87.9% (p = 0.570)

Statistically significant difference b/w groups: © by authorweeks 4 & 8: p<0.0001 N (obs) RAL 39 34 35 35 31 29 TDF/FTC 40 36 37 34 32 33 ESCMID Online Lecture Library Bedimo R et al. IAS 2011. Abstract MOPE214. NEAT 001/ANRS 143: Study design

Randomisation* . Design W96 1 : 1 Open‐label

>18 years RAL 400 mg BID 800 ARV‐naïve patients DRV/RTV§ 800/100 mg QD (4pills +1 BID) HIV RNA > 1,000 c/mL CD4 cell count ≤ 500/mm3 No major IAS mutations TDF/FTC fdc QD

(2009) on genotype DRV/RTV§ 800/100 mg QD (4pills QD)

Planned study duration : 96 weeks after enrolment of the last patient © by author * Randomization will be stratified by: § At starting point RTV old formulation will be • Country used, an amendment for the use of heat-stable • Participation at viro-immunological sub-studyv tablets of RTV will be presented during the trial ESCMID Online Lecture Library MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients: Wk 48 Results

HIV-1 RNA < 400 copies/mL 100 89.8 86.9 80 83.6 74.6 60 HIV-1 RNA < 50 copies/mL 40 MVC + ATV/RTV (n = 59) Patients (%) 20 TDF/FTC + ATV/RTV (n = 61) 0 0 4 8 12 16 20 24 28 32 36 40 44 48 © Wkby author . Frequency of all-grade adverse events similar between arms – Grade 3/4 adverse events, including hyperbilirubinemia, numerically higher in MVC arm

Portsmouth S, ESCMIDet al. IAS 2011. Abstract Online TUAB0103. Lecture Library When to start antiretroviral therapy Should this influence sequencing of ARVs ?

CD4+ Cell EACS DHHS IAS Count .< 350 cells/mm³ . Start . Start . Start

.350-500 cells/mm³ . Start if…© by. Start author . Start

.>500 . Generally . . Considered cells/mm³ deferred Start/Optional ESCMID Online Lecture Library Background: Cross-Study Comparison of Treatment-Naive Clinical Trials HIV RNA <50 copies/mL at Week 48

GS-103 QUAD (n=353)12 90 GS-102 QUAD (n=348)11 88 GS-103 ATV+RTV (n=355)12 87 STARTMRK RAL (n=281)8 86 GS-102 Atripla (n=352)11 84 ARTEMIS DRV+RTV (n=343)7 84 ECHO/TRHIVR RPV (n=550)10 83 NRTI backbone ECHO/TRHIVR EFV (n=546)10 82 FTC/TDF STARTMRK EFV (n=282)8 82 GS 934 EFV (n=244)4 80 3TC/ABC ARTEMIS LPV/r (n=346)7 78 3TC/ZDV CASTLE ATV+RTV (n=440)6 78 3TC+TDF ABT 730 LPV/r qd (n=333)5 77 CASTLE LPV/r (n=443)6 76 ABT 730 LPV/r bid (n=331)5 76 GS-903 EFV (n=299)9 76 ASSERT EFV (n=193)1 71 GS 934 EFV (n=243)4 © by author 70 MERIT ES MVC (n=311)3 68 MERIT ES EFV (n=303)3 68 HEAT LPV/r (n=343)2 68 HEAT LPV/r (n=345)2 67 ASSERT EFV (n=192)1 59 0 1020304050607080 90 100 ESCMID% ofOnline Patients with HIV-1 Lecture RNA <50 copies/mL Library at Week 48 This slide depicts data from multiple studies published from 2004-2012. Not all regimens have been compared head-to-head in a clinical trial Elvitegravir/Cobicistat/FTC/TDF (Quad) vs. ATV/r + FTC/TDF (Study 236‐103) < 50 c/mL Through Week 48 100 92% 90 88%

M=F) 80

(ITT, 70 Diff: 3.5% (95% CI: ‐1.0 to 8.0) 60 c/mL At baseline QUAD <50 50 Majority Patients had CD4 >350 ATV/r RNA

40 and VL<100000 HIV 30 with 20 10 © by author Percent 0 BL248121624324048 Week ESCMID Online Lecture Library DeJesus E, et al. 19th CROI; Seattle, WA; March 5‐8, 2012. Abst. 627. Abacavir ,Rilpivirine, lopinavir High Viral Load and Low CD4 count

It appears that there are more VFs in the high VL strata

and if CD4 is low Where do we place Abacavir ,rilpivirine and lopinavir in our treatment strategies?

ESCMID Online Lecture Library A5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count ABC/3TC Week 192 from TDF/FTC Randomization

n=98 n=78 n=80 n=153 n=39 n=273 n=23 n=184 n=80 n=83 n=70 n=158 n=55 n=289 n=20 n=173 35 VF 23 VF 19 VF 10 VF 6 VF 28 VF 5 VF 29 VF 6 VF 17 VF 9 VF 19 VF 8 VF 29 VF 2 VF 24 VF Free of Virologic Failure Free of Virologic Probability of Remaining © by author

• Increased risk of VF with baseline lower CD4 or higher VL in those assigned ABC/3TC • Results confirm previously reported analysis based on screening viral load ESCMID Online Lecture Library Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535. Rilpivirine‐caution in low CD4 and high VL Pooled ECHO and THRIVE: Response with Baseline Viral Load >100,000 c/mL by Baseline CD4

Response in Patients with Baseline Viral Load >100,000 c/mL RPV Week 48 (N=317) EFV Week 48 (N=353) 100 RPV Week 96 (N=317) EFV Week 96 (N=353) 90 (%)

80 SE

+ 70

60 c/mL

50 VL <50 40 with

30 20

Patients 10 61 77 57 71 72 78 62 72 82 82 76 79 87 84 83 77 0 <50 ≥50–<200 ≥200–<350 ≥350 Baseline© CD4 by cell count, author cells/mm3 N= 28 31 28 31 116 121 116 121 119 131 119 131 54 70 54 70

• For baseline viral load >100,000 c/mL: ESCMID– Virologic failure Online rates higher Lecture for RPV than EFVLibrary Cohen C, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 626. Which boosted PI is best at High Viral loads? Boosted PIs in ARV-naïve patients: (96 weeks)

ARTEMIS1 CASTLE2 (ITT-E, TLOVR) (ITT, NC=F) Patients with HIV-RNAPatients with <50copeis/mL(%)

LPV/r QD or BID HIV-RNAPatients with <50copeis/mL(%) LPV/r 400/100 mg BID 100 DRV/r 800/100 mg QD 100 ATV/r 300/100 mg QD 90 90 81 80 75 76 80 75 74 70 70 63 70 66 60 60 50 50 40 40 30 30 20 20 10 10 n=226 n=226 n=120 n=117 n=218 n=217 n=225 n=223 0 © by author0 <100 000 ≥ 100 000 <100 000 ≥ 100 000 Baseline HIV RNA (copies/mL)

LPV/r QD is not approved in the EU. Data in figures are from different studies and cannot be compared directly ITT, intent ESCMIDto treat; ITT-E, intent to treat, exposed; Online TLOVR, time to loss of Lecturevirological response; VL, viral load;Library NC=F, non-completer = failure Adapted from: 1. Mills A, et al. 48th ICAAC. Washington DC, Oct 25–28, 2008, Abstract H-1250c; 2. Molina JM, et al. 48th ICAAC. Washington, DC, Oct 25–28, 2008, Abstract H-1250d Which Boosted PI is best at Low CD4 Counts? CASTLE: ITT-confirmed virological response (NC=F) by baseline CD4 cell count

Week 961 ≥200 cells/mm3 3 100 100–<200 cells/mm p=NS 50–<100 cells/mm3 90 p=NS R <50 cells/mm3 76 78 es 80 71 71 69 70 69 p 70 58 o 60 n de 50 rs 40 <5 30 0 c/ 20 © by author m 10 L 0 ( 222 106 45 58 228 134 29 48 % ) ATV/r LPV/r p-values areESCMID from Cochran–Armitage trend test Online(post hoc analysis) Lecture Library 1 Molina J-M, et al. ICAAC/IDSA, Washington, USA, 2008, Poster H-1250d ARTEMIS: response by baseline CD4 at Week 96 (ITT-TLOVR)

DRV/r 800/100 mg QD LPV/r QD or BID 100 Patients VLwith <50 copies/mL (%) p=0.345a p=0.009a

80 79 79 75 60 65

n=202 n=198 n=141 n=148 0 © by author ≥200 <200

Baseline CD4 cell count (cells/mm3) aChi square analysis ESCMID Online Lecture Library Mills A, et al. 48th ICAAC Conference. 2008, Washington DC; Abstract H-1250c. Abacavir ,Rilpivirine, Lopinavir/r

Can you sequence to these drugs when the Viral

load has become undetectable and the CD4 has increased?

Maybe…..© by author Some issues remain ESCMID Online Lecture Library Abacavir and Lopinavir and cardiac disease D:A:D: Recent and/or Cumulative Antiretroviral Exposure and Risk of MI

NRTI 1.9 1.9

1.5 1.5 1.2 1.2

1.0 1.0 95%CI 95%CI yes/no

0.8 0.8 exposure/year RR of cumulative 0.6 0.6

RR of recent* exposure RR of recent* ZDV ddI ddC d4T 3TC ABC TDF # PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 # MI: 523 331 148 40 554 221 139 † NNRTI 1.2 PI 1.13 1.1 © by author

95%CI 1.0 exposure/year

RR of cumulative 0.9 IDV NFV LPV/RTV SQV NVP EFV # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 # MI: 298 197 150 221 228 221 ESCMID*Current or within last Online 6 months. †Approximate Lecture test for heterogeneity: Library P = 0.02 •Lundgren JD, et al. CROI 2009. Abstract 44LB.. FDA Meta-Analysis No Association Between ABC and MI

Forest Plot of Meta Analysis Results: Trials Sorted Based on Duration of Person –Years of Follow-up Risk Difference Study ABC Non‐ABC • 26 RCTs involving ABC (95% CI) Non‐ABC Worse ABC Worse − 5028 subjects on ACTG 368 xii 0/140 (0%) 0/143 (0%) 0 (‐2.73, 2.87) ABC, 4840 controls COL30305 0/58 (0%) 0/29 (0%) 0(‐13.79, 6.38) − Average 1.62 person/years of ACTG 372A xiii 4/116 (3.45%) 3/113 (2.65%) 0.79 (‐4.77, 6.54) ACTG A5202 xiv 2/923 (0.22%) 5/925 (0.54%) ‐0.32 (‐1.08, 0.33) F/U ABCDE xv 0/115 (0%) 2/122 (1.64%) ‐1.64 (‐6.17, 1.64) FIRST xvi 0/93 (0%) 0/89 (0%) 0(‐4.49, 4.13) • Overall events/subjects: xvii ACTG 5095 6/758 (0.79%) 1/376 (0.27%) 0.53 (‐0.75, 1.5) 28/5628 ABC vs. ACTG A5110 xviii 0/48 (0%) 0/53 (0%) 0 (‐7.01, 8.34) STEAL xix 4/178 (2.25%) 1/175 (0.57%) 1.68 (‐1.27, 5.17) 22/4840 controls (OR 1.02 NEFA xx 1/149 (0.67%) 0/311 (0%) 0.67 (‐0.55, 4.04) CNAF3007 1/96 (1.04%) 1/91 (1.1%) ‐0.06 (‐5.23, 4.9) 95%CI 0.56, 1.84) CNA30017 0/80 (0%) 2/127 (1.57%) ‐1.57 (‐5.61, 3.38) ESS 40003 0/51 (0%) 0/44 (0%) 0 (‐9.09, 7.08) • Authors conclude that the CNAA3006 0/102 (0%) 0/103 (0%) 0 (‐3.79, 3.88) findings ‘raise significant NZTA4002 0/150 (0%) 3/152 (1.97%) ‐1.97 (‐5.94, 0.58) uncertainty about the CNA109586 0/192 (0%) 1/193 (0.52%) ‐0.52 (‐3.12, 1.55) CNAB3014 0/165 (0%) 0/164 (0%) 0 (‐2.42, 2.4) likelihood of an ABC-MI risk ESS40002 1/85 (1.18%) 0/166 (0%) 1.18 (‐1.14, 7.08) BIOCOMBO xxi 1/167 (0.6%) 1/166 (0.6%) 0 (‐3.15, 3.11) association’ CNAB3002 0/91 (0%) 0/93 (0%) 0 (‐4.35, 4.19) EPZ104057© by 1/343 (0.29%) author 0/345 (0%) 0.29 (0.86, 1.75) CNA30024 1/324 (0.31%) 0/325 (0%) 0.31 (0.91, 1.86) CNAC3005 1/262 (0.38%) 0/264 (0%) 0.38 (‐1.13, 2.29) ESS100327 0/137 (0%) 1/141 (0.71%) ‐0.71 (‐4.27, 2.21) CNAC3003 1/156 (0.54%) 0/80 (0%) 0.64 (‐4.21, 3.6) CNAB3001 0/49 (0%) 1/50 (2%) ‐2(‐11.05, 5.37)

Mantel‐Haenszel 0.01 (‐0.26, 0.27) ESCMID Online Lecture-5.0% Library -2.5% 0.0% 2.5% 5.0% Ding X, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 808. Should we sequence based on ease of administration?

Regimen Dosing Food requirements EFV/TDF/FTC . 1 pill once daily . Empty stomach (recommended dosing at bedtime) ATV/RTV + . 3 pills once daily . Must be taken with food TDF/FTC . Must be separated from proton-pump inhibitors DRV/RTV + . 4 pills once daily . Must be taken with food TDF/FTC RAL + TDF/FTC . 3 pills divided across . With or without food 2 daily doses© by author RPV/TDF/FTC . 1 pill once daily . Must be taken with at least 500 cal of food . May not take with proton-pump inhibitors ESCMID Online Lecture. ? High viralLibrary load efficacy Better adherence with once-daily antiretroviral Regimens

One-daily Twice-daily Weight Association measure Author [ref] Year N/Mean/SD N/Mean/SD (%) with 95% CI

Benson 2004 294/90/18.3 146/90/17.2 10.34% Boyle 2008 205/87.1/31 95/77.1/31 4.53% Eron 2004 19/94/18.3 19/92/17.2 2.40% Gallant 2006 244/90/11.7 243/87/14 12.91% Kubota 2006 411/94.3/15.8 195/92.9/15.7 12.07% Molina 2007 115/99.8/11 75/92.6/9.4 11.53% Parienti 2007 27/95/6.2 25/93.3/8.3 9.30% Porthsmouth 2005 22/96.1/3.6 21/95.8/3.1 13.50% Rode 2008 310/90.8/20.7 296/83.8/20.7 10.74% Ruane 2006 18/85.4/9.1 13/84.4/12 4.34% Sosa 2005 119/93/18.3 117/93/17.2 8.34% META-ANALYSIS: 100% 2.88 (0.98 to 4.78)

Favours twice-daily Favours once-daily

ESCMID Online Lecture Library Adapted from Parienti J-J et al Clin Infect Dis 2009; 48:484–488. Should we sequence based on pill burden? Single Pill Regimens (STRs)

2 already Licensed in EU and USA- © byAtripla author and eviplera Quad Pill almost here Dolutegravir and 3TC / abacavir in development Darunavir and cobicistat and FTC in ESCMID Onlinedevelopment Lecture Library An evolving competitive landscape Single Tablet regimens

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 www.clinicaltrials.gov and Cobicistat Lersivirine 1. http://www.aidsmeds.com/articles/hiv_complera_gilead_1667_20970.shtml 2. http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle_pf&id=1580287 DRV/FTC/GS-7340/COBI 3. http://www.viivhealthcare.com/media-room/press-releases/2011-02-03.aspx (2017?)2 4. http://www.abbott.com/press-release/2011-july15.htmESCMID Online Lecture Library 5. http://www.gilead.com/pr_1596378 Preference of medication questionnaire in patients randomized to EFV/FTC/TDF Single tablet

% reporting was "much better" that EFV/FTC/TDF Week 4 Week 12 Week 24 Week 36 Week 48 n = 182 188 185 179 172 n = total number of patients taking the questionnaire

Hodder et al. 9th InternationaESCMIDl Congress on Drug Online Therapy in Lecture Library HIV Infection, November 9–13 2008, Glasgow, UK Should we sequence based on potential Toxicity ?

TOXICITY.

MorenoESCMID et al. Congreso Online GESIDA Lecture2010. PO 27. Libraryclinicaloptions.com/hiv Should we sequence based on potential Toxicity ? • FTC/3TC very low incidence of toxicity • Efavirenz well recognised neuropsychiatric effects but managed well in practice • Few side effects to Raltegravir • Few side effects of atazanavir (Hyperbilirubinaemia and triglycerides) and darunavir (rash and© triglycerides) by author • Tenofovir potential renal and bone toxicity

ESCMID Online Lecture Library ACTG 5202 Atazanavir/r vs Efavirenz – overall population Median Change in Creatinine Clearance Atazanavir/r vs Efavirenz (Overall As-Treated)

Wk 48, p=0.17 Wk 48 Wk 48, p=0.001 Wk 96, p=0.33 Wk 96, p<0.001 Creatinine Clearance, (mL/min) 10 Wk 96 7.8 p-values: Change in Calculated Change in 8 ATV/r vs EFV 6.1 6 4.9 4.3 4.1 4 3.1

2 ATV/r 0

Daar, E. et al. 17thESCMID CROI, San Francisco, CA, 2010, Online presentation 59LB. Lecture Library D:A:D: ARV use (per year) and Risk of ceGFR<70 and CKD from eGFR>90 Univariate Multivariate* ceGFR<70 CKD Incidence Rate Ratio (95% CI) Incidence Rate Ratio (95% CI) 1.31 1.25 Tenofovir 1.18 Tenofovir 1.08 1.22 1.33 Lopinavir/r 1.11 Lopinavir/r 1.24 1.44 1.34 1.20 1.16 Atazanavir/r 1.15 Atazanavir/r 1.03 1.04 0.80

Atazanavir 1.13 Atazanavir 1.17 1.03 1.11 1.15 1.20 Other PI/r 1.04 © by authorOther PI/r 1.08 Abacavir Abacavir Decreased risk Increased risk Decreased risk Increased risk

* Adjusted for gender, race, HIV risk group, enrolment cohort, Prior AIDS, HBV/HCV status, smoking status, hypertension, diabetes, prior CV event, baseline eGFR, age (per 10 yrs), CD4ESCMID per doubling/nadir, VL and cumulativeOnline exposure (per Lecture year) tdf, ind, lpv/r, atv, atv/r, Library abc and other PI/r Ryom L, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 865. ACTG 5202 Atazanavir/r vs Efavirenz – overall population Median Change in Fasting Lipids (mg/dL) Atazanavir/r vs Efavirenz, Week 48 (Overall As-Treated) Cholesterol LDL HDL Triglycerides 50 p<0.001 45 p-values: 40 ATV/r vs EFV 40

Change mg/dL 35 29 p=0.07 30 p<0.001 p<0.001 24 25 22 20,5 20 p<0.001 p=0.26 p=0.002 15 14 13 12 p<0.001 13 15 10 10 8 8 10 4,8 5 2 0 N= 326 290 326 300 303 270 310© 281by author322 288 324 299 325 289 324 300

ATV/r + ABC/3TC ATV/r + TDF/FTC EFV + ABC/3TC EFV + TDF/FTC

Daar, E. et al. 17thESCMID CROI, San Francisco, CA, 2010, Online presentation 59LB. Lecture Library SPIRAL: PI/r to Raltegravir Switch Improves Lipids

Median Percentage Change in Lipids following Switch from PI/r to RAL

p <0.0001 p <0.0001 p =0.0069 p <0.0017 p =0.10

Conclusion: PI/r to RAL switch results in significantly improved lipids, but no change in ESCMID Total/HDLOnline cholesterol Lecture ratio. Library Martinez E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 834. ACTG 5224s

Bone mineral density and ARVs Mean (95% CI) Percent Change in Lumbar Spine BMD (ITT)

* *

* -linear regressionESCMID Online Lecture Library No significant interaction of NRTI and NNRTI/PI components (p=0.63) Should we sequence based on Cost? The rise of Generics

Advantages Disadvantages

. Clear cost benefit . May involve change of regimen for patients who are currently on coformulated drugs or single-tablet regimens • Either switch to different coformulated drug or to the same drugs administered separately with generic substitutions . Possible problems with adherence © by author

ESCMID Online Lecture Library An evolving competitive landscape Generics

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

. Limited access Could sequence without resistance tests if develops virological failure or clinical progression on initial regimen . from NNRTI plus 2 nucleos(t)ides to Boosted PI plus integrase or CCR5 or tenofovir . But this strategy is not proven and drugs not all available © by author

ESCMID Online Lecture Library Sequencing-conclusions

. Individual regimen choices will still be important and switchingto different regimens will be based on regimen acceptability, tolerability and resistance . Few data sets to validate a sequencing approach . Little desire at present for formal sequencing in guidelines . Sequencing may be useful where there are limited drugs with non overlapping resistance and toxicity profiles and limited access to resistance© by testing- author but need access to drugs!

ESCMID Online Lecture Library