Debating view on less ART. Strategies under evaluation

Debating view on less ART Strategies under evaluation Andrea De Luca Dipartimento Biotecnologie Mediche Università di Siena Department of Infectious Diseases, Siena University Hospital, Italy

Conflicts of interest Research grants from: ViiV Healthcare Gilead (Fellowship Program) Merck, Sharp and Dohme Paid consultancies: ViiV Healthcare Gilead Sciences Merck, Sharp and Dohme Janssen Bristol-Myers Squibb

Outline Regimens with reduced number of drugs Use in clinical practice Evidence from studies First-line Switch in virosuppressed individuals

10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Proportion of mono/dual PI therapies according to calendar period of starting for 2017, first 6 months 0.8% 1.7% 5.2% 3.2% 6.4% 4.2% 8.9% 1.7% 2006-2008 2009-2011 2012-2014 2015-2017 Dual Mono June 2017 Report

350 300 250 200 150 100 50 0 Most used DRV-containing mono/dual therapies 295 226 137 63 49 33 32 29 54 DRV/r DRV/r,RAL 3TC,DRV/r ETV,DRV/r DRV/r,DGV DRV,cob DRV/r,MRV 3TC,DRV,cob other Most used ATV-containing mono/dual therapies 200 165 150 114 100 50 47 34 59 0 3TC,ATV/r ATV/r ATV/r,RAL ATV,RAL other June 2017 Report

DGV-containing mono/dual therapies according to calendar period 140 133 120 100 80 60 40 49 44 20 18 10 19 0 3TC,DGV DRV/r,DGV RPV,DGV DRV,DGV,cob ATV,DGV other June 2017 Report

June 2017 Report 100% 90% 80% 70% Proportion of patients with a VL<=80 copies/ml at 12 months from starting their first ART regimen by calendar year of initiation 85.5% 88.8% 90.5% 88.9% 88.1% 89.9% 91.2% 94.3% 95.4% 95.7% 83.1% 75.0% 78.1% 80.5% 77.1% 60% 50% 40% 30% 20% 10% 58.1% 52.5% 43.6% 38.3% 17.0% 0% 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

3.7% 0.50% 4.4% 7.8% 4.42% 6.2% 7.3% 13.0% 9.7% 16.7% 20.6% 15.56% 8.7% 16.5% 11.5% 11.93% 9.2% 18.9% 11.2% 7.91% 5.2% 6.8% 25.7% 22.1% 21.4% 21.22% 21.8% 25.24% 40.9% 36.4% 44.9% 51.4% 57.1% 52.7% 61.2% 70% Reasons for stopping at least one drug of the first ART regimen within 1 year, according to calendar period of starting N = therapy interruptions per period 60% 50% 40% 30% 20% 10% 0% 1997-1999 (N=602) 2000-2002 (N=294) 2003-2005 (N=257) 2006-2008 (N=218) 2009-2011 (N=455) 2012-2014 (N=735) 2015-2017 (N=206) FAILURE OTHER PATIENT'S DECISION SIMPLIFICATION TOXICITY for 2017, first 6 months June 2017 Report

Monotherapies? PI/r monotherapies Inferior to triple, but very rare resistance selection Reinduction + 2NA works DRV/r more solid data: inferior with nadir CD4<200 DTG monotherapy: catastrophe Inferior AND resistance selection How to throw away the most precious ARV class

% HIV-RNA <200 c/ml DOMONO DTG as Maintenance Monotherapy For HIV-1 100 80 60 40 20 DOMONO is a multicenter randomised non-inferiority trial comparing 96 patients on DTG 50mg QD monotherapy vs cart 0 Viral Suppression at W48 On-Treatment Analysis p=0.03 92% 98% DTG Mono (N=96) cart (N=152) Pt Characteristics of Virologic Failures on DTG Monotherapy* BL 3 rd agent (with F/TDF) Timing of Failure HIV-RNA at Failure (c/ml) Integrase Sequence at Failure 1 RPV W4 71,600 No RAMs 2 EFV W12 678 Not successful 3 RPV W30 3,510 No RAMs 4 RPV W30 1,570 S230R 5 DTG W36 1,440 Not successful 6 RPV W48 4,990 No RAMs 7 NVP W60 3,470 R263K 8 NVP W72 4,180 N155H * All CD4 T-cell nadir 210 cellsmm 3 and >95% adherence (according to clinician) Study prematurely discontinuation due to predefined stopping rule (emergent INSTI resistance) Wijting I, et al. CROI 2017. Seattle, WA. Poster #451LB DTG monotherapy efficacy was inferior by Week 48

REDOMO: Pathways of Resistance in Subjects Failing DTG Monotherapy Outcomes in Patients Failing DTG Monotherapy after Switch International, multi-cohort, retrospective study characterizing resistance of subjects who switched to DTG monotherapy 50 mg QD (n=122) Monotherapy (N=122) Virologic Failures (%) Blanco JL, et al. CROI 2017. Seattle, WA. Oral #42 Bi / Tri-therapy (N=1,082) 9% (n=11) 6% (n=64) 11 subjects in monotherapy arm experienced virologic failures 45% - first INSTI 64% - 95% adherence 72% - 3 years virologic suppressed prior to switch Resistance Selection (%) 82% Monotherapy Bi / Tri-therapy High rate of genotypic resistance selection after DTG monotherapy failure Summary of available studies: InSTI resistance in 15 of 20 9/11 0% Median time from VF until genotypic resistance testing: 5 weeks (IQR: 3-14) DTG monotherapy VFs led to different mutation pathways (92Q,118R,148X and 155H)

Less toxic than dual? Why mono? With 3TC/FTC no/minimal added toxicity Less resistance selection (with PI/r) More resistance selection to 3TC/FTC or other classes?

Dual therapies in naives Study regimen control n Efficacy outcome Benefits/Harms Gardel LPV/r+3TC LPV/r+2NA 416 Non-inferior (but comparator suboptimal) Less AE, no resistance PADDLE DTG+3TC no 20 18/20 <50 cps at 48w 1 suicide, 1PDVF resuppressed (no change) ACTG A5353 DTG+3TC no 120 31% VL>100K. 90% VS. 3 PDVF (1 with M184V and R263R/K) ANDES DRV/r+3TC DRV/r+TVD 145 24w: VL<400 in 95% vs 97% 24w VL>100K all <400 GEMINI DTG+3TC DTG+TVD 700 ONGOING Modern DRV/r+MVC QD DRV/r+TVD 804 Inferior Bone NEAT001 DRV/r+RAL DRV/r+TVD 805 Non-inferior, inferior with CD4<200 or VL>100K Bone, egfr/insti-r selection

ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF for ART-Naive Pts Randomized, open-label phase IV study in Argentina Interim Analysis Wk 24 Primary Endpoint Wk 48 ART-naive pts with HIV-1 RNA > 1000 copies/ml (N = 145) Baseline: 24% HIV-1 RNA > 100,000 copies/ml HIV-1 RNA < 400 c/ml (ITT) at Wk 24, n/n (%) DRV/RTV + 3TC DRV/RTV + 3TC/TDF Overall 71/75 (95) 68/70 (97) BL HIV-1 RNA > 100,000 copies/ml 20/20 (100) 15/15 (100) 1 virologic failure with DRV/RTV + 3TC/TDF DRV/RTV + 3TC QD (n = 75) DRV/RTV + 3TC/TDF QD (n = 70) Dosing: DRV/RTV, 800/100 mg; 3TC, 300 mg; 3TC/TDF, 300/300 mg. Sued O, et al. IAS 2017. Abstract MOAB0106LB. Slide credit: clinicaloptions.com

HIV-1 RNA (copies/ml) ACTG A5353: HIV-1 RNA Levels and DTG Concentration in Pts Experiencing PDVF Pt 1 BL HIV-1 RNA > 100,000 copies/ml Pt 2 BL HIV-1 RNA 100,000 copies/ml Off DTG Pt 3 BL HIV-1 RNA 100,000 copies/ml Off DTG 1,000,000 100,000 10,000 1000 100 50 0 0 2 4 8 12 16 20 24 32 Study Wk None 4000 3000 2000 1000 0 1,000,000 100,000 10,000 1000 100 50 0 None M184V M184V R263RK 0 2 4 8 12 16 20 24 32 Study Wk 4000 3000 2000 1000 0 1,000,000 100,000 10,000 1000 100 50 0 Study Wk V1061 0 2 4 8 12 16 20 24 32 4000 3000 2000 1000 0 DTG Concentration (ng/ml) HIV-1 RNA (copies/ml) DTG concentration (ng/ml) HIV-1 RNA < limit of detection No detectable DTG Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB. Reproduced with permission. Slide credit: clinicaloptions.com

Dual RCT in treatment naive: unsuccessful studies DRV/r + MVC inferior to 2NA + DRV/r Well powered ATV/r + MVC inferior to 2NA + ATV/r Small, limited power ATV/r + RAL inferior to ATV/r + 2NA More jaundice, InSTI resistance selection

Study Maintenance dual ART: completed prospective trials Previous regimen Study regimen control n Main Efficacy outcome Benefits/Harms ATLAS-M ATV/r+2NA ATV/r+3TC ATV/r+2NA 266 Non-inferior (superior) egfr, bone, AE/lipids SALT Any triple ATV/r+3TC ATV/r+2NA 273 Non-inferior Less AE/lipids OLE LPV/r+2NA LPV/r+3TC LPV/r+2NA 250 Non-inferior No/lipids DUAL DRV/r+2NA DRV/r+3TC DRV/r+2NA 257 Non-inferior MOBIDIP bpi+2na bpi+3tc bpi 265 Dual>mono (VF 48w 3% vs 24.8%) All had previous M184V PROBE PI/r+2NA DRV/r+RPV continue 60 Non-Inferior Bone, immune activation/lipids Multineka LPV/r+2NA LPV/r+NVP LPV/r+2NA 67 Non-inferior GUSTA Any triple DRV/r+MVC qd cont 133 Inferior AE, Bone, AP MARCH PI/r+2NA PI/r+MVC bid 2NRTI+MVC bid cont 395 PI/r+MVC inferior

Maintenance dual ART: completed prospective trials Study Previous regimen Study regimen control n Main Efficacy outcome Benefits/Harms LATTE CAB+2NA CAB+RPV IM EFV+2NA 243 Non-inferior LATTE-2 CAB (oral)+abc/3t C CAB+RPV IM q4w or q8w CAB (oral)+abc/ 3TC 309 Non-inferior Patients satisfaction/isr SWORD Any triple DTG+RPV continue 1024 Non-inferior Improved BMD and bone turnover markers SPARE LPV+TVD DRV/r+RAL LPV+TVD 58 egfr urinary b2m improved Harness Any triple ATV/r+RAL ATV/r+2NA 109 Inferior KITE 2NA+X LPV/r+RAL continue 60 Non-inferior no/lipids ANRS 167 LAMIDOL DOLULAM Triple (81% bpi, 26% RAL) 2NA+X DTG+3TC no 104 97% success w48 (1 PDVF) Some excluded after induction (VF, tox) DTG+3TC no 27 2 years: no VF 63% had historical RNA or DNA with M184I/V

ATV/r+3TC: ATLAS-M 96 weeks

Efficacy endpoint analyses at 96 weeks 12% (95% CI 1.2; 22.8) 12.8% (95% CI 1.9; 23.7) 13.5% (95% CI 2.7; 24.3) 14.3% (95% CI 3.4; 25.2)

Causes of treatment failure ATV/rit+3TC N=133 ATV/rit+2 NRTIs N=133 Any cause 30 (22.6) 46 (34.6) 0.030 Virological Failure 2 (1.5)* 9 (6.8) 0.060 Adverse events (potentially treatment-related) i 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) ii 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 Values are expressed as n (%) * One VF at baseline, before treatment simplification. p Notes: i. DT: skin rash (w4), renal colic (w26 and w49), biliary colic (w60), pancreatitis (w62), hypertriglyceridemia (w72), creatinine increase (w75); TT: creatinine increase (w3 and w7), osteopenia (w16), renal colic (w24, w60, w63, w77, w80), drug nephropathy (w43), proteinuria (w84), hyperbilirubinemia (w84). ii. DT: sudden death (w10 and w78, suspect cardiac events), thyroid carcinoma (w24); TT: spinal disc herniation (w3), pneumonia (w12), abdominal cancer (w48), creatinine increase (w60), lung cancer (w72).

Virological failures ID Visit HIV-RNA (cp/ml) CD4 (cells/µl) Comments Dual therapy arm 40 BL 1.452 904 VF at BL, before treatment simplification. GRT: no resistance. 164 W12 64 606 Triple therapy arm 85 W24 16.667 435 No subsequent data, lost to follow-up. 247 W24 7.684 895 VF with low VL (64 and 248 cp/ml); after re-intensification with TDF, subsequent VL 83 cp/ml then <40 cp/ml. GRT: no resistance. Treatment change to elvitegravir/cobicistat/ tenofovir/emtricitabine with virological suppression. GRT PR: 58E. 137 W36 2.797 626 VL <50 cp/ml without treatment change. GRT: no resistance. 168 W36 1.854 597 VL <50 cp/ml without treatment change. GRT: no resistance. 23 W48 26.720 305 VL <50 cp/ml without treatment change. GRT: no resistance. 107 W48 99.999 349 Subsequently lost to follow up. GRT PR: no resistance. 174 W60 22.572 341 230 w84 55 1.137 78 w96 109 674 No subsequent data, lost to follow-up. Subsequent follow up not available. GRT PR: no resistance, RT: 101Q, 138A, 179I (intermediate R to ETR, RPV). VF with low VL (55 and 78 cp/ml); treatment change to abacavir/lamivudine+dolutegravir with virological suppression. GRT PR: no resistance RT:215S.

Evolution of renal function

Bone outcomes at 96 weeks Changes in BMD at 96W (%) Dual arm TT arm 2.53 1.77 0.69 0.57 Lumbar Spine Total Hip Femoral neck n=73 DT arm: 41 TT arm: 32 p= ns -1.48 p= ns p= 0.02-2.95 Bone turnover biomarkers (%) Dual arm TT arm p= ns 31.83 14.7 p= ns p= ns p= ns PTH Vitamin D Osteocalcin FAO -15.62-2.64-50.91-45.2-23.3-14.1

DUAL-GESIDA 8014: Dual DRV/RTV + 3TC vs Triple DRV/RTV + FTC/TDF or ABC/3TC Randomized, multicenter, open-label, phase IV noninferiority trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 (ITT-e, FDA snapshot analysis) Pts with HIV-1 RNA < 50 copies/ml for > 6 mos; on triple therapy* 2 mos; HBsAg negative (N = 257) Stratified by baseline NRTI Pulido F, et al. HIV Glasgow 2016. Abstract O331. Switch to DRV/RTV + 3TC QD (n = 129) Continue Previous Triple Therapy* (n = 128) *Previous triple therapy regimens: DRV/RTV + FTC/TDF or DRV/RTV + ABC/3TC. Wk 48 Primary endpoint

Sensitivity analysis Proportion ofpatients with HIV viral load <50 copies/ml (%) Difference (%) IC 95% 12 0 3.4-3.8 5.7-2.2 3.9-3.4 2.4-1.7-5.8-12 -11-10.2-10.7 DUAL TRIPLE 100% 89% 93% 87% 89% 89% 93% 97% 98% 80% 60% 40% 20% 0% ITT-e (snapshot) ITT (snapshot) Per-Protocol (snapshot) Observed data Observed data: excluding non-virological reasons for failure. DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results 28

Resistance testing (attempted in all rebounds with viral loads > 400 HIV-RNA copies/ml) GROUP Week HIV-RNA 50 c/ml week 48 (SNAPSHOT) 1 st viral load 2 nd viral load Genotype Mutations DUAL Baseline Yes 80 800 Yes None DUAL 24 Yes 988 259 Failed DUAL 32 No 6,805 165 Yes None TRIPLE 24 No 427 <20 Failed TRIPLE 24 No 447,557 5,621 Yes V10I, W71T, D76W DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results 29

ANRS 167 LAMIDOL DTG + 3TC as Maintenance Therapy Joly V, et al. CROI 2017. Seattle, WA. Poster #458 Inclusion Criteria Current: 2 NRTIs + either NNRTI, PI, or INSTI Maximum of 2 previous ART modifications (simplification or one tolerability switch) Suppressed <50 c/ml for 2 years with no blips in previous 6 months * Wild type virus CD4 nadir >200 cells/mm 3 INDUCTION DTG + 2 NRTIs (n=110) MAINTENANCE DTG + 3TC (n=104) Baseline Week 8 Week 48 & 56 Outcomes INDUCTION: 95% (104/110) eligible for dual therapy MAINTENANCE: 97% (101/104) remained suppressed 1 virologic failure: W4 with VL 84 c/ml 1 therapeutic failure: W40 with blip VL 59 c/ml 1 lost to follow-up: W32 Switching to DTG+3TC maintained virologic suppression in patients without history of virologic failure >18 years Normal labs & HBsAg negative * Subjects were on current ART for a median of 4 years (range: 0.5-11.3) 6 subjects were ineligible for Phase 2: 3 with detectable VL and 3 with AEs (1 serious AE of suicide ideation)

3TC+PI/r dual therapies as maintenance strategies: resistance at failure 4 randomized controlled studies: 2 ATV/r+3TC (ATLAS, SALT), 96W 1 LPV/r+3TC (OLE) 1 DRV/r+3TC (DUET) NO EMERGING RESISTANCE MUTATIONS AT FAILURE (1 case of M184V in the 3-drug arm of SALT) In observational studies: 1 case of resistance to ATV (V32I-M46L- I50L-V82A) (no M184V) Role of previous M184V in 3TC + PI/r or DTG? 31

Patients baseline characteristics in DT group (n=454) M184V- (n=365) M184V+ (n=89) p Age, years* 47 (40;54) 52 (48;57) <0.001 Male gender 265 (73%) 52 (58%) 0.008 Caucasian 322 (88%) 86 (97%) 0.081 Risk factor sexual IDU other 28% 232 (64%) 44(12%) 89 (24%) 58 (65%) 21 (24%) 10 (11%) HCV co-infection 68 (19%) 24 (27%) 0.570 HBsAg+ 14 (4%) 2 (2%) 0.279 3TC+DRV/r Previous AIDS events 41 (11%) 16 (18%) 0.085 Years from HIV diagnosis* 8 (4;14) 19 (16;23) 3TC+DTG <0.001 Years from first cart initiation* 37% 6 (3;11) 17 (13;19) 3TC+RAL <0.001 CD4 nadir, cells/µl* 224 (81;310) 131 (52;199) <0.001 CD4, cells/µl* 627 (462;786) 616 (409;899) 0.310 Previous major PI resistance mutations 12 (3%) 29 (33%) <0.001 Type of DT: 3TC+PI/r 254 (70%) 67 (75%) 0.290 3TC+INI 111 (30%) 22 (25%) Calendar year of BL 2014 (2013;2015) 2014 (2012; 2015) 0.174 Gagliardini R 15th European MHH, 2017 Values are expressed as n (%) except for * median (IQR) Dual therapies 1% 10% 24% 3TC+LPV/r 3TC+ATV/r 0.002

Virological outcomes on dual therapies Overall incidence of VF: 2.35 per 100 PYFU 13 over 572 PYFU in M184V- pts (2.27 per 100 PYFU) 4 over 153 PYFU in M184V+ pts (2.63 per 100 PYFU) 3 DRV/r+3TC, 1 ATV/r+3TC Median follow-up: 1.2 years (IQR 0.6-2.4) Estimated probability of remaining free from VF with dual therapy at 3 years M184V- 92.5% (95% CI 87.2; 97.8) M184V+ 92.5% (95% CI 85.0; 99.9) p=0.824 Virological blips occurred in 29/352 (8%) M184V- pts and 15/84 (18%) M184V+ (p=0.009). Gagliardini R 15th European MHH, 2017

Virological outcomes on dual therapies vs monotherapies Overall dual therapy versus monotherapy Dual therapy M184V+ versus monotherapy Estimated probability of remaining free of VF at 3 years DT 92.5% (95% CI 87.9; 97.0) Mono 81.5% (95% CI 73.1; 89.9) p<0.001 Estimated probability of remaining free of VF at 3 years DT M184V+ 92.5% (95% CI 85.0; 99.9) Mono 81.5% (95% CI 73.1; 89.9) p=0.049 Gagliardini R 15th European MHH, 2017

HIV-1 RNA <50 c/ml, % SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR Snapshot Outcomes at Week 48 (Pooled) 100 80 60 40 20 95 95 Virologic outcomes DTG + RPV (n=513) CAR (n=511) Adjusted treatment difference (95% CI)* CAR -0.2-3.0 2.5 DTG + RPV 0 Virologic success <1 1 Virologic non-response 5 4 No virologic data -8-6 -4-2 0 2 4 6 8 Percentage-point difference * Adjusted for age and baseline 3 rd agent. Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB

Mean Adjusted Change in BMD From BL (%) SWORD 1 & 2 Substudy: BMD Impact of Switch From TDF-Based ART to DTG + RPV Randomized, open-label, multicenter phase III trials demonstrated that switch to DTG + RPV noninferior to remaining on baseline ART at Wk 48 in virologically suppressed pts [1] Current analysis assessed BMD in pts who continued on TDF-containing triple ART regimen or switched from TDF-containing triple ART to DTG + RPV (N = 102) [2] Change From BL in BMD at Wk 48 2.5 1.5 0.5 P =.014 1.34 0.05 P =.039 1.46 0.15 DTG + RPV (n = 46) Continued TDF-based ART (n = 35) -0.5-1.5-2.5 BL 48 Wks BL 48 Wks *Primary endpoint. Total Hip* Lumbar Spine 1. Llibre JM, et al. CROI 2017. Abstract 44LB. 2. McComsey G, et al. IAS 2017. Abstract TUPDB0205LB. Reproduced with permission. Slide credit: clinicaloptions.com

Pts (%) LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART Cabotegravir: INSTI formulated as PO tablet and for long-acting IM injection LATTE-2: phase IIb study in which pts randomized to CAB 400 mg IM + RPV 600 mg Q4W, CAB 600 mg IM + RPV 900 mg Q8W, or CAB 30 mg PO + ABC/3TC 600/300 mg QD after induction/ virologic suppression with oral CAB + ABC/3TC (N = 309) [1,2] 100 80 60 40 20 94 87 84 0 Virologic Success* *HIV-1 RNA < 50 copies/ml. References in slidenotes. Wk 96 Virologic Efficacy CAB IM + RPV Q4W (n = 115) CAB IM + RPV Q8W (n = 115) CAB PO + ABC/3TC (n = 56) Treatment Difference vs CAB PO (95% CI) CAB IM Q4W: 3.0% (-8.4% to 14.4%) CAB IM Q8W: 10.0% (-0.6% to 20.5%) 13 14 4 0 2 2 Virologic Nonresponse No Virologic Data At 96 wks, ~ 30% of pts receiving IM injection experienced ISR 99% of ISRs mild/moderate Withdrawals between Wks 48 and 96: CAB IM arms, n = 4 (n = 1 for AE, n = 3 withdrew consent); CAB PO arm, n = 3 (all withdrew consent) No additional PDVFs after Wk 48 in any arm ~ 88% of pts receiving CAB IM very satisfied to continue present treatment at Wk 96 vs 43% receiving CAB PO Phase III maintenance trials (ATLAS and FLAIR) moving forward with Q4W dose [3,4] Slide credit: clinicaloptions.com

Dual therapies: considerations Most solid evidence of efficacy in maintenance therapy PI/r+3TC (..and M184V does not preclude its activity): no resistance selection DTG+RPV Caveat: PI/r tolerability? Toxicity benefits of dual vs triple: Bone and renal, due to TDF discontinuation Will TAF avoid the need of dual? Reduced costs Not for all dual therapies DTG + 3TC future game changer? Naive, maintenance Beyond efficacy, tolerability and costs will still count Previous M184V? Resistance selection?