20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia DTG-Based Regimens Are Active in INI-Naive Patients With a History of NRTI Resistance Jim Demarest, 1 Mark Underwood, 2 Marty St Clair, 2 David Dorey, 3 Steve Almond, 3 Robert Cuffe, 4 Dannae Brown, 5 Garrett Nichols 6 1 ViiV Healthcare, Global R&D, Research Triangle Park, NC, USA; 2 GlaxoSmithKline, Clinical Virology, Research Triangle Park, NC, USA; 3 GlaxoSmithKline, Clinical Statistics, Mississauga, Canada; 4 ViiV Healthcare, Statistics, London, United Kingdom; 5 ViiV Healthcare, Medical Affairs, Abbotsford, Australia; 6 GlaxoSmithKline, Infectious Disease R&D, Research Triangle Park, NC, USA

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Introduction Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB Raffi et al. Lancet. 2013;381: Walmsley et al. N Engl J Med. 2013;369: Clotet et al. Lancet. 2014;383: Cahn et al. Lancet. 2013;382: Dolutegravir (DTG, Tivicay  ) has exhibited potent antiviral efficacy in Phase 3 studies of more than 1800 integrase inhibitor (INI)-naive patients 1-4 All subjects were screened for resistance Individuals with resistance were excluded from treatment naïve studies Baseline resistance was used as inclusion criteria and to select background regimens in SAILING Here we present post-hoc analyses of virologic failure by background regimen and baseline resistance in SAILING

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Potent and Durable Efficacy in Treatment-Naive Subjects Across the DTG Phase III Program Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB Raffi et al. Lancet Infect Dis. 2013;13: Walmsley et al. CROI 2014, Boston, MA. Abstract Clotet et al. Lancet. 2014;383: StudySPRING-2 (Wk 96) 1 SINGLE (Wk 96) 2 FLAMINGO (Wk 48) 3 RegimenDTG + 2 NRTI RAL + 2 NRTI DTG + ABC/3TC EFV/TDF/FTCDTG + 2 NRTI DRV/r + 2 NRTI <50 c/mL, a n/N (%) 332/411 (81%) 314/411 (76%) 331/414 (80%) 302/419 (72%) 217/242 (90%) 200/242 (83%) PDVF, b n (%) 22 (5%)29 (7%)25 (6%) 2 (<1%) DTG demonstrated statistical superiority in SINGLE and FLAMINGO in a pre-specified analysis In DTG treated individuals: No treatment-emergent resistance through 96 weeks in SPRING-2 and SINGLE No treatment-emergent resistance through 48 weeks in FLAMINGO a FDA Snapshot algorithm. b Protocol-defined virologic failure.

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia SAILING: DTG Superior to RAL in Treatment- Experienced, INI-Naive Adult Subjects Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. Cahn et al. Lancet. 2013;382(9893): DTG 50 mg QD plus background regimen (n=354) RAL 400 mg BID plus background regimen (n=361) HIV RNA ≥400 c/mL Resistant to ≥2 classes of ARVs Background regimen = 1-2 agents, at least 1 fully active 71% 64% Week 48 <50 c/mL P=0.03 Significantly less resistance at PDVF with DTG vs RAL at Wk 48 Emergent genotypic/phenotypic resistance: INI: DTG (4/354, 1%) vs RAL (17/361, 5%) p=0.003 Background: DTG (4/354, 1%) vs RAL (12/361, 3%) Protocol-defined virologic failure (PDVF), defined as plasma HIV-1 RNA decrease 1 log 10 c/mL increase above any nadir of ≥400 c/mL); BR, background regimen.

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. Response by DRV/r Use: Baseline Strata (SAILING, Week 48 Analysis) Cahn et al. Lancet. 2013;382: Supplemental Appendix. Baseline Stratification Virologic Response (<50 c/mL) Responders/Total n, (%) DTG (n=354) RAL (n=361) Difference (95% CI) DRV/r Use No143/214 (67%)126/209 (60%)6.5% (-2.6 to 15.7) Yes, with primary PI mutations 58/68 (85%)50/75 (67%)18.6% (5.0 to 32.2) Yes, without primary PI mutations 50/72 (69%)54/77 (70%)-0.7% (-15.4 to 14.1)

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Protocol-Defined Virologic Failure in Subjects by Type of Background Regimen (SAILING, Week 48 Analysis) Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. a Protocol-defined virologic failure (PDFV), defined as plasma HIV-1 RNA decrease 1 log 10 c/mL increase above any nadir of ≥400 c/mL). DTG n with PDVF a /N (%) RAL n with PDVF a /N (%) Overall21/354 (6)45/361 (12) NRTI-only background regimens*0/327/32 (22) PI-containing background regimens18/300 (6)36/305 (12) Other background regimens3/22 (14)2/24 (8) *All received 2 NRTI with exception of one subject on DTG (received only 1 NRTI)

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia No PDVF for DTG Subjects Receiving Only NRTIs Regardless of Number of Active NRTIs (SAILING, Week 48 Analysis) Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). DTG n with PDVF/N RAL n with PDVF/N (%) NRTI-only background regimens0/327/32 (22) 2 fully active NRTIs a 0/163/19 1 fully active NRTIs0/124/13 0 fully active NRTIs0/1- Missing phenotype0/3-

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia No PDVF for DTG Subjects with M184V Detected and Receiving 3TC or FTC Plus a Second NRTI (SAILING, Week 48 Analysis) Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). TAM, thymidine analogue mutation. DTG n with PDVF/N RAL n with PDVF/N M184V patients who received 3TC/FTC plus a second NRTI 0/134/12 Activity of second NRTI by phenotype a Fully active0/104/12 Reduced susceptibility0/1NA Missing phenotype0/2NA In presence/absence of TAMs 0 TAMs0/103/10 1 TAMsNA1/1 ≥2 TAMs0/30/1

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Lower PDVF Incidence for DTG Subjects with TAMs Than for Subjects on RAL (SAILING, Week 48 Analysis) Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). TAM, thymidine analogue mutation. DTG n with PDVF/N (%) RAL n with PDVF/N (%) All patients with TAMs10/164 (6)17/166 (10) TAMs + less than fully active 2nd agent NRTI of ABC, TDF, AZT, or ddI a 3/241/19 + third agent (PI)2/19 1/15 + third agent (MVC)0/1 0/2 + third agent (NNRTI)1/3 0/2 + third agent (NRTI)0/1 - NRTI = 3TC or FTC 0/1 - NRTI = Other - -

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Lower PDVF Incidence for Subjects Receiving DTG + PI/r Versus Those on RAL + PI/r (SAILING; Week 48 Analysis) Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). b DRV also determined as fully active by genotype (Stanford): 6/102 (6%) vs 11/126 (9%). DTG n with PDVF/N (%) RAL n with PDVF/N (%) PI-containing background regimens a 18/300 (6)36/305 (12) 1 fully active PI18/289 (6)32/295 (11) DRV/r b 6/130 (5)12/145 (8) LPV/r6/93 (6)9/90 (10) Other6/66 (9)11/60 (18) 0 fully active PI 0/7 3/8 Missing phenotype 0/4 1/2

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Conclusions Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. Treatment-naive subjects No resistance detected to DTG or to the 2 NRTIs (ABC/3TC or TDF/FTC) through 96-week (SPRING-2, SINGLE) or 48-week (FLAMINGO) follow-up Treatment-experienced, INI-naive subjects (SAILING; 48 Week) No observed virologic failures in this limited set of subjects receiving DTG + 2 NRTIs, even without full backbone activity Further studies with larger numbers of subjects and longer follow-up are required to confirm these findings The resistance profile for DTG will be defined further by use in clinical practice and additional clinical trials

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Acknowledgments Patients and their supporters DTG study investigators Study teams and colleagues at ViiV Healthcare and GSK These studies were sponsored by ViiV Healthcare Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.

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20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Resistance Testing in Phase III Studies of DTG Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104. * The assay for RT/PRO and IN is only validated for HIV RNA >400 c/ml Ongoing studies will store samples to allow future analysis Viral load at PDVF: SPRING-2 HIV RNA >50 c/mLHIV RNA >400 c/mL* PDVF Detection PDVF Confirmation PDVF Detection PDVF Confirmation DTG22/22 6/221/22 RAL29/29 4/295/29 Samples from baseline and PDVF detection were evaluated for resistance, regardless of plasma HIV-1 RNA (Monogram Biosciences) No plasma was stored from confirmatory (unscheduled) visit VL at confirmatory visit tends to decrease with adherence counselling