Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice Tseng, and Dr. Stephen Shafran

The 13 th European AIDS Conference (EACS) Meeting October 12-15, 2011 Belgrade, Serbia

OVERVIEW STARTMRK 192 VIKING 24 ATL to CPL TDR in MSM

Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK J. K. Rockstroh, A. Lazzarin, J. Zhao, A. Rodgers, M. J. DiNubile, B-Y. Nguyen, R. Leavitt, H. Teppler, and P. Sklar for the STARTMRK Study Team EACS UPDATE

STARTMRK 192 BACKGROUND At 192 weeks, RAL was non-inferior compared to EFV With non-completer-as-failure (NC = F), VL < 50 at 192 = 76% vs. 67% 95% CI of 9% [2, 16] favouring RAL Presented at EACS: week 192 secondary observed-failure (OF) analysesMETHODS ARV naïve, blinded and randomized to RAL (BID) + TVD or EFV (QHS) + TVD Viral susceptibility to EFV, FTC, & TDF, VL > 5000, any CD4 Planned 240 weekRESULTS Wk 192 OF analyses 235/281 (84%) RAL vs. 222/282 (79%) in EFV group were included…CONCLUSIONS Both treatment groups showed generally consistent virologic and immunologic outcomes at Wk 192, including high viral loads Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Proportion of Patients with <50 vRNA c/mL at Wk 192 by Demographic Factors (OF Approach) Race White Black Asian Hispanic Multiracial Total214/235 (91)189/222 (85) EFV Group n/N (%) Difference in Response Rates % (95% CI) RAL Group n/N (%) Age (years)  Median >Median 109/122 (89) 105/113 (93) 105/129 (81) 84/93 (90) Gender Male Female 173/191 (91) 41/44 (93) 157/185 (85) 32/37 (86) Viral Subtype Clade B Non-Clade B 164/181 (91) 47/51 (92) 149/177 (84) 35/40 (88) 86/93 (92) 21/24 (88) 31/34 (91) 47/53 (89) 28/30 (93) 75/83 (90) 17/22 (77) 25/28 (89) 44/57 (77) 28/32 (88) Favors EFVFavors RAL Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Proportion of Patients with <50 vRNA c/mL at Wk 192 by Baseline Prognostic Factors (OF Approach) Total214/235 (91)189/222 (85) Difference in Response Rates % (95% CI) EFV Group n/N (%) RAL Group n/N (%) Baseline Plasma HIV RNA (c/mL)  100,000 >100,000 98/105 (93) 116/130 (89) 86/106 (81) 103/116 (89) Baseline CD4 Counts (cells/mm 3 )  50 >50 and  200 >200 17/22 (77) 84/88 (95) 113/125 (90) 25/29 (86) 71/85 (84) 93/108 (86) Hepatitis Status Hepatitis B or C Positive Both Hepatitis B and C Negative 11/12 (92) 203/223 (91) 12/13 (92) 177/209 (85) Favors EFVFavors RAL Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

% Responders with vRNA <50 c/mL (n/N) Change from BL CD4 Count (cells/mm 3 ) NC = FOF RAL 76.2 (214/281) 91.1 (214/235) 361 EFV 67.0 (189/282) 85.1 (189/222) 301 Δ RAL - EFV 9.0* (1.6, 16.4) 6.0* (0.1, 12.2) 60 (24, 95) *p-value for non-inferiority <0.001 Summary of Efficacy at Week 192 Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

MLMC Clinical Trends: Sept 2011 MLMC Database: September 2011 Utilization of EFV+TVD and RAL+TVD, most recent CD4 and VL Viral Load (copies/mL)CD4 Count (cells/µL) Regimen # of Patients <50 90 Days ,000 >10,000< >500 FTC + TDF + EFV %96.1%3.7%2.0%2.6% 10.9%30.9%55.6% FTC + TDF +RAL7695.8%97.1%1.4%0%2.8%6.9%4.2%22.2%66.7% Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

MLMC Clinical Trends: Sept 2011 Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

STARTMRK 192 BACKGROUND At 192 weeks, RAL was non-inferior compared to EFV With non-completer-as-failure (NC = F), VL < 50 at 192 = 76% vs. 67% 95% CI of 9% [2, 16] favouring RAL Presented at EACS: week 192 secondary observed-failure (OF) analysesMETHODS ARV naïve, blinded and randomized to RAL(BID) + TVD or EFV(QHS) + TVD Viral susceptibility to EFV, FTC, & TDF, VL > 5000, any CD4 planned 240 weekRESULTS Wk192 OF analyses 235/281 (84%) RAL vs. 222/282 (79%) in EFV group were included…CONCLUSIONS Both treatment groups showed generally consistent virologic and immunologic outcomes at Wk 192, including high viral loads Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK. [Poster PS1/1] Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Dolutegravir (DTG, S/GSK ) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study V Soriano, J Cox, JJ Eron, et al. EACS UPDATE

VIKING 24 OBJECTIVES Assess Dolutegravir (DTG) in patients with Raltegravir (RAL) resistanceMETHODS 2 sequential cohorts with resistance to RAL and ≥2 other ARV classes Received DTG 50mg QD (Cohort 1) or 50mg BID (Cohort 2) Continued with failing background to day 11, then optimized Needed at least 1 fully active ARV in OBRRESULTS Baseline and antiviral responses at day 11 and Week 24: (see table) Self limited grade 1-2 diarrhea most common AE in 3 & 7 subjects in Cohorts I & II respectivelyCONCLUSIONS DTG exerts potent antiviral activity in highly treatment experienced RAL resistant patients Confirms DTG 50mg BID for phase III trial in subjects with RAL or EVG (ongoing) Soriano V, et al. Dolutegravir (DTG, S/GSK ) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study. [Poster PS1/2]. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Key Baseline CharacteristicsCohort I (n=27) DTG QD Cohort II (n=24) DTG BID Median CD4+ cells/mm Median HIV-1 RNA log 10 c/mL Q148 + ≥ 19 (33%)11 (46%) N155 or Y143 or other18 (67%)13 (54%) Median RAL FC (range)> 161 ( >max > 128 ( >max) Median years prior ARV1415 PSS of OBR =0/1/≥212/7/81/9/14 VIKING 24 Baseline Responses at Day 11 Soriano V, et al. Dolutegravir (DTG, S/GSK ) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study. [Poster PS1/2]. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Antiviral Response to DTG Cohort I (n=27) DTG QD Cohort II (n=24) DTG BID Plasma HIV-1 RNA log 10 c/mL reduction at Day 11* (S.D. = -0.77)-1.76 (S.D. = 0.54) % < 50 c/mL (TLOVR) at Wk 2411/27 (41%)18/24 (75%) % < 400 c/mL (TLOVR) at Wk 2414/27 (52%)20/24 (83%) % < 2 c/mL (TLOVR) at Wk 243/27 (11%)9/24 (38%) *p = for treatment difference was derived using multivariate linear regression model (F-test) by adjusting for baseline viral load, DTG, FC, IN genotypic pathway, PSS of failing background regimen. VIKING 24 Antiviral Response at Week 24 Soriano V, et al. Dolutegravir (DTG, S/GSK ) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study. [Poster PS1/2]. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

MLMC Clinical Trends: Sept 2011 “Other Classes” MaravirocEnfuvirtideRaltegravirStudy/Placebo Soriano V, et al. Dolutegravir (DTG, S/GSK ) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study. [Poster PS1/2]. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

EACS UPDATE ATL to CPL Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects C Cohen, A Mills, E DeJesus, B Rashbaum, C Brinson, K Yale, S Ramanathan, H Wang, A Jandourek, and A Cheng.

ATL to CPL BACKGROUND A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV C min up to 25% for 4 weeks Clinical implications evaluated here, switching suppressed HIV-1 infected patients from EFV to RPVMETHODS Open labelled, EFV/TDF/FTC STR > 3 months, change due to intolerance Evaluate efficacy at 12 weeks, planned 48 weeks PK assessed weeks 1, 2, 4, 6, 8 & 12 along with safety and tolerabilityRESULTS 100% maintain <50 at 12 weeks, no A/E’s discontinuations RPV C trough at “therapeutic levels” at 2 week post-switchCONCLUSIONS Brief EFV inductive effects on RPV metabolism may not be clinically relevant in suppressed patients Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Study Schema and Endpoints FTC/RPV/TDF STR Primary endpoint:% of subjects with HIV-1 RNA <50 c/mL at Week 12 post-switch - ITT population FDA Snapshot Analysis Secondary endpoints: Safety of FTC/RPV/TDF over 24 & 48 wks HIV-1 RNA <50 c/mL at Week 24 and Week 48 Pharmacokinetics of RPV after switching ITT = intent to treat 12 Wks48 Wks n=50 Stable on EFV/FTC/TDF for ≥ 3 months VL <50 c/mL ≥ 8 wks No genotypic resistance eGFR > 50 mL/min 24 Wks Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Primary Endpoint: HIV-1 RNA <50 copies/mL at Week 12 (FDA Snapshot Analysis – ITT Population). % HIV-1 RNA < 50c/mL 49/49 100% 95% CI (92.7, 100.0) calculated using the 2-sided exact method Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Secondary Endpoint: RPV PK after Switching from EFV EFV mean C trough above IC 90 (~10 ng/ml*) up to ~4 weeks No subject had RPV below quantifiable levels at any visit RPV mean C trough within historic range by 2 weeks *protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43; Week RPV C trough Mean (%CV), ng/ml 252 (47) (51) - 84 (76) Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

ATL to CPL BACKGROUND A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV C min up to 25% for 4 weeks Clinical implications evaluated here, switching suppressed HIV-1 infected patients from EFV to RPVMETHODS Open labelled, EFV/TDF/FTC STR >3 months, change due to intolerance Evaluate efficacy at 12 weeks, planned 48 weeks PK assessed weeks 1, 2, 4, 6, 8 & 12 along with safety and tolerabilityRESULTS 100% maintain <50 at 12 weeks, no A/E’s discontinuations RPV C trough at “therapeutic levels” at 2 week post-switchCONCLUSIONS brief EFV inductive effects on RPV metabolism may not be clinically relevant in suppressed patients Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Transmission of HIV Resistant to Non-nucleoside RT Inhibitors in MSM in Europe D. Frentz, D.A.M.C. van de Vijver, A. Abecasis, J. Albert, L. Bruun Jorgensen, O. Hamouda, C. Kuecherer, J.-C. Schmit, D. Struck, A.- M. Vandamme, J. Vercauteren, B. Asjo, C. Balotta, D. Beshkov, R. Camacho, A. Griskevicius, Z. Grossman, A. Horban, T. Kolupajeva, K. Korn, L. Kostrikis, K. Liitsola, M. Linka1, D. Otelea, D. Paraskevis, R. Paredes, M. Poljak, E. Puchhammer-Stockl, R. Schuurman2, A. Sonnerborg, D. Stanekova, M. Stanojevic, S. Zidovec Lepej, A.M.J. Wensing, C.Boucher, on behalf of the SPREAD-Programme EACS UPDATE TDR in MSM

TDR in MSM BACKGROUND Prospective monitoring of Transmission of Drug Resistance HIV (TDR) 26 European countries METHODS 4317 patients newly diagnosed Risk group and geographical stratification RESULTS 48% MSM ( n = 2072), 56% Western European origin NRTI BL Resistance stable from 2002 to 2007 PI BL Resistance decreased from 2002 to 2007 NNRTI BL Resistance increased from 2003 to 2007 Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

TDR in MSM RESULTS Clades: B (63%), A (11%) and C (7%) Overall prevalence of TDR was 8.8% in 2003 and 9.5% in 2007 By risk factors: MSM: 11.1% Heterosexuals: 6.6% IDU: 5.1% Transmitted NRTI resistance remained constant at 5%. A decline in PI resistance was observed 3.9% in 2002 to 1.6% in 2007 (p=0.001) Resistance to NNRTIs doubled 2.0% in 2002 to 4.1% in 2007 (p=0.004) 58% carrying a K103N amino acid substitution The significant increase in resistance to NNRTIs and decrease in resistance to PIs were only observed in MSM (p=0.03 and p=0.005, respectively), but not in the heterosexual patients (p=0.68 and p=0.14, respectively). Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Clinical Trends: Sept BL Genotypes MLMC vs. European Trends Group European CohortMLMC Cohort All Baseline Genotypes Stanford Scores >30>60 Overall8.8%9.5%10.8%7.4% MSM11.1%10.2%6.4% Heterosexual6.6%9.2%6.1% IDU5.1%4.0% NNRTI Resistance2.0%4.1%4.9%4.8% PI Resistance3.9%1.6%3.0%2.4% NRTI Resistance~5.0% 7.0%3.0% Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

TDR in MSM BACKGROUND Prospective monitoring of transmission of drug resistance HIV (TDR) 26 European countries METHODS 4317 patients newly diagnosed Risk group and geographical stratification RESULTS 48% MSM, 56% Western European origin NRTI BL Resistance stable from 2002 to 2007 PI BL Resistance decreased from 2002 to 2003 NNRTI BL Resistance increased from 2003 to 2007 CONCLUSIONS Sharp increase in transmitted NNRTI resistance in MSM in Europe requires further action given NNRTIs are commonly used in 1 st line therapy Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe. Presented at the 13 th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.