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

EACS UPDATE

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

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) analyses

METHODS

• ARV naïve, blinded and randomized to RAL (BID) + TVD or EFV (QHS) • Viral susceptibility to EFV, FTC, & TDF, VL > 5000, any CD4 • Planned 240 week + TVD

RESULTS

• 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)

RAL Group n/N (%)

214/235 (91)

EFV Group n/N (%)

189/222 (85)

Difference in Response Rates % (95% CI)

Total Age (years)  Median >Median Gender Male Female Race White Black Asian Hispanic Multiracial 109/122 (89) 105/113 (93) 173/191 (91) 41/44 (93) 86/93 (92) 21/24 (88) 31/34 (91) 47/53 (89) 28/30 (93) 105/129 (81) 84/93 (90) 157/185 (85) 32/37 (86) 75/83 (90) 17/22 (77) 25/28 (89) 44/57 (77) 28/32 (88) Viral Subtype Clade B Non-Clade B 164/181 (91) 47/51 (92) 149/177 (84) 35/40 (88) -50 -25 Favors EFV 0 25 50 Favors 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)

Total Baseline Plasma HIV RNA (c/mL)  100,000 >100,000 Baseline CD4 Counts (cells/mm 3 )  50 >50 and  200 >200 Hepatitis Status Hepatitis B or C Positive Both Hepatitis B and C Negative

RAL Group n/N (%)

214/235 (91) 98/105 (93) 116/130 (89) 17/22 (77) 84/88 (95) 113/125 (90) 11/12 (92) 203/223 (91)

EFV Group n/N (%)

189/222 (85)

Difference in Response Rates % (95% CI)

86/106 (81) 103/116 (89) 25/29 (86) 71/85 (84) 93/108 (86) 12/13 (92) 177/209 (85) -50 -25 Favors EFV 0 25 50 Favors 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.

Summary of Efficacy at Week 192

RAL EFV Δ RAL - EFV % Responders with vRNA <50 c/mL (n/N) NC = F OF

76.2 (214/281) 91.1 (214/235) 67.0 (189/282)

9.0* (1.6, 16.4)

85.1 (189/222)

6.0* (0.1, 12.2)

*

p

-value for non-inferiority <0.001

Change from BL CD4 Count (cells/mm 3 ) OF

361 301

60 (24, 95)

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

Regimen MLMC Database: September 2011 Utilization of EFV+TVD and RAL+TVD, most recent CD4 and VL FTC + TDF + EFV # of Patients 493 <50 91.7% Viral Load (copies/mL) <50 On Rx>90 Days 96.1% 50 400 3.7% 400 10,000 2.0% >10,000 2.6% CD4 Count (cells/µL) <200 200 350 350 500 >500 2.6% 10.9% 30.9% 55.6% FTC + TDF +RAL 76 95.8% 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

MLMC First ARV Regimens - Most Commonly Prescribed by Calendar Year Regimen

*FTC*TDF*EFV *FTC*TDF*RAL *FTC*TDF*STUDY *FTC*TDF*DRV*/r *FTC*TDF*LPV/r *FTC*TDF*EFV *FTC*TDF*DRV*/r *FTC*TDF*RAL *FTC*TDF*ATV*/r *STUDY/PLACEBO

# of Patients September 2011

50 7 5 5 5

2010

67 20 11 9 9

% of Patients

47.2% 6.6% 4.7% 4.7% 4.7% 40.4% 12.0% 6.6% 5.4% 5.4% 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) analyses

METHODS

• 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 week

RESULTS

• 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.

EACS UPDATE

Dolutegravir (DTG, S/GSK1349572) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study

V Soriano, J Cox, JJ Eron, et al.

VIKING 24

OBJECTIVES

• Assess Dolutegravir (DTG) in patients with Raltegravir (RAL) resistance

METHODS

• 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 OBR

RESULTS

• 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 respectively

CONCLUSIONS

• 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/GSK1349572) 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.

VIKING 24 Baseline Responses at Day 11

Key Baseline Characteristics

Median CD4+ cells/mm 3 Median HIV-1 RNA log 10 c/mL Q148 + ≥ 1 N155 or Y143 or other Median RAL FC (range) Median years prior ARV PSS of OBR =0/1/≥2

Cohort I (n=27) DTG QD

114 4.5

9 (33%) 18 (67%) > 161 (0.67 - >max 14 12/7/8

Cohort II (n=24) DTG BID

202 4.3

11 (46%) 13 (54%) > 128 (0.78 - >max) 15 1/9/14 Soriano V, et al. Dolutegravir (DTG, S/GSK1349572) 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.

VIKING 24 Antiviral Response at Week 24

Antiviral Response to DTG Cohort I (n=27) DTG QD

Plasma HIV-1 RNA log 10 c/mL reduction at Day 11* -1.45 (S.D. = -0.77)

Cohort II (n=24) DTG BID

-1.76 (S.D. = 0.54) % < 50 c/mL (TLOVR) at Wk 24 % < 400 c/mL (TLOVR) at Wk 24 % < 2 c/mL (TLOVR) at Wk 24 11/27 (41%) 14/27 (52%) 3/27 (11%) 18/24 (75%) 20/24 (83%) 9/24 (38%) *p = 0.017 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.

Soriano V, et al. Dolutegravir (DTG, S/GSK1349572) 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”

Maraviroc Enfuvirtide Raltegravir

Soriano V, et al. Dolutegravir (DTG, S/GSK1349572) 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.

Study/Placebo

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 RPV

METHODS

• 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 tolerability

RESULTS

• 100% maintain <50 at 12 weeks, no A/E’s discontinuations • RPV C trough at “therapeutic levels” at 2 week post-switch

CONCLUSIONS

• 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

•n=50 •Stable on EFV/FTC/TDF for ≥ 3 months •VL <50 c/mL ≥ 8 wks •No genotypic resistance •eGFR > 50 mL/min

FTC/RPV/TDF STR

12 Wks 24 Wks 48 Wks

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 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)

100%

100% 80% 60% 40% 20% 0%

49/49

FTC/RPV/TDF

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 ng/ml*) up to ~4 weeks (~10 • No subject had RPV below quantifiable levels at any visit • RPV mean C trough within historic range by 2 weeks Week 2 4-12 RPV C trough Mean (%CV), ng/ml 52 (47) 66 (51) - 84 (76) *protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43;2019-2030 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 RPV

METHODS

• 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 tolerability

RESULTS

• 100% maintain <50 at 12 weeks, no A/E’s discontinuations • RPV C trough at “therapeutic levels” at 2 week post-switch

CONCLUSIONS

• 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.

EACS UPDATE TDR in MSM

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

TDR in MSM

BACKGROUND

• Prospective monitoring of Transmission of Drug Resistance HIV (TDR) • 26 European countries

METHODS

• 4317 patients newly diagnosed 2002-2007 • 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 2011 - BL Genotypes MLMC vs. European Trends

European Cohort Group

Overall MSM Heterosexual IDU NNRTI Resistance PI Resistance NRTI Resistance 2002 8.8% 2.0% 3.9% ~5.0% 2007 9.5% 11.1% 6.6% 5.1% 4.1% 1.6% ~5.0%

MLMC Cohort All Baseline Genotypes Stanford Scores

>30 >60 10.8% 10.2% 7.4% 6.4% 9.2% 4.0% 4.9% 3.0% 7.0% 6.1% 4.0% 4.8% 2.4% 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 2002-2007 • 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.