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Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings

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.

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Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings

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  1. 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

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

  3. STARTMRK 192 VIKING 24 ATL to CPL TDR in MSM Overview

  4. 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

  5. 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 • 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. STARTMRK 192

  6. RAL Group n/N (%) EFV Group n/N (%) Difference in Response Rates % (95% CI) Total 214/235 (91) 189/222 (85) Age (years)Median>Median 109/122 (89) 105/113 (93) 105/129 (81) 84/93 (90) GenderMaleFemale 173/191 (91)41/44 (93) 157/185 (85) 32/37 (86) RaceWhiteBlackAsianHispanicMultiracial 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) Viral SubtypeClade BNon-Clade B 164/181 (91)47/51 (92) 149/177 (84)35/40 (88) -50 -25 0 25 50 Favors EFV Favors RAL Proportion of Patients with <50 vRNA c/mL at Wk 192by Demographic Factors (OF Approach) 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  7. RAL Group n/N (%) EFV Group n/N (%) Difference in Response Rates % (95% CI) Total 214/235 (91) 189/222 (85) 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/mm3)50>50 and 200>200 17/22 (77)84/88 (95) 113/125 (90) 25/29 (86) 71/85 (84)93/108 (86) -50 -25 0 25 50 Hepatitis StatusHepatitis B or C PositiveBoth Hepatitis B and C Negative 11/12 (92) 203/223 (91) 12/13 (92)177/209 (85) Favors EFV Favors RAL Proportion of Patients with <50 vRNA c/mL at Wk 192by Baseline Prognostic Factors (OF Approach) 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  8. 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  9. 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  10. 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  11. 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. STARTMRK 192

  12. EACS UPDATE V Soriano, J Cox, JJ Eron, et al. Dolutegravir (DTG, S/GSK1349572) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study

  13. 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. VIKING 24

  14. VIKING 24 Baseline Responses at Day 11 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  15. VIKING 24 Antiviral Response at Week 24 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  16. MLMC Clinical Trends: Sept 2011 “Other Classes” Maraviroc Enfuvirtide Raltegravir Study/Placebo 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 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

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

  18. BACKGROUND • A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV Cmin 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 Ctrough 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) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. ATL to CPL

  19. 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 48 Wks 24 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) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  20. % HIV-1 RNA < 50c/mL 49/49 Primary Endpoint: HIV-1 RNA <50 copies/mL at Week 12 (FDA Snapshot Analysis – ITT Population) 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) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. .

  21. Secondary Endpoint: RPV PK after Switching from EFV *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) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. • EFV mean Ctrough above IC90 (~10 ng/ml*) up to ~4 weeks • No subject had RPV below quantifiable levels at any visit • RPV mean Ctrough within historic range by 2 weeks

  22. BACKGROUND • A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV Cmin 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 Ctrough 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) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia. ATL to CPL

  23. EACS UPDATETDR in MSM Transmission of HIV Resistantto Non-nucleoside RT Inhibitorsin 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

  24. 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 TDR in MSM Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe.Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  25. 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). TDR in MSM Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe.Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  26. Clinical Trends: Sept 2011 - BL Genotypes MLMC vs. European Trends Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe.Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

  27. 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 1st line therapy TDR in MSM Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe.Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

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