THE BODY PRO The HIV Resource for Health Professionals Faculty: David Wohl, M.D. Associate Professor of Medicine at the University of North Carolina at Chapel Hill The Body PRO Covers ICAAC/IDSA 2008 Washington, D.C.; October 25-28, 2008 Copyright © 2008 The HealthCentral Network, Inc. All rights reserved. This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO. David Wohl, M.D. Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA Faculty for This Activity David Wohl, M.D. Dr. Wohl is an associate professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections. Dr. Wohl is an investigator in the NIAID-sponsored AIDS Clinical Trials Group (ACTG) and a member of the ACTG Complications of HIV Disease Research Agenda Committee. His research focuses on metabolic and infectious complications of HIV and its therapies, as well as issues related to medication adherence and access to care -- particularly among incarcerated inmates with HIV infection. Disclosures Dr. Wohl has been a consultant for Abbott Laboratories, Tibotec and Merck & Co. He has served on speaker bureaus for Abbott, Gilead, Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec and Merck. In addition, he has received research support from Abbott, Roche and Merck. This activity is supported by an educational grant from

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Patient Disposition Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. 281 Treated with RAL* 24 (8.5%) Discontinued due to: 8- Adverse events 4- Lack of efficacy 3- Lost to follow-up 9- Other events Randomized 1:1 to RAL or EFV arms 282 Treated with EFV* 257 (91.5%) Completed 48 weeks 247 (87.6%) Completed 48 weeks 35 (12.4%) Discontinued due to: 17- Adverse events 2- Lack of efficacy 7- Lost to follow-up 9- Other events *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Baseline Characteristics Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. RAL*EFV* # Patients Treatedn = 281n = 282 Age (Mean, Years)3837 % Male8182 % Non-White5956 vRNA Copies/mL (Geometric Mean)103,205106,215 % With vRNA > 10 5 Copies/mL5551 Mean CD4+ Count (Cells/μl) % With CD4+ ≤ 200 Cells/μl4748 % Hepatitis B or C77 % Non-Clade B2117 *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Percent of Patients With HIV RNA < 50 Copies/mL (95% CI) (Non-Completer = Failure) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Number of Contributing Patients *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Time to Virologic Response (HIV RNA < 50 Copies/mL) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Number of Patients at Risk Efavirenz 600 mg QHS* Raltegravir 400 mg BID* Log-Rank P Value < Weeks Cumulative Virologic Response Rate (%) *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Change From Baseline in CD4+ Cell Count (95%) (Observed Failure) Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved Raltegravir 400 mg BID* Efavirenz 600 mg QHS* Number of Contributing Patients *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Resistance by Week 48 In Patients With Virologic Failure* Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. *Virologic failure: Non-responder: (1) HIV RNA > 50 copies/mL at the time of discontinuation or (2) HIV RNA > 50 copies/mL at Week 24 Virologic rebound: HIV RNA > 50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response No known RAL resistance mutation n = 5 4 Sens to TDF/FTC, 1 not tested Known RAL resistance mutation n = 4 3 Res to FTC, 1 not tested IN gene could not be amplified n = 3 IN Mutations: n = 2 G140S+Q148H/R n = 1 Y143H+L74M+E92Q+T97A n = 1 Y143R RAL Failures vRNA > 400c/mL n = 12 No known EFV resistance mutation n = 3 3 Sens to TDF/FTC Known EFV resistance mutation n = 3 1 Res to FTC RT gene no data n = 2 EFV Failures vRNA > 400c/mL n = 8 VL Failures n = 27 RAL n = 39 EFV

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Most Common ‡ Drug-Related ¥ Clinical Adverse Events Of Moderate or Severe Intensity Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. ‡ Present in ≥ 2% of either treatment group ¥ Determined by investigator to be possibly, probably or definitely related to any drug in the treatment regimen *In combination with TDF/FTC 8 (2.8) 0 (0.0) Rash 7 (2.5) 0 (0.0) Rash Maculo-Papular 8 (2.8) 3 (1.1) Diarrhea 8 (2.8) 4 (1.4) Fatigue 10 (3.5) 8 (2.8) Nausea 9 (3.2)10 (3.6) Insomnia 18 (6.4) 4 (1.4) Dizziness 13 (4.6)11 (3.9) Headache n (%) EFV* n = 282 RAL* n = 281

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Grade 3/4 ‡ Laboratory Abnormalities Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Laboratory Blood TestToxicity Criteria ‡ RAL* n = 281 EFV* n = 282 n (%) Absolute Neutrophil Count < 750 cells/µL5 (1.8) 3 (1.1) Hemoglobin < 7.5 gm/dL2 (0.7) Platelet Count < 50 k/µL0 (0.0) 1 (0.4) Fasting LDL Cholesterol ≥ 190 mg/dL3 (1.1)10 (3.6) Fasting Total Cholesterol > 300 mg/dL0 (0.0) 7 (2.5) Fasting Triglycerides > 750 mg/dL1 (0.4) 3 (1.1) Fasting Glucose > 250 mg/dL1 (0.4) 0 (0.0) Total Bilirubin > 2.5 x ULN2 (0.7) 0 (0.0) Alkaline Phosphatase > 5 x ULN0 (0.0) 2 (0.8) Aspartate Aminotransferase > 5 x ULN6 (2.1) 5 (1.8) Alanine Aminotransferase > 5 x ULN5 (1.8) 6 (2.1) ‡ Grades 3/4 by DAIDS criteria *In combination with TDF/FTC

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA STARTMRK: Change From Baseline In Fasting Serum Lipids Week 48 Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved. Lipid-Lowering RxRAL* # (%)EFV *# (%) Added Rx3 (1)11 (4) Increased Rx4 (1) ‡ P < ‡ * * *In combination with TDF/FTC ‡ ‡ ‡ T CHOL/HDL Mean Change (Ratio) RAL EFV P = 0.292

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: Phase III Study Design Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: Viral Load < 50 Copies/mL To Week 48 (ITT-TLOVR) Estimated difference in response vs LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) p<0.001 Estimated difference in response vs. LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) P < Estimated difference in response vs. LPV/r for superiority: ITT = 5.5% (95% CI –0.3;11.2) P = % 78% Time (weeks) Patients With VL < 50 Copies/mL (% [±SE]) LPV/r QD or BID (n = 346) DRV/r QD (n = 343) 2 Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: Viral Load < 50 Copies/mL To Week 96 (ITT-TLOVR)* Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: Virologic Response at Week 96 in the TLOVR Non-VF Censored Population ‡ Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: VF Analysis Over 96 Weeks Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARTEMIS: Median Lipid Levels at Baseline and Week 96 Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA CASTLE: Study Design Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA CASTLE: HIV RNA < 50 Copies/mL (CVR, NC = F) Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA CASTLE: Selected Grade 3-4 Laboratory Abnormalities Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA CASTLE: CVR (HIV RNA < 50 Copies/mL) Treatment Outcomes at Week 96 Among Subjects With Advanced Disease Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA HEAT: Methods Ben Young et al. ICAAC/IDSA 2008; abstract H Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA HEAT: Virologic Failure by Baseline HIV-1 RNA Strata and Failure Criterion Ben Young et al. ICAAC/IDSA 2008; abstract H Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA HEAT: Summary of Treatment Emergent Resistance in Subjects With Protocol-Defined Virologic Failure Ben Young et al. ICAAC/IDSA 2008; abstract H Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARIES: Study Design Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARIES: Proportion of Subjects With vRNA < 50 Copies/mL and < 400 Copies/mL Through Week 36, ITT-E Population Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ARIES: Overall and Stratified Results by Baseline Viral Load Through Week 36, ITT-E Population Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a. Copyright GlaxoSmithKline. Used with permission, 2008.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA MERIT: Phase III Trial Design Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint) Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA MERIT: Patients With a D/M Tropism Result Using the Enhanced Sensitivity Trofile Assay Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA MERIT: Re-analysis With Enhanced Trofile At Screening Identified ~50% of Patients Who Displayed D/M Virus on Study Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA MERIT: Percentage of Patients With HIV-1 RNA < 400 and < 50 Copies/mL At Week 48 Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ACTG 5211: Coreceptor Tropism by The Original and Enhanced Trofile Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission. 25/114 Enhanced Trofile reclassified 25 individuals with R5 virus at screen 15/25 were VCV recipients 12/15 had early detection of X4 virus on study (before week 8) by original Trofile Original TrofileEnhanced Trofile ScreenEntryOn studyDM at Screen (n, %) R5DMDM/X47/12, 58% R5 DM/X49/18, 50% R5 9/84, 11%

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA ACTG 5211: Viral Load Reduction in Subjects With R5 Virus at Screen by the Original & Enhanced Trofile Assays Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission Placebo Placebo Day 14Week 24 Change in Viral Load (Log10 HIV-1 RNA) Original Enhanced

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA NA-ACCORD: Distribution of 8,374 Study Patients First CD4+ Count Between 351 – 500 Measured 1996 – 2006 No Prior AIDS Diagnosis or ARVs (n = 8,374) Defer HAART n = 5,901 Initiate HAART n = 2,473 Transit to CD4+ < 350 Defer HAART n = 2,229 Initiate HAART n = 1,220 No Transit n = 2,452 Deaths (Person-Years) in Cohort Analysis 100 (5,815)137 (5,526)209 (5,295)221 (8,358) Percent Censored in IPW Analysis 57%0%10%0% Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA NA-ACCORD: Baseline Characteristics In Study Patients Defer HAART n = 5,901 Initiate HAART n = 2,473 Follow Up Person-Years16,6368,358 Hepatitis C Virus Infection (%)*3427 History of Injection Drug Use (%)*2116 Males (%)7583 Median Age Years (IQR)38 (32, 45)40 (34, 48) Median CD4+ Count Cells/mm 3 (IQR)432 (391, 468)421 (386, 459) Median log 10 HIV RNA Copies/mL (IQR)*4.1 (3.3, 4.6)4.3 (3.1, 4.9) White (%)3839 *Among patients with known status Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA NA-ACCORD: Results of Subset Analysis Both a history of IDU and HCV infection were significantly associated with increased risk of mortality RH95% CIP Value When Restricting the Analysis to Patients With Data Regarding History of Injection Drug Use (IDU) and Adjusting for IDU , When Restricting the Analysis to Patients With Data Regarding Hepatitis C Virus (HCV) Infection and Adjusting for HCV , 2.1< RH = relative hazard of death for deferral of HAART; CI = confidence interval Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA NA-ACCORD: Inverse Probability Weighted Cox Regression Multivariate Analysis RH*95% CIP Value Deferral of HAART at 351 – , 2.1< Older Age (Per 10 Years)1.61.5, 1.8< Female Sex1.10.9, Baseline CD4 Count (Per 100 Cells/mm 3 ) , Results were similar when restricting the analysis to the 77% of participants with baseline HIV RNA data Adjusted RH for deferral vs. immediate treatment was also 1.7; 95% C.I. was 1.4, 2.2; and P value was < HIV RNA was not an independent predictor of mortality RH = relative hazard; CI = confidence interval *Stratified by cohort and year Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

The Body PRO Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA This presentation was created to accompany The Body PRO's summaries of key research presented at ICAAC/IDSA 2008, by David Wohl, M.D. The Body PRO's extensive coverage of ICAAC/IDSA 2008 also includes: –Summaries and analyses of research on a wide array of clinical subjects. –Interviews with top researchers discussing the results of noteworthy studies. –Audio podcasts you can play online or download to your computer or MP3 player. –Narrated, online slide presentations highlighting major study results. Visit TheBodyPRO.com/ICAAC2008 today for a full listing of our conference coverage! Disclaimer: The Body PRO is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body PRO should not be used for diagnosing or treating a health problem or a disease.