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The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention

The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy July 17-20, 2011. CME Disclaimer.

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The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention

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  1. The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention Rome, ItalyJuly 17-20, 2011

  2. CME Disclaimer These slides may not be published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications

  3. Accreditation and Designation Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. The Association of Nurses in AIDS Care is an approved provider of continuing nursing education by the Virginia Nurses Association Continuing Education Approval Committee, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is approved for 1.0 contact hours by the Association of Nurses in AIDS Care. This program contains 1.0 hour of pharmacology content. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-11-097-H02-P). This slide kit is accredited for one hour of continuing education credit. The University of Florida College of Pharmacy will mail Statements of Continuing Education Credit within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form. Supported by an independent educational grant from Gilead Sciences Medical Affairs.

  4. Faculty:CME Course Director Harold A. Kessler, MD Professor of Medicine and Immunology/Microbiology Associate Director, Section of Infectious Diseases Rush University Medical Center Chicago, Illinois

  5. Faculty:Content Development and Training Calvin J. Cohen, MD, MSc Research Director CRI New England Harvard Vanguard Medical Associates Clinical InstructorHarvard Medical School Boston, Massachusetts Ian Frank, MD Professor of MedicineDirector, Anti-Retroviral Clinical Research University of Pennsylvania Philadelphia, Pennsylvania W. David Hardy, MD Director, Division of Infectious Diseases Cedars-Sinai Medical Center Associate Professor of Medicine-in Residence David Geffen School of Medicine at UCLA Los Angeles, California Paul E. Sax, MD Clinical Director Division of Infectious Diseases & HIV Program Brigham & Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

  6. Faculty:CME Reviewer David M. Simon, MD, PhD Associate Professor Section of Infectious Diseases Rush University Medical Center Chicago, Illinois

  7. Disclosure Information • It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME • Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months • If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content

  8. Disclosure Information:CME Course Director • Harold A. Kessler, MD • Grants/Research Support • None • Consultant • None • Speakers’ Bureau • None • Stock Shareholder • Abbott Laboratories, GlaxoSmithKline, Merck • Other Financial or Material Support • None

  9. Disclosure Information:CME Course Director • Calvin J. Cohen, MD, MSc • Grants/Research Support • Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec • Consultant • Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec • Speakers’ Bureau • Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec • Stock Shareholder • None • Other Financial or Material Support • None

  10. Disclosure Information:CME Course Director • Ian Frank, MD • Grants/Research Support • GlaxoSmithKline • Consultant • Gilead Sciences, Tibotec • Speakers’ Bureau • None • Stock Shareholder • None • Other Financial or Material Support • None

  11. Disclosure Information:CME Course Director • W. David Hardy, MD • Grants/Research Support • Bionor, Gilead Sciences, GlaxoSmithKline, Pfizer, ViiV • Consultant • Bionor, Gilead Sciences, GlaxoSmithKline, Pfizer, ViiV • Speakers’ Bureau • None • Stock Shareholder • Merck (< $5,000) • Other Financial or Material Support • None

  12. Disclosure Information:CME Course Director • Paul E. Sax, MD • Grants/Research Support • Gilead Sciences, GlaxoSmithKline, Merck, Tibotec • Consultant • Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Tibotec • Speakers’ Bureau • None • Stock Shareholder • None • Other Financial or Material Support • None

  13. Disclosure Information:CME Reviewer • David M. Simon, MD, PhD • Grants/Research Support • None • Consultant • None • Speakers’ Bureau • None • Stock Shareholder • None • Other Financial or Material Support • None

  14. Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, Association of Nurses in AIDS Care, or the University of Florida College of Pharmacy The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before using any medication mentioned in this program

  15. Learning Objectives (CME, CE) • Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: • Initiate ARV therapy in ARV-naïve patients based upon the most current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks. • Prescribe ARV therapy in ARV-naïve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events. • Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care. • Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

  16. Learning Objectives (CPE) • Upon completion of this activity, the pharmacist should be able to: • Determine when the most current clinical data indicates the potential benefits of ARV therapy outweigh the potential risks in ARV-naïve patients. • Recommend the most appropriate ARV therapy for ARV-naïve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data. • Utilize recent study results regarding the pharmacological management of HIV-positive patients in your clinical practice to improve patient care. • Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

  17. Studies in ARV-Naïve Patients W. David Hardy, MD Director, Division of Infectious Diseases Cedars-Sinai Medical Center Associate Professor of Medicine-in-Residence David Geffen School of Medicine at UCLA Los Angeles, CA

  18. HPTN 052: Study Design HIV-infected Subjects with CD4 350 to 550 Cells/mm3 Serodiscordant Couples Randomization Immediate ART CD4 350-550 Delayed ART CD4 <250 886 Index Partners 877 Index Partners 184 Initiated Therapy 886 Initiated Therapy Hessinapour M. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0104.

  19. HPTN 052: Baseline Characteristics Hessinapour M. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0104.

  20. HPTN 052: Virologic and Immunologic Response to ART Immunologic Response • Virologic Efficacy: • Immediate arm: 90% (90% non-Africa; 91% Africa) had viral load <400 cps/mL at 1 year • Delayed arm: 93% (96% non-Africa; 85% Africa) had viral load <400 cps/mL at 1 year • Virologic failures: Immediate 5.1% vs. 2.7% Delayed • 67% began a second regimen (Immediate) vs. 60% (Deferred) Immediate Delayed Subjects Contributing Data 880183 842149 78596 57755 39033 Hessinapour M. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0104.

  21. HPTN 052: Clinical Endpoints • 105 individuals had a primary clinical endpoint: Immediate 40 vs. 65 delayed [HR=0.6 (0.4,0.9), P=0.01] • Development of extrapulmonary TB was the main difference between the two groups (P<0.002) • Increased mortality with delayed treatment, but not significant [HR=0.77, (0.34,1.76), P>0.5] • Adverse events: immediate 24% vs. 5% delayed Grinstein B, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0105.

  22. SENSE: Trial Design • Double-blinded, active controlled to Week 48 • Inclusion: Treatment naïve, HIV RNA >5,000 copies/mL • No genotypic mutations to NRTIs, NNRTIs or PIs • Predicted Phenotypic sensitivity to NNRTIs and selected NRTIs ETR 400 mg OD + 2 NRTIs (n=79) Unblinding Follow-up 157 subjects EFV 600 mg OD + 2 NRTIs (n=78) Unblinding Follow-up 6 weeks 48 weeks 2-8 weeks 4 weeks Two investigator-selected NRTIs (AZT+3TC; ABC+3TC; TDF+FTC) Primary endpoint: Neuropsychiatric adverse events up to Week 12 Rockstroh J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE025.

  23. SENSE: Baseline Characteristics (ITT) * Significant difference in baseline NRTI/NNRTI resistance between arms, but most patients had single mutations and were still NRTI/NNRTI sensitive (5 were protocol violators) Rockstroh J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE025.

  24. SENSE: Grade 1 - 4 Drug-related Neuropsychiatric Adverse Event Prevalence through 48 Weeks (ITT) P<0.001 P=0.001 P=0.013 P=0.014 P=0.111 P=0.011 Rockstroh J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE025.

  25. SENSE: Summary Efficacy at Week 48 (ITT TLOVR) – by Type of Response (%) Mean change in CD4 cell count from BL at week 48 (observed data): EFV 236 cells/mm3 vs. ETR 232 cells/mm3 Rockstroh J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE025.

  26. SPRING-1: Dolutegravir (DTG, S/GSK1349572) in ART-naïve Adults • Phase IIb dose-ranging, partially-blinded, N ~200 ART-naïve patients • All arms include 2 NRTI backbone given once daily • Primary endpoint: % <50 c/mL at 16 weeks (TLOVR) DTG 10 mg 50 mg DTGSelected Dose DTG 25 mg HIV-1 RNA >1,000 c/mL CD4 ≥200 cells/mm3 1:1:1:1 Randomization DTG 50 mg • Stratified by • HIV RNA >100,000 • or ≤ 100,000 • ABC/3TC and TDF/FTC EFV 600 mg EFV 600 mg Wk 48 Interim Analysis Wk 96 van Lunzen J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0102.

  27. SPRING-1: Baseline Characteristics van Lunzen J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0102.

  28. SPRING-1: Antiviral Activity through Week 48 • Mean CD4 cell changes from BL: EFV: +180 cells vs. DTG: +200-240 cells (P=0.076) • Resistance: 3/150 (2%) DTG VFs (>400 c/mL); none in 50 mg arm 1 - M184V; No integrase mutations van Lunzen J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0102.

  29. SPRING-1: Adverse Events • Events leading to withdrawal: • DTG (n=2): dyspepsia and Burkitt’s lymphoma • EFV (n=4): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity • Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine van Lunzen J, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0102.

  30. Study A4001078: MVC + ATV/r vs. FTC/TDF + ATV/r in Treatment-naïve Patients Patient Eligibility Criteria • R5 HIV at screening • ≥16 years of age • HIV-1RNA ≥1,000 copies/mL • CD4 ≥100 cells/mm3 • No evidence of resistance to ATV/r, TDF, or FTC Randomization 1:1N=121 FTC/TDF + ATV/r (300/100 mg QD) MVC (150 mg QD) + ATV/r (300/100 mg QD) Screening(6 weeks) 0 16 wk 24 wk 48 wk Interim analyses Primary analysis Week 2 First 15 US patients Serial PK of MVC Portsmouth S, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0103.

  31. Study A4001078: Baseline Characteristics Portsmouth S, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0103.

  32. Study A4001078: HIV-1 RNA <50 copies/mL at Week 48 • Change in median CD4+ cell count over 48 weeks (LOCF): MVC+ATV/r 173 vs. TDF/FTC + ATV/r 187 cells/mm3 • VF and Resistance: 7/9 MVC and 3/3 TDF/FTC subjects >50 cps/mL at 48 weeks resuppressed post 48 wks • No genotypic or phenotypic resistance observed Portsmouth S, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0103.

  33. Study A4001078: Safety 7 patients in the MVC + ATV/r group and 3 patients in the FTC/TDF group switched their ATV/r to DRV/r or LPV/r per protocol due to intolerability or hyperbilirubinemia Portsmouth S, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0103.

  34. ECHO and THRIVE: 96 Week Follow-Up 48 Weeks Primary Analysis 96 Weeks Final Analysis ECHO (TMC278-C209) RPV 25 mg qd + TDF/FTC + EFV placebo qd (N=346) N=690 Patients 1:1 EFV 600 mg qd + TDF/FTC + RPV placebo qd (N=344) THRIVE (TMC278-C215) RPV 25 mg qd + 2 N(t)RTIs* + EFV placebo qd (N=340) N=678 Patients 1:1 EFV 600 mg qd + 2 N(t)RTIs* + RPV placebo qd (N=338) *Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC Cohen C, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE032.

  35. Pooled ECHO and THRIVE: VL <50 copies/mL Over 96 Weeks (ITT-TLOVR) RPV 25 mg qd (N=686) 100 EFV 600 mg qd (N=682) 78% 80 78% 60 Per protocol responses: RPV: 79% EFV: 78% Snapshot responses: RPV: 76% EFV: 77% Responders (%, 95% CI) 40 20 0 0 2 4 8 12 16 24 32 40 48 60 72 84 96 Time (weeks) Mean change in CD4 cell count from baseline at Week 48 (NC=F): RPV +228 vs. EFV +219cells/mm3 Cohen C, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE032.

  36. Pooled ECHO and THRIVE: Virologic Outcomes and Resistance After 96 Weeks • Similar rates of VF in both groups after 48 wks • Emergence of mutations after 48 wks was similar in both groups RPV 7 (39%) vs. EFV 6 (43%) • Pooled Grade 2-4 adverse events from wk 48-96: RPV 14 (2%) vs. EFV 26 (4%) (P<0.001) Cohen C, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TULBPE032.

  37. Treatment Experienced Patients and New Antivirals Calvin J. Cohen, MD, MSc Research Director, CRI New England Harvard Vanguard Medical Associates Clinical Instructor Harvard Medical School Boston, MA

  38. SWIFT: ABC/3TC to TDF/FTC Switch Trial • N=311 • On ABC/3TC + any PI/r for ≥3 mo • HIV RNA <200 c/mL ≥3 mo • Any CD4 count • No hx of resistance to study drugs • Primary Endpoint was the percentage who had a viral load <200 c/mL through 48 weeks • Used TLOVR definition of failure: virologic failure, premature discontinuations, ARV changes • -12% margin for definition of Non-inferiority FTC/TDF + PI/r n=155 48 weeks 3TC/ABC + PI/r n=156 • Most Frequent PI used • >10% use in both arms Campo R, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB03.

  39. SWIFT: Primary Endpoint TLOVR Response Rate Difference: 3% (-5%, +11%) Virologic Failure (>200 c/mL): • 3 TDF/FTC, 11 ABC/3TC • No resistance detected in the subset of virologic failures that qualified for genotyping % TLOVR Responders HIV-1 RNA < 200 c/mL Campo R, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB03.

  40. SWIFT: Changes in Fasting Lipids at Week 48 All Changes in mg/dL Campo R, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB03.

  41. SWIFT: Estimated GFR Outcomes Through 48 Weeks Cockcroft-Gault 120 100 • 4.5 • - 8.3 80 Estimated GFR by IBW CG (mL/min) P=0.012 60 40 FTC/TDF 3TC/ABC 20 0 0 4 12 24 36 48 Week 155 153 147 144 139 137156 153 150 146 142 139 FTC/TDF3TC/ABC MDRD Results: ABC/3TC -4.2 vs. TDF/FTC -9.2 (P=0.008) Campo R, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB03.

  42. Subanalysis of MOTIVATE 1 and 2: Maraviroc QD or BID Plus boosted-PI in Treatment-Experienced Patients • MOTIVATE 1 and 2: Maraviroc vs. placebo in treatment experienced patients • Comparison of MVC 150 mg QD, MVC 150 mg BID and placebo in pts also taking a boosted PI • PK exposures to MVC 150 mg QD in presence of most ritonavir boosted PIs similar to currently approved dose in treatment-naïve patients • Analysis restricted to those confirmed R5 by ESTA test Difference and 97.5% CI: MVC QD vs. PBO: 28% (16-39) MVC BID vs. PBO: 31% (18-43) 85/187 84/176 14/85 Hardy D, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0106.

  43. Elvitegravir vs. Raltegravir:Study Design • Choice of fully active PI and 3rd agent were based on resistance testing • If M184V or M184I, optional to also add FTC or 3TC N = 702 1:1 randomization • Primary Endpoint: HIV-1 RNA <50 c/mL through 48 weeks (FDA TLOVR) • Non-inferiority Study • Lower limit of the 95% Conf Interval: -10% Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB05.

  44. EVG vs. RAL: Baseline Characteristics and Background Regimens Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB05.

  45. EVG vs. RAL: Week 48 Results 95%CI: -6% to 8.2%, p=0.001 for noninferiority Integrase Resistance: RAL: 21% EVG: 27% CD4 Change: RAL: +147/mm3 EVG: +138/mm3 * 1. Responder: achieved and maintained confirmed HIV-1 RNA <50 copies/mL through Week 48 2. Drug DC due to Other: Lack of Efficacy, Lost to Follow-up, Non-compliance, Investigator Discretion, Pregnancy, Protocol Violation, Withdrew Consent Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB05.

  46. EVG vs. RAL: Select Adverse Events and Labs *Diarrhea nearly all grade 2 (P-value=0.023) **P-value=0.020 ***P-value=0.009 Molina JM, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. WELBB05.

  47. TDF/FTC plus LRV 500 mg QD Double Blind Study Randomized 1:1:1 TDF/FTCplusLRV750mgQD TDF/FTCplusEFV600mgQD Lersivirine in ARV-Naïve Patients: Phase 2b Trial Design • Planned interim analysis at week 24 • Primary endpoint at week 48: HIV RNA <50 c/mL • Pts followed to week 96 • Eligibility criteria • HIV-1 RNA ≥1,000 c/mL • CD4 >200/mm3 • Absence of any RT mutations (using standard genotyping) • Randomization stratified by: • Viral load (< or ≥100,000 c/mL) • Geographic region Vernazza P, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0101.

  48. Lersivirine: Week 48 Virologic Outcomes Vernazza P, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0101.

  49. Lersivirine: Reported Adverse Events Vernazza P, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUAB0101.

  50. Metabolic and Other Adverse Events Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV ProgramBrigham and Women's Hospital Associate Professor of Medicine, Harvard Medical SchoolBoston, MA

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