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Introduction and Program Overview

Introduction and Program Overview. Program Chair John G. Bartlett, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, MD. Housekeeping Notes. Please be sure that you have a workbook.

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Introduction and Program Overview

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  1. Introduction and Program Overview Program Chair John G. Bartlett, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, MD

  2. Housekeeping Notes • Please be sure that you have a workbook. • Question cards are in your workbook. Please jot down your questions, and members of our staff will pick them up during the course of the meeting.

  3. Housekeeping Notes (cont’d) • We will be using an Audience Response System (ARS) to present a series of questions during the meeting • At slide prompts, please key in your answers to these questions on the keypads provided • Please return your ARS keypad at the end of the program • CME credit will be awarded online through the University of Kentucky website.

  4. Program Overview After completing this activity, clinicians will have gained a working knowledge of the most recent US Department of Health and Human Services (DHHS) guidelines for the use of antiretroviral therapy (ART) and be familiar with the results from the most recent study data on specific risks and benefits of specific ART with respect to the overall health of the patient. With this knowledge, clinicians will understand the benefits and risks of early ART initiation and be better able to choose optimal antiviral agents for their patients at the beginning of HIV treatment as well as manage long-term therapy, taking into account resistance, aging, and the whole health of the patient.

  5. Educational Objectives Upon completion of this activity, participants should be able to: • DISCUSS the changes to the DHHS guidelines regarding the initiation of ART and the risks and benefits associated with early ART initiation in HIV patients • EVALUATE the benefits and risks of the various ART regimens recommended by the latest DHHS guidelines and define the most important factors for choosing an appropriate ART in a treatment-naïve HIV patient • ASSESS the concept of stable therapy and describe the circumstances in which it is appropriate to switch a virologically suppressed HIV patient to a different ART regimen

  6. Educational Objectives (cont’d) • DEVELOP and implement strategies to identify and manage antiretroviral resistance in order to optimize long-term viral suppression • ASSESS the role of the recently FDA-approved ART agents in the management of HIV infection and develop strategies to integrate the new agents into current treatment paradigms • RECOGNIZE the role of comorbidities (eg, hepatitis B or C (HBV or HCV) coinfection, cardiovascular disease, renal disease, diabetes, dyslipidemia) when choosing appropriate ART regimens and articulate how specific ART choices interact with those comorbidities

  7. Accreditation Statement NURSING Creative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CEC provides this activity for 2.0 contact hours. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products discussed in conjunction with an activity. PHARMACY The University of Kentucky College of Pharmacy is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program has been assigned ACPE # 022-999-08-128-L02-P and will award 2.0 contact hours (0.20 CEUs) of continuing pharmacy education credit in states that recognize ACPE providers. Statements of credit will indicate hours and CEUs based on participation and will be issued online at the conclusion of the activity. Successful completion includes signing in at registration, attending the entire session for which credit is claimed, completing the activity evaluation and requesting credit online at conclusion of the activity. The College complies with the Criteria for Quality for continuing education programming.

  8. Accreditation Statement (cont’d) MEDICINE This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the University of Kentucky College of Medicine and HealthmattersCME. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the presentations is provided solely by presenters who have been selected for presentations because of recognized expertise in their field.

  9. Disclosure Statements (cont’d) The University of Kentucky Colleges of Pharmacy and Medicine adheres to ACCME and ANCC Essential Areas and Policies, including the Standards for Commercial Support regarding industry support of continuing medication education. In order to resolve any identified conflicts of interest, disclosure information is provided during the planning process to ensure resolution of any identified conflicts. Disclosure of faculty and commercial relationships, as well as the discussion of unlabeled/investigational use of any drug, device, or procedure by the faculty, are made known below. John G. Bartlett, MD • HIV Advisory Board: Abbott, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Pfizer • Policy Advisory Board: Johnson & Johnson • Contract research support: Gilead Sciences, Inc. Calvin J. Cohen, MD • Speaker’s Bureau: GlaxoSmithKline, Bristol-Myers Squibb, Gilead Sciences, Tibotec, Merck, Pfizer Inc • Contract research support: GlaxoSmithKline, Bristol-Myers Squibb, Gilead Sciences, Tibotec, Merck, Pfizer Inc • Consultant: GlaxoSmithKline, Bristol-Myers Squibb, Gilead Sciences, Tibotec, Merck, Pfizer Inc

  10. Disclosure Statements Sally Hodder, MD • Speaker’s Bureau: Bristol-Myers Squibb • Contract research support: Bristol-Myers Squibb, Gilead Sciences, Pfizer Inc, Tibotec • Consultant: Boehringer Ingelheim, Bristrol-Myers Squibb, Gilead Sciences, Tibotec • Spouse’s financial interest: Retired Merck employee Martin Markowitz, MD • Advisory Board: Merck, Gilead Sciences, Sequoia, GlaxoSmithKline • DSMB Committee: Quintiles • Speaker Consultant: Merck Paul E. Sax, MD • Consultant: Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, • Teaching Honoraria: Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec • Grant support: Merck

  11. Agenda The following topics will be discussed: • Treatment Initiation: Who, When, and With What? • Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted? • Treating HIV in Special Populations • Examining the Role of the Newer Antiretroviral Agents in the Current Armamentarium and Their Promise for the Future

  12. How to Obtain CME Credit • Complete this activity in its entirety • After the activity, go to www.cecentral.com/getcredit • Enter activity code XLN09089 • Log in or register for a free account • Complete activity evaluation and get credit. A printable certificate will be issued

  13. Paul E. Sax, MD Harvard Medical School Boston, MA Treatment Initiation: Who, When, and With What?

  14. Case Presentation A 49-year-old man with acute HIV infection diagnosed 2 weeks into illness; his CD4 cell count is 650, HIV RNA > 750,000 c/mL, resistance test pending; symptoms improving

  15. VOTE

  16. Audience Response Question Start therapy with efavirenz (EFV)-based regimen Start therapy with boosted PI-based regimen Defer starting therapy until resistance testing is back, then begin based on results Discuss pros/cons of treatment with patient; base recommendations on his preference Defer therapy; advise repeat HIV RNA and CD4 in 1-2 months Something else How would you manage this patient?

  17. Primary HIV Infection Guidelines IAS-USA “Although knowledge continues to evolve regarding the pathogenesis of primary HIV infection, no definitive evidence has emerged that supports routine initiation of antiretroviral therapy in primary HIV infection.” JAMA. 2008;300(5):555-570. DHHS “Providers should consider enrolling patients with acute HIV into a clinical trial …Since clinically significant resistance to PIs is less common than resistance to NNRTIs in treatment-naïve persons who harbor drug resistant virus, consideration should be given to using a PI- based regimen if therapy is initiated before drug resistance test results are available” DHHS Guidelines, January 2008.

  18. Case Presentation A 38-year-old female hairdresser, new HIV diagnosis Asymptomatic except for 0.5-cm posterior cervical nodes CD4 770 cells/mm3, HIV RNA 35,000 copies/mL. No resistance on genotype

  19. VOTE

  20. Audience Response Question How would you manage this patient? Treat Monitor

  21. Audience Response Question If you chose to treat, what was the primary reason? Prevention of AIDS-related complications Prevention of non–AIDS-related complications Reduction in risk of viral transmission Better tolerability of antiretroviral therapy (ART) with higher CD4 cell count Greater likelihood of achieving a normal CD4 and/or undetectable HIV RNA

  22. Audience Response Question If you chose not to treat, what was the primary reason? Daily medication adverse effects Long-term medication adverse effects Lack of data on improved outcomes when starting with high CD4 Poor adherence might lead to resistance, reducing future options Cost of therapy

  23. DHHS Guidelines 2008: When To Start HBV, hepatitis B virus. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.

  24. 2008 IAS-USA Guidelines: When to Start Recommendations for initiating antiretroviral therapy in treatment-naïve adults with established HIV-1 infectiona a. In nonpregnant adults only. For all individuals, regardless of whether they are receiving treatment, intensive counseling to prevent secondary transmission is recommended. b. Considerations include high viral load (>100,000 HIV RNA copies/mL), rapid decline in CD4 cell count (>100/ mm3 per year), high risk of cardiovascular disease, active hepatitis B or C coinfections, or presence of HIV-associated nephropathy. Hammer S, et al. JAMA. 2008;300(5):555-570.

  25. Association Between Current CD4 Cell Count and Non-AIDS Complications Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.

  26. Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy 1000 1000 800 800 600 600 400 400 200 200 0 0 0 240 144 48 96 192 288 336 0 1 2 3 4 5 Johns Hopkins HIV Clinical Cohort ATHENA National Cohort Mean CD4 Cell Count (cells/mm3) Years on ART Weeks From Starting ART Keruly J, et al. Clin Infect Dis. 2007;44(3):441-446; Gras L, et al;.J Acquir Immune Defic Syndr. 2007;45(2):183-192.

  27. Case Presentation A 38-year-old female hairdresser, new HIV diagnosis; asymptomatic except for 0.5-cm posterior cervical nodes; CD4 770, HIV RNA 35,000 copies/mL, no resistance on genotype Patient has hypertension (HTN), diet-controlled diabetes mellitus (DM), and is African American; creatinine normal She is sexually active, “usually” with condoms; is not interested in becoming pregnant

  28. VOTE

  29. Audience Response Question Which NRTI pair would you choose? Abacavir/lamivudine (ABC/3TC) Tenofovir/emtricitabine (TDF/FTC) Zidovudine/lamivudine (ZDV/3TC)

  30. 2008 IAS-USA Guidelines: Recommended NRTI Components for Initial ARV Therapy Hammer S, et al. JAMA. 2008;300(5):555-570.

  31. VOTE

  32. Audience Response Question ABC/3TC TDF/FTC ZDV/3TC I would not use NRTIs as part of initial therapy If her calculated creatinine clearance (CrCl) by MDRD or Cockcroft-Gault were = 45 cc/min and HIV RNA > 100K c/mL, what NRTI pair would you choose? (HLA-B*5701 neg)

  33. A5202: Study Design Phase IIIB, randomized, partially blinded, 4-arm equivalence study Enrolled between September 2005 and November 2007; follow-up 96 weeks after last subject enrolled Arm TDF/FTC QD TDF/FTC QD A EFV EFV QD QD HIV-1 RNA ≥1000 c/mL Any CD4+ count > 16 years of age ABC/3TC Placebo QD ABC/3TC Placebo QD ABC/3TC QD ABC/3TC QD EFV EFV B QD QD ART ART - - naïve naïve TDF/FTC Placebo QD TDF/FTC Placebo QD 1858 enrolled N=1858 Randomized 1:1:1:1 Randomized 1:1:1:1 TDF/FTC QD TDF/FTC QD C ATV/r ATV/r QD QD Stratified by HIV-1 RNA (< or ≥ 100,000 copies/mL) ABC/3TC Placebo QD ABC/3TC Placebo QD ABC/3TC QD ABC/3TC QD ATV/r ATV/r D QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD Sax P, et al. XVII IAC; 2008; Mexico City. Abstract THAB0303.

  34. A5202: Results of >100,000 c/mL Stratum P<.0001 33% (130/398) Patient Percent P=.0003 19% (78/399) 14% (57/398) 7% (26/399) HR=2.33 (95% CI 1.46-3.72) HR=1.89 (95% CI 1.43-2.50) Virologic Failure Meeting Safety End Point Sax P, et al. XVII IAC; 2008; Mexico City. Abstract THAB0303.

  35. HEAT: HIV-1 RNA <50 c/mL at Week 96 (ITT-E, M=F) ABC/3TC + LPV/r (n=343) 100 TDF/FTC + LPV/r (n=345) 80 63 60 58 58 58 56 60 Percentage of subjects (%) 40 20 0 ≥100,000 All <100,000 Baseline HIV RNA Smith K, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. LBPE1138.

  36. VOTE

  37. Audience Response Question What “third drug” would you choose? Ritonavir-boosted atazanavir (ATV/r) Ritonavir-boosted darunavir (DRV/r) Efavirenz (EFV) Ritonavir-boosted fosamprenavir (FPV/r) Ritonavir-boosted lopinavir (LPV/r) Ritonavir-boosted saquinavir (SQV/r)

  38. IAS-USA Guidelines: Recommended Third- Drug Component for Initial ARV Therapy Hammer S, et al. JAMA 2008;300(5):555-570.

  39. ACTG 5142: 96-Week Outcomes (ITT) CD4+ Cell-Count Δ from BL: +239 vs +285 vs +268 (P=.01) Patients (%) EFV vs LPV: P=.006 EFV vs LPV/EFV: P=.5 LPV vs LPV/EFV: P=.13 EFV vs LPV: P=.003 EFV vs LPV/EFV: P=.123 LPV vs LPV/EFV: P=.183 ITT = intent to treat; ACTG = AIDS Clinical Trials Group. Riddler S, et al. XVI IAC; 2006; Toronto. Abstract THLB0204.

  40. ACTG 5142: Resistance or Failure Is More Likely With EFV than LPV/r *Some genotype assays pending. †Defined as 30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M. ‡P<.05 compared with LPV/EFV. ║P<.05 compared with LPV. §P<.05 compared with EFV. Riddler SA, et al. N Engl J Med. 2008;358(20):2095-2106.

  41. CASTLE 96 Weeks: HIV RNA < 50 c/mL (CVR NC = F) 100 ATV/RTV n = 440 LPV/RTV n = 443 80 60 HIV RNA < 50 c/mL: 74% ATV/RTV vs 68% LPV/RTV Difference estimate: 6.1 (95% CI, 0.3%–12.0%)* Percent Responders 40 20 0 B/L 36 84 12 48 60 96 24 72 Weeks * p<0.05

  42. ARTEMIS: VL <50 copies/mLto Week 96 (ITT-TLOVR) ITT-Analysis DRV/r qd (N=343) 100 LPV/r qd or bid (N=346) 90 80 70 79% 60 70.8% 50 40 % Response (± SE): VL <50 copies/mL (TLOVR) 30 Estimated difference in response vs LPV/r for noninferiority: PP=8.4% (95% CI 1.91;14.83) p<0.001 Estimated difference in response vs LPV/r for superiority: ITT=8.3% (95% CI 1.82;14.73) p=0.012 20 10 0 BAS W8 W16 W24 W36 W48 W60 W72 W84 W96 Time (in weeks)

  43. Summary: Which Boosted PI? LPV/r Pros: coformulated; least expensive Cons: 200 mg/d of RTV (lipids, GI), 4 pills/d ATV/r Pros: lowest pill burden, 100 mg/d of RTV, small effect on lipids; better efficacy at 96 weeks than LPV/r Cons: need to take with food; interaction with proton pump inhibitors; jaundice FPV/r Pros: 100 mg/d RTV Cons: sulfonamide; cross-resistance with DRV DRV/r Pros: 100 mg/d of RTV; small effect on lipids; better efficacy at 96 weeks than LPV/r Cons: need to take with food, sulfonamide; should it be saved?

  44. Initial Therapy: Areas of Uncertainty Whom to treat Patients with acute HIV Asymptomatic HIV, high CD4 cell count Partner uninfected When to treat Active opportunistic infection, concomitant substance abuse What to treat with Optimal NRTI pair with comorbidities, high HIV RNA Optimal third drug: EFV vs boosted PI vs raltegravir

  45. Calvin Cohen, MD Harvard Medical School CRI New England Boston, MA Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted?

  46. Modifying Virologically Suppressive Therapy First: do no harm Maintain virologic control Maintain CD4 responses Second: address shortcomings of existing regimen Simplification: fewer pills, less frequent dosing Substitutions: address long-term toxicity issues associated with some antiretrovirals when better alternatives exist

  47. Case Presentation Mr LA is a 37-year-old Latino male who’s been taking zidovudine/lamivudine (ZDV/3TC) plus efavirenz (EFV) for 2 years His viral load (VL) is <50 copies/mL He feels well, looks well, and is adherent He is concerned about his risk of developing the lipoatrophy that he sees in others

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