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DHS/PP HIV/AIDS 2008 Update

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  • Transcript

    • 1. DHS/PP HIV/AIDS 2008 Update David H. Spach, MD Clinical Director, NWAETC Professor of Medicine Division of Infectious Diseases University of Washington, Seattle
    • 2. HIV/AIDS 2008 Update
      • HIV Epidemiology
      • HIV Rapid Testing
      • 2008 DHHS ARV Therapy Guidelines
      • Antiretroviral Therapy: New Information in 2008
      • New Scientific Discoveries
      DHS/PP
    • 3. Epidemiology DHS/PP
    • 4. Question
      • In August 2008, the CDC reported their use of new epidemiologic methods that has led to significant revisions in the estimates of HIV incidence in the United States.
      From: CDC & Prevention. JAMA 2008;300:520-9. DHS/PP
    • 5. In this recent report, which one of the following statements is TRUE regarding HIV infections in the United States in 2006?
      • The number of estimated new infections in 2006 has been revised to a lower number (now 32,000 instead of 40,000)
      • The rate (per 100,000 persons) of new infections in blacks was 7x whites
      • Heterosexual sex has replaced male-to-male sex as the leading transmission category for new infections
      • The number of new infections in women was greater than men
    • 6. DHS/PP
      • “ Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300.” CDC & Prevention. JAMA 2008;300(5):520-9.
      • “ ... the level of new HIV infections in the United States is higher than had previously been known, in fact approximately 40% higher than early estimates…” Kevin Fenton, MD, PhD Centers for Disease Control & Prevention.
    • 7. Estimated Rates* of New US HIV Infections, 2006 From: CDC & Prevention. JAMA 2008;300:520-9. *Per 100,000 population DHS/PP
    • 8. New US HIV Infections (%) by Race/Ethnicity, 2006 From: CDC & Prevention. JAMA 2008;300 (5):520-9. DHS/PP
    • 9. New US HIV Infections, by Gender, 2006 From: CDC & Prevention. JAMA 2008;300 (5):520-9. DHS/PP
    • 10. New US HIV Infections (%) by Transmission Category, 2006 From: CDC & Prevention. JAMA 2008;300 (5):520-9. DHS/PP
    • 11.
      • What impact do you think the new CDC epidemiologic data will have on the AETCs?
      DHS/PP
    • 12. HIV Rapid Testing DHS/PP
    • 13. Rapid HIV Tests
      • In the June 18, 2008 issue of the MMWR, the NY City Department of Health and the CDC reported a problem with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test.
      DHS/PP
    • 14. What was the reported problem with the OraQuick rapid HIV test?
      • Contamination of test kits with mold
      • Kits were shipped too close to the expiration date
      • Failure of external Kit Controls to validate the assay
      • Increased numbers of False-Positive results with oral fluid samples
    • 15. DHS/PP Persons NOT Infected with HIV
    • 16. Rapid HIV Testing DHS/PP OraQuick Rapid ORAL HIV Test Confirmatory HIV Test (EIA/WB) Preliminary Positive Positive EIA WB Reactive Oral Fluid Oral
    • 17. Possible Revised Approach: Rapid HIV Testing DHS/PP OraQuick Rapid HIV Tests Confirmatory HIV Test (EIA & WB) Preliminary Positive Reactive Positive Reactive Oral Oral Fluid
    • 18. EXAMPLE: Specificity of HIV Antibody Test DHS/PP Persons NOT Infected with HIV (N = 15)
    • 19. EXAMPLE: Specificity of HIV Antibody Test DHS/PP Antibody Test Result: Persons NOT Infected with HIV
    • 20. EXAMPLE: Specificity of HIV Antibody Test DHS/PP Test Results = N =15 “ False Positive” True Negatives N = 13 N = 2 + +
    • 21. EXAMPLE: Specificity of HIV Antibody Test DHS/PP Specificity = True Negatives True Negatives + False Positives Specificity = 13 13 + 2 Specificity = .87 = 87% 13 15 = + = .87
    • 22. HIV Antibody Testing in Low Prevalence Setting DHS/PP N =1,000 persons 1% Infected with HIV (1% Prevalence) 990 HIV-Negative 10 HIV-Infected
    • 23. HIV Antibody Testing in Low Prevalence Setting DHS/PP N =1,000 persons 1% Infected with HIV (1% Prevalence) 990 HIV-Negative HIV Test Specificity 99.0%
    • 24. HIV Antibody Testing in Low Prevalence Setting DHS/PP N =1,000 persons 1% Infected with HIV (1% Prevalence) 990 HIV-Negative HIV Test Specificity 99.0% 980 True Negative 10 False Positives
    • 25. HIV Antibody Testing in Low Prevalence Setting DHS/PP N =1,000 persons 1% Infected with HIV (1% Prevalence) 990 HIV-Negative 10 HIV-Infected HIV Test Specificity 99.0% 980 True Negative 10 False Positives 10 HIV-Infected 0 False Positives HIV Test Sensitivity 99.0%
    • 26. HIV Antibody Testing in Low Prevalence Setting DHS/PP N =1,000 persons 1% Infected with HIV (1% Prevalence) 990 HIV-Negative 10 HIV-Infected HIV Test Specificity 99.0% 10 False Positives 10 HIV-Infected HIV Test Sensitivity 99.0%
    • 27. Antiretroviral Therapy 2008 DHHS Guidelines DHS/PP
    • 28. DHHS ARV Guidelines Initiating Antiretroviral Therapy
      • As a group, make a list of at least 5 recommendations regarding initiating antiretroviral therapy that are new/different in current 2008 guidelines when compared with guidelines that existed one year ago at this time (at that time October 2006 most recent updated version). 1. 2. 3. 4. 5.
      DHS/PP
    • 29. DHHS ARV Guidelines Initiating Antiretroviral Therapy
      • NEW RECOMMENDATIONS 1. New CD4 threshold (350 cells/mm 3 in 2008 instead of 200) 2. New indications for starting ARV (chronic HBV, HIVAN) in 2008 3. Less impact of HIV RNA level in 2008 4. Zidovudine-lamivudine removed from preferred list in 2008 5. Abacavir-lamivudine added to preferred list in 2008 6. Do HLA-B5701 testing if considering using abacavir
      DHS/PP
    • 30. Initiating Antiretroviral Therapy January 2008 DHHS Guidelines Year 1 DHS/PP *Initiate Antiretroviral Therapy Consider Antiretroviral Therapy 350 500 Source: DHHS Guidelines. www.aidsinfo.nih.gov
    • 31. Initiating Antiretroviral Therapy January 2008 DHHS Guidelines Year 1 DHS/PP *Initiate Antiretroviral Therapy Consider Antiretroviral Therapy 350 500 Source: DHHS Guidelines. www.aidsinfo.nih.gov *Other Reasons to Initiate ARV Rx - AIDS-defining Illness - Chronic HBV - HIV-associated nephropathy - Pregnancy
    • 32. We know the DHHS recommendations, but what you think is the correct CD4 count to initiate ARV Rx (assume client adherent & willing)?
      • CD4 count < 200 cells/mm 3
      • CD4 count 200-350 cells/mm 3
      • CD4 count 350-500 cells/mm 3
      • All patients regardless of CD4 count
    • 33. DHHS Panel: January 2008 ARV Therapy Guidelines Initial Therapy: Preferred Regimens Picture NNRTI Efavirenz Column B 2-NRTI Tenofovir/Emtricitabine ( Truvada ) Abacavir/Lamivudine ( Epzicom ): for patients who test negative for HLA-B5701 Column A DHS/PP PI Atazanavir + Ritonavir Fosamprenavir + Ritonavir BID Lopinavir/ritonavir ( Kaletra ) BID Construct Regimen by choosing one component from Column A and one component from Column B Source: DHHS Guidelines. www.aidsinfo.nih.gov
    • 34. Recent Concerns Regarding Abacavir
      • D:A:D Study 1 - Recent use (within prior 6 months) of abacavir or didanosine associated with increased risk for myocardial infarction; relative risk 1.94 with abacavir
      • SMART Study 2 - N = 5472; Use of abacavir associated with increased risk for myocardial infarction - Relative risk 4.3 with abacavir
      • Glaxo Data 3 - N = > 14, 600. Retrospective analysis of 54 company-sponsored clinical trials showed no increased risk of MI with abacavir use
      • ACTG 5202 4 - N = 5472; Higher failure rate in abacavir-containing regimens with HIV RNA > 100,000 copies/ml
      DHS/PP 1. Lancet 2008;371:1417-26 2. Lundgren J, et al. IAC. 2008; Abstract THAB0305. 3. CutrelI A, et al. 2008; Abstract WEAB006. 4. Sax P, et al. IAC. 2008; Abstract THAB0303.
    • 35. DHS/HIV/PP
      • “ At this point, the Panel concludes that the preliminary information available for these studies does not warrant a change in its current recommendations regarding the use of antiretroviral drugs in adults and adolescents.”
      Source: DHHS Guidelines. www.aidsinfo.nih.gov DHHS Panel
    • 36. DHS/PP Antiretroviral Therapy New Information in 2008
    • 37. Host Cellular Receptors CD4, CCR5, & CXCR4 DHS/PP Host Cell Membrane CD4 Receptor Extracellular Space Intracellular Space CCR5 CXCR4 Co-Receptors
    • 38. HIV (R5) Viral Entry: Co-Receptor Binding DHS/PP Host Cell Membrane CD4 Receptor Extracellular Space Intracellular Space R5 HIV CXCR4 CCR5
    • 39. Entry Inhibitor: Maraviroc ( Selzentry ) DHS/PP Host Cell Membrane CD4 Receptor Extracellular Space Intracellular Space R5 HIV Maraviroc CXCR4 CCR5
    • 40. HIV Co-Receptor Tropism Assay Monogram Biosciences Trofile Assay DHS/PP R5-Tropic X4-Tropic R5X4 (Dual)-Tropic Mixed Tropic HIV-1 Tropism Assay
    • 41. Question
      • A new HIV Tropism ( Trofile ) assay is now available.
      From: Monogram Biosciences DHS/PP
    • 42. What is the major difference in the new ENHANCED Trofile assay when compared with the older Trofile assay?
      • The new assay has a lower limit of detection of minor species (<1% compared with previous lower limit of 10%)
      • Results can be obtained in 7 days with the new assay
      • The new assay is accurate with very low HIV RNA levels (accurate down to 100 copies/ml)
      • The new assay detects CCR5 mutants resistant to Maraviroc
    • 43. HIV Co-Receptor Tropism Assay Monogram Biosciences ENHANCED Trofile Assay DHS/PP
      • Viral Load Required - Above 1,000 copies/ml
      • Detection of Minor Species - Reliably detected at 0.3%
      R5-Tropic X4-Tropic R5X4 (Dual)-Tropic Mixed Tropic HIV-1 Tropism Assay
    • 44. . DHS/PP Tenofovir + Lamivudine + Efavirenz (n = 38) Eligibility - HIV-infected - Treatment Naive - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm 3 - Randomized, double-blind Tenofovir + Lamivudine + Raltegravir* (n = 160) From: Markowitz M, et al. 17th IAC2008;Abstract TUAB0102. Tenofovir + 3TC + (Efavirenz or Raltegravir) Antiretroviral Naïve: Protocol 004 Protocol 004 N = 198 *Up to week 48, raltegravir dosed bid at 200, 400, 600, or 800 mg After week 48, all raltegravir dosed at 400 mg bid 1x 4x
    • 45. Tenofovir + 3TC + (Efavirenz or Raltegravir) Week 96 Data DHS/PP * CD4 counts higher in LPV-RTV arms From: Markowitz M, et al. 17th IAC.2008;Abstract TUAB0102.
    • 46.
      • Resistance Pathways - Q148 R/H/K + Subsequent Mutations - N155 H + Subsequent Mutations
      • Y143 CHR identified as possible pathway
      • Q148 R/H/K plus G140 S depend on R/H/K
      • N155 H plus E92 Q increases resistance
      Raltegravir: Resistance DHS/PP 1 288 H K R Q N H Genotype: Mutations 148 155 HIV Integrase Resistance to Raltegravir CTD NTD 50 212 Integrase Amino acids CCD 1 288 C H R Y 143 NTD CTD CCD 50 212 Catalytic Core Domain N Terminal Domain C Terminal Domain
    • 47. Baseline NNRTI Resistance & Response to Etravirine DUET 1 & 2 Studies DHS/PP Virologic Response: Week 24 From: Cahn P, et al. 2007 ICAAC. Abstract H-717.
      • Background - Pooled data from DUET 1 & 2
      • Patients (N = 599) - ARV experienced - Failed NNRTI regimen - 3 or more PI mutations - HIV RNA > 1,000 copies/ml
      • Etravirine Associated Mutations (n = 13) - V90I - A98G - L100I - K101E/P - V106I, - V179D/F - Y181C/I/V - G190S/A
      Study Design
    • 48. Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive STUDY C204 From: Pozniak A, et al. 17th IAC. 2008; Abstract 144-LB. Study Design: Phase II Results (ITT): 96 Weeks DHS/PP P = 0.04 P = 0.003 * CD4 counts higher in LPV-RTV arms INVESTIGATIONAL
      • Background - N = 368 - ARV-naïve - HIV RNA > 5,000 copies/ml - Randomized, double-blind
      • Regimens (all include 2 NRTIs*) - Efavirenz: 600 mg qd - Rilpivirine: 25 mg qd - Rilpivirine: 75 mg qd - Rilpivirine: 150 mg qd
      *Zidovudine + Lamivudine (75%) *Tenofovir + Emtricitabine (25%) 25 mg
    • 49.
      • Does anyone have questions or want to bring up any other important recent information recent antiretroviral therapy?
      DHS/PP
    • 50. DHS/PP New Scientific Discoveries
    • 51. A Cure for HIV?
      • In July 2008, our patients starting coming in asking about the news reports regarding the newly discovered cure for HIV. The report that came out in July 2008 was related to HIV gp120 (envelope).
      gp120 gp41 Envelope HIV
    • 52. What new therapeutic strategy was discovered?
      • A CD4 coating molecule that is an inhibitor of gp120-CD4 binding
      • Use of Abzymes to destroy a critical region of gp120
      • A new enzyme that cause gp120 to separate from gp41
      • A new particle that destroys the human co-receptor CCR5 and thus prevents gp120-CCR5 binding
    • 53. HIV: Basic Structure DHS/PP gp120 gp41 Envelope
    • 54. HIV: Envelope DHS/PP HIV gp120 gp41
    • 55. HIV: gp120 DHS/PP From: Zolla-Pazner S. Nat Rev Immunol 2004;4:199-212.
    • 56. HIV: gp120 DHS/PP From: Zolla-Pazner S. Nat Rev Immunol 2004;4:199-212. L G L L T R D G G N N N N HIV superantigen region Conserved Region Important in CD4 Binding L G L L T R D G G N N N N AA 421-433
    • 57. HIV Cell Binding and Entry DHS/PP Host Cell Membrane CD4 Receptor Extracellular Space Intracellular Space HIV CCR5 gp120
    • 58. Abzyme (Catalytic Antibody) DHS/PP From: Planque S, et al. Auoimmun Rev. 2008;7:473-9. Y Abzymes - Antibodies with enzymatic activity - Can break down thousands of virus particles per molecule of abzyme
    • 59. HIV: gp120 DHS/PP L G L L T R D G G N N N N Abzyme L G L L T R D G G N N N N Y Y From: Planque S, et al. Auoimmun Rev. 2008;7:473-9.
    • 60. HIV gp120: Abzyme Interaction DHS/PP HIV gp120 Y
    • 61. HIV gp120: Abzyme Interaction DHS/PP HIV gp120 Y Y
    • 62. HIV gp120: Abzyme Interaction DHS/PP HIV gp120 Y Y
    • 63. Abzyme (Catalytic Antibody) DHS/PP From: Planque S, et al. Auoimmun Rev. 2008;7:473-9. Y Y Y Y HIV-Negative Patients with Lupus (SLE) Abzyme
    • 64. HIV Life Cycle: Host Cell Defenses HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA
    • 65. HIV Life Cycle: Cellular Restriction HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA HUMAN APOBEC 3G HUMAN APOBEC 3G Tetherin Tetherin
    • 66. Viral Defenses: HIV Accessory Proteins DHS/PP HIV Accessory Proteins Viral Inhibitor Factor (Vif) Viral Protein U (Vpu) Vif Vpu
    • 67. Cellular Restriction and Viral Defenses DHS/PP APOBEC 3G Human: Cellular Restriction HIV: Viral Defense Vif Tetherin Vpu
    • 68. Host Defense: ABOBEC 3G HIV Nucleus Host Cell CD4 CCR5 HIV RNA Reverse Transcription HIV DNA Reverse Transcriptase Host Protein APOBEC 3G
    • 69. HIV: Reverse Transcription HIV RNA HIV Reverse Transcriptase Human Nucleotides Human Cell
    • 70. APOBEC 3G & Production of Defective HIV DNA HIV RNA HIV Reverse Transcriptase Human Nucleotides Human Cell G to A Hypermutation Human APOBEC 3G Defective HIV DNA
    • 71. HIV Defense (Vif) of APOBEC 3G HIV RNA HIV Reverse Transcriptase Human Cell Human APOBEC 3G Defective HIV DNA Vif HIV Accessory Protein
    • 72. HIV Defense (Vif) of APOBEC 3G HIV RNA HIV Reverse Transcriptase Human Cell NORMAL HIV DNA Vif Human APOBEC 3G
    • 73. HIV Life Cycle: Budding HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA
    • 74. Host Defense: Tetherin HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA Tetherin HUMAN Tetherin From: Neil SJ, et al. Nature2008;45: 425-31.
    • 75. HIV Defense (Vpu) Defense of Tetherin HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA Tetherin Vpu HIV Accessory Protein From: Neil SJ, et al. Nature2008;45: 425-31.
    • 76. HIV Defense (Vpu) Defense of Tetherin HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV mRNA Gag Gag-Pol HIV DNA Vpu Tetherin HIV Accessory Protein
    • 77. Translation of Basic Science Discoveries to Potential Future Therapies
      • Abzyme - Isolate/develop compounds that inactivate key gp120 segment
      • Human APOBEC-3G and Vif - Develop Vif inhibitors - Develop APOBEC-3G-like compounds that cause hypermutations in HIV DNA formation
      • Human Tetherin and Vpu - Develop Vpu inhibitors - Develop tetherin-like compounds
      DHS/PP Y APOBEC 3G Vpu L G L L T R D G G N N N N Vif Tetherin HIV HIV Human Human
    • 78. TRUE or FALSE. In the US, in 2006, there were more NEW HIV infections involving MEN than WOMEN?
      • TRUE
      • FALSE
    • 79. With regard to HIV testing, if SPECIFICITY is how accurately you identify people who don’t have HIV infection, what do you think SENSITIVITY is?
      • The number of false-negatives
      • How accurately you identify people who truly have HIV infection
      • The inverse prevalence of the disease
    • 80. How did the drugs Raltegravir (Integrase Inhibitor) and Rilpivarine (NNRTI) fare in terms of virologic responses when compared head-to-head with Efavirenz (combined with 2 nucleosides)?
      • They were clearer superior to efavirenz
      • About the same as efavirenz
      • They were clearer inferior to efavirenz
    • 81. According to the 2008 DHHS Guidelines, which of the following are indications to initiate ARV therapy?
      • CD4 count < 350 cells/mm 3
      • Chronic active hepatitis B virus infection
      • HIV-associated nephropathy
      • All of the above
    • 82. MATCH EM UP
      • Enzyme that destroys part of gp120
      • Human protein that causes defective RT
      • Human protein that prevents HIV release
      DHS/PP Y APOBEC 3G L G L L T R D G G N N N N Tetherin
    • 83. What does HIV use to neutralize these human cellular restriction proteins ?
      • HIV Protease
      • HIV reverse transcriptase
      • HIV accessory proteins
      Vpu Vif
    • 84. HIV/AIDS 2008 Update: Summary
      • HIV Epidemiology
      • HIV Rapid Testing
      • 2008 DHHS ARV Therapy Guidelines
      • Antiretroviral Therapy: New Information in 2008
      • New Scientific Discoveries
      DHS/PP
    • 85. DHS/PP Questions?