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15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update

15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach, MD & Chris Behrens, MD.

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15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update

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  1. 15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach, MD & Chris Behrens, MD

  2. 2009: New Insights into HIV Pathogenesis and Antiretroviral Therapy UpdateDavid H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/PP

  3. New Insights into the Pathogenesis and Natural History of HIV DHS/PP

  4. Natural History of Untreated HIV Acute HIV 1 Acute CD4Depletion Year 1 DHS/PP

  5. Natural History of Untreated HIV Acute HIV 1 2 Acute CD4Depletion Immune Activation Year 1 DHS/PP

  6. Natural History of Untreated HIV Acute HIV 1 2 3 Acute CD4Depletion Immune Activation Immune Suppression Year 1 DHS/PP

  7. Natural History of Untreated HIV Acute HIV Immune Activation Year 1 DHS/PP

  8. CD8 Natural History Phases Normal Intestine Epithelium CD4 Acute HIV Infection HIV Destruction of CD4 Cells in Gut Profound Loss of Intestinal CD4 Cells From: Mehandru S. PRN Notebook. December 2007.

  9. CD8 Natural History Phases Normal Intestine Epithelium CD4 Acute HIV Infection HIV Destruction of CD4 Cells in Gut Profound Loss of Intestinal CD4 Cells From: Mehandru S. PRN Notebook. December 2007.

  10. CD8 Natural History Phases Normal Intestine Epithelium CD4 Acute HIV Infection HIV Destruction of CD4 Cells in Gut Profound Loss of Intestinal CD4 Cells From: Mehandru S. PRN Notebook. December 2007.

  11. CD8 Natural History Phases Normal Intestine Epithelium CD4 Acute HIV Infection HIV Destruction of CD4 Cells in Gut Profound Loss of Intestinal CD4 Cells From: Mehandru S. PRN Notebook. December 2007.

  12. Reasons for Massive Gut Mucosal CD4 Depletion • Large Population of Preferred Target Cells for Acute Infection- Gut: 50-70% express CCR5- Blood: 10-20% express CCR5 • Dense Clustering of Cells in GI Mucosa- Close proximity leads to cell-to-cell HIV transmission • Binding to Integrin Receptor (alpha-4, beta7)- This integrin receptor preferentially expressed on gut CD4 cells DHS/PP

  13. Normal Gut CD8 CD4 Normal Gut MODIFIED From: Mehandru S. PRN Notebook. December 2007.

  14. CD4 Depleted Gut: Consequences Enteropathy- Diarrhea- Malabsorption- Increased Gut Permeability CD8 CD4 CD4 Depleted Gut MODIFIED From: Mehandru S. PRN Notebook. December 2007.

  15. CD4 Depleted Gut: Bacterial Translocation Bacterial Translocation CD8 CD4 CD4 Depleted Gut MODIFIED From: Mehandru S. PRN Notebook. December 2007.

  16. Gut Involvement in Chronic Inflammatory State Massive Gut CD4 Cell Depletion Increased Gut Permeability Bacterial Translocation Structural Damage Enteropathy Increased Bacterial LPS Chronic Inflammation DHS/PP

  17. Natural History Phases: Interventions • Phase 1: Acute CD4 Depletion- Gut depletion severe within 4 weeks- Vaccine that would lessen effect on “GALT” • Phase 2: Inflammation and Immune activation- Antiretroviral Therapy: ? Optimal Timing- Gut Repair/Restoration- Specific Anti-Inflammatory/Immunosuppressant • Phase 3: Immune Suppression- OI Treatment and Prophylaxis- Antiretroviral Therapy DHS/PP

  18. Which ritonavir boosted protease inhibitor regimen is best?

  19. TDF-FTC + (Atazavir-RTV or Lopinavir-RTV)CASTLE Study Study Design HIV RNA < 50 copies/ml*: Week 48 • Patients (N = 883) - ARV naïve, HIV RNA > 5,000 copies/ml - Randomized trial • Regimens (backbone TDF-FTC qd) - Atazanavir 300 mg qd + RTV 100 mg qd - LPV-RTV* (400-100 mg bid) * Capsules during first 48 weeks <100k * TLOVR = Time to Loss of Virologic Response From: Molina JM, et al. Lancet 2008;72:646-55. DHS/PP

  20. ABC + 3TC + (Fosamprenavir-RTV or Lopinavir-RTV)KLEAN-ESS100732 Study Design Results*: 48 Weeks (TLOVR) • Patients (N = 887) - ARV naïve, HIV RNA > 1,000 copies/ml - Randomized trial • Regimens (backbone ABC + 3TC qd) - FosAmp 700 mg bid + RTV 100 mg bid - LPV-RTV (400-100 mg bid) * TLOVR = Time to Loss of Virologic Response * No differences in response in patients with HIV RNA > 100K From: Eron J et al. Lancet 2006;368:476-82. DHS/PP

  21. Saquinavir-RTV vs. Lopinavir-RTV in ARV-NaiveGEMINI Study Study Design Results*: 48 Weeks (ITT) • Patients (N = 337) - Open-label, randomized trial - ARV naïve, HIV RNA > 10,000 copies/ml - CD4 count < 350 cells/mm3 • Regimens (backbone TDF + FTC qd) - Saquinavir + RTIV (1000/100 mg bid) - Lopinavir-RTV (400-100 mg bid) * ITT = Intention to Treat From: Walmsley S, et al. JAIDS 2009;50(5):367-74. DHS/PP

  22. Darunavir + RTV vs Lopinavir-RTV in ARV-NaiveARTEMIS Trial: 48 Week Data Study Design Results*: 48 Weeks (ITT-TLOVR) • Patients (N = 689) - ARV-naive - HIV RNA > 5,000 copies/ml - Randomized trial (non-blinded) • Regimens (All Received TDF-FTC*) - ^Darunavir-RTV: 800/100 mg qd -+LPV-RTV: 400/100 mg bid or 800/200 mg qd P < 0.05 P < 0.06 ^ Darunavir: 400 mg tablets * TDF = tenofovir 300 mg; FTC = emtricitabine 200 mg+ Lopinavir-RTV: 77% bid; 15% qd; 7% both qd & bid <100k *TLOVR-Time to Loss of Virologic Response;Non-completer = Failure From: Ortiz R, et al. AIDS 2008;22:189-97. DHS/PP

  23. Ritonavir-Boosted PIs • CASTLE- Atazanavir + Ritonavir = Lopinavir-ritonavir • KLEAN- Fosamprenavir + Ritonavir = Lopinavir-ritonavir • GEMINI- Saquinavir + Ritonavir = Lopinavir-ritonavir • ARTEMIS- Darunavir + Ritonavir > Lopinavir-ritonavir DHS/PP

  24. Update on Raltegravir

  25. HIV Life Cycle: Integration Integration Integrase Nucleus CCR5 CD4 HIV RNA HIV DNA HIV Proviral DNA HIV Host Cell

  26. HIV Integrase From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) DHS/PP

  27. PREINTEGRATION COMPLEX-HOST DNA BINDING LEDGF/p75 Host DNA From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) Spach

  28. STRAND TRANSFER Reaction Catalyzed by HIV Integrase From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) Spach

  29. STRAND TRANSFER HIV DNA Host DNA Host DNA From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) Spach

  30. STRAND TRANSFER Host DNA HIV DNA Host DNA From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) Spach

  31. Integrase InhibitorsStrand Transfer Inhibitors HIV DNA 3’ Hydroxyl Group Host DNA Integrase InhibitorStrand Transfer Inhibitors 3’ Hydroxyl Group From: HIV Integration. HIV Web Study (www.HIVwebstudy.org) Spach

  32. Raltegravir (Isentress) • Class- Integrase Inhibitor • Dose- 400 mg PO bid (400 mg tabs) • Adverse Effects- Diarrhea, increased CPK (with statin)- No adverse effects on lipids DHS/PP

  33. Tenofovir-Emtricitabine + (Efavirenz or Raltegravir)Antiretroviral Naïve: STARTMRK . STARTMRK ProtocolN = 563 Eligibility - HIV-infected - Treatment Naïve - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm3 - No baseline resistance to TDF or FTC - Randomized, double-blind Tenofovir-Emtricitabine + Efavirenz^ (n = 282) 1x 1x Tenofovir-Emtricitabine + Raltegravir* (n = 281) ^Efavirenz: 600 mg*Raltegravir: 400 mg bid From: Lennox J, et al. Lancet. 2009;July 31 [E=pub ahead of print]. DHS/PP

  34. Tenofovir-Emtricitabine + (Efavirenz or Raltegravir)Antiretroviral Naïve: STARTMRK 48 Week Data From: Lennox J, et al. Lancet. 2009;July 31 [E=pub ahead of print]. DHS/PP

  35. Rifampin and Raltegravir • Rifampin 600 mg/d with Raltegravir 400 mg bid- Raltegravir AUC decreased 40%- Raltegravir MIC decreased 61% • Recommendation with use of rifampin and raltegravir- Increase raltegravir to 800 mg bid DHS/HIV/PP

  36. Questions DHS/PP

  37. Benefits reduced morbidity & mortality immune system recovery Drawbacks Toxicities potential for developing resistance expense When Should Patients with HIV be Treated with HAART?

  38. Benefits reduced morbidity & mortality immune system recovery Reduced infectivity Reduce immune activation? Drawbacks Toxicities potential for developing resistance expense When Should Patients with HIV be Treated with HAART?

  39. Initiation of Antiretroviral Therapy: Key Considerations • Symptoms & Opportunistic Infections • Anticipated Adherence - patient ‘readiness’ • CD4 count

  40. CD4-guided initiation of Antiretroviral Therapy for the asymptomatic patient Acute HIV 500 350 200 Year 1 DHS/PP

  41. CD4-guided initiation of Antiretroviral Therapy for the asymptomatic patient Acute HIV “Clinical Latency” “Asymptomatic” 500 350 200 Year 1 DHS/PP

  42. Initiating ART for asymptomatic patients2006 WHO Guidelines Do not Treat 500 350 consider treatment; start before CD4 drops below 200 200 Treat Year 1 Source: WHO ART Guidelines, 2006 DHS/PP

  43. Initiating Antiretroviral Therapy2008 United States DHHS Guidelines Do not Treat 500 Consider Treatment 350 200 Treat Year 1 DHS/PP Source: DHHS Guidelines. www.aidsinfo.nih.gov

  44. Mounting Evidence that Earlier Initiation of Therapy results in better clinical outcomes 1. Interim analysis, June 2009 2. JID 2008;197:1133–1144 3. 16th CROI, Montreal, 2009 Abstract 72LB 4. N Engl J Med 2009;360.

  45. NA-ACCORD • 17,517 asymptomatic, ARV-naive patients with HIV infection in North America who received medical care 1996 through 2005 • stratified according to their CD4+ count at baseline: 351 to 500 cells per cubic millimeter or more than 500 cells per cubic millimeter • compared survival between patients who started antiretroviral therapy within the given CD4+ stratum with those who waited until after the CD4+ count fell below the stratum. N Engl J Med 2009;360.

  46. NA-ACCORD: Results Analysis #1: 500>CD4>350 Analysis #2: CD4> 500 • N=8362 patients • 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. • Among patients in the deferred-therapy group there was an increase in the risk of death of 69% • N=9155 patients • 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. • Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% N Engl J Med 2009;360.

  47. Initiating Antiretroviral Therapy for the asymptomatic patient 500 350 200 Year 1 DHS/PP

  48. SMART Study CD4+ cell count >350 cells/mm3 N= 5,472 n = 2,720 n = 2,752 Drug Conservation (DC) Defer use of ART until CD4+ < 250; episodic ART based on CD4+ cell count to increase counts to > 350 Viral Suppression (VS) Continuous use of ART to maintain viral load as low as possible Primary Endpoint: Opportunistic Disease or Death

  49. Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events Hazard Ratio (DC/VS) (95% CI) No. of Patients with Events Rate** Endpoint DC VS 3.6 Serious AIDS 59 1.30.4 1.6 Serious non-AIDS* 186 3.22.0 1.9 Serious AIDS or 239 4.42.4non-AIDS 0.1 1 10 Favors VS ► Favors DC ► • Cardiovascular, renal, hepatic, non-AIDS malignancy, others • ** Per 100 person-years Curr Opin HIV AIDS 2008;3:112-117

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