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Welcome to I-TECH HIV/AIDS Clinical Seminar Series 15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach,

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Presentation on theme: "Welcome to I-TECH HIV/AIDS Clinical Seminar Series 15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach,"— Presentation transcript:

1 Welcome to I-TECH HIV/AIDS Clinical Seminar Series 15 October, 2009 New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach, MD & Chris Behrens, MD

2 DHS/PP 2009: New Insights into HIV Pathogenesis and Antiretroviral Therapy Update David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle

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

4 Natural History of Untreated HIV Year 1 DHS/PP Acute HIV Acute CD4 Depletion 1

5 Natural History of Untreated HIV Year 1 DHS/PP Acute HIV Immune Activation Acute CD4 Depletion 12

6 Natural History of Untreated HIV Year 1 DHS/PP Acute HIV Immune Suppression Acute CD4 Depletion 231 Immune Activation

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

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

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

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

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

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

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

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

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

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 From: Molina JM, et al. Lancet 2008;72:646-55. TDF-FTC + (Atazavir-RTV or Lopinavir-RTV) CASTLE Study  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) Study Design HIV RNA < 50 copies/ml*: Week 48 DHS/PP * Capsules during first 48 weeks * TLOVR = Time to Loss of Virologic Response <100k

20 From: Eron J et al. Lancet 2006;368:476-82. ABC + 3TC + (Fosamprenavir-RTV or Lopinavir-RTV) KLEAN-ESS100732  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) Study DesignResults*: 48 Weeks (TLOVR) DHS/PP * No differences in response in patients with HIV RNA > 100K * TLOVR = Time to Loss of Virologic Response

21 From: Walmsley S, et al. JAIDS 2009;50(5):367-74. Saquinavir-RTV vs. Lopinavir-RTV in ARV-Naive GEMINI Study  Patients (N = 337) - Open-label, randomized trial - ARV naïve, HIV RNA > 10,000 copies/ml - CD4 count < 350 cells/mm 3  Regimens (backbone TDF + FTC qd) - Saquinavir + RTIV (1000/100 mg bid) - Lopinavir-RTV (400-100 mg bid) Study DesignResults*: 48 Weeks (ITT) DHS/PP * ITT = Intention to Treat

22 From: Ortiz R, et al. AIDS 2008;22:189-97. Darunavir + RTV vs Lopinavir-RTV in ARV-Naive ARTEMIS Trial: 48 Week Data  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 Study DesignResults*: 48 Weeks (ITT-TLOVR) DHS/PP ^ Darunavir: 400 mg tablets * TDF = tenofovir 300 mg; FTC = emtricitabine 200 mg + Lopinavir-RTV: 77% bid; 15% qd; 7% both qd & bid *TLOVR-Time to Loss of Virologic Response; Non-completer = Failure P < 0.06 P < 0.05 <100k

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 HIV RNA HIV Nucleus Host Cell CD4 CCR5 HIV Proviral DNA Integration HIV DNA Integrase

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

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

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

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

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

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

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^ (n = 282) Eligibility - HIV-infected - Treatment Naïve - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm 3 - No baseline resistance to TDF or FTC - Randomized, double-blind Tenofovir-Emtricitabine + Raltegravir* (n = 281) Tenofovir-Emtricitabine + (Efavirenz or Raltegravir) Antiretroviral Naïve: STARTMRK STARTMRK Protocol N = 563 ^Efavirenz: 600 mg *Raltegravir: 400 mg bid 1x From: Lennox J, et al. Lancet. 2009;July 31 [E=pub ahead of print].

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

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 DHS/PP Questions

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

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

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 Year 1 DHS/PP 350 500 200 Acute HIV

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

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

43 Initiating Antiretroviral Therapy 2008 United States DHHS Guidelines Year 1 DHS/PP Treat Consider Treatment 350 500 Source: DHHS Guidelines. www.aidsinfo.nih.gov Do not Treat 200

44 Mounting Evidence that Earlier Initiation of Therapy results in better clinical outcomes StudyTypeSettingMain Findings CIPRA 001 1 RCTHaitiDeferring ART until CD4<200 associated with higher mortality than starting when CD4 between 200 and 350 SMART substudy 2 RCTEurope, Australia Deferring ART until CD4<250 associated with higher mortality than starting when CD4 between 350 and 250 ART-CC 3 ObsEurope, North America Significant increase in risk of AIDS and death when therapy was delayed until patients CD4+ counts fell below 350 cells/mm3 compared to earlier treatment. NA- ACCORD 4 ObsNorth America Lower mortality in those who initiated in 350-500 range than those who deferred; Lower mortality in those who initiated at CD4 > 500 than in those who deferred 1. Interim analysis, June 2009 2. JID 2008;197:1133–1144 3. 16 th 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  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. Analysis #1: 500>CD4>350Analysis #2: CD4> 500

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

48

49 SMART Study Drug Conservation (DC) Defer use of ART until CD4+ 350 Viral Suppression (VS) Continuous use of ART to maintain viral load as low as possible CD4+ cell count >350 cells/mm 3 N= 5,472 n = 2,752 n = 2,720 Primary Endpoint: Opportunistic Disease or Death

50 Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events No. of Patients with Events Endpoint Serious AIDS591.30.4 Favors VS ► ► Favors DC Hazard Ratio (DC/VS) (95% CI) Rate** DCVS 3.6 1.9 Serious non-AIDS*1863.22.0 1.6 Cardiovascular, renal, hepatic, non-AIDS malignancy, others ** Per 100 person-years Serious AIDS or 2394.42.4 non-AIDS Curr Opin HIV AIDS 2008;3:112-117 0.1110

51 Unchecked HIV replication T cell apoptosis immunosuppression Unifying Framework HIV-Associated Immune Activation Adapted from Wafa El-Sadr, IAS 2009

52 Unifying Framework HIV-Associated Immune Activation Unchecked HIV replication T cell apoptosis immunosuppression Unchecked HIV replication Inflammation & coagulopathy non-AIDS morbidity & mortality – Coronary Artery Dz - Liver disease – Osteoporosis - Neurocognitive decline – Renal disease - Malignancies Ross, NEJM 1999 Adapted from Wafa El-Sadr, IAS 2009

53 C Reactive Protein Levels Increase over Time prior to AIDS Diagnosis C reactive protein, geometric mean ug/L Months from AIDS Diagnosis Lau et al, Arch Intern Med 2006 AIDS

54 Change from Baseline to Month 1 SMART Study Effect of ART Interruption on Biomarkers Change from Baseline to Month 1 SMART Study MarkerDC GroupVS Group N Median M1-bl (IQR) N P- value 1 IL-62470.60 (-0.17-1.87) 2490.12 (-0.88-0.97) <.0001 D-dimer2480.05 (-0.07-0.18) 2480.00 (-0.13-0.08) <.0001 1 Wilcoxon 2-sided test comparing DC and VS from baseline to month 1

55 Natural Course of HIV Infection Year 1 DHS/PP 350 500 200 “Clinical Latency”

56 Natural Course of HIV Infection Year 1 DHS/PP 350 500 200 “Clinical Latency” Chronic Inflammation => ongoing morbidity & mortality

57 Natural Course of HIV Infection Year 1 DHS/PP 350 500 200 “Clinical Latency” Chronic Inflammation => ongoing morbidity & mortality

58 Initiating Antiretroviral Therapy for the Asymptomatic Patient: future guidelines? Year 1 DHS/PP Initiate Antiretroviral Therapy 500 350 200

59 JAMA, June 10, 2009—Vol 301, No. 22 Bull World Health Organ 2009;87:488

60 HIV transmission rate, per coital act, by plasma viral load of source partner - Rakai HIV transmission rate (per coital act) The LancetThe Lancet Volume 357, Issue 9263, 14 April 2001, Pages 1149-1153olume 357, Issue 9263

61 AIDS 2009, 23:1397–1404 Risk of HIV Transmission by VL & ART Use

62 Mathematical Model: Universal ART in SA Lancet, Volume 373, Issue 9657, Pages 48 - 57, 3 January 2009

63 Extra slides

64 Dramatic Increase in Access to ART; Low & Middle Income Countries

65 START Study HIV-infected, ART-naïve CD4+ count > 500 cells/mm 3 Early ART Group Initiate ART immediately Deferred ART Group Defer ART until CD4+ count < 350 cells/mm 3 or AIDS Primary Outcome Serious AIDS, Serious non-AIDS Events or Death Measurement of biomarkers

66 Effect of Rosuvastatin on CVD in General Population with High CRP & Low LDL- Jupiter Study Ridker et al, N Engl J Med 2008 Cumulative Incidence Years

67 Atorvastatin Placebo Atorvastatin Placebo Week 0 2048 Arm A Arm B 28 A5275 – Pilot Study of Effects of Atorvastatin on Biomarkers in HIV WASHOUTWASHOUT Biomarkers of Inflammation, Coagulopathy, Angiogenesis, and T-lymphocyte Activation HIV infected On boosted-PI regimen with HIV RNA <50 copies/ml LDL < 130 mg/dl D-dimer >0.34

68 HIV: Natural History Year 1 DHS/PP Acute HIV

69 Initiating Antiretroviral Therapy 2007 CAREC/CHART Guidelines Year 1 DHS/PP Offer treatment; start before CD4 < 200 Treatment generally not recommended* 350 500 Source: CAREC/CHART ART Guidelines, 2007 200 Treat Do not Treat

70 Thank you! Next session: 22 October, 2009 Listserv: itechdistlearning@u.washington.eduitechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

71 Welcome to I-TECH HIV/AIDS Clinical Seminar Series Next session: 22 October, 2009 Roy Colven, MD HIV Dermatology: Virtual Dermatology

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