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DHS/PP

2006 Asilomar HIV/AIDS Medical Update David H. Spach, MD Clinical Director, NWAETC Professor of Medicine Division of Infectious Diseases University of Washington, Seattle. DHS/PP. Asilomar 2006 HIV/AIDS Medical Update Outline. Update on DHHS Antiretroviral Therapy Guidelines

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DHS/PP

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  1. 2006 Asilomar HIV/AIDS Medical UpdateDavid H. Spach, MDClinical Director, NWAETCProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/PP

  2. Asilomar 2006 HIV/AIDS Medical Update Outline • Update on DHHS Antiretroviral Therapy Guidelines • New Data with Established Antiretroviral Medications • New Medications • O-Receptor Inhibitors DHS/PP

  3. Antiretroviral TherapyDHHS May 2006 Guidelines DHS/PP

  4. HIV: Antiretroviral Therapy Nucleoside RTI Nucleotide RTI Entry Inhibitors RT HIV RNA HIV DNA HIV Nucleus Protease Inhibitors Host Cell Non-Nucleoside RTI

  5. Initiating Antiretroviral Therapy • A 37-year-old HIV-infected woman presents for follow-up to consider starting antiretroviral therapy. Laboratory studies show a CD4 count of 395 cells/mm3 and a HIV RNA level of 88,000 copies/ml; repeat testing one month later shows basically the same values. • Assuming she is motivated and able to take antiretroviral therapy, what would the May 2006 DHHS Antiretroviral Therapy guidelines recommend?1. Start antiretroviral therapy.2. Offer therapy after discussing the pros and cons.3. Defer antiretroviral therapy and continue to follow. DHS/PP

  6. DHHS Panel: May 2006 Antiretroviral GuidelinesInitial Therapy, Chronically Infected DHS/PP Source: http://wwwaidsinfo.nih.gov

  7. Initiating Antiretroviral Therapy Acute HIV Infection 350 350 200 200 Year 1 DHS/PP

  8. DHHS Panel: October 2006 ARV Therapy GuidelinesInitial Therapy: Preferred Regimens Construct Regimen by choosing one component from Column A and one component from Column B Column A Column B NNRTIEfavirenz PIAtazanavir + Ritonavir Fosamprenavir + Ritonavir BIDLopinavir/ritonavir BID 2-NRTITenofovir/Emtricitabine Zidovudine/Lamivudine Picture Source: www.aidsinfo.nih.gov DHS/PP

  9. DHHS Panel: October 2006 ARV Therapy GuidelinesInitial Therapy: Alternative Regimens Construct Regimen by choosing one component from Column A and one component from Column B Column A Column B NNRTINevirapine PIAtazanavir (unboosted)Fosamprenavir (unboosted) Fosamprenavir + ritonavir qdLopinavir/ritonavir qd 2-NRTIAbacavir/Lamivudine Didanosine + Lamivudine Picture Source: www.aidsinfo.nih.gov DHS/PP

  10. DHHS Panel: 2006 Antiretroviral GuidelinesInitial Therapy: Preferred Regimens NNRTI-Based Regimens PI-Based Regimens Efavirenz+Lamivudine or Emtricitabine+ Zidovudine or Tenofovir Lopinavir-Ritonavir+Lamivudine or Emtricitabine + Zidovudine Picture Source: www.aidsinfo.nih.gov DHS/PP

  11. Resistance Testing in Antiretroviral Naive • A 35-year-old HIV-infected man presents new to your clinic. He first tested positive for HIV 3 years ago. His most recent lab studies showed a CD4 count of 288 cells/mm3 and a HIV RNA of 59,000 copies/ml. He is antiretroviral therapy naïve and he has never had a resistance test. The decision is made to start antiretroviral therapy. • Based on October 2006 DHHS Antiretroviral Therapy Guidelines, what would you recommend regarding resistance testing. 1. No reason to do since was infected more than 3 years ago.2. Obtain genotype resistance assay.3. Obtain phenotype resistance assay.4. Obtain both genotype and phenotype resistance assay. DHS/PP

  12. October 2006 DHHS ARV Therapy GuidelinesNew Recommendation for Resistance Testing • The Panel recommends performance of genotypic resistance testing prior to initiation of antiretroviral therapy in patients with acute or chronic HIV infection.(BIII) • Genotypic resistance testing may be considered in patients entering into care but not yet requiring therapy.(CIII) DHS/PP

  13. Antiretroviral TherapyNew Data with Established Medications DHS/PP

  14. To D/C 3TC or Not To D/C 3TC • A patient with advanced HIV disease has a genotype showing highly-resistant HIV, including a M184V. The patient will be starting on a new regimen that will include Enfuvirtide (Fuzeon) and Darunavir (Prezista). • The patient is taking lamivudine (Epivir). As part of the new regimen, do you think there is any benefit in continuing lamivudine? 1. Yes2. No 3. Not sure DHS/PP

  15. HIV RNA Response to ZDV, 3TC, & ZDV + 3TC 0.5 0.0 ZDV only -0.5 3TC (150 mg BID)/ZDV 3TC 300 mg BID only -1.0 3TC (300 mg BID)/ZDV -1.5 ZDV: 200 mg q8h -2.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Treatment time (weeks) From: Eron JJ, et al. N Engl J Med 1995;333:1662-9. DHS/PP

  16. HIV RNA Response to ZDV, 3TC, & ZDV + 3TC 0.5 0.0 -0.5 3TC 300 mg BID only -1.0 -1.5 3TC Resistance (M184V) -2.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Treatment time (weeks) From: Eron JJ, et al. N Engl J Med 1995;333:1662-9. DHS/PP

  17. Lamivudine Monotherapy versus Treatment Interruption in Patients with M184V Mutation Patients on failing therapy requesting treatment interruptionCD4 > 500HIV RNA > 1,000M184V Mutationn = 58 All ARV Meds Discontinuedn = 29 Lamivudine 300 mg qdn = 29 Resume Therapy- CD4 < 350 - CDC B or C Event From: Castagna A, et al. AIDS. 2006;20:795-803. DHS/PP

  18. Lamivudine Monotherapy versus Treatment Interruption in Patients with M184V Mutation Change in CD4 Cell Count -141 -215 Change in CD4 Cell % -3% -8%* Change in HIV RNA +0.57 log +1.11 log** > Grade 3 Adverse Events 7% 31%+ Immunologic/Clinical Failure 41% 69% Lamivudine Continued All ARVs Stopped Parameter at Week 48 *P = 0.001**P = 0.002+P < 0.001 Patients who continued on Lamivudine had less fit virus (decreased replicative capacity) From: Castagna A, et al. AIDS. 2006;20:795-803. DHS/PP

  19. Lamivudine No Lamivudine Change in CD4 Cell Count Immunologic/Clinical Failure No Lamivudine Change in CD4 Percent Lamivudine Change in HIV RNA From: Castagna A, et al. AIDS. 2006;20:795-803. DHS/PP

  20. Continuing Lamivudine (or Emtricitabine) with M184V Potential Benefits • Partial Virologic Response (0.4-0.5 log) • Immunologic Benefit • Delays/Prevents formation of TAMs • Increases activity of zidovudine in presence of TAMs • Slightly increases activity of tenofovir DHS/PP

  21. Abacavir Use in NRTI-Experienced Patients • A patient with advanced HIV disease has previously received zidovudine (Retrovir), Lamivudine (Epivir), and Nevirapine (Viramune) and on this regimen developed virologic breakthrough. You order a genotype to help in are constructing a new PI-based second-line regimen. As part of the new regimen, you are considering using abacavir (Ziagen). • With which of the following would you expect essentially no virologic response to abacavir? 1. M184V2. M184V + 2-3 Thymidine Analogue Mutations (TAMs*)3. M184V + > 4 Thymidine Analogue Mutations (TAMs*)4. Both 2 and 3 *TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219Q/E DHS/PP

  22. Abacavir Response with Prior NRTI Use • M184V Alone- Does not appear to impact response to AbacavirHarrigan PR, et al. JID 2000;181:912-20. Lanier ER, et al. Antivir Ther 2004;9:37-45. • M184V + 2-3 Thymidine Analogue Mutations (TAMs*)- Impairs virologic response to AbacavirLanier ER, et al. Antivir Ther 2004;9:37-45. • M184V + > 4 Thymidine Analogue Mutations (TAMs*)- No virologic response to AbacavirLanier ER, et al. Antivir Ther 2004;9:37-45. *TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219Q/E DHS/PP

  23. Lopinavir-Ritonavir versus Fosamprenavir + Ritonavir • A 28-year-old antiretroviral therapy naïve HIV-infected man presents for follow-up to start antiretroviral therapy. His most recent labs showed a CD4 count of 224 cells/mm3 and a HIV RNA level of 164,000 copies/ml. He is ready to start antiretroviral therapy. He has battled depression and insomnia and the decision is made not to use efavirenz (Sustiva). • Which of the following statements best categorizes data from the recently published KLEAN study, which compared lopinavir-ritonavir (Kaletra) to Fosamprenavir (Lexiva) plus Ritonavir (Norvir); both were used with a backbone of abacavir + lamivudine (Epzicom)?1. These regimens performed equally, regardless of baseline values.2. Lopinavir-ritonavir was superior at all baseline HIV RNA levels.3. Lopinavir-ritonavir was superior, but only at baseline HIV RNA levels > 100,000. DHS/PP

  24. ABC + 3TC + (Fos-Amp-RTV or LPV-RTV)KLEAN-ESS100732 Study Design Results*: 48 Weeks (ITT) • 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) * No differences in response in patients with HIV RNA > 100K From: Eron J et al. Lancet 2006;368:476-82. DHS/PP

  25. 2NRTIs + LPV-RTV versus 2NRTIs + EFVACTG 5142 Study Study Design Results*: 96 Weeks (ITT) • Patients (N = 887) - ARV naïve - HIV RNA > 2,000 copies/ml - Any CD4 count - Randomized trial • Regimens - 2 NRTIs + LPV-RTV - 2 NRTIs + EFV - LPV-RTV + EFV From: Riddler SA, et al. XVI International AIDS Conference. 2006; Abstract THLB024. * Significantly higher CD4 counts in LPV-RTV Arms DHS/PP

  26. 3-Drug Versus 4-Drug Regimen • A antiretroviral-naïve patient with a CD4 cell count of 125 cells/mm3 and a HIV RNA of 187,000 copies/ml is getting ready to start antiretroviral therapy. • Based on new data from ACTG 5095 what would you recommend regarding a 4-drug regimen (3 NRTIs + EFV) versus a 3-drug regimen (2 NRTIs + EFV). 1. Expect a similar response with 3-drug and 4-drug regimens2. The 4-drug regimen clearly better 3. The 3-drug regimen clearly better DHS/PP

  27. Initial Treatment for HIVThree versus Four Drug Regimen: ACTG 5095 Study Design HIV RNA < 50 Copies/ml (ITT) • Patients (N = 765 received treatment) - ARV naïve, HIV RNA > 400 copies/ml - Randomized trial, double-blinded • Regimens - Zidovudine + Lamivudine + Efavirenz - Zidovudine + Lamivudine + Efavirenz + Abacavir • Baseline Characteristics - Mean CD4 = 240 cells/mm3 - Mean HIV RNA = 72,444 copies/ml - HIV RNA > 100,000 = 41% 4-Drug Regimen 3-Drug Regimen From: Gulick RM, et al. JAMA. 2006;296:769-81. DHS/PP

  28. Antiretroviral TherapyNewer Medications DHS/PP

  29. Tenofovir + Emtricitabine + Efavirenz (Atripla) • Classification: (2) nRTI + (1) nNRTI • Dose: 1 pill qd- Tenofovir 300 mg- Emtricitabine 200 mg- Efavirenz: 600 mg • Meal Restrictions: without food • Strong data from Study 934 • Adverse Effects: CNS (efavirenz) Atripla DHS/PP

  30. TDF + FTC + EFV versus ZDV + 3TC + EFVStudy GS934 Study Design Results: 48 Weeks (ITT) • Patients (N = 517 randomized) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized trial • Regimens (N = 487) - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz • No patient developed K65R • Development of M184V - 3% in Combivir arm - 1% in Truvada arm P = 0.002 P = 0.02 From: Gallant JE et al. N Engl J Med. 2006;354:251-60. DHS/PP

  31. Tipranavir (Aptivus) • Which of the following is TRUE regarding the use of Tipranavir (Aptivus)?1. It can be used with or without Ritonavir in treatment-naïve patients 2. Tipranavir + Ritonavir is superior to Lopinavir-Ritonavir in treatment-naïve patients3. Side effects include hepatotoxicty and intracranial hemorrhage4. PRAMs* accurately predict Tipranavir response *Protease Resistance Associated Mutations (30, 82, 84, 90) DHS/PP

  32. Tipranavir (Aptivus) Tipranavir + Ritonavir • Classification- Protease Inhibitor • Dose: 2 pills bid with Ritonavir- Tipranavir: 500 mg bid- Ritonavir: 200 mg bid • Meal Restrictions- Must take with food • Indication- For highly PI-resistant • Adverse Effects- Hepatotoxicity; intracranial hemorrhage DHS/PP

  33. Tipranavir (Aptivus) in Antiretroviral Naïve PatientsBI 1182.33 • Background- N = 558 ARV naïve patients • Regimens (NRTIs as Backbone)- Tipranavir 500 mg bid + Ritonavir 200 mg bid- Tipranavir 500 mg bid + Ritonavir 100 mg bid- Lopinavir/Ritonavir 400/100 mg bid • Results- Ritonavir 200 mg bid arm stopped because of increased hepatotoxicity- Ritonavir 100 mg bid arm stopped because of poor efficacy compared with Lopinavir/Ritonavir DHS/PP

  34. Tipranavir (Aptivus) Adverse Effects • Hepatotoxicity- Black box warning- Fatalities have been reported- Extra vigilance in patients with hepatitis B or C • Intracranial Hemorrhage- Dear Healthcare Provider letter issued on June 30, 2006- Intracranial hemorrhage in 14 of 6840 on RTV-boosted tipranavir - 8 of 14 with intracranial hemorrhage have died • Sulfonamide Component- Caution in patients with known sulfa allergy DHS/PP

  35. Darunavir (Prezista), formerly TMC-114 Darunavir + Ritonavir • Classification- Protease Inhibitor • Dose: 2 pills bid with Ritonavir- Darunavir: 600 mg bid- Ritonavir: 100 mg bid • Meal Restrictions- Take with food • Indication- For PI-resistant • Adverse Effects- GI, rash (sulfonamide component) am pm DHS/PP

  36. Darunavir/Ritonavir 600/100 mg bid Analysis Analysis from Power Studies 1, 2, and 3 Study Design 24 Week Data • Background - Darunavir is novel PI - Active against PI-resistant isolates - POWER 1, 2, & 3 Studies • Patients - Prior Failure of PI regimen - 1 or more PI mutation - HIV RNA > 1,000 copies/ml • Regimens (all + OBR) - Darunavir: 600 mg/RTV 100 mg bid - Comparator PI Duranavir + Ritonavir: 45% with HIV RNA < 50 From: De Meyer S, et al. 13th CROI. 2006: Abstract 157. DHS/PP

  37. Predictors of Darunavir (Prezista) ResponseAnalysis from Power Studies 1, 2, and 3 • Baseline total PI Mutations-> 10 protease mutations associated with decreased response • Baseline mutations associated with reduced response- V32I, L33F, I47V, I54L, L89V • Virologic failure associated with emergence of these 5 mutations • Tipranavir increased only by median 0.82 in rebounders at failure From: De Meyer S, et al. 13th CROI. 2006: Abstract 157. DHS/PP

  38. Antiretroviral TherapyCo-Receptor Inhibitors DHS/PP

  39. HIV Cell Binding and Entry DHS/HIV/PP From: Levy J. N Engl J Med 1996;335:1528-30.

  40. HIV Cell Binding and Entry 1 2 3 CD4 CCR5 CXCR4 CCR5 Fusion Domain Fusion Domain From: Levy J. N Engl J Med 1996;335:1528-30. DHS/HIV/PP

  41. HIV Cell Binding and Entry CD4 Cell R5 HIV CCR5 CD4 CXCR4 DHS/PP

  42. HIV Cell Binding and Entry CD4 Cell X4 HIV CCR5 CD4 CXCR4 Effect of X4 HIV- More rapid progression- Syncitium induction DHS/PP

  43. HIV Infection: Natural History R5 HIV R5 HIV R5 HIV X4 HIV AIDS Year 1 DHS/PP

  44. HIV Infection: Natural History R5 HIV X4 HIV AIDS Year 1 DHS/ARV Rx/PP DHS/PP

  45. Inhibitors of HIV Cell Binding and Entry HIV CD4 Cell Maraviroc Fusion Domain CCR5 CD4 CXCR4 Fusion Domain DHS/PP

  46. HIV Cell Binding and Entry CD4 Cell R5 HIV CCR5 CD4 CXCR4 DHS/PP

  47. HIV Cell BindingPotential Shift from R5 HIV to X4 HIV CD4 Cell R5 HIV CCR5 CD4 X4 HIV CXCR4 DHS/PP

  48. HIV Cell BindingPotential Shift from R5 HIV to X4 HIV CD4 Cell R5 HIV CCR5 X4 HIV CD4 CXCR4 DHS/PP

  49. INVESTIGATIONAL Maraviroc (UK-427,857): CCR5 Receptor Antagonist • Novel entry inhibitor (CCR5 Inhibitor) • Provides approximately 1.5 log decrease as monotherapy • BID dosing likely • Levels of maraviroc increased with most Pis (no change with TPV) • Levels of maraviroc decreased with efavirenz • Optimal dose unknown DHS/PP

  50. INVESTIGATIONAL HIV Co-Receptor AssayMonogram Biosciences Trofile Assay • Assay Measures HIV Tropism - R5 Tropic - X4 Tropic - Dual Tropic • Analyzes Entire Envelope Gene R5 Tropic HIV X4 Tropic HIV Dual Tropic HIV Mixed Tropic HIV DHS/PP

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