1. 2004 Asilomar HIV/AIDS Medical Update David H. Spach, MD Medical Director, Northwest AIDS Education and Training Center Professor of Medicine, Division of Infectious Diseases University of Washington, Seattle DHS/PP

2. HIV/AIDS: 2004 Antiretroviral Therapy Update  Hepatitis and HIV Update  New Antiretroviral Guidelines  New Medications  Lipoatrophy DHS/PP

3. Hepatitis and HIV Update DHS/PP

4. Treatment of HCV in HIV-Infected Persons APRICOT TRIAL  Background - N = 868 - All with baseline biopsy  Evaluation - SVR: HCV RNA<50 IU/ml at week 72  Regimens - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a - PEG-IFN alpha-2a + Ribavirin Study Design SVR 72 Week Data From: Torriani FJ, et al. N Engl J Med 2004;351:438-50. DHS/PP

5. Treatment of HCV in HIV-Infected Persons ACTG A5071 Study  Background - N = 133 - All with baseline biopsy  Evaluation - SVR: HCV RNA<60 IU/ml at week 72  Regimens - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a + Ribavirin Study Design SVR 72 Week Data From: Chung R, et al. N Engl J Med 2004;351:451-9. DHS/PP

6. Case History: HCV Rx & Interaction with ARV Meds A 46-year-old HIV-infected man is taking his third antiretroviral regimen and this “salvage” regimen consists of stavudine plus didanosine plus lopinavir- ritonavir. His CD4 count is 410 cells/mm 3 and his HIV RNA is less than 50 copies/ml. He is co-infected with HCV and the plan is to treat him with peg-interferon plus ribavirin. DHS/PP

7. Case History: HCV Rx & Interaction with ARV Meds Which of the following is TRUE? 1. Stavudine will increase ribavirin levels and increase the severity of anemia. 2. Ribavirin will increase the intracellular concentration of didanosine’s active metabolite and thus increase the risk of didanosine-related toxicity. 3. Didanosine will increase interferon levels and increase the degree of leukopenia. 4. Lopinavir-ritonavir is contraindicated in persons on peg- interferon because of the increased risk of hepatotoxicity. DHS/PP

8. Ribavirin and Didanosine Interaction DHS/PP

9. GB Virus C Interaction with HIV DHS/PP

10. Case History: GB Virus C Which of the following is BEST DESCRIBES GB Virus C and HIV? 1. It is a hepatitis virus that is present in 20% of HIV-infected persons. 2. It is a rare hepatitis virus that causes acute liver failure if an HIV- infected person is already infected with hepatitis B virus. 3. This virus markedly increases the risk of transmission of HIV. 4. This virus may delay progression of HIV disease by increasing levels of chemokines that block HIV entry into cells. DHS/PP

11. GB Virus C Background Information  First isolated in 1995  Single stranded RNA flavivirus  Genetically similar to hepatitis C virus  NOT a hepatitis virus  No clear disease state in humans  Approximate seroprevalence rates (+E2 antibody) - Healthy US blood donors: 16% - IDU: 70% DHS/PP

12. GB Virus C and Survival of HIV-Infected Men Kaplan Meier Survival Curve +/- GBV-C Viremia) From: Xiang J, et. al. N Engl J Med 2001;345:707-14. N = 362 HIV-Infected Patients 40% positive for GBV-C viremia DHS/PP

13. GB Virus C and Survival of HIV-Infected Men From: Williams CF, et. al. N Engl J Med 2004;350:981-90. DHS/PP “GBV-C viremia was significantly associated with prolonged survival among HIV-positive men 5 to 6 years after HIV seroconversion, but not at 12 to 18 months, and the loss of GBV-C RNA by 5 to 6 years after HIV seroconversion was associated with the poorest prognosis. Understanding the mechanisms of interaction between GBV-C and HIV may provide insight into the progression of HIV disease.”

14. Molecular Interactions Between HIV & GB Virus-C From: Pomerant, RJ, et. al. N Engl J Med 2004;350:963-5. DHS/PP

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

16. CD4 Cell R5 HIV Chemokines: Natural Ligand For CCR5 CCR5 CXCR4 CD4 DHS/PP Rantes MIP-1 alpha MIP-1 beta Chemokines

17. CD4 Cell R4 HIV HIV Cell Binding and Entry CCR5 CXCR4 CD4 DHS/PP

18. CD4 Cell R4 HIV SDF-1: Natural Ligand For CXCR4 CCR5 CXCR4 CD4 DHS/PP SDF-1

19. DHS/PP CD4 Cell Peripheral Lymphocyte GB Virus C Inhibition of HIV Replication by GB Virus C From: Xiang, J, et. al. Lancet 2004;363:2040-6. CCR5 CXCR4 CD4 HIV

20. DHS/PP CD4 Cell HIV Peripheral Lymphocyte GB Virus C Inhibition of HIV Replication by GB Virus C From: Xiang, J, et. al. Lancet 2004;363:2040-6. CCR5 CXCR4 CD4

21. DHS/PP CD4 Cell HIV Peripheral Lymphocyte GB Virus C Inhibition of HIV Replication by GB Virus C From: Xiang, J, et. al. Lancet 2004;363:2040-6. CCR5 CXCR4 CD4 Rantes MIP-1 alpha MIP-1 beta SDF-1

22. DHS/PP CD4 Cell HIV Peripheral Lymphocyte GB Virus C Inhibition of HIV Replication by GB Virus C From: Xiang, J, et. al. Lancet 2004;363:2040-6. CCR5 CXCR4 CD4 Rantes MIP-1 alpha MIP-1 beta SDF-1

23. Antiretroviral Therapy New DHHS Guidelines DHS/PP

24. Case History: Initiating Antiretroviral Therapy A 34-year-old HIV-infected man presents for follow-up with a CD4 count of 316 cells/mm 3 and an HIV RNA = 72,000 copies/ml. His most recent CD4 count 3 months ago was 323 cells/mm 3. He is motivated to take antiretroviral therapy if you think it would be indicated for him. He has never taken any meds for his HIV disease. Assume the patient is likely to have excellent adherence. Would you recommend starting ARV therapy now? 1. Yes 2. No, you would wait until CD4 count less than 300 cells/mm 3. 3. No, you would wait until CD4 count less than 200 cells/mm 3. DHS/PP

25. DHHS Panel: 2004 Antiretroviral Guidelines Initial Therapy, Chronically Infected Clinical CategoryCD4 Cell Count Plasma HIV RNA Recommendation Symptomatic (AIDS, severe symptoms) Any value Treat Asymptomatic, AIDS<200/mm 3 Any valueTreat Asymptomatic>200/mm 3 but <350/mm 3 Any valueGenerally offered; controversy exists. Asymptomatic>350/mm 3 >55,000 copies/mlSome experts would recommend initiating therapy. Asymptomatic>350/mm 3 <55,000 copies/mlMany experts would defer therapy and observe. Source: http://www.aidsinfo.nih.org DHS/PP

26. Starting Antiretroviral Therapy Acute HIV Infection Year 1 350 200 350 DHS/PP

27. DHHS Panel: 2004 Antiretroviral Guidelines Initial Therapy: Preferred Regimens Picture Efavirenz + Lamivudine + Zidovudine or Stavudine or Tenofovir Source: www.aidsinfo.nih.gov PI-Based Regimens Lopinavir/Ritonavir (Kaletra) + Lamivudine + Zidovudine or Stavudine NNRTI-Based Regimens DHS/PP

28. Antiretroviral Therapy Newer Medications DHS/PP

29. FDA-Approved HIV Antiretroviral Medications in US AZT ddI ddC d4T FTC NFV DLV EFV ABC AMP LPV-RTV TDF IDV RTV SQV 3TC FPV ATZ EFV DHS/PP NVP

30. DHS/PP FDA-Approved HIV Antiretroviral Medications in US AZT ddI ddC d4T FTC EFV ABC AMP NVP IDV RTV SQV 3TC FPV ATZ EFV AZT-3TCAZT-3TC-ABC TDF LPV-RTV DLV NFV ABC-3TC TDF-FTC

31. HIV: Antiretroviral Therapy HIV RNAHIV DNA HIV Nucleus Host Cell Non-Nucleoside RTI Protease Inhibitors Nucleoside Analogue RTI RT Entry Inhibitors DHS/PP

32. Emtricitabine/FTC (Emtriva) Classification: nRTI Activity: HIV and HBV Dose: 200 mg PO qd Meal Restrictions: none Potency: in vitro more potent than Lamivudine Resistance Profile: similar to Lamivudine (M184V) Adverse Effects: well-tolerated DHS/PP

33. From: Saag M, et al. JAMA 2004;292:180-9. Emtricitabine versus Stavudine: 301A Study ddI + EFV + either Emtricitabine or Stavudine  Patients (N = 571 randomized) - ARV naïve, HIV RNA > 5,000 copies/ml - Randomized, double-blind - Median HIV RNA = 4.8 log 10 (both groups) - Mean CD4 = 312 cells/mm 3 (Emtricitabine) - Mean CD4 = 324 cells/mm 3 (Stavudine)  Regimens* -*Emtricitabine + ddI + EFV - Stavudine + ddI + EFV Study DesignResults: 24 Weeks (ITT) Study stopped at 24 weeks after preliminary analysis DHS/PP

34. Tenofovir plus Emtricitabine (Truvada) Classification: nRTI Dose: 1 pill qd (Tenofovir 300 mg + Emtricitabine 200 mg) Meal Restrictions: none Preliminary 24 week data from Study 934 very promising Adverse Effects: well-tolerated DHS/PP

35. From: Gilead Sciences, Press Release Aug 26, 2004. TDF + FTC + EFV versus ZDV + 3TC + EFV Study 934  Patients (N = 517) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized  Regimens - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz Study DesignResults: 24 Weeks (ITT) DHS/PP

36. Abacavir plus Lamivudine (Epzicom) Classification: nRTI Dose: 1 pill qd (Abacavir 600 mg + Lamivudine 300 mg) Active component of abacavir (carbovir-P-P-P) has long half-life Meal Restrictions: none Adverse Effects: hypersensitivity reaction with Abacavir DHS/PP

37. Plasma Abacavir & Intracellular Carbovir-TP PK From: Piliero P. JAIDS. 2004;37:S2-12. CBV-TP t 1/2 = 20.64 hours Concentration DHS/PP

38. Enfuvirtide/T-20 (Fuzeon) Classification: fusion inhibitor (36 amino acid peptide) Dose: 90 mg sq bid Indications: salvage therapy Adverse Effects: local injection site reactions Cost: > $20,000 per year DHS/PP

39. Enfuvirtide (Fuzeon) for Drug-Resistant HIV TORO-1 Study (North & South America)  Background - N = 491 - Very heavily pretreated  Baseline (Control Group) - Median HIV RNA = 5.2 log 10 copies/ml - Median CD4 = 87 cells/mm 3  Baseline (Enfuvirtide Group) - Median HIV RNA = 5.2 log 10 copies/ml - Median CD4 = 75 cells/mm 3  Regimens - Optimized Background (3-5 ARVs) - Optimized Background + *Enfuvirtide Study Design (TORO-1) 24 Week HIV RNA Data From: Lalezari JP, et al. N Engl J Med 2003;348:2175-85. *Enfuvirtide (Fuzeon): 90 mg sq bid P < 0.001 DHS/PP

40. Strategic Use of Enfuvirtide/T-20 (Fuzeon) Early Virologic Failure - Likely to be very effective with other new medications Late Virologic Failure - Highly likely to fail if used as the only new effective drug added to failing regimen Recommendation - Defer until you have at least two effective agents available DHS/PP

41. Antiretroviral Therapy Resistance DHS/PP

42. K65R Mutation Which of the following is TRUE regarding the K65R mutation? 1. It reduces the activity of abacavir and tenofovir 2. It is more likely to occur if a patient is taking zidovudine. 3. It causes cross resistance to efavirenz and nevirapine. 4. It is the most important protease inhibitor mutation DHS/PP

43. . Treatment Failure and Development of K65R Mutation Summary of Prospective Studies From: Ruane P & Luber AD. Med Gen Med 2004;6:31. DHS/PP

44. Impact of the K65R Mutation  Common Resistance Mutation in Triple-NRTI Regimens that do not Contain Zidovudine or Stavudine  Reduces Activity of Tenofovir, Lamivudine, & Abacavir  Causes Hypersusceptibility to Zidovudine or Stavudine From: Ruane P & Luber AD. Med Gen Med 2004;6:31. DHS/PP

45. From: Campbell TB, et al. 12th International Resistance Workshop. 2003. Abstract 140. Benefit of Lamivudine with M184V Mutation  Patients (N = 4) - Highly treatment-experienced - Failing antiretroviral regimen - All receiving Lamivudine - All with M184V mutation  Intervention - Stop Lamivudine Study Design Results + M184V- M184V Lamivudine Stopped DHS/PP

46. Antiretroviral Therapy Lipoatrophy (fat wasting) DHS/PP

47. Lipoatropy (Fat Wasting) Lipoatrophy Fat Wasting Higher Risk Stavudine Didanosine Low Risk Tenofovir Abacavir Lamivudine Emtricitabine DHS/PP

48. Lamivudine + Efavirenz + either Tenofovir or Stavudine Study 903: Toxicity Analysis Study Design Limb Fat From: Gallant JE, et al. JAMA 2004;292:192-201. P < 0.001  Background - N = 600 enrolled - Antiretroviral therapy naive - Mean HIV RNA = 4.9 log 10 - Mean CD4 = 279 cells/mm 3  Regimens - TFV + 3TC + EFV (n = 299) - d4T + 3TC + EFV (n = 301) TFV = Tenofovir (Viread) 3TC = Lamivudine (Epivir) d4T = Stavudine (Zerit) EFV = Efavirenz (Sustiva) DHS/PP

49. Lipoatrophy: Effects of Switching Nucleoside Analogs MITOX Study  Methods - Randomized, open-labeled - 111 patients with lipoatrophy - Patients on stavudine (n = 85) - Patients on zidovudine (n = 26)  Regimen Changes - Switch stavudine/zidovudine to abacavir - Continue current regimen (no switch)  Measurements - Dual-energy x-ray absorptiometry Study Design Week 24 Change in Limb Fat From: Carr A, et al. JAMA 2002;288:207-15. P = 0.02 DHS/PP

50. Lipoatrophy: Switching Stavudine to Abacavir or Zidovudine *TARHEEL Study  Methods (N = 118) - Open-labeled switch study - Patients on stavudine with lipoatrophy  Regimen Changes - Switch stavudine to abacavir (n = 86) - Switch stavudine to zidovudine (n = 32)  Measurements - Dual-energy x-ray absorptiometry (DEXA) - Computerized tomography Study Design 48 Week Data: %Change in Fat (DEXA) From: McComsey G, et al. Clin Infect Dis 2004;38:263-70. *Trial to Assess Regression of Hyperlactatemia & Evaluate Established Lipodystrophy DHS/PP

51. Poly-L-Lactic Acid/New-Fill (Sculptra) Approved by FDA on August 3, 2004 Indication: facial lipoatrophy (facial wasting) in HIV-infected persons Manufacturer: Dermik laboratories (Aventis) Mechanism of Action - poly-L-lactic acid (PLLADegrades injected into deep dermis - Increases fibroblast numbers and collagen production Adverse Effects - Nodules, redness, swelling, bruising DHS/PP

52. Polylactic Acid (Sculptra) for HIV-1 Facial Lipoatrophy From: Valentin MA, et al. AIDS 2003;17:2471-7.  Patients - N = 50 - Fat thickness < 2 mm in upper cheek  New Fill Injections - Bilateral deep dermal injections - 0, 2, 4, 6 weeks  Follow-Up - Ultrasound measurements of face Study Design Facial Thickness > 10 mm DHS/PP

53. Polylactic Acid/New Fill (Sculptra) for HIV Facial Lipoatrophy From: Valentin MA, et al. AIDS 2003;17:2471-7. DHS/PP

54. Summary DHS/PP