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2005 Asilomar HIV/AIDS Medical Update David H. Spach, MD Clinical Director, Northwest AIDS Education and Training Center Professor of Medicine, Division of Infectious Diseases University of Washington, Seattle. DHS/PP. HIV/AIDS: 2005 Antiretroviral Therapy Update.

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  1. 2005 Asilomar HIV/AIDS Medical UpdateDavid H. Spach, MDClinical Director, Northwest AIDS Education and Training CenterProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington, Seattle DHS/PP

  2. HIV/AIDS: 2005 Antiretroviral Therapy Update • Hepatitis C & HIV Co-Infection Update • Hepatitis B & HIV Co-Infection Update • New Antiretroviral Guidelines • New Medications • Future Medications DHS/PP

  3. HCV and HIV Co-Infection Update DHS/PP

  4. HCV Therapy: Terminology Week 0 Week 12 Week 48 Week 72 Treatment (48 Weeks) Post-Treatment (24 Weeks) Early Virologic Response (EVR)HCV < 100 copies/mlORHCV RNA decrease > 2 log End of Treatment Response (ETR)HCV RNA undetectable Sustained Virologic Response (SVR)HCV RNA undetectable DHS/PP

  5. Case History: HCV Rx • A 38-year-old HIV and HCV co-infected man is evaluated for treatment of HCV. Labs- CD4 cell count 486 cells/mm3 (on no ARV Rx)- HCV genotype 1- HCV RNA level of 2,000,000 copies/ml- Liver Bx: Metavir Stage 3 fibrosis • What would be the preferred therapy for his hepatitis C?1. Interferon + Ribavirin x 24 weeks2. Peginterferon + Ribavirin x 24 weeks 3. Peginterferon + Ribavirin x 48 weeks4. Peginterferon + Ribavirin x 96 weeks DHS/PP

  6. Progression of HCV Treatment SuccessSustained Virologic Response From: Strader DB, et al. Hepatology 2004;39:1147-71. DHS/PP

  7. Treatment of HCV in HIV-Infected PersonsAPRICOT TRIAL (“Pegasys”) Study Design SVR: 24 Week Post-Treatment • Background - N = 868 - All with baseline biopsy • Evaluation - SVR: HCV RNA <50 IU/ml at week 72 • Regimens (48 Weeks of Therapy) - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a - PEG-IFN alpha-2a + Ribavirin Dosing- Interferon alpha-2a: 3 million IU sq 3x/week - Peginterferon alpha-2a: 180 ug sq q week- Ribavirin: 800 mg PO qd From: Torriani FJ, et al. N Engl J Med 2004;351:438-50. DHS/PP

  8. Treatment of HCV in HIV-Infected PersonsACTG A5071 Study (“Pegasys”) Study Design SVR: 24 Week Post-Treatment • Background - N = 133 - All with baseline biopsy • Evaluation - SVR: HCV RNA < 60 IU/ml at week 72 • Regimens (48 Weeks of Therapy) - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a + Ribavirin Dosing- Interferon alpha-2a: 6 million IU sq 3x/week x 12 weeks, then 3 million IU sq 3x/week- Peginterferon alpha-2a: 180 ug sq q week- Ribavirin: 800 mg PO qd From: Chung R, et al. N Engl J Med 2004;351:451-9. DHS/PP

  9. Results of HCV & HIV Co-Infection Treatment TrialsPeginterferon + Ribavirin x 48 Weeks Peginterferon-2a Peginterferon-2a Peginterferon-2b DHS/PP

  10. Case History: HCV Rx • The patient (HCV Genotype 1) is started on Peginterferon alpha-2b plus Ribavirin. His 12 week HCV RNA level is 1,300,000 copies/ml (baseline pretreatment HCV RNA was 2,000,000). • What can we predict regarding the sustained virologic response (SVR) based on this 12 week HCV RNA value? 1. The 12 weak early virologic response (EVR) does NOT reliably predict SVR in HIV-infected patients2. He has approximately a 30% chance of having a SVR 3. He has approximately a 15% chance of having a SVR4. He has less than 10% chance of having a SVR DHS/PP

  11. 12 Week Early Virologic Response (EVR) Predicts SVRAPRICOT TRIAL (“Pegasys”) 12 Week EVR- HCV RNA < 50 copies/ml OR- HCV RNA decrease > 2 log From: Torriani FJ, et al. N Engl J Med 2004;351:438-50. DHS/PP

  12. Case History: HCV Rx • A 34-year-old HIV and HCV co-infected woman is evaluated for treatment of HCV. Labs- CD4 cell count 510 cells/mm3 (on no ARV Rx)- HCV genotype 3- HCV RNA level of 1,860,000 copies/ml- Liver Bx: Metavir Stage 3 fibrosis • What would recommend for therapy in this HIV-infected patient with HCV genotype 3?1. Peginterferon + Ribavirin x 12 weeks 2. Peginterferon + Ribavirin x 24 weeks 3. Peginterferon + Ribavirin x 48 weeks4. Peginterferon + Ribavirin x 72 weeks DHS/PP

  13. Peginterferon + Ribavirin for HCV Genotypes 2 or 348 Weeks versus 28 Weeks (Romance 2 Trial) Study Design SVR: 24 Week Post-Treatment • Background - N = 128 - HCV & HIV Co-Infected - All with HCV genotype 2 or 3 - CD4 > 200 and HIV RNA < 10,000 • Regimen - Peginterferon alpha-2a + Ribavirin • Evaluation - Week 24: HCV RNA (57% HCV RNA -) - Those with (-) HCV RNA randomized to stop therapy or receive 24 more weeks From: Zanini B, et al. 3rd IAS Path & Treatment. 2005: MoPpLB0103. DHS/PP

  14. Case History: HCV Rx • A 29-year-old HCV and HIV co-infected woman is started on Peginterferon alpha-2a (180 ug sq once weekly) plus Ribavirin (400 mg bid) for HCV genotype 1. After 6 weeks of therapy, her Hb decreases from 14 to 10 g/dL. All other labs without a significant change. She weighs 71 kg. • What would you recommend doing regarding the patient’s development of anemia? 1. No change needed; Hb likely will improve in next 4 weeks2. Decrease ribavirin dose to 600 mg3. Start recombinant erythropoetin 40,000 units sq weekly4. Decrease Peginterferon to 150 uq sq once weekly DHS/PP

  15. Ribavirin Dosing During Therapy • Impact of Ribavirin Dosing on SVR- Near or optimal ribavirin dose associated with better SVR • Ribavirin Target Dosing- Dose > 800 mg/d OR > 10.6 mg/kg/d- Most critical in first 20 weeks • Use Recombinant Erythropoeitin/Epotin Alpha (Epogen;Procrit)- Initiate for Hb < 12 g/dL- Dose: 40,000 sq 1 x/w & increase to 60,000 sq/w if needed DHS/PP

  16. HCV Therapy: Future Needs • Improved Initial Response Rates with Genotype 1 • Better Tolerated Therapy- Viramidine (Ribavirin prodrug); less anemia- Peptide aptemers (Inhibit HCV NS3 serine protease) • Less Frequent Injections- Albumin Interferon • Therapies for Peginterferon + Ribavirin Non-Responders- Maintenance PEG-INF- Valopictadine (NM 283) + PEG-INF? DHS/PP

  17. Viramidine Adenosine Deaminase NH3 Viramidine Ribavirin Liver Inactive MetaboliteICN3297 Adenosine Deaminase DHS/Viral/PP

  18. Case History: HCV Rx & Interaction with ARV Meds • Which of the following is TRUE regarding treatment of HCV in a HIV-infected person taking antiretroviral therapy? 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

  19. Ribavirin and Didanosine Interaction DHS/PP

  20. HBV and HIV Co-Infection Update DHS/PP

  21. HIV/HBV: Initiating HBV Therapy • A 36-year-old caucasian man with HIV and HBV co-infection: • CD4 520, VL 18,000; Never on HAART. • Persistent 3-5x increase in ALT/AST levels. • HBsAg+; HBeAg+; HBV DNA: 6 x 108 IU/ml. • Liver biopsy not performed • Which of the following drugs has significant activity against Hepatitis B virus but NOT HIV?1. Entecavir (Baraclude)2. Ribavirin (Rebetol, Copegus) 3. Emtricitabine (Emtriva)4. Valacyclovir (Valtrex) DHS/HIV/PP

  22. FDA-Approved Therapies for HBV Infection *Dose given for HBeAg+ (duration 4-6 months) Dose for HBeAg(-): 5-6 x 106 3x/week x 48 weeks DHS/HBV/PP

  23. Non FDA-Approved Therapies for HBV DHS/HBV/PP

  24. Entecavir (Baraclude) • Classification: nRTI (guanosine analogue) • Active against HBV: wild-type & Lamivudine-resistant • Dosing- 0.5 mg and 1.0 mg tablets- Initial Rx: 0.5 mg PO qd- Lamivudine-resistant/failure: 1.0 mg PO qd • Efficacy: Improves liver histology & degree of fibrosis • Adverse Effects: flare of hepatitis when drug stopped • HIV Activity: Entecavir does not have activity against HIV DHS/HIV/AIDS/PP

  25. Peginterferon-alpha-2a vs Lamivudine vs BothHBeAg-Negative Chronic HBV Study Design Response: 24 Weeks Post Rx • Methods - N = 537 adults - HBeAg(-), chronic HBV • Regimens (48 Weeks of Therapy) - PegINF-alpha-2a: 180 ug qweek - Lamivudine: 100 mg PO qd - PegINF-alpha-2a + Lamivudine • Major Measurements - Virologic: HBV DNA < 20,000 - Biochemical: Normalization of ALT - Loss of HBsAg From: Marcellin P, et al. N Engl J Med 2004;351:1206-17.

  26. HIV/HBV: Initiating HBV Therapy • The following 3 patients are co-infected with HBV and HIV. All 3 patients have HBsAg(+), persistent elevations of ALT (> 2-3x), and HBV DNA levels > 106. None of the patients have ever received ARV Rx or HBV Rx. Regarding treatment, assume they are willing, able, and adherent. • Patient 1: CD4 490, HIV RNA=23,000; HBeAg(+). • Patient 2: CD4 524; HIV RNA=38,000; HBeAg(-). • Patient 3: CD4 210; HIV RNA = 112,000; HBeAg(+). • QuestionHow would you approach treatment of HBV infection is these 3 patients? DHS/HIV/PP

  27. Chronic HBV & HIV: Initiating HBV TherapyRecommendations from an International Panel HIV ARV Indicated No Yes HBeAg (+) Tenofovir plusLamivudine (or Emtricitabine)plus NNRTI or PI No Yes Entecavir or Adefovir Peginterferon From: Soriano V, et al. AIDS 2005;19:221-40. DHS/HIV/PP

  28. HIV/HBV: Monitoring Response • A 41-year-old woman with HIV and HBV co-infection: • CD4 220, VL 88,000; Never on HAART. • Labs show 3-4x increase in ALT/AST levels. • HBsAg(+); HBeAg(+); HBV DNA: 4 x 109 IU/ml. • Started on Tenofovir-DF + Lamivudine + Efavirenz • In terms of HBV infection and treatment, which of the following is the LEAST LIKELY goal to achieve during therapy?1. HBV DNA level decrease to less than 5,000 copies/ml2. HBeAg becomes negative and anti-HBe becomes positive3. HBsAg becomes negative and anti-HBsAg becomes positive4. The progression to cirrhosis is delayed DHS/HIV/PP

  29. HBV Therapy: Goals • Delay/Stop progression of liver cirrhosis • Decrease (but not eliminate) risk of HCC • Suppress HBV DNA • Cause ALT to normalize • Shift HBeAg(+) to HBeAg(-) & HBeAb(-) to HBeAb(+) • Shift HBsAg(+) to HBsAg(-) & HBsAb(-) to HBsAb(+): Rare • Eradicate HBV: Rare DHS/HIV//PP

  30. HBV: Loss of Response with NRTIsResistance to NRTIs HBV Reverse Transcriptase Mutations From: Nunez M, et al. Lancet ID 2005;5:374-82. DHS/HIV//PP

  31. HIV/HBV: Screening for HCC • A 53-year-old man with HIV and HBV co-infection and has known cirrhosis. • CD4 420, VL < 50 copies/ml • Taking Tenofovir + Emtricitabine + Ritonavir + Atazanavir • Labs show normal ALT/AST levels. • HBsAg(+); HBeAg(+); HBV DNA: 1500 IU/ml (baseline 14,000,000). • Which of the following is TRUE regarding hepatocellular carcinoma?1. The patient no longer has risk since his HBV DNA level is < 10,000 copies/ml?2. His risk is lower since he has cirrhosis3. His risk is higher because he has HBeAg+4. His risk is lower because he is older than 45 DHS/HIV/PP

  32. Chronic HBV: Risk Factors for HCC • Age > 45 • Male gender • Detectable HBV DNA • HBeAg (+) • Presence of cirrhosis • Co-infection with HCV DHS/HIV//PP

  33. Chronic HBV & Risk of HCC 12 10 8 6 4 2 0 n=11,893 men, Taiwan HBsAg+, HBeAg+ Percent cumulative incidence HBsAg+, HBeAg- HBsAg-, HBeAg- 0 1 2 3 4 5 6 7 8 9 10 Year Yang HI, et al. N Engl J Med. 2002;347:168-74.

  34. Chronic HBV: Screening for HCC2004 AASLD Guidelines • “HBV carriers at high risk for HCC such as men over 45 years, persons with cirrhosis, and persons with a family history of HCC, should be screened periodically with both AFP and US.” • “While there are insufficient data to recommend routine screening in low-risk patients with chronic HBV infection, periodic screening for HCC with AFP in carriers from endemic areas should be considered.” From: Lok AS, McMahon BJ. 2004 AASLD Guidelines DHS/HIV//PP

  35. Chronic HBV: Screening for HCC2005 HIV-HBV International Panel • “Screening for this neoplasia (HCC) with ultrasonography and alpha-fetoprotein should be performed in all HBV/HIV cirrhotic patients every 6 months.” From: Soriano V et al. AIDS 2005:19:221-40. DHS/HIV//PP

  36. Antiretroviral TherapyNew DHHS Guidelines DHS/PP

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

  38. Case History: Initiating Antiretroviral Therapy • A 34-year-old HIV-infected man presents for follow-up with a CD4 count of 316 cells/mm3 and an HIV RNA = 72,000 copies/ml. His most recent CD4 count 3 months ago was 323 cells/mm3. • 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. Yes2. No, but you would have started if HIV RNA > 100,000 copies/ml3. No, you would wait until CD4 count less than 300 cells/mm3.4. No, you would wait until CD4 count less than 200 cells/mm3. DHS/PP

  39. 2005 ARV Guidelines: Recent Major Changes • List 5 or more changes in the DHHS guidelines that have occurred in the past 12 months?1. 2.3.4.5. DHS/PP

  40. 2005 ARV Guidelines: Recent Major Changes • Major Changes since September 2004:1. HIV RNA “threshold” changed from 55,000 to 100,000 2. Stavudine move from preferred to alternative3. Emtricitabine added as a preferred drug in PI- and NNRTI-based regimens 4. Nevirapine NOT recommended (even as alternative) regimen for initial ARV Rx in women with CD4 > 250 and men with CD4 > 400 5. Rifampin can NOT be used safely with ritonavir-boosted PI regimens6. Tenofovir + Didanosine should NOT be used together for initial Rx7. Once daily Lopinavir-Ritonavir (6 capsules qd) added for ARV-naïve patients DHS/PP

  41. DHHS Panel: 2005 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

  42. TDF-FTC + (LPV-RTV qd or LPV-RTV bid) Study 418 Study Design HIV RNA < 50 copies/ml: 48 Weeks • Patients (N = 109) - ARV naïv - HIV RNA > 1,000 copies/ml - Randomized trial • Regimens - Backbone: Tenofovir + Emtricitabine - Lopinavir-Ritonavir (800/200 mg qd) - Lopinavir-Ritonavir (400/100 mg bid) Diarrhea- 16% in qd regimen- 5% in bid regimen From: Gathe J et al. 11th CROI:2004: Abstract 570. DHS/PP

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

  44. Antiretroviral TherapyNewer Medications DHS/PP

  45. 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

  46. TDF + FTC + EFV versus ZDV + 3TC + EFVStudy 934 Study Design Results: 48 Weeks (ITT) • Patients (N = 509) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized trial • Regimens - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz From: Pozniak AL et al. 3rd IAS Path & Treatment. 2005: Abstract WeOa0202. DHS/PP

  47. Tipranavir (Aptivus) • Which of the following is NOT TRUE regarding the use of Tipranavir (Aptivus) in a patient who is highly antiretroviral therapy experienced and has failed several previous regimens?1. It should always be used with Ritonavir2. If tolerated, it should be combined with Lopinavir-Ritonavir3. Response rates are significantly better if used with Enfuvirtide4. Tipranavir has been associated with cases of severe liver toxicity DHS/PP

  48. Tipranavir-r versus LPV-r in PI-Experienced Patients Study Design HIV RNA Reduction > 1 log10 • Background - Tipranavir is novel nonpeptidic PI - Patients failing PI-containing HAART - HIV RNA > 1,000 copies/ml - > 2 PI mutations • Regimens - Optimized background regimen - With/without Enfuvirtide - Randomized to CPI-r* versus Tip-r** *Most chose LPV-r: subset analysis of LPV-r**Tipranavir 500 mg bid + Ritonavir 200 mg bid From: Cooper D, et al. 12th CROI. 2005: Abstract 560. DHS/PP

  49. Response to Tipranavir-Ritonavir in Advanced Salvage Tipranavir-Ritonavir + OBR Tipranavir-Ritonavir + OBR + Enfuvirtide 50 50 DHS/ARV Rx/PP

  50. Pharmacokinetics of Tipranavir Combined with other PIs Study Design Tipranavir-r Effect on PIs • Background - N = 173 - Patients failing PI-containing HAART - HIV RNA > 1,000 copies/ml - > 3 PI mutations (33, 82, 84, 90) • Regimens (OBR in All Arms) - TPR/RTV/Control (500/200) bid - TPR/AMP/RTV (500/600/200) bid - TPR/SQV/RTV (500/1000/200) bid - TPR/LPV/RTV (500/400/100) bid From: Walmsley S, et al. 15th International AIDS Conference, 2004: Abstract WeOrB1236. DHS/PP

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