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  1. HIV/AIDS Antiretroviral Therapy: 2001 David H. Spach, MDMedical Director, AIDS EducationNorthwest AIDS Education & Training CenterAssociate Professor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/HIV/AIDS/PP

  2. Antiretroviral Therapy: 2001 • Initial Therapy • Resistance/Failure • Antiretroviral Toxicity • Structured Treatment Interruptions • Postexposure Prophylaxis • Discontinuing OI Prophylaxis DHS/HIV/ARV RX/PP

  3. Initial Therapy DHS/HIV/ARV RX/PP

  4. HIV: Case History • A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years. Her labs show a CD4 count is 485 and his viral load is 88,000.a) Would you start antiretroviral therapy?b) Would your answer been different if her viral load was 6,000? c) If you start, what kind of response are you looking for? DHS/ HIV/PP

  5. HIV: Antiretroviral Therapy Nucleoside Analogues HIV RNA DNA Nucleus Host Cell Non-Nucleosides Protease Inhibitors FrAdapted from: Walker B. IDSA 1998

  6. NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Preferred Regimens CD4 < 350 cells/mm3or HIV RNA > 30,000 (bDNA) HIV RNA > 55,000 (RT-PCR)or HIV-Related Manifestations 2 Nucleoside Analogues + Efavirenz 2 Nucleoside Analogues + Protease Inhibitor 2 Nucleoside Analogues + 2 Protease Inhibitors Picture Source: DHS/ARV Rx/PP

  7. NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Preferred Regimens Efavirenz Indinavir Nelfinavir Ritonavir + Indinavir Ritonavir + Lopinavir Ritonavir + Saquinavir Column A Column B Stavudine + Didanosine Stavudine + Lamivudine Zidovudine + Didanosine Zidovudine + Lamivudine DHS/ARV Rx/PP

  8. NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Alternative Regimens Column B Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC Column A Didanosine + Lamivudine Zidovudine + Zalcitabine DHS/ARV Rx/PP

  9. Efavirenz: Study 006 • Patients (N=450)- CD4 > 50 cells/mm3 - HIV RNA > 10,000 copies/ml- Naive to PI, non-nucleoside, and 3TC • Regimens- AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV From: Staszewski S. N Engl J Med 1999;341:1865-73. DHS/ARV Rx /PP

  10. Abacavir: Study 3005AZT + 3TC + ABC vs AZT + 3TC + IDV Study Design 48 Week Data: HIV RNA <50 • Patients (N = 562)- Antiretroviral-naive adults - HIV RNA > 10,000 - CD4 > 100 cells/mm3 • Regimens - AZT + 3TC + Abacavir (ABC) - AZT + 3TC + Indinavir (IDV) HIV RNA > 100,000 From: Staszewski S. JAMA 2001;285:1155-63. DHS/ ARV Rx /PP

  11. Antiretroviral Therapy: Optimal Response Medications Started 50 50 DHS/ARV Rx/PP

  12. HIV: Case History • A 32-year-old man with an HIV RNA level of 313,000 and a CD4 count of 22 cells/mm3 presents with PCP and newly diagnosed with HIV; he was probably infected about 7 years ago. He is highly motivated and states he will take any regimen you recommend for him.a) What would you recommend? b) Would you order resistance testing prior to starting therapy? DHS/ HIV/PP

  13. Resistance Testing: Acute vs. Established HIV Acute HIV Established HIV No ARV Rx Wild-type HIV From Resistant HIV

  14. Resistance/Failure DHS/HIV/ARV RX/PP

  15. HIV: Case History • A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 starts on a regimen of Zidovudine (Retrovir) plus Lamivudine (Epivir) plus Nelfinavir (Viracept) and has an initial excellent response (HIV RNA < 50 at months 3, 6, and 9). At the 12 month visit, he asks how many missed doses in a month would it take for resistance to develop. a) How would you answer this? DHS/ HIV/PP

  16. Adherence and Virologic Failure N = 81 Patients on Protease Inhibitor-Based RX From: Paterson Dl et al. Ann Intern Med 2000;133:21-30. DHS/ARV Rx /PP

  17. HIV: Case History • This 12 month HIV RNA level comes back at 624 copies per ml. The lab is repeated 2 weeks later and returns at 822 copies/ml. a) Would you do a resistance test? DHS/ HIV/PP

  18. Use of Resistance Testing: Recommendations Clinical Setting Recommendation Virologic failure during HAART Suboptimal suppression (Initiation of Rx) Acute HIV Chronic HIV (Initiation of Rx) After stopping ARV Rx HIV RNA < 1,000 Recommend Recommend Consider Not Recommended Not Recommended Not Recommended From: 2001 DHHS/NIH Antiretroviral Therapy Guidelines DHS/ARV Rx/PP

  19. Antiretroviral Therapy: Viral Failure Medications Started 500 500 50 50 DHS/ARV Rx/PP

  20. Antiretroviral Therapy: Failure to Suppress Medications Started 500 500 50 50 DHS/ARV Rx/PP

  21. HIV Resistance Testing Assays • Genotypic Assays - Detect mutations in RT & Protease genes - Generally require > 1,000 copies/ml • Phenotypic Assays - Determine amount of drug required to suppress HIV replication in vitro - Generally require > 1,000 copies DHS/HIV/ARV RX/PP

  22. HIV Resistance TestingVirtual Phenotype Genotype Access Data HIV RT Protease Genotype & Phenotype Data Virtual Phenotype

  23. HIV Primary Infection Isolates N = 108 PatientsNewly HIV-Infected Phenotypic Data: 10-fold Resistance From: Little SJ. JAMA 1999;282:1142-9.Little SJ. 8th Conf Retrovirus. Abstract 756 DHS/HIV/Resistance /PP

  24. HIV: Case History • A 29-year-old woman with a CD4 count of 336 and a HIV RNA of 94,000 starts on Stavudine/d4T (Zerit) + Lamivudine/3TC (Epivir) + Nevirapine (Viramune). She does well for about 9 months with HIV RNA of <50 copies/ml. She starts to develop breakthrough viremia, with HIV RNA levels increasing from <50, to 323, to 978, to 1786. Resistance testing shows the K103N mutation suggesting resistance to Nevirapine (Viramune).a) Would you recommend switching the Nevirapine (Viramune) to Efavirenz (Sustiva)? DHS/ HIV/PP

  25. HIV: Case History • A 35-year-old man with a CD4 count of 236 is started on AZT + 3TC (Combivir) + Indinavir (Crixivan); he does well for approximately 6 months (at one point with HIV RNA < 50), but on last 2 visits has HIV RNA levels greater than 500 (1220 and 2480). He states recently he has had a mild depression and has experienced trouble with the Indinavir (Crixivan) schedule. Resistance testing is ordered.a) Why should you specifically ask if they are taking any naturopathic or herbal medicines? b) What are some of the options you have? Will adding a non-nucleoside be important? DHS/ HIV/PP

  26. HIV: Case History • A 59-year-old man with a baseline CD4 count of 45 and baseline HIV RNA 86,000 starts on Stavudine (Zerit) + Lamivudine (Epivir) + Indinavir (Crixivan). He has excellent response for 2 years (with HIV RNA < 50), but develops significant peripheral neuropathy and stops taking the d4T (Zerit) on his own. HIV RNA now is 3,900 and repeat 2 weeks later is 5,700. Resistance testing shows reverse transcriptase gene with 184 (M184V); protease gene shows 46 (M46I) and 82 (V82S). a) What type of response would you expect from Abacavir (Ziagen)?b) If you saw an insertion mutation (for reverse transcriptase gene) at Q151M or at 69 what would you conclude?c) Is Indinavir (Crixivan) likely to continue to work? DHS/ HIV/PP

  27. HIV: Case History • A 38-year-old woman has an HIV RNA of 176,000 and a CD4 count of 79; she is started on d4T (Zerit) + 3TC (Epivir) + nelfinavir (Viracept) and does well for 3 months with an HIV RNA of 485 at month 3. At month 4 the HIV RNA is 920 and at month 5 it is 3010; she admits to intermittent problems with adherence, but now has the situation under control and is reliably taking her medications. Genotypic resistance testing is performed. The RT gene shows the 184 mutation, but no mutations to suggest d4T resistance; protease gene shows the 30 mutation (D30N). a) Does the lack of resistance with d4T influence you?b) Do you think this patient has resistance to nelfinavir (Viracept) and do you think they would respond to a salvage regimen? DHS/ HIV/PP

  28. Antiretroviral Toxicity DHS/HIV/ARV RX/PP

  29. HIV: Case History • A 34-year-old man with a CD4 count of 326 and an HIV RNA load of 56,000 is started on an antiretroviral therapy regimen of Zidovudine + Lamivudine (Combivir) + Nevirapine (Viramune). Two weeks into the regimen the patient is tolerating the combination well, but at week 3 he calls and says he has severe fatigue and his urine looks dark. The patient has a 1-month follow-up visit in 1 week. a) What is likely going on?b) Should the patient come in to the clinic now or reasonable to wait several days to see if it resolves? DHS/ HIV/PP

  30. HIV Postexposure ProphylaxisSerious Adverse Events Associated with Nevirapine N = 22 Serious Adverse Events - Hepatotoxicity = 12 (2 with liver failure) - Skin Reaction = 14 From: CDC. MMWR 2001;49 (51);1153-6. DHS/HIV/AIDS /PP

  31. HIV: Case History • A 31-year-old man has a CD4 count of 221 and an HIV RNA of 144,000 and has been on a regimen of Zidovudine (Retrovir) + Didanosine (Videx) + Indinavir (Crixivan) + Ritonavir (Norvir) and has had a very good response to this therapy. He calls with left-sided back pain and dark urine.a) What should you do?b) Can they continue this regimen?c) What may help to prevent this? DHS/ HIV/PP

  32. HIV: Case History • A 29-year-old woman has a CD4 count of 134 and an HIV RNA of 43,000 and has been on salvage regimen of Zidovudine (Retrovir) + Didanosine (Videx) + Hydroxyurea (Hydrea) + Nevirapine (Viramune) + Nelfinavir (Viracept) and she has had a very good response to this therapy. She calls stating she has been vomiting for two days and has terrible abdominal pain, especially after she eats.a) What could be going on and what labs would you order?b) Could the Hydroxyurea be contributing to the problem? DHS/ HIV/PP

  33. HIV: Case History • A 35-year-old woman with a CD4 count of 423 and an HIV RNA level of 64,000 starts on Zidovudine + Lamivudine + Abacavir (Trizivir). After approximately 2 weeks of starting the medication, she develops fatigue, a low grade fever, sore throat, and a mild non-productive cough. She states one of her kids has recently had a “cold”.a) What are you worried about and what further questions would you ask?b) Is it safe to continue the regimen for another day or two? DHS/ HIV/PP

  34. Abacavir (Ziagen) Hypersensitivity • Incidence and Timing- Incidence < 3%- Onset typically within 4 weeks • Symptoms- Rash- Fever - Nausea- Throat/mouth lesions- Conjunctivitis/respiratory symptoms From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353 From DHS/ARV Rx/PP

  35. HIV: Case History • A 29-year-old HIV-infected woman has done very well on a regimen of Stavudine (Zerit) + Lamivudine (Epivir) + Ritonavir (Norvir) + Amprenavir (Agenerase), but presents with 3 weeks of severe fatigue. A chemistry panel shows a decreased HCO3- level. They are breathing deeper and faster than usual. a) What could be going on?b) What further lab tests would be appropriate to order?c) How would you manage this? DHS/ HIV/PP

  36. Hyperlactatemia & Lactic Acidosis Symptoms • Nausea/vomiting • Abdominal pain • Malaise/fatigue • Anorexia • Hyperventilation/dyspnea DHS/HIV/ARV RX/PP

  37. Hyperlactatemia & Lactic Acidosis Pathogenesis NRTI inhibits mitochondrial DNA polymerase-gamma Blocks oxidative phosphorylation Shifts to anaerobic metabolism via Kreb’s cycle Increased serum lactate levels DHS/HIV/ARV RX/PP

  38. Hyperlactatemia & Lactic Acidosis Proposed Definitions • Mild Hyperlactatemia- Lactate level > 2 and < 5 mmol/L- Estimated 10-20% frequency • Serious Hyperlactatemia - Lactate level > 5 mmol/L - Estimated 1-2% frequency • Lactic Acidosis - Lactate level > 5 mmol/L + HCO3- < 20 mmol/L - Estimated < 1% frequency From: Brinkman K. Clin Infect Dis 2000;31:167-9. DHS/HIV/ARV RX/PP

  39. Hyperlactatemia & Lactic AcidosisMeasuring Serum Lactate Levels • Have person rest for 5-10 minutes • Draw without tourniquet (if possible) • Avoid fist clinching • Place on ice and promptly send to lab • If increased, repeat with no EtOH x 24h DHS/HIV/ARV RX/PP

  40. HIV: Case History • A 248-year-old HIV-infected man has done very well on a regimen of Zidovudine + Lamivuine (Combivir) + Ritonavir (Norvir) + Saquinavir (Fortivase), but develops an increased cholesterol (ranging 250-275). The increased cholesterol has not responded to diet therapy. a) What would you recommend?b) What would you have done if triglycerides had also been markedly increased? DHS/ HIV/PP

  41. Hyperlipidemia and ARV Therapy Increased LDL Increased LDL and TG Increased TG Lipid Abnormality Recommendation Statin Statin or Fibrate Fibrate From: Dube MP et al. Clin Infect Dis 2000;31:1216-24. DHS/ARV Rx/PP

  42. Lipid Lowering Agents and ARV Therapy Agent Recommendation Pravastatin Atorvastatin Lovastatin Simvastatin Gemfibrozil Fenofibrate Niacin No dose adjustment Dose titration Avoid Avoid No dose adjustment No dose adjustment Avoid From: Dube MP et al. Clin Infect Dis 2000;31:1216-24. DHS/ARV Rx/PP

  43. HIV: Case History • A 44-year-old man with a baseline CD4 count of 34 and HIV RNA of 106,000 has taken Stavudine (Zerit) + Lamivudine (Epivir) + Indinavir (Crixivan) for approximately 3 years with an excellent response. He now has a CD4 of 301 and an HIV RNA < 50, but has developed significant fat accumulation (abdominal, neck, and breast region) and fat wasting in the face and buttock region. He wants to explore options for improving the fat maldistribution problem. a) Would it likely help to switch the antiretroviral therapy?b) What about Liposuction? Testosterone? Growth hormone? Metformin DHS/ HIV/PP

  44. Metformin Therapy in Lipodystrophy Syndrome N = 26 P = 0.005 P = 0.08 From: Hadigan C et al. JAMA 2000;284:472-7. DHS/ARV Rx /PP

  45. Structured Treatment Interruptions DHS/HIV/ARV RX/PP

  46. HIV: Case History • A 38-year-old man has a CD4 count of 47 and an HIV RNA of 325,000 and has been on a multiple different antiretroviral regimens but does not have long-term tolerance for any regimen. He currently is taking Zidovudine + Lamivuine (Combivir) + Ritonavir/Lopinavir (Kaletra). He comes in asking about treatment interruptions a) How should you respond?b) What are the reasonable goals? DHS/ HIV/PP

  47. Antiretroviral Therapy: Treatment Interruptions • Temporary interruption • Structured treatment interruption (STI) • Interruption prior to salvage therapy DHS/HIV/ARV RX/PP

  48. ARV RX: Temporary Interruption Start Rx Restart Rx 50 50 Stop Rx DHS/ARV Rx/PP

  49. ARV RX: Structured Treatment Interruptions Start Rx Start Rx Start Rx Start Rx 50 50 Stop Rx Stop Rx Stop Rx DHS/ARV Rx/PP

  50. ARV RX: Interruption Prior to Salvage Rx Start Rx Start Salvage Rx Stop Rx 50 50 DHS/ARV Rx/PP