18. HIV Life Cycle and Drug Targets Reverse Transcriptase Inhibitors Integrase Inhibitors Protease Inhibitors Entry Inhibitors
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24. When to Start HAART Defer therapy < 100,000 CD4 T cells > 350/mm 3 Asymptomatic Most clinicians recommend deferring therapy, but some will treat > 100,000 CD4 T cells > 350/mm 3 Asymptomatic Treatment should be offered following full discussion of pros/cons Any value CD4 T cells > 200/mm 3 but < 350/mm 3 Asymptomatic Treat Any value CD4 T cells < 200/mm 3 Asymptomatic Treat Any value Any value AIDS-defining illness or severe symptoms Recommendation Plasma HIV RNA CD4T Cell Count Clinical Category
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28. Starting Recommendations Treatment- naive Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. (DHHS) Updated October 2006. Abacavir/lamivudine (BII) Didanosine + lamivudine (BII) Nevirapine Atazanavir (unboosted) (BII) (BII) Fosamprenavir (unboosted) (BII) Fosamprenavir +ritonavir q Day (AII) Lopinavir/ritonavir q Day (BII) Alternative ( order) Tenofavir/emtracitabine (AII) Zidovudine/lamivudine (AII) Efavirenz Atazanavir + ritonavir (AIII) (AII) Fosamprenavir +ritonavir BID (AII) Lopinavir/ritonavir BID (AII) Preferred ( order) 2-NRTI NNRTI PI Column B Column A
65. Agents not Recommended as Initial Therapy Inferior virologic efficacy, ↑ AE than alt Zalcitabine-AZT Lack of data in treatment-naïve Tipranavir (boosted) ↑ pill burden, Inferior virologic efficacy Saquinavir (unboosted) High pill burden, GI intolerance Ritonavir mono PI High incidence of nephrolithiases Indinavir (boosted) Tid with meals; fluid requirements Indinavir (unboosted) No trial experience in naïve, SC bid Enfuvirtide ↑ rate of virologic failure, rapid selection of resistance, potential for CD4 decline ddI + tenofovir Inferior virologic efficacy; tid dosing Delavirdine Lack of data in treatment-naïve Darunavir (boosted) Reasons for not recommending Drug
66. Agents not Recommended at Any Time Antagonistic effect on HIV-1 D4T + AZT Additive peripheral neuropathy D4T + Zalcitabine In vitro antagonism 3TC + Zalcitabine Similar resistance profile Emtricitabine + 3TC Teratogenic Efavirenz in pregnancy ↑ LA with hepatic steatosis +/- pancreatitis in pregnancy (fatal) DDI + stavudine Additive hyperbilirubinemia Atazanavir +Indinavir ↑ early virologic non-response Triple NRTI Rapid development of resistance Dual-NRTI Rapid development of resistance Monotherapy NRTI or NNRTI Reasons for not recommending Drug
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68. Activity of ART with Mutations An Update and Review of Antiretroviral Therapy Pharmacotherapy 2006;26(8):1111-33 Class resistance K103N NNRTIs Primary mutations, ↑ mutations = MDR L90M, L10I, 154V, M46I, 184V PI Resistant Decreased activity with ↑ number of mutations Activity may be resensitized with M184V Resistant Activity may be resensitized to tenofovir, AZT, D4T L74V TAMs Tams + M184V K65R K65R + M184V Abacavir Tenofovir Decreased activity with increased number of mutations TAMs = M41L, D67N, K70R/Q/N, T215F/Y Stavudine- zidovudine Resistant Sensitive M184V TAMs Lamivudine-emtricitabine Multiple drug resistance, sensitive to LMV and tenofovir May be sensitive to only tenofovir Multidrug resitance likely May have activity against tenofovir Q151M Q151M + M184V T69S insertion + TAMs T69S + M184V NRTIs Result Mutation ART
71. Frequency of Initial AIDS-Defining Diagnosis Pneumocystis Jirvoveci 42 75-85 HIV wasting syndrome 11 70-90 Candida esophagitis 15 20-30 Kaposi’s sarcoma 11 15-25 HIV-associated dementia 4 40-70 Disseminated CMV 4 80-90 Toxoplasmosis encephalitis 3 5-15 Disseminated MAC 5 30-40 Lymphoma 4 3-5 Chronic mucocutaneous herpes simplex 1 10-25 Cryptococcus meningitis - 8-12 Cryptosporidiosis 2 5-10 Tuberculosis 5 4-20 % among all without proph 1997 %
72. Prevention of OI TB (latent) PPD + (> 5mm) INH 300 mg/day + pyridoxin 50 mg/day PCP CD4 < 200/mm 3 TMP-SMX 1 DS or SS/day or CD4% <14, thrush Toxoplasmosis CD4 < 100/mm 3 TMP-SMX 1 DS/day + anti-Tox IgG MAC CD4 < 50/mm 3 Azithromycin 1200 mg/wk Clarithromycin 500 mg bid Varicella Exposure to VZIG 6.25 mL IM < 96 hr chickenpox/zoster Disease Indication Preferred Regimen Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service
73. OI Treatment OI Preferred Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004 CS for focal lesion edema Secondary prophylaxis can be discontinued ss of TE are gone and CD4 > 200 cells/uL for > 6 months Pyrimethamine (leucovorin) + CD 600 mg IV or PO q6h Acute therapy Pyrimethamine 200 mg PO x1, then 50 mg (< 60 kg) q/day + sulfadiazine 1,000 (<60 kg) PO q6h + leucovorin 10-20 mg PO q/day TE Other Issues Indications for CS PaO2 <70 mm/Hg Prednisone 40 mg PO bid days 1-5, then q day days 6-10, then 20 mg q day days 11-21 Secondary prophylaxis can be discontinued when CD4 > 200 cells/uL for > 3 months Alternatives For severe PCP : Pentamidine 4mg/kg IV q/day Mild-mod: Dapsone 100 mg PO q/day + TMP 15 mg/kg/day PO (divided tid) Primaquine 15-30 mg PO q/day + CD 600-900 mg IV q6-8h or CD 300-450 mg PO q6-8h Acute therapy TMP-SMX 15-20 mg TMP/kg/day IV divided q6-8h or same dose PO x 21 days Chronic maintenance therapy TMP-SMX 1-DS or SS PO/day Alt: Dapsone 100 mg/day Dapsone 50 mg/day + pyrimethamine 50 mg and leukovorin 25 mg PO q/wk Dapsone 200 mg + pyremethamine 75 mg + leukovorin 25 mg PO/wk Pentamidine aerosole 300 mg/mo Atovaquone 1,500 mg PO/day TMP-SMX 1-DS TIW PCP
74. OI Treatment OI Preferred Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004 Therapeutic CSF punctures to ↓ ICP Secondary prophylaxis can be discontinued if asymptomatic and CD4 > 100-200 cells/uL for > 6 months Amphotericin or fluconazole 400 -800 po or IV mg/day for less severe disease Fluconazole + flucytosine Acute therapy Ampho B 0.7 mg/kg IV q/day+ flucytosine 25 mg/kg po qid x 2 weeks followed by fluconazole 400 mg po q/day for 8 weeks or until CSF sterile Chronic maintenance therapy Fuconazole 200 mg po q/day Crypto Other Issues NSAIDS or CS if IRS Secondary prophylaxis can be discontinued in patients who completed 12 mo/tx remain asymptomatic CD4 > 100 for > 6 mo Alternatives Azithromycin 500-600 mg po q/day Alt: 3-4 th drug in pts with more severe disseminated disease Ciprofloxacin 500-750 po bid or Levo 500 mg po/day or Amikacin 10-15 mg/kg IV q/day At least 2 drugs as initial therapy Clarithromycin 500 mg PO bid + ETH 15 mg/kg PO q day Consider adding a 3 rd agent for CD4 < 50, high mycobacterial load, or in absence of ART; Rifabutin 300 mg po/day Chronic maintenance therapy Clarithromycin 500 mg PO bid + ETH 15 mg/kg/day +/- Rifabutin 300 mg po/day lifelong until sustained immunity MAC
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