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HIV Resistance: Introduction

HIV Resistance: Introduction. Myron S. Cohen, MD J. Herbert Bate Professor of Medicine, Microbiology and Immunology and Epidemiology Director, UNC Center for Infectious Diseases The University of North Carolina at Chapel Hill. Disclosures. Nothing to disclose.

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HIV Resistance: Introduction

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  1. HIV Resistance: Introduction Myron S. Cohen, MD J. Herbert Bate Professor of Medicine, Microbiology and Immunology and Epidemiology Director, UNC Center for Infectious Diseases The University of North Carolina at Chapel Hill

  2. Disclosures • Nothing to disclose

  3. Question: What geographic region are you from? North America Europe Asia/Pacific Rim Africa South America

  4. Question: What is your primary area of responsibility? Administration Research Clinical Industry Other

  5. Question: How long have you been involved in HIV care? < 5 years 6-10 years 10-15 years 15-20 years > 20 years

  6. HIV Resistance Topics • Transmission, resistance, and compartments (Cohen) • Prevalence of transmitted resistance (Pillay) • Selective pressure, resistance, and patient care (Eron) • Testing for resistance (Sax) • who, what, when, where, why and how??? • Moderator (Smith) • Summary (Cohen) Booth and Geretti. JAC 2007;59:1047-56.

  7. Infectious Susceptibility Inoculum (concentration) Hereditary resistance Phenotypic factors Innate resistance Acquired (immune) resistance Transmission of HIV:Biological Requirements Cohen and Galvin. Nat Microbiol Rev. 2004;2:33-42.

  8. Blood Viral Load and HIV-1 Transmission Quinn et al. NEJM 2000;342:921-9.

  9. Viremia and Shedding in Acute HIV 9 7 Blood 5 log10 HIV-1 RNA copies per mL 3 Semen 1 0 4 8 12 16 20 24 28 Weeks Since Acute HIV infection Dumond et al. AIDS. 2007;21:1899-1908.

  10. Resistance and the Spreadof HIV • Resistance markers and sexual networks • Brenner et al. JID 2007;195:951-9. • Brenner et al. J Virol. 2002;76:1753-61. • Resistance and representation: Ecological Analysis • Corvasce et al. Antivir Ther. 2006;11:329-34. • Turner et al. JAIDS 2004;37:1627-31. • Yerly et al. Antivir Ther. 2004;93:75-84. • de Mendoza et al. Clin Infect Dis. 2004;39:1231-8. • Violin et al. JAIDS 2004;36:761-4. • UK Collaborative study. BMJ 2001;322:1087-8.

  11. Resistant Variants Missing • 220 recent and 373 chronic infections • Resistance in chronics = 72.4% • one class 29.0% • two classes 27.6% • three classes 15.8% • In recently infected patients = 10.5% • one class 9.1% • two classes 1.4% • three classes 0% • OR 0.39, p<.0001 Yerly et al. Antivir Ther. 2004;93:75-84.

  12. HIV Diminished Representation • Comparison of resistant variants in a “potential transmitters” (n=380/552) vs. • “Primary” HIV Infection (n=59/305) …M184V was under-represented -PHI/PT 0.14 vs. 0.93 for other mutations -M184V lower plasma viremia (0.8 logs) Turner et al. JAIDS 2004;37:1627-31.

  13. HIV Resistance and Compartments

  14. 0 50% 100% 150% 200% 500% 600% ABC (150%) ZDV (200%) TDF (500%) 3TC (600%) IDV (100%) ENF (ND) d4T (2%) EFV (3%) SQV (3%) RTV (3%) LPV (5%) NFV (5%) Male Genital Tract Exposure (% of blood plasma) APV (20%) NVP (70%) NRTI PI NNRTI FI Cohen et al. adapted from Ann Intern Med. 2007;146:591-601.

  15. 3TC (400%) FTC (600%) TDF (400%) ddI (100%) IDV (200%) SQV(ND) ZDV (200%) EFV (0.6%) ABC (150%) d4T (4%) RTV (20%) DLV (20%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Female Genital Tract Exposure (% of blood plasma) 0 200% 400% 600% NRTI PI NNRTI Cohen et al. adapted from Ann Intern Med. 2007;146:591-601.

  16. HIV Resistance and the Genital Tract (examples…not inclusive) • Eron JJ, Vernazza PL, Johnston DM, et al. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. • AIDS 1998;12:F181-9. • Si-Mohamed A, Kazatchkine M, Heard I, et al. Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy. • JID 2000;182:112-22. • Solas C, Lafeuillade A, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. • Antimicrob Agents Chemother. 2003;47:238-43.

  17. Resistant Variants in Semen Sequential sampling in blood and semen Persistent HIV resistant variants in semen >3 years after HIV acquisition (2/5) Onward transmission of resistant variants (n=2) Smith et al. JID 2007:196:356

  18. The End of the Beginning…of this program • Transmitted resistance is observed, albeit perhaps selective • Viral resistance patterns likely affect the probability of transmission through reduced viral fitness, replication and viral concentration or “other factors” yet to be determined • Minor variants not detected through bulk sequencing may prove important • The effects of resistance on transmission could ultimately affect the selection of initial therapy, as well as the public health implications of the choice of combinations of agents

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