10. Antiretroviral Therapy

10. Antiretroviral Therapy - Overview of Antiretroviral...

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1 Overview of Antiretroviral Therapy Alice Tseng, Pharm.D., FCSHP Immunodeficiency Clinic, Toronto General Hospital Assistant Professor, Faculty of Pharmacy, University of Toronto February 6 th , 2009 Outline • Significant milestones • Antiretroviral pharmacology • Antiretrovirals in clinical practice • Advances in treatment options • Evolution of treatment strategies NNRTI ’93 ’93 ’94 ’94 ’96 ’96 ’97 ’97 ’98 ’98 ’99 ’99 ’00 ’00 ’01 ’01 ‘02 ‘02 ’90 ’90 ’91 ’91 ’92 ’92 NRTI PI Between ’87 and ’95, 4 antiretrovirals were launched. Since ’95, 27 new products have been introduced. Approved Antiretrovirals AZT ritonavir Saquinavir -hgc hgc indinavir Saquinavir -sgc sgc Lopinavir Lopinavir- ritonavir nelfinavir abacavir AZT/3TC ddI ddC d4T 3TC AZT/3TC/ABC delavirdine efavirenz nevirapine ’03 tenofovir FTC atazanavir ‘04 ‘04‘05 ‘05 ’95 amprenavir fosamprenavir ‘08 ABC/3TC TDF/FTC Combination product Fusion Inhibitor Key: ‘07 tipranavir ‘06 darunavir TDF/FTC/EFV Integrase Inhibitor ’87 enfuvirtide raltegravir CCR5 inhibitor maraviroc etravirine
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2 Decline in Mortality with Increased Use of Protease Inhibitors From a cohort of 1255 patients with CD4 count <100 cel s/mm 3 Palel a FJ Jr, et al. N Engl J Med . 1998;338:853-860 Use of Protease Inhibitors Deaths Deaths per 100 Person-Years 40 30 20 10 0 1994 1995 1996 1997 0% 20% 40% 60% 80% 100% Therapy With a Protease Inhibitor (% of patient days) Decline in OIs with Increased Use of Protease Inhibitors No. of Opportunistic Infections per 100-Person Years (% of patient-days) 0% 20% 40% 60% 80% 100% 1994 1995 1996 1997 Use of Protease Inhibitors Cytomegalovirus M. avium complex P. carinii pneumonia 0 5 10 15 20 From a cohort of 1255 patients with CD4 count <100 cel s/mm 3 Palel a FJ Jr, et al. N Engl J Med . 1998;338:853-860 dbb.urmc.rochester.edu/labs/smith/research_3.htm Nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) Non- nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Fusion inhibitor (FI) Coreceptor antagonists (CCR5 inhibitors) Integrase Inhibitors
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3 Nature Medicine 2003
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4 Nonnucleoside Reverse Transcriptase Inhibitors Inhibitors (NNRTIs) (NNRTIs) Long half-life allows QD or BID dosing, low pill burden Toxicities: rash, hypersensitivity, hepatitis (esp. NVP) NNRTIs are potent CYP3A inducers, associated with numerous drug interactions Low genetic barrier to resistance (single mutation, I.e., K103N = resistance to entire class) – 2 nd generation NNRTIs (etravirine, rilpivirine) work when primary resistance mutations exist to first generation NNRTIs Non Non-Nucleoside Reverse Transcriptase Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in Clinical Practice Efavirenz
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  • Spring '10
  • Crandall
  • Antiretroviral drug, Protease inhibitor, Reverse Transcriptase Inhibitors, protease inhibitors, transcriptase inhibitors

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10. Antiretroviral Therapy - Overview of Antiretroviral...

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