1. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 94 Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections

2. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 22 Drugs for HIV Infection and Related Opportunistic Infections  Human immunodeficiency virus is a retrovirus (HIV-1 and HIV-2)  HIV has RNA as genetic material  Uses reverse transcriptase to convert RNA into DNA and integrase to insert its DNA into ours  Target cells: CD4 T cells (helper lymphocytes)  Transmission via blood and body fluids  Virus is present in all body fluids 2

3. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 33 Human Immunodeficiency Virus  Promotes immunodeficiency by killing CD4 T lymphocytes  Transmission of HIV  Clinical progression  Difference between HIV and AIDS  Global epidemic  Standard antiretroviral therapy (ART)  Reduced AIDS deaths by 72%  Highly active antiretroviral therapy (HAART) 3

4. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 44 Summary of Human Immunodeficiency Virus (HIV) Infection on the Immune System 4

5. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 55 Classification of Antiretroviral Drugs  Five types of antiretroviral drugs  Inhibit enzymes required for HIV  Reverse transcriptase inhibitors  Integrase strand transfer inhibitors  Protease inhibitors  Block viral entry into cells  Fusion inhibitors  CCR5 antagonists 5

6. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 66 Stages of Viral Infection in Host Cell 6

7. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 77 Life Cycle and Possible Sites of Therapeutic Intervention of (HIV) 7

8. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 88 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)  Zidovudine [Retrovir]  Inhibits HIV replication by suppressing synthesis of viral DNA  Adverse effects  Hematologic toxicity  Lactic acidosis with hepatomegaly  Myopathy  Gastrointestinal effects  Central nervous system (CNS) reactions  Others  Drug interactions 8

9. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 99 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)  Differ from NRTIs in structure and mechanism of action  NNRTIs bind to active center of reverse transcriptase and cause direct inhibition  Active as they are administered 9

10. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 10 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)  Efavirenz [Sustiva]  Nevirapine [Viramune]  Delavirdine [Rescriptor]  Etravirine [Intelence]  Rilpivirine [Edurant] 10

11. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 11 NNRTIs  Efavirenz [Sustiva]  Preferred agent for treating HIV  Only NNRTI recommended for first-line therapy of HIV infection  Drug interactions  Adverse effects  Transient adverse CNS effects in 50% of patients  Rash  Teratogenicity 11

12. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 12 Protease Inhibitors  Among the most effective antiretroviral drugs  Nine are available  Used in combination with NRTIs; can reduce viral load to an undetectable level  Resistance 12

13. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 13 Protease Inhibitors  Adverse effects  Hyperglycemia/diabetes  Fat redistribution  Hyperlipidemia  Reduced bone density  Increased bleeding in people with hemophilia  Reduced bone mineral density  Elevation of serum transaminase  Drug interactions 13

14. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 14 Protease Inhibitors  Lopinavir/ritonavir  Ritonavir  Indinavir  Saquinavir  Nelfinavir  Fosamprenavir  Atazanavir  Tipranavir  Darunavir 14

15. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 15 HIV Integrase Strand Transfer Inhibitors  Raltegravir [Isentress]  Indicated for combined use with other antiretroviral agents to treat adults infected with HIV-1  Adverse side effects  Insomnia, headache, and rare hypersensitivity reactions  FDA pregnancy risk: Category C 15

16. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 16 Enfuvirtide [Fuzeon]  HIV fusion inhibitor  Widely known as T-20  First and only HIV fusion inhibitor  Blocks entry of HIV into CD4 T cells  Twice-daily subQ dosing  Adverse effects  Injection-site reactions, pneumonia, and hypersensitivity reactions 16

17. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 17 Maraviroc [Selzentry]  CCR5 antagonist  Indicated for combined use with other antiretroviral drugs to treat patients age 16 years or older who are infected with CCR5- tropic HIV-1 strains  Adverse effects  Drug interactions 17

18. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 18 Principal Laboratory Tests Used to Guide Therapy  CD4 T-cell counts: Principal indicator of how much immunocompetence remains  Plasma HIV RNA (viral load) assays: Ongoing treatment of HIV infection is guided primarily by monitoring viral load, which is determined by measuring HIV RNA in plasma 18

19. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 19 HIV Drug Resistance  In most cases, resistance emerges over the course of treatment as a result of nonadherence to the prescribed regimen  Rarely, resistance results from primary infection with a drug-resistant HIV variant  Resistance tests can be used to guide drug selection, especially when changing a regimen that has failed 19

20. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 20 HIV Treatment in Pregnancy  Same principles that guide antiretroviral therapy in nonpregnant adults  Mother-to-child transmission HIV  Risk for transmission can be greatly reduced by ART, which minimizes maternal viral load  The same general principles apply to children 20

21. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 21 HIV Treatment  Treatment of young patients  Treatment of older patients  Preventing HIV infection with drugs  Pre- and postexposure prophylaxis  Preventing perinatal HIV transmission  Prophylaxis and treatment of opportunistic infections 21

22. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 22 HIV Vaccines  Obstacles to vaccine development  Current status of vaccine development 22