1. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 93 Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections

2. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.2 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 – blood and body fluids  Virus present in all body fluids

3. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.3 Human Immunodeficiency Virus  Promotes immunodeficiency by killing CD4 T lymphocytes  Difference between HIV and AIDS  Global epidemic  Standard antiretroviral therapy (ART)  Reduced AIDS deaths by 72%  HAART – highly active antiretroviral therapy

4. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4 Fig. 93-1. Structure of the human immunodeficiency virus. Note that HIV has two single strands of RNA, and that each strand is associated with a molecule of reverse transcriptase. (gp 41 = glycoprotein 41, gp120 = glycoprotein 120.)

5. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.5 Fig. 93-2. Replication cycle of the human immunodeficiency virus. See text for description of events. (CCR5 = CCR5 co-receptor, CD4 = CD4 receptor, CXCR4 = CXCR4 co-receptor, dsDNA = double-stranded DNA, gp120 = glycoprotein 120, mRNA = messenger RNA, ssDNA = single-stranded DNA, ssRNA = single-stranded RNA.)

6. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.6

7. 7 Classification of Antiretroviral Drugs  Five types of antiretroviral drugs  Inhibit enzymes required for HIV  Reverse transcriptase inhibitors  Integrase inhibitors  Protease inhibitors  Block viral entry into cells  Fusion inhibitors  CCR5 antagonists

8. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.8 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)  Zidovudine (Retrovir)  Inhibits HIV replication by suppressing synthesis of viral DNA  Adverse effects  Anemia and neutropenia  Lactic acidosis/hepatic steatosis (rare)  Gastrointestinal effects  CNS reactions  Drug interactions

9. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9

10. 10 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)  Differ from the NRTIs in structure and mechanism of action  NNRTIs bind to the active center of reverse transcriptase and cause direct inhibition  Active as they are administered  See Table 93-4

11. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.11 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)  Efavirenz (Sustiva)  Nevirapine (Viramune)  Delavirdine (Rescriptor)  Etravirine (Intelence)

12. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.12 NNRTIs  Efavirenz (Sustiva)  Preferred agent for treating HIV  Only NNRTI recommended for first-line therapy for HIV infection  Drug interactions  Adverse effects  Teratogenicity  Transient adverse CNS effects in 50% of patients  Rash

13. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13 Protease Inhibitors  Among the most effective antiretroviral drugs available  Used in combination with NRTIs – can reduce viral load to an undetectable level  Resistance  Drug interactions  P450 inhibitors  P450 inducers  P450 substrates  Herb interactions

14. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.14 Protease Inhibitors  Adverse effects  Hyperglycemia/diabetes  Fat malredistribution  Hyperlipidemia  Reduced bone density  Hepatotoxicity  Increased bleeding in hemophiliacs  Reduced bone mineral density  Elevation of serum transaminase

15. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.15 Protease Inhibitors  Lopinavir/ritonavir (Kaletra)  Ritonavir (Norvir)  Indinavir (Crixivan)  Saquinavir (Invirase, Fortovase)  Nelfinavir (Viracept)  Amprenavir (Agenerase)

16. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.16 Protease Inhibitors  Fosamprenavir (Lexiva)  Atazanavir (Reyataz)  Tipranavir (plus Ritonavir)  Darunavir (plus Ritonavir)

17. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.17 HIV Integrase Strand Transfer Inhibitors  Raltegravir (Isentress) approved in 2007  First and only member of this new class of antiretroviral drugs  Adverse side effects  Diarrhea, nausea, fatigue, headache, and itching  FDA Pregnancy Risk Category C

18. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.18 Enfuvirtide (Fuzeon)  HIV fusion inhibitor  Widely known as T-20  First and only HIV fusion inhibitor  Blocks entry of HIV into CD4 T cells  BID subQ dosing costs $20,000 a year  Adverse effects  Injection site reactions, pneumonia, and hypersensitivity reactions

19. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.19 Maraviroc (Selzentry)  CCR5 antagonist  Approved in 2007  Indicated only for combined use with other antiretroviral drugs in treatment-experienced adults infected with CCR5-tropic HIV-1 strains that are resistant to multiple drugs

20. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20 Laboratory Monitoring for HIV Infection and Drug Therapy  Viral load (plasma HIV RNA)  Best measurement for predicting clinical outcome  CD4 T-cell counts

21. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.21 HIV Treatment in Pregnancy  Same principles that guide antiretroviral therapy in nonpregnant adults  Mother-to-child transmission HIV  Occurs primarily during labor and delivery  Risk for transmission can be greatly reduced by ART, which minimizes maternal viral load  The same general principles also apply to children

22. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.22 Treatment  Prophylactic drugs can reduce the risk for infection after accidental exposure  Advanced HIV disease may need prophylactic antibiotics because of decreased CD4 T cell counts  PCP most common opportunistic infection  Trimethoprim plus sulfamethoxazole