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Chapter 93

Chapter 93. Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections. 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

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Chapter 93

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  1. Chapter 93 Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections

  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. 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. 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. 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. 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

  7. 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

  8. 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

  9. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Efavirenz (Sustiva) • Nevirapine (Viramune) • Delavirdine (Rescriptor) • Etravirine (Intelence)

  10. 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

  11. 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

  12. 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

  13. Protease Inhibitors • Lopinavir/ritonavir (Kaletra) • Ritonavir (Norvir) • Indinavir (Crixivan) • Saquinavir (Invirase, Fortovase) • Nelfinavir (Viracept) • Amprenavir (Agenerase)

  14. Protease Inhibitors • Fosamprenavir (Lexiva) • Atazanavir (Reyataz) • Tipranavir (plus Ritonavir) • Darunavir (plus Ritonavir)

  15. 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

  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 • BID subQ dosing costs $20,000 a year • Adverse effects • Injection site reactions, pneumonia, and hypersensitivity reactions

  17. 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

  18. Laboratory Monitoring for HIV Infection and Drug Therapy • Viral load (plasma HIV RNA) • Best measurement for predicting clinical outcome • CD4 T-cell counts

  19. 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

  20. 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

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