antiretrovirals

• HAART (ART) stands for Highly Active Antiretroviral Therapy, which is a combination of at least 3 drugs
• The goals of ART are to suppress the HIV virus, restore immune function, and reduce morbidity and mortality associated with HIV infection
• In the case of an accidental needlestick with blood from an HIV-infected patient with a CD4 count of 50/μL and a viral RNA load of > 107 copies/mL, the most appropriate course of action is to treat with full doses of zidovudine for 4 weeks
• Antiretroviral classes include:

  • NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, “Nukes”)
  • NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, “Non-Nukes”)
  • PIs (Protease Inhibitors)
  • Fusion Inhibitors
  • Chemokine Receptor Antagonists
  • Integrase Inhibitors
• Antiretroviral therapy (ART) or HAART is a combination of at least 3 drugs, usually 2 NRTIs and 1 NNRTI or 1-2 PIs, or triple NRTIs
• First-line ART regimen involves combining NRTIs, which may have interactions, competition for the same enzymes, overlapping toxicities, and nucleoside analogues that are activated by the same enzymes
• Recommended NRTI combinations include:

  • Stavudine and Lamivudine
  • Zidovudine and Didanosine
  • Zidovudine and Lamivudine
• NRTIs (Nucleoside Reverse Transcriptase Inhibitors) mechanism of action involves nucleoside analogs that are triphosphorylated inside lymphocytes to active compounds, leading to termination of viral DNA synthesis after incorporation
• NRTI class toxicities include lactic acidosis, hepatomegaly with steatosis, peripheral neuropathy, lipoatrophy, and pancreatitis
• NRTI combinations and their standard doses include:

  • Lamivudine/Zidovudine (COM) Combivir
  • Abacavir/Lamivudine/Zidovudine (TZV) Trizivir
  • Tenofovir/Emtricitabine Truvada
  • Abacavir/Lamivudine Epzicom
  • Tenofovir/Emtricitabine/Efavirenz Atripla
• NNRTIs (Non-nucleoside Reverse Transcriptase Inhibitors) directly bind to reverse transcriptase to inhibit transcription and do not require phosphorylation to be active
• Common NNRTIs include:

  • Delavirdine (DLV)
  • Nevirapine (NVP)
  • Efavirenz (EFV)
• New NNRTI Etravirine (ETR) is a second-generation NNRTI that is taken with food, active against most resistant strains, and has reduced CNS toxicity and is safe in the first trimester
• Protease Inhibitors (PIs) mechanism of action involves binding to protease enzyme preventing the cleavage and inhibiting the assembly of new HIV viruses
• Moderate and severe rash are common adverse effects associated with NNRTIs
• A new NNRTI, Etravirine (ETR), is a second-generation NNRTI that is taken with food, active against most resistant strains, and has reduced CNS toxicity and is safe in the first trimester
• Protease inhibitors (PIs) bind to protease, preventing cleavage and inhibiting the assembly of new HIV viruses
• Common side effects of Protease Inhibitors (PIs) include:

  • GI intolerance
  • Diarrhea
  • Dyspepsia
  • Nausea
  • Vomiting
  • Flatulence
  • Nephrolithiasis
  • Rash
• Protease inhibitors can increase lipids and cause insulin resistance
• Ritonavir is used to "boost" C min and increase t½ of other protease inhibitors
• Fusion Inhibitor Enfuvirtide (T-20, ENF):

  • Side effects: injection site reaction, hypersensitivity
  • Resistance: changes in gp41 (cell surface protein)
• Chemokine Receptor Antagonist active against all R5 trophic HIV strains:

  • Maraviroc (MVC)
• Integrase Inhibitor Raltegravir (RAL):

  • Dosed 400mg twice daily
  • No drug interactions with CYP450 enzymes inducers/inhibitors
  • Used as part of salvage regimen for ART experienced patients
  • Common side effects: diarrhea, nausea, headache, fever
• Maturation Inhibitor Bevirimat:

  • Under clinical trial III
  • Binds to the gag protein, not protease, causing virus particles to lack functional capsid protein and have structural defects
  • Protease inhibitor-resistant HIV-1 is sensitive to bevirimat in vitro
• Antiretrovirals cannot kill the existing virus; they can only prevent the production of new virus
• The six antiretroviral classes are:

  • Nucleoside reverse transcriptase inhibitors (NRTI)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTI)
  • Protease inhibitors (PI)
  • Fusion inhibitors (FI)
  • Integrase inhibitors
  • Chemokine receptor antagonist
• The new class of drugs are effective in treating treatment experienced patients and are also used as salvaging protocol