HAART

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  • Antiretroviral drugs
    • nucleoside reverse transcriptase inhibitors (NRTIs)
      • act by competitively inhibiting HIV-encoded RNA-dependent DNA polymerase (reverse transcriptase)
      • cause chain termination that decreases viral DNA synthesis and virus replication.
      • They prevent infection but do not clear cells already infected.
      • must first undergo intracellular phosphorylation to be active.
      • Zidovudine(AZT)
        • a pyrimidine analogue
        • adverse effects of zidovudine,
          • headache, diarrhea, and fever
          • dose-limiting toxicitiesare granulocytopenia and anemia.
        • reduces the rate of progression of HIV.
        • When given to pregnant women starting in the second trimester, then during labor, and then to the newborn, the vertical transmission of HIV is reduced by up to 25%.
        • This agent is also used for postexposure prophylaxis.
      • Didanosine(ddI)
        • Purine analogue
        • Requires administration on an empty stomach.
        • Dose limiting toxicities
          • Pancreatitis
          • sensory peripheral neuropathy
          • optic neuritis.
      • Stavudine
        • thymidine nucleoside analogue
        • Except for acid lability, stavudine, a, is similar to didanosinein pharmacokinetics, therapeutic use, and adverse effects that typically resolved with discontinuation.
      • Zalcitabine(ddC)
        • also cause chain termination of viral DNA elongation.
        • Reversible peripheral neuropathymay limit the use of this agent in 30% of patients.
      • Lamivudine(3TC),emtricitabine ,abacavir(ABC)
        • Lamivudine
          • a cytosine analogue
          • Side effects include headache and GI upset
        • Emtricitabine
          • a fluorinated analog of lamivudine with a long half-life
          • allows for once-daily dosing.
        • Abacavir
          • a guanosine analogue
          • Occasional fatal hypersensitivity reactions
        • Tenofovir (TDF)
          • an analogue of adenosine
          • This agent is more convenient than older antiretroviral agents in that it has a once-daily dosing schedule.
          • Most common side effects are GI.
    • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
      • NNRTIs act similarly to NRTIs
      • These agents do not require phosphorylationfor their activity
      • Nevirapine (NVP)
        • Nevirapine is used in combination regimens
        • It has also recently been shown to reduce vertical transmission of HIV from mother to newborn when used as monotherapy (MCQ)
        • Adverse effects
          • Steven-Johnson syndrometoxic epidermal necrolysis
          • hepatotoxicity.
        • Drug interactions
          • Concurrent use of nevirapine and ketoconazole
            • increase plasma levels of the nevirapine, while decreasing levels of the ketoconazole due to nevirapine induces CYP3A
          • The levels of the drug are reduced when coadministered with rifampin.
      • Delavirdine(DLV),Efavirenz(EFV)
        • Delavirdine
          • Side effects ofDLVinclude rash and GI upset
          • drug is metabolized by CYP3A system.
          • Drug interaction should be monitored.
        • Efavirenz(EFV)
          • dosed once daily
          • is also metabolized by CYP3A
          • Main side effects of this agent are dizziness, insomnia, confusion, amnesia, nightmares, and other CNS effects (MCQ)
          • These are observed in up to 50% of patients and usually abate with time.

2

    • HIV-1 protease inhibitors
      • competitively inhibit viral-induced Gag-Pol polyprotein cleavage by HIV-1 protease, a step necessary for virion maturation
      • leads to clearance of the immature virion.
      • used in combination with nucleoside analogues to delay and possibly
      • reverse the clinical progression of AIDS.
      • frequently associated with development of lipodystrophy  (MCQ)
      • have significant drug interactions due to inhibition of CYP3A4.
      • Resistance due to changes in the protease gene has been described
      • Resistance is more common when
        • patients are noncompliant
        • patients take drug ‘‘holidays’’
        • when inhibitors are used as monotherapy
        • given at subtherapeutic doses.
      • Saquinavir
        • bioavailability of this agent is reduced by other drugs that increase liver microsomal enzyme activity
        • it is increased by drugs that inhibit enzyme activity.
        • Saquinavir is well tolerated,
        • because of its limited bioavailabilitydue to extensive first-pass metabolism, it has only a modest effect
        • For greater efficacy, it is often co-administered with ritonavir, a protease inhibitor
        • The most common adverse effects include GI disturbances and rash.
      • Ritonavir
        • Close monitoring of other agents patients are using is recommended.
        • Ritonavir is extensively inhibits many liver cytochrome P 450 enzymes
        • leading to accumulation of many drugs that are metabolized by this system (including saquinavir).
        • It also induces some forms of cytochrome P-450 enzymes, leading to reduced bioavailability of other drugs.
        • adverse effect profile
          • moderate GI disturbances, headache, fatigue
          • taste disturbances, and perioral paresthesia.
      • Lopinavir–ritonavir
        • combination is shown to enhance efficacy of both drugs while reducing toxicity.
      • Indinavir
        • Like ritonavir, it interferes with liver microsomal enzyme metabolism, but not to the same extent, and it inhibits the metabolism of some drugs and vice versa.
        • Indinavir is well tolerated
        • Mild GI symptoms
        • reversible nephrolithiasiscan develop  (MCQ)
          • due to precipitation in the renal collecting duct system
          • can be prevented with attention to hydration
        • Indirect hyperbilirubinemiais also common. (MCQ)
      • Nelfinavir,Amprenavir,Fosamprenavir
        • These agents exhibit drug interactions similar to those of indinavir.
        • Moderate diarrhea and fatigue have been reported.
        • Amprenavirmay cause severe rashes
          • it is usually coadministered with ritonavir.
        • Fosamprenavir
          • a prodrug of amprenavir
          • allows for reduced daily dosing.
      • Atazanavir
        • Common adverse effects GI disturbances and indirect hyperbilirubinemia with jaundice.
        • Atazanavir, like other PIs, inhibits CYP3A4 and CYP 2C9with a great likelihood of drug– drug interactions.
      • Tipranavir
        • bioavailability is increased with a high-fat meal (MCQ)
        • undergoes extensive first-pass metabolism
        • therefore, is co-administered with ritonavir.
        • Its most common adverse effects are GI disturbances and rash(it contains a sulfonamide moiety).
        • Its use is also associated with development of hepatic dysfunction (black box warning).
    • Anti-HIV agents—fusion inhibitors.
      • Enfuvirtide
        • blocks entry of virus into the cell by binding to viral gp41 glycoprotein
        • This drug is administered subcutaneously,
        • injection site reactions being the most common side effect.
        • It is used in combination therapies.
    • Highly active antiretroviral therapy (HAART)
      • usually 3–4 agents from several different classes, that are used in treatment of HIV/AIDS to prevent development of resistance.

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