Chapter 40 Antiretrovirals
didanosine and zalcitabine
Additive or synergistic effect against HIV
Purpose of Antiretroviral Therapy
All antiretroviral drugs have similar therapeutic effects in that they reduce the viral load. A viral load of less than 50 copies/mL is considered to be an undetectable viral load and is a primary goal of antiretroviral therapy.
ganciclovir and ribavirin
Antagonize the antiviral action of zidovudine
Classification
Antiretroviral Drugs
Contraindications
Because of the potentially fatal outcome of HIV infection, the only usual contraindication to a given medication is known severe drug allergy or other intolerable toxicity. Most of the current antiretroviral drug classes have several alternative drugs to choose from, if a patient is especially intolerant of a given drug.
Mechanism of Action
CCR5 antagonists, work by selectively and reversibly binding to the type 5 chemokine co-receptors located on the CD4 cells that are used by the HIV virion to gain entry to the cells.
Drugs metabolized by the CYP3A4 hepatic microsomal enzyme system (azole antifungals, clarithromycin, doxycycline, erythromycin, isoniazid, nefazodone, nicardipine, protease inhibitors, quinidine, statins, telithromycin, and verapamil)
Competition for metabolism resulting in elevated blood levels and potential toxicity Increased plasma concentrations of rifabutin and ketoconazole Increased metabolism of indinavir
rifampin and rifabutin
Decreased nevirapine serum concentration
Oral contraceptives
Decreased plasma concentrations of oral contraceptives
Protease inhibitors
Decreased plasma concentrations of protease inhibitors
Treatment
Despite the effectiveness of HAART, prescribers may still need to alter a given patient's drug regimen in cases of major drug intolerance (see Adverse Effects) or drug resistance. A given patient's HIV strain can still evolve and mutate over time, which allows it to become resistant to any drug therapy, especially when that therapy is used for a prolonged period of time.
Sub classifications
Entry Inhibitor-CCR5 Coreceptor Antagonist (Also Known as CCR5 Kntagonist)
Sub classifications
Fusion Inhibitor
Adverse Effects
HAART treatment is strongly correlated with increased mortality from HCV-induced liver disease, because the anti-HIV drugs produce strain on the liver as these drugs are metabolized via the liver. A major adverse effect of protease inhibitors is lipid abnormalities, including lipodystrophy, or redistribution of fat stores under the skin. This condition often results in cosmetically undesirable outcomes for the patient, such as a "hump" at the posterior base of the neck and also a skeletonized (bony) appearance of the face. In addition, dyslipidemias such as hypertriglyceridemia can occur, and insulin resistance and type 2 diabetes symptoms can result. The increase in long-term antiretroviral drug therapy due to prolonged disease survival has led to the emergence of another long-term adverse effect associated with these medications— bone demineralization and possible osteoporosis.
Drugs metabolized by the CYP3A4 hepatic microsomal enzyme system (see indinavir)
Increased metabolism of these drugs
acyclovir
Increased neurotoxicity
Cytotoxic drugs
Increased risk for hematologic toxicity
Protease inhibitors
Increased serum concentrations of tenofovir
interferon beta
Increased serum levels of zidovudine
Sub classifications
Integrase Strand Transfer Inhibitor
CYP3A4 inducers (phenytoin, carbamazepine, rifampin)
May decrease effects of maraviroc
St. John's wort
May decrease effects of maraviroc
rifampin
May decrease effects of raltegravir
atazanavir (with or without ritonavir)
May increase effects of raltegravir
CYP3A4 inhibitors (see indinavir)
May increase maraviroc toxicity
acyclovir, cidofovir, ganciclovir, valacyclovir
May increase serum concentrations of tenofovir
Sub classifications
Nonnucleoside Reverse Transcriptase Inhibitors and Nucleoside Reverse Transcriptase Inhibitors
Sub classifications
Protease Inhibitors
Quick Info
Single-drug therapy was most common in the early years of the HIV epidemic, partly due to a lack of treatment options. However, both the development of multiple antiretroviral drugs and the emergence of resistant viral strains have given rise to combination drug therapy as the current standard of care.
Indications
The only usual indication for all of the current antiretroviral drugs is active HIV infection. Prophylactic therapy is also given to individuals such as health care workers and high-risk infants with a known potential exposure to HIV
Mechanism of Action
This compound works by inhibiting viral fusion. This is the process by which an HIV virion attaches to (fuses with) the membrane of a host cell (T lymphocyte) before infecting it in preparation for viral replication.
Interactions
indinavir
Mechanism of Action
integrase inhibitors work by inhibiting the catalytic activity of the enzyme integrase thus preventing integration of the proviral gene into human DNA
Interactions
maraviroc
Interactions
nevirapine
Mechanism of Action
protease inhibitors work by inhibiting the protease retroviral enzyme. This enzyme promotes the breakup of chains of protein molecules at designated points, a process necessary for viral replication.
Interactions
raltegravir
Most effective treatment of AIDS
referred to as highly active antiretroviral therapy (HAART). HAART usually includes at least three medications. The most commonly recommended drug combinations include two or three NRTIs; two NRTIs plus one or two protease inhibitors; or an NRTI plus an NNRTI with one or two protease inhibitors.
Mechanism of Action
reverse transcriptase inhibitors work by blocking activity of the enzyme reverse transcriptase. Reverse transcriptase promotes the synthesis of new viral DNA molecules from the RNA genome.
Interactions
tenofovir
Interactions
zidovudine