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