C H A P T E R 1 0
Antiviral agents
141
CCR5
coreceptor antagonist
In 2007, another new class of drugs was introduced for
the treatment of HIV. Maraviroc (
Celsentri
) is a CCR5
coreceptor antagonist. It blocks the receptor site to
which the HIV virus needs to interact to enter the cell. It
is indicated for the treatment of HIV in adults as part of
combination therapy with other antiviral agents. Mara-
viroc is rapidly absorbed from the GI tract, metabolised
in the liver and excreted primarily through the faeces. It
has a half-life of 14 to 18 hours. Maraviroc should not
be used with known hypersensitivity to any component
of the drug or by breastfeeding women. Caution should
be used in the presence of liver disease or co-infection
with hepatitis B because of the risk of serious hepatic
toxicity. People at increased risk for cardiovascular
events or with hypotension should be monitored very
closely if this is the drug of choice for them. As with
other antiviral agents, it should be used in pregnancy
only if the benefit outweighs the potential risk to the
fetus.
Severe hepatotoxicity has been reported with this
drug, often preceded by a systemic allergic reaction
with eosinophilia and rash. Regular monitoring of liver
function should be routine when using this drug. CNS
effects including dizziness and changes in consciousness
have been reported; people experiencing these should
be cautioned to take measures to assure safety. People
may also be at increased risk of infections because of the
way the drug affects the cell membrane of the CD4 cells.
Appropriate precautions are necessary.
There is a risk of increased serum levels and
toxicity when combined with cytochrome P450 CYP3A
inhibitors (ketoconazole, lopinavir/ritonavir, ritonavir,
saquinavir, atazanavir), and the maraviroc dose should
be adjusted accordingly. Decreased serum levels and
loss of effectiveness may occur if maraviroc is combined
with CYP3A inducers (rifampicin, efavirenz), and the
maraviroc dose should be adjusted accordingly. Individ-
uals should not use St John’s wort while on this drug
because there is a loss of antiviral effects when the two
are combined.
I
ntegrase
inhibitor
In late 2007, another class of drugs—integrase inhibi-
tors—was introduced to treat HIV infection. The drug
raltegravir (
Isentress
) belongs to this class. Raltegravir
inhibits the activity of the virus-specific enzyme inte-
grase, an encoded enzyme needed for viral replication.
Blocking this enzyme prevents the formation of the
HIV-1 provirus and leads to a decrease in viral load
and increase in active CD4 cells. It is reserved for use in
people who have been treated with other antiviral agents
and have evidence of a return to viral replication.
Raltegravir is rapidly absorbed from the GI tract
and metabolised in the liver. It has a half-life of 3 hours
and is excreted primarily in the faeces.
Raltegravir is contraindicated with known hyper-
sensitivity to any component of the drug, as initial
treatment in adults, for use in children and for breast-
feeding women. Caution should be used if the person is
at risk for rhabdomyolysis or myopathy and during preg-
nancy. People taking this drug must be very careful to
Prototype summary: Maraviroc
Indications:
Combination antiretroviral treatment
of adults infected with CCR5-tropic HIV-1 who
have evidence of viral replication and HIV-1 strains
resistant to multiple antiretroviral agents.
Actions:
Selectively binds to the human chemokine
receptor CCR5 on the cell membrane, preventing
interaction of HIV-1 and CCR5, which is necessary
for the HIV to enter the cell; HIV cannot enter the
cell and cannot multiply.
Pharmacokinetics:
Route
Onset
Peak
Oral
Slow
0.5–4 hours
T
1/2
:
14 to 28 hours; metabolised in the liver,
excreted in the faeces and urine.
Adverse effects:
Dizziness, paraesthesias, nausea,
vomiting, diarrhoea, cough, URI, fever,
musculoskeletal symptoms, hepatotoxicity.
Prototype summary: Raltegravir
Indications:
In combination with other antiviral
agents for the treatment of HIV-1 infection in
treatment-experienced adults who have evidence
of viral replication and HIV-1 strains resistant to
multiple antiretroviral agents.
Actions:
Inhibits the activity of the virus-specific
enzyme integrase, an encoded enzyme needed for
viral replication. Blocking this enzyme prevents
the formation of the HIV-1 provirus and leads to
a decrease in viral load and an increase in active
CD4 cells.
Pharmacokinetics:
Route
Onset
Peak
Oral
Rapid
3 hours
T
1/2
:
9 hours; metabolised in the liver, excreted in
the faeces and urine.
Adverse effects:
Headache, dizziness, nausea,
vomiting, diarrhoea, fever, rhabdomyolysis.
