C H A P T E R 1 0
Antiviral agents
139
non-nucleoside antivirals; these combinations are often
used, and the person needs to be monitored very closely.
There have been reports of severe drowsiness and
lethargy if zidovudine is combined with cyclosporin;
warn the person to take appropriate safety precautions.
P
rotease
inhibitors
The
protease inhibitors
block protease activity within
the HIV virus. The protease inhibitors that are avail-
able for use include atazanavir (
Reyataz
), darunavir
(
Prezista
), fosamprenavir (
Telzir
), indinavir (
Crixivan
),
lopinavir (
Kaletra
), ritonavir (
Norvir
), saquinavir
(
Invirase
) and tipranavir (
Aptivus
).
Therapeutic actions and indications
Protease is essential for the maturation of an infectious
virus; without it, an HIV particle is immature and non-
infective, unable to fuse with and inject itself into a cell.
All of these drugs are used as part of combination therapy
for the treatment of HIV infection (see Table 10.3).
Pharmacokinetics
Atazanavir is rapidly absorbed from the GI tract and
can be taken with food. After metabolism in the liver,
it is excreted in the urine and faeces with a half-life of
6.5 to 7.9 hours. It is not recommended for people with
severe hepatic impairment; for those with moderate
hepatic impairment, the dose should be reduced.
Fosamprenavir is rapidly absorbed after oral admini
stration, reaching peak levels in 1.5 to 4 hours. It is
metabolised in the liver and excreted in urine and faeces.
Indinavir is rapidly absorbed from the GI tract,
reaching peak levels in 0.8 hour. Indinavir is metabo-
lised in the liver by the cytochrome P450 system. It is
excreted in the urine with a half-life of 1.8 hours. People
with hepatic or renal impairment are at risk for increased
toxic effects, necessitating a reduction in dose.
Lopinavir is used as a fixed combination drug that
combines lopinavir and ritonavir. The ritonavir inhibits
the metabolism of lopinavir, leading to increased lopina-
vir serum levels and effectiveness. It is readily absorbed
from the GI tract, reaching peak levels in 3 to 4 hours,
and undergoes extensive hepatic metabolism by the
cytochrome P450 system. Lopinavir is excreted in urine
and faeces.
Tipranavir is used for the treatment of HIV infec-
tion in adults in combination with 200 mg of ritonavir.
It is taken orally with food, two 250-mg capsules each
day with the ritonavir. It is slowly absorbed, reaching
peak levels in 2.9 hours. It is metabolised in the liver
with a half-life of 4.8 to 6 hours; excretion is through
urine and faeces.
Ritonavir is rapidly absorbed from the GI tract,
reaching peak levels in 2 to 4 hours. Ritonavir undergoes
extensive metabolism in the liver and is excreted in
faeces and urine.
Saquinavir is slowly absorbed from the GI tract
and is metabolised in the liver by the cytochrome P450
mediator, so it must be used cautiously in the presence of
hepatic dysfunction. It is primarily excreted in the faeces
with a short half-life.
Because therapy for HIV infection involves the use
of several different antiviral drugs, many are now avail-
able as combination drugs, which reduces the number of
tablets a person has to take each day. Box 10.4 discusses
combination drugs.
Contraindications and cautions
Of the protease inhibitors listed, saquinavir is the
only agent that has not been shown to be teratogenic;
however, its use during pregnancy should be limited.
Saquinavir crosses into breast milk, and women are
advised not to breastfeed while taking this drug. For the
People who are taking combination drug therapy for
HIV infection may have to take a very large number
of pills each day. Keeping track of these pills and
swallowing such a large number each day can be an
overwhelming task. In an effort to improve compliance
and make it easier for some of these people, some anti-
HIV agents are now available in combination products.
Combivir
is a combination of 150 mg lamivudine
and 300 mg zidovudine. The person takes one tablet
twice a day. Because this is a fixed combination drug, it
is not the drug of choice for people who require a dose
reduction owing to renal impairment or adverse effects
that limit dose tolerance.
Trizivir
combines 300 mg abacavir, 150 mg
lamivudine and 300 mg zidovudine. The person
takes one tablet twice a day. Because this is a fixed
combination drug, it is not the drug of choice for people
who require a dose reduction owing to renal impairment
or adverse effects that limit dose tolerance. People taking
Trizivir
should be warned at the time the prescription
is filled about the potentially serious hypersensitivity
reactions associated with abacavir and should be given a
written list of warning signs to watch for.
In 2005, a new combination product was approved
to make compliance with an HIV drug regimen easier.
Truvada
(200 mg emtricitabine with 300 mg tenofovir)
is a once-a-day tablet. People should be stabilised on
each antiviral individually before being switched to the
combination form.
The year 2009 saw another combination product,
Atripla
—600 mg efavirenz, 200 mg emtricitabine
and 300 mg tenofovir—which is recommended for
people 18 years of age and older who have already been
stabilised on each antiviral individually.
■■
BOX 10.4
Fixed combination drugs for treatment
of HIV infection
