C H A P T E R 1 0
Antiviral agents
135
Loss of T cell function causes
acquired immune
deficiency syndrome (AIDS)
and
AIDS-related complex
(ARC)
, diseases that are characterised by the emergence
of a variety of opportunistic infections and cancers that
occur when the immune system is depressed and unable to
function properly. The HIV mutates over time, presenting
a slightly different configuration with each new genera-
tion. Treatment of AIDS and ARC has been difficult for
two reasons: (1) the length of time the virus can remain
dormant within the T cells (i.e. months to years), and
(2) the adverse effects of many potent drugs, which may
include further depression of the immune system. A com-
bination of several different antiviral drugs is used to
attack the virus at various points in its life cycle to achieve
maximum effectiveness with the least amount of toxicity.
The types of antiviral agents that are used to treat HIV
infections are the non-nucleoside and nucleoside reverse
transcriptase inhibitors, the protease inhibitors and three
newer classes of drugs—the
fusion inhibitors
,
CCR5
coreceptor antagonists
, and
integrase inhibitors
(Table
10.3). Collectively, these drugs are known as antiretrovi-
ral agents. The HIV virus poses a serious health risk. The
person and the family of the person diagnosed with HIV
infection will need tremendous support and teaching to
cope with the disease and its treatment. See Box 10.3 for
public education information regarding AIDS.
N
on
-
nucleoside reverse transcriptase
inhibitors
The non-nucleoside reverse transcriptase inhibitors have
direct effects on the HIV virus activities within the
cell. The non-nucleoside reverse transcriptase inhibi-
tors available include efavirenz (
Stocrin
) and nevirapine
(
Viramune
).
Therapeutic actions and indications
The
non-nucleoside reverse transcriptase inhibitors
bind
directly to HIV reverse transcriptase, blocking both
RNA and DNA-dependent DNA polymerase activities.
They prevent the transfer of information that would
allow the virus to carry on the formation of viral DNA.
As a result, the virus is unable to take over the cell and
reproduce. These antiviral agents are indicated for the
treatment of people with documented AIDS or ARC
who have decreased numbers of T cells and evidence of
increased opportunistic infections in combination with
other antiviral drugs (see Table 10.3).
Pharmacokinetics
Efavirenz is absorbed rapidly from the GI tract,
reaching peak levels in 3 to 5 hours. Efavirenz is
metabolised in the liver by the cytochrome P450 system
and is excreted in the urine and faeces with a half-life
of 52 to 76 hours.
Nevirapine is recommended for use in adults and
children older than 2 months. After rapid GI absorption
with a peak effect occurring at 4 hours, nevirapine is
metabolised by the cytochrome P450 system in the liver.
Excretion is through the urine with a half-life of 45 hours.
Contraindications and cautions
There are no adequate studies of non-nucleoside reverse
transcriptase inhibitors in pregnancy, so use should
be limited to situations in which the benefits clearly
outweigh any risks.
Adverse effects
The adverse effects most commonly experienced with
these drugs are GI related—dry mouth, constipation
or diarrhoea, nausea, abdominal pain and dyspepsia.
Dizziness, blurred vision and headache have also been
reported. A flu-like syndrome of fever, muscle aches and
pains, fatigue and loss of appetite often occurs with the
anti-HIV drugs, but these signs and symptoms may also
be related to the underlying disease.
Clinically important drug–drug interactions
There is a risk of serious adverse effects if efavirenz is
combined with midazolam, rifabutin, triazolam or ergot
derivatives; these combinations should be avoided. There
may be a lack of effectiveness if nevirapine is combined
with hormonal contraceptives or protease inhibitors.
St John’s wort should not be used with these drugs;
a decrease in antiviral effects can occur.
Prototype summary: Nevirapine
Indications:
Treatment of HIV-1–infected people
who have experienced clinical or immunological
deterioration, in combination with other
antiretrovirals.
Actions:
Binds to HIV-1 reverse transcriptase and
blocks replication of the HIV by changing the
structure of the HIV enzyme.
Pharmacokinetics:
Route
Onset
Peak
Oral
Rapid
4 hours
T
1/2
:
45 hours, then 25 to 30 hours; metabolised in
the liver and excreted in the urine.
Adverse effects:
Headache, nausea, vomiting,
diarrhoea, rash, liver dysfunction, chills, fever.
N
ucleoside reverse transcriptase
inhibitors
The
nucleoside reverse transcriptase inhibitors
(Table 10.3) were the first class of drugs developed to
