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Human immunodeficiency virus (HIV) strikes the immune system,
specifically targeting CD4 T lymphocytes. Depletion of CD4 cells
ultimately leads to profound immunosuppression. Acquired immune
deficiency syndrome (AIDS) is symptomatic disease, characterized
by the development of a wide spectrum of opportunistic infections
and malignancies either acquired or reactivated as a result of the
immunosuppression caused by HIV. Worldwide, HIV/AIDS is
a global health problem, affecting over 40 million people, with
over 70% of infected individuals living in sub-Saharan
Africa. In the United States, it is estimated that 1 million people
are currently living with HIV/AIDS. While primary routes
of infection in developed countries include male homosexual intercourse
and intravenous drug use, primary routes of infection in developing
countries include heterosexual contact and vertical transmission
from mother to child.
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To understand the drugs used in the treatment of HIV, the life
cycle of HIV must be briefly examined (Figure 28–3). HIV
is a retrovirus, meaning that it
is an enveloped virus with a single-stranded RNA, not DNA, genome.
Before HIV can enter CD4 cells, viral glycoproteins in the envelope
bind to CD4 and chemokine receptors. Next, the virus fuses with
the host cell membrane and uncoats as it enters the host cell. After uncoating,
viral replication depends on the viral reverse
transcriptase enzyme, which
transcribes the viral genome from RNA into DNA. This newly formed
double-stranded DNA is integrated into the human host’s
genome by an integrase enzyme. Integrated viral DNA is then transcribed
by a host polymerase enzyme into
messenger RNA, which is translated into proteins that assemble into
immature noninfectious virions that bud from the host cell membrane.
Proteolytic cleavage allows maturation into fully infectious virions.
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As we mark the completion of the first 25 years of the HIV/AIDS
epidemic, there is no cure for HIV infection or AIDS. However, pharmacologic
therapy can dramatically improve the length and quality of life
for infected individuals, and can delay the onset of AIDS. Without
pharmacologic treatment, most patients die within a few years after
the onset of symptoms. Currently, the standard of care in treating
HIV infection involves initiating highly active antiretroviral therapy (HAART) that
requires three to four antiretroviral drugs. If possible, HAART
is initiated before symptoms appear. The goal of combination regimens
is to inhibit or stop viral replication at a number of different
steps (Figure 28–3). Compared with the administration of
a single antiretroviral agent, combination therapy increases the
efficacy of drug therapy, decreases the risk of developing drug
resistance, and reduces viral load. Six classes of antiretroviral
agents are currently available: nucleoside reverse transcriptase
inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors
(NNRTIs), protease inhibitors (PIs), a fusion inhibitor, an integrase
inhibitor, and an entry receptor blocker (Table 28–2).
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Drug combinations are tailored to each patient depending on many
variables, including potency and susceptibility, patient tolerance,
convenience, and adherence to drug regimen. With the exception of
the fusion inhibitor, the anti-HIV agents are all available as oral
formulations. Drug management of HIV/AIDS is subject to
change as newer agents become available. New pharmacotherapies are
being sought that offer the advantages of once-daily dosing, smaller
pill size, lower incidence of adverse effects, new viral targets,
and activity against virus that is resistant to other agents.
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Nucleoside Reverse
Transcriptase Inhibitors
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The NRTIs were the first group of drugs used to treat HIV infection.
NRTIs selectively inhibit the HIV viral reverse transcriptase (Figure
28–3). The reverse transcriptase incorporates the phosphorylated
NRTI (instead of a natural nucleotide) into the growing DNA chain,
thus preventing complete conversion of viral RNA into DNA. If used
as single agents to treat HIV, resistance emerges rapidly. However,
resistance is rare in combination regimens. The NRTIs include zidovudine, didanosine, zalcitabine, lamivudine,
stavudine, and abacavir. Details
about each of these drugs follow.
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Severe toxic effects are associated with most NRTIs, with the
exception of lamivudine (3TC). All of the NRTIs have the potential
to cause a rare, but serious, lactic acidosis and severe hepatic
steatosis, likely due to mitochondrial damage in liver cells. Risk
factors include obesity, prolonged treatment with NRTIs, and preexisting
liver dysfunction. Symptoms include severe nausea, vomiting, and
persistent abdominal pain. NRTI administration will often be suspended
in these cases.
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Zidovudine (ZDV), formerly called
azidothymidine, or AZT, was the first antiretroviral drug approved
for HIV treatment. Zidovudine is still frequently used in combination
drug regimens. It is also used in prophylaxis against HIV infection
through accidental needle sticks and via vertical transmission from
mother to fetus. Zidovudine is active orally and is distributed
to most tissues, including the CNS. The primary adverse effect is
myelosuppression, which may be severe enough to require transfusions.
Gastrointestinal distress, headaches, myalgia, agitation, and insomnia
may also occur, but tend to decrease or resolve during therapy.
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Didanosine (ddI) should be taken
on an empty stomach to maximize bioavailability. The major clinical
toxicity of didanosine (and to a lesser extent zalcitabine and stavudine)
is dose-dependent pancreatitis. This occurs more frequently in alcoholic
patients and those with hypertriglyceridemia. Other adverse effects
include painful peripheral distal neuropathy, diarrhea, and CNS
toxicity (headache, irritability, insomnia). Patients on didanosine
also must have frequent retinal examinations because of reports
of retinal changes and optic neuritis.
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Zalcitabine (ddC) has relatively
high oral bioavailability, but plasma levels decrease significantly
when the drug is taken with food or antacids. The major adverse
effect is peripheral neuropathy, which can be treatment limiting
in 10 to 20% of patients. The neuropathy appears to be
slowly reversible if treatment is discontinued promptly. Other major
toxicities include oral and esophageal ulcerations and pancreatitis.
Headache, arthralgias, myalgias, nausea, and rash may occur, but
tend to resolve during therapy.
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Unlike didanosine and zalcitabine, the bioavailability of lamivudine (3TC) is high and not food-dependent.
It is commonly used as a component in HAART, as well as in the treatment
of hepatitis B infections (see discussion below). Lamivudine is
one of the best-tolerated NRTIs. Potential adverse effects are generally
mild and include headache, fatigue, and gastrointestinal discomfort.
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Stavudine (d4T) also has good oral
bioavailability that is not food dependent. The major adverse effect
of stavudine is dose-related peripheral sensory neuropathy. The
incidence of these symptoms increases with coadministration of other
neuropathy-inducing NRTIs such as didanosine and zalcitabine. Symptoms
usually resolve completely if stavudine is discontinued. Other potential adverse
effects include pancreatitis and arthralgias. As discussed above,
all NRTIs have the potential to cause lactic acidosis with hepatic
steatosis. However, these toxicities tend to occur more frequently
in patients receiving stavudine than in those receiving other NRTIs.
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Abacavir has good oral bioavailability
that is unaffected by food. In a small percentage of patients taking abacavir,
potentially fatal hypersensitivity reactions can occur. Symptoms
usually occur in the first 6 weeks of therapy and include fever,
malaise, vomiting, diarrhea, and anorexia.
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Tenofovir (a nucleotide) inhibits
the HIV reverse transcriptase and becomes incorporated into the
DNA, causing chain termination. Its bioavailability increases after
ingestion of a high-fat meal, so patients are advised to ingest
tenofovir with a meal. Gastrointestinal irritation is the most common adverse
effect, but this rarely requires discontinuation of therapy.
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Nonnucleoside
Reverse Transcriptase Inhibitors
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The NNRTIs interrupt transcription of viral RNA into DNA by a
different mechanism than the NRTIs. The NNRTIs bind directly to
the viral reverse transcriptase (Figure 28–3), change the shape
of the enzyme, and inhibit DNA synthesis. Thus, unlike the NRTIs,
which become incorporated into the viral DNA, NNRTI agents inactivate
the reverse transcriptase to prevent DNA formation. Like the NRTIs,
resistance can occur rapidly if these drugs are used as monotherapy.
As a class, adverse effects associated with NNRTI administration
include varying levels of gastrointestinal distress and skin rashes.
NNRTI agents are metabolized by the cytochrome P450 (CYP450) system, which increases
the likelihood of drug-drug adverse interactions. Drugs in the NNRTI
class include nevirapine, delavirdine, and efavirenz.
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Oral bioavailability of nevirapine is good, and is not affected
by food intake. Nevirapine is typically used as a component in HAART.
It is also used prophylactically as a single dose to HIV-infected
mothers at the onset of labor and to the neonate. Nevirapine can
cause severe hypersensitivity reactions such as Stevens-Johnson
syndrome and a life-threatening toxic epidermal necrolysis.
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Delavirdine’s oral bioavailability
is good, but it is reduced by antacids. Delavirdine causes rash
in about 20% of patients, although the rash is not life-threatening.
Other adverse effects include headache, nausea, fatigue, and diarrhea.
Because it has been shown to cause birth defects in animals, women
should take precautions against pregnancy while taking delavirdine.
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Efavirenz is generally used in
combination with two NRTIs. The bioavailability of efavirenz increases
after a high-fat meal. Adverse effects include CNS dysfunction (dizziness,
drowsiness, headache, confusion, agitation, delusions, nightmares),
skin rash, and increases in plasma cholesterol. Dosing at bedtime
may be helpful for decreasing perception of some of the CNS effects.
Pregnancy should also be avoided in women taking efavirenz because
of fetal abnormalities observed in animals.
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Assembly of infectious HIV virions depends on HIV-1 protease
(Figure 28–3). Protease inhibitors (PIs) result in production
of immature, noninfectious virions. As a class, the PIs in HAART drug combinations lead to the development of carbohydrate and lipid
metabolic dysregulation. This syndrome includes hyperglycemia, insulin
resistance, and hyperlipidemia. A lipodystrophy, or selective redistribution
of fat, also occurs. Thus, patients may acquire a cushingoid appearance: buffalo
hump, gynecomastia, abdominal obesity, and peripheral wasting. Incidence
of the syndrome is about 30 to 50% of those patients on
a HAART regimen containing PIs, with a median onset time of about
1 year after onset of treatment. Owing to these side effects, AIDS
patients receiving PIs within a HAART regimen often receive counseling
about heart disease as a new complication. Like the NNRTI agents,
PIs are metabolized by the CYP450 system, increasing the likelihood
of drug-drug adverse interactions. Six PIs are available for HIV
treatment, and these are used in combinations with NRTIs and NNRTIs.
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Indinavir must be taken on an empty
stomach for maximal absorption. To avoid renal damage (nephrolithiasis),
patients should consume at least 48 oz of water daily. Other adverse
effects include nausea, diarrhea, and thrombocytopenia.
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Bioavailability of ritonavir increases
when given with food. The most common adverse effects are gastrointestinal
disturbances, paresthesias (peripheral and circumoral), altered
(bitter) taste, and hypertriglyceridemia. During the first weeks
of therapy, nausea, vomiting, and abdominal pain usually occur and patients
should be warned to expect these symptoms.
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Saquinavir should be taken with
food to improve its bioavailability and to decrease gastrointestinal
distress. Other adverse effects include rhinitis, headache, and
neutropenia.
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Nelfinavir has higher absorption
when taken with food. Its primary adverse effect is dose-limiting
diarrhea, although this symptom often responds to antidiarrheal
medications.
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Amprenavir is rapidly absorbed
from the gastrointestinal tract, and it can be taken with or without
food; however, high-fat meals may decrease absorption and should
be avoided. Common side effects are gastrointestinal distress, perioral
paresthesias, depression, and rash. In a small percentage of cases,
amprenavir has caused life-threatening rashes, including Stevens-Johnson
syndrome, severe enough for the drug to be discontinued.
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Lopinavir is often administered
with ritonavir because of enhanced efficacy and improved tolerability. Absorption
is enhanced with food. Adverse effects include nausea, vomiting,
diarrhea, pancreatitis, and asthenia (decrease in strength).
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Enfuvirtide represents a new class
of antiretroviral agents. The drug binds to a portion of the viral
envelope and prevents conformational changes required for fusion
of the viral and human cellular membranes (Figure 28–3).
Unlike other anti-HIV drugs, enfuvirtide is not available in oral
formulations. It is administered subcutaneously in combination with
other antiretrovirals in treatment-experienced patients with persistent
HIV-1 replication despite current therapy. Injection site reactions
and hypersensitivity may occur.
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Raltegravir is an inhibitor of
viral integrase, the enzyme required for integration of the viral
DNA with that of the host. Block of this step (Figure 28–3)
prevents replication of the viral genome. The drug is active by
the oral route and is not affected by food. The drug is well tolerated
but headache and gastrointestinal disturbances have been reported.
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HIV Entry Receptor
Blocker
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Maraviroc combines with a chemokine
receptor on lymphocytes and prevents the binding of HIV to cell-surface
receptors, a step required for entry into host cells (Figure 28–3).
It is orally active and always used with other anti-HIV drugs. Toxicity
includes hypersensitivity reactions and hepatotoxicity.