Lippincott Chapter 45: Antiviral Drugs

Question 1

FOR RESPIRATORY VIRUS INFECTIONS

Answer 1

Amantadine SYMMETREL
Oseltamivir TAMIFLU
Ribavirin COPEGUS, REBETOL, RIBAPAK,
RIBASPHERE, VIRAZOLE
Rimantadine FLUMADINE
Zanamivir RELENZA

Question 2

FOR HEPATIC VIRAL INFECTIONS

Answer 2

Adefovir HEPSERA
Boceprevir VICTRELIS
Interferon INTRON, AVONEX
Lamivudine EPIVIR-HBV
Telbivudine TYZEKA
Tenofovir VIREAD

Question 3

FOR HERPESVIRUS
AND CYTOMEGALOVIRUS INFECTIONS

Answer 3

Acyclovir ZOVIRAX
Cidofovir VISTIDE
Famciclovir FAMVIR
Triuridine VIROPTIC
Foscarnet FOSCAVIR
Ganciclovir CYTOVENE
Penciclovir DENAVIR
Valacyclovir VALTREX
Valganciclovir VALCYTE

Question 4

FOR HIV: NUCLEOSIDE AND NUCLEOTIDE
REVERSE TRANSCRIPTASE INHIBITORS

Answer 4

Abacavir ZIAGEN
Didanosine VIDEX
Emtricitabine EMTRIVA
Lamivudine EPIVIR
Stavudine ZERIT
Tenofovir VIREAD
Zidovudine RETROVIR

Question 5

FOR HIV: NONNUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS

Answer 5

Delavirdine RESCRIPTOR
Efavirenz SUSTIVA
Etravirine INTELENCE
Rilpivirine EDURANT

Question 6

FOR HIV: PROTEASE INHIBITORS

Answer 6

Atazanavir REYATAZ
Darunavir PREZISTA
Fosamprenavir LEXIVA
Indinavir CRIXIVAN
Lopinavir/ritonavir KALETRA
VIRACEPT
Ritonavir NORVIR
Saquinavir INVIRASE
Tipranavir APTIVUS
Nelfinavir VIRACEPT

Question 7

FOR HIV: ENTRY INHIBITORS

Answer 7

Enfuvirtide FUZEON
Maraviroc SELZENTRY

Question 8

FOR HIV: INTEGRASE INHIBITORS

Answer 8

Dolutegravir
Elvitegravir
Raltegravir

Question 9

FOR HIV: FIXED DOSE COMBINATIONS

Answer 9

Lamivudine + abacavir EPZICOM
Emtricitabine + tenofovir TRUVADA
Zidovudine + lamivudine COMBIVIR
Efavirenz + emtricitabine + tenofovir
Rilpivirine + tenofovir + emtricitabine
Zidovudine + lamivudine + abacavir
Elvitegravir + cobicistat + tenofovir +
emtricitabine STRIBILD

Question 10

A. Neuraminidase inhibitors.

Answer 10

A. Neuraminidase inhibitors
The neuraminidase inhibitors oseltamivir [os-el-TAM-i-veer] and
zanamivir [za-NA-mi-veer] are effective against both type A and type
B influenza viruses. They do not interfere with the immune response
to influenza vaccine. Administered prior to exposure, neuraminidase
inhibitors prevent infection and, when administered within 24 to 48
hours after the onset of symptoms, they modestly decrease the inten-
sity and duration of symptoms.
1. Mechanism of action: Influenza viruses employ a specific neur-
aminidase that is inserted into the host cell membrane for the pur-
pose of releasing newly formed virions. This enzyme is essential
for the virus life cycle. Oseltamivir and zanamivir selectively inhibit
neuraminidase, thereby preventing the release of new virions and
their spread from cell to cell.

2. Pharmacokinetics: Oseltamivir is an orally active prodrug that
   is rapidly hydrolyzed by the liver to its active form. Zanamivir is
   not active orally and is administered via inhalation. Both drugs are
   eliminated unchanged in the urine (Figure 45.2).
3. Adverse effects: The most common adverse effects of oselta-
   mivir are gastrointestinal (GI) discomfort and nausea, which can
   be alleviated by taking the drug with food. Irritation of the respira-
   tory tract occurs with zanamivir. It should be used with caution in
   individuals with asthma or chronic obstructive pulmonary disease,
   because bronchospasm may occur.
4. Resistance: Mutations of the neuraminidase enzyme have been
   identified in adults treated with either of the neuraminidase inhibi-
   tors. These mutants, however, are often less infective and virulent
   than the wild type.

Question 11

B. Adamantane antivirals

Answer 11

The therapeutic spectrum of the adamantane derivatives, amanta-
dine [a-MAN-ta-deen] and rimantadine [ri-MAN-ta-deen], is limited to
influenza A infections. Due to widespread resistance, the adaman-
tanes are not recommended in the United States for the treatment or
prophylaxis of influenza A.
1. Mechanism of action: Amantadine and rimantadine interfere with
the function of the viral M2 protein, possibly blocking uncoating of
the virus particle and preventing viral release within infected cells.
2. Pharmacokinetics: Both drugs are well absorbed after oral admin-
istration. Amantadine distributes throughout the body and readily
penetrates into the central nervous system (CNS), whereas riman-
tadine does not cross the blood–brain barrier to the same extent.
Amantadine is primarily excreted unchanged in the urine, and dos-
age reductions are needed in renal dysfunction. Rimantadine is
extensively metabolized by the liver, and both the metabolites and
the parent drug are eliminated by the kidney (Figure 45.3).
3. Adverse effects: Amantadine is mainly associated with CNS
adverse effects, such as insomnia, dizziness, and ataxia. More
serious adverse effects may include hallucinations and seizures.
Amantadine should be employed cautiously in patients with psy-
chiatric problems, cerebral atherosclerosis, renal impairment, or
epilepsy. Rimantadine causes fewer CNS reactions. Both drugs
cause GI intolerance. They should be used with caution in pregnant
and nursing mothers.
4. Resistance: Resistance can develop rapidly, and resistant strains
can be readily transmitted to close contacts. Resistance has been
shown to result from a change in one amino acid of the M2 matrix
protein. Cross-resistance occurs between the two drugs.

Question 12

Ribavirin

Answer 12

Ribavirin [rye-ba-VYE-rin], a synthetic guanosine analog, is effective
against a broad spectrum of RNA and DNA viruses. For example, riba-
virin is used in treating immunosuppressed infants and young children with severe RSV infections. Ribavirin is also effective in chronic hepa-
titis C infections when used in combination with interferon-α.
1. Mechanism of action: Ribavirin inhibits replication of RNA and
DNA viruses. The drug is first phosphorylated to the 5′-phosphate
derivatives, the major product being the compound ribavirin tri-
phosphate, which exerts its antiviral action by inhibiting guanosine
triphosphate formation, preventing viral messenger RNA (mRNA)
capping, and blocking RNA-dependent RNA polymerase.
2. Pharmacokinetics: Ribavirin is effective orally and by inhalation.
An aerosol is used in the treatment of RSV infection. Absorption
is increased if the drug is taken with a fatty meal. The drug and its
metabolites are eliminated in urine (Figure 45.4).
3. Adverse effects: Side effects of ribavirin include dose-dependent
transient anemia. Elevated bilirubin has also been reported. The
aerosol may be safer, although respiratory function in infants can
deteriorate quickly after initiation of aerosol treatment. Therefore,
monitoring is essential. Ribavirin is contraindicated in pregnancy
(Figure 45.5).

Question 13

TREATMENT OF HEPATIC VIRAL INFECTIONS

A. Interferons

Answer 13

A. Interferons
Interferons [in-ter-FEER-on] are a family of naturally occurring, induc-
ible glycoproteins that interfere with the ability of viruses to infect
cells. The interferons are synthesized by recombinant DNA technol-
ogy. At least three types of interferons exist—α, β, and γ (Figure 45.7).
One of the 15 interferon-α glycoproteins, interferon-α-2b has been
approved for treatment of hepatitis B and C, condylomata acuminata,
and cancers such as hairy cell leukemia and Kaposi sarcoma. In
“pegylated” formulations, bis-monomethoxy polyethylene glycol has been covalently attached to either interferon-α-2a or -α-2b to increase
the size of the molecule. The larger molecular size delays absorption
from the injection site, lengthens the duration of action of the drug,
and also decreases its clearance.
1. Mechanism of action: The antiviral mechanism is incompletely
understood. It appears to involve the induction of host cell enzymes
that inhibit viral RNA translation, ultimately leading to the degrada-
tion of viral mRNA and tRNA.
2. Pharmacokinetics: Interferon is not active orally, but it may be
administered intralesionally, subcutaneously, or intravenously. Very
little active compound is found in the plasma, and its presence is
not correlated with clinical responses. Cellular uptake and metabo-
lism by the liver and kidney account for the disappearance of inter-
feron from the plasma. Negligible renal elimination occurs.
3. Adverse effects: Adverse effects include flu-like symptoms, such
as fever, chills, myalgias, arthralgias, and GI disturbances. Fatigue
and mental depression are common. These symptoms subside
with continued administration. The principal dose-limiting toxicities
are bone marrow suppression, severe fatigue and weight loss, neu-
rotoxicity characterized by somnolence and behavioral disturbances,
autoimmune disorders such as thyroiditis and, rarely, cardiovascular
problems such as heart failure. Interferon may also potentiate myelo-
suppression caused by other bone marrow–suppressive agents

Question 14

B. Lamivudine

Answer 14

This cytosine analog is an inhibitor of both hepatitis B virus (HBV)
and human immunodeficiency virus (HIV) reverse transcriptases
(RTs). Lamivudine [la-MI-vyoo-deen] must be phosphorylated by host
cellular enzymes to the triphosphate (active) form. This compound
competitively inhibits HBV RNA-dependent DNA polymerase. As with
many nucleotide analogs, the intracellular half-life of the triphosphate
is many hours longer than its plasma half-life. The rate of resistance
is high following long-term therapy with lamivudine. Lamivudine is
well absorbed orally and is widely distributed. It is mainly excreted
unchanged in urine. Dose reductions are necessary when there is
moderate renal insufficiency. Lamivudine is well tolerated, with rare
occurrences of headache and dizziness.

Question 15

C. Adefovir

Answer 15

Adefovir dipivoxil [ah-DEF-o-veer die-pih-VOCKS-ill] is a nucleotide
analog that is phosphorylated by cellular kinases to adefovir diphos-
phate, which is then incorporated into viral DNA. This leads to termi-
nation of chain elongation and prevents replication of HBV. Adefovir
is administered once a day and is renally excreted via glomerular fil-
tration and tubular secretion. As with other agents, discontinuation of
adefovir may result in severe exacerbation of hepatitis. Nephrotoxicity
may occur with chronic use, and the drug should be used cautiously
in patients with existing renal dysfunction. Adefovir may raise levels
of tenofovir through competition for tubular secretion, and concurrent
use should be avoided.

Question 16

Entecavir

Answer 16

Entecavir [en-TECK-ah-veer] is a guanosine nucleoside analog for
the treatment of HBV infections. Following intracellular phosphoryla-
tion to the triphosphate, it competes with the natural substrate, deoxy-
guanosine triphosphate, for viral RT. Entecavir is effective against
lamivudine-resistant strains of HBV and is dosed once daily. The drug
is primarily excreted unchanged in the urine and dosage adjustments
are needed in renal dysfunction. Concomitant use of drugs with renal
toxicity should be avoided.

Question 17

Telbivudine

Answer 17

Telbivudine [tel-BIV-yoo-dine] is a thymidine analog that can be used
in the treatment of HBV. Telbivudine is phosphorylated intracellularly
to the triphosphate, which can either compete with endogenous thy-
midine triphosphate for incorporation into DNA or be incorporated into
viral DNA, where it serves to terminate further elongation of the DNA
chain. The drug is administered orally, once a day. Telbivudine is elimi-
nated by glomerular filtration as the unchanged drug. The dose must
be adjusted in renal failure. Adverse reactions include fatigue, head-
ache, diarrhea, and elevations in liver enzymes and creatine kinase.

Question 18

Tenofovir (see tenofovir under Section VI - NRTIs)

Question 19

Boceprevir and telaprevir

Answer 19

Boceprevir [boe-SE-pre-vir] and telaprevir [tel-A-pre-vir] are the
first oral direct-acting antiviral agents for the adjunctive treatment of
chronic HCV genotype 1. These HCV NS3/4A serine protease inhibi-
tors covalently and reversibly bind to the NS3 protease active site, thus
inhibiting viral replication in host cells. Both drugs are potent inhibitors
of viral replication; however, they have a low barrier to resistance and,
when used as monotherapy, resistance quickly develops. Therefore,
boceprevir or telaprevir should be used in combination with peginter-
feron alfa and ribavirin in order to improve response rates and reduce
the emergence of viral resistance. Boceprevir is administered with
food to improve absorption. The absorption of telaprevir is enhanced
when it is administered with non–low-fat food. The metabolism of
boceprevir and telaprevir occurs via CYP450 isoenzymes. Because
both drugs are strong inhibitors of CYP3A4/5 and are also partially
metabolized by CYP3A4/5, they have the potential for complex drug
interactions. Common adverse events with boceprevir include anemia
and dysgeusia. Telaprevir is associated with rash, anemia, and ano-
rectal discomfort.

Question 20

TREATMENT OF HERPESVIRUS INFECTIONS

Acyclovir

Answer 20

Acyclovir [ay-SYE-kloe-veer] (acycloguanosine) is the prototypic anti-
herpetic therapeutic agent. Herpes simplex virus (HSV) types 1 and 2,
varicella-zoster virus (VZV), and some Epstein-Barr virus–mediated
infections are sensitive to acyclovir. It is the treatment of choice in
HSV encephalitis. The most common use of acyclovir is in therapy for
genital herpes infections. It is also given prophylactically to seroposi-
tive patients before bone marrow transplant and post–heart transplant
to protect such individuals from herpetic infections.
1. Mechanism of action: Acyclovir, a guanosine analog, is mono-
phosphorylated in the cell by the herpesvirus-encoded enzyme
thymidine kinase (Figure 45.8). Therefore, virus-infected cells are
most susceptible. The monophosphate analog is converted to the
di- and triphosphate forms by the host cell kinases. Acyclovir tri-
phosphate competes with deoxyguanosine triphosphate as a sub-
strate for viral DNA polymerase and is itself incorporated into the
viral DNA, causing premature DNA chain termination.
2. Pharmacokinetics: Acyclovir is administered by intravenous
(IV), oral, or topical routes. [Note: The efficacy of topical applica-
tions is questionable.] The drug distributes well throughout the
body, including the cerebrospinal fluid (CSF). Acyclovir is par-
tially metabolized to an inactive product. Excretion into the urine
occurs both by glomerular filtration and tubular secretion (Figure
45.9). Acyclovir accumulates in patients with renal failure. The valyl
ester, valacyclovir [val-a-SYE-kloe-veer], has greater oral bioavail-
ability than acyclovir. This ester is rapidly hydrolyzed to acyclovir
and achieves levels of the latter comparable to those of acyclovir
following IV administration.
3. Adverse effects: Side effects of acyclovir treatment depend on
the route of administration. For example, local irritation may occur
from topical application; headache, diarrhea, nausea, and vomit-
ing may result after oral administration. Transient renal dysfunction
may occur at high doses or in a dehydrated patient receiving the
drug intravenously.
4. Resistance: Altered or deficient thymidine kinase and DNA poly-
merases have been found in some resistant viral strains and are
most commonly isolated from immunocompromised patients. Cross-
resistance to the other agents in this family occurs.

Question 21

Cidofovir

Answer 21

B. Cidofovir
Cidofovir [si-DOE-foe-veer] is approved for the treatment of cytomeg-
alovirus (CMV) retinitis in patients with AIDS. [Note: CMV is a member
of the herpesvirus family.] Cidofovir is a nucleotide analog of cyto-
sine, the phosphorylation of which is not dependent on viral or cellular
enzymes. It inhibits viral DNA synthesis. Slow elimination of the active
intracellular metabolite permits prolonged dosage intervals and elimi-
nates the permanent venous access needed for ganciclovir therapy.
Cidofovir is administered intravenously. Intravitreal injection (injection
into the vitreous humor between the lens and the retina) of cidofovir
is associated with risk of hypotony and uveitis and is reserved for
extraordinary cases. Cidofovir produces significant renal toxicity (Figure 45.10), and it is contraindicated in patients with preexisting
renal impairment and in those taking nephrotoxic drugs. Neutropenia
and metabolic acidosis also occur. Oral probenecid and IV normal
saline are coadministered with cidofovir to reduce the risk of neph-
rotoxicity. Since the introduction of highly active antiretroviral therapy
(HAART), the prevalence of CMV infections in immunocompromised
hosts has markedly declined, as has the importance of cidofovir in the
treatment of these patients.

Question 22

Foscarnet

Answer 22

C. Foscarnet
Unlike most antiviral agents, foscarnet [fos-KAR-net] is not a purine
or pyrimidine analog. Instead, it is a phosphonoformate (a pyrophos-
phate derivative) and does not require activation by viral (or cellular)
kinases. Foscarnet is approved for CMV retinitis in immunocompro-
mised hosts and for acyclovir-resistant HSV infections. Foscarnet
works by reversibly inhibiting viral DNA and RNA polymerases,
thereby interfering with viral DNA and RNA synthesis. Mutation of the
polymerase structure is responsible for resistant viruses. Foscarnet
is poorly absorbed orally and must be injected intravenously. It must
also be given frequently to avoid relapse when plasma levels fall. It
is dispersed throughout the body, and greater than 10% enters the
bone matrix, from which it slowly leaves. The parent drug is eliminated
by glomerular filtration and tubular secretion (Figure 45.11). Adverse
effects include nephrotoxicity, anemia, nausea, and fever. Due to che-
lation with divalent cations, hypocalcemia and hypomagnesemia are
also seen. In addition, hypokalemia, hypo- and hyperphosphatemia,
seizures, and arrhythmias have been reported.

Question 23

Ganciclovir

Answer 23

Ganciclovir [gan-SYE-kloe-veer] is an analog of acyclovir that has
greater activity against CMV. It is used for the treatment of CMV retini-
tis in immunocompromised patients and for CMV prophylaxis in trans-
plant patients.
1. Mechanism of action: Like acyclovir, ganciclovir is activated
through conversion to the nucleoside triphosphate by viral and cel-
lular enzymes. The nucleotide inhibits viral DNA polymerase and
can be incorporated into the DNA resulting in chain termination.
2. Pharmacokinetics: Ganciclovir is administered IV and distrib-
utes throughout the body, including the CSF. Excretion into the
urine occurs through glomerular filtration and tubular secretion
(Figure 45.12). Like acyclovir, ganciclovir accumulates in patients
with renal failure. Valganciclovir [val-gan-SYE-kloe-veer], an oral
drug, is the valyl ester of ganciclovir. Like valacyclovir, valganci-
clovir has high oral bioavailability, because rapid hydrolysis in the
intestine and liver after oral administration leads to high levels of
ganciclovir.
3. Adverse effects: Adverse effects include severe, dose-dependent
neutropenia. Ganciclovir is carcinogenic as well as embryotoxic
and teratogenic in experimental animals.
4. Resistance: Resistant CMV strains have been detected that have
lower levels of ganciclovir triphosphate.

Question 24

Penciclovir and famciclovir

Answer 24

Penciclovir [pen-SYE-kloe-veer] is an acyclic guanosine nucleoside
derivative that is active against HSV-1, HSV-2, and VZV. Penciclovir is
only administered topically (Figure 45.13). It is monophosphorylated
by viral thymidine kinase, and cellular enzymes form the nucleoside
triphosphate, which inhibits HSV DNA polymerase. Penciclovir tri-
phosphate has an intracellular half-life much longer than acyclovir tri-
phosphate. Penciclovir is negligibly absorbed upon topical application
and is well tolerated. Famciclovir [fam-SYE-kloe-veer], another acy-
clic analog of 2′-deoxyguanosine, is a prodrug that is metabolized to
the active penciclovir. The antiviral spectrum is similar to that of gan-
ciclovir, and it is approved for treatment of acute herpes zoster, geni-
tal HSV infection, and recurrent herpes labialis. The drug is effective
orally (Figure 45.13). Adverse effects include headache and nausea.

Question 25

Trifluridine

Answer 25

Trifluridine [trye-FLURE-i-deen] is a fluorinated pyrimidine nucleoside
analog that is structurally similar to thymidine. Once converted to the
triphosphate, the agent is believed to inhibit the incorporation of thy-
midine triphosphate into viral DNA and, to a lesser extent, lead to the
synthesis of defective DNA that renders the virus unable to replicate.
Trifluridine is active against HSV-1, HSV-2, and vaccinia virus. It is
indicated for treatment of HSV keratoconjunctivitis and recurrent epi-
thelial keratitis. Because the triphosphate form of trifluridine can also
incorporate to some degree into cellular DNA, the drug is considered
to be too toxic for systemic use. Therefore, the use of trifluridine is
restricted to a topical ophthalmic preparation. A short half-life neces-
sitates that the drug be applied frequently. Adverse effects include a
transient irritation of the eye and palpebral (eyelid) edema.
Figure 45.14 summarizes selected antiviral agents.

Question 26

OVERVIEW OF THE TREATMENT
FOR HIV INFECTION

Acyclovir

Answer 26

Metabolized to acyclovir triphosphate,

Treats Herpes simplex, varicella-zoster, cytomegalovirus
which inhibits viral DNA polymerase

Question 27

Amantadine

Answer 27

Amantadine Blockage of the M2 protein ion channel
and its ability to modulate intracellular pH

Treats influenza A

Question 28

Cidofovir

Answer 28

Inhibition of viral DNA polymerase

Treats Cytomegalovirus; indicated only for virus-induced retinitis

Question 29

Famciclovir

Answer 29

Same as penciclovir

Treats Herpes simplex, varicella-zoster

Question 30

Foscarnet

Answer 30

Inhibition of viral DNA polymerase and
reverse transcriptase at the
pyrophosphate-binding site

Treats Cytomegalovirus, acyclovir-resistant herpes simplex, acyclovir-resistant varicella-zoster

Question 31

Ganciclovir

Answer 31

Inhibits viral DNA polymerase, treats cytomegalovirus

Question 32

Interferon-α

Answer 32

Induction of cellular enzymes that interfere with viral protein synthesis

Treats
Hepatitis B and C, human herpesvirus 8, papilloma virus,
Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia

Question 33

Lamivudine

Answer 33

Inhibition of viral DNA polymerase and Hepatitis B (chronic cases), human
reverse transcriptase

Treats Hepatitis B (chronic cases), human immunodeciency virus type 1

Question 34

Oseltamivir

Answer 34

Inhibition of viral neuraminidase

Treats influenza A

Question 35

Penciclovir

Answer 35

Metabolized to penciclovir triphosphate, which inhibits viral DNA polymerase

Treats Herpes simplex

Question 36

Ribavirin

Answer 36

Interference with viral messenger RNA

Treats Lassa fever, hantavirus (hemorrhagic fever renal syndrome),
hepatitis C (in chronic cases in combination with interferon-α
and in combination both with interferon-α and HCV protease
inhibitor for HCV genotype I), RSV in children and infants

Question 37

Rimantadine

Answer 37

Blockage of the M2 protein ion channel
and its ability to modulate intracellular pH

Treats influenza A

Question 38

Valacyclovir

Answer 38

Same as Acyclovir

Treats Herpes simplex, varicella-zoster, cytomegalovirus

Question 39

Zanamivir

Answer 39

Inhibition of viral neuraminidase, treats influenza A

Question 40

NRTIS USED TO TREAT HIV INFECTION

Overviews

Answer 40

Overview of NRTIs
1. Mechanism of action: NRTIs are analogs of native ribosides
(nucleosides or nucleotides containing ribose), which all lack a
3′-hydroxyl group. Once they enter cells, they are phosphorylated by
cellular enzymes to the corresponding triphosphate analog, which
is preferentially incorporated into the viral DNA by RT. Because
the 3′-hydroxyl group is not present, a 3′,5′-phosphodiester bond
between an incoming nucleoside triphosphate and the growing DNA

chain cannot be formed, and DNA chain elongation is terminated.
Affinities of the drugs for many host cell DNA polymerases are lower
than they are for HIV RT, although mitochondrial DNA polymerase
γ appears to be susceptible at therapeutic concentrations.
2. Pharmacokinetics: The NRTIs are primarily renally excreted,
and all require dosage adjustment in renal insufficiency except
abacavir, which is metabolized by alcohol dehydrogenase and
glucuronyl transferase.
3. Adverse effects: Many of the toxicities of the NRTIs are believed
to be due to inhibition of the mitochondrial DNA polymerase in
certain tissues. As a general rule, the dideoxynucleosides, such as
didanosine and stavudine, have a greater affinity for the mitochon-
drial DNA polymerase, leading to toxicities such as peripheral neu-
ropathy, pancreatitis, and lipoatrophy. When more than one NRTI is
given, care is taken to avoid overlapping toxicities. All of the NRTIs
have been associated with a potentially fatal liver toxicity charac-
terized by lactic acidosis and hepatomegaly with steatosis.
4. Drug interactions: Due to the renal excretion of the NRTIs, there
are not many drug interactions encountered with these agents
except for zidovudine and tenofovir.
5. Resistance: NRTI resistance is well characterized, and the most
common resistance pattern is a mutation at viral RT codon 184,
which confers a high degree of resistance to lamivudine and
emtricitabine but, more importantly, restores sensitivity to zidovu-
dine and tenofovir. Because cross-resistance and antagonism
occur between agents of the same analog class (thymidine, cyto-
sine, guanosine, and adenosine), concomitant use of agents with
the same analog target is contraindicated (for example, zidovudine
and stavudine are both analogs of thymidine and should not be
used together).

Question 41

Zidovudine

Answer 41

Zidovudine [zye-DOE-vyoo-deen], the pyrimidine analog, 3′-azido-
3′-deoxythymidine (AZT), was the first agent available for the treat-
ment of HIV infection. AZT is approved for the treatment of HIV in
children and adults and to prevent perinatal transmission of HIV. It
is also used for prophylaxis in individuals exposed to HIV infection.
AZT is well absorbed after oral administration. Penetration across the
blood–brain barrier is excellent, and the drug has a half-life of 1 hour
with an intracellular half-life of approximately 3 hours. Most of the
drug is glucuronidated by the liver and then excreted in the urine
(Figure 45.17). AZT is toxic to bone marrow and can cause anemia
and neutropenia. Headaches are also common. Both stavudine and
ribavirin are activated by the same intracellular pathways and should
not be given with AZT.

Question 42

Stavudine

Answer 42

Stavudine (d4T)
Stavudine [STAV-yoo-deen] is an analog of thymidine approved for
the treatment of HIV. The drug is well absorbed after oral adminis-
tration, and it penetrates the blood–brain barrier. The majority of the
drug is excreted unchanged in the urine. Renal impairment interferes
with clearance. Stavudine is a strong inhibitor of cellular enzymes such as the DNA polymerases, thus reducing mitochondrial DNA synthesis
and resulting in toxicity. The major and most common clinical toxic-
ity is peripheral neuropathy, along with headache, rash, diarrhea, and
lipoatrophy.

Question 43

Didanosine (ddI)

Answer 43

Upon entry of didanosine [dye-DAN-oh-seen] (dideoxyinosine, ddI)
into the host cell, ddI is biotransformed into dideoxyadenosine triphos-
phate (ddATP) through a series of reactions that involve phosphoryla-
tions and aminations. Like AZT, the resulting ddATP is incorporated
into the DNA chain, causing termination of chain elongation. Due to
its acid lability, absorption is best if ddI is taken in the fasting state.
The drug penetrates into the CSF but to a lesser extent than does
AZT. Most of the parent drug appears in the urine (Figure 45.18).
Pancreatitis, which may be fatal, is a major toxicity with ddI and
requires monitoring of serum amylase. The dose-limiting toxicity of ddI
is peripheral neuropathy. Because of its similar adverse effect profile,
concurrent use of stavudine is not recommended.

Question 44

Tenofovir (TDF)

Answer 44

Tenofovir [te-NOE-fo-veer] is a nucleotide analog, namely, an acyclic
nucleoside phosphonate analog of adenosine 5′-monophosphate. It
is converted by cellular enzymes to the diphosphate, which is the
inhibitor of HIV RT. Cross-resistance with other NRTIs may occur.
Tenofovir has a long half-life, allowing once-daily dosing. Most of the
drug is recovered unchanged in the urine. Serum creatinine must be
monitored and doses adjusted in renal insufficiency. GI complaints
are frequent and include nausea and bloating (Figure 45.19). The
drug should not be used with ddI due to drug interactions. Tenofovir
decreases the concentrations of the PI atazanavir such that atazanavir
must be boosted with ritonavir if these agents are given concurrently.

Question 45

Lamivudine 3TC

Answer 45

Lamivudine [la-MI-vyoo-deen] (2′-deoxy-3′-thiacytidine, 3TC) inhibits
the RT of both HIV and HBV. However, it does not affect mitochon-
drial DNA synthesis or bone marrow precursor cells, resulting in less
toxicity. It has good bioavailability on oral administration, depends on
the kidney for excretion, and is well tolerated.

Question 46

Emtricitabine (FTC)

Answer 46

. Emtricitabine (FTC)
Emtricitabine [em-tri-SIGH-ta-been], a fluoro derivative of lamivudine,
inhibits both HIV and HBV RT. Emtricitabine is well absorbed after
oral administration. Plasma half-life is about 10 hours, whereas it has
a long intracellular half-life of 39 hours. Emtricitabine is eliminated
essentially unchanged in urine. It has no significant interactions with
other drugs. Headache, diarrhea, nausea, and rash are the most
common adverse effects. Emtricitabine may also cause hyperpigmen-
tation of the soles and palms. Withdrawal of emtricitabine in HBV-
infected patients may result in worsening hepatitis.

Question 47

Abacavir (ABC)

Answer 47

Abacavir [a-BA-ka-veer] is a guanosine analog. Abacavir is well
absorbed orally. It is metabolized to inactive metabolites via alcohol dehydrogenase and glucuronyl transferase, and metabolites appear
in the urine (Figure 45.20). Common adverse effects include GI dis-
turbances, headache, and dizziness. Approximately 5% of patients
exhibit the “hypersensitivity reaction,” which is usually characterized
by drug fever, plus a rash, GI symptoms, malaise, or respiratory dis-
tress (Figure 45.21). Sensitized individuals should never be rechal-
lenged because of rapidly appearing, severe reactions that may lead
to death. A genetic test (HLA-B*5701) is available to screen patients
for the potential of this reaction. Figure 45.22 shows some adverse
reactions commonly seen with nucleoside analogs.

Question 48

NNRTIS USED TO TREAT HIV INFECTION

Nevirapine (NVP)

Answer 48

Nevirapine [ne-VYE-ra-peen] is used in combination with other antiret-
roviral drugs for the treatment of HIV infections in adults and children.
Due to the potential for severe hepatotoxicity, nevirapine should not
be initiated in women with CD4 cell counts greater than 250 cells/mm3
or in men with CD4 cell counts greater than 400 cells/mm3
. Nevirapine
is well absorbed orally. The lipophilic nature of nevirapine accounts
for its wide tissue distribution, including the CNS, placenta (transfers
to the fetus), and breast milk. Nevirapine is metabolized via hydrox-
ylation and subsequent glucuronide conjugation. The metabolites
are excreted in urine (Figure 45.23). Nevirapine is an inducer of the
CYP3A4 isoenzymes, and it increases the metabolism of a number of
drugs, such as oral contraceptives, ketoconazole, methadone, quini-
dine, and warfarin. The most frequently observed adverse effects are
rash, fever, headache, and elevated serum transaminases and fatal
hepatotoxicity. Severe dermatologic effects have been encountered,
including Stevens-Johnson syndrome and toxic epidermal necrolysis.
A 14-day titration period at half the dose is mandatory to reduce the
risk of serious epidermal reactions and hepatotoxicity.

Question 49

Delavirdine (DLV)

Answer 49

Delavirdine [de-LA-vir-deen] is not recommended as a preferred or
alternate NNRTI in the current HIV guidelines due to its inferior antivi-
ral efficacy and inconvenient (three times daily) dosing.

Question 50

Efavirenz (EFV)

Answer 50

Efavirenz [e-FA-veer-enz] is the preferred NNRTI. Following oral
administration, efavirenz is well distributed, including to the CNS
(Figure 45.24). It should be administered on an empty stomach to
reduce adverse CNS effects. Most of the drug is bound to plasma albu-
min at therapeutic doses. A half-life of more than 40 hours accounts
for its recommended once-a-day dosing. Efavirenz is extensively metabolized to inactive products. The drug is a potent inducer of
CYP450 enzymes and, therefore, may reduce the concentrations of
drugs that are substrates of the CYP450. Most adverse effects are
tolerable and are associated with the CNS, including dizziness, head-
ache, vivid dreams, and loss of concentration (Figure 45.25). Nearly
half of patients experience these complaints, which usually resolve
within a few weeks. Rash is another common adverse effect. Efavirenz
should be avoided in pregnant women.

Question 51

Etravirine (ETR)

Answer 51

Etravirine [et-ra-VYE-rine] is a second-generation NNRTI active
against many HIV strains that are resistant to the first-generation
NNRTIs. HIV strains with the common K103N mutation that are resis-
tant to the first-generation NNRTIs are fully susceptible to etravirine.
Etravirine is indicated for HIV treatment–experienced, multidrug-
resistant patients who have evidence of ongoing viral replication. The
bioavailability of etravirine is enhanced when taken with a high-fat
meal. Although it has a half-life of approximately 40 hours, it is indi-
cated for twice-daily dosing. Etravirine is extensively metabolized to
inactive products and excreted mainly in the feces. Because etravirine
is a potent inducer of CYP450, the doses of CYP450 substrates may
need to be increased when given with etravirine. Rash is the most
common adverse effect.

Question 52

Rilpivirine (RPV)

Answer 52

Rilpivirine [ril-pi-VIR-een] is approved for HIV treatment-naïve patients
in combination with other antiretroviral agents. It is administered orally
once daily with meals and has pH-dependent absorption. Therefore,
it should not be coadministered with proton pump inhibitors and
requires dose separation from H2
-receptor antagonists and antac-
ids. Rilpivirine is highly bound to plasma proteins, primarily albumin.
Rilpivirine is a substrate of CYP3A4, and coadministration with other
medications that are inducers or inhibitors of this isoenzyme may
affect levels of the drug. Rilpivirine is mainly excreted in the feces.
Cross-resistance to other NNRTIs is likely after virologic failure and
development of rilpivirine resistance. The most common adverse
reactions are depressive disorders, headache, insomnia, and rash.

Question 53

PROTEASE INHIBITORS USED TO TREAT
HIV INFECTION

Answer 53

Inhibitors of HIV protease have significantly altered the course of this
devastating viral disease. Within a year of their introduction in 1995, the
number of deaths in the United States due to AIDS declined, although
the trend appears to be leveling off (Figure 45.26).
A. Overview
These potent agents have several common features that characterize
their pharmacology.
1. Mechanism of action: All of the drugs in this group are revers-
ible inhibitors of the HIV aspartyl protease (retropepsin), which is
the viral enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes (RT, protease, and integrase)
and several structural proteins. The inhibition prevents maturation
of the viral particles and results in the production of noninfectious
virions.
2. Pharmacokinetics: High-fat meals substantially increase the bio-
availability of some PIs, such as nelfinavir and saquinavir, whereas
the bioavailability of indinavir is decreased, and others are essen-
tially unaffected. The HIV PIs are all substantially bound to plasma
proteins. All are substrates for the CYP3A4 isoenzyme, and indi-
vidual PIs are also metabolized by other CYP450 isoenzymes.
Metabolism is extensive, and very little of the PIs are excreted
unchanged in urine. Dosage adjustments are unnecessary in renal
impairment.
3. Adverse effects: PIs commonly cause nausea, vomiting, and diar-
rhea (Figure 45.27). Disturbances in glucose and lipid metabolism
also occur, including diabetes, hypertriglyceridemia, and hyper-
cholesterolemia. Chronic administration results in fat redistribution,
including loss of fat from the extremities, fat accumulation in the
abdomen and the base of the neck (“buffalo hump”; Figure 45.28),
and breast enlargement. These physical changes may indicate to
others that an individual is HIV infected.
4. Drug interactions: Drug interactions are a common problem
for all PIs, because they are not only substrates but also potent
inhibitors of CYP450 isoenzymes. Drug interactions are, therefore,
quite common. Drugs that rely on metabolism for their termina-
tion of action may accumulate to toxic levels. Examples of poten-
tially dangerous interactions from drugs that are contraindicated
with PIs include rhabdomyolysis from simvastatin or lovastatin,
excessive sedation from midazolam or triazolam, and respiratory
depression from fentanyl (Figure 45.29). Other drug interactions
that require dosage modification and cautious use include warfa-
rin, sildenafil, and phenytoin (Figure 45.30). In addition, inducers
of CYP450 isoenzymes may decrease PI plasma concentrations
to suboptimal levels, contributing to treatment failures. Thus, drugs
such as rifampin and St. John’s wort are also contraindicated with
PIs.
5. Resistance: Resistance occurs as an accumulation of stepwise
mutations of the protease gene. Initial mutations result in decreased
ability of the virus to replicate, but as the mutations accumulate, viri-
ons with high levels of resistance to the protease inhibitors emerge.
Suboptimal concentrations of PI result in the more rapid appear-
ance of resistant strains.

Question 54

Ritonavir (RTV)

Answer 54

Ritonavir [ri-TOE-na-veer] is no longer used as a single PI but,
instead, is used as a pharmacokinetic enhancer or “booster” of other
PIs. Ritonavir is a potent inhibitor of CYP3A, and concomitant rito-
navir administration at low doses increases the bioavailability of the
second PI, often allowing for longer dosing intervals. The resulting
higher Cmin levels of the “boosted” PI also help to prevent the develop-
ment of resistance. Therefore, “boosted” PIs are preferred agents in the HIV treatment guidelines. Metabolism and biliary excretion are
the primary methods of elimination. Ritonavir has a half-life of 3 to
5 hours. Because it is primarily an inhibitor of CYP450 isoenzymes,
numerous drug interactions have been identified. Nausea, vomiting,
diarrhea, headache, and circumoral paresthesias are among the
more common adverse effects

Question 55

Saquinavir (SQV)

Answer 55

To maximize bioavailability, saquinavir [sa-KWIH-na-veer] is always
given along with a low dose of ritonavir. High-fat meals also enhance
absorption. Elimination of saquinavir is primarily by hepatic metab-
olism, followed by biliary excretion. Its half-life is 7 to 12 hours,
requiring twice-daily dosing. The most common adverse effects of
saquinavir include headache, fatigue, diarrhea, nausea, and other
GI disturbances. Increased levels of hepatic aminotransferases have
been noted, particularly in patients with concurrent hepatitis B or C
infections.

Question 56

Indinavir (IDV)

Answer 56

Indinavir [in-DIH-na-veer] is well absorbed orally and, of all the PIs,
is the least protein bound. Acidic gastric conditions are necessary for
absorption. Absorption is decreased when administered with meals,
although a light, low-fat snack is permissible. Indinavir has the short-
est half-life of the PIs, at 1.8 hours. Boosting with ritonavir overcomes
this problem and also permits twice-daily dosing. Indinavir is exten-
sively metabolized, and the metabolites are excreted in the feces and
urine. The dosage should, therefore, be reduced in the presence of
hepatic insufficiency. GI symptoms and headache are the predomi-
nant adverse effects. Indinavir characteristically causes nephrolithia-
sis and hyperbilirubinemia. Adequate hydration is important to reduce
the incidence of kidney stone formation, and patients should drink
at least 1.5 L of water per day. Fat redistribution is particularly trouble-
some with this drug.

Question 57

Nelfinavir (NFV)

Answer 57

Nelfinavir [nel-FIN-a-veer] is well absorbed and does not require
strict food or fluid conditions, although it is usually given with food.
Nelfinavir undergoes metabolism by several CYP450 isoenzymes.
It is the only PI that cannot be boosted by ritonavir, because it is
not extensively metabolized by CYP3A. The half-life of nelfinavir is
5 hours. Diarrhea is the most common adverse effect and can be
controlled with loperamide.

Question 58

Fosamprenavir (FPV)

Answer 58

Fosamprenavir [fos-am-PREN-a-veer] is a prodrug that is metabo-
lized to amprenavir following oral absorption. Its long plasma half-
life permits twice-daily dosing. Coadministration of ritonavir increases
the plasma levels of amprenavir and lowers the total daily dose.
Fosamprenavir boosted with ritonavir is one of the alternative PIs
according to the current HIV treatment guidelines. Nausea, vomiting,
diarrhea, fatigue, paresthesias, and headache are common adverse
effects.

Question 59

Lopinavir (LPV/r)

Answer 59

Lopinavir [loe-PIN-a-veer] is an alternative PI, according to the HIV
treatment guidelines. Lopinavir has very poor bioavailability, which is
substantially enhanced by including a low-dose ritonavir booster in
the formulation. GI adverse effects and hypertriglyceridemia are the
most common adverse effects of lopinavir. Enzyme inducers as well
as St. John’s wort should be avoided, because they lower the plasma
concentrations of lopinavir. Because the oral solution contains alco-
hol, disulfiram or metronidazole administration can cause unpleasant
reactions.

Question 60

Atazanavir (ATV)

Answer 60

Atazanavir [ah-ta-ZA-na-veer] is a preferred PI. Atazanavir is well
absorbed orally. It must be taken with food, because food increases
absorption and bioavailability. The drug is highly protein bound
and undergoes extensive metabolism by CYP3A4 isoenzymes.
It is excreted primarily in bile. It has a half-life of about 7 hours,
but it may be administered once daily. Atazanavir is a competitive
inhibitor of glucuronyl transferase, and benign hyperbilirubinemia
and jaundice are known adverse effects. In the heart, atazana-
vir prolongs the PR interval. Atazanavir exhibits a decreased risk
of hyperlipidemia compared with other PIs. Unboosted atazanavir
is contraindicated with concurrent use of proton pump inhibitors,
and administration must be spaced apart from H2-blockers and
antacids.

Question 61

Tipranavir (TPV)

Answer 61

Tipranavir [ti-PRA-na-veer] is a nonpeptide PI that inhibits HIV pro-
tease in viruses that are resistant to the other PIs. Tipranavir is well
absorbed when taken with food. The half-life is 6 hours, and it must be
administered twice daily in combination with ritonavir. Adverse effects
are similar to those of the other PIs, with the exception of severe
and fatal hepatitis and rare cases of intracranial hemorrhage. Most
patients experiencing these severe adverse effects have underlying
comorbidities. Tipranavir is useful in “salvage” regimens in patients
with multidrug resistance

Question 62

Darunavir (DRV)

Answer 62

Darunavir [da-RU-na-veer] is a preferred PI and is always given
along with a low dose of ritonavir. Darunavir is approved for ini-
tial therapy in treatment-naïve HIV-infected patients, as well as for
treatment-experienced patients with HIV that is resistant to other PIs.
Darunavir must be taken with food to increase absorption. The elimi-
nation half-life is 15 hours when combined with ritonavir. Darunavir
is extensively metabolized by the CYP3A enzymes and is also an
inhibitor of the CYP3A4 isoenzyme. Adverse effects are similar to
those of the other PIs. In addition, darunavir therapy has been asso-
ciated with a rash.
A summary of PIs is presented in Figure 45.31.

Question 63

ENTRY INHIBITORS USED TO TREAT
HIV INFECTION

Enfuvirtide

Answer 63

Enfuvirtide [en-FU-veer-tide] is a fusion inhibitor. For HIV to gain entry
into the host cell, it must fuse its membrane with that of the host cell.
This is accomplished by changes in the conformation of the viral
transmembrane glycoprotein gp41, which occurs when HIV binds to
the host cell surface. Enfuvirtide is a polypeptide that binds to gp41,
preventing the conformational change. Enfuvirtide, in combination
with other antiretroviral agents, is approved for therapy of treatment-
experienced patients with evidence of viral replication despite ongoing
antiretroviral drug therapy. As a peptide, it must be given subcutane-
ously. Most of the adverse effects are related to the injection, includ-
ing pain, erythema, induration, and nodules, which occur in almost
all patients. Enfuvirtide must be reconstituted prior to administration.

Question 64

Maraviroc

Answer 64

Maraviroc [ma-RAV-i-rok] is another entry inhibitor. Because it is well
absorbed orally, it is formulated as an oral tablet. Maraviroc blocks the
CCR5 coreceptor that works together with gp41 to facilitate HIV entry
through the membrane into the cell. HIV may express preference for either
the CCR5 coreceptor or the CXCR4 coreceptor, or both (dual-tropic).
Prior to use of maraviroc, a test to determine viral tropism is required
to distinguish whether the strain of HIV virus uses the CCR5 corecep-
tor, the CXCR4 coreceptor, or is dual-tropic. Only strains of HIV that use
CCR5 to gain access to the cell can be successfully treated with mara-
viroc. Maraviroc is metabolized by CYP450 liver enzymes, and the dose
must be reduced when given with most PIs or strong CYP450 inhibitors.
Conversely, it should be increased in patients receiving efavirenz, etra-
virine, or strong CYP450 inducers. Maraviroc is generally well tolerated.

Question 65

INTEGRASE INHIBITORS USED TO TREAT
HIV INFECTION

Raltegravir

Answer 65

In combination with other antiretroviral agents, raltegravir [ral-TEG-ra-
veer] is approved for both initial therapy of treatment-naïve patients
and treatment-experienced patients with evidence of viral replication
despite ongoing antiretroviral drug therapy. Raltegravir has a half-life of
approximately 9 hours and is dosed twice daily. The route of metabolism
is UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation
and, therefore, drug interactions with CYP450 inducers, inhibitors, or
substrates do not occur. Raltegravir is well tolerated, although serious
adverse effects, such as elevated creatine kinase with muscle pain
and rhabdomyolysis and possible depression with suicidal ideation,
have been reported.

Question 66

Elvitegravir

Answer 66

Elvitegravir [el-vi-TEG-ra-vir] is currently only available in a fixed-
dose combination single tablet containing tenofovir, emtricitabine,
elvitegravir, and cobicistat. [Note: Cobicistat is a pharmacokinetic
enhancer or booster drug used in combination treatments of HIV
since it inhibits CYP3A enzymes.] The half-life of elvitegravir is
3 hours when administered alone, but increases to approximately
9 hours when boosted by cobicistat. Pharmacokinetic boosting
of elvitegravir allows it to be dosed orally once daily with food.
However, it can also lead to clinically significant drug interactions.
Elvitegravir is highly bound to plasma proteins and is primar-
ily metabolized in the liver via CYP3A, and to a lesser extent via
UGT1A1/3 glucuronidation. It is mainly excreted in the feces. The
most common adverse effect of elvitegravir is nausea, although
cobicistat may also cause elevations in serum creatinine due to
inhibition of tubular creatinine secretion. Cross-resistance between
raltegravir and elvitegravir is high.

Question 67

Dolutegravir

Answer 67

Dolutegravir [doe-loo-TEG-ra-vir] is rapidly absorbed following oral
administration. Dolutegravir is highly protein bound and undergoes
extensive hepatic metabolism. Metabolism primarily occurs through
UGT1A1 with minor contributions from CYP3A4. Potent inducers
and/or inhibitors of UGT1A1 and CYP3A4 can significantly alter
dolutegravir concentrations. More than half the dose is eliminated
unchanged in the feces; nearly a third is eliminated as metabolites
in the urine. It is an inhibitor of the renal transport protein OCT2 and
can result in mild, benign, and reversible elevation in serum creati-
nine. Dolutegravir can be given once daily without the use of a phar-
macokinetic booster in patients without preexisting INSTI resistance.
Twice-daily dosing is recommended for INSTI treatment-experienced
patients or when strong UGT1A1 or CYP3A inducers are present.
Depending on the specific genetic profile, some patients with ralte-
gravir and elvitegravir resistance mutations maintain susceptibility to
dolutegravir.