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35
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C H A P T E R

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Antiviral Drugs
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CHAPTER CONTENTS
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Principles of Antiviral Therapy Inhibitors of Human Immunodeficiency Virus
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Inhibition of Early Events Inhibitors of Hepatitis C Virus
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Inhibition of Viral Nucleic Acid Synthesis Inhibition of Viral Protein Synthesis
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Inhibitors of Herpesviruses Interferon
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Inhibitors of Retroviruses Fomivirsen
Inhibitors of Hepatitis B Virus Inhibition of Release of Virus
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Inhibitors of Hepatitis C Virus Chemoprophylaxis
Inhibitors of Other Viruses Pearls
Inhibition of Integrase Self-Assessment Questions
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Inhibition of Cleavage of Precursor Polypeptides Practice Questions: USMLE & Course Examinations
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(Protease Inhibitors)
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PRINCIPLES OF ANTIVIRAL viral disease, the virus has spread throughout the body and
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it is too late to interdict it. Furthermore, some viruses (e.g.,

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THERAPY herpesviruses) become latent within cells, and no current
m

Compared with the number of drugs available to treat
bacterial infections, the number of antiviral drugs is very
small. The major reason for this difference is the diffi-
m
m
antiviral drug can eradicate them.
Another limiting factor is the emergence of drug-resistant
viral mutants. For example, when drug-resistant mutants of

m
culty in obtaining selective toxicity against viruses; HIV emerge, it requires that drug regimens be changed.
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their replication is intimately involved with the normal Also, treatment of HIV infection uses multiple drugs, often
synthetic processes of the cell. Despite the difficulty, sev- from different classes, so that if mutants resistant to one
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eral virus-specific replication steps have been identified drug emerge, another drug will still be effective.
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that are the site of action of effective antiviral drugs

(Table 35–1). Table 35–2 describes the mode of action of fre
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antiviral drugs that block early events in viral replication,
INHIBITION OF EARLY EVENTS
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and Table 35–3 describes the mode of action of antiviral

drugs that block viral nucleic acid synthesis. Figure 35–1 Amantadine (α-adamantanamine, Symmetrel) is a
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shows the replication of a model virus and the site of action three-ring compound (Figure 35–3) that blocks the rep-
m

of drugs used to treat various viral infections. Figure 35–2
shows the replication of human immunodeficiency virus
(HIV) and the site of action of drugs used to treat HIV
infection.
m
lication of influenza A virus. It prevents replication by
inhibiting uncoating of the virus by blocking the “ion
channel” activity of the matrix protein (M2 protein) in
the virion. Absorption and penetration occur normally,

Another limitation of antiviral drugs is that they are but transcription by the virion RNA polymerase does
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relatively ineffective because many cycles of viral replica- not because uncoating cannot occur. This drug specifi-
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tion occur during the incubation period when the patient cally inhibits influenza A virus; influenza B and C viruses
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is well. By the time the patient has a recognizable systemic are not affected.
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269
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270 PART III Basic Virology
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TABLE 35–1 Stage of Viral Replication Inhibited by Antiviral Drugs

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Stage of Viral Replication Inhibited
f Effective Antiviral Drugs

f
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Early events (entry or uncoating of the virus) Amantadine, rimantadine, enfuvirtide, maraviroc, palivizumab
oo

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Nucleic acid synthesis by herpesviruses Acyclovir, ganciclovir, valacyclovir, valganciclovir, penciclovir, famciclovir,
cidofovir, trifluridine, foscarnet
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Nucleic acid synthesis by human immunodeficiency Zidovudine, lamivudine, emtricitabine, didanosine, stavudine, abacavir,
m

m
virus (HIV) tenofovir, nevirapine, delavirdine, efavirenz, etravirine, rilpivirine
Nucleic acid synthesis by hepatitis B virus (HBV) Adefovir, entecavir, lamivudine, telbivudine, tenofovir
Nucleic acid synthesis by hepatitis C virus (HCV) RNA polymerase inhibitors: sofosbuvir, dasabuvir
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m
NS5A inhibitors: ledipasvir, ombitsavir
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Nucleic acid synthesis by other viruses Ribavirin
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Integrase that integrates HIV DNA into cellular DNA Raltegravir, elvitegravir, dolutegravir
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Cleavage of precursor polypeptides Protease inhibitors of HIV: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir,
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atazanavir, darunavir, lopinavir, tipranavir
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Protease inhibitors of hepatitis C virus: boceprevir, simeprevir, telaprevir,
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paritaprevir
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Protein synthesis directed by viral mRNA Interferon, fomivirsen
Release of influenza virus from infected cell Oseltamivir, zanamivir
m

m
Despite its efficacy in preventing influenza, it is not virus from binding to receptors on the surface of respiratory
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widely used in the United States because the vaccine is pre- tract mucosal cells. It is used to prevent bronchiolitis and
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ferred for the high-risk population. Furthermore, most pneumonia in premature or immunocompromised infants.
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isolates have become resistant to amantadine. The main side
effects of amantadine are central nervous system altera-
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tions such as dizziness, ataxia, and insomnia. Rimantadine INHIBITION OF VIRAL NUCLEIC
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(Flumadine) is a derivative of amantadine and has the same ACID SYNTHESIS
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mode of action but fewer side effects.
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Enfuvirtide (Fuzeon) is a synthetic peptide that binds Inhibitors of Herpesviruses
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to gp41 on the surface of HIV, thereby blocking the entry of Nucleoside Inhibitors
the virus into the cell. It is the first of a new class of anti-
m

m
These drugs are analogues of nucleosides that inhibit the
HIV drugs known as “fusion inhibitors” (i.e., they prevent
DNA polymerase of one or more members of the herpesvi-
the fusion of the viral envelope with the cell membrane).
rus family. For example, acyclovir inhibits the DNA poly-
Maraviroc (Selzentry) blocks the binding of HIV to
m

m
merase herpes simplex virus types 1 and 2 (HSV-1 and -2)
CCR-5—an important coreceptor for those strains of HIV
and varicella-zoster virus but not cytomegalovirus (CMV).
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that use CCR-5 for entry into the cell. The drug binds to
CCR-5 and blocks the interaction of gp120, an HIV enve- 1. Acyclovir—Acyclovir (acycloguanosine, Zovirax) is a
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lope protein, to CCR-5 on the cell surface. guanosine analogue that has a three-carbon fragment in
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Palivizumab (Synagis) is a monoclonal antibody place of the normal sugar, ribose, which has five carbons fre
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directed against the fusion protein of respiratory syncytial (see Figure 35–3). The term acyclo refers to the fact that
virus (RSV). Palivizumab neutralizes RSV by binding to the the three-carbon fragment does not have a sugar ring
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fusion protein on the surface of RSV, thereby preventing the structure (a = without, cyclo = ring).
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m

TABLE 35–2 Antiviral Drugs That Block Early Events

Antiviral Drug Mode of Action Virus Inhibited
m

Amantadine, rimantadine Inhibits uncoating by blocking M2 matrix protein Influenza virus

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co

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Enfuvirtide Inhibits fusion by binding to gp41 of human immunodeficiency virus (HIV) HIV
e.

e.

e.

e.

Maraviroc Inhibits attachment to cell surface receptor CCR-5 HIV

fre

fre

fre

fre

Palivizumab Monoclonal antibody that blocks binding of viral fusion protein to receptor Respiratory syncytial virus
on respiratory mucosal cell
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CHAPTER 35 Antiviral Drugs 271
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TABLE 35–3 Antiviral Drugs That Block Viral Nucleic Acid Synthesis

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Mode of Action
f Antiviral Drugs

f
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Inhibition of DNA polymerase of herpesviruses 1. Nucleoside inhibitors: acyclovir, ganciclovir, valacyclovir, valganciclovir,
oo

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penciclovir, famciclovir, cidofovir, trifluridine
2. Nonnucleoside inhibitors: foscarnet
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Inhibition of reverse transcriptase of human 1. Nucleoside inhibitors: zidovudine, lamivudine, emtricitabine, didanosine,
m

m
immunodeficiency virus (HIV) stavudine, abacavir, tenofovir
2. Nonnucleoside inhibitors: nevirapine, delavirdine, efavirenz, etravirine, rilpivirine
Inhibition of reverse transcriptase of hepatitis B virus Adefovir, entecavir, lamivudine, telbivudine
m

m
Inhibition of RNA polymerase of hepatitis C virus Sofosbuvir, dasabuvir
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Inhibition of NS5A protein of hepatitis C virus Ledipasvir, ombitsavir
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Inhibition of nucleic acid synthesis by other viruses Ribavirin
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Acyclovir is active primarily against HSV-1 and -2 is active primarily against these viruses. It has no activity
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and varicella-zoster virus (VZV). It is relatively non- against CMV. Once the drug is phosphorylated to acy-
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toxic, because it is activated preferentially within virus- clovir monophosphate by the viral thymidine kinase,
infected cells. This is due to the virus-encoded cellular kinases synthesize acyclovir triphosphate, which
m

thymidine kinase, which phosphorylates acyclovir
much more effectively than does the cellular thymidine
kinase. Because only HSV-1, HSV-2, and VZV encode a
m
m
inhibits viral DNA polymerase much more effectively
than it inhibits cellular DNA polymerase. Acyclovir
causes chain termination because it lacks a hydroxyl

m
kinase that efficiently phosphorylates acyclovir, the drug group in the 3′ position.
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co
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Attachment
inhibited by
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palivizumab (RSV)
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Virion
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Nucleus
Receptor
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Uncoating
inhibited by
amantadine
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m
(influenza)
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Progeny
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genomes
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fre
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mRNAs Precursor
id to

polyproteins Release of virus

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p s in

Nucleic acid inhibited by

Tr

ns
ly

b
a

synthesis la t em a oseltamivir and

io n A s s leoc
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inhibited by c zanamivir
Protein synthesis nu
(influenza)
m

1. Acyclovir - (HSV, VZV)
2. Ganciclovir - (CMV)
3. Foscarnet - (HSV, CMV)
4. Cidofovir - (CMV)
m
inhibited by
1. Interferon α and β Precursor
(Interferon α used protein processing
clinically against inhibited by
HBV and HCV)

m
5. Ribavirin - (RSV) boceprevir and
6. Adefovir, entecavir, 2. Fomivirsen (CMV) telaprevir (HCV)
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telbivudine (HBV)
7. Sofosbuvir (HCV)
e.

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8. Ledipasvir (HCV)
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fre

FIGURE 35–1 Replicative cycle of a model virus showing the site of action of drugs used to treat various viral infections. CMV, cytomega-
lovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella-zoster virus.
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 e

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272 PART III Basic Virology
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Inhibited by entry inhibitors

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(enfuvirtide, maraviroc)
f

f
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Virion
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CD4 Nucleus
CCR5
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or CXCR4
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Provirus
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Integration Transcription
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RNA genomes
Reverse
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transcription
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mRNAs Precursor Cleavage
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id to
polyproteins by

p s in
Inhibited by

Tr
protease
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ns

ly
DNA copy b

a
reverse transcriptase la t em a
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inhibitors (zidovudine of genome io n A s s leoc
and others) nuc
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Inhibited
by protease
Inhibited by integrase
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inhibitors
inhibitors (raltegravir) (indinavir
and others)

FIGURE 35–2 Replicative cycle of human immunodeficiency virus (HIV) showing the site of action of drugs used to treat HIV infection.
m

m
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sf

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O
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O O F
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H F
N N N C
HN HN
F
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H
N N O N
N N
m

m
H2N H2N
HOCH2 O
HO H2C
O O
CH2 CH2 CH CH2
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m
HO H2C HO H 2C
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co
HO
Acyclovir Ganciclovir Trifluridine
e.

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(acycloguanosine)
fre

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fre

O
O fre
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HO P C O
O
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OH
OH CH3
H2N C N HN
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Foscarnet
N O N H
N
m

HOCH2 O HOCH2 O
NH2•HCl
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m
co

co

co

co

co

HO OH N3
Ribavirin Amantadine Zidovudine
e.

e.

e.

e.

(azidothymidine)
fre

fre

fre

fre

FIGURE 35–3 Structures of some medically important antiviral drugs.

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CHAPTER 35 Antiviral Drugs 273
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In Herpesvirus-Infected Cells
f

f
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ks
Herpesvirus-encoded Cellular Cellular
thymidine kinase kinase kinase
oo

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ACV ACV-MP ACV-DP ACV-TP
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ACV-TP is incorporated into the growing herpesvirus DNA chain and, acting as a chain terminator,
m

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inhibits viral DNA polymerase.

In Uninfected Cells
m

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Cell-encoded
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thymidine kinase
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ACV No ACV-MP
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Because no ACV-MP is made, no ACV-DP or ACV-TP can be made either.
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FIGURE 35–4 Acyclovir (ACV) is phosphorylated to ACV-MP very effectively by herpesvirus-encoded thymidine kinase but very poorly by
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cell-encoded thymidine kinase. The thymidine kinases encoded by herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV) are par-
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eb
ticularly active on ACV; the thymidine kinases encoded by cytomegalovirus and Epstein–Barr virus are not. This accounts for the selective action
of ACV in cells infected by HSV-1, HSV-2, and VZV. The fact that ACV-TP is not made in uninfected cells explains why ACV has so few side effects
m

m
(i.e., why DNA synthesis is not inhibited in uninfected cells). ACV-MP, ACV monophosphate; ACV-DP, ACV diphosphate; ACV-TP, ACV
triphosphate.
m

m
co

co

co

co

co
To recap, the selective action of acyclovir is based on genitalis and in herpes zoster. Penciclovir cream (Denavir)
two features of the drug. (1) Acyclovir is phosphorylated is used in the treatment of recurrent orolabial herpes sim-
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to acyclovir monophosphate much more effectively by plex. Famciclovir (Famvir), when taken orally, is converted
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herpesvirus-encoded thymidine kinase than by cellular to penciclovir and is used to treat herpes zoster and herpes
sf

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sf
thymidine kinase. It is therefore preferentially activated in simplex infections.
k

k
herpesvirus-infected cells and much less so in uninfected
oo

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oo
2. Ganciclovir—Ganciclovir (dihydroxypropoxymethyl-
cells, which accounts for its relatively few side effects. guanine, DHPG, Cytovene) is a nucleoside analogue of
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eb
(2) Acyclovir triphosphate inhibits herpesvirus-encoded guanosine with a four-carbon fragment in place of the
DNA polymerase much more effectively than it does cel- normal sugar, ribose (see Figure 35–3). It is structurally
m

lular DNA polymerase. It therefore inhibits viral DNA
synthesis to a much greater extent than cellular DNA
synthesis (Figure 35–4).
m
m
similar to acyclovir but is more active against CMV than
is acyclovir. Ganciclovir is activated by a CMV-encoded
phosphokinase in a process similar to that by which acy-

m
Topical acyclovir is effective in the treatment of primary clovir is activated by HSV. Isolates of CMV resistant to
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genital herpes and reduces the frequency of recurrences ganciclovir have emerged, mostly due to mutations in the
while it is being taken. However, it has no effect on latency UL97 gene that encodes the phosphokinase.
e.

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e.

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or on the rate of recurrences after treatment is stopped.
Ganciclovir is effective in the treatment of retinitis
fre

fre

fre

Acyclovir is the treatment of choice for HSV-1 encephalitis

and is effective in preventing systemic infection by HSV-1 caused by CMV in patients with acquired immunodefi- fre
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ciency syndrome (AIDS) and is useful in other dissemi-
or VZV in immunocompromised patients.
nated infections, such as colitis and esophagitis, caused by
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oo

Acyclovir-resistant mutants have been isolated from

this virus. The main side effects of ganciclovir are leukope-
HSV-1 and VZV-infected patients. Resistance is most often
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nia and thrombocytopenia as a result of bone marrow sup-

due to mutations in the gene encoding the viral thymidine
pression. Valganciclovir, which can be taken orally, is also
m

kinase. This results in reduced activity of or the total

effective against CMV retinitis.
absence of the virus-encoded thymidine kinase.
Acyclovir is well tolerated and causes few side effects— 3. Cidofovir—Cidofovir (hydroxyphosphonylmethoxy-
m

even in patients who have taken it orally for many years to propylcytosine, HPMPC, Vistide) is an analogue of cyto-
suppress genital herpes. Intravenous acyclovir may cause sine that lacks a ribose ring. Cidofovir does not have to be
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co

co

renal or central nervous system toxicity. phosphorylated and therefore is not dependent on the
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e.

e.

Derivatives of acyclovir with various properties are now action of a virus-encoded phosphokinase. It is useful in the
fre

fre

fre

fre

available. Valacyclovir (Valtrex) achieves a high plasma treatment of retinitis caused by CMV and in severe human
concentration when taken orally and is used in herpes papillomavirus infections. It may be useful in the treatment
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oo

oo

oo
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274 PART III Basic Virology
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e.

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of severe molluscum contagiosum in immunocompro- the virus in cell culture. The main adverse effects of zid-

re

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re
mised patients. Kidney damage is the main side effect. ovudine are bone marrow suppression and myopathy.
f

f
ks

ks

ks

ks
4. Trifluridine—(trifluorothymidine, Viroptic) is a 2. Lamivudine—Lamivudine (dideoxythiacytidine,
oo

oo

oo

oo
nucleoside analogue in which the methyl group of thymi- Epivir, 3TC) is a nucleoside analogue that causes chain
dine contains three fluorine atoms instead of three hydro- termination during DNA synthesis by the reverse tran-
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eb

eb

eb
gen atoms (see Figure 35–3). The drug is phosphorylated scriptase of HIV. When used in combination with AZT, it
to the triphosphate by cellular kinases and incorporated is very effective both in reducing the viral load and in
m

into DNA. Because it has a high frequency of mismatched
pairing to adenine, it causes the formation of faulty prog-
eny DNA and mRNA. However, because it is incorpo-
m
m
elevating the CD4 cell count. Lamivudine is also used in
the treatment of chronic hepatitis B because it inhibits the
reverse transcriptase of hepatitis B virus. It is one of the

m
rated into normal cell DNA as well as viral DNA, it is too best tolerated of the nucleoside inhibitors, but adverse
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co
toxic to be used systemically. It is the drug of choice for effects such as neutropenia, pancreatitis, and peripheral
e.

e.

e.

e.
the topical treatment of keratoconjunctivitis caused by neuropathy do occur.
herpes simplex virus.
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3. Emtricitabine—Emtricitabine (Emtriva), a derivative
sf

sf

sf

sf
of lamivudine, is also useful and well tolerated. A combi-
Nonnucleoside Inhibitors
k

k
nation of emtricitabine and tenofovir (Truvada) can be
oo

oo

oo

oo
Nonnucleoside inhibitors inhibit the DNA polymerase of used for preexposure prophylaxis for men who have sex
herpesviruses by mechanisms distinct from the nucleoside with men as well as for postexposure prophylaxis.
eb

eb

eb

eb
analogues described previously. Foscarnet is the only
approved drug in this class at this time. 4. Didanosine—Didanosine (dideoxyinosine, Videx,
m

1. Foscarnet—Foscarnet (trisodium phosphonoformate,
Foscavir), unlike the previous drugs, which are nucleoside
m
m
ddI) is a nucleoside analogue that causes chain termina-
tion during DNA synthesis; it is missing hydroxyl groups
on the ribose. The administered drug ddI is metabolized

m
analogues, is a pyrophosphate analogue (see Figure 35–3). to ddATP, which is the active compound. It is effective
co

co

co

co

co
It binds to DNA polymerase at the pyrophosphate cleav- against DNA synthesis by the reverse transcriptase of
age site and prevents removal of the phosphates from
e.

e.

e.

e.
HIV and is used to treat patients with AIDS who are
nucleoside triphosphates (dNTP). This inhibits the addi- intolerant of or resistant to zidovudine. The main adverse
re

re

re

re
tion of the next dNTP and, as a consequence, the exten- effects of didanosine are pancreatitis and peripheral
sf

sf

sf

sf
sion of the DNA strand. neuropathy.
k

k
Foscarnet inhibits the DNA polymerases of all herpesvi-
oo

oo

oo

oo
ruses, especially HSV and CMV. Unlike acyclovir, it does 5. Stavudine—Stavudine (didehydrodideoxythymidine,
not require activation by thymidine kinase. It is useful in d4T, Zerit) is a nucleoside analogue that causes chain
eb

eb

eb

eb
the treatment of retinitis caused by CMV, but ganciclovir is termination during DNA synthesis. It inhibits DNA syn-
m

the drug of first choice for this disease. Foscarnet is also
used to treat patients infected with acyclovir-resistant
mutants of HSV-1 and VZV.
m
m
thesis by the reverse transcriptase of HIV and is used to
treat patients with advanced AIDS who are intolerant of
or resistant to other approved therapies. The main

m
adverse effect is peripheral neuropathy.
co

co

co

co

co
Inhibitors of Retroviruses 6. Abacavir—Abacavir (Ziagen) is a nucleoside ana-
logue of guanosine that causes chain termination during
e.

e.

e.

e.
Nucleoside Inhibitors
DNA synthesis. It is available through the “expanded
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The selective toxicity of zidovudine, lamivudine, emtric-
itabine, didanosine, zalcitabine, stavudine, abacavir, and access” program to those who have failed currently avail-
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tenofovir is based on their ability to inhibit DNA synthesis able drug regimens. Abacavir is used in combination with
by the reverse transcriptase of HIV to a much greater either a protease inhibitor, typically darunavir and ritona-
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extent than they inhibit DNA synthesis by the DNA poly- vir, or zidovudine plus lamivudine. The main adverse
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merase in human cells. These drugs are collectively called effects are liver damage and severe hypersensitivity reac-
nucleoside reverse transcriptase inhibitors (NRTIs). The tions. Patients who have an HLA-B1701 allele are more
m

effect of these drugs on the replication of HIV is depicted likely to have a severe hypersensitivity reaction, such as
in Figure 35–2. fever, rash, or respiratory problems, to abacavir. Patients
should be tested for this gene before being prescribed
m

1. Zidovudine—Zidovudine (azidothymidine, Retrovir, abacavir. If patients develop hypersensitivity symptoms,

AZT) is a nucleoside analogue that causes chain termina-
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abacavir should be immediately and permanently

tion during DNA synthesis; it has an azido group in place discontinued.
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e.

e.

of the hydroxyl group on the ribose (see Figure 35–3). It

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is particularly effective against DNA synthesis by the 7. Tenofovir—Tenofovir (Viread) is an acyclic phospho-
reverse transcriptase of HIV and inhibits the growth of nate that is an analogue of adenosine monophosphate.
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CHAPTER 35 Antiviral Drugs 275
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e.

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e.

e.
It is a reverse transcriptase inhibitor that acts by chain transcriptase) of hepatitis B virus (HBV). It is used for the

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termination. It is approved for use in patients who have treatment of chronic active hepatitis caused by this virus.
f

f
developed resistance to other reverse transcriptase inhibi-
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tors and in those who are starting treatment for the first Entecavir
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time. It should be used in combination with other anti- Entecavir (Baraclude) is a guanosine analogue that inhibits
HIV drugs. The main adverse effects are liver damage, the DNA polymerase (reverse transcriptase) of HBV. It has
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lactic acidosis, and renal failure. no activity against the DNA polymerase (reverse transcrip-
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tase) of HIV. It is approved for the treatment of adults with
Nonnucleoside Inhibitors chronic HBV infection.
Unlike the drugs described earlier, the drugs in this group
Lamivudine
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are not nucleoside analogues and do not cause chain ter-
Lamivudine is described in the section “Inhibitors of
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mination. The nonnucleoside reverse transcriptase inhibi-
tors (NNRTIs) act by binding near the active site of the Retroviruses.”
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reverse transcriptase and inducing a conformational
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change that inhibits the synthesis of viral DNA. NNRTIs Telbivudine
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should not be used as monotherapy because resistant Telbivudine (Tyzeka) is a thymidine analogue that inhibits
the DNA polymerase (reverse transcriptase) of HBV but
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mutants emerge rapidly. Strains of HIV resistant to one
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NNRTI are usually resistant to others as well. NNRTIs are has no effect on the reverse transcriptase of HIV. It is useful
typically used in combination with one or two nucleoside in the treatment of chronic HBV infection.
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analogues.
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Tenofovir
1. Nevirapine—Nevirapine (Viramune) is usually used Tenofovir is described in the section “Inhibitors of
in combination with zidovudine and didanosine. There is Retroviruses.”
no cross-resistance with the nucleoside inhibitors of
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reverse transcriptase described previously. The main side
Inhibitors of Hepatitis C Virus
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effect of nevirapine is a severe skin rash (Stevens-Johnson
syndrome). 1. RNA polymerase inhibitors
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Sofosbuvir
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2. Delavirdine—Delavirdine (Rescriptor) is effective
Sofosbuvir (Sovaldi) is a uridine analogue that inhibits the
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in combination with either zidovudine or zidovudine
RNA polymerase of HCV. It acts as a chain terminating
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plus didanosine. The main side effect of delavirdine is a
drug. It is useful in the treatment of chronic HCV infection
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skin rash.
caused by genotypes 1, 2, 3, and 4.
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3. Efavirenz—Efavirenz (Sustiva) is effective in combi-
nation with zidovudine plus lamivudine. The most com- Dasabuvir
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mon side effects are referable to the central nervous
system, such as dizziness, insomnia, and headaches.
m
m
Dasabuvir is a nonnucleoside inhibitor of the RNA poly-
merase of HCV. Its precise mode of action is uncertain as of
this writing. It is available in combination with ombitsavir

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4. Etravirine—Etravirine (Intelence) is a second- (an NS5A inhibitor), paritaprevir (a protease inhibitor) and
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generation NNRTI useful in treatment-experienced ritonavir (a booster of protease inhibitor activity). This
patients who have significant viremia. It is most effective
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four-drug combination is called Viekira.
when given in combination with two protease inhibitors,
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darunavir and ritonavir. The most common adverse

effect is a rash, and Stevens-Johnson syndrome has
2. NS5A inhibitors fre
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Ledipasvir
occurred, albeit rarely.
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Ledipasvir is an inhibitor of NS5A, an RNA-binding pro-

5. Rilpivirine—Rilpivirine (Edurant) is a second-gener- tein required for the activity of the RNA polymerase of
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ation NNRTI useful in treatment-naïve adult patients. It HCV. Ledipasvir is available in combination with sofosbu-
is most effective when used in combination with either
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vir (Harvoni) and is useful in the treatment of chronic

tenofovir or emtricitabine. The most common adverse HCV infection caused by genotype 1.
effects are depression and insomnia.
Ombitsavir
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Ombitsavir is another NS5A inhibitor that is available in

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Inhibitors of Hepatitis B Virus combination with dasabuvir (a polymerase inhibitor), pari-

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Adefovir taprevir (a protease inhibitor) and ritonavir (a booster of

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Adefovir (Hepsera) is a nucleotide analogue of adenosine protease inhibitor activity). This four-drug combination is
monophosphate that inhibits the DNA polymerase (reverse called Viekira.
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276 PART III Basic Virology
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Inhibitors of Other Viruses viral protease, thereby preventing the protease from cleav-

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ing the viral precursor. These drugs inhibit production of
Ribavirin
f

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infectious virions but do not affect the proviral DNA and
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Ribavirin (Virazole) is a nucleoside analogue in which a therefore do not cure the infection.
triazole-carboxamide moiety is substituted in place of the
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Monotherapy with PIs should not be used because resis-
normal purine precursor aminoimidazole-carboxamide tant mutants emerge rapidly. These drugs typically are
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(see Figure 35–3). The drug inhibits the synthesis of gua- prescribed in combination with reverse transcriptase inhib-
nine nucleotides, which are essential for both DNA and
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RNA viruses. It also inhibits the 5′ capping of viral mRNA.
Ribavirin aerosol is used clinically to treat pneumonitis
caused by respiratory syncytial virus (RSV) in infants and
m
m
itors, such as zidovudine and lamivudine. Ritonavir is typi-
cally used in combination with another PI, as in the
commonly used combination lopinavir/ritonavir (Kaletra).

m
Ritonavir inhibits the enzymes that metabolize the other
to treat severe influenza B infections. PI, which effectively raise the concentration of the other
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drug (e.g., lopinavir in the Kaletra combination). Ritonavir
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INHIBITION OF INTEGRASE “boosts” lopinavir is the way to remember it.
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The side effects of PIs include nausea, diarrhea, and
Raltegravir (Isentress) is an integrase inhibitor (i.e., it abnormal fat accumulation in the back of the neck that can
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blocks the HIV-encoded integrase that mediates the inte- result in a “buffalo hump” appearance. These abnormal fat
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gration of the newly synthesized viral DNA into host cell
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deposits can be disfiguring and cause patients to stop tak-
DNA). Two additional integrase inhibitors are available: ing the drug. The fat deposits are a type of lipodystrophy;
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dolutegravir (Tivicay) and elvitegravir (Stribild). the metabolic process by which this occurs is unknown.
Indinavir can cause kidney stones; thus extra water should
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be consumed to reduce the likelihood of stone formation.
INHIBITION OF CLEAVAGE OF
PRECURSOR POLYPEPTIDES Inhibitors of Hepatitis C Virus
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(PROTEASE INHIBITORS)
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Boceprevir (Victrelis), simeprevir (Olysio), telaprevir
Inhibitors of Human Immunodeficiency (Incivek), and paritaprevir (component of Viekira) are PIs
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that block a serine protease required for the replication of
Virus
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hepatitis C virus. They are approved for the treatment of
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Members of the protease inhibitor (PI) class of drugs, such chronic hepatitis C caused by hepatitis C virus (genotype 1)
as saquinavir (Invirase, Fortovase), indinavir (Crixivan),
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in combination with peginterferon and ribavirin. The
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ritonavir (Norvir), lopinavir/ritonavir (Kaletra), atazanavir most important adverse effect of these drugs is anemia.
(Reyataz), tipranavir (Aptivus), amprenavir (Agenerase) Paritaprevir is an inhibitor of HCV protease that is avail-
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and its prodrug fosamprenavir (Lexiva), darunavir (Prezista), able in combination with ombitsavir (an NS5A inhibitor),
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and nelfinavir (Viracept), inhibit the protease encoded by dasabuvir (a polymerase inhibitor), and ritonavir (a booster
HIV (Figure 35–5). The protease cleaves the gag and pol of protease inhibitor activity). This four-drug combination
precursor polypeptides to produce several nucleocapsid is called Viekira.
proteins (e.g., p24) and enzymatic proteins (e.g., reverse
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transcriptase) required for viral replication. These inhibi-
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tors contain peptide bonds that bind to the active site of the INHIBITION OF VIRAL PROTEIN
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SYNTHESIS
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Interferon fre
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H3C CH3
The mode of action of interferon is described in Chapter 33.
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O C
H
Recombinant alpha interferon is effective in the treatment
N H O CH2 C N CH3
H of some patients with chronic hepatitis B and chronic hepa-
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N C C CH2 H titis C infections. Note that the use of alpha interferon and
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C C N C N
H
pegylated alpha inteferon (see next paragraph) for chronic
O H CH2 H H OH HCV infection has been significantly reduced due to the
H availability of newer less toxic drug regimens.
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C It also causes regression of condylomata acuminata
O NH2
lesions caused by human papillomavirus and the lesions of
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FIGURE 35–5 Structure of the protease inhibitor saquinavir. Kaposi’s sarcoma caused by human herpesvirus-8.
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Note the presence of several peptide bonds, which interact with the Pegylated interferon (peginterferon), which is alpha
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active site of the protease. An arrow indicates one of the peptide interferon conjugated to polyethylene glycol, is used for the
bonds. treatment of chronic hepatitis B and C. The advantage of
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CHAPTER 35 Antiviral Drugs 277
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TABLE 35–4 Chemoprophylactic Use of Drugs Described in This Chapter

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f Number of Chapter for

f
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Drug Use Additional Information
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Amantadine Prevention of influenza during outbreaks caused by influenza A virus 39
Acyclovir Prevention of disseminated HSV or VZV disease in immunocompromised 37
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patients
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Ganciclovir Prevention of disseminated CMV disease in immunocompromised 37
patients, especially retinitis in AIDS patients
Oseltamivir Prevention of influenza during outbreaks caused by influenza A and 39
B virus
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Palivizumab Prevention of bronchiolitis and pneumonia caused by respiratory syncytial 39
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virus in infants
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Zidovudine or nevirapine Prevention of HIV infection of neonate 45
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Tenofovir, emtricitabine, and raltegravir Prevention of HIV infection in needle-stick injuries 45
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Tenofovir, plus emtricitabine Pre-exposure prophylaxis of HIV infection in high risk individuals 45
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AIDS = acquired immunodeficiency syndrome; CMV = cytomegalovirus; HIV = human immunodeficiency virus; HSV = herpes simplex virus; VZV = varicella-zoster virus.
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pegylated interferon is that it has a longer half-life than This enzyme is located on the surface of influenza virus
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unconjugated alpha interferon and can be administered
once a week instead of three times a week.
m
m
and is required for the release of the virus from infected
cells. Inhibition of release of influenza virus limits the
infection by reducing the spread of virus from one cell to

m
Fomivirsen another. These drugs are effective against both influenza
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A and B viruses, in contrast to amantadine, which is
Fomivirsen (Vitravene) is an antisense DNA that blocks the
effective only against influenza A virus. These drugs are
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replication of CMV. Antisense DNA is a single-stranded
effective against strains of influenza virus resistant to
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DNA whose base sequence is the complement of the viral
amantadine.
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mRNA. Antisense DNA binds to the mRNA within the
infected cell and prevents it from being translated into viral
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protein. Fomivirsen is approved for the intraocular treat-
ment of CMV retinitis. It is the first and, at present, the CHEMOPROPHYLAXIS
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only antisense molecule to be approved for the treatment of In most instances, the antiviral agents described in this
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m
human disease. chapter are used to treat infectious diseases. However, there
are times when they are used to prevent diseases from
occurring—a process called chemoprophylaxis. Table 35–4
INHIBITION OF RELEASE OF VIRUS
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describes the drugs used for this purpose and the situations
Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir in which they are used. For more information, see the
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(Rapivab) inhibit the neuraminidase of influenza virus. chapters on the individual viruses.
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PEARLS
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• Selective toxicity is the ability of a drug to inhibit viral replica- • Maraviroc inhibits the binding of the gp120 of HIV to the CCR-5
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tion without significantly damaging the host cell. It is difficult receptor on the cell.
to achieve a high degree of selective toxicity with antiviral
m

• Enfuvirtide is a “fusion inhibitor.” It inhibits the fusion of HIV

drugs because the virus can only replicate within cells and uses with the cell membrane by binding to gp41, an envelope pro-
many cellular functions during replication. tein of HIV.
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Inhibitors of Early Events Inhibitors of Herpesviruses: Nucleoside Inhibitors

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• Amantadine inhibits the uncoating of influenza A virus by • Acyclovir inhibits the DNA polymerase of herpes simplex
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blocking “ion channel” activity of the viral matrix protein virus (HSV) type 1, HSV-2, and varicella-zoster virus (VZV).
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(M2 protein). The drug has no effect on influenza B or C viruses. Acyclovir must be activated within the infected cell by a
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278 PART III Basic Virology
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virus-encoded thymidine kinase that phosphorylates the Inhibitors of Hepatitis C Virus
drug. Acyclovir is not phosphorylated in uninfected cells, and
f

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• Sofosbuvir inhibits RNA polymerase and is useful in the
cellular DNA synthesis is not inhibited. Selective toxicity is high,
treatment of chronic HCV infection.
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and there are very few adverse effects.
• Ledipasvir inhibits NS5A protein of HCV thereby inhibiting
• Acyclovir is a chain-terminating drug because it lacks a
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synthesis of the progeny RNA genomes of HCV.
hydroxyl group in the 3′ position. It does not have a ribose ring
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(i.e., it is acyclo, meaning without a ring). The absence of this
hydroxyl group means the next nucleoside triphosphate can- Inhibitors of Other Viruses
not be added and the replicating DNA chain is terminated. • Ribavirin is a guanosine analogue that can inhibit nucleic acid
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• Acyclovir inhibits viral replication but has no effect on the synthesis of several viruses. It is useful in severe respiratory
latency of HSV-1, HSV-2, and VZV.
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syncytial virus infections.
• Ganciclovir action is very similar to that of acyclovir, but it is effec-
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tive against cytomegalovirus (CMV), whereas acyclovir is not. Integrase Inhibitors
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• Raltegravir, elvitegravir, and dolutegravir inhibit the integrase
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Inhibitors of Herpesviruses: Nonnucleoside Inhibitors encoded by HIV, which blocks the integration of HIV DNA into
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host cell DNA.
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• Foscarnet inhibits the DNA polymerase of all herpesviruses
but is clinically useful against HSV and CMV. It is a pyrophos-
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phate analogue that inhibits the cleavage of pyrophosphate Protease Inhibitors
from the nucleoside triphosphate that has been added to the
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• Indinavir and other similar drugs inhibit the virus-encoded
growing DNA chain.
protease of HIV. Inhibition of the protease prevents cleavage
of precursor polypeptides, which prevents formation of the
Inhibitors of Retroviruses: Nucleoside Inhibitors (NRTIs)
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structural proteins of the virus. Synthesis of infectious virus is
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• Zidovudine inhibits the DNA polymerase (reverse transcrip- inhibited, but the viral DNA integrated into the host cell DNA is
tase) of HIV. It is a chain-terminating drug because it has an unaffected.
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azide group in place of the hydroxyl group in the 3′ position. • Boceprevir, simeprevir, telaprevir, and paritaprevir inhibit the
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Unlike acyclovir, it does not require a viral-encoded kinase to be protease of hepatitis C virus.
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phosphorylated. Cellular kinases phosphorylate the drug, so it is
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active in uninfected cells and significant adverse effects can occur. Inhibitors of Viral Protein Synthesis
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• Other drugs with the same mode of action include lamivudine,
• Interferons inhibit virus replication by degrading mRNA
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didanosine, emtricitabine, stavudine, abacavir, and tenofovir.
and blocking protein synthesis. (See Chapter 33 for more
m

m
information.) Pegylated interferon-alpha is used in the treat-
Inhibitors of Retroviruses: Nonnucleoside Inhibitors ment of chronic hepatitis B and acute hepatitis C.
(NNRTIs) • Fomivirsen is an antisense DNA that binds to the mRNA of CMV,
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• Nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine which prevents the mRNA from being translated into viral
inhibit the DNA polymerase (reverse transcriptase) of HIV proteins.
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but are not nucleoside analogues.
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Inhibitors of Release of Virus
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Inhibitors of Hepatitis B Virus • Zanamivir and oseltamivir inhibit the neuraminidase of fre
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• Adefovir, entecavir, lamivudine, and telbivudine inhibit the both influenza A and B viruses. This inhibits the release
DNA polymerase of hepatitis B virus (HBV). These drugs are of progeny virus, which reduces spread of virus to neigh-
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useful in the treatment of chronic HBV infection. boring cells.

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SELF-ASSESSMENT QUESTIONS (D) Ritonavir inhibits the virus-encoded protease that is required
to cleave viral precursor polypeptides into functional proteins.
1. Regarding the mode of action of antiviral drugs, which one of the (E) Zidovudine inhibits the virus-encoded RNA polymerase that is
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following is the MOST accurate? required to synthesize viral mRNA.

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(A) Amantadine inhibits the virus-encoded DNA polymerase that 2. Which one of the following best describes the action of oseltami-
is required to synthesize viral progeny DNA. vir (Tamiflu)?
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(B) Lamivudine inhibits the cell-encoded RNA polymerase that is (A) Inhibits reverse transcriptase
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required to synthesize viral genome. (B) Inhibits the RNA-dependent RNA polymerase in the virion
(C) Raltegravir inhibits the translation of viral mRNA into viral (C) Inhibits the DNA-dependent RNA polymerase in the infected
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proteins. cell
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CHAPTER 35 Antiviral Drugs 279
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(D) Inhibits viral protein synthesis by binding to the 60S ribosomal ANSWERS
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subunit
f(E) Inhibits the neuraminidase required for release of virus from 1. (D)

f
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the infected cell 2. (E)
3. (D)
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3. Which one of the following is a well-described adverse effect of the
protease inhibitors used in the treatment of HIV infection? 4. (E)
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(A) Bone marrow suppression
(B) Central nervous system disturbances
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(C) Drug-induced hepatitis PRACTICE QUESTIONS: USMLE &
(D) Lipodystrophy COURSE EXAMINATIONS
(E) Peripheral neuropathy
Questions on the topics discussed in this chapter can be found
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4. Regarding acyclovir, which one of the following is the MOST
in the Basic Virology section of Part XIII: USMLE (National
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accurate?
(A) Bone marrow suppression is a significant adverse effect. Board) Practice Questions starting on page 720. Also see Part
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(B) It terminates the latent state of both herpes simplex virus type XIV: USMLE (National Board) Practice Examination starting
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1 and type 2. on page 751.
(C) It inhibits the virus-encoded thymidine kinase that is required
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to synthesize viral DNA.
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(D) Resistance to acyclovir is primarily caused by proton pumps
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that export the drug from the cell.
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(E) It is a chain-terminating drug because it does not have a com-
plete ribose ring and therefore lacks a hydroxyl group in the
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correct position.
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