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Journal of Clinical Virology 30 (2004) 115–133

Review
Antiviral drugs in current clinical use夽
Erik De Clercq∗
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received in revised form 12 February 2004; accepted 12 February 2004

Abstract

The current armamentarium for the chemotherapy of viral infections consists of 37 licensed antiviral drugs. For the treatment of human
immunodeficiency virus (HIV) infections, 19 compounds have been formally approved: (i) the nucleoside reverse transcriptase inhibitors
(NRTIs) zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; (ii) the nucleotide reverse transcriptase
inhibitor (NtRTI) tenofovir disoproxil fumarate; (iii) the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine
and efavirenz; (iv) the protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir (combined with ritonavir at a 4/1
ratio) and atazanavir; and the viral entry inhibitor enfuvirtide. For the treatment of chronic hepatitis B virus (HBV) infections, lamivudine
as well as adefovir dipivoxil have been approved. Among the anti-herpesvirus agents, acyclovir, valaciclovir, penciclovir (when applied
topically), famciclovir, idoxuridine and trifluridine (both applied topically) as well as brivudin are used in the treatment of herpes simplex
virus (HSV) and/or varicella-zoster virus (VZV) infections; and ganciclovir, valganciclovir, foscarnet, cidofovir and fomivirsen (the latter
upon intravitreal injection) have proven useful in the treatment of cytomegalovirus (CMV) infections in immunosuppressed patients (i.e.
AIDS patients with CMV retinitis). Following amantadine and rimantadine, the neuraminidase inhibitors zanamivir and oseltamivir have
recently become available for the therapy (and prophylaxis) of influenza virus infections. Ribavirin has been used (topically, as aerosol) in
the treatment of respiratory syncytial virus (RSV) infections, and the combination of ribavirin with (pegylated) interferon-alpha has received
increased acceptance for the treatment of hepatitis C virus (HCV) infections.
© 2004 Elsevier B.V. All rights reserved.

Keywords: Antiviral drugs; HIV; HBV; HSV; VZV; CMV; HCV; Influenza; RSV

1. Introduction 2. Anti-HIV compounds

The current antiviral drug armamentarium comprises al- 2.1. Nucleoside reverse transcriptase inhibitors
most 40 compounds that have been officially approved for (NRTIs)
clinical use. Most of the approved drugs date from the last 5
years, and at least half of them are used for the treatment of • Zidovudine
human immunodeficiency virus (HIV) infections. The other ◦ Structure (Fig. 1): 3 -azido-2 ,3 -dideoxythymidine,
antivirals that are currently available are primarily used for azidothymidine (AZT), ZDV, Retrovir® .
the treatment of hepatitis B virus (HBV), herpesvirus (herpes ◦ Activity spectrum: HIV (types 1 and 2).
simplex virus (HSV), varicella-zoster virus (VZV), and cy- ◦ Mechanism of action: targeted at the reverse tran-
tomegalovirus (CMV)), influenza virus, respiratory syncytial scriptase (RT) of HIV, acts as chain terminator in
virus (RSV) and hepatitis C virus (HCV) infections. This ar- the RT reaction, following intracellular phosphory-
ticle should be considered as an update of the review article lation to AZT 5 -triphosphate, and, after removal of
on “Antiviral drugs: current state of the art” published previ- the diphosphate group, incorporation of AZT 5 -mo-
ously in the Journal of Clinical Virology (De Clercq, 2001). nophosphate at the 3 -end of the viral DNA chain
(Scheme 1).
◦ Principal indication(s): HIV infection, in combination
夽 According to the Keynote lecture presented at the ESCV (Euro-
with other anti-HIV agents (such as lamivudine and
pean Society of Clinical Virology) Winter Meeting, 15–17 January 2004,
Copenhagen, Denmark.
abacavir).
∗ Tel.: +32-16-337341; fax: +32-16-337340. ◦ Administered: orally at 600 mg per day (two 300 mg
E-mail address: erik.declercq@rega.kuleuven.ac.be (E. De Clercq). tablets daily).

1386-6532/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2004.02.009
116 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

O O
CH3 N
HN HN

O N N
N
HO HO
O O

Didanosine
N3
Fig. 2.
Zidovudine

Fig. 1.
◦ Administered: orally at 400 mg per day (Videx® : two
• Didanosine 100 mg tablets twice a day or two 200 mg tablets
◦ Structure (Fig. 2): 2 ,3 -dideoxyinosine (ddI), Videx® , once a day; Videx® EC: one 400 mg capsule once a
Videx® EC. day).
◦ Activity spectrum: HIV (types 1 and 2). • Zalcitabine
◦ Mechanism of action: targeted at HIV RT, acts as chain ◦ Structure (Fig. 3): 2 ,3 -dideoxycytidine (ddC), Hivid® .
terminator, following intracellular phosphorylation to ◦ Activity spectrum: HIV (types 1 and 2).
2 ,3 -dideoxyadenosine (ddA) 5 -triphosphate, and, af- ◦ Mechanism of action: targeted at HIV RT, acts as chain
ter removal of the diphosphate group, incorporation of terminator, following intracellular phosphorylation to
ddA 5 -monophosphate at the 3 -end of the viral DNA ddC 5 -triphosphate, and, after removal of the diphos-
chain. phate group, incorporation of ddC 5 -monophosphate
◦ Principal indication(s): HIV infection, especially at the 3 -end of the viral DNA chain.
advanced HIV disease, in combination with other ◦ Principal indication(s): HIV infection, especially in
anti-HIV agents. adult patients with advanced HIV disease that are in-

Scheme 1. Mechanism of action of azidothymidine (AZT). AZT needs to be phosphorylated, in three steps, to the triphospate form before it can interfere
with the reverse transcriptase reaction (after De Clercq, 2002a).
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 117

NH2 NH2

N N

O N O N
HO
O HO S

O
Zalcitabine
Lamivudine
Fig. 3.
Fig. 5.

tolerant or unresponsive to zidovudine, in combination ◦ Administered: orally at 300 mg per day (one 150 mg
with other anti-HIV agents (not didanosine). tablet twice a day, or one 300 mg tablet once a day).
◦ Administered: orally at 2.25 mg per day (one 0.75 mg In the treatment of HIV infections, lamivudine can be
tablet every 8 h). combined with zidovudine (Combivir® ), or with zi-
• Stavudine dovudine and abacavir (Trizivir® ). Combivir® tablets
◦ Structure (Fig. 4): 2 ,3 -didehydro-2 ,3 -dideoxythymi- contain 300 mg zidovudine and 150 mg lamivudine per
dine (d4T), Zerit® . tablet and are administered orally (two tablets daily).
◦ Activity spectrum: HIV (types 1 and 2). Trizivir® tablets contain 300 mg zidovudine, 150 mg
◦ Mechanism of action: targeted at HIV RT, acts as chain lamivudine and 300 mg abacavir per tablet and are ad-
terminator, following intracellular phosphorylation to ministered orally (two tablets daily). Lamivudine is ad-
d4T 5 -triphosphate, and, after removal of the diphos- ministered orally at 100 mg per day in the treatment of
phate group, incorporation of d4T 5 -monophosphate HBV infections, currently as monotherapy; in the fu-
at the 3 -end of the viral DNA chain. ture, possibly in combination with adefovir dipivoxil.
◦ Principal indication(s): HIV infection, especially • Abacavir
advanced HIV disease, in combination with other ◦ Structure (Fig. 6): (1S,4R)-4-[2-amino-6-(cyclopropyl-
anti-HIV agents. amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol su-
◦ Administered: orally at 80 mg per day (one 40 mg cap- ccinate (ABC), Ziagen® .
sule every 12 h). ◦ Activity spectrum: HIV (types 1 and 2).
• Lamivudine ◦ Mechanism of action: targeted at HIV RT, acts as chain
◦ Structure (Fig. 5): (−)-␤-l-3 -thia-2 ,3 -dideoxycytidine terminator, following intracellular phosphorylation and
(3TC), Epivir® , Zeffix® . conversion (deamination) to the 5 -triphosphate of the
◦ Activity spectrum: HIV (types 1 and 2) and HBV. corresponding guanosine analogue (carbovir), and, af-
◦ Mechanism of action: targeted at HIV RT and HBV ter removal of the diphosphate group, incorporation of
RT, acts as chain terminator, following intracellular carbovir 5 -monophosphate at the 3 -end of the viral
phosphorylation to 3TC 5 -triphosphate, and, after re- DNA chain.
moval of the diphosphate group, incorporation of 3TC ◦ Principal indication(s): HIV infection, in combination
5 -monophosphate at the 3 -end of the viral DNA chain. with other anti-HIV agents such as zidovudine and
◦ Principal indication(s): HIV and HBV infections: for lamivudine (see above).
HIV infection, in combination with other anti-HIV ◦ Administered: orally at 600 mg per day (two 300 mg
agents (such as zidovudine and abacavir). tablets daily).

O NH

CH3 N
HN N
COOH
H2 N N N H2C
O N
HO HO H2C
O COOH

Stavudine Abacavir

Fig. 4. Fig. 6.
118 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

NH2 removal of the diphosphate group, incorporation at the


F
3 -end of the viral DNA chain (Scheme 2).
N ◦ Principal indication(s): HIV infection in combina-
tion with other anti-HIV agents such as lamivudine
O N and efavirrenz (see below); should, however, not be
combined with the combination of lamivudine plus
HO S
abacavir.
◦ Administered: orally at a once-daily dose of a 300 mg
O
tablet.
Emtricitabine
2.3. Non-nucleoside reverse transcriptase inhibitors
Fig. 7. (NNRTIs)

• Emtricitabine • Nevirapine
◦ Structure (Fig. 7): (−)-␤-l-3 -thia-2 ,3 -dideoxy-5- ◦ Structure (Fig. 9): 11-cyclopropyl-5,11-dihydro-4-
fluorocytidine ((−)-FTC) Emtriva® . methyl-6H-dipyrido[3,2-b:2 ,3 -f][1,4]diazepin-6-one,
◦ Activity spectrum: HIV and HBV. Viramune® .
◦ Mechanism of action: similar to that of 3TC. ◦ Activity spectrum: HIV type 1.
◦ Principal indication(s): HIV and HBV infections; has ◦ Mechanism of action: targeted at an allosteric “pocket”,
been recently approved for the treatment of HIV in- non-substrate binding site of the HIV-1 reverse tran-
fections; is currently in Phase III clinical trials for the scriptase (as illustrated for UC781 in Scheme 3).
treatment of HBV infections; will likely be used (in ◦ Principal indication(s): HIV-1 infection, in combina-
the future) in combination with tenofovir disoproxil fu- tion with other anti-HIV agents, particularly NRTIs.
marate as a single tablet to be administered orally once ◦ Administered: orally at 200 mg per day for the first 14
daily. days (one 200 mg tablet per day), then 400 mg per day
◦ Administered: orally at a once-daily 200 mg capsule. (two daily 200 mg tablets).
• Delavirdine
2.2. Nucleotide reverse transcriptase inhibitors ◦ Structure (Fig. 10): 1-(5-methanesulfonamido-1H-
(NtRTIs) indol-2-yl-carbonyl)-4-[3-(1-methylethyl-amino)pyrid-
inyl)piperazine monomethane sulfonate, Rescriptor® .
• Tenofovir disoproxil ◦ Activity spectrum: HIV type 1.
◦ Structure (Fig. 8): fumarate salt of bis(isopropoxy- ◦ Mechanism of action: similar to that of nevirapine.
carbonyloxymethyl) ester of (R)-9-(2-phosphonylme- ◦ Principal indication(s): HIV-1 infection, in combina-
thoxypropyl)adenine, or bis(POC)PMPA, Viread® . tion with other anti-HIV agents (primarily NRTIs).
◦ Activity spectrum: HIV (types 1 and 2) and various ◦ Administered: orally at 1200 mg per day (two 200 mg
other retroviruses, and HBV. tablets three times a day).
◦ Mechanism of action: serves as oral prodrug of teno- • Efavirenz
fovir (PMPA) that is targeted at HIV RT (and HBV ◦ Structure (Fig. 11): (−)6-chloro-4-cyclopropylethynyl-
RT), and acts as chain terminator, following intracellu- 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-
lar phosphorylation to the diphosphate form, and, after one, Sustiva® , Stocrin® .
◦ Activity spectrum: HIV type 1.
◦ Mechanism of action: similar to that of nevirapine.
NH2 ◦ Principal indication(s): HIV-1 infection, in combina-
N tion with other anti-HIV agents (primarily NRTIs and
N NtRTIs).
N ◦ Administered: orally at 600 mg per day (as a once-daily
N
O 600 mg tablet, preferably at bedtime to improve toler-
(CH3)2CH O C O CH2 O O ability of CNS side effects).
P O
(CH3)2CH O C O CH2 O
2.4. Protease inhibitors (PIs)
O CH 3 COOH
HC
• Saquinavir
HC ◦ Structure (Fig. 12): cis-N-tert-butyl-decahydro-2-[2(R)-
COOH
hydroxy-4-phenyl-3(S)-[[N-2-quinolylcarbonyl-l-aspa-
Tenofovir disoproxil fumarate
raginyl]-amino]butyl]-(4aS–8aS)-isoquinoline-3(S)-ca-
Fig. 8. rboxamide methane sulfonate, hard gel capsules,
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 119

Scheme 2. Mechanism of antiviral action of tenofovir (PMPA). PMPA needs to be phosphorylated, in one or two steps, to the diphosphate form before
it interferes, as chain terminator, with the reverse transcriptase reaction (after De Clercq, 2003a).

Invirase® , also available as soft gelatin capsules


(Fortovase® ).
◦ Activity spectrum: HIV (types 1 and 2).
O ◦ Mechanism of action: transition-state, hydroxyethylene-
CH3 H
N based, peptidomimetic inhibitor of HIV protease (as
illustrated for KNI272 in Scheme 4).
◦ Principal indication(s): HIV infection, in combination
N
N N with other anti-HIV agents (NRTIs and some PIs (i.e.
ritonavir)).
◦ Administered: orally at 3600 mg per day (six 200 mg
Nevirapine soft gelatin capsules three times a day (Fortovase® )) or
Fig. 9. 1800 mg per day (three 200 mg hard gel capsules three
120 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

CH3 CH3 CH3


CH
SO2
NH
NH
N N
N N
O
CH3SO3H
Delavirdine

Fig. 10.

F3C
Cl
O

Scheme 3. Interaction of HIV-1 RT with a prototype NNRTI (UC781). N O


H
Features stabilizing the complex between the human immunodeficiency
virus 1 (HIV-1) reverse transcriptase (RT) and the non-nucleoside reverse Efavirenz
transcriptase inhibitor UC781. The hydrogen bond with K101, and the
two methyl-group–aromatic-ring interactions are shown explicitly. Other Fig. 11.
main hydrophobic contacts are shown with bold lines; minor ones are
shown with faint lines (after De Clercq, 2002a).

times a day (Invirase® )), to be taken with a meal or up O


H
to two hours after a full meal. N
• Ritonavir N N N
H
◦ Structure (Fig. 13): [5S-(5R,8R,10R,11R)]-10-hydroxy- O NH2 OH
2-methyl-5-(1-methylethyl)-1-[2-(methylethyl)-4-thia- O NH
zolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tet- O
CH3SO2 OH H 3C CH 3
raazatridecan-13-oic acid 5-thiazolylmethyl ester,
Norvir® . CH3
Saquinavir
◦ Activity spectrum: HIV (types 1 and 2).
◦ Mechanism of action: as for saquinavir. Fig. 12.

Scheme 4. Interaction of HIV protease with a prototype PI (KNI272). Ribbon diagram of human immunodeficiency virus (HIV) protease complexed with
the peptidomimetic protease inhibitor KNI272; derived from the crystal structure. The inhibitor is shown as a space-filling model, and the two active-site
aspartic acids are shown as sticks; both have standard CPK coloring (after De Clercq, 2002a).
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 121

H3C CH3
O O
H
N
S N N N O N
H H
N CH3 O OH S
H3C
CH3

Ritonavir

Fig. 13.

◦ Principal indication(s): HIV infection, in combina- CH3


tion with other anti-HIV agents (NRTIs and PIs (i.e. H3C CH 3
saquinavir)).
O NH
◦ Administered: orally at 1200 mg per day (six 100 mg S
CH 3 O
capsules, twice a day to be taken with food). CH3SO 2 OH
• Indinavir HO
N N
◦ Structure (Fig. 14): [(1S,2R,5(S)-2,3,5-trideoxy-N- H
OH
(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-pyridinylmethyl)-1-pi-
perazinyl]- 2- (phenylmethyl - d - erythro)pentonamide,
Nelfinavir
Crixivan® .
◦ Activity spectrum: HIV (types 1 and 2). Fig. 15.
◦ Mechanism of action: as for saquinavir.
◦ Principal indication(s): HIV infection, in combination ◦ Administered orally at 2250 mg per day (three 250 mg
with other anti-HIV agents (i.e., NRTIs). tablets three times a day) or 2500 mg per day (five
◦ Administered: orally at 2400 mg per day (two 400 mg 250 mg tablets twice a day), to be taken with a
capsules every 8 h to be taken on empty stomach), plus meal.
hydration (at least 1.5 l liquid daily). • Amprenavir
• Nelfinavir ◦ Structure (Fig. 16): (3S)-tetrahydro-3-furyl-N-[(S,2R)-
◦ Structure (Fig. 15): [3S-(3R,4aR,8aR,2 S)]-2-[2 -hydro- 3-(4-amino-N-isobutylbenzene-sulfonamido)-1-benzyl-
xy-3 -phenylthiomethyl-4 -aza-5 -oxo-5 -[2 -methyl-3- 2-hydroxypropyl]carbamate, Agenerase® , Prozei® .
hydroxyphenyl)-pentyl]-3-(N - (tert-butyl) - carboxami- ◦ Activity spectrum: HIV (types 1 and 2).
de)-decahydro isoquinoline methane sulfonate, ◦ Mechanism of action: as for saquinavir.
Viracept® . ◦ Principal indication(s): HIV infection, in combination
◦ Activity spectrum: HIV (types 1 and 2). with other anti-HIV agents (i.e. NRTIs).
◦ Mechanism of action: as for saquinavir. ◦ Administered orally at 2400 mg per day (eight 150 mg
◦ Principal indication(s): HIV infection, in combination capsules twice a day, to be taken with or without food,
with other anti-HIV agents (i.e. NRTIs). but not with a high-fat meal).

N OH NH2
H
N N O
N O O
S
O O N N O
O NH HO H
OH CH3
H 3C CH3
CH3 CH3
Indinavir Amprenavir

Fig. 14. Fig. 16.


122 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

◦ Principal indication(s): HIV infection, in combination


with other anti-HIV agents (i.e. NRTIs).
◦ Administered: orally, as Kaletra® , at 1000 mg per day
CH3 OH
H O (three 166.6 mg capsules twice a day; each capsule con-
O N
N
N NH taining 133.3 mg lopinavir + 33.3 mg ritonavir), to be
H taken with food.
O O
CH3 H3C C H3
• Atazanavir
◦ Structure (Fig. 18): 1-[4-(pyridin-2-yl)phenyl]-5(S)-
2,5-bis-{[N-(methoxycarbonyl)-l-tert-leucinyl]amino}-
Lopinavir 4(S)-hydroxy-6-phenyl-2-azahexane, CGP 73547,
BMS-232632, Reyataz® .
Fig. 17.
◦ Activity spectrum: HIV (type 1 and type 2).
◦ Mechanism of action: as for saquinavir.
◦ Principal indication(s): HIV infection, in combination
with other anti-HIV agents (i.e. NRTIs) (Hussar, 2003).
◦ Administered: orally at 400 mg per day (once daily two
N 200 mg capsules), to be taken with food.

2.5. Viral entry inhibitors


O OH O
H H
N N N O • Enfuvirtide
O N
H
N
H ◦ Structure (Fig. 19): 36-amino acid peptide, corre-
O O sponding to amino acid residues 643-678 of the viral
glycoprotein precursor gp160 (or amino acid residues
127–162 of the viral glycoprotein gp41), DP-178,
pentafuside, T-20, Fuzeon® .
Atazanavir ◦ Activity spectrum: HIV-1.
Fig. 18. ◦ Mechanism of action: inhibits virus-cell fusion, through
a coil–coil interaction with its homologous region in
gp41 (Scheme 5).
• Lopinavir ◦ Principal indication(s): HIV infection, in combination
◦ Structure (Fig. 17): N-(4(S)-(2-(2,6-dimethylphenoxy)- with other anti-HIV agents; has been recently approved
acetylamino)-3(S)-hydroxy-5-phenyl-1(S)-benzylpent- for clinical use following demonstration of antiretrovi-
yl)-3-methyl-2(S)-(2-oxo(1,3-diazaperhydroinyl)butan- ral and immunologic benefit when added onto an op-
amine, combined with ritonavir at 4/1 ratio; ABT-378/r, timized antiretroviral regimen (Lalezari et al., 2003;
Kaletra® . Lazzarin et al., 2003).
◦ Activity spectrum: HIV (types 1 and 2). ◦ Administered: by subcutaneous injection, twice daily at
◦ Mechanism of action: as for saquinavir. a dose of 90 mg.

Membrane
Fusion Leucine zipper spanning
peptide region region 152 amino acids
NH2 C C COOH
517 532 558 595 643 678 689 710
DP-107 DP-178

YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF

Enfuvirtide
Fig. 19.
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 123

Scheme 5. Model for HIV-1 Envelope fusion with the cell membrane and inhibition of fusion by enfuvirtide (T20). Binding of CD4 to the gp120
subunit induces exposure of a conserved region in gp120 implicated in coreceptor binding. Binding to coreceptor could bring the viral envelope in closer
proximity to the target membrane, enabling the fusion peptide to insert in the bilayer, or it could impact formation of the six-helix bundle, the transition
to which leads to membrane fusion. Enfuvirtide binds to the grooves on the outside of the triple-stranded coiled-coil formed by the NH2 -terminal helices.
Therefore, it prevents transition to the six-helix bundle and membrane fusion (after Doms and Moore, 2000).

3. Anti-HBV compounds Marcellin et al., 2003). Adefovir dipivoxil has been,


but is no longer, pursued for the treatment of HIV
• Lamivudine infections.
Lamivudine (Fig. 5) is used for the treatment of both ◦ Administered: orally as a single dose of 10 mg per day.
HIV and HBV infections, for the latter at an oral dose of • Emtricitabine
100 mg per day. Emtricitabine (Fig. 7) has been recently licensed for the
• Adefovir dipivoxil treatment of HIV infections and is being pursued for the
◦ Structure (Fig. 20); bis(pivaloyloxymethyl)ester of treatment of HBV infections.
9-(2-phosphonylmethoxyethyl)adenine, or bis(POM)-
PMEA, Hepsera® .
◦ Activity spectrum: HBV, HIV and other retroviruses, 4. Anti-herpesvirus compounds
and, to a lesser extent, also herpesviruses (HSV, CMV,
etc.). 4.1. HSV and VZV inhibitors
◦ Mechanism of action: serves as oral prodrug of adefovir
(PMEA) that is targeted at HBV RT (and HIV RT), and • Acyclovir
acts as chain terminator, following intracellular phos- ◦ Structure (Fig. 21): 9-(2-hydroxyethoxymethyl)guanine,
phorylation to the diphosphate form, and incorporation acycloguanosine (ACG), acyclovir, aciclovir (ACV),
at the 3 -end of the viral DNA chain (Scheme 6). Zovirax® .
◦ Principal indication(s): HBV infection, where it has ◦ Activity spectrum: HSV (types 1 and 2) and VZV.
proven successful in the treatment of lamivudine- ◦ Mechanism of action: targeted at the viral DNA poly-
resistant HBV infections (Hadziyannis et al., 2003; merase, acts as chain terminator, following intracellular
phosphorylation to ACV triphosphate and incorpora-
NH2 tion of ACV monophosphate at the 3 -end of the viral
DNA chain (Scheme 7). The first phosphorylation step
N is catalyzed by the virus-encoded thymidine kinase
N
(TK), which explains the specificity of acyclovir for
N N HSV-1, HSV-2 and VZV.
O
◦ Principal indication(s): mucosal, cutaneous and sys-
(CH3)3C C O CH2 O O temic HSV-1 and HSV-2 infections (including herpetic
P O
(CH3)3C C O CH2 O keratitis, herpetic encephalitis, genital herpes, neona-
O
tal herpes and herpes labialis) and VZV infections
(including varicella and herpes zoster).
Adefovir dipivoxil
◦ Administered: orally at 1000 mg per day (five 200 mg
Fig. 20. tablets (genital herpes)) or 4000 mg per day (four times
124 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

Scheme 6. Mechanism of antiviral action of adefovir (PMEA). PMEA needs to be phosphorylated, in one or two steps, to the diphosphate form before
it interferes, as chain terminator, with the reverse transcriptase reaction (after De Clercq, 2003a).

five 200 mg tablets (herpes zoster)), topically as a 3% ◦ Activity spectrum: as for acyclovir.
ophthalmic cream (herpetic keratitis) or 5% cream ◦ Mechanism of action: serves as oral prodrug of acy-
(herpes labialis), or intravenously at 30 mg/kg per day clovir, then acts as described for acyclovir.
(herpetic encephalitis, and other severe HSV or VZV ◦ Principal indication(s): HSV and VZV infections
infections). that can be approached by oral therapy (i.e. gen-
• Valaciclovir ital herpes, herpes zoster). Also used in the pro-
◦ Structure (Fig. 22): l-valine ester of acyclovir (VACV), phylaxis of CMV infections in transplant recipi-
Zelitrex® , Valtrex® . ents.
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 125

O O

N N
HN HN

H 2N N N H2N N N

O
H
HO O H2N C C O O
CH
Acyclovir H3C C H3

Fig. 21. Valaciclovir

Fig. 22.

◦ Administered: orally at 1000 mg per day (two 500 mg • Famciclovir


tablets (genital herpes)) up to 3000 mg per day (three ◦ Structure (Fig. 24): diacetyl ester of 9-(4-hydroxy-
times two 500 mg tablets (herpes zoster)). 3-hydroxymethyl-but-1-yl)-6-deoxyguanine (FCV),
• Penciclovir Famvir® .
◦ Structure (Fig. 23): 9-(4-hydroxy-3-hydroxymethyl- ◦ Activity spectrum: HSV-1, HSV-2 and VZV.
but-1-yl)guanine (PCV), Denavir® , Vectavir® . ◦ Mechanism of action: serves as oral prodrug of
◦ Activity spectrum: HSV-1, HSV-2 and VZV. penciclovir (to which it is converted by hydrol-
◦ Mechanism of action: essentially similar to that of acy- ysis of the two acetyl groups and oxidation at
clovir. the 6-position), then acts as described for penci-
◦ Principal indication(s): mucocutaneous HSV infec- clovir.
tions, particularly recurrent herpes labialis (cold sores). ◦ Principal indication(s): HSV-1, HSV-2 and VZV in-
◦ Administered: topically as a 1% cream. fections.

Scheme 7. Mechanism of antiviral action of acyclovir (ACV). ACV targets viral DNA polymerases, such as the herpesvirus (HSV) DNA polymerase. Before
it can interact with viral DNA synthesis, it needs to be phosphorylated intracellularly, in three steps, to the triphosphate form. The first phosphorylation
step is ensured by the HSV-encoded thymidine kinase (TK), and is therefore confined to virus-infected cells (after De Clercq, 2002a).
126 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

O O

N CF3
HN HN

H2N N N O N
HO
O

HO

OH
Trifluridine
OH
Penciclovir Fig. 26.

Fig. 23.
◦ Principal indication(s): HSV keratitis.
◦ Administered: topically as eye drops (0.1%) or oph-
N
N thalmic cream.
• Trifluridine
N
H 2N N ◦ Structure (Fig. 26): 5-trifluoromethyl-2 -deoxyuridine,
O trifluorothymidine (TFT), Viroptic® .
◦ Activity spectrum: HSV-1, HSV-2 and VZV.
H 3C O ◦ Mechanism of action: inhibits conversion of dUMP to
dTMP by thymidylate synthase, following intracellular
phosphorylation to TFT 5 -monophosphate.
H3C O ◦ Principal indication(s): HSV keratitis.
◦ Administered: topically as eye drops (1%) or oph-
O thalmic cream.
Famciclovir • Brivudin
◦ Structure (Fig. 27): (E)-5-(2-bromovinyl)-2 -deoxyuri-
Fig. 24.
dine, bromovinyldeoxyuridine (BVDU), Zostex® ,
Zonavir® , Zerpex® .
◦ Activity spectrum: HSV (type 1), VZV and some other
◦ Administered: orally at 750 mg per day (250 mg tablet
(veterinarily important) herpesviruses.
every 8 h, three times a day), or 1500 mg per day
◦ Mechanism of action: targeted at the viral DNA poly-
(500 mg every 8 h).
merase, can act as competitive inhibitor (with respect to
• Idoxuridine
the normal substrate, dTTP) after intracellular phospho-
◦ Structure (Fig. 25): 5-iodo-2 -deoxyuridine (IDU,
rylation to BVDU 5 -triphosphate; can also act as alter-
IUdR), Herpid® , Stoxil® , Idoxene® , Virudox® , etc.
nate substrate and be incorporated into the viral DNA,
◦ Activity spectrum: HSV-1, HSV-2 and VZV.
thus leading to a reduced integrity and functioning of
◦ Mechanism of action: incorporated into (viral/cellular)
the viral DNA (Scheme 8). The first and second phos-
DNA, following intracellular phosphorylation to IDU
phorylation steps are catalyzed by the virus-encoded
5 -triphosphate (in virus-infected and uninfected cells).
(HSV-1 TK, VZV TK), which explains the remarkable
specificity of BVDU for these viruses.

O O

I Br
HN HN

O N O N
HO HO
O O

OH OH
Idoxuridine Brivudin

Fig. 25. Fig. 27.


E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 127

Scheme 8. Mechanism of antiviral action of BVDU. Following uptake by the (virus-infected) cells, BVDU is phosphorylated by the virus-encoded
thymidine kinase (TK) to the 5 -monophosphate (BVDU-MP) and 5 -diphosphate (BVDU-DP), and further onto the 5 -triphosphate (BVDU-TP) by cellular
kinases, i.e. nucleoside 5 -diphosphate (NDP) kinase. BVDU-TP can act as a competitive inhibitor/alternative substrate of the viral DNA polymerase,
and as a substrate it can be incorporated internally (via internucleotide linkages) into the (growing) DNA chain (after De Clercq, 2002b).

◦ Principal indication(s): HSV-1 and VZV infections, ◦ Activity spectrum: HSV (types 1 and 2), CMV and some
particularly herpes zoster, but also HSV-1 keratitis and other herpesviruses.
herpes labialis. Brivudin has been licensed for the treat- ◦ Mechanism of action: targeted at the viral DNA poly-
ment of herpes zoster in immunocompetent patients in merase, where it mainly acts as chain terminator, fol-
a number of European countries. lowing intracellular phosphorylation to GCV triphos-
◦ Administered: orally at 125 mg per day, once-daily phate and incorporation of GCV monophosphate at the
(herpes zoster); can also be administered topically, as 3 -end of the viral DNA chain. First phosphorylation
0.1–0.5% eye drops (herpetic keratitis) or 5% cream step is catalyzed by the HSV-encoded thymidine kinase
(herpes labialis). (TK) or CMV-encoded protein kinase (PK), which ex-
plains the specificity of ganciclovir for HSV and CMV,
4.2. CMV inhibitors respectively.
◦ Principal indication(s): CMV infections, particularly
• Ganciclovir CMV retinitis in immunocompromised (i.e. AIDS) pa-
◦ Structure (Fig. 28): 9-(1,3-dihydroxy-2-propoxyme- tients (treatment and prevention).
thyl)guanine (DHPG), (GCV), Cymevene® , Cytovene® . ◦ Administered: intravenously at 10 mg/kg per day (2 ×
5 mg/kg, every 12 h) for induction therapy; orally at
O 3000 mg per day (three times four 250 mg capsules)
for maintenance therapy and for prevention; intraocular
N
HN (intravitreal) implant (Vitrasert∗ ) of 4.5 mg ganciclovir
as localized therapy of CMV retinitis.
N
H2N N • Valganciclovir
◦ Structure (Fig. 29): l-valine ester of ganciclovir
(VGCV), Valcyte® .
HO O ◦ Activity spectrum: as for GCV.
◦ Mechanism of action: serves as oral prodrug of GCV,
then acts as described for GCV.
OH ◦ Principal indication(s): CMV infections. Oral val-
ganciclovir is expected to replace intravenous gan-
Ganciclovir
ciclovir in both the therapy and prevention of CMV
Fig. 28. infections.
128 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

O NH 2

N N
HN

H2 N N N N O

HO O
O P O
H HO
H2N C C O O
CH OH
H3C CH3
OH Cidofovir

Valganciclovir Fig. 31.

Fig. 29.

◦ Mechanism of action: targeted at the viral DNA poly-


◦ Administered: orally at 900 mg per day (two 450 mg merase, acts as chain terminator, following intracellu-
tablets daily) for maintenance therapy (900 mg twice lar phosphorylation to the diphosphate form, and in-
daily for induction therapy). corporation at the 3 -end of the viral DNA chain (two
• Foscarnet sequential incorporations needed for chain termination
◦ Structure (Fig. 30): trisodium phosphonoformate, fos- in the case of CMV DNA synthesis) (Scheme 9).
carnet sodium, Foscavir® . ◦ Principal indications(s): officially licensed for the treat-
◦ Activity spectrum: herpesviruses (HSV-1, HSV-2, VZV, ment of CMV retinitis in AIDS patients. Also shown
CMV, etc.) and also HIV. to be effective in the treatment of acyclovir-resistant
◦ Mechanism of action: pyrophosphate analogue, inter- (viral TK-deficient) HSV infections, recurrent genital
feres with the binding of the pyrophosphate (diphos- herpes, genital warts, CIN-III (cervical intraepithelial
phate) to its binding site of the viral DNA polymerase, neoplasia grade III), laryngeal and cutaneous papillo-
during the DNA polymerization process. matous lesions, molluscum contagiosum lesions, orf le-
◦ Principal indication(s): CMV retinitis in AIDS pa- sions, adenovirus infections and progressive multifocal
tients, and mucocutaneous acyclovir-resistant (viral leukoencephalopathy (PML).
TK-deficient) HSV and VZV infections in immuno- ◦ Administered: intravenously (Vistide® ) at 5 mg/kg per
compromised patients. week during the first 2 weeks, then 5 mg/kg every
◦ Administered: intravenously at 180 mg/kg per day other week, with sufficient hydration and under cover
(3 × 60 mg/kg, every 8 h) for induction therapy of of probenecid to prevent nephrotoxicity. Can also be
CMV retinitis; intravenously at 120 mg/kg per day administered topically as a 1% gel or cream.
(3 × 40 mg/kg, every 8 h) for maintenance therapy of • Fomivirsen
CMV retinitis and for therapy of acyclovir-resistant ◦ Structure (Fig. 32): antisense oligodeoxynucleotide
mucocutaneous HSV or VZV infections in immuno- composed of 21 phosphorothioate-linked nucleosides,
compromised patients. Dose adjustments for changes ISIS 2922, Vitravene® .
in renal function are imperative. ◦ Activity spectrum: CMV.
• Cidofovir ◦ Mechanism of action: being complementary in base
◦ Structure (Fig. 31): (S)-1-(3-hydroxy-2-phosphonyl- sequence, it hybridizes with, and thus blocks expres-
methoxypropyl)cytosine (HPMPC), (CDV), Vistide® , sion (translation) of, the CMV immediate early 2 (IE2)
ForvadeTM . mRNA.
◦ Activity spectrum: herpesviruses (HSV-1, HSV-2, ◦ Principal indication(s): CMV retinitis (in AIDS pa-
VZV, CMV, etc.), papilloma-, polyoma-, adeno- and tients).
poxviruses. ◦ Administered : intraocularly (intravitreally).

O
O 5'-d-[G*C*G*T*T*T*G*C*T*C*T*T*C*T*T*C*T*T*G*C*G]_3'
-
O P C 3 Na+ sodium salt
O-
O- * = racemic phosphorothioate

Foscarnet Fomivirsen

Fig. 30. Fig. 32.


E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 129

Scheme 9. Mechanism of antiviral action of cidofovir (HPMPC). HPMPC needs to be phosphorylated, in two steps, to the diphosphate form before
it interferes, as chain terminator (following two consecutive incorporations in the case of CMV) with the DNA polymerase reaction (after De Clercq,
2003a).

5. Anti-influenza virus compounds (including ribavirin) ◦ Principal indication(s): influenza A virus infections
(prevention and early therapy). Also used in the treat-
• Amantadine ment of Parkinson’s disease.
◦ Structure (Fig. 33): tricyclo[3.3.1.1.3,7 ]decane-1-amine ◦ Administered: orally at 200 mg per day (two times a
hydrochloride, 1-adamantanamine, amantadine HCl, 100 mg capsule).
Symmetrel® , Mantadix® , Amantan® , etc. • Rimantadine
◦ Activity spectrum: influenza A virus. ◦ Structure (Fig. 34): ␣-methyltricyclo[3.3.1.1.3,7 ]de-
◦ Mechanism of action: blocks M2 ion channel, and thus cane-1-methanamine hydrochloride, ␣-methyl-1-ada-
prevents the passage of H+ ions that are required for mantanemethylamine HCl, Flumadine® .
the necessary acidity to allow for the viral uncoating ◦ Activity spectrum: influenza A virus.
process (decapsidation). ◦ Mechanism of action: as for amantadine.
130 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

H HO OH
H
OH O O
NH2.HCl HN
H
O OH

H CH3 NH NH2
Amantadine
NH
Fig. 33. Zanamivir
H Fig. 35.

(sialidase) (Scheme 10), and keeps the virus trapped


NH2.HCl onto the infected cells (viral neuraminidase is respon-
H sible for cleavage of N-acetylneuraminic acid from the
CH 3 influenza virus receptor so that progeny virus particles
H can be released from the infected cells).
◦ Principal indication(s): influenza A and B virus infec-
Rimantadine
tions (therapy and prevention).
Fig. 34. ◦ Administered: by (oral) inhalation, at a dosage of 20 mg
per day (two times 5 mg, every 12 h) for 5 days. Treat-
◦ Principal indication(s): influenza A virus infections ment to be started as early as possible, and certainly
(prevention and early therapy). within 48 h, after onset of the symptoms.
◦ Administered: orally at 300 mg per day (two times • Oseltamivir
150 mg). ◦ Structure (Fig. 36): ethyl ester of (3R,4R,5S)-4-acetami-
• Zanamivir do-5-amino-3-(1-ethylpropoxy)-1-cyclohexane-1-carb-
◦ Structure (Fig. 35): 4-guanidino-2,4-dideoxy-2,3- oxylic acid, GS 4104, Ro 64-0796, Tamiflu® .
didehydro-N-acetylneuraminic acid, 5-acetylamino-4- ◦ Activity spectrum: influenza (A and B) virus.
[(aminoiminomethyl)amino]-2,6- anhydro-3,4, 5- tride- ◦ Mechanism of action: as for zanamivir.
oxy-d-glycero-d-galacto-non-2-enonic acid, CG 167, ◦ Principal indication(s): as for zanamivir.
Relenza® . ◦ Administered: orally at 150 mg per day (two times a
◦ Activity spectrum: influenza (A and B) virus. 75 mg capsule, every 12 h) for 5 days. Treatment should
◦ Mechanism of action: N-acetylneuraminic acid (sialic be started as early as possible, and certainly within 48 h,
acid) analogue, inhibits influenza viral neuraminidase after onset of the symptoms.

Scheme 10. Interaction of the neuraminidase inhibitor oseltamivir with influenza virus neuraminidase, derived from the crystal structure (after De Clercq,
2002a).
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 131

6. Current state of the art


O
O A total of 37 antiviral compounds (not including interfer-
HN ons or immunoglobulins) have momentarily been licensed
O O for the treatment of HIV, HBV, herpesvirus, influenza virus
CH3 NH NH2 and/or HCV infections. In the preceding sections these com-
pounds have been discussed from the following viewpoints:
NH chemical structure, activity spectrum, mechanism of action,
principal clinical indication(s), route(s) of administration
Oseltamivir and dosage. Other points that need to be considered before
Fig. 36. the full clinical potential of any given drug could be ap-
preciated, are: (i) duration of treatment, (ii) single- versus
multiple-drug therapy, (iii) pharmacokinetics, (iv) drug in-
• Ribavirin teractions, (v) toxic side effects and (vi) development of re-
◦ Structure (Fig. 37): 1-␤-d-ribofuranosyl-1H-1,2,4-tri- sistance.
azole-3-carboxamide, Virazole® , Virazid® , Viramid® . A particular issue that may be important in the clini-
◦ Activity spectrum: various DNA and RNA viruses, cal setting is whether the listed anti-HIV agents would be
in particular orthomyxoviruses (influenza A and equally suited for the treatment of HIV-2 and HIV-1 infec-
B), paramyxoviruses (measles, respiratory syncy- tions. As reported by Witvrouw et al. (2004), the NRTIs and
tial virus (RSV)) and arenaviruses (Lassa, Junin, the NtRTI tenofovir are equally active against HIV-1 and
etc.). HIV-2; for the NNRTIs, anti-HIV activity is confined to the
◦ Mechanism of action: the principal target for ribavirin HIV-1 strains; protease inhibitors are equally active against
(in its 5 -monophosphate form) is IMP dehydrogenase, HIV-1 and HIV-2, although amprenavir shows reduced ac-
that converts IMP to XMP, a key step in the de novo tivity against HIV-2, and, likewise, enfuvirtide has reduced
biosynthesis of GTP and dGTP. In its 5 -triphosphate inhibitory activity against HIV-2.
form, ribavirin can also interfere with the viral RNA As to the duration of treatment, this may vary from a
polymerase and the 5 -capped oligonucleotide primer few days (HSV, VZV, influenza virus infections) to several
formation required for transcription of the influenza months or years (HIV, HBV and HCV infections), depend-
RNA genome. ing on whether we are dealing with an acute (primary (i.e.
◦ Principal indication(s): as a small size droplet aerosol, influenza) or recurrent (i.e. HSV, VZV)) infection or chronic,
in the treatment of RSV infections in high-risk infants, persistent (i.e. HIV, HBV, HCV) infection. For HIV infec-
and in combination with interferon-␣ (Intron A® , as in tions it is still being evaluated whether long-term treatment
Rebetron® ) or pegylated interferon-␣ (PEG-INTRON® can be interrupted, without loss of benefit (or increased ben-
or Pegasys® ) in the treatment of hepatitis C virus efit) to the patient (structured treatment interruption, STI).
(HCV) infections. While the short-term treatment (5–7 days) of HSV, VZV
◦ Administered: orally at doses of 800–1200 mg per and influenza virus infections, and even the more prolonged
day, in the treatment of HCV infections; or by treatment of CMV infections, can be based on single-drug
aerosol (solution of 20 mg/ml), which has proved su- therapy, for the long-term treatment of HIV infections
perior to placebo aerosol in the treatment of RSV combination of several drugs in a triple-drug cocktail (also
infections. referred to as HAART for “highly active anti-retroviral
therapy”) has become the standard procedure, and likewise,
the long-term treatment of HBV infections may in the future
also evolve from single- to dual- or triple-drug therapy.
O Pharmacokinetic parameters to be addressed, when evalu-
ating the therapeutic potential, include bioavailability (upon
H 2N N either topical, oral or parenteral administration), plasma pro-
N
tein binding affinity, distribution through the organism (pen-
N etration into the CNS, when this is needed), metabolism
through the liver (i.e. cytochrome P-450 drug-metabolizing
HO enzymes) and elimination through the kidney. Particularly
O
when concocting the multiple-drug combinations for the
treatment of HIV infection, possible drug–drug interactions
HO OH should be taken into account: i.e. some compounds act as
P-450 inhibitors and others as P-450 inducers, and this may
Ribavirin
greatly influence the plasma drug levels achieved, especially
Fig. 37. in the case of NNRTIs and PIs.
132 E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133

Toxic side effects, both short- and long-term, must be as emtricitabine (already in use for HIV/AIDS), are com-
considered when the drugs have to be administered for a ing along; and for HCV, a variety of compounds targeted at
prolonged period, as in the treatment of HIV infections. either the viral protease, helicase or RNA-dependent RNA
These side effects may seriously compromise compliance polymerase (RDRP) are currently under intensive scrutiny
(adherence to drug intake), and could, at least in part, be (see, for example, Lamarre et al., 2003 for the NS3 pro-
circumvented by a reduction of the pill burden to, ideally, tease inhibitor BILN 2061). Also for the herpesviruses (i.e.
once-daily dosing. HSV), new antivirals have been described that target the he-
Finally, resistance development may be an important is- licase/primase complex, terminase complex or UL97 pro-
sue, again for those compounds that have to be taken for a tein kinase (Eizuru, 2003), and, likewise, new inhibitors are
prolonged period, as is generally the case for most of the on the horizon for CMV (De Clercq, 2003b) and VZV (De
NRTIs, NNRTIs and PIs currently used in the treatment of Clercq, 2003d).
HIV infections. Yet, the nucleoside phosphonate analogues
(NtRTIs) tenofovir and adefovir do not readily or rapidly
lead to resistance development, even after more than 1 year 8. Appraisal of clinical utility
of therapy (for HIV and HBV, respectively). Resistance has
been noted with HBV against lamivudine after long-term Currently licensed antiviral drugs are particularly fo-
therapy (>6 months), but, if resistant to lamivudine, HBV cussed on the treatment of HIV, HBV, herpesvirus, influenza
infections remain amenable to treatment with adefovir dip- virus and HCV infections, and, so are most of forthcoming
ivoxil. As has been occasionally observed in immunosup- antiviral compounds that are in (pre)clinical development.
pressed patients, HSV may develop resistance to acyclovir, For the treatment of HIV/AIDS there are now 19
and CMV to ganciclovir, but, if based on ACV TK or CMV anti(retro)viral drugs available, and to achieve the largest
PK deficiency, these resistant viruses remain amenable to possible benefit, these drugs have to be combined in
treatment with foscarnet and/or cidofovir. In immunocom- multiple-drug regimens. Numerous drug combinations
petent patients, treated for an acute or episodic HSV, VZV could be envisaged. Those that have been generally used
or influenza virus infection, short-term therapy is unlikely consist of two NRTIs, or one NRTI and one NtRTI (teno-
to engender any resistance problems. fovir disoproxil fumarate (TDF)), to which is then added
one NNRTI or one PI. Because of the long-term side effects
(such as lipodystrophy, diabetes and cardiovascular distur-
7. Antiviral agents in (pre)clinical development bances) associated with the PIs that have been longest in
use, there is a tendency for starting anti-HIV therapy with
In addition to the 37 antiviral compounds that are currently PI-sparing regimens.
available, there are another 40 or so that are presently under One such regimen that has proven to be quite efficacious
(pre)clinical development. in the treatment of HIV infections, and seems to be well tol-
For HIV (De Clercq, in press), these include the virus erated, is the combination of TDF with 3TC (lamivudine)
adsorption inhibitors (cosalane derivatives, cyanovirin-N, and efavirenz. In the future, 3TC may be replaced in this
cyclotriazadisulfonamide (CADA) derivatives, teicoplanin regimen by (−)FTC (emtricitabine), which could be formu-
aglycons and BMS-378806); the CXCR4 antagonist lated with TDF in a single pill (to be taken once daily).
AMD070 (De Clercq, 2003c); the CCR5 antagonists Combinations of TDF with purine NRTIs such as abacavir
SCH-C, SCH-D, TAK-220, spirodiketopiperazine E913, or didanosine should be avoided, as these have been shown
MRK-1 (CMPD167), and trisubstituted pyrrolidines; the not to achieve the expected reductions in viral load. Enfuvir-
NRTIs (±)-2 -deoxy-3 -oxa-4 -thiacytidine (dOTC) and the tide represents a new dimension in anti-HIV therapy, which
5-fluoro-substituted derivative thereof (FdOTC), amdoxovir could be added onto any (optimized background) regimen,
(DAPD), Reverset (␤-d-d4FC) and alovudine (FddThd); the but, because of the costs involved and the fact it has to be ad-
NNRTIs UC-781, SJ-3366, DPC-083, (+)-calanolide A, ministered subcutaneously (twice daily), enfuvirtide should
capravirine (AG1549, S-1153) and dapivirine (TMC-125); be primarily reserved for salvage therapy.
the integrase inhibitors S-1360 (and other diketoacid deriva- For the treatment of HBV infections, 2 compounds,
tives), 1,6-naphthyridine-7-carboxamide, 8-hydroxy-[1,6] lamivudine and adefovir dipivoxil, besides human inter-
naphthyridine and pyranodipyrimidine (PDP) derivatives; feron, are currently available. TDF is recommended for use
and peptidomimetic (i.e. TMC-126) and non-peptidomimetic in HIV-infected patients who are co-infected with HBV.
(i.e. tipranavir, PNU-140690) protease inhibitors. Of these Whether the treatment of HBV infections should be based
compounds, tipranavir as well as some of the NRTIs (e.g. upon multiple-drug regimens (so as to minimize the emer-
Reverset) and NNRTIs (e.g. capravirine, dapivirine) may gence of virus-drug resistance), as in the case of HIV/AIDS,
nowadays seem closest to eventual regulatory approval. needs to be addressed in future studies. Possible dual-drug
For HBV, in addition to the licensed drugs lamivudine and regimens that could be envisaged for chronic hepatitis B are
adefovir dipivoxil, a number of new nucleoside analogues, adefovir dipivoxil combined with lamivudine (or emtric-
viz. entacavir, l-dT and the valine ester of l-dC, as well itabine).
E. De Clercq / Journal of Clinical Virology 30 (2004) 115–133 133

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