2004 Antiviral Drugs In Current Clinical Use

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 almost 40 compounds that have been officially approved for 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 human immunodeficiency virus (HIV) infections. The other antivirals that are currently available are primarily used for the treatment of hepatitis B virus (HBV), herpesvirus (herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV)), influenza virus, respiratory syncytial virus (RSV) and hepatitis C virus (HCV) infections. This article should be considered as an update of the review article on “Antiviral drugs: current state of the art” published previously in the Journal of Clinical Virology (De Clercq, 2001).

2.1. Nucleoside reverse transcriptase inhibitors (NRTIs)

夽 According to the Keynote lecture presented at the ESCV (European Society of Clinical Virology) Winter Meeting, 15–17 January 2004, Copenhagen, Denmark. ∗ Tel.: +32-16-337341; fax: +32-16-337340. E-mail address: [email protected] (E. De Clercq).

1386-6532/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2004.02.009

• Zidovudine ◦ Structure (Fig. 1): 3 -azido-2 ,3 -dideoxythymidine, azidothymidine (AZT), ZDV, Retrovir® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: targeted at the reverse transcriptase (RT) of HIV, acts as chain terminator in the RT reaction, following intracellular phosphorylation to AZT 5 -triphosphate, and, after removal of the diphosphate group, incorporation of AZT 5 -monophosphate at the 3 -end of the viral DNA chain (Scheme 1). ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (such as lamivudine and abacavir). ◦ Administered: orally at 600 mg per day (two 300 mg tablets daily).

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O CH3

HN O

O

O

N3

Zidovudine Fig. 1.

• Didanosine ◦ Structure (Fig. 2): 2 ,3 -dideoxyinosine (ddI), Videx® , Videx® EC. ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: targeted at HIV RT, acts as chain terminator, following intracellular phosphorylation to 2 ,3 -dideoxyadenosine (ddA) 5 -triphosphate, and, after removal of the diphosphate group, incorporation of ddA 5 -monophosphate at the 3 -end of the viral DNA chain. ◦ Principal indication(s): HIV infection, especially advanced HIV disease, in combination with other anti-HIV agents.

N

N

N HO

HO

N

HN

O

Didanosine Fig. 2.

◦ Administered: orally at 400 mg per day (Videx® : two 100 mg tablets twice a day or two 200 mg tablets once a day; Videx® EC: one 400 mg capsule once a day). • Zalcitabine ◦ Structure (Fig. 3): 2 ,3 -dideoxycytidine (ddC), Hivid® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: targeted at HIV RT, acts as chain terminator, following intracellular phosphorylation to ddC 5 -triphosphate, and, after removal of the diphosphate group, incorporation of ddC 5 -monophosphate at the 3 -end of the viral DNA chain. ◦ Principal indication(s): HIV infection, especially in 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).

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NH2

NH2 N

N O HO

O

N O

HO

N

S O

Zalcitabine

Lamivudine

Fig. 3.

Fig. 5.

tolerant or unresponsive to zidovudine, in combination with other anti-HIV agents (not didanosine). ◦ Administered: orally at 2.25 mg per day (one 0.75 mg tablet every 8 h). • Stavudine ◦ Structure (Fig. 4): 2 ,3 -didehydro-2 ,3 -dideoxythymidine (d4T), Zerit® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: targeted at HIV RT, acts as chain terminator, following intracellular phosphorylation to d4T 5 -triphosphate, and, after removal of the diphosphate group, incorporation of d4T 5 -monophosphate at the 3 -end of the viral DNA chain. ◦ Principal indication(s): HIV infection, especially advanced HIV disease, in combination with other anti-HIV agents. ◦ Administered: orally at 80 mg per day (one 40 mg capsule every 12 h). • Lamivudine ◦ Structure (Fig. 5): (−)-␤-l-3 -thia-2 ,3 -dideoxycytidine (3TC), Epivir® , Zeffix® . ◦ Activity spectrum: HIV (types 1 and 2) and HBV. ◦ Mechanism of action: targeted at HIV RT and HBV RT, acts as chain terminator, following intracellular phosphorylation to 3TC 5 -triphosphate, and, after removal of the diphosphate group, incorporation of 3TC 5 -monophosphate at the 3 -end of the viral DNA chain. ◦ Principal indication(s): HIV and HBV infections: for HIV infection, in combination with other anti-HIV agents (such as zidovudine and abacavir).

◦ Administered: orally at 300 mg per day (one 150 mg tablet twice a day, or one 300 mg tablet once a day). In the treatment of HIV infections, lamivudine can be combined with zidovudine (Combivir® ), or with zidovudine and abacavir (Trizivir® ). Combivir® tablets contain 300 mg zidovudine and 150 mg lamivudine per tablet and are administered orally (two tablets daily). Trizivir® tablets contain 300 mg zidovudine, 150 mg lamivudine and 300 mg abacavir per tablet and are administered orally (two tablets daily). Lamivudine is administered orally at 100 mg per day in the treatment of HBV infections, currently as monotherapy; in the future, possibly in combination with adefovir dipivoxil. • Abacavir ◦ Structure (Fig. 6): (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate (ABC), Ziagen® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: targeted at HIV RT, acts as chain terminator, following intracellular phosphorylation and conversion (deamination) to the 5 -triphosphate of the corresponding guanosine analogue (carbovir), and, after removal of the diphosphate group, incorporation of carbovir 5 -monophosphate at the 3 -end of the viral DNA chain. ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents such as zidovudine and lamivudine (see above). ◦ Administered: orally at 600 mg per day (two 300 mg tablets daily). NH

O CH3

HN O HO

N O

N

N H2 N

N

N

H2C H2C

HO

Stavudine

Abacavir

Fig. 4.

Fig. 6.

COOH

COOH

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removal of the diphosphate group, incorporation at the 3 -end of the viral DNA chain (Scheme 2). ◦ Principal indication(s): HIV infection in combination with other anti-HIV agents such as lamivudine and efavirrenz (see below); should, however, not be combined with the combination of lamivudine plus abacavir. ◦ Administered: orally at a once-daily dose of a 300 mg tablet.

NH2 F

N O HO

N

S O

Emtricitabine

2.3. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Fig. 7.

• Emtricitabine ◦ Structure (Fig. 7): (−)-␤-l-3 -thia-2 ,3 -dideoxy-5fluorocytidine ((−)-FTC) Emtriva® . ◦ Activity spectrum: HIV and HBV. ◦ Mechanism of action: similar to that of 3TC. ◦ Principal indication(s): HIV and HBV infections; has been recently approved for the treatment of HIV infections; is currently in Phase III clinical trials for the treatment of HBV infections; will likely be used (in the future) in combination with tenofovir disoproxil fumarate as a single tablet to be administered orally once daily. ◦ Administered: orally at a once-daily 200 mg capsule. 2.2. Nucleotide reverse transcriptase inhibitors (NtRTIs) • Tenofovir disoproxil ◦ Structure (Fig. 8): fumarate salt of bis(isopropoxycarbonyloxymethyl) ester of (R)-9-(2-phosphonylmethoxypropyl)adenine, or bis(POC)PMPA, Viread® . ◦ Activity spectrum: HIV (types 1 and 2) and various other retroviruses, and HBV. ◦ Mechanism of action: serves as oral prodrug of tenofovir (PMPA) that is targeted at HIV RT (and HBV RT), and acts as chain terminator, following intracellular phosphorylation to the diphosphate form, and, after NH2 N

N N

O

(CH3)2CH O C O CH2

O

(CH3)2CH O C O CH2

O

P

O

N

O

O

COOH

CH 3 HC HC

COOH

Tenofovir disoproxil fumarate Fig. 8.

• Nevirapine ◦ Structure (Fig. 9): 11-cyclopropyl-5,11-dihydro-4methyl-6H-dipyrido[3,2-b:2 ,3 -f][1,4]diazepin-6-one, Viramune® . ◦ Activity spectrum: HIV type 1. ◦ Mechanism of action: targeted at an allosteric “pocket”, non-substrate binding site of the HIV-1 reverse transcriptase (as illustrated for UC781 in Scheme 3). ◦ Principal indication(s): HIV-1 infection, in combination with other anti-HIV agents, particularly NRTIs. ◦ Administered: orally at 200 mg per day for the first 14 days (one 200 mg tablet per day), then 400 mg per day (two daily 200 mg tablets). • Delavirdine ◦ Structure (Fig. 10): 1-(5-methanesulfonamido-1Hindol-2-yl-carbonyl)-4-[3-(1-methylethyl-amino)pyridinyl)piperazine monomethane sulfonate, Rescriptor® . ◦ Activity spectrum: HIV type 1. ◦ Mechanism of action: similar to that of nevirapine. ◦ Principal indication(s): HIV-1 infection, in combination with other anti-HIV agents (primarily NRTIs). ◦ Administered: orally at 1200 mg per day (two 200 mg tablets three times a day). • Efavirenz ◦ Structure (Fig. 11): (−)6-chloro-4-cyclopropylethynyl4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2one, Sustiva® , Stocrin® . ◦ Activity spectrum: HIV type 1. ◦ Mechanism of action: similar to that of nevirapine. ◦ Principal indication(s): HIV-1 infection, in combination with other anti-HIV agents (primarily NRTIs and NtRTIs). ◦ Administered: orally at 600 mg per day (as a once-daily 600 mg tablet, preferably at bedtime to improve tolerability of CNS side effects). 2.4. Protease inhibitors (PIs) • Saquinavir ◦ Structure (Fig. 12): cis-N-tert-butyl-decahydro-2-[2(R)hydroxy-4-phenyl-3(S)-[[N-2-quinolylcarbonyl-l-asparaginyl]-amino]butyl]-(4aS–8aS)-isoquinoline-3(S)-carboxamide methane sulfonate, hard gel capsules,

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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).

CH3

N

◦ ◦

O

H N

N

◦ N

◦ Nevirapine Fig. 9.

Invirase® , also available as soft gelatin capsules (Fortovase® ). Activity spectrum: HIV (types 1 and 2). Mechanism of action: transition-state, hydroxyethylenebased, peptidomimetic inhibitor of HIV protease (as illustrated for KNI272 in Scheme 4). Principal indication(s): HIV infection, in combination with other anti-HIV agents (NRTIs and some PIs (i.e. ritonavir)). Administered: orally at 3600 mg per day (six 200 mg soft gelatin capsules three times a day (Fortovase® )) or 1800 mg per day (three 200 mg hard gel capsules three

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CH3 SO2

CH3

CH NH

NH N

N

N

N O CH3SO3H

Delavirdine Fig. 10.

F3C

Cl

O N H

Scheme 3. Interaction of HIV-1 RT with a prototype NNRTI (UC781). Features stabilizing the complex between the human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) and the non-nucleoside reverse transcriptase inhibitor UC781. The hydrogen bond with K101, and the two methyl-group–aromatic-ring interactions are shown explicitly. Other 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 to two hours after a full meal. • Ritonavir ◦ Structure (Fig. 13): [5S-(5R,8R,10R,11R)]-10-hydroxy2-methyl-5-(1-methylethyl)-1-[2-(methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester, Norvir® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: as for saquinavir.

O

Efavirenz Fig. 11.

H N

N

O N H NH2

O O CH3SO2 OH

N OH O H 3C

NH CH 3 CH3

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).

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H3C

CH3

O S

N N

CH3

N H

121

O

H N O

OH

N H

N

O S

H3C CH3

Ritonavir Fig. 13.

◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (NRTIs and PIs (i.e. saquinavir)). ◦ Administered: orally at 1200 mg per day (six 100 mg capsules, twice a day to be taken with food). • Indinavir ◦ Structure (Fig. 14): [(1S,2R,5(S)-2,3,5-trideoxy-N(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-pyridinylmethyl)-1-piperazinyl]- 2- (phenylmethyl - d - erythro)pentonamide, Crixivan® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: as for saquinavir. ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (i.e., NRTIs). ◦ Administered: orally at 2400 mg per day (two 400 mg capsules every 8 h to be taken on empty stomach), plus hydration (at least 1.5 l liquid daily). • Nelfinavir ◦ Structure (Fig. 15): [3S-(3R,4aR,8aR,2 S)]-2-[2 -hydroxy-3 -phenylthiomethyl-4 -aza-5 -oxo-5 -[2 -methyl-3hydroxyphenyl)-pentyl]-3-(N - (tert-butyl) - carboxamide)-decahydro isoquinoline methane sulfonate, Viracept® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: as for saquinavir. ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (i.e. NRTIs).

N

OH

H N

N

N O H 3C

O

NH

HO CH3

CH3 H3C CH 3

O

HO

S

O

N H

N

CH 3 NH CH3SO 2 OH

OH

Nelfinavir Fig. 15.

◦ Administered orally at 2250 mg per day (three 250 mg tablets three times a day) or 2500 mg per day (five 250 mg tablets twice a day), to be taken with a meal. • Amprenavir ◦ Structure (Fig. 16): (3S)-tetrahydro-3-furyl-N-[(S,2R)3-(4-amino-N-isobutylbenzene-sulfonamido)-1-benzyl2-hydroxypropyl]carbamate, Agenerase® , Prozei® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: as for saquinavir. ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (i.e. NRTIs). ◦ Administered orally at 2400 mg per day (eight 150 mg capsules twice a day, to be taken with or without food, but not with a high-fat meal).

NH2 O

O

O O

N H

N OH

CH3

S

O CH3

CH3

Indinavir

Amprenavir

Fig. 14.

Fig. 16.

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OH

CH3

O

H N

O

◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents (i.e. NRTIs). ◦ Administered: orally, as Kaletra® , at 1000 mg per day (three 166.6 mg capsules twice a day; each capsule containing 133.3 mg lopinavir + 33.3 mg ritonavir), to be taken with food. • Atazanavir ◦ Structure (Fig. 18): 1-[4-(pyridin-2-yl)phenyl]-5(S)2,5-bis-{[N-(methoxycarbonyl)-l-tert-leucinyl]amino}4(S)-hydroxy-6-phenyl-2-azahexane, CGP 73547, BMS-232632, Reyataz® . ◦ 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 200 mg capsules), to be taken with food.

O CH3

NH

N

N H

O C H3

H3C

Lopinavir Fig. 17.

N

2.5. Viral entry inhibitors O O

OH

H N

N H

O N

H N

N H

O

• Enfuvirtide ◦ Structure (Fig. 19): 36-amino acid peptide, corresponding 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® . ◦ Activity spectrum: HIV-1. ◦ Mechanism of action: inhibits virus-cell fusion, through a coil–coil interaction with its homologous region in gp41 (Scheme 5). ◦ Principal indication(s): HIV infection, in combination with other anti-HIV agents; has been recently approved for clinical use following demonstration of antiretroviral and immunologic benefit when added onto an optimized antiretroviral regimen (Lalezari et al., 2003; Lazzarin et al., 2003). ◦ Administered: by subcutaneous injection, twice daily at a dose of 90 mg.

O O

Atazanavir Fig. 18.

• Lopinavir ◦ Structure (Fig. 17): N-(4(S)-(2-(2,6-dimethylphenoxy)acetylamino)-3(S)-hydroxy-5-phenyl-1(S)-benzylpentyl)-3-methyl-2(S)-(2-oxo(1,3-diazaperhydroinyl)butanamine, combined with ritonavir at 4/1 ratio; ABT-378/r, Kaletra® . ◦ Activity spectrum: HIV (types 1 and 2). ◦ Mechanism of action: as for saquinavir.

Fusion peptide

Membrane spanning region 152 amino acids

Leucine zipper region

NH2

C C 517 532

558

595

COOH 643

DP-107

678 689

710

DP-178

YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF

Enfuvirtide Fig. 19.

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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 • Lamivudine Lamivudine (Fig. 5) is used for the treatment of both HIV and HBV infections, for the latter at an oral dose of 100 mg per day. • Adefovir dipivoxil ◦ Structure (Fig. 20); bis(pivaloyloxymethyl)ester of 9-(2-phosphonylmethoxyethyl)adenine, or bis(POM)PMEA, Hepsera® . ◦ Activity spectrum: HBV, HIV and other retroviruses, and, to a lesser extent, also herpesviruses (HSV, CMV, etc.). ◦ Mechanism of action: serves as oral prodrug of adefovir (PMEA) that is targeted at HBV RT (and HIV RT), and acts as chain terminator, following intracellular phosphorylation to the diphosphate form, and incorporation at the 3 -end of the viral DNA chain (Scheme 6). ◦ Principal indication(s): HBV infection, where it has proven successful in the treatment of lamivudineresistant HBV infections (Hadziyannis et al., 2003; NH2 N

N N

O (CH3)3C

C

(CH3)3C

C

O O

CH2

O

CH2

O

O P

O

Adefovir dipivoxil Fig. 20.

O

N

Marcellin et al., 2003). Adefovir dipivoxil has been, but is no longer, pursued for the treatment of HIV infections. ◦ Administered: orally as a single dose of 10 mg per day. • Emtricitabine Emtricitabine (Fig. 7) has been recently licensed for the treatment of HIV infections and is being pursued for the treatment of HBV infections.

4. Anti-herpesvirus compounds 4.1. HSV and VZV inhibitors • Acyclovir ◦ Structure (Fig. 21): 9-(2-hydroxyethoxymethyl)guanine, acycloguanosine (ACG), acyclovir, aciclovir (ACV), Zovirax® . ◦ Activity spectrum: HSV (types 1 and 2) and VZV. ◦ Mechanism of action: targeted at the viral DNA polymerase, acts as chain terminator, following intracellular phosphorylation to ACV triphosphate and incorporation of ACV monophosphate at the 3 -end of the viral DNA chain (Scheme 7). The first phosphorylation step is catalyzed by the virus-encoded thymidine kinase (TK), which explains the specificity of acyclovir for HSV-1, HSV-2 and VZV. ◦ Principal indication(s): mucosal, cutaneous and systemic HSV-1 and HSV-2 infections (including herpetic keratitis, herpetic encephalitis, genital herpes, neonatal herpes and herpes labialis) and VZV infections (including varicella and herpes zoster). ◦ Administered: orally at 1000 mg per day (five 200 mg tablets (genital herpes)) or 4000 mg per day (four times

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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% ophthalmic cream (herpetic keratitis) or 5% cream (herpes labialis), or intravenously at 30 mg/kg per day (herpetic encephalitis, and other severe HSV or VZV infections). • Valaciclovir ◦ Structure (Fig. 22): l-valine ester of acyclovir (VACV), Zelitrex® , Valtrex® .

◦ Activity spectrum: as for acyclovir. ◦ Mechanism of action: serves as oral prodrug of acyclovir, then acts as described for acyclovir. ◦ Principal indication(s): HSV and VZV infections that can be approached by oral therapy (i.e. genital herpes, herpes zoster). Also used in the prophylaxis of CMV infections in transplant recipients.

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125

O

O N

HN H 2N

N

N

N

HN H2N

N

N

O HO

O

Acyclovir Fig. 21.

H2N

H C

C

O

O

CH C H3 H3C

Valaciclovir Fig. 22.

◦ Administered: orally at 1000 mg per day (two 500 mg tablets (genital herpes)) up to 3000 mg per day (three times two 500 mg tablets (herpes zoster)). • Penciclovir ◦ Structure (Fig. 23): 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (PCV), Denavir® , Vectavir® . ◦ Activity spectrum: HSV-1, HSV-2 and VZV. ◦ Mechanism of action: essentially similar to that of acyclovir. ◦ Principal indication(s): mucocutaneous HSV infections, particularly recurrent herpes labialis (cold sores). ◦ Administered: topically as a 1% cream.

• Famciclovir ◦ Structure (Fig. 24): diacetyl ester of 9-(4-hydroxy3-hydroxymethyl-but-1-yl)-6-deoxyguanine (FCV), Famvir® . ◦ Activity spectrum: HSV-1, HSV-2 and VZV. ◦ Mechanism of action: serves as oral prodrug of penciclovir (to which it is converted by hydrolysis of the two acetyl groups and oxidation at the 6-position), then acts as described for penciclovir. ◦ Principal indication(s): HSV-1, HSV-2 and VZV infections.

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).

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O

O

N

HN H2N

N

N

CF3

HN O HO

N O

HO OH

Trifluridine

OH

Fig. 26.

Penciclovir Fig. 23.

N

N H 2N

N

N

O H 3C

O

H3C

O

O Famciclovir Fig. 24.

◦ Administered: orally at 750 mg per day (250 mg tablet every 8 h, three times a day), or 1500 mg per day (500 mg every 8 h). • Idoxuridine ◦ Structure (Fig. 25): 5-iodo-2 -deoxyuridine (IDU, IUdR), Herpid® , Stoxil® , Idoxene® , Virudox® , etc. ◦ Activity spectrum: HSV-1, HSV-2 and VZV. ◦ Mechanism of action: incorporated into (viral/cellular) DNA, following intracellular phosphorylation to IDU 5 -triphosphate (in virus-infected and uninfected cells).

◦ Principal indication(s): HSV keratitis. ◦ Administered: topically as eye drops (0.1%) or ophthalmic cream. • Trifluridine ◦ Structure (Fig. 26): 5-trifluoromethyl-2 -deoxyuridine, trifluorothymidine (TFT), Viroptic® . ◦ Activity spectrum: HSV-1, HSV-2 and VZV. ◦ Mechanism of action: inhibits conversion of dUMP to dTMP by thymidylate synthase, following intracellular phosphorylation to TFT 5 -monophosphate. ◦ Principal indication(s): HSV keratitis. ◦ Administered: topically as eye drops (1%) or ophthalmic cream. • Brivudin ◦ Structure (Fig. 27): (E)-5-(2-bromovinyl)-2 -deoxyuridine, bromovinyldeoxyuridine (BVDU), Zostex® , Zonavir® , Zerpex® . ◦ Activity spectrum: HSV (type 1), VZV and some other (veterinarily important) herpesviruses. ◦ Mechanism of action: targeted at the viral DNA polymerase, can act as competitive inhibitor (with respect to the normal substrate, dTTP) after intracellular phosphorylation to BVDU 5 -triphosphate; can also act as alternate substrate and be incorporated into the viral DNA, thus leading to a reduced integrity and functioning of the viral DNA (Scheme 8). The first and second phosphorylation steps are catalyzed by the virus-encoded (HSV-1 TK, VZV TK), which explains the remarkable specificity of BVDU for these viruses. O

O I

HN O HO

O

N O

OH

Br

HN

HO

N O

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, particularly herpes zoster, but also HSV-1 keratitis and herpes labialis. Brivudin has been licensed for the treatment of herpes zoster in immunocompetent patients in a number of European countries. ◦ Administered: orally at 125 mg per day, once-daily (herpes zoster); can also be administered topically, as 0.1–0.5% eye drops (herpetic keratitis) or 5% cream (herpes labialis). 4.2. CMV inhibitors • Ganciclovir ◦ Structure (Fig. 28): 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), (GCV), Cymevene® , Cytovene® . O N

HN H2N

HO

N

N

O

OH

Ganciclovir Fig. 28.

◦ Activity spectrum: HSV (types 1 and 2), CMV and some other herpesviruses. ◦ Mechanism of action: targeted at the viral DNA polymerase, where it mainly acts as chain terminator, following intracellular phosphorylation to GCV triphosphate and incorporation of GCV monophosphate at the 3 -end of the viral DNA chain. First phosphorylation step is catalyzed by the HSV-encoded thymidine kinase (TK) or CMV-encoded protein kinase (PK), which explains the specificity of ganciclovir for HSV and CMV, respectively. ◦ Principal indication(s): CMV infections, particularly CMV retinitis in immunocompromised (i.e. AIDS) patients (treatment and prevention). ◦ Administered: intravenously at 10 mg/kg per day (2 × 5 mg/kg, every 12 h) for induction therapy; orally at 3000 mg per day (three times four 250 mg capsules) for maintenance therapy and for prevention; intraocular (intravitreal) implant (Vitrasert∗ ) of 4.5 mg ganciclovir as localized therapy of CMV retinitis. • Valganciclovir ◦ Structure (Fig. 29): l-valine ester of ganciclovir (VGCV), Valcyte® . ◦ Activity spectrum: as for GCV. ◦ Mechanism of action: serves as oral prodrug of GCV, then acts as described for GCV. ◦ Principal indication(s): CMV infections. Oral valganciclovir is expected to replace intravenous ganciclovir in both the therapy and prevention of CMV infections.

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O

NH 2 N

HN H2 N

N

N

H C

C

N P

O

O

O

O

HO

O H2N

N

O

HO

CH CH3 H3C

OH OH

Cidofovir Fig. 31.

Valganciclovir Fig. 29.

◦ Administered: orally at 900 mg per day (two 450 mg tablets daily) for maintenance therapy (900 mg twice daily for induction therapy). • Foscarnet ◦ Structure (Fig. 30): trisodium phosphonoformate, foscarnet sodium, Foscavir® . ◦ Activity spectrum: herpesviruses (HSV-1, HSV-2, VZV, CMV, etc.) and also HIV. ◦ Mechanism of action: pyrophosphate analogue, interferes with the binding of the pyrophosphate (diphosphate) to its binding site of the viral DNA polymerase, during the DNA polymerization process. ◦ Principal indication(s): CMV retinitis in AIDS patients, and mucocutaneous acyclovir-resistant (viral TK-deficient) HSV and VZV infections in immunocompromised patients. ◦ Administered: intravenously at 180 mg/kg per day (3 × 60 mg/kg, every 8 h) for induction therapy of CMV retinitis; intravenously at 120 mg/kg per day (3 × 40 mg/kg, every 8 h) for maintenance therapy of CMV retinitis and for therapy of acyclovir-resistant mucocutaneous HSV or VZV infections in immunocompromised patients. Dose adjustments for changes in renal function are imperative. • Cidofovir ◦ Structure (Fig. 31): (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), (CDV), Vistide® , ForvadeTM . ◦ Activity spectrum: herpesviruses (HSV-1, HSV-2, VZV, CMV, etc.), papilloma-, polyoma-, adeno- and poxviruses.

O -

O

P O-

O C

O-

3 Na+

◦ Mechanism of action: targeted at the viral DNA polymerase, acts as chain terminator, following intracellular phosphorylation to the diphosphate form, and incorporation at the 3 -end of the viral DNA chain (two sequential incorporations needed for chain termination in the case of CMV DNA synthesis) (Scheme 9). ◦ Principal indications(s): officially licensed for the treatment of CMV retinitis in AIDS patients. Also shown to be effective in the treatment of acyclovir-resistant (viral TK-deficient) HSV infections, recurrent genital herpes, genital warts, CIN-III (cervical intraepithelial neoplasia grade III), laryngeal and cutaneous papillomatous lesions, molluscum contagiosum lesions, orf lesions, adenovirus infections and progressive multifocal leukoencephalopathy (PML). ◦ Administered: intravenously (Vistide® ) at 5 mg/kg per week during the first 2 weeks, then 5 mg/kg every other week, with sufficient hydration and under cover of probenecid to prevent nephrotoxicity. Can also be administered topically as a 1% gel or cream. • Fomivirsen ◦ Structure (Fig. 32): antisense oligodeoxynucleotide composed of 21 phosphorothioate-linked nucleosides, ISIS 2922, Vitravene® . ◦ Activity spectrum: CMV. ◦ Mechanism of action: being complementary in base sequence, it hybridizes with, and thus blocks expression (translation) of, the CMV immediate early 2 (IE2) mRNA. ◦ Principal indication(s): CMV retinitis (in AIDS patients). ◦ Administered : intraocularly (intravitreally).

5'-d-[G*C*G*T*T*T*G*C*T*C*T*T*C*T*T*C*T*T*G*C*G]_3' sodium salt * = 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) • Amantadine ◦ Structure (Fig. 33): tricyclo[3.3.1.1.3,7 ]decane-1-amine hydrochloride, 1-adamantanamine, amantadine HCl, Symmetrel® , Mantadix® , Amantan® , etc. ◦ Activity spectrum: influenza A virus. ◦ Mechanism of action: blocks M2 ion channel, and thus prevents the passage of H+ ions that are required for the necessary acidity to allow for the viral uncoating process (decapsidation).

◦ Principal indication(s): influenza A virus infections (prevention and early therapy). Also used in the treatment of Parkinson’s disease. ◦ Administered: orally at 200 mg per day (two times a 100 mg capsule). • Rimantadine ◦ Structure (Fig. 34): ␣-methyltricyclo[3.3.1.1.3,7 ]decane-1-methanamine hydrochloride, ␣-methyl-1-adamantanemethylamine HCl, Flumadine® . ◦ Activity spectrum: influenza A virus. ◦ Mechanism of action: as for amantadine.

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HO

H

OH H OH

NH2.HCl

H

O

O

OH CH3 NH

H Amantadine

O

HN NH2

NH Zanamivir

Fig. 33.

H

Fig. 35.

NH2.HCl H CH 3 H

Rimantadine Fig. 34.

◦ Principal indication(s): influenza A virus infections (prevention and early therapy). ◦ Administered: orally at 300 mg per day (two times 150 mg). • Zanamivir ◦ Structure (Fig. 35): 4-guanidino-2,4-dideoxy-2,3didehydro-N-acetylneuraminic acid, 5-acetylamino-4[(aminoiminomethyl)amino]-2,6- anhydro-3,4, 5- trideoxy-d-glycero-d-galacto-non-2-enonic acid, CG 167, Relenza® . ◦ Activity spectrum: influenza (A and B) virus. ◦ Mechanism of action: N-acetylneuraminic acid (sialic acid) analogue, inhibits influenza viral neuraminidase

(sialidase) (Scheme 10), and keeps the virus trapped onto the infected cells (viral neuraminidase is responsible for cleavage of N-acetylneuraminic acid from the influenza virus receptor so that progeny virus particles can be released from the infected cells). ◦ Principal indication(s): influenza A and B virus infections (therapy and prevention). ◦ Administered: by (oral) inhalation, at a dosage of 20 mg per day (two times 5 mg, every 12 h) for 5 days. Treatment to be started as early as possible, and certainly within 48 h, after onset of the symptoms. • Oseltamivir ◦ Structure (Fig. 36): ethyl ester of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexane-1-carboxylic acid, GS 4104, Ro 64-0796, Tamiflu® . ◦ Activity spectrum: influenza (A and B) virus. ◦ Mechanism of action: as for zanamivir. ◦ Principal indication(s): as for zanamivir. ◦ Administered: orally at 150 mg per day (two times a 75 mg capsule, every 12 h) for 5 days. Treatment should be started as early as possible, and certainly within 48 h, 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).

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6. Current state of the art O O HN O

O CH3 NH

NH2

NH

Oseltamivir Fig. 36.

• Ribavirin ◦ Structure (Fig. 37): 1-␤-d-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, Virazole® , Virazid® , Viramid® . ◦ Activity spectrum: various DNA and RNA viruses, in particular orthomyxoviruses (influenza A and B), paramyxoviruses (measles, respiratory syncytial virus (RSV)) and arenaviruses (Lassa, Junin, etc.). ◦ Mechanism of action: the principal target for ribavirin (in its 5 -monophosphate form) is IMP dehydrogenase, that converts IMP to XMP, a key step in the de novo biosynthesis of GTP and dGTP. In its 5 -triphosphate form, ribavirin can also interfere with the viral RNA polymerase and the 5 -capped oligonucleotide primer formation required for transcription of the influenza RNA genome. ◦ Principal indication(s): as a small size droplet aerosol, in the treatment of RSV infections in high-risk infants, and in combination with interferon-␣ (Intron A® , as in Rebetron® ) or pegylated interferon-␣ (PEG-INTRON® or Pegasys® ) in the treatment of hepatitis C virus (HCV) infections. ◦ Administered: orally at doses of 800–1200 mg per day, in the treatment of HCV infections; or by aerosol (solution of 20 mg/ml), which has proved superior to placebo aerosol in the treatment of RSV infections.

O H 2N

N N

HO

N

O

HO

OH

Ribavirin Fig. 37.

A total of 37 antiviral compounds (not including interferons or immunoglobulins) have momentarily been licensed for the treatment of HIV, HBV, herpesvirus, influenza virus and/or HCV infections. In the preceding sections these compounds have been discussed from the following viewpoints: chemical structure, activity spectrum, mechanism of action, principal clinical indication(s), route(s) of administration and dosage. Other points that need to be considered before the full clinical potential of any given drug could be appreciated, are: (i) duration of treatment, (ii) single- versus multiple-drug therapy, (iii) pharmacokinetics, (iv) drug interactions, (v) toxic side effects and (vi) development of resistance. A particular issue that may be important in the clinical setting is whether the listed anti-HIV agents would be equally suited for the treatment of HIV-2 and HIV-1 infections. As reported by Witvrouw et al. (2004), the NRTIs and the NtRTI tenofovir are equally active against HIV-1 and HIV-2; for the NNRTIs, anti-HIV activity is confined to the HIV-1 strains; protease inhibitors are equally active against HIV-1 and HIV-2, although amprenavir shows reduced activity against HIV-2, and, likewise, enfuvirtide has reduced inhibitory activity against HIV-2. As to the duration of treatment, this may vary from a few days (HSV, VZV, influenza virus infections) to several months or years (HIV, HBV and HCV infections), depending on whether we are dealing with an acute (primary (i.e. influenza) or recurrent (i.e. HSV, VZV)) infection or chronic, persistent (i.e. HIV, HBV, HCV) infection. For HIV infections it is still being evaluated whether long-term treatment can be interrupted, without loss of benefit (or increased benefit) to the patient (structured treatment interruption, STI). While the short-term treatment (5–7 days) of HSV, VZV and influenza virus infections, and even the more prolonged treatment of CMV infections, can be based on single-drug therapy, for the long-term treatment of HIV infections combination of several drugs in a triple-drug cocktail (also 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. Pharmacokinetic parameters to be addressed, when evaluating the therapeutic potential, include bioavailability (upon either topical, oral or parenteral administration), plasma protein binding affinity, distribution through the organism (penetration into the CNS, when this is needed), metabolism through the liver (i.e. cytochrome P-450 drug-metabolizing enzymes) and elimination through the kidney. Particularly when concocting the multiple-drug combinations for the treatment of HIV infection, possible drug–drug interactions should be taken into account: i.e. some compounds act as P-450 inhibitors and others as P-450 inducers, and this may greatly influence the plasma drug levels achieved, especially in the case of NNRTIs and PIs.

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Toxic side effects, both short- and long-term, must be considered when the drugs have to be administered for a prolonged period, as in the treatment of HIV infections. These side effects may seriously compromise compliance (adherence to drug intake), and could, at least in part, be circumvented by a reduction of the pill burden to, ideally, once-daily dosing. Finally, resistance development may be an important issue, again for those compounds that have to be taken for a prolonged period, as is generally the case for most of the NRTIs, NNRTIs and PIs currently used in the treatment of 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 of therapy (for HIV and HBV, respectively). Resistance has been noted with HBV against lamivudine after long-term therapy (>6 months), but, if resistant to lamivudine, HBV infections remain amenable to treatment with adefovir dipivoxil. As has been occasionally observed in immunosuppressed patients, HSV may develop resistance to acyclovir, and CMV to ganciclovir, but, if based on ACV TK or CMV PK deficiency, these resistant viruses remain amenable to treatment with foscarnet and/or cidofovir. In immunocompetent patients, treated for an acute or episodic HSV, VZV or influenza virus infection, short-term therapy is unlikely to engender any resistance problems.

7. Antiviral agents in (pre)clinical development In addition to the 37 antiviral compounds that are currently available, there are another 40 or so that are presently under (pre)clinical development. For HIV (De Clercq, in press), these include the virus adsorption inhibitors (cosalane derivatives, cyanovirin-N, cyclotriazadisulfonamide (CADA) derivatives, teicoplanin aglycons and BMS-378806); the CXCR4 antagonist AMD070 (De Clercq, 2003c); the CCR5 antagonists SCH-C, SCH-D, TAK-220, spirodiketopiperazine E913, MRK-1 (CMPD167), and trisubstituted pyrrolidines; the NRTIs (±)-2 -deoxy-3 -oxa-4 -thiacytidine (dOTC) and the 5-fluoro-substituted derivative thereof (FdOTC), amdoxovir (DAPD), Reverset (␤-d-d4FC) and alovudine (FddThd); the NNRTIs UC-781, SJ-3366, DPC-083, (+)-calanolide A, capravirine (AG1549, S-1153) and dapivirine (TMC-125); the integrase inhibitors S-1360 (and other diketoacid derivatives), 1,6-naphthyridine-7-carboxamide, 8-hydroxy-[1,6] naphthyridine and pyranodipyrimidine (PDP) derivatives; and peptidomimetic (i.e. TMC-126) and non-peptidomimetic (i.e. tipranavir, PNU-140690) protease inhibitors. Of these compounds, tipranavir as well as some of the NRTIs (e.g. Reverset) and NNRTIs (e.g. capravirine, dapivirine) may nowadays seem closest to eventual regulatory approval. For HBV, in addition to the licensed drugs lamivudine and adefovir dipivoxil, a number of new nucleoside analogues, viz. entacavir, l-dT and the valine ester of l-dC, as well

as emtricitabine (already in use for HIV/AIDS), are coming along; and for HCV, a variety of compounds targeted at either the viral protease, helicase or RNA-dependent RNA polymerase (RDRP) are currently under intensive scrutiny (see, for example, Lamarre et al., 2003 for the NS3 protease inhibitor BILN 2061). Also for the herpesviruses (i.e. HSV), new antivirals have been described that target the helicase/primase complex, terminase complex or UL97 protein kinase (Eizuru, 2003), and, likewise, new inhibitors are on the horizon for CMV (De Clercq, 2003b) and VZV (De Clercq, 2003d).

8. Appraisal of clinical utility Currently licensed antiviral drugs are particularly focussed on the treatment of HIV, HBV, herpesvirus, influenza virus and HCV infections, and, so are most of forthcoming antiviral compounds that are in (pre)clinical development. For the treatment of HIV/AIDS there are now 19 anti(retro)viral drugs available, and to achieve the largest possible benefit, these drugs have to be combined in multiple-drug regimens. Numerous drug combinations could be envisaged. Those that have been generally used consist of two NRTIs, or one NRTI and one NtRTI (tenofovir 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 disturbances) associated with the PIs that have been longest in use, there is a tendency for starting anti-HIV therapy with PI-sparing regimens. One such regimen that has proven to be quite efficacious in the treatment of HIV infections, and seems to be well tolerated, is the combination of TDF with 3TC (lamivudine) and efavirenz. In the future, 3TC may be replaced in this regimen by (−)FTC (emtricitabine), which could be formulated with TDF in a single pill (to be taken once daily). Combinations of TDF with purine NRTIs such as abacavir or didanosine should be avoided, as these have been shown not to achieve the expected reductions in viral load. Enfuvirtide represents a new dimension in anti-HIV therapy, which could be added onto any (optimized background) regimen, but, because of the costs involved and the fact it has to be administered subcutaneously (twice daily), enfuvirtide should be primarily reserved for salvage therapy. For the treatment of HBV infections, 2 compounds, lamivudine and adefovir dipivoxil, besides human interferon, are currently available. TDF is recommended for use in HIV-infected patients who are co-infected with HBV. Whether the treatment of HBV infections should be based upon multiple-drug regimens (so as to minimize the emergence of virus-drug resistance), as in the case of HIV/AIDS, needs to be addressed in future studies. Possible dual-drug regimens that could be envisaged for chronic hepatitis B are adefovir dipivoxil combined with lamivudine (or emtricitabine).

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The treatment of HSV and VZV infections is since many years fairly well consolidated: it is based on the use of acyclovir, valaciclovir or famciclovir, and in some European countries, also brivudin (BVDU). Here, there is no need for drug combination therapy, as virus-drug resistance has only rarely proved to be a problem, and, if so (in severely immunocompromised patients), therapy could be switched to, for example, foscarnet or cidofovir. The latter two drugs, which must be administered intravenously, are also used in the treatment of CMV infections in immunosuppressed patients, mostly as second choice following the use of (val)ganciclovir. For the therapy and prophylaxis of influenza virus infections the neuraminidase inhibitors zanamivir and oseltamivir have acquired increased momentum (the latter being more practical as it can be administered orally whereas the former has to be inhaled). These neuraminidase inhibitors may be expected to be effective against new influenza virus types or variants for which no vaccines are available. Finally, for the treatment of HCV infections, the combination of ribavirin with pegylated IFN is the current choice of treatment, although it provides a durable response in only a varying percentage of the patients.

Acknowledgements I thank Christiane Callebaut and Inge Aerts for their dedicated editorial assistance.

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