Drug Profile

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CONTENTS

Overview of the market

Introduction tothe compound

Pharmacodynamics

Pharmacokinetics& metabolism

Clinical efficacy

Safety & tolerability

Regulatory affairs

Expert opinion

Five-year view

Key issues

References

Affiliations

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Adefovir dipivoxil in thetreatment of chronic hepatitis B virus infectionStephanos J Hadziyannis† and George V PapatheodoridisAdefovir dipivoxil (Hepsera®, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- andpost-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir®, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.

Expert Rev. Anti-infect. Ther. 2(4), 475–483 (2004)

†Author for correspondenceDepartment of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, 11526 Athens, GreeceTel.: +30 210 697 2937Fax: +30 210 697 2974hadziyannis@ath.forthnet.gr

KEYWORDS:adefovir, adefovir dipivoxil, antiviral therapy, chronic hepatitis B, hepatitis B virus nucleotide analog

Overview of the marketChronic infection with hepatitis B virus (HBV)is a global health problem with significant mor-bidity and mortality [1,2]. The risk for the devel-opment of cirrhosis and hepatocellular carci-noma is considerable, particularly in patientsexhibiting high HBV replication with livernecroinflammation and fibrosis, such as inchronic hepatitis B (CHB) [1,2]. Until recently,the only licensed drugs for the treatment ofCHB were interferon (IFN)-α and the oralnucleoside analog lamivudine (Epivir®, Glaxo-SmithKline) [1,2]. Both of these agents havelimited efficacy in achieving sustained off-ther-apy remission [1–4]. Moreover, IFN-α has sev-eral side effects and is poorly tolerated, whilelamivudine, which is well-tolerated and has anexcellent safety profile, frequently selects resist-ant HBV mutants, culminating in virologicand biochemical breakthroughs, particularly inlong-term therapeutic regimens [1–3,5].Recently, a new nucleotide analog, adefovirdipivoxil (ADV; Hepsera®, Gilead Sciences),has been approved for the treatment of HBV,which has a good safety profile and is effectiveagainst wild-type and lamivudine-resistantHBV mutants [6].

This review will focus on the efficacy ofADV in the treatment of chronic HBV-relatedliver disease. In particular, all major preclinicaland clinical studies published as full papers orimportant abstracts presented in recent majorliver meetings will be reviewed.

Introduction to the compoundChemistryAdefovir is an acyclic analog of the nucleotidedeoxyadenosine-5´-monophosphate (dAMP)(FIGURE 1) that has potent antiviral activityagainst HBV and other viruses [6]. It isadministered orally in the form of its pro-drug, ADV. ADV, which is adefovir esteri-fied with two pivalic acid molecules, hasgood oral availability and is rapidly con-verted to adefovir in plasma or tissues. Ade-fovir is subsequently converted by the cellu-lar adenylate kinase to its final active moiety,adefovir diphosphate [7]. Adefovir diphos-phate is an analog of deoxyadenosine-5´-tri-phosphate but without a 3´-hydroxylic root,and therefore it competes with the naturaldeoxyadenosine triphosphate (dATP) duringHBV DNA synthesis by the HBV polymerase;when adefovir diphosphate is incorporated

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Hadziyannis & Papatheodoridis

476 Expert Rev. Anti-infect. Ther. 2(4), (2004)

into the HBV DNA chain, it discontinues further elongationof the DNA chain and therefore causes termination of HBVreplication [8].

PharmacodynamicsIn vitro activityIn vitro studies have shown that adefovir diphosphate selectivelyinhibits the HBV polymerase, since the concentrations requiredto inhibit enzymatic activity by 50% (IC50) were reported to be0.1 µmol/l for HBV polymerase and more than 100 µmol/l forhuman DNA-α polymerase [9]. Moreover, the inhibition con-stant (Ki) for adefovir diphosphate against HBV polymerase wasfound to be 0.1 µmol/l, which is four to 704-fold lower than theKi for the various human DNA polymerases [10]. Similar find-ings have also been reported in a variety of HBV DNA produc-ing human hepatoma cell lines [6,9]. In vitro studies in humanhepatoblastoma (Hep)G2 cells or human skeletal muscle cellshave also shown that adefovir has no substantial effect on themitochondrial DNA content [11].

In several HBV DNA-producing human hepatoma cell lines,the adefovir IC50 values for HBV DNA synthesis were found torange from 0.2 to 2.5 µmol/l [9,12–14], and to be significantlylower than the concentrations required to inhibit 50% ofhuman cell growth or human DNA synthesis (50% cytotoxicconcentration) [9,12–15].

Viral resistanceTo date, there are two recognized ADV-resistant HBV mutations:rtN236T and rtA181V [16,17]. The rtN236T mutation is themost frequent and is associated with the selection of a novelasparagine to threonine substitution at residue rt236 in domainD of the HBV polymerase [18,19]. It should be noted, however,that the incidence of ADV-resistant mutations has been foundto be very low, with a cumulative probability of 0% after48 weeks [20], 1.6 to 3% after 96 weeks [18,21], and 3.9% after144 weeks of ADV therapy for all treated patients with chronicHBV infection; or 5.9% in the subset of patients with hepatitisB e antigen (HBeAg)-negative CHB [17,22].

Patients developing the rtN236T mutation experiencerebound in HBV DNA of greater than 1 log10 from nadir,with an increase in alanine aminotransferase (ALT) activity

[17]. In vitro studies show that strains carrying the rtN236Tsubstitution exhibit a six- to 14-fold reduced susceptibility toADV [18]. The model structure of the reverse transcriptase ofHBV suggests that the rtN236T mutant may have a morefavorable interaction with the γ-phosphate of dATP comparedwith adefovir diphosphate, thus favoring the selective use ofthe natural substrate and not adefovir diphosphate [23]. ThertN236T mutant HBV strain has been found to be suscepti-ble to L-deoxythymidine (telbivudine [Idenix Pharmaceuti-cals]) and entecavir (BMS-200475, Bristol–Myers Squibb)in vitro, and fully susceptible to lamivudine both in vitro andin vivo [23,24]. The significance of the rtA181V mutation isnot clear and needs to be characterized further.

Pharmacokinetics & metabolismThe pharmacokinetics of ADV have been studied in both healthyvolunteers and patients with chronic HBV infection, as well as inpatients with renal or hepatic impairment [7,25,26]. ADV isabsorbed rapidly after oral administration without significant dif-ferences between healthy subjects and CHB patients [25]. In18 healthy subjects, the mean peak plasma concentration (Cmax)after a single dosing of ADV at 10 mg was 20.4 ng/ml, and themedian area under the plasma concentration–time curve (AUC)was 192 ng*h/ml. Similarly, in 14 CHB patients, the Cmax aftersingle or multiple dosing of ADV 10 mg once daily was found tobe 17.5 or 18.3 ng/ml, respectively. The AUC was 210 or204 ng*h/ml, respectively [25]. In the same study, it was shown thatADV pharmacokinetics were not affected by food and thereforethe drug can be taken without regard to meals [25].

ADV is readily converted to adefovir in plasma and tissuesby extracellular kinases. It has a plasma half-life of 5 to 7 hand is excreted in urine [7]. After being transported intracellu-larly by a receptor-based mechanism, adefovir is phosphor-ylated to its diphosphate form by cellular adenylate kinase.Adefovir diphosphate has not been detected extracellularlyand, in an in vitro study, its intracellular half-life has beenshown to be 16 to 18 h [7].

The pharmacokinetics of ADV have been shown toremain unchanged in patients with hepatic impairment(Child–Pugh class B or C) or mild renal impairment (creatinine clearance 50–80 ml/min) and therefore no change in ADV dosing

Extracellularkinases

Cellularadenylate kinase

Adefovir dipivoxil Adefovir Adefovir diphosphate

NN

N NO

O

OO

O O

NH2

O

O

PO-O

O-PO

O

O-

NN

N NOP

NH2

O

O

O-

NN

N NOP

O

NH2

O-

O-+ Formaldehyde+ Pivalic acid

Figure 1. Adefovir dipivoxil, adefovir and adefovir diphosphate. Adefovir dipivoxil is a prodrug with good oral bioavailability and is rapidly converted by extracellular kinases to adefovir, which is subsequently converted by the cellular adenylate kinase to its final active moiety, adefovir diphosphate.

Adefovir dipivoxil

www.future-drugs.com 477

Tabl

e 1.

Eff

icac

y of

ade

fovi

r di

pivo

xil i

n ch

roni

c he

pati

tis

B pa

tien

ts w

ith

or w

itho

ut r

esis

tanc

e to

lam

ivud

ine.

Stu

dyH

BeAg

st

atus

Du

rati

on(w

eeks

)Tr

eatm

ent

Pati

ents

Med

ian

base

line

seru

mH

BV D

NA§

Med

ian

HBV

DN

Ach

ange

§

HBV

DN

A un

dete

ctab

le§§

HBe

Ag

sero

conv

ersi

onAL

T no

rmal

izat

ion

His

tolo

gica

l im

prov

emen

t§§§

Ref.

Drug

Dose

(mg/

day)

n%

n/N

%n/

N%

n/N

%

Phas

e III

rand

omiz

ed p

lace

bo-c

ontr

olle

d tr

ials

in n

aive

CH

B pa

tient

s and

ext

ensi

on d

ata

Had

ziya

nnis

N

egat

ive

48 48

PLA

ADV

10

61 123

7.1

7.1

-1.4

1

-3.9

2

01

632

51

NA

NA

NA

NA

17/5

91

84/1

162

29 72

19/5

71

77/1

212

33 64

[32]

Had

ziya

nnis

N

egat

ive

96AD

V10

79-

-3.5

5671

NA

NA

47/6

473

[21]

Had

ziya

nnis

N

egat

ive

144

ADV

1067

--3

.653

79N

AN

A43

/62

69[2

]

Mar

celli

n Po

sitiv

e48 48 48

PLA

ADV

ADV

10 30

167

171

173

8.3

8.3

8.4

-0.6

1

-3.5

2

-4.8

2

01

362

672

21 39

9/16

13

20/1

714

23/1

654

6 12 14

26/1

641

81/1

682

93/1

692

16 48 55

41/1

461

89/1

502

98/1

452

28 59 68

[29]

Phas

eII

rand

omiz

ed tr

ials

in n

aive

CH

B pa

tient

sSu

ng

Posi

tive

52

52

LAM

+AD

V

LAM

+PL

A

55 57

8.8

9.2

-5.4

-4.8

21 23

38 40

10/5

3

11/5

4

19 20

25/5

23

39/5

64

48 70

[64]

Rand

omiz

ed c

ontr

olle

d tr

ials

in C

HB

patie

nts w

ith re

sist

ance

to L

AMPe

ters

Po

sitiv

e 4

8

48

48

ADV

ADV

+LA

M

LAM

10 100

19 20 19

8.4

7.9

8.2

-4.0

2

-3.6

2 01

53 73 04

26 35

2/19

1/18

0/19

11 6

9/19

5

10/1

95

1/19

6

47 53 5

[43]

Will

ems

Posi

tive/

nega

tive

52

52

ADV

+LA

M

PLA

+LA

M

46 49

8.9

8.7

-4.5

3

+0.3

4

9/46

5

0/48

6

203/

40

1/42

8 2

14/4

63

3/47

4

30 6

[42]

p-va

lues

for c

ompa

rison

s be

twee

n gr

oups

(mar

ked

by s

uper

scrip

ts) o

f the

abo

ve s

tudi

es: 1

vs.

2, p

<0.

001;

3 v

s. 4,

p<

0.05

; 5 v

s. 6,

p<

0.00

5.§ Se

rum

HBV

DN

A in

log 1

0co

pies

/ml.

§§Se

rum

HBV

DN

A un

dete

ctab

le b

y a

poly

mer

ase

chai

n re

actio

n as

say

with

sen

sitiv

ity o

f 400

to 1

000

copi

es/m

l.§§

§ His

tolo

gica

l im

prov

emen

t def

ined

as

a re

duct

ion

by a

t lea

st tw

o po

ints

in th

e Kn

odel

l nec

roin

flam

mat

ory

scor

e w

ith n

o w

orse

ning

of f

ibro

sis.

ADV:

Ade

fovi

r; AL

T: A

lani

ne a

min

otra

nsfe

rase

; CH

B: C

hron

ic h

epat

itis

B; H

BeAg

: Hep

atiti

s B

e an

tigen

; HBV

: Hep

atiti

s B

viru

s; L

AM: L

amiv

udin

e; N

A: N

ot a

pplic

able

; n/N

: Num

ber/

tota

l num

ber;

PLA:

Pla

cebo

.

Hadziyannis & Papatheodoridis

478 Expert Rev. Anti-infect. Ther. 2(4), (2004)

is required in such patients [26]. In contrast, Cmax and AUCvalues were shown to be significantly increased in patients withmoderate or severe renal impairment (creatinine clearance<50 ml/min) or those requiring hemodialysis, who requiremodified ADV dosing with adjustment in dosage intervals(ADV 10 mg every other day is usually recommended) [26,27].

ADV seems to have a low potential for interactions withother drugs, since it has been shown to have no effect on any ofthe common enzymes of cytochrome P450 [6]. In healthy sub-jects, ADV was found to have no significant interaction withother drugs (lamivudine, paracetamol, ibuprofen, and antibiot-ics including trimethoprim–sulfamethoxasole [Septrin®, Glaxo-SmithKline]) [28]. A small increase in adefovir exposure wasobserved when ADV was coadministered with ibuprofen(Cmax: 33%; AUC: 23%), but it was not considered sufficientto necessitate a change in the drug dosage [28].

Clinical efficacyThe efficacy of ADV therapy, given alone or in combinationwith other therapeutic agents, has been evaluated in severalrandomized, double-blind trials, as well as in open-label stud-ies including various subgroups of CHB patients (TABLE 1).ADV therapy was usually administered at a dose of 10 mgonce daily, except for one trial in which a 10 mg and a higher30 mg ADV daily dose were evaluated [29]. Since the 30 mgADV dose was found to be associated with an increased riskof renal damage without offering any therapeutic benefit overthe 10 mg ADV dose [29], the 10 mg ADV dose administeredonce daily is the recommended and approved dosage for thetreatment of CHB.

Efficacy in patients with HBeAg-positive CHBIn HBeAg-positive CHB, the therapeutic efficacy of ADVmonotherapy, given orally at a dose of 10 or 30 mg once daily,has been evaluated in a multicenter, randomized, placebo-controlled trial (GS-98-437) that included 515 patients [29].After 48 weeks of treatment, ADV achieved significant histo-logic improvement compared with placebo, which was theprimary end point of this trial. In particular, histologicimprovement, defined as a reduction of at least two points inthe necroinflammatory score and no concurrent worsening ofthe Knodell fibrosis score, was observed in 53% of patientstreated with ADV at 10 mg, 59% of patients treated withADV 30 mg and only 25% of placebo treated patients(p < 0.001 for the comparisons of placebo with any of theADV treated group) [29]. ADV therapy was also found to besignificantly superior to placebo for all secondary end points.At 48 weeks, loss of HBeAg was detected in 24 or 27% (pla-cebo: 11%, p < 0.001), HBeAg seroconversion to anti-HBe in12 or 14% (placebo: 6%, p < 0.05), undetectable serum HBVDNA by a sensitive polymerase chain reaction (PCR) assay(sensitivity: 400 copies/ml) in 21 or 39% (placebo: 0%,p < 0.001), and normalization of ALT in 48 or 55% (placebo:16%, p < 0.001) of patients treated with ADV 10 or 30 mg,respectively [29].

Similarly to what has previously been observed in HBeAg-positive CHB patients treated with IFN-α or lamivudine, higherbaseline ALT levels were also associated with improved efficacy ofADV therapy [30].

Data on the efficacy of long-term ADV therapy in HBeAg-positive CHB patients have also been presented. In one Phase IIextension study including 28 such patients, ADV therapy main-tained biochemical and virologic remission at 2 years without sig-nificant toxicity and without any evidence of viral resistance [31].The extension of the GS-98-437 trial of ADV in 85 patients withHBeAg-positive CHB showed that the rate of loss of HBeAgincreased to 44% and the rate of anti-HBe development to 23%at 72 weeks of ADV therapy [GILEAD SCIENCES, DATA ON FILE] [29].

Efficacy in patients with HBeAg-negative CHBIn HBeAg-negative CHB patients, the therapeutic efficacy ofADV monotherapy given orally at a dose of 10 mg once daily,has been evaluated in a multicenter, randomized, double-blind,placebo-controlled trial (GS-98-438), that included185 patients [32]. Similar to the observations in the HBeAg-posi-tive CHB trial [30], ADV therapy was proved to be significantlymore effective than placebo for all end points [32]. At 48 weeks,histologic improvement, which was again the primary endpoint, was achieved in 64% of patients treated with ADV, com-pared with 33% of those treated with placebo (p < 0.001). ADVtherapy was also found to effectively suppress biochemical activ-ity and HBV replication during the first 48 weeks of therapy[32]. In particular, ALT normalized in 72 and 29% (p < 0.001)and serum HBV DNA was undetectable by PCR in 51 and 0%of the 123 ADV and the 61 placebo treated patients, respec-tively (p < 0.001). Median serum HBV DNA levels dropped at48 weeks compared with baseline, by 3.9 log10 in the ADVgroup and 1.35 log10 in the placebo group (p < 0.001) [32].

Whether ADV courses of finite duration can achieve sustainedresponses maintained after drug discontinuation in a sizeableproportion of HBeAg-negative CHB patients, is currentlyunknown [3,33]. However, most on-therapy responders areexpected to relapse soon after the discontinuation of a 48-weekcourse of ADV therapy. Therefore, long-term ADV treatmentwill probably be needed in order to maintain on-therapyresponses [3,5].

The extension of the GS-98-438 trial has provided data for thesafety and efficacy of 2-year [21] and very recently, of 3-yearcourses of ADV therapy in patients with HBeAg-negative CHB[22]. On-therapy biochemical and virologic responses were foundto be maintained during the second and third year of ADV ther-apy without significant toxicity [21,22] and with infrequent devel-opment of viral resistance (cumulative probability: 3% at 2 yearsand 5.9% at 3 years) [17,18,21,22]. In particular, serum HBV DNAlevels undetectable by PCR were maintained in 71 and 79%, andnormal ALT levels in 73 and 69% of ADV-treated patients at theend of the second and third year of therapy, respectively [21,22].Liver biopsies performed at week 96 in a subset of the overallcohort of this study suggested that additional histological benefitis obtained with the extension of ADV treatment [21].

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Besides the data on extended ADV therapy, data for patientswho discontinue ADV after 48 weeks of therapy are also availa-ble, since approximately a third of the total patient population(or half of the patients initially treated with ADV) of theGS-980-438 trial switched to placebo after the first year of ther-apy. Most patients who switched from ADV to placebo duringthe second year of this trial experienced biochemical and viro-logic relapses (undetectable serum HBV DNA by PCR: 8%) aswell as reversal of the histologic improvement gained during thefirst year of active treatment [21]. Moreover, post-treatment flaresin serum ALT levels were seen in a proportion of patients afterstopping ADV [21]. Although these events were likely to be self-limiting and not associated with hepatic decompensation, theynevertheless emphasize the need for careful monitoring ofpatients discontinuing ADV therapy.

Efficacy in patients with resistance to lamivudineThe wide use of lamivudine in CHB during the past 5 years hasresulted in a constant increase of patients with lamivudine-resistant HBV strains due to mutations in the tyrosine–methio-nine–aspartate–aspartate (YMDD) motif of the HBV polymer-ase [5]. ADV is the only approved agent that has been shown tobe effective in patients with resistance to lamivudine [33–35].ADV has also been found to have similar antiviral efficacyagainst all types of lamivudine-resistant YMDD mutant HBVstrains [36].

In recent clinical trials, the addition of ADV to lamivudinetherapy after the development of lamivudine resistance hasbeen shown to be an effective therapeutic option in transplantpatients and those with CHB or decompensated cirrhosis, irre-spective of HBeAg status [37–41]. In particular, in 95 CHBpatients with resistance to lamivudine who continued takinglamivudine, virologic responses at 48 weeks (defined as reduc-tion in serum HBV DNA levels to less than 105 copies/ml orunder 2 log10) were observed in 85% (39/46) of patients whoreceived additional ADV therapy and in only 11% of thosewho received placebo (p < 0.001) and normalization of ALT in31 and 6% of cases, respectively (p = 0.002) [40]. In a largestudy including 324 HBV decompensated cirrhotics (n = 128)or transplant patients (n = 196) with resistance to lamivudine,ADV therapy achieved a significant reduction in serum HBVDNA levels (undetectable HBV DNA by PCR: 81 and 34%;median reduction in serum HBV DNA levels: 4.1 log10 and4.3 log10, respectively), frequent normalization of liver func-tion tests (ALT, albumin, bilirubin and prothrombin time: 76,81, 50 and 83% of decompensated cirrhotics or 49, 76, 75 and20% of transplant patients, respectively) and improvement inChild–Pugh score (>90% of patients in both cohorts) [39]. Sim-ilar findings have also been reported in other studies includingsmaller numbers of such patients [37,38,40–42].

The efficacy of ADV monotherapy for the treatment ofcompensated CHB patients with lamivudine resistance hasbeen evaluated in a recently published randomized studyincluding 59 patients with HBeAg-positive CHB [43]. In thissetting, ADV monotherapy and the combination of ADV plus

lamivudine were found to achieve similar rates of biochemicaland virologic remission during the 48 weeks of therapy, bothbeing significantly superior to the continuation of lamivudinealone [43]. It should be noted, however, that the number ofpatients included in this trial was relatively small (approximately20 per treatment arm) and that patients who received ADVmonotherapy experienced ALT flares (increase of ALT over fivetimes the upper limit of normal usually within the first 12 weeksfollowing the initiation of ADV) more frequently than thepatients who received the combination of ADV and lamivudine(7/19, 37% vs. 2/20, 10%, respectively; p = 0.065) [43]. More-over, the 48-week duration of this trial might be too short aperiod to reveal any potential benefit of the combination ther-apy, since resistance to ADV starts to appear after 2 years oftherapy [18,20–22]. Thus, whether CHB patients with resistanceto lamivudine should switch to ADV monotherapy immediatelyor following a period of concurrent lamivudine therapy, orwhether they should receive long-term ADV and lamivudinecombination therapy cannot, as yet, be definitely answered.

Efficacy in CHB patients coinfected with HIVADV has been evaluated for the treatment of HIV/HBVcoinfected patients with resistance to lamivudine. In anopen-label trial including 35 HIV-1/HBV coinfectedpatients who had developed resistance during lamivudinetherapy (150 mg twice daily) as part of their antiretroviralregimen, the addition of ADV (10 mg once daily) for48 weeks resulted in a median of 4 log10 copies/ml drop inserum HBV DNA levels without significant adverse events[44]. Thus, ADV appears to be an effective anti-HBV agent,even in HIV/HBV coinfected patients with resistance tolamivudine. It should be noted, however, that ADV therapy atthe dose of 10 mg once daily was found to have no effect onHIV RNA or CD4 cell count [44]. Therefore, tenofovir diso-proxil fumarate (Viread®, Gilead Sciences), which has beenlicensed for HIV infected patients and has been shown to beactive against both HIV and wild or lamivudine-resistant HBVstrains [45–48], may be the preferable agent to use as part of thehighly active antiretroviral regimens in this setting [48,49].

Safety & tolerabilityADV therapy is generally well-tolerated and has a good safetyprofile. Although high ADV doses (60 or 120 mg daily in non-HBV patients or 30 mg in CHB patients) have been associatedwith an increased risk of nephrotoxicity, usually after 20 ormore weeks of treatment [29,50], the experience with the cur-rently recommended 10 mg daily dose demonstrates that therisk of nephrotoxicity is low even after 3 years of therapy[21,22,29,32]. In the two multicenter, randomized, placebo-con-trolled Phase III trials, the 10 mg daily dose of ADV given for48 weeks was found to be very well-tolerated, with a safety pro-file similar to placebo [29,32]. The safety profile of the 10 mgADV daily dose was also reported to be excellent at the end ofthe second and third years of treatment, similar to thatobserved during the first 48 weeks of therapy [21,22]. Moreover,

Hadziyannis & Papatheodoridis

480 Expert Rev. Anti-infect. Ther. 2(4), (2004)

it has been shown that the 10 mg ADV dose approved for CHBcan be safely administered even in patients with hepatic or mildrenal impairment [39]. Dosing interval adjustments are recom-mended only for patients with a creatinine clearance of lessthan 50 ml/min and patients requiring hemodialysis [26].

Regulatory affairsIn both the USA and Europe, ADV therapy has been approvedfor the treatment of all subgroups of CHB infected patients withactive viral replication and evidence of liver damage, who requiretherapeutic intervention: patients with CHB or decompensatedHBV cirrhosis or HBV transplant patients, irrespective ofHBeAg status and of the development of lamivudine resistance.

Expert opinionThe development of ADV has offered hepatologists a valuabletherapeutic option against HBV. ADV monotherapy, givenorally at a daily dose of 10 mg, is well-tolerated, safe and effec-tive in all subgroups of patients with CHB infection[29,32,34,39,40,51]. It has also been shown that ADV is equallyeffective against both wild-type, precore mutant and lamivu-dine-resistant HBV strains, as well as against all HBV geno-types [52]. Thus, since treatment with any of the currentlyavailable therapeutic agents (IFN-α, lamivudive, ADV) mayachieve sustained off-therapy responses in only a minority ofCHB-infected patients, eventually most (>70–80%) of themwill have to undergo long-term viral suppressive treatmentwith well-tolerated and safe antiviral agents aiming to main-tain on-therapy remission and prevent worsening of fibrosis[1,33,34,53]. Lamivudine therapy is potent, well-tolerated, safeand relatively inexpensive, but its long-term efficacy isrestricted by progressively increasing rates of viral resistancefollowed by increasing viremia levels, culminating in biochem-ical breakthroughs with an ultimately adverse effect on liverhistology [54,55]. On the other hand, ADV is more expensive

than lamivudine, but it is also well-tolerated and safe andachieves long-term maintenance of viral suppression, biochemi-cal normalization and histological improvement, combined witha delayed and infrequent incidence of viral resistance (as clearlyshown in HBeAg-negative CHB [21,22]). All these propertiesmake ADV an important drug for the treatment of HBV infec-tion and an excellent candidate for the long-term managementof CHB-related liver disease.

Five-year viewADV therapy has, and will probably maintain an importantrole in the new era of anti-HBV management, in which long-term maintenance treatment with safe and well-tolerated anti-viral agents is considered to be the realistic therapeuticapproach for most CHB patients [3,6,56,57]. The choice of ADVas a first-line, long-term therapy is based on its efficacy and par-ticularly on its high threshold for viral resistance. Newer anti-HBV agents, mainly nucleoside analogs currently under evalua-tion with more pronounced and rapid suppression of HBV rep-lication, are expected to enter the armamentarium against HBVinfection in the next few years [8]. They may achieve higherrates of initial virologic or biochemical responses, but the ratesof viral resistance during long-term therapy have not yet beenevaluated and may be a relatively frequent problem makingthem unsuitable for effective long-term therapy [4,33,34]. Theefficacy of immunomodulatory approaches (such as inter-leukin-2 or -12, IFN-γ, or vaccine-based therapies) havebeen relatively disappointing [4,33].

Finite courses of treatment with pegylated IFN-α mayimprove the sustained off-therapy response rates achieved withconventional IFN treatment, but the majority of treated CHBpatients will still fail to respond to this agent [58–60]. Moreover,similarly to standard IFN-α, pegylated IFN-α will not beadministered in decompensated cirrhotics or HBV transplantpatients [3].

Key issues

• Adefovir dipivoxil (ADV) is a prodrug of adefovir, an acyclic analog of the nucleotide deoxyadenosine-5´-monophosphate that has potent antiviral activity against hepatitis B virus (HBV) and other viruses. ADV, which is adefovir esterified with two pivalic acid molecules, has good oral availability and is rapidly converted to adefovir in plasma or tissues. Adefovir is converted to adefovir diphosphate intracellularly, which selectively inhibits the HBV polymerase.

• ADV is given orally at a dose of 10 mg once daily and its pharmacokinetics are not affected by food, hepatic impairment or mild renal impairment. Adjustment in the ADV dosing intervals is only required in patients with moderate or severe renal impairment (creatinine clearance <50 ml/min) or those requiring hemodialysis.

• Randomized, placebo-controlled, Phase III trials have shown that ADV therapy is effective in both hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B and that its efficacy is maintained even after 3 years of therapy (at least in HBeAg-negative chronic hepatitis B). Moreover, the addition of ADV has been shown to be effective in patients with compensated or decompensated HBV chronic liver disease or HBV transplant patients who develop resistance to lamivudine.

• ADV has been proven to be safe and well-tolerated even after 3 years of therapy and to be associated with low rates of viral resistance with a cumulative probability of 0% after 48 weeks, 3% after 96 weeks and 6% after 144 weeks of therapy. These characteristics and the continued efficacy of prolonged treatment with ADV make this drug a good candidate for long-term maintenance therapy of chronic HBV-related liver disease.

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ReferencesPapers of special note have been highlighted as:

• of interest

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• Demonstrates the safety and sustained efficacy of 3 years of therapy with adefovir dipvoxil in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.

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The results from combination therapies with conventionalor pegylated IFN-α and nucleoside analogs in CHB have beenrather disappointing [59–63], while the combination of ADVand lamivudine was not found to be superior to monotherapy[43,64]. On the other hand, a combination of antiviral agentsmay be used as long-term maintenance treatment either innaive or lamivudine-resistant patients, particularly in overt anddecompensated HBV cirrhosis. In fact, patients with resistance

to an antiviral agent seem to be the group that will benefitmost from combination therapy [65]. The safety and efficacyprofile of ADV and the delayed and infrequent HBV resistanceduring its long-term administration support the suggestionthat this antiviral agent will remain as a first-line anti-HBVagent in the future, particularly suitable for long-lasting andeven indefinite monotherapy or combination therapy withother antiviral agents.

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•• Randomized, multicenter, placebo-controlled trial demonstrating the safety and efficacy of a 48-week course with adefovir dipivoxil in patients with HBeAg-positive chronic hepatitis B.

30 Marcellin P, Chang TT, Lim SG et al. Baseline ALT predicts histological and serological response in patients with HBeAg+ chronic hepatitis B treated with adefovir dipivoxil (ADV). J. Hepatol. 36(Suppl. 1), 122–123 (2002).

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•• Randomized, multicenter, double-blind, placebo-controlled trial demonstrating the safety and efficacy of a 48-week course with adefovir dipivoxil in patients with HBeAg-negative chronic hepatitis B.

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•• Large study showing the safety and efficacy of the addition of adefovir dipivoxil in patients with decompensated hepatitis B virus (HBV) cirrhosis or post-transplant HBV recurrence who develop resistance to lamivudine.

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•• Demonstrates the safety and efficacy of the addition of adefovir dipivoxil in patients with compensated or decompensated chronic HBV-related liver disease who develop resistanceto lamivudine.

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• Demonstrates that adefovir dipivoxil monotherapy may have the same efficacy with the combination of adefovir dipivoxil and lamivudine in the treatment of lamivudine-resistant patients with HBeAg-positive chronic hepatitis B.

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Affiliations• Stephanos J Hadziyannis

Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, 11526 Athens, GreeceTel.: +30 210 697 2937Fax: +30 210 697 2974hadziyannis@ath.forthnet.gr

• George V PapatheodoridisSecond Department of Internal Medicine, Medical School of Athens University, Hippokration General Hospital, 114 Vas. Sophias Avenue, 11527 Athens, GreeceTel.: +30 210 777 4742Fax: +30 210 770 6871gpapath@cc.uoa.gr