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original article

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 359;23 www.nejm.org december 4, 20082442

Tenofovir Disoproxil Fumarate versus

Adefovir Dipivoxil for Chronic Hepatitis BPatrick Marcellin, M.D., E. Jenny Heathcote, M.D., Maria Buti, M.D., Ed Gane, M.D.,Robert A. de Man, M.D., Zahary Krastev, M.D., George Germanidis, M.D.,

Sam S. Lee, M.D., Robert Flisiak, M.D., Kelly Kaita, M.D., Michael Manns, M.D.,Iskren Kotzev, M.D., Konstantin Tchernev, M.D., Peter Buggisch, M.D.,

Frank Weilert, M.D., Oya Ovung Kurdas, M.D., Mitchell L. Shiffman, M.D.,Huy Trinh, M.D., Mary Kay Washington, M.D., Jeff Sorbel, M.S., Jane Anderson, Ph.D.,

Andrea Snow-Lampart, B.S., Elsa Mondou, M.D., Joe Quinn, M.P.H.,and Franck Rousseau, M.D.

From Hpital Beaujon, Assistance Pub-lique Hpitaux de Paris, University of Paris7 and INSERM Unit 773, Centre de Re-cherches Claude Bernard sur les HepatitesVirales, Clichy, France (P.M.); Universityof Toronto, Toronto (E.J.H.), University ofCalgary, Calgary, AB (S.S.L.), and JohnBuhler Research Centre, University of Man-itoba, Winnipeg (K.K.) all in Canada;Hebron Hospital, Barcelona (M.B.); Mid-dlemore Hospital, Auckland (E.G.), andWaikato Hospital, Hamilton (F.W.) bothin New Zealand; Erasmus University Med-ical Center, Rotterdam, the Netherlands(R.A.D.); University Hospital Saint IvanRilsky, Sofia (Z.K.), University HospitalSveta Marina, Varna (I.K.), and MedicalUniversity, Sofia (K.T.) all in Bulgaria;Papageorgiou General Hospital of Thes-saloniki, Thessaloniki, Greece (G.G.); Med-ical University of Bialystok, Bialystok, Poland(R.F.); Medizinische Hochschule, Han-nover (M.M.), and Medizinische Univer-sittsklinik Eppendorf, Hamburg (P.B.) both in Germany; Haydarpasa NumuneHospital, Istanbul, Turkey (O.O.K.); Vir-ginia Commonwealth University MedicalCenter, Richmond (M.L.S.); San Jose Gas-troenterology, San Jose, CA (H.T.); Vander-bilt University Medical Center, Nashville(M.K.W.); and Gilead Sciences, Durham,NC (J.S., J.A., A.S.-L., E.M., J.Q., F.R.).Ad-dress reprint requests to Dr. Rousseau atGilead Sciences, 4611 University Dr., Dur-ham, NC, or at [email protected]. Marcellin and Heathcote contributedequally to this article.The investigators who enrolled participantsin this trial are listed in the Appendix.N Engl J Med 2008;359:2442-55.Copyright 2008 Massachusetts Medical Society.

A B S T R A C T

Background

Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitorof human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus(HBV) polymerase.Methods

In two double-blind, phase 3 studies, we randomly assigned patients with hepatitisB e antigen (HBeAg)negative or HBeAg-positive chronic HBV infection to receivetenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primaryefficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter(69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodellnecroinflammation score of 2 or more points without worsening fibrosis) at week 48.

Secondary end points included viral suppression (i.e., an HBV DNA level of

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Tenofovir DF vs. Adefovir Dipivoxil for Chronic Hepatitis B

n engl j med 359;23 www.nejm.org december 4, 2008 2443

Chronic hepatitis B virus (HBV) infec-tion is a major health problem. 1-3 Sincemost patients with chronic HBV infectionrequire long-term therapy, 4-6 there is a need fornew drugs with potent antiviral activity and estab-lished long-term safety, as well as a proven lowrate of HBV antiviral resistance, a high geneticbarrier (i.e., requiring more than one amino acidsubstitution to confer resistance to HBV treat-ment), or both.

The ultimate goal of treatment of chronicHBV infection is to prevent liver complications.This goal is seldom achieved through hepatitis Bsurface antigen (HBsAg) loss and seroconver-sion, which are associated with sustained im-munologic and virologic control of the virus. Inhepatitis B e antigen (HBeAg)positive chronicHBV infection, HBeAg loss and seroconversionare associated with a reduction in HBV DNAlevels but they are not curative, and the emer-gence of precore escape mutations may lead toactive HBeAg-negative, chronic hepatitis with at-tendant long-term complications. 7 Maintenanceof viral suppression with oral therapy is oftenthe best that can be achieved. Viral suppressionmaintained by treatment with lamivudine hasbeen shown to reduce the progression of the dis-ease to decompensation and the development ofhepatocellular carcinoma in patients with cir-rhosis. 8

Seven drugs are licensed for the treatment ofchronic HBV infection: lamivudine, 9 interferonalfa,10,11 adefovir dipivoxil, 12 peginterferon alfa-2a,13 entecavir, 14 telbivudine, 15 and tenofovir diso-proxil fumarate (DF). Interferons are not recom-mended for use in patients with decompensationor immunosuppression; they may have treatment-limiting side effects, and they require parenteraladministration. Oral nucleosides, although po-tent, have been limited by the development ofresistance mutations in the HBV polymerasereverse transcriptase. 16,17

Tenofovir DF, the oral prodrug of tenofovir, isa nucleotide analogue that inhibits viral poly-merases by direct binding, and after incorpora-tion into DNA, by termination of the DNA chaindue to the absence of a requisite 3 hydroxyl onthe tenofovir molecule. 18

Tenofovir DF is currently approved in theUnited States and more than 50 other countriesfor the treatment of human immunodeficiency

virus type 1 (HIV-1), and it was recently approved

for the treatment of chronic HBV infection in theUnited States, Canada, Europe, Australia, andTurkey.

Tenofovir is a potent and selective inhibitor ofHBV DNA polymerasereverse transcriptase in

vitro.19 It remains active against lamivudine-resis-tant HBV, 20-23 and it has known activity againstHBV both in patients with HBV monoinfection 24-26 and in patients with HIV-1 and HBV coinfection. 27-29 Two phase 3 studies were designed to comparethe safety and efficacy of tenofovir DF at a dose of300 mg with adefovir dipivoxil at a dose of 10 mg,administered once daily, in HBeAg-negative pa-tients (Study 102) or HBeAg-positive patients(Study 103).

Methods

Study Design

With the use of a central, interactive voice-responsesystem (ClinPhone), we randomly assigned pa-tients in a 2:1 ratio to receive tenofovir DF oradefovir dipivoxil. The treatment assignments

were stratified according to serum alanine amino-transferase level (

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were given the option to begin treatment withopen-label tenofovir DF for up to 7 more years.Blinding of the original treatment assignment

was maintained. Patients who discontinued dou-ble-blind treatment were followed after treatmentfor 24 weeks or until the initiation of an alterna-tive hepatitis B therapy.

Resistance surveillance included genotypicanalysis of the HBV polymerase in all patients atbaseline, in patients with viremia who had anHBV DNA level of 400 copies per mill iliter (69 IUper milliliter) or more at week 48 (or at the timethat treatment was discontinued, in the case ofpatients who did not complete 48 weeks of treat-ment), and in patients with virologic breakthrough(i.e., a confirmed HBV DNA level of 400 copiesper milliliter after a documented level of lessthan 400 copies per milliliter or a confirmed log 10 increase of 1.0 or more from the nadir level). Thepopulation-based dideoxy sequencing assay usedhas a viral-load requirement of 400 copies permilliliter or more. Resistance surveillance testing

was conducted by Gilead Sciences.During double-blind treatment, an external

independent data monitoring committee reviewedthe safety results five times. The study was con-ducted in accordance with international scientificand ethical standards, including but not limitedto the International Conference on Harmoniza-tion Guidelines for Good Clinical Practice andthe Declaration of Helsinki. The study was ap-proved by independent ethics committees or in-stitutional review boards at the study sites. Writteninformed consent was obtained from all patientsbefore any procedures were performed.

The studies were designed by Gilead Sciencesin collaboration with their scientific advisors, andthe primary end point was negotiated with theFood and Drug Administration. Clinical data werecollected and monitored by ICON Clinical Re-search (in North America, Western Europe, andthe Asia-Pacific region) and Quintiles (in Eastern

Europe). Data from case-report forms were en-tered into the database by ICON Clinical Research(Dublin), and the data were unblinded for sta-tistical analysis after the database was locked.Gilead Sciences performed all statistical analysesand wrote the manuscript in collaboration withthe lead academic authors. The academic authors

vouch for the veracity and completeness of thereported data and data analyses.

Study Population

The studies enrolled patients 18 to 69 years ofage who had HBeAg-negative or HBeAg-positivechronic hepatitis B with compensated liver dis-ease and pretreatment liver-biopsy specimens thatshowed a Knodell necroinflammatory score of3 or more (on a scale of 0 to 18, with higher scoresindicating more severe chronic hepatitis). All pa-tients had been HBsAg-positive for at least 6 monthsbefore screening. In Study 102, patients had ala-nine aminotransferase levels that were more than1 time and less than 10 times the upper limit ofthe normal range and HBV DNA levels that werehigher than 10 5 copies per milli liter. Patients ei-ther had received less than 12 weeks of treatment

with any nucleoside or nucleotide or had receivedlamivudine or emtricitabine for at least 12 weeks(the lamivudine-treatment subgroup). In Study103, patients had alanine aminotransferase levelsthat were more than 2 times and less than 10times the upper limit of the normal range andHBV DNA levels of more than 10 6 copies per milli-liter; these patients had received less than 12

weeks of treatment with any nucleoside or nucleo-tide. Key exclusion criteria were coinfection withHIV-1 or hepatitis C or D virus, evidence of hepa-tocellular carcinoma, a creatinine clearance ofless than 70 ml per minute, a hemoglobin levelof less than 8 g per deciliter, a neutrophil countof less than 1000 per cubic millimeter, and liverdecompensation or failure.

End Points

The primary efficacy end point at week 48 wasdefined as the combination of an HBV DNA levelof less than 400 copies per milliliter and histo-logic improvement (i.e., a reduction of 2 or morepoints in the Knodell necroinflammatory score

without an increase in f ibrosis). HBV DNA wasmeasured with the use of the Roche Cobas Taq-Man polymerase-chain-reaction assay, which hasa lower limit of quantitation of 169 copies per

milliliter (29 IU per milliliter). Since the viral-load requirement for the population-based dide-oxy sequencing assay used for resistance surveil-lance was 400 copies per milliliter, this was thethreshold level for the primary end point. Pairedliver-biopsy slides (i.e., a specimen from the firstbiopsy, performed before treatment, and a speci-men from the second biopsy, performed duringtreatment) were evaluated by one independent

The New England Journal of MedicineDownloaded from nejm.org on July 29, 2012. For personal use only. No other uses without permission.

Copyright 2008 Massachusetts Medical Society. All rights reserved.

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central pathologist, who remained unaware ofboth the assigned treatment and the biopsy se-quence; biopsy slides were scored according tothe Knodell schema. 30

Secondary end points included HBV DNA andalanine aminotransferase levels over time and theproportion of patients with HBV DNA levels ofless than 400 copies per milliliter, normalized ala-nine aminotransferase levels, histologic improve-ment, HBeAg and HBsAg loss and seroconversion,and resistance mutations in HBV polymerase.

Safety Analysis

The safety analyses included all patients who re-ceived at least one dose of a study drug and allevents that occurred during double-blind treat-ment. Adverse events, serious adverse events, labo-ratory abnormalities, discontinuation of the studydrug due to adverse events, and deaths were eval-uated. In this protocol, alanine aminotransferaseflares, were considered to be serious adverseevents. Flares were defined as an alanine amino-transferase level that was more than twice thebaseline level and more than 10 times the upperlimit of the normal range, with or without asso-ciated symptoms, or a confirmed elevation in thealanine aminotransferase level with confirmedchanges outside the normal range in other labo-ratory values that were suggestive of worseninghepatic function (i.e., a total bilirubin level 2 mgper deciliter [34 mol per liter] above the baseline

value, a prothrombin time 2 seconds higher thanthe baseline value or an international normalizedratio 0.5 over baseline, or a serum albumin level1 g per deciliter below the baseline value).

Resistance Surveillance and Baseline

Genotyping

Phylogenetic mapping of individual HBsAg nucleo-tide sequences was used to determine the viralgenotype (A through H) at baseline. At week 48,changes in the HBV polymerasereverse-tran-

scriptase region from baseline were identif ied inpatients with either persistent viremia or viro-logic breakthrough. Changes in the amino acidsequence of the HBV polymerasereverse-tran-scriptase domain were further evaluated to deter-mine whether these substitutions occurred at poly-morphic or conserved sites. All conserved sitesubstitutions were phenotypically assessed within vitro cell-culture assays to measure susceptibil-

ity to tenofovir. Polymorphic changes were alsophenotyped if they occurred in more than onepatient.

Statistical Analysis

The primary end point was a composite of HBVDNA suppression and histologic improvement.The population for analysis included all patients

who were randomly assigned to treatment and who received at least one dose of study medica-tion; no patient was excluded from the analysisbecause of a protocol deviation. In Study 102, wecalculated that the planned sample size of 300patients (200 in the tenofovir DF group and 100 inthe adefovir dipivoxil group) would provide atleast 85% power to detect an absolute dif ferenceof 19% in the proportion of patients with a com-plete response at week 48, on the basis of a two-sided significance level of 0.05 and assuming acomplete response rate of 28% in the adefovirdipivoxil group. In Study 103, we calculated thatthe planned sample size of 240 patients (160 in thetenofovir DF group and 80 in the adefovir dipivoxilgroup) would provide at least 85% power to detectan absolute difference of 13% in the proportion ofpatients with a complete response at week 48, onthe basis of a two-sided significance level of 0.05and assuming an 18% response rate in the adefo-

vir dipivoxil group.The difference between treatment groups was

evaluated with the use of a two-sided 95% confi-dence interval stratified according to the baselinelevel of alanine aminotransferase (in Study 102,a value that was less than or equal to twice theupper limit of the normal range vs. a value that

was more than twice the upper l imit; in Study103, a value that was less than or equal to fourtimes the upper limit of the normal range vs. a

value that was more than four times the upperlimit). For the intention-to-treat analysis, patients

who did not have paired liver-biopsy specimensthat could be evaluated or who did not undergo

HBV DNA assessment were considered not tohave had treatment responses.Finally, observed data (on-treatment analysis)

for the HBV DNA and alanine aminotransferaselevels over time as well as the proportion of pa-tients with an HBV DNA level of less than 400copies per milliliter were analyzed.

To assess whether the treatment effect wasconsistent among the different patient subpopu-



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Table 1. Demographic and Baseline Characteristics of the Study Patients.*

Characteristic HBeAg-Positive Patients HBeAg-Negative Patients

Tenofovir DF(N = 176)

Adefovir Dipivoxil(N = 90)

Tenofovir DF(N = 250)

Adefovir Dipivoxil(N = 125)

Mean age yr 3411 3412 4410.6 4310.0Race no. (%)

White 92 (52) 46 (51) 161 (64) 81 (65)Asian 64 (36) 32 (36) 63 (25) 30 (24)Black 13 (7) 5 (6) 8 (3) 4 (3)Other 7 (4) 7 (8) 18 (7) 10 (8)

Male sex no. (%) 119 (68) 64 (71) 193 (77) 97 (78)Geographic region no. (%)

Europe 97 (55) 49 (54) 158 (63) 76 (61)North America 47 (27) 24 (27) 53 (21) 29 (23)Australia or New Zealand 32 (18) 17 (19) 39 (16) 20 (16)

Mean Knodell necroinflammatory score 8.32.14 8.32.27 7.82.44 7.92.18Knodell fibrosis score no./total no. (%)

0 0/172 (0) 0/87 (0) 0/250 (0) 1/125 (1)1 77/172 (45) 33/87 (38) 107/250 (43) 51/125 (41)3 61/172 (35) 37/87 (43) 96/250 (38) 48/125 (38)4 34/172 (20) 17/87 (20) 47/250 (19) 25/125 (20)Missing data 4/176 (2) 3/90 (3) 0/250 (0) 0/125 (0)

Mean Knodell fibrosis score 2.31.23 2.41.19 2.31.21 2.41.23Mean HBV DNA log10 copies/ml 8.641.076 8.880.930 6.861.31 6.981.27Alanine aminotransferase

Mean IU/ml 142102.81 155121.49 127.5101.21 163.6146.02

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positive patients ( Table 2 ). Histologic improve-ment was similar between treatment groups; mostpatients had reduced necroinflammation, and fewpatients had worsening fibrosis.

Among the HBeAg-negative patients, 93% ofall the patients who received tenofovir DF had aplasma HBV DNA level of less than 400 copiesper milliliter by week 48 (intention-to-treat analy-sis), and 97% of whose who were receiving teno-fovir DF at week 48 had an HBV DNA level of lessthan 400 copies per milliliter (observed data)(Table 2 ). At week 24, a total of 85% of the pa-tients who received tenofovir DF had HBV DNAsuppression below this level (Fig. 1A). The changein the level of HBV DNA was characterized by aprecipitous decrease by week 4. At week 12, themean HBV DNA level was 3 log 10 copies per milli-liter as compared with a baseline HBV DNA levelof approximately 7 log 10 copies per milliliter(Fig. 2A). Patients with lower baseline HBV DNAlevels had undetectable levels of HBV DNA soonerthan did patients with higher baseline levels(Fig. 3A and 3B).

Among HBeAg-positive patients, 76% of pa-tients who received tenofovir DF had an HBVDNA level of less than 400 copies per milliliterat week 48, and 49% of patients who receivedtenofovir DF had an HBV DNA level of less than400 copies per milliliter at week 24. With the useof observed data, 83% of the patients receivingtenofovir DF treatment at week 48 had an HBVDNA level of less than 400 copies per milliliter(Fig. 1B and Table 2 ). HBV DNA suppression wascharacterized by a rapid 4.5-log reduction in theHBV DNA level by week 12, with complete viralsuppression in increasing numbers of patientsover time (Fig. 2B).

An evaluation of the treatment response insubgroups defined by baseline characteristicsshowed no significant interactions at the 0.01alpha level. Among patients treated with tenofo-

vir DF, 90% of patients who had received lami-

vudine versus 88% of those who had not receivedlamivudine had HBV DNA suppression to lessthan 400 copies per milliliter (see the forest plotsin the Supplementary Appendix).

Biochemical and Serologic Response

At baseline, 94% of patients in Study 102 and97% of patients in Study 103 had elevated alanineaminotransferase levels (>34 IU per milliliter in

women and >43 IU per milliliter in men). In Study

102 (HBeAg-negative patients), similar propor-tions of patients in the two treatment groups hadnormalized alanine aminotransferase levels at

week 48, whereas in Study 103 (HBeAg-positivepatients), a significantly greater proportion of pa-tients in the tenofovir DF group had normalizedalanine aminotransferase levels (68% vs. 54%,P = 0.03). Overall, at week 48, patients who receivedtenofovir DF had a mean alanine aminotransferaselevel of approximately 35 IU per milliliter ( Table 2 ).In Study 103, similar proportions of patients inthe tenofovir DF group and the adefovir dipivoxilgroup had HBeAg seroconversion (21% and 18%,respectively, P = 0.36), and significantly more pa-tients in the tenofovir DF group had HBsAg loss(3% vs. 0%, P = 0.02) ( Table 2 ). Two patients withHBsAg loss also had seroconversion to antibod-ies against hepatitis B surface antigen (anti-HBsantibodies). All five patients who lost HBsAg were

white (three men and two women), and theyranged in age from 24 to 44 years; two patients

were infected with HBV genotype A, and threepatients infected with HBV genotype D. Four ofthe f ive patients had bridging fibrosis or cirrhosisat study entry. None of the patients who wereHBeAg-seronegative at baseline (i.e., all the pa-tients in Study 102) had HBsAg loss or serocon-

version.

Resistance Surveillance

No genotypic substitutions in polymerasereversetranscriptase associated with decreased sensitiv-ity to tenofovir were detected among patients whoreceived tenofovir DF and were evaluated at week48 in either Study 102 or 103. Among the 426 pa-tients receiving tenofovir DF, 39 patients (8 pa-tients in Study 102 and 31 patients in Study 103)had viremia (an HBV DNA level 400 copies permilliliter); 10 had virologic breakthrough and 29did not. Fifteen patients had polymorphic sitechanges, 2 had conserved site changes, 11 had nochange, and 10 could not be genotyped. One ad-

ditional patient, who discontinued treatment early,had virus with polymorphic site changes. The twoconserved site changes occurred without viro-logic breakthrough; phenotypic evaluation showedeither full susceptibility to tenofovir DF or a non-

viable, nonreplicative virus in cell culture. Of the10 patients with virologic breakthrough, 7 had nochanges, and 3 had polymorphic changes but notthe same changes. Successful phenotyping in 6 ofthese 10 patients showed full phenotypic suscep-



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tibility to tenofovir in vitro. Phenotypic analysisfor the remaining four patients could not to beperformed because of a low viral load that didnot allow for amplification and cloning of thefull-length HBV genome. A documented historyof nonadherence to treatment, serum tenofovirDF levels below the level of quantitation (10 ng permilliliter), or both findings that suggested

nonadherence may have contributed to viro-logic breakthrough in at least two thirds of thesepatients.

Among the 215 patients who were randomlyassigned to receive adefovir dipivoxil, the rtN236Tmutation developed in 1 patient, and the rtA181Tmutation developed in 3 patients. Clonal analy-sis of the patients baseline HBV revealed thepresence of quasi-species with the rtA181T muta-tion (0.2 to 11.3%) and the rtM204I mutation (1.2to 16.1%), indicating previous exposure to lami-

vudine or infection with a lamivudine-resistant virus. These results are consistent with previousstudies that showed a higher rate of adefovir-dipivoxil resistance in patients with lamivudine-resistant virus. 31,32

Safety

The safety profi les observed in both studies wereconsistent with the known safety profiles fortenofovir DF in patients with HIV infection andfor the safety profiles for adefovir dipivoxil inpatients with HBV infection. 33,34 Nausea was theonly adverse event that consistently occurred morefrequently in the group of patients who receivedtenofovir DF than in the group of patients whoreceived adefovir dipivoxil. Among the cases ofnausea that were considered to be related to teno-fovir DF, nausea was mild except for one case ofgrade 2 (moderate) nausea ( Table 3 ).

In both studies, similar proportions of pa-tients in the two treatment groups had a seriousadverse event, and few events were considered tobe related to the study drug ( Table 3 ). Overall, theonly serious clinical adverse event reported inmore than one patient was hepatocellular carci-noma (in three patients in Study 102), which isa known complication of chronic HBV infection.No deaths were reported during either study. Thefollowing five adverse events led to discontinua-tion of tenofovir DF in Study 102 and occurredin one patient each: anorexia, bladder neoplasm,

fatigue, cervical carcinoma, and feeling hot. Nopatient in Study 103 discontinued tenofovir DFbecause of an adverse event.

The frequency of alanine aminotransferaseflares during treatment was similar in the twogroups ( Table 3 ). Nearly all alanine aminotrans-ferase flares occurred within the first 8 weeksafter the start of treatment with tenofovir DF,

were limited to increases in aminotransferaselevels that were greater than 10 times the upper

100

H B V D N A S u p p r e s s

i o n (

% o

f p a t

i e n

t s )

80

90

70

60

40

30

10

50

20

00 4 128 16 20 24 28 4844403632

Tenofovir DF (N=250)

Adefovir dipivoxil (N=125)

Weeks in Study

B HBeAg-Positive Patients (Study 103)

A HBeAg-Negative Patients (Study 102)

P

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limit of the normal range and twice the baselinelevel, with continued and profound decreasesin the HBV DNA level, and resolved within 4 to8 weeks without interruption or discontinuationof treatment. Grade 4 alanine aminotransferaseflares were associated with HBeAg loss or sero-conversion in 63% of patients, one of whomeventually had seroconversion to anti-HBs anti-bodies.

There was no evidence of compromised renalfunction or renal tubular dysfunction in any pa-tient who received tenofovir DF ( Table 3 ). Noneof the patients who received tenofovir DF had aconfirmed increase from baseline in the serumcreatinine level of 0.5 mg per deciliter (44.2 molper liter) or more or a confirmed calculatedcreatinine clearance of less than 50 millilitersper minute (Table 3). In Study 103, there was aconfirmed increase in the serum creatinine levelof 0.5 mg per deciliter above baseline in onepatient who received adefovir dipivoxil.

Discussion

In patients with compensated chronic HBV infec-tion, tenofovir DF was superior to adefovir dipiv-oxil with respect to the primary end point ofantiviral efficacy. Viral suppression occurred inapproximately 80% of HBeAg-positive patients and95% of HBeAg-negative patients who receivedtenofovir DF, and almost three fourths of the pa-tients had histologic improvement. In both stud-ies, histologic improvement was similar in the twotreatment groups at 48 weeks. Multiple reportshave shown that maintenance of viral suppressionis a key determinant of therapeutic outcomes forpatients with chronic HBV infection 8,35-37 ; thesereports include a review of 26 prospective clinicaltrials showing that a sustained HBV DNA response

was correlated with serologic, histologic, or bio-chemical responses. 38

HBsAg loss or seroconversion heralds durable

immune control of the virus. In the phase 3 studyinvolving HBeAg-positive patients, the proportionof patients with loss of HBsAg during the 48-

week treatment period was significantly higherin the tenofovir DF group than in the adefovirdipivoxil group. In the absence of HBsAg loss,long-term treatment with oral therapies is oftenrequired to maintain viral suppression. Conse-quently, well-tolerated, potent therapies that offera strong genetic barrier against the development

of resistance are desirable, since antiviral resis-tance and poor adherence are key risk factors fortreatment failure and subsequent reversal of clini-cal improvement. 39-43 The high proportion of pa-tients who received tenofovir DF and had viralsuppression portends a potential long-term ad-

vantage in preventing the emergence of resistanceand attendant loss of response. No genotypic

M e a n H

B V D N A

( l o g 1 0 c

o p

i e s / m

l )

1

2

3

4

5

6

7

8

0 4 128 16 20 24 28 4844403632

Tenofovir DF

Adefovir dipivoxil

Tenofovir DF

Adefovir dipivoxil

Weeks in Study


A HBeAg-Negative Patients (Study 102)

P

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1

C h a n g e i n

H B V D N A

( l o g 1 0 c o

p i e s / m

l )10

23

56

8

4

7

92 43 6 75 8 9 10 11

Baseline HBV DNA (log10 copies/ml) Baseline HBV DNA (log 10 copies/ml)


A HBeAg-Negative Patients (Study 102)Baseline

Limit of the assay

1

10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 4

1

C h a n g e i n

H B V D N A

( l o g 1 0 c

o p

i e s / m

l )10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 8 1

10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 12

1

C h a n g e

i n H B V D N A

( l o g 1 0

c o p

i e s / m

l )10

23

56

8

4

7

92 43 6 75 8 9 10 11

Baseline HBV DNA (log10 copies/ml) Baseline HBV DNA (log 10 copies/ml)

Baseline

Limit of the assay

1

10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 4

1

C h a n g e

i n H B V D N A

( l o g 1 0

c o p

i e s / m

l )10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 8 1

10

23

56

8

4

7

92 43 6 75 8 9 10 11

Week 12

l



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substitutions in polymerasereverse transcriptaseassociated with either decreased sensitivity totenofovir or known resistance to other anti-HBVtherapies were detected in either the HBeAg-negative patients or the HBeAg-positive patientsafter 48 weeks of treatment, but resistance pat-terns with long-term treatment are not known.In an effort to define the resistance profile fortenofovir DF, resistance surveillance will con-tinue for at least 7 more years.

Figure 3 (facing page). Reduction in HBV DNA fromBaseline through Week 12 in Patients Receiving Teno-fovir DF.The plots show the kinetics of HBV DNA viral suppres-sion in HBeAg-negative patients (Study 102) (Panel A)and HBeAg-positive patients (Study 103) (Panel B) re-ceiving tenofovir DF. Each dot represents an individual

patient. The diagonal line represents the lower limit ofquantification of the Roche Cobas TaqMan assay (169copies per milliliter [29 IU per milliliter]).

Table 3. Clinical Adverse Events and Laboratory Abnormalities.

VariableTenofovir DF

(N = 426)Adefovir Dipivoxil

(N = 215)

no. (%)

Adverse events*

Any adverse event 317 (74) 158 (73)

Headache 55 (13) 30 (14)

Nasopharyngitis 42 (10) 24 (11)

Nausea 40 (9) 6 (3)

Fatigue 36 (8) 16 (7)

Upper abdominal pain 30 (7) 11 (5)

Back pain 30 (7) 10 (5)

Diarrhea 28 (7) 11 (5)

Dizziness 24 (6) 7 (3)

Procedural pain 16 (4) 12 (6)

Pharyngolaryngeal pain 15 (4) 11 (5)

Upper respiratory tract infection 13 (3) 11 (5)

Grade 24 adverse events 128 (30) 68 (32)

Serious adverse events 27 (6) 14 (7)

Serious adverse events considered to be related to study drug 7 (2) 5 (2)

ALT flare 6 (1) 4 (2)

Thrombocytopenia 1 (10 ULN) and 2 baseline value 11 (3) 4 (2)

Confirmed serum creatinine increase of 0.5 mg/dl above baseline value 0 1 (

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No safety signals were observed for tenofovirDF in patients with chronic HBV infection. Al-though renal events have been observed with theuse of tenofovir DF in patients with HIV infection,predominantly in patients with preexisting renaldisease, no renal toxic effects were observed dur-ing 48 weeks of treatment with tenofovir DF inpatients with chronic HBV infection who had pre-served renal function at baseline. In these studiesof tenofovir DF for chronic HBV infection, there

were insufficient data to characterize exacerbationafter treatment. However, there is a known riskafter discontinuation of any oral anti-HBV treat-ment, and monitoring of liver-function tests forseveral months is required. Alanine amino trans-ferase flares during treatment with tenofovir DF

were infrequent, transient, and associated withcontinuous and profound decreases in the HBVDNA level. Seroconversion to anti-HBe antibodiesin a majority of these patients suggested enhancedimmunologic activity against HBV that coincided

with a treatment-induced reduction in the viralload. Treatment with nucleoside analogues alsocan result in lactic acidosis and hepatomegaly withsteatosis, but no patients in these studies had theseadverse events.

In these 48-week phase 3 studies, tenofovir DF was shown to be a potent therapy for the treatmentof HBeAg-negative and HBeAg-positive chronicHBV infection. Tenofovir DF was just as effective insuppressing HBV DNA levels in patients who hadnot received treatment as in patients who had pre-

viously received lamivudine. In light of its favorablelong-term safety record in patients with HIV-1 in-fection, tenofovir DF should be considered for thetreatment of chronic HBV infection.

Supported by Gilead Sciences.Dr. Marcellin reports receiving grant support and lecture and

consulting fees from HoffmannLa Roche, Schering-Plough,Gilead Sciences, Bristol-Myers Squibb, and Idenix-Novartis andgrant support and consulting fees from Vertex, Human GenomeSciences, Cytheris, InterMune, Wyeth, Pharmasset , and Tibotec;Dr. Heathcote, receiving consulting fees and grant support fromOrtho Biotech, Indenix Pharmaceuticals, Human Genome Sci-ences, Gilead Sciences, GlaxoSmithKline, Debio, Schering-

Plough, Vertex, and HoffmannLa Roche; Dr. Buti, receivinglecture and consulting fees from Gilead Sciences and Novartisand lecture fees from Bristol-Myers Squibb; Dr. Gane, receivingconsulting fees from GlaxoSmithKline and consulting and lec-ture fees from Novartis; Dr. de Man, receiving consulting andlecture fees and grant support from Gilead Sciences, consultingfees and grant support from Bristol-Myers Squibb, consultingfees from Novartis, and lecture fees from UCB; Dr. Lee, receiv-ing consulting and lecture fees and grant support from GileadSciences, Bristol-Myers Squibb, and HoffmannLa Roche, con-sulting fees from Novartis, and grant support from the Canadi-an Institutes of Health Research and the Canadian Liver Foun-dation; Dr. Flisiak, receiving consulting and lecture fees fromBristol-Myers Squibb, consulting fees from Human Genome Sci-ences, and lecture fees from HoffmannLa Roche and Schering-Plough; Dr. Kaita, receiving consulting and lecture fees fromGilead Sciences and Novartis and lecture fees from Schering-Plough; Dr. Manns, receiving consulting and lecture fees fromGilead Sciences, Novartis, Bristol-Myers Squibb, and HoffmannLa Roche and lecture fees from GlaxoSmithKline; Dr. Buggisch,receiving lecture fees from Bristol-Myers Squibb, Novartis, andGilead Sciences; Dr. Weilert, receiving consulting fees fromBristol-Myers Squibb; Dr. Shiffman, receiving consulting andlecture fees and grant support from Gilead Sciences, lecture feesand grant support from Bristol-Myers Squibb, and grant supportfrom HoffmannLa Roche; Dr. Trinh, receiving consulting andlecture fees, grant support, and nonprofit support from Bristol-Myers Squibb and Gilead Sciences, holding equity ownership orstock in Gilead Sciences, and receiving grant support fromHoffmannLa Roche and nonprofit support from Novartis; Dr.Washington, receiving consulting fees from Gilead Sciences;

and Mr. Sorbel, Mr. Quinn, Ms. Snow-Lampart, and Drs. Ander-son, Mondou, and Rousseau, being employees of and holdingequity in Gilead Sciences. No other potential conflict of interestrelevant to this article was reported.

Presented in part at the 58th annual meet ing of the Ameri-can Association for the Study of Liver Diseases, Boston, No-

vember 2, 2007.

Appendix

In addition to the authors, the following investigators participated in the two studies: Australia W. Cheng, D. Crawford, P. Desmond, J. George, P. Gow, I. Kronborg, M. Ngu, S. Roberts, J. Sasadeusz, W. Sievert, S. Strasser; Bulgaria R. Balabanska; Canada F.Anderson, R. Myers, M. Sherman; Czech Republic P. Husa, J. Sperl, P. Urbanek, M. Volfova; France K. Barange, Y. Benhamou, J.Bronowicki, C. Hezode, F. Habersetzer, P. Mathurin, C. Trepo, J. Zarski; Germany T. Berg, W. Boecher, P. Gerken, T. Heintges, H.Hinrichsen, D. Huppe, S. Kaiser, S. Mauss, B. Moller, G. Teuber, R. Zachoval, S. Zeuzem; Greece G. Dalekos, S. Hadziyannis, G.Kitis; Italy P. Andreone, M. Rizzetto; New Zealand C. Moyes, N. Stace; Poland M. Beniowski, A. Gladysz, W. Halota, A. Hor-ban, W. Kryczka, T. Mach; Spain J. Calleja, T. Casanovas, J. Enriquez, M. Prieto; Turkey U. Akarka, S. Gurel, S. Ozenirler, H.Senturk, N. Tozun; United Kingdom G. Dusheiko, D. Mutimer, R. Williams; United States N. Afdahl, M. Bennett, N. Bzowej, S.Chan, A. DiBisceglie, P. Gaglio, N. Gitlin, S. Gordon, K. Hu, I. Jacobson, L. Jeffers, A. Lok, P. Martin, T. Min, T. Nguyen, P. Pockros,N. Ravendhran, R. Rubin, V. Rustgi, M. Tong, H. Tsai, C. Wang, Z. Younossi.

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