A Phase 4, Randomized, Open-label, Active-Controlled, Superiority Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Combination with Peginterferon α-2a (Pegasys®) versus Standard of Care Tenofovir Disoproxil Fumarate Monotherapy or Peginterferon α-2a Monotherapy for 48 Weeks in Non-Cirrhotic Subjects with HBeAg-Positive or HBeAg-Negative Chronic Hepatitis B (CHB)

See 1.1 Background of the protocol on page 18

The primary objective of this study is to evaluate the efficacy of TDF plus
Peginterferon *-2a (PEG) combination therapy for 48 weeks versus standard of
care TDF monotherapy or PEG monotherapy for 48 weeks in non-cirrhotic CHB
subjects as determined by loss of HBsAg.

The secondary objectives of this study are to evaluate:
• efficacy of TDF (48 weeks) plus PEG (16 weeks) combination therapy versus
standard of care TDF monotherapy or PEG monotherapy for 48 weeks in
non-cirrhotic CHB subjects as determined by loss of HBsAg
• virological response (HBV DNA < 117 IU/mL)
• serological responses (HBeAg loss and seroconversion, and HBsAg
seroconversion)
• Biochemical response (ALT < 30 for males and <19 for females (based on AASLD
2008 guidelines); ALT <42 for males and <32 for females (based on central lab
ULN for ALT)

Additional objectives of this study are:
• to quantify HBsAg decline
• to evaluate the proportion of subjects requiring re-treatment post cessation
of therapy according to protocol-specified algorithm
• to evaluate the proportion of subjects who discontinue treatment
• to evaluate difference in incidence rate of select adverse events
• to evaluate data on biomarkers to explore associations with treatment
responses (including adverse events)

This is a randomized, open-label, active-controlled, superiority study to
evaluate safety and the proportion of subjects with HBsAg loss in subjects who
were treated with combination of TDF plus PEG versus standard of care TDF or
PEG for 48 weeks.
Seven hundred and twenty non-cirrhotic adult subjects with chronic hepatitis B
(CHB), either HBeAg+ or HBeAg-, will be randomized in a 1:1:1:1 ratio to one of
the 4 treatment arms A, B, C and D. Arms A and B are test arms. Arms C and D
are control arms.
Arm A: Subjects (n=180) will be treated with TDF and PEG concomitantly for 48
weeks.
Arm B: Subjects (n=180) will be treated with TDF and PEG concomitantly for 16
weeks followed by TDF alone for another 32 weeks (total 48 weeks).
Arm C: Subjects (n=180) will be treated with TDF continuously through 120 weeks.
Arm D: Subjects (n=180) will be treated with PEG for 48 weeks.

After completing 48 weeks study treatment, subjects in Arms A, B and D will be
followed for 24 weeks (between Week 48 and 72) for off-treatment follow-up.
Subsequently, there will be an extended follow-up period for 48 weeks (between
Week 72 and 120). Subjects in Arm C will receive continuous TDF treatment and
will be followed throughout the 120 weeks

Randomization across treatment arms will be stratified by HBeAg status and
viral genotype at screening resulting in ten strata, HBeAg + with genotypes A,
B, C, D, E-H and HBeAg- with genotypes A, B, C, D, E-H. Enrollment will be
monitored to ensure adequate representation of either HBeAg status and across
the common genotypes A, B, C, and D.

Subjects who experience loss of HBsAg during the first 48 weeks will continue
treatment until Week 48.
Subjects in Arm C who lose HBsAg after 48 weeks will continue on study
treatment based on the following criteria:
•If loss of HBsAg occurs during Week 48-72, subject will continue until Week 72.
•If loss of HBsAg occurs after Week 72, subjects will continue treatment until
two consecutive visits confirming negative results.
Subjects who do not lose HBsAg will continue on study treatment until Week 120.

For subjects in Arms A, B, and D who lose HBsAg after starting retreatment with
TDF during the post-week 48 period, these subjects will continue TDF for an
additional 24 weeks while participating in the trial.

During the immediate 24-week off-treatment follow-up period, subjects in Arms
A, B and D will be monitored every 2 weeks for the first 12 weeks (between Week
48 and Week 60) and every 4 weeks for the second 12 weeks (between Week 60 and
72). Subjects meeting one or more of the criteria mentioned in the protocol, at
any time while off-treatment during the study duration of 120 weeks, will be
recalled for prompt evaluation for flare management and re-treatment with TDF.

Subjects requiring re-treatment with TDF will be expected to continue on TDF
until the end of the study (Week 120). Upon completion of 120 weeks of study
treatment, subjects may continue on TDF therapy (not provided by the study) or
initiate other OAV therapy per local standard of care at the investigator*s
discretion.

The proportion of subjects receiving re-treatment according to the protocol
defined criteria above and the proportion of subjects who discontinue treatment
will be observed among the different treatment arms.

Analyses are planned at the conclusion of the study for the purpose of
establishing association between markers of disease activities and treatment
response. For subjects who provide a separate consent, a blood samples will be
collected for pharmacogenomic analysis in all countries except Indiafor the
exploration of genetic markers that may be predictive of virologic response and
the tolerability of HBV therapies.

At sites participating in the liver biopsy substudy, subjects who consent to
participate in the liver biopsy substudy will undergo a first liver biopsy
prior to their first dose and a second liver biopsy at Week 96(±2 weeks).. In
consented subjects who require a new biopsy to enter the main study, the
screening biopsy may be used both to qualify the subject for the study and for
the substudy. Alternatively, qualified subjects may have a biopsy taken
between Screening and Baseline Visits as long as the procedure is performed
after proper consent for the substudy has been obtained. Liver biopsies will be
evaluated for clinical/histological, and, if appropriate and possible, for
molecular correlates of treatment outcome. Declining consent for participation
in the biopsy substudy will not disqualify the subject from participating in
the main part of the study.

Tenofovir disoproxil fumarate (TDF) 300 mg PO once daily in combination with
Peginterferon α-2a (PEG), 180 µg subcutaneous injection once weekly

Peginterferon α-2a (PEG), 180 *g, will be administered weekly by subcutaneous
injection for the specified period of time (see Study Design, Arms A and B).
Pegasys® prefilled syringes (Roche Pharmaceuticals) will be supplied by Gilead
Sciences.

An overview of the risks are described in the informed consent form: "Appendix
3: Side effects and risks"