Dose-finding Study of GSK2248761 in Antiretroviral Therapy-experienced Subjects With NNRTI-resistant HIV Infection

Study SGN113399 is a Phase 2b randomized, partially-blinded, multicenter, parallel-group,
dose-ranging study to be conducted in HIV-1 infected ART-experienced adults with documented
NNRTI resistance.

A minimum of 150 subjects will be randomized 1:1:1 to one of two GSK2248761 doses or a
control regimen containing ETV (50 subjects per group); all subjects will also receive
darunavir/ritonavir and raltegravir. The trial will be partially blinded, i.e. subjects
receiving GSK2248761 and the investigators will be blinded to the dose they receive. Subjects
will not be blinded to whether they receive GSK2248761 or ETV.

Randomization will be stratified by:

- HIV-1 VL at screening, <50,000 copies/mL or >/50,000 copies/mL, and

- Darunavir susceptibility (screening phenotype fold change <7 or >/7 to 20)

Background ART will be administered open-label.

The primary endpoint analysis will take place after all subjects have completed Week 16. An
optimal dose of GSK2248761 will be determined by the Week 16 analysis; this dose selection
will be confirmed using an analysis from all subjects following completion of Week 24. If
there is a clear efficacy, safety or tolerability advantage driving dose selection for
GSK2248761, then all subjects receiving the non-selected dose of GSK2248761 will be switched
to the selected dose following dose confirmation, after all subjects have completed Week 24.
If no differentiation of dose can be made based on objective measures of efficacy, safety or
tolerability, then both doses will be continued through Week 48.

After Week 48, all subjects will be expected to obtain local access to all commercially
available ART.

No regimen switches of either background ART (DRV/r and RAL) or test agent or control
(GSK2248761 and ETV) are allowed during the 48 week period of the study.

Study Endpoints/Assessments Subjects will have assessments performed which will include
baseline demographics, disease characteristics, pharmacogenetics (PGx) and safety (laboratory
and clinical evaluations). On study safety, efficacy, virologic, immunologic, and PK
evaluations will also be conducted.

The primary endpoint will be the proportion of subjects with HIV-1 RNA <50copies/mL at Week
16. Dose selection will be based primarily on antiviral activity and tolerability in
conjunction with immunologic, safety, virologic resistance and PK measures. Data from the
Week 24 analysis will be used to confirm dose selection.

ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of
updating systems to reflect the change in sponsorship

Inclusion Criteria:

- HIV-1 infected adults greater than or equal to 18 years of age. Females are eligible
to enter and participate in the study if she is (1) non-childbearing potential, (2)
child bearing potential with negative pregnancy test at screening and Day 1 and agrees
to use protocol-specified methods of birth control while on study.

- HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to
400copies/mL

- Previously received or current treatment with antiretroviral therapy (HAART) for HIV-1
infection (patient may be off ART at time of screening)

- HIV-1 harboring NNRTI resistance by screening genotype (defined as the presence of at
least 1 NNRTI resistance-associated mutations)

Exclusion Criteria:

- Any pre-existing physical or mental condition (including substance abuse disorder)
which, in the opinion of the Investigator, may interfere with the subject's ability to
comply with the dosing schedule and/or protocol evaluations or which may compromise
the safety of the subject

- Any condition which, in the opinion of the Investigator, may interfere with the
absorption, distribution, metabolism or excretion of the drug or render the subject
unable to take oral medication

- Women who are currently breastfeeding

- Any evidence of an active Centers for Disease and Prevention Control (CDC) Category C
disease [CDC, 1993], except cutaneous Kaposi's sarcoma not requiring systemic therapy

- History of ongoing or clinically relevant hepatitis within the previous 6 months,
including chronic hepatitis B virus (HBV) infection (HBsAg positive). Asymptomatic
individuals with chronic hepatitis C virus (HCV) infection will not be excluded,
however Investigators must carefully assess if therapy specific for HCV infection is
required; subjects who are anticipated to require such therapy during the randomized
portion of the study must be excluded

- History of liver cirrhosis with or without hepatitis viral co-infection

- Ongoing or clinically relevant pancreatitis

- History of the following cardiac diseases: myocardial infarction, congestive heart
failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia

- Personal or known family history of prolonged QT syndrome

- History or presence of allergy or intolerance to the study drugs or their components,
or a history of drug or other allergy that, in the opinion of the Principal
Investigator, contraindicates their participation. In addition, if heparin is used
during PK sampling, subjects with a history of sensitivity to heparin or
heparin-induced thrombocytopenia should not be enrolled

- HIV-1 genotype results with any of the following will be excluded: (1)Any screening
genotype with virus showing a Y181 mutation in combination with any other NNRTI
resistance-associated mutations, (2) Any screening genotype with virus showing a Y181I
or Y188L alone or in combination with any other NNRTI resistance-associated mutations

- HIV-1 phenotype results with any of the following will be excluded: (1) Any screening
phenotype with virus showing etravirine fold change >10, (2) Any screening phenotype
with virus showing darunavir fold change > 20, (3) Any screening phenotype with virus
showing raltegravir fold change >1.5

- Any acute laboratory abnormality at screening, which, in the opinion of the
Investigator, would preclude the subject's participation in the study of an
investigational compound. Any verified Grade 4 laboratory abnormality at screening
would exclude a subject from study participation unless the Investigator can provide a
compelling explanation for the laboratory result(s) and has the assent of the medical
monitor

- Any of the following laboratory values at screening: (1) Creatinine clearance <50
mL/min via Cockroft-Gault method, (2) Alanine aminotransferase (ALT) greater than or
equal to 5 times ULN. Subjects with ALT >2xULN but <5xULN may participate in the
study, if in the opinion of the Investigator and GSK medical monitor the lab
abnormality will not interfere with the study procedures or compromise subject safety,
(3) Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin
greater than or equal to 1.5xULN (with >35% direct bilirubin

- Any clinically significant finding on screening electrocardiograph (ECG), specifically
(a single repeat is allowed to determine eligibility): (1) Heart rate <45 and >100bpm
(males), <50 and >100bpm (females); Note: A heart rate from 100 to 110 BPM can be
rechecked within 30 minutes to verify eligibility, (2) QRS duration >120msec, (3) QTc
interval >450msec, (4) Non-sustained (greater than or equal to 3 consecutive beats) or
sustained ventricular tachycardia, (5) Sinus pauses >2.5 seconds, (6) 2nd degree (Type
II) or higher AV (Atrioventricular) block, (7) Evidence of WPW (Wolff-Parkinson-White)
syndrome (ventricular preexcitation), (8) Pathologic Q waves (defined as Q wave
>40msec OR depth >0.4 mV, (9) Any other abnormality which in the opinion of the
investigator would interfere with the safety of the subject

- Treatment with any of the following agents within 28 days prior to screening, or has
an anticipated need for these agents during the study: (1) radiation therapy or
cytotoxic chemotherapeutic agents, (2) immunomodulators (such as systemic
corticosteroids, interleukins, or interferons); Note: Subjects using short-term (<7
day) steroid tapers and inhaled corticosteroids are eligible for enrollment, (3) Any
non-protocol-specified agent with documented activity against HIV-1 in vitro

- Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening

- Receipt of an experimental drug and/or vaccine within 28 days or 5 half-lives, or
twice the duration of the biological effect of the experimental drug or vaccine,
whichever is longer, prior to screening

- Immunization within 28 days prior to first dose of IP