Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents

DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study is to
evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG in HIV-1
infected infants, children, and adolescents.

Participation in this study will last approximately 48 weeks, followed by long-term safety
follow-up that will last for about 3 years. Participants may be receiving other
antiretroviral (ARV) medications while in this study; these medications will be prescribed by
participants' doctors and will not be provided by the study. This study has two stages. Stage
I will evaluate the short-term tolerability and safety of DTG, allowing the selection of a
dose for further study in Stage II. Stage II will then provide long-term safety,
tolerability, and efficacy data for DTG. Participants will be assigned to one of eight
cohorts depending on age (4 weeks to younger than 18 years of age). Participants in cohorts I
and IIA will receive DTG film-coated tablets; participants in cohort IIB will receive DTG
granules for oral suspension or DTG dispersible tablets; participants in cohorts III and IV
will receive DTG granules for oral suspension; and participants in cohorts III-DT, IV-DT, and
V-DT will receive DTG dispersible tablets. Participants will receive DTG orally once or twice
daily, depending on which other ARV medications they are receiving. (All eight cohorts will
be included in Stage I of the study; however, Stage II of the study will not include cohort
IIB).

Stage I participants will undergo a physical examination and have blood drawn at each of 10
study visits, occurring on Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and
48. Stage I participants will also have their blood drawn 8 times over 24 hours during the
Day 5 (+5 days) study visit to measure the amount of drug in the blood stream. Stage II
participants will undergo a physical examination and have blood drawn at each study visit
(Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48). Blood, plasma, and urine will
also be stored and tested to measure immune response. Females of childbearing potential will
undergo pregnancy testing at every study visit. Questionnaires and assessments will be
performed at select study visits.

After 48 weeks, all participants will enter long-term safety follow-up and will continue to
receive DTG. During this time, participants will undergo a physical examination, blood
collection, and questionnaires at most study visits (every 12 weeks for about 3 years).

Note: In January 2018, all participants on DTG granules for oral suspension were recommended
to transition to DTG dispersible tablets. Cohorts III and IV are closed to further
enrollments.

Inclusion Criteria:

- At least 4 weeks but younger than 18 years of age at study entry

- Confirmed HIV-1 infection defined as positive results from two samples collected at
different time points (see protocol for more information)

- Participants must belong to one of the ARV exposure groups below:

- 1) ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for
prevention of perinatal transmission)

- Previously took ARVs for treatment, but not currently taking ARVs:

- Must have been off treatment for greater than or equal to 4 weeks prior to
screening, OR

- Currently taking ARVs for treatment but failing:

- Must be on an unchanged, failing therapeutic regimen within the 4 to 12 weeks
prior to screening (less than or equal to 1 log drop in HIV-1 RNA within the 4 to
12 weeks prior to screening). NOTE: To meet this criterion, two HIV RNA levels
are required: one from a date between 4-12 weeks prior to study screening and a
second one at study screening. The HIV RNA level at screening must be higher
than, equal to, or less than or equal to 1 log lower than the prior HIV RNA
level. NOTE: Dose adjustments for growth or formula substitutions (i.e.,
switching from single agent to fixed dose combination) during this 4 to 12 week
period, substitutions of one ARV within the same class for toxicity or
tolerability management, or discontinuation of ARVs are permitted between the HIV
RNA measurements and screening or enrollment. OR

- For participants less than 2 years of age, initiated ARVs for treatment less than
4 weeks prior to screening.

- 2) ARV treatment naive (no exposure to ARVs for treatment; could have received ARVs
for prophylaxis or prevention of perinatal transmission)

- If an infant has received nevirapine (NVP) as prophylaxis to prevent perinatal
transmission, he or she must have not received NVP for at least 14 days prior to
enrollment into Stage I or II.

- HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening. NOTE: For
participants enrolling into cohorts IV, IV-DT, and V-DT, the HIV RNA test performed at
screening may be pending at the time of enrollment. If the screening HIV RNA is less
than or equal to 1000 c/mL, the participant should discontinue study drug (see the
protocol for more information).

- Demonstrated ability or willingness to swallow assigned study medications. NOTE: Film
coated tablets MAY NOT be crushed or dissolved. Dispersible tablets MAY NOT be cut and
must be used in five milligram intervals.

- Parent or legal guardian able and willing to provide signed informed consent.

- Female participants of reproductive potential, defined as having reached menarche, and
who are engaging in sexual activity that could lead to pregnancy, must agree to use
two contraceptive methods while on study and for two weeks after stopping study drug.

- Males engaging in sexual activity that could lead to HIV-1 transmission must use a
condom.

- Optimized background therapy (OBT):

- Participants who are both greater than or equal to 2 years of age and
ARV-treatment experienced (meeting entry criterion) must have available at least
one fully active drug for the OBT to enroll. If screening genotype testing is
inconclusive, historical genotypes obtained within 1 year of screening will be
considered by the Protocol Team for determination of fully active drugs.

- Participants who are greater than or equal to 2 years of age and ARV-treatment
naive (meeting entry criterion) can enroll if genotype testing has been obtained
with results pending.

- Participants less than 2 years of age (either ARV-treatment experienced or ARV
treatment naïve) can enroll if genotype testing has been obtained with results
pending.

Exclusion Criteria:

- Presence of any active AIDS-defining opportunistic infection

- At enrollment, participant less than 3.0 kg

- Known Grade 3 or greater of any of the following laboratory toxicities within 30 days
prior to study entry: neutrophil count, hemoglobin, platelets, aspartate
aminotransferase (AST), alanine transaminase (ALT), lipase, serum creatinine and total
bilirubin. A single repeat within the 30 days is allowed for eligibility
determination. NOTE: Grade 3 total bilirubin is allowable, if the participant is on
atazanavir (ATV).

- ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE:
Grade 4 total bilirubin is allowable, if the participant is on ATV.

- The following liver toxicities within 30 days prior to study entry: ALT greater than
3x the upper limit of normal (ULN) AND direct bilirubin is greater than 2x ULN

- Any prior history of malignancy, with the exception of localized malignancies such as
squamous cell or basal cell carcinoma of the skin

- Clinical or symptomatic evidence of pancreatitis, as determined by the clinician

- Use of any disallowed medications at time of screening (see the protocol for a
complete list of disallowed medications)

- Known history of exposure to integrase inhibitor treatment by the participant or
participant's mother prior to delivery/cessation of breastfeeding

- Known resistance to an integrase inhibitor

- Women who are pregnant or breastfeeding.

- Participant is currently participating in or has participated in a study with a
compound or device that is not commercially available within 30 days of signing
informed consent, unless permission from both Protocol Teams is granted

- Participant is unlikely to adhere to the study procedures, keep appointments, or is
planning to relocate during the study to a non-IMPAACT study site

- Any clinically significant diseases (other than HIV infection) or clinically
significant findings during the screening medical history or physical examination
that, in the investigator's opinion, would compromise the outcome of this study

- Participant has used, or anticipates using, chronic systemic immunosuppressive agents
or systemic interferon (e.g., for treatment of hepatitis C virus [HCV] infection)
within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g.,
prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses
(less than or equal to 30 days) are permitted. (See protocol for more information on
disallowed medications.)

- Any condition that would, in the opinion of the site investigator, place the
participant at an unacceptable risk of injury or render the participant unable to meet
the requirements of the protocol.

- Active tuberculosis (TB) disease and/or requirement for treatment that includes
rifampin at the time of the screening visit. However, participants who need rifampin
treatment while on DTG will be allowed to continue in P1093 provided the DTG dose is
adjusted according to the protocol.