Atazanavir Used in Combination With Other Anti-HIV Drugs in HIV-Infected Infants, Children, and Adolescents

Advancements in HAART for HIV-infected children and adolescents are hindered by patient
nonadherence. The availability of a powder formulation and the once-daily dosing schedule
make ATV an attractive agent for improved adherence in pediatric treatment regimens. This
study was designed to provide pharmacokinetic (PK) data to guide dosing recommendations for
ATV, when given concurrently with or without low-dose RTV boost, in infants, children, and
adolescents. During the study, the safety and tolerance of ATV (with or without low-dose
RTV) were closely monitored, and virologic efficacy data were obtained.

There were two parts to this study. Step I took place in the United States and South Africa,
and were further divided into two sets of groups, Parts A and B. Part A participants
received ATV only and Part B participants received ATV with low-dose RTV boost. All
participants received ATV once a day with 2 other antiretroviral drugs (not provided by the
study). In Part B only, participants received ATV with a low dose of RTV. Participants were
placed into 1 of 8 groups (Groups 1 to 4 for Part A; Groups 5 to 8 for Part B) with respect
to age and study drug formulation. Participants in Groups 1 and 5 were infants between ages
3 months and 1 day (91 days) and 2 years (less than or exactly 730 days) and took ATV in
powder form. Participants in Groups 2, 3, 6, and 7 were children between 2 years and 1 day
(731 days) old and 13 years old. Groups 2 and 6 received ATV in powder form, while Groups 3
and 7 received the capsule form. Patients in Groups 4 and 8 were adolescents between 13
years and 1 day old and 21 years old (not including the 22nd birthday) and took ATV in
capsule form. As of 01/02/2008 a new group, 5A was opened for enrollment. Participants in
Group 5A were between 3 months and 6 months old and took ATV in powder form plus a low-dose
RTV booster.

For each group, enrollment started with five participants per group. All participants were
evaluated for PK and safety criteria, adjusting the dose of ATV until one was found that
passes both sets of criteria. Then five additional participants were enrolled, with
enrollment continuing for each group once all participants within that group meet the PK
criteria. For groups receiving RTV (Groups 5 to 8), additional criteria must be met for each
dose of ATV studied. In addition to the PK and safety evaluations, 24-hour post-dose
concentrations (Cmin) were monitored in the first 10 participants enrolled for a dose of ATV
before more participants were enrolled and studied at that same dose. Note that in Protocol
Version 5.0, South African (S.A.) sites were allowed to enroll patients in study groups
3,4,5,6,7,8. As a result, the study design has been modified to further stratify study
groups 3, 4, 5, 6, 7, 8 (at the final recommended dose), by country, i.e., U.S.A. versus
S.A., such that 10 evaluable study subjects will be accrued in parallel to each study
group-country cohort.

Clinic visits will be every 4 weeks through Week 48, then every 8 weeks until the last
participant to enroll in the study has reached Week 96 of his/her treatment. If, after 56
weeks, a participant has a toxic reaction to a nucleoside/tide reverse transcriptase
inhibitor (NRTI) in their medication regimen, the regimen may be changed to a different
NRTI. At every visit, participants will undergo a complete medical history and physical
exam, cardiac conduction evaluation, and urine and blood collection. Participants of
childbearing age will have a pregnancy test performed at each visit.

Step II will only be open to South African subjects who are virologically responding to
treatment when the last enrollee into either part of Step I (Part A or Part B) has completed
96 weeks of treatment (end of Step I) . All such participants will be given ATV in capsule
form at the same dose they received at the end of Step I, as well as the other
antiretrovirals they were receiving during Step I. Step II will continue until ATV is
approved in South Africa and readily available by individual prescription, and participants
will have a study visit every 12 weeks.

Note that the following ATV doses were independently evaluated for each group during the
dose-finding stage based on the description above: Group 1 ATV Powder (310mg/m^2,
620mg/m^2); Group 2 ATV Powder (310mg/m^2, 620mg/m^2); Group 3 ATV Capsule (310mg/m^2,
415mg/m^2, 520mg/m^2); Group 4 ATV Capsule (310mg/m^2, 520mg/m^2, 620mg/m^2); Group 5 ATV
Powder + RTV (310mg/m^2); Group 6 ATV Powder +RTV (310mg/m^2); Group 7 ATV Capsule + RTV
(310mg/m^2, 205mg/m^2); Group 8 ATV Capsule + RTV (310mg/m^2, 205mg/m^2); Group 5A ATV
Powder + RTV (310mg/m^2). All these dosing groups are presented in Participant Flow groups
to show the total number of participants enrolled, but only the participants enrolled at the
final group doses are presented in the subsequent results.

The following groups satisfied the safety and PK guidelines specified in the protocol:
Groups 3,4,6,7,8. Groups 5 and 5A did not satisfy the protocol-defined pharmacokinetic
criteria. There was considerable inter-subject variability in systemic exposures in this age
group, such that a dose escalation to 415mg/m^2 may have resulted in ATV exposures greater
than 90,000 ng*hr/mL in some children. Thus, a further dose increase in Groups 5 and 5A was
not attempted.

These are the final dose for each group: Groups 1 and 2 (Final dose was not established);
Group 3 ATV Capsule (520mg/m^2); Group 4 ATV Capsule (620mg/m^2); Group 5 ATV Powder
(310mg/m^2) + RTV; Group 6 ATV Powder (310mg/m^2) +RTV; Group 7 ATV Capsule (205mg/m^2) +
RTV; Group 8 ATV Capsule (205mg/m^2) + RTV; Group 5A ATV Powder (310mg/m^2) + RTV.

Inclusion Criteria for Step I:

- Age: 91 days to 21 years of age (not including the 22nd birthday).

- A confirmed diagnosis of HIV infection defined by the current definition of the
IMPAACT Virology Core Laboratory Committee. More information about this criterion can
be found in the protocol.

- Viral load greater than or equal to 5,000 copies/mL

- Any CDC clinical classification and immune status

- Antiretroviral treatment-naïve or -experienced study candidates must be able to add
two new NRTIs as part of their new therapy in this protocol, or have genotypic
evidence of sensitivity to two NRTIs (the NRTIs must be used in combinations
recommended in the Guidelines for the Use of Antiretroviral Agents in Pediatric and
Adolescent HIV Infection). More information about this criterion can be found in the
protocol.

- Study candidates must show evidence of retained phenotypic sensitivity to ATV
(resistance index ratio of less than 10) when the subject has failed (after at least
12 weeks of therapy) two or more courses of PI containing regimens. More information
about this criterion can be found in the protocol.

- Demonstrated ability and willingness to swallow study medications

- Study candidate, parent, or legal guardian must be able and willing to provide signed
informed consent

- Female participants who are sexually active and able to become pregnant must use two
methods of birth control. More information about this criterion can be found in the
protocol.

- Males participating in the study must not attempt to impregnate a female, or
participate in sperm donation programs. Males engaging in sexual activity that could
lead to pregnancy must use a condom.

- Study candidates with a history of undefined syncope will require a complete cardiac
conduction evaluation at screening [e.g., ECG, 24-hour monitoring (Holter), and
exercise test (if age appropriate)]. This evaluation must rule-out any cardiac
conduction abnormalities.

Exclusion Criteria for Step I:

- Active hepatitis

- Presence of an acute serious/invasive infection requiring therapy at the time of
enrollment

- Hypersensitivity to any component of the formulation of ATV

- Chemotherapy for active malignancy

- Pregnant or breastfeeding

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

- Any laboratory or clinical toxicity greater than Grade 2 at entry

- Documented history of cardiac conduction abnormalities or significant cardiac
dysfunction

- History of undefined syncope that cannot be ruled out as related to cardiac
conduction abnormalities

- Family history of prolonged QTc-interval syndrome, Brugada syndrome, or
right-ventricular (RV) dysplasia

- Corrected QTc-Interval greater than 440 msec at screening

- Prolonged PR-Interval greater than 0.200 seconds (200 ms) on ECG at screening (study
candidates greater than or equal to 13 years of age)

- PR-Interval greater than 98th percentile on ECG at screening (study candidates less
than 13 years of age)

- Cardiac rhythm abnormalities:

1. A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block)
occurring during waking hours on ECG at screening

2. A type II second-degree AV-block (Mobitz type II heart-block) at any time on ECG
at screening

3. A complete AV-block at any time on ECG at screening

4. A heart rate less than the 2nd percentile for age of the normal heart rate range
on ECG at screening

- Prolonged therapy with intravenous pentamidine for acute Pneumocystis Carinii
Pneumonia (PCP) within three months of entry

Inclusion Criteria for Step II:

- Any South African subject enrolled into either part of Step I, who is virologically
successful by Week 96 of when the last study participant enrolled into the respective
part of Step I

- Female participants who are sexually active and able to become pregnant must continue
using two methods of birth control. More information about this criterion can be
found in the protocol.

- Males who continue participation in the study must not attempt to impregnate a woman,
or participate in sperm donation programs. Males engaging in sexual activity that
could lead to pregnancy must use a condom.

Exclusion Criteria for Step II:

- A South African participant who meets any of the criteria for treatment
discontinuation by Week 96 of when the last participant enrolled into either part of
Step I

- A South African participant who meets any of the exclusion criteria from Step I by
Week 96 of when the last participant enrolled into either part of Step I