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

• Grade 3 or 4 toxicity attributed to study treatment [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: Yes ]
• Failure to achieve a 1 Log(10) reduction in RNA at Week 16 [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• Plasma HIV RNA level that is increased by greater than or equal to 1 log from baseline at any time, confirmed by a second specimen [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• Plasma HIV RNA level confirmed to be greater than 10,000 copies/mL at Week 24 [ Time Frame: Measured at Week 24 ] [ Designated as safety issue: No ]
• Plasma HIV RNA level confirmed to rebound at or after Week 24 by greater than 1 log from the lowest HIV RNA level achieved, provided the lowest level was greater than 1,000 [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
  If the lowest level was less than 1,000 copies/mL, then a confirmed plasma HIV RNA rebound to greater than 10,000 copies/mL.
• 1 Log(10) drop from baseline RNA at Week 16 [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• RNA less than 400 copies/mL (standard assay) [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• RNA less than 50 copies/mL (ultra-sensitive assay) [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• Grade 3 or 4 toxicities [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: Yes ]
• Pharmacokinetic parameters, as specified in the protocol [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]

• Viral load, as measured by RNA PCR [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• CD4 count and percent [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• CD8 count and percent [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]
• Markers of cellular activation [ Time Frame: Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96 ] [ Designated as safety issue: No ]

The purpose of this study is to find a safe and tolerable dose of the protease inhibitor (PI) atazanavir (ATV), with or without a low-dose boost of the PI ritonavir (RTV), when taken with other anti-HIV drugs in HIV infected infants, children, and adolescents.

Advancements in anti-HIV drugs for HIV infected children and adolescents have been hard to make, in part because these patients often do not take the drugs as prescribed. ATV may be a better option because it is available in the form of powder which children and adolescents may be more willing to take regularly. Using a low dose of RTV as a boosting agent for ATV may also increase the chances of virologic response of highly active antiretroviral treatment (HAART)-experienced patients. This study will try to find safe and tolerable doses of ATV with or without low-dose RTV boost in infants, children, and adolescents. For this study, participants will be enrolled in the United States and South Africa.

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 is 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) will be closely monitored, and virologic efficacy data will be obtained.

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

For each group, enrollment will start with five participants per group. All participants will be evaluated for PK and safety criteria, adjusting the dose of ATV until one is found that passes both sets of criteria. Then five additional participants will be 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) will be monitored in the first 10 participants enrolled for a dose of ATV before more participants can be enrolled and studied at that same dose. 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 be open only to South African participants of Step I who have responded to treatment by the 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.

• Drug: ATV
  Participants will receive varying doses of ATV, depending on their age and weight. The medication will be administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants are in.
• Drug: Ritonavir
  Administered as 100 mg capsules or oral solution.

• Experimental: Step I: Group 1
  Group 1 will enroll participants between 91 days of age and 2 years of age. They will receive ATV (powder) and two NRTIs.
  Intervention: Drug: ATV
• Experimental: Step I: Group 2
  Group 2 will enroll participants between 2 years and 1 day of age and 13 years of age. They will receive ATV (powder) and two NRTIs.
  Intervention: Drug: ATV
• Experimental: Step I: Group 3
  Group 3 will enroll participants between 2 years and 1 day of age and 13 years of age. They will receive ATV (capsule) and two NRTIs.
  Intervention: Drug: ATV
• Experimental: Step I: Group 4
  Group 4 will enroll participants between 13 years and 1 day of age and 21 years of age. They will receive ATV (capsule) and two NRTIs.
  Intervention: Drug: ATV
• Experimental: Step I: Group 5
  Group 5 will enroll participants between 91 days of age and 2 years of age. They will receive ATV (powder), ritonavir, and two NRTIs.
  Interventions:

  • Drug: ATV
  • Drug: Ritonavir
• Experimental: Step I: Group 5a
  Group 5a will enroll participants between 91 days of age and 180 days of age. They will receive ATV (powder), ritonavir, and two NRTIs.
  Interventions:

  • Drug: ATV
  • Drug: Ritonavir
• Experimental: Step I: Group 6
  Group 6 will enroll participants between 2 years and 1 day of age and 13 years of age. They will receive ATV (powder), ritonavir, and two NRTIs.
  Interventions:

  • Drug: ATV
  • Drug: Ritonavir
• Experimental: Step I: Group 7
  Group 7 will enroll participants between 2 years and 1 day of age and 13 years of age. They will receive ATV (capsule), ritonavir, and two NRTIs.
  Interventions:

  • Drug: ATV
  • Drug: Ritonavir
• Experimental: Step I: Group 8
  Group 8 will enroll participants between 13 years and 1 day of age and 21 years of age. They will receive ATV (capsule), ritonavir, and two NRTIs.
  Interventions:

  • Drug: ATV
  • Drug: Ritonavir

Inclusion Criteria for Group 5A Step I:

• Age: 91 days to 180 days of age
• 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

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• International Maternal Pediatric Adolescent AIDS Clinical Trials Group