• Grade 3 or 4 toxicities as defined in protocol [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Pharmacokinetic parameters [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

• Viral load [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Cd4 count and percentage [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• CD8 count and percentage [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Markers of cellular activation [ Time Frame: Throughout study ] [ 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, also known as BMS-232632 or ReyatazTM), 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 for these patients 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, patients will be enrolled in the U.S. 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 is open in the U.S. and South Africa, and is 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 patients receive ATV once a day with 2 other antiretroviral drugs (not provided by the study), and in Part B patients only (Groups 5 to 8), ATV is given with a low dose of RTV. Patients are 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. Patients in Groups 1 and 5 are infants age 3 months and 1 day (91 days) up to 2 years (less than or exactly 730 days) and take ATV in powder form. Patients in Groups 2, 3, 6, and 7 are children age 2 years and 1 day (731 days) or more up to 13 years. Groups 2 and 6 receive ATV in powder form, while Groups 3 and 7 receive the capsule form. Patients in Groups 4 and 8 are adolescents age 13 years and 1 day up to 21 years (not including the 22nd birthday) and 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 age 3 months to 6 months and will take ATV in powder form plus a low dose RTV booster.

For each group, enrollment starts with 5 patients per group, with all patients evaluated for PK and safety criteria, adjusting the dose of ATV until one is found that passes both sets of criteria. Then 5 additional patients are enrolled, with enrollment continuing for each group once all patients 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 postdose concentrations (Cmin) will be monitored in the first 10 patients enrolled for a dose of ATV before more patients can be enrolled and studied at that same dose. Clinic visits are every 4 weeks through Week 48, then every 8 weeks until the last patient to enroll in the study has reached Week 96 of his/her treatment. At every visit, patients undergo a complete medical history and physical exam, cardiac conduction evaluation, and urine and blood collection. Patients of childbearing age have a pregnancy test performed at each visit.

Step II is 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 the course of 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: Atazanavir
• Drug: Ritonavir

• Active Comparator: Participants will receive ATV along with 2 other antiretrovirals as determined by study investigators. Participants in this group will be stratified by age and may receive ATV as either a powder or capsule.
• Active Comparator: Participants in this group will receive ATV plus a low-dose RTV booster and 2 other antiretrovirals as determined by study investigators. Participants in this group will be stratified by age and may receive ATV as a powder or capsule.

• Barreiro P, Rendon A, Rodriguez-Novoa S, Soriano V. Atazanavir: the advent of a new generation of more convenient protease inhibitors. HIV Clin Trials. 2005 Jan-Feb;6(1):50-61. Review.
• Fraaij PL, van Kampen JJ, Burger DM, de Groot R. Pharmacokinetics of antiretroviral therapy in HIV-1-infected children. Clin Pharmacokinet. 2005;44(9):935-56.
• Kashuba AD. Drug-drug interactions and the pharmacotherapy of HIV infection. Top HIV Med. 2005 Jun-Jul;13(2):64-9. Review.
• Moyle G. Overcoming obstacles to the success of protease inhibitors in highly active antiretroviral therapy regimens. AIDS Patient Care STDS. 2002 Dec;16(12):585-97. Review.
• Pontali E. Facilitating adherence to highly active antiretroviral therapy in children with HIV infection: what are the issues and what can be done? Paediatr Drugs. 2005;7(3):137-49. Review.

Inclusion Criteria:

[Note: Groups 1,2,3,4,5,6,7, and 8 are no longer open to accrual.]

• Have HIV infection.
• Have a viral load (amount of HIV in the blood) of 5,000 copies/ml or more.
• Are able to take 2 nucleoside reverse transcriptase inhibitors (NRTIs) that they have never taken before.
• Take a test showing they can respond to atazanavir.
• Are able and willing to swallow the study drugs.
• Are 3 months and 1 day (91 days) to 21 years old.
• Agree to practice abstinence or use effective barrier method of birth control if they are able to become pregnant.
• Have signed consent of parent or guardian if under 18 years of age.
• Are willing to undergo complete cardiac conduction evaluation at screening.
• For Step II, are South African participants from Step I that are virologically successful by Week 96 of the last study patient enrolled in their respective part of Step I.

Exclusion Criteria:

• Have hepatitis.
• Have a serious infection that requires treatment at the time of study entry.
• Are allergic to atazanavir.
• Are receiving chemotherapy for cancer.
• Have any serious conditions (other than HIV infection) at study entry that might affect the results of the study.
• Are pregnant or breastfeeding.
• Show toxicity at study entry.
• Are receiving certain drugs or treatments.
• Are receiving pentamidine (by vein) for Pneumocystis carinii pneumonia within 3 months of study entry; ongoing monthly treatment with orally inhaled pentamidine for prophylaxis is not excluded.
• Have a history of significant cardiac abnormalities or dysfunction.
• For Step II, virologic failure or the investigator deems discontinuation appropriate based on toxicity/tolerability.

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