• Number of Grade 3 or higher signs, symptoms, or laboratory abnormalities experienced [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Change in immunologic outcome, defined as the change in CD4% from baseline to 4 years [ Time Frame: At baseline visit and 4 years after study entry ] [ Designated as safety issue: No ]
• Time to a significant HIV-related clinical event, defined as the time to first new CDC Category diagnosis (except for recurrent bacterial infections) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Whether or not a child switched regimens [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Time to HIV-1 RNA of 400 copies/ml or greater during first-line therapy or permanent discontinuation of first-line therapy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Time to HIV-1 RNA of 30,000 copies/ml or greater during second-line therapy or permanent discontinuation of second-line therapy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Whether or not a child has an HIV-1 RNA level of less than 400 copies/ml at Week 24 and has not permanently discontinued first-line therapy prior to that week [ Time Frame: At Week 24 ] [ Designated as safety issue: No ]
• Whether or not a child has a HIV-1 RNA level less than 400 copies/ml regardless of therapy at that time [ Time Frame: At Week 24 ] [ Designated as safety issue: No ]

• Number of Grade 3 or higher signs, symptoms, or laboratory abnormalities experienced
• change in immunologic outcome, defined as the change in CD4% from baseline to 4 years
• time to a significant HIV-related clinical event, defined as the time to first new CDC Category diagnosis (except for recurrent bacterial infections)
• whether or not a child switched regimens
• time to HIV-1 RNA of 30,000 copies/ml or greater during second-line therapy or permanent discontinuation of second-line therapy
• whether or not a child has an HIV-1 RNA level of less than 400 copies/ml at Week 24 and has not permanently discontinued first-line therapy prior to that week
• whether or not a child has a HIV-1 RNA level less than 400 copies/ml at Week 204 regardless of therapy at that time

Little is known about what treatment combinations are best for HIV infected children. This study will examine the long-term effectiveness of different anti-HIV drug combinations in children and strategies for switching treatment if the first treatment does not work. The study will enroll children who have not previously taken anti-HIV medication. Participants in this study will be recruited in both the United States and in Europe.

Some European children may also enroll in a substudy that will observe changes in body fat in children taking anti-HIV medications.

Antiretroviral therapy in children aims to prolong clinical and immunologic health. Currently, there are no data defining a particular highly active antiretroviral therapy (HAART) strategy as the optimal first-line therapy for children. This study will evaluate the long-term efficacy of two HAART regimens used as initial therapy: 1) two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI), and 2) two NRTIs plus a nonnucleoside reverse transcriptase inhibitor (NNRTI). It will also evaluate different strategies for switching therapy when the initial regimen fails. The long-term nature of this study should clarify whether early switching of therapy improves immunologic and virologic outcomes, or results in a more rapid exhaustion of treatment options. The study will be conducted in the United States and in Europe.

Participants in this study will have a CD4 cell count and viral load test during a screening visit. Participants will have an entry visit that will include blood and urine tests, a neurologic exam, a chest X-ray, and a behavioral and learning development exam. Participants will then be randomly assigned to one of four groups: Groups 1A and 1B will receive two NRTIs plus a PI; Groups 2A and 2B will receive two NRTIs plus an NNRTI. The medications allowed in the study are: abacavir, didanosine, emtricitabine, emtricitabine/tenofovir disoproxil fumarate, lamivudine, lamivudine/zidovudine, stavudine, tenofovir disoproxil fumarate, zalcitabine, and zidovudine (NRTIs); efavirenz and nevirapine (NNRTIs); efavirenz/emtricitabine/tenofovir disoproxil fumurate (NNRTI/NRTI); and amprenavir,atazanavir, darunavir, fosamprenavir calcium, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir, and tipranavir (PIs).

For participants whose initial regimen fails, or who experience clinical disease progression (indicated by the development of a new CDC Category C diagnosis) or other clinical disease progression at or after Week 24 of first-line therapy, second-line therapy will be strongly encouraged. (However, if poor adherence is suspected as a possible reason for an increase in HIV viral load, the site and the clinician should try to improve patient adherence and obtain additional confirmatory viral load values within a five-week time frame.) In second-line therapy, participants who initially took NRTIs with a PI will switch to NRTIs and an NNRTI. Participants who initially took NRTIs and an NNRTI will switch to NRTIs and a PI. The timing of the switch will be based on the participant's group: Groups 1A and 2A will switch to second-line treatment when viral load is 1,000 copies/ml or greater; Groups 1B and 2B will switch to second-line treatment when viral load is 30,000 copies/ml or greater. Participants who fail second-line therapy will discontinue study treatment and will be offered the best available therapy at the discretion of the clinician.

Participants will have study visits at Weeks 2, 4, 8, 12, 16, 24, and every 12 weeks thereafter until the drug regimen is switched to second-line treatment. Participants will then have a re-entry visit and the schedule of visits will restart. Participants will be in the study between 4 and 8 years, depending on when they enroll. All study visits will include medical history, a physical exam, and blood collection. Urine collection will occur at most visits. Participants will be asked to complete adherence questionnaires and will undergo neuropsychological assessments at selected visits.

All participants in this study are encouraged to coenroll in ACTG 219C, Long-Term Effects of HIV Exposure and Infection in Children. Participants in the European portion of the study may be asked to enroll in a substudy to observe the development and progression of lipodystrophy syndrome in children.

• Experimental: Two NRTIs plus a PI with a regimen change recommended at when viral load is 1000 copies/ml or higher
• Experimental: 2 NRTIs plus 1 PI with a regimen change recommended when viral load is 30,000 copies/ml or higher
• Experimental: 2 NRTIs plus a NNRTI with a regimen change recommended when viral load reaches 1,000 copies/ml or higher
• Experimental: 2 NRTIs plus an NRTI with a regimen change recommended when viral load reaches 30,000 copies/ml or higher

• Brogly S, Williams P, Seage GR 3rd, Oleske JM, Van Dyke R, McIntosh K; PACTG 219C Team. Antiretroviral treatment in pediatric HIV infection in the United States: from clinical trials to clinical practice. JAMA. 2005 May 11;293(18):2213-20.
• Havens PL. Principles of antiretroviral treatment of children and adolescents with human immunodeficiency virus infection. Semin Pediatr Infect Dis. 2003 Oct;14(4):269-85. Review.
• Hoody DW, Fletcher CV. Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children. Semin Pediatr Infect Dis. 2003 Oct;14(4):286-94. Review.
• McKinney RE Jr, Cunningham CK. Newer treatments for HIV in children. Curr Opin Pediatr. 2004 Feb;16(1):76-9. Review.

Note: Per the 06/28/05 amendment of this trial, emtricitabine, emtricitabine/tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate have been added to the list of medications that may be included in a participant's treatment regimen.

Inclusion Criteria:

• Older than 30 days and younger than 18 years of age (may enroll up to the day before their 18th birthday)
• HIV infected
• Not previously on HAART or received anti-HIV drugs for less than 56 consecutive days after birth to prevent mother-to-infant HIV transmission. Participants who have previously received nevirapine for the prevention of mother-to-infant HIV transmission are not eligible for this study.
• Willing to use acceptable methods of contraception

Exclusion Criteria:

• Grade 3 or 4 clinical or laboratory toxicity. More information on this criterion can be found in the protocol.
• Active opportunistic infection or a serious bacterial infection at the time of study entry
• Pancreas, nervous system, blood, liver, or kidney problems that make it impossible to take study medications
• Taking any medication that cannot be combined with the study medications in first-line therapy
• Received therapy for cancer
• Pregnant or breastfeeding

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Pediatric European Network for Treatment of AIDS