To compare the effectiveness of treatment with zidovudine (AZT) compared to didanosine (ddI) and compared to the combination of AZT and ddI as determined by survival and disease progression. To compare the relative safety and tolerance of AZT versus ddI versus AZT plus ddI in symptomatic HIV infected children; to compare the virological and immunological parameters in the three treatment groups. AZT has been shown to delay the progression of AIDS in HIV infected individuals. However, bone marrow toxicity is a frequent adverse effect. Also, HIV resistance to AZT sometimes occurs in patients who initially respond to treatment, but later have progression of the disease. Thus, new drug treatments are needed. Studies of ddI in adults and children indicate some effectiveness of the drug. A direct comparison of AZT and ddI treatment in children has not been made. Combination antiviral treatment (AZT plus ddI) may give added therapeutic benefit to children.

AZT has been shown to delay the progression of AIDS in HIV infected individuals. However, bone marrow toxicity is a frequent adverse effect. Also, HIV resistance to AZT sometimes occurs in patients who initially respond to treatment, but later have progression of the disease. Thus, new drug treatments are needed. Studies of ddI in adults and children indicate some effectiveness of the drug. A direct comparison of AZT and ddI treatment in children has not been made. Combination antiviral treatment (AZT plus ddI) may give added therapeutic benefit to children.

Patients are placed by random selection into one of three groups to receive either AZT alone, ddI alone, or AZT and ddI. This is a double-blind study: neither patient nor treating physician knows which group patient is in. If patients are receiving either AZT or ddI alone and they develop drug toxicity (after dose reduction), or if HIV disease progresses, the alternative single drug is offered. If patients receiving both drugs develop drug toxicity (despite dose reduction) or if HIV disease progresses, they discontinue study drug and are offered the best alternative therapy. PER AMENDMENT 6/26/95: Initial monotherapy AZT arm is unblinded and no further crossover therapy for any arm is permitted. Patients who reach crossover criteria on initial blinded ddI or AZT+ddI will be unblinded and permanently discontinued from study drugs.

• Drug: Zidovudine
• Drug: Didanosine

• Raskino C, Pearson DA, Baker CJ, Lifschitz MH, O'Donnell K, Mintz M, Nozyce M, Brouwers P, McKinney RE, Jimenez E, Englund JA. Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team. Pediatrics. 1999 Sep;104(3):e32.
• Grubman S. Pediatric treatment update. GMHC Treat Issues. 1996 Mar;10(3):7-9. No abstract available.
• Glick ME. CTG studies yield results. AIDS Clinical Trials Group. NIAID AIDS Agenda. 1995 Spring;:8-9. No abstract available.
• Rogers MF, Mofenson LM, Moseley RR. Reducing the risk of perinatal HIV transmission through zidovudine therapy: treatment recommendations and implications. J Am Med Womens Assoc. 1995 May-Aug;50(3-4):78-82, 93. Review.
• Nielsen K, Wei LS, Sim MS, Deveikis A, Keller M, Stiehm ER, Frenkel LM, Bryson YJ. Correlation of clinical progression in human immunodeficiency virus-infected children with in vitro zidovudine resistance measured by a direct quantitative peripheral blood lymphocyte assay. J Infect Dis. 1995 Aug;172(2):359-64.
• Palumbo PE, Raskino C, Fiscus S, Pahwa S, Fowler MG, Spector SA, Englund JA, Baker CJ. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA. 1998 Mar 11;279(10):756-61.
• McKinney RE Jr, Wilfert C. Growth as a prognostic indicator in children with human immunodeficiency virus infection treated with zidovudine. AIDS Clinical Trials Group Protocol 043 Study Group. J Pediatr. 1994 Nov;125(5 Pt 1):728-33.
• James JS. AZT, ddI, and ddC combinations at FDA advisory hearing. Food and Drug Administration. AIDS Treat News. 1996 Apr 5;(no 244):6. No abstract available.
• Englund JA, Baker CJ, Raskino C, McKinney RE, Petrie B, Fowler MG, Pearson D, Gershon A, McSherry GD, Abrams EJ, Schliozberg J, Sullivan JL. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997 Jun 12;336(24):1704-12.
• Capparelli EV, Englund JA, Connor JD, Spector SA, McKinney RE, Palumbo P, Baker CJ. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol. 2003 Feb;43(2):133-40.
• Chantry CJ, Byrd RS, Englund JA, Baker CJ, McKinney RE Jr; Pediatric AIDS Clinical Trials Group Protocol 152 Study Team. Growth, survival and viral load in symptomatic childhood human immunodeficiency virus infection. Pediatr Infect Dis J. 2003 Dec;22(12):1033-9.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Acetaminophen, ibuprofen, or aspirin, but not on a continual basis for > 72 hours.
• Systemic ketoconazole and fluconazole for acute therapy.

Recommended:

• Prophylaxis for PCP. (Primary prophylaxis with TMP / SMX is encouraged.) IV pentamidine may be used in selected cases if not administered on a weekly basis.

Patients must have the following:

• HIV infection.
• Children randomized prior to their eighteenth birthday are eligible. Co-enrollment in either ACTG 179 or 189 is permitted.

Prior Medication:

Allowed:

• Up to six weeks of antiretroviral or immunomodulator treatment excluding steroids and intravenous immunoglobulin.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Active malignancy.
• Pancreatitis or history of pancreatitis within one year prior to study entry associated with compatible symptoms.
• History of uncontrolled seizure disorder.
• Grade 3 or higher peripheral neuropathy.
• Cardiomyopathy.

Concurrent Medication:

Excluded:

• Chemotherapy for malignancy.
• Oral acidifying agents.
• Acetaminophen, ibuprofen, or aspirin on a continual basis for > 72 hours.
• Ketoconazole or fluconazole for prophylaxis.
• Drugs with potential to cause peripheral neuropathy or pancreatitis should not be given daily for > 4 weeks.

Patients with the following are excluded:

• Active malignancy.
• Pancreatitis or history of pancreatitis within one year prior to study entry associated with compatible symptoms.
• History of uncontrolled seizure disorder.
• Grade 3 or higher peripheral neuropathy.

Prior Medication:

Excluded:

• Steroids.
• Intravenous immunoglobulin.
• Antiretroviral drugs or specific immunomodulator treatment (excluding steroids and intravenous immunoglobulin) for > 6 weeks and within 7 days prior to study entry.

Prior Treatment:

Excluded:

• Red blood cell transfusion within four weeks prior to study entry.

Ongoing drug or alcohol use.

• Bristol-Myers Squibb
• Glaxo Wellcome