The purpose of this study is to compare the effects of anti-HIV drug courses of different lengths in infants who became HIV infected at birth.

Study hypothesis: Starting anti-HIV treatment when infants are between 6 and 12 weeks of age, followed by interruption of therapy, will be safe and effective and will show a long-term health benefit in these infants. This study will recruit participants in South Africa.

Condition	Treatment or Intervention	Phase
HIV Infections	Drug: Zidovudine  Drug: Lamivudine  Drug: Lopinavir/ritonavir  Drug: Didanosine  Drug: Abacavir sulfate  Drug: Nevirapine  Drug: Efavirenz	Phase III

Further Study Details: 

Primary Outcomes: Time to failure of first-line antiretroviral therapy of death; Failure of CD4% to reach a level of at least 20% by Week 24 of therapy (initial therapy or restart) or CD4% falls below 20% on two occasions, within 4 weeks, at any time after the first 24 weeks of therapy (initial therapy or restart); Development of severe CDC Stage B or Stage C disease, as defined in the protocol; Development of toxicity requiring more than one drug substitution within the same class or a switch to a new class of drugs (regimen-limiting toxicity failure) or requiring a permanent treatment discontinuation
Expected Total Enrollment:  415

In South Africa, an estimated 250,000 infants are born to HIV infected mothers each year. A high percentage of perinatal HIV infections are due to inadequate or absent mother-to-child transmission prophylaxis. Unfortunately, even with optimal prophylaxis, relatively large numbers of HIV infected infants will continue to be born and will require antiretroviral therapy (ART). Determining the appropriate times for initiating and interrupting treatment to benefit long-term prognosis in infants is a significant health challenge. Evidence suggests that starting ART early during acute infection will provide long-term benefit. However, longer duration of treatment increases the chance of developing drug-resistant virus, and continuous therapy begun early leads to long-term complications in children. This study will evaluate the efficacy of three different short-course ART strategies in HIV infected infants from South Africa.

This study will last at least 3.5 years. There are two parts to this study. In Part A, infants with a baseline CD4 percentage (CD4%) of at least 25% and HIV infection diagnosed between 6 and 12 weeks of age will be randomly assigned to one of three treatment strategy arms. Arm 1 infants will have ART deferred until it is clinically needed. Arm 2 infants will receive ART for approximately 40 weeks until their first birthday. Arm 3 infants will receive ART for approximately 96 weeks until their second birthday. Treatment in all three arms of Part A will begin with first-line treatment of zidovudine, lamivudine, and lopinavir/ritonavir. First-line ART will be restarted after interruption in Arms 2 and 3 if the CD4% falls below 20% or if the infant develops a severe CDC Stage B or C disease.

In Part B, infants with a baseline CD4% less than 25% will be randomly assigned to either Arm 2 or Arm 3, and will restart ART after treatment interruption when the CD4% falls below 20% or if the infant develops a severe CDC Stage B or C disease. First-line ART will continue until infants reach a study endpoint; when this occurs, infants will then change to second-line therapy. Second-line ART will consist of didanosine, abacavir sulfate, and nevirapine or efavirenz.

Follow-up visits will take place for 3.5 to 5 years, depending on time of enrollment. All infants will receive routine immunizations and cotrimoxazole prophylaxis from age 6 until Week 40. Study visits will occur at study entry, Weeks 2, 4, 8, 12, 24, 32, 40, 48, and every 12 weeks thereafter. At these visits, infants will have vital sign measurements, a physical exam, and a medical history evaluation. Blood and urine collection will occur at all study visits. Infants' parents or guardians will also be asked to complete an adherence questionnaire.

Ages Eligible for Study:  6 Weeks   -   12 Weeks,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria for Infants:

• HIV infected
• Antiretroviral naive. Infants who have previously received antiretroviral drugs used to prevent mother-to-child transmission are eligible for the study.
• Parent or legal guardian is willing to provide written informed consent and comply with the study requirements

Exclusion Criteria for Infants:

• Any major life-threatening congenital abnormalities
• Severe Centers for Disease Control (CDC) Stage B or C disease
• Hemoglobin, electrolyte, creatinine, or clinical toxicity of Grade 3 or higher at screening
• Any acute or clinically significant medical event that would preclude participation in the study
• Use of investigational drugs
• Require certain drugs
• Inability to tolerate oral medication
• Birth weight less than 4.4 lbs (2 kg)

South Africa, Cape Town
      Children's Infectious Diseases, Clinical Research Unit, Tygerberg Children's Hospital, University of Stellenbosch, Parow,  Cape Town,  7505,  South Africa
South Africa, Johannesburg
      Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Soweto,  Johannesburg,  2013,  South Africa

Study chairs or principal investigators

James McIntyre, MBChB, MRCOG,  Principal Investigator,  Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand   
Avy Violari, MBChB, FCP (SA),  Study Chair,  Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand   
Mark F. Cotton, MBChB, MMed,  Study Chair,  Department of Pediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch   

Study ID Numbers:  CIPRA-SA Project 2; CHER
Record last reviewed:  January 2005
Last Updated:  February 4, 2005
Record first received:  February 4, 2005
ClinicalTrials.gov Identifier:  NCT00102960
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08