Official Title: “A Phase III, Randomized, Open-Label Trial to Evaluate Strategies for Providing Antiretroviral Therapy to Infants Shortly After Primary Infection in a Resource Poor Setting”

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 Type: Interventional

Study Design: Treatment, Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: February 2007

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 benefits. 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 two 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 two treatment strategy arms. 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 both arms of Part A will begin with first-line, continuous treatment of zidovudine, lamivudine, and lopinavir/ritonavir. Those who were initially deferred treatment in Arm 1 will be reassessed for initiation of first-line, continuous ART.

In Part B, infants with a baseline CD4% less than 25% will now receive continuous ART. Those who previously had an interruption in treatment will receive continuous ART. First-line treatment of zidovudine, lamivudine, and lopinavir/ritonavir 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 (sulfamethoxazole/trimethoprim) prophylaxis from age 6 weeks until Week 40. Study visits will occur at study entry, Weeks 2, 4, 8, 12, 24, 32, 40, and 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.

Participants enrolled in CIPRA-ZA Project 2 are encouraged to enroll in an observational substudy organized by the Wistar Institute (Dr. Luis Montaner, Principal Investigator), in conjunction with the CIPRA team. This study is entitled,"Pediatric Immune Correlates of Early Anti-HIV Therapy." The goal of this 5-year substudy is to evaluate 120 HIV infected children from the parent study twice a year and compare them to HIV uninfected age-matched controls.

Children will be evaluated by (a) characterization and identification of the innate and adaptive immune reconstitution outcomes of early (9 or 21 months) therapy in infants infected with HIV at birth and (b) identification of immune correlate outcomes to clinical progression within a period of 2 to 3 years of follow-up after stopping therapy.

Intervention(s) in this Clinical Trial

• Drug: Abacavir sulfate
  • Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
• Drug: Didanosine
  • Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Guidelines for switching from first line to second line therapy are available in the protocol.
• Drug: Efavirenz
  • Second Line Regimen: taken orally once daily. Dosage depends on weight. Guidelines for switching from first line to second line therapy are available in the protocol.
• Drug: Lamivudine
  • First Line Regimen: 4 mg/kg taken orally twice daily
• Drug: Lopinavir/Ritonavir
  • First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
• Drug: Nevirapine
  • Second Line Regimen: 120 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
• Drug: Ritonavir
  • Second Line Regimen: Dosage depends on age and weight. Guidelines for switching from first line to second line therapy are available in the protocol.
• Drug: Sulfamethoxazole/Trimethoprim
  • 400 mg sulfamethoxazole/80 mg trimethoprim taken daily orally from Weeks 6 through 40
• Drug: Zidovudine
  • First Line Regimen: 240 mg/m^2 taken orally twice daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1A
  • For participants with a CD4 count of at least 25%, ART deferred until necessary
• Experimental: 2A
  • For participants with a CD4 count of at least 25%, receive 40 weeks of ART until first birthday
• Experimental: 3A
  • For participants with a CD4 count of at least 25%, receive ART for 96 weeks until second birthday
• Experimental: 2B
  • For participants with a CD4 count less than 25%, receive ART for 40 weeks until first birthday
• Experimental: 3B
  • For participants with a CD4 count less than 25%, receive ART for 96 weeks until second birthday

Primary Measures

• Time to failure of first-line antiretroviral therapy or death
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Failure of CD4 percentage (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)
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Development of severe CDC Stage B or Stage C disease, as defined in the protocol
  • Time Frame: Throughout study
    Safety Issue?: Yes
• 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
  • Time Frame: Throughout study
    Safety Issue?: Yes

Inclusion Criteria for Infants:

• NOTE: Per Letter of Amendment dated 04/04/07, Part B of this study is no longer recruiting participants.
• 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 willing to provide informed consent and comply with study requirements

Exclusion Criteria for Infants:

• Any major life-threatening congenital abnormalities
• Severe CDC Stage B or C disease
• Liver enzyme, absolute neutrophil count, 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 medications
• Inability to tolerate oral medication
• Birth weight less than 2 kg (4.4 lbs)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Weeks

Maximum Age for this Clinical Trial: 12 Weeks

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

James McIntyre, MBChB, MRCOG Principal Investigator Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand  

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00102960

Study ID Number: CIPRA-ZA Project 2

ClinicalTrials.gov Identifier: NCT00102960

Health Authority: United States: Food and Drug Administration

Click here for more information about abacavir sulfate

Click here for more information about didanosine

Click here for more information about efavirenz

Click here for more information about lamivudine

Click here for more information about lopinavir/ritonavir

Click here for more information about nevirapine

Click here for more information about ritonavir

Click here for more information about sulfamethoxazole/trimethoprim

Click here for more information on after birth care for HIV positive women and their babies

Click here for more information about HIV and pregnancy

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