Anti-HIV Drugs for Treating Infants Who Acquired HIV Infection at Birth

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00102960
First received: February 4, 2005
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Abacavir sulfate
Drug: Didanosine
Drug: Efavirenz
Drug: Lamivudine
Drug: Lopinavir/Ritonavir
Drug: Nevirapine
Drug: Zidovudine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Time to failure of first-line antiretroviral therapy or death [ Time Frame: Throughout study ] [ Designated as 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 ] [ Designated as 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 ] [ Designated as safety issue: Yes ]
  • Development of severe CDC Stage B or Stage C disease, as defined in the protocol [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Confirmed HIV-1 RNA value of at least 10,000 copies per/ml recorded on two consecutive separate occasions after 24 weeks of treatment (initial therapy or restart) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Occurrence of severe CDC Stage B or Stage C disease or death (cumulative after 3.5 years) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Occurence of Grade 3 or 4 (clinical or laboratory) adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Time from randomization to starting or needing to start continuous therapy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Hospital admissions, time to first hospital admission, and duration of hospitalization [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Cumulative viral resistance mutations at the time of failure of first line therapy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  • Time to death or death with a life threatening stage C event or HIV event associated with permanent end-organ damage [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Enrollment: 451
Study Start Date: July 2005
Study Completion Date: January 2013
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1A
For participants with a CD4 count of at least 25%, ART deferred until necessary
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.
Other Names:
  • ABC
  • Ziagen
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.
Other Names:
  • ddI
  • Videx
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.
Other Names:
  • EFV
  • Stocrin
Drug: Lamivudine
First Line Regimen: 4 mg/kg taken orally twice daily
Other Names:
  • 3TC
  • Epivir
Drug: Lopinavir/Ritonavir
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Other Names:
  • LPV/r
  • Kaletra
Drug: Nevirapine
Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Other Names:
  • NVP
  • Viramune
Drug: Zidovudine
First Line Regimen: 240 mg/m^2 taken orally twice daily
Other Names:
  • AZT
  • Retrovir
Experimental: 2A
For participants with a CD4 count of at least 25%, receive 40 weeks of ART until first birthday
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.
Other Names:
  • ABC
  • Ziagen
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.
Other Names:
  • ddI
  • Videx
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.
Other Names:
  • EFV
  • Stocrin
Drug: Lamivudine
First Line Regimen: 4 mg/kg taken orally twice daily
Other Names:
  • 3TC
  • Epivir
Drug: Lopinavir/Ritonavir
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Other Names:
  • LPV/r
  • Kaletra
Drug: Nevirapine
Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Other Names:
  • NVP
  • Viramune
Drug: Zidovudine
First Line Regimen: 240 mg/m^2 taken orally twice daily
Other Names:
  • AZT
  • Retrovir
Experimental: 3A
For participants with a CD4 count of at least 25%, receive ART for 96 weeks until second birthday
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.
Other Names:
  • ABC
  • Ziagen
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.
Other Names:
  • ddI
  • Videx
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.
Other Names:
  • EFV
  • Stocrin
Drug: Lamivudine
First Line Regimen: 4 mg/kg taken orally twice daily
Other Names:
  • 3TC
  • Epivir
Drug: Lopinavir/Ritonavir
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Other Names:
  • LPV/r
  • Kaletra
Drug: Nevirapine
Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Other Names:
  • NVP
  • Viramune
Drug: Zidovudine
First Line Regimen: 240 mg/m^2 taken orally twice daily
Other Names:
  • AZT
  • Retrovir
Experimental: 1B
For participants with a CD4 count less than 25%, receive continuous ART
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.
Other Names:
  • ABC
  • Ziagen
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.
Other Names:
  • ddI
  • Videx
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.
Other Names:
  • EFV
  • Stocrin
Drug: Lamivudine
First Line Regimen: 4 mg/kg taken orally twice daily
Other Names:
  • 3TC
  • Epivir
Drug: Lopinavir/Ritonavir
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Other Names:
  • LPV/r
  • Kaletra
Drug: Nevirapine
Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Other Names:
  • NVP
  • Viramune
Drug: Zidovudine
First Line Regimen: 240 mg/m^2 taken orally twice daily
Other Names:
  • AZT
  • Retrovir

Detailed Description:

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 receive continuous ART. First-line ART will be started in Arm 1 or restarted after interruption in Arms 2 and 3 if the appropriate criteria as defined in the protocol is met. 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, nevirapine and efavirenz.

Follow-up visits will take place for 3.5 to 6 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, 16, 20, 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.

  Eligibility

Ages Eligible for Study:   6 Weeks to 12 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Infants:

NOTE: Per Letter of Amendment dated 04/04/07, Part B of this study is no longer recruiting participants. Per Letter of Amendment dated 09/16/08 Arm 1 of this study is longer recruiting.

  • 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. Randomization can take place as soon as the incurrent illness has resolved if the child is still less than or equal to 12 weeks of age.
  • Use of investigational drugs
  • Require certain medications. More information on this criterion can be found in the protocol.
  • Inability to tolerate oral medication
  • Birth weight less than 2 kg (4.4 lbs)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00102960

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

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00102960     History of Changes
Other Study ID Numbers: CIPRA ZA 002, 10404, CHER, 5R01AI062512-02, CIPRA-SA Project 2
Study First Received: February 4, 2005
Last Updated: July 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Infant
Perinatal
HIV
Disease Transmission, Vertical
Anti-Retroviral Agents
Treatment Interruption
Treatment Naive
Acute Infection
Mother-to-Child Transmission

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Didanosine
Zidovudine
Nevirapine
Lamivudine
Efavirenz
Abacavir
Ritonavir
Anti-HIV Agents
Lopinavir
Anti-Retroviral Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014