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

Condition(s) targeted: HIV Infections

Intervention: Abacavir sulfate (Drug); Didanosine (Drug); Efavirenz (Drug); Lamivudine (Drug); Lopinavir/Ritonavir (Drug); Nevirapine (Drug); Ritonavir (Drug); Sulfamethoxazole/Trimethoprim (Drug); Zidovudine (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

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

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.

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

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

Primary outcome:

Time to failure of first-line antiretroviral therapy or death

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)

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

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 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.

Minimum age: 6 Weeks. Maximum age: 12 Weeks. Gender(s): Both.

Criteria:

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)

Children's Infectious Diseases, Clinical Research Unit, Tygerberg Children's Hospital, University of Stellenbosch, Parow, Cape Town 7505, South Africa

Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Soweto, Johannesburg 2013, South Africa

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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Related publications:

Faye A, Bertone C, Teglas JP, Chaix ML, Douard D, Firtion G, Thuret I, Dollfus C, Monpoux F, Floch C, Nicolas J, Vilmer E, Rouzioux C, Mayaux MJ, Blanche S; French Perinatal Study. Early multitherapy including a protease inhibitor for human immunodeficiency virus type 1-infected infants. Pediatr Infect Dis J. 2002 Jun;21(6):518-25.

Faye A, Le Chenadec J, Dollfus C, Thuret I, Douard D, Firtion G, Lachassinne E, Levine M, Nicolas J, Monpoux F, Tricoire J, Rouzioux C, Tardieu M, Mayaux MJ, Blanche S; French Perinatal Study Group. Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. Clin Infect Dis. 2004 Dec 1;39(11):1692-8. Epub 2004 Nov 05.

Havens PL, Waters D. Management of the infant born to a mother with HIV infection. Pediatr Clin North Am. 2004 Aug;51(4):909-37, viii. Review.

King SM; American Academy of Pediatrics Committee on Pediatric AIDS; American Academy of Pediatrics Infectious Diseases and Immunization Committee. Evaluation and treatment of the human immunodeficiency virus-1--exposed infant. Pediatrics. 2004 Aug;114(2):497-505.

Starting date: July 2005
Ending date: May 2009
Last updated: May 28, 2008