Clinical trial NCT00080119: Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV
Official title: A Randomized, Double Blind, Placebo Controlled Trial to Determine the Efficacy of Isoniazid (INH) in Preventing Tuberculosis Disease and Latent Tuberculosis Infection Among Infants With Perinatal Exposure to HIV
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: HIV Infection
Tuberculosis
Pneumocystis Jiroveci Pneumonia
Keywords: Treatment Naive
INH Prophylaxis
HIV Seronegativity
Lead sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Comprehensive International Program of Research on AIDS
name: Secure the Future Foundation
First posted: 2004-03-25
Enrollment: 1354
Sex: ALL
Minimum age (years): 91
Maximum age (years): 120
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study was to determine if the antibiotic isoniazid (INH) prevented TB infection in infants born to HIV-infected mothers.

Detailed description: Tuberculosis (TB) and the Human Immunodeficiency Virus (HIV) are major public health problems in southern Africa, and the incidence of TB in South Africa is among the highest in the world. TB is caused by the highly contagious bacterium Mycobacterium tuberculosis. The use of Isoniazid (INH) prophylaxis in adults has been associated with reduced risk of TB disease in high-risk populations. Delay in initiating INH prophylaxis in children has resulted in more cases of childhood TB infection. This study evaluated the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV-infected mothers in southern Africa.

Infants were randomly assigned to receive either INH or placebo by mouth daily, beginning between the 91st and 120th day of life, and at least 90 days after Bacille Calmette-Guerin (BCG) vaccination. At sites in South Africa, HIV-infected infants received daily trimethoprim/sulfamethoxazole (TMP/SMX) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV-uninfected infants received TMP/SMX until at least 6 months of age.

The study was to follow participants for 192 weeks. Study visits occurred at study entry and every 12 weeks until week 192. A physical exam and blood collection occurred at each study visit. Infants were assessed for peripheral neuropathy every 12 weeks until week 96 and for TB at weeks 96, 144, and 192. The study also assessed medication adherence.

As of November 12, 2008, follow-up was revised. All participants were permanently discontinued from study follow-up by February 28, 2009 and no later than May 31, 2009. Only clinical evaluations were performed for all participants. For HIV-infected participants, the study drug was stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug was discontinued immediately.

Eligibility criteria: Inclusion Criteria:

* Mother is HIV-infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available.
* Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry
* Able to complete all study requirements
* Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants
* Parent or legal guardian able and willing to provide signed informed consent
* Plan to live in the study area for at least 4 years
* For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at \>= 4 weeks of age

Exclusion Criteria:

* Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease
* Previous receipt of INH
* Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry
* Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease
* Chronic persistent diarrhea
* Failure to thrive
* Contraindications for use of INH or TMP/SMX
* Require certain medications
* Known or suspected immune system diseases other than HIV
* Current or previous diagnosis of or treatment for cancer
* Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent
* Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded.
* Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening
* Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry
* Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study

Primary outcomes:
measure: Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children
timeFrame: Through to week 96
measure: Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
Secondary outcomes:
measure: Time From Randomization to Development of TB Infection or Death Among HIV-infected Children
timeFrame: Through to week 96
measure: Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children
timeFrame: Through to week 96
measure: Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
measure: Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
measure: Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
measure: Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
measure: Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
timeFrame: Through to week 96
Other outcomes:
Locations:
city: Gaborone
country: Botswana
facility: Princess Marina Hospital
city: Cape Town
country: South Africa
facility: University of Cape Town, Red Cross Children's Hospital
city: Cape Town
country: South Africa
facility: University of Stellenbosch, Tygerberg Hospital
city: Durban
country: South Africa
facility: Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban
city: Johannesburg
country: South Africa
facility: Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital
city: Johannesburg
country: South Africa
facility: Chris Hani Baragwanath Hospital, Harriet Shezi Clinic
Study officials:
affiliation: University of Witwatersrand, South Africa
name: Shabir Madhi, MD
role: STUDY_CHAIR
affiliation: UMDNJ - New Jersey Medical School
name: George McSherry, MD
role: STUDY_CHAIR
affiliation: University of Miami
name: Charles D. Mitchell, MD
role: STUDY_CHAIR
References:
citation: Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84.
citation: Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003 May 12;163(9):1009-21. doi: 10.1001/archinte.163.9.1009.
citation: de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. 2004;55:283-301. doi: 10.1146/annurev.med.55.091902.103753.
citation: Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis. 2003 Oct 15;188(8):1146-55. doi: 10.1086/378676. Epub 2003 Sep 30.
citation: Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S; PACTG 1041 Team. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis. 2008 Feb;12(2):225-7.
citation: Cotton M, Kim S, Rabie H, Coetzee J, Nachman S. A window into a public program for prevention of mother to child transmission of HIV: evidence from a prospective clinical trial. South Afr J HIV Med. 2009 Jan 1;10(4):16-19. doi: 10.4102/sajhivmed.v10i4.257.
citation: Gupta A, Montepiedra G, Gupte A, Zeldow B, Jubulis J, Detrick B, Violari A, Madhi S, Bobat R, Cotton M, Mitchell C, Spector S; IMPAACT NWCS113 and P1041 Study Team. Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.
citation: Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, Jean-Philippe P, McSherry G, Mitchell C; P1041 Study Team. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011 Jul 7;365(1):21-31. doi: 10.1056/NEJMoa1011214.