Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

Condition(s) targeted: HIV Infection; Tuberculosis; Pneumocystis Jiroveci Pneumonia

Intervention: Isoniazid (INH) (Drug); Trimethoprim/Sulfamethoxazole (TMP/SMX) (Drug); Isoniazid Placebo (PL) (Drug)

Phase: Phase 2/Phase 3

Status: Terminated

Sponsored by: International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Official(s) and/or principal investigator(s):
Shabir Madhi, MD, Study Chair, Affiliation: University of the Witwatersrand
George McSherry, MD, Study Chair, Affiliation: UMDNJ - New Jersey Medical School
Charles D. Mitchell, MD, Study Chair, Affiliation: University of Miami

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.

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 design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Primary outcome:

Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children

Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children

Secondary outcome:

Time From Randomization to Development of TB Infection or Death Among HIV-infected Children

Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children

Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children

Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children

Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

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.

Minimum age: 91 Days. Maximum age: 120 Days. Gender(s): Both.

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

Princess Marina Hospital, Gaborone, Botswana

University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa

University of Stellenbosch, Tygerberg Hospital, Cape Town, South Africa

Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban, Durban 4001, South Africa

Chris Hani Baragwanath Hospital, Harriet Shezi Clinic, Johannesburg, South Africa

Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital, Johannesburg 2013, South Africa

Click here for more information about isoniazid

Click here for more information about sulfamethoxazole/trimethoprim

Haga clic aquí para ver información sobre este ensayo clínico en español.

Related publications:

Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84. Review.

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. Review.

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. Review.

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. Epub 2003 Sep 30. Review.

Starting date: February 2004
Last updated: February 10, 2011