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

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

Intervention: Isoniazid (Drug); Sulfamethoxazole/Trimethoprim (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

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

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

HIV infected women in southern Africa have a high risk of tuberculosis (TB) infection. Children born to HIV infected mothers may be more likely to be exposed to and become infected with TB, and children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study is to determine if the antibiotic isoniazid (INH) will prevent TB infection in infants born to HIV infected mothers in southern Africa.

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: Prevention, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome:

Time from randomization 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, and time from randomization to development of TB disease among HIV infected and perinatally exposed, HIV uninfected children

Time from randomization to death among HIV infected and perinatally exposed, HIV uninfected children

Population pharmacokinetics (PK) model of isoniazid (INH) among HIV infected and perinatally exposed, HIV uninfected children at two dosing interval time points on two separate occasions (at Cape Town and Durban only)

Time from randomization to development of TB infection among HIV infected children

Time from randomization to AIDS-defining illness or death among HIV infected children

Time from randomization to development of TB disease among perinatally exposed, HIV uninfected children

Time from randomization to new first Grade 3 or higher sign or symptom

Detailed description: TB and 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 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 will evaluate the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV infected mothers in southern Africa.

Infants will be 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 will receive daily sulfamethoxazole/trimethoprim (SMX/TMP) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV uninfected infants will receive SMX/TMP until at least 6 months of age. In Malawi, HIV exposed infants will be given SMX/TMP until they are confirmed HIV negative at 18 months of age; HIV infected infants will continue receiving prophylaxis.

This study will last 192 weeks. Study visits will occur at study entry and every 12 weeks until Week 192. A physical exam and blood collection will occur at each study visit. Infants will be assessed for peripheral neuropathy every 12 weeks until Week 96 and for TB at Weeks 96, 144, and 192. The study will also assess medication adherence.

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

- Normal truncated Denver Developmental Test for peripheral neuropathy at study entry

- Normal deep tendon reflexes and muscle bulk, tone, and strength at study entry

- Plan to live in the study area for at least 4 years

Exclusion Criteria:

- Previous diagnosis of TB infection

- 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

- Significant drop in weight or failure to gain weight appropriately during a 2- to

3-month period

- Contraindications for use of INH or SMX/TMP

- 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

Chris Hani Baragwanath Hospital, Harriet Shezi Clinic, Johannesburg, South Africa; Recruiting
Wilma Pelser, RN, Phone: 27 119899704, Email: pelserw@hivsa.com

University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa; Recruiting
Marque F. Venter, Phone: 27 216897462, Email: venterm@ich.uct.ac.za

University of Stellenbosch, Tygerberg Hospital, Cape Town, South Africa; Recruiting
Joan Coetzee, CPN, Phone: 27 832759577, Email: joan@sun.ac.za

Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital, Johannesburg 2013, South Africa; Recruiting
Tiro Mathabela, BA, CCRC, RN, Phone: 27 11 933-9630, Email: tmathabela@paedshiv.co.za

Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban, Durban 4001, South Africa; Recruiting
Sally Pillay, Phone: 27 31 620 4729, Email: pillays@ukzn.ac.za

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.

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: March 2006
Ending date: October 2009
Last updated: September 24, 2008