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

NCT ID: NCT00080119

Last Updated: 2019-02-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 1354 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-02-29
• Study Completion Date: 2009-05-31

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.

Conditions

HIV Infection; Tuberculosis; Pneumocystis Jiroveci Pneumonia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

HIVneg/INH

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid (INH)10-20 mg/kg orally once a day for 96 weeks + Trimethoprim/Sulfamethoxazole (TMP/SMX) 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

Group Type: EXPERIMENTAL

Isoniazid (INH)

Intervention Type: DRUG

Antibiotic for the prevention and treatment of TB

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Intervention Type: DRUG

Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)

HIVneg/PL

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

Group Type: PLACEBO_COMPARATOR

Isoniazid Placebo (PL)

Intervention Type: DRUG

Isoniazid placebo and TMP/SMX

HIVpos/INH

HIV-infected (HIVpos) children receiving Isoniazid (INH) 10-20 mg/kg orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

Group Type: EXPERIMENTAL

Isoniazid (INH)

Intervention Type: DRUG

Antibiotic for the prevention and treatment of TB

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Intervention Type: DRUG

Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)

HIVpos/PL

HIV-infected (HIVpos) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

Group Type: PLACEBO_COMPARATOR

Isoniazid Placebo (PL)

Intervention Type: DRUG

Isoniazid placebo and TMP/SMX

Interventions

Isoniazid (INH)

Antibiotic for the prevention and treatment of TB

Intervention Type: DRUG

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)

Intervention Type: DRUG

Isoniazid Placebo (PL)

Isoniazid placebo and TMP/SMX

Intervention Type: DRUG

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

• Minimum Eligible Age: 91 Days
• Maximum Eligible Age: 120 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Comprehensive International Program of Research on AIDS

OTHER

Sponsor Role: collaborator

Secure the Future Foundation

OTHER

Sponsor Role: collaborator

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

IMPAACT

Principal Investigators

Shabir Madhi, MD

Role: STUDY_CHAIR

University of Witwatersrand, South Africa

George McSherry, MD

Role: STUDY_CHAIR

UMDNJ - New Jersey Medical School

Charles D. Mitchell, MD

Role: STUDY_CHAIR

University of Miami

Locations

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, , South Africa

Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital

Johannesburg, , South Africa

Chris Hani Baragwanath Hospital, Harriet Shezi Clinic

Johannesburg, , South Africa

Countries

Botswana; South Africa

References

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

Reference Type: BACKGROUND

PMID: 15875917 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12742798 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14746522 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14551885 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18230259 (View on PubMed)

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.

Reference Type: RESULT

PMID: 20607114 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26872154 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 21732834 (View on PubMed)

Other Identifiers

U01AI068632

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PACTG P1041

Identifier Type: -

Identifier Source: org_study_id