Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children
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ClinicalTrials.gov Identifier: NCT00330304 |
Recruitment Status :
Completed
First Posted : May 26, 2006
Last Update Posted : April 22, 2019
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Condition or disease | Intervention/treatment | Phase |
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Tuberculosis | Drug: Isoniazid Drug: Cotrimoxazole Drug: isoniazid Other: placebo | Phase 3 |
Tuberculosis (TB) and HIV are dual pandemics occurring in South Africa. Prevention of TB and the subsequent decline in immune function in HIV-infected children is an important strategy to reduce mortality. Isoniazid (INH) prophylaxis reduces TB incidence in HIV-infected adults, but the efficacy in HIV-infected children has not been studied. In 2003, the investigators therefore began a double blind placebo controlled trial to investigate the impact of INH prophylaxis on mortality, morbidity and TB incidence in HIV-infected children. Interim analysis found a striking reduction in mortality and TB with a decrease in mortality in excess of 50% and 60% respectively, in children on INH. Based on this, the placebo arm was terminated; the study continued as a trial of thrice versus daily INH and cotrimoxazole (CTX). Although the results indicate an important benefit in children on INH, it is unknown what the long term efficacy and safety of INH prophylaxis is, what the optimal regime is and whether this pertains to children on HAART (who formed a minority of the cohort but who are still at risk for TB).
Aim To investigate the efficacy, safety and tolerability of INH and CTX as prophylactic strategies for HIV-infected children in a high TB prevalence area.
Objectives
- To compare the long term impact of two different INH preventive regimens (daily versus thrice weekly) on TB incidence, occurrence of INH resistance in patients with culture-confirmed TB, mortality, incidence of adverse reactions and adherence
- To compare the long term impact of two different CTX prophylactic regimens (daily versus thrice weekly) on mortality, frequency and duration of hospitalization, type of serious infections, nasopharyngeal carriage of bacteria and development of antimicrobial resistance, adherence and incidence of adverse reactions
- To investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART
Methods A prospective randomized double blind placebo controlled study of INH versus placebo in newly recruited HIV-infected children who are stable on HAART. In addition, an extended follow-up study of children already randomised to thrice weekly or daily INH and CTX. Children will be followed for 2 years with regular clinical evaluation, adherence assessment and laboratory monitoring. Outcomes measured will be mortality, TB incidence, morbidity, adherence and tolerability.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 450 participants |
Allocation: | Randomized |
Intervention Model: | Factorial Assignment |
Masking: | Double |
Primary Purpose: | Prevention |
Official Title: | Long Term Study of 2 Isoniazid (INH) Prophylactic Regimens With Concomitant Cotrimoxazole (CTX) in HIV-infected Children - Impact on Morbidity, Mortality, Bacterial Resistance and Incidence of Tuberculosis |
Actual Study Start Date : | January 2003 |
Actual Primary Completion Date : | November 15, 2011 |
Actual Study Completion Date : | November 15, 2011 |

Arm | Intervention/treatment |
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Experimental: Isoniazid preventive therapy
HIV infected children living in a high TB prevalence area receive isonaizid prophylaxis daily, together with cotrimoxazole prohpylaxis either 3 times a week or daily.
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Drug: Isoniazid
isoniazid 10mg/kg orally, daily, for study period Drug: Cotrimoxazole Cotrimoxazole given 3 times a week or daily, orally, for study period Drug: isoniazid Isoniazid, 10mg/kg daily for study period |
Placebo Comparator: Placebo
HIV infected children living in a high TB prevalence area receive placebo once daily
|
Drug: Cotrimoxazole
Cotrimoxazole given 3 times a week or daily, orally, for study period Other: placebo Placebo tablet identicle in appearance to intervention: isoniazid table |
- TB incidence [ Time Frame: Jan 2003 to July 2011 ]
- Mortality [ Time Frame: Jan 2003 to July 2011 ]
- intercurrent infections [ Time Frame: Jan 2003 to July 2011 ]
- adherence [ Time Frame: Jan 2003 to July 2011 ]
- adverse events [ Time Frame: Jan 2003 to July 2011 ]
- antimicrobial resistance [ Time Frame: Jan 2003 to July 2011 ]

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Ages Eligible for Study: | 8 Weeks to 15 Years (Child) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- HIV-infected children
- Resident in Cape Town
- Informed consent obtainable
- weight > 2.5kg
- Access to transport
- HAART use for not less than 2 months but not more than 12 months with no significant demonstrated toxicity and good adherence
Exclusion Criteria:
- Chronic diarrhoea
- Current use of INH prophylaxis
- Prior hypersensitivity to INH prior history of allergy to sulphur drugs
- Prior history of allergy to sulphur drugs
- Severe anaemia (haemoglobin less than 7 gm/dl)
- Neutropenia (absoloute neutrophil count less than 400 cells)
- Thrombocytopenia (platelet count < 50 000/uL)
- Non-reversible renal failure
- Clinical hepatitis
- Exposure to household TB contact, requiring INH prophylaxis

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00330304
South Africa | |
Red Cross Childrens Hospital | |
Cape Town, Western Cape, South Africa, 7700 | |
Tygerberg Hospital | |
Cape Town, Western Cape, South Africa |
Principal Investigator: | Heather J Zar, MD PHd | University of Cape Town | |
Principal Investigator: | Mark Cotton, Md PhD | University of Stellenbosch |
Responsible Party: | Heather Zar, Professor, University of Cape Town |
ClinicalTrials.gov Identifier: | NCT00330304 |
Other Study ID Numbers: |
299/2005 |
First Posted: | May 26, 2006 Key Record Dates |
Last Update Posted: | April 22, 2019 |
Last Verified: | April 2019 |
Tuberculosis Child HIV prophylaxis mortality |
Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Isoniazid Trimethoprim, Sulfamethoxazole Drug Combination Antitubercular Agents Anti-Bacterial Agents |
Anti-Infective Agents Fatty Acid Synthesis Inhibitors Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Anti-Infective Agents, Urinary Renal Agents Antimalarials Antiprotozoal Agents Antiparasitic Agents |