Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children

Study Overview
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Brief Summary
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The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce mortality and infections in HIV-infected children and is currently the recommended standard of care. However, isoniazid has only been studied in HIV-infected adults (in whom it has been shown to substantially reduce the incidence of tuberculosis). In a randomised controlled study of isoniazid in HIV-infected children, the investigators found that INH reduced mortality and tuberculosis incidence in excess of 50%; the data safety monitoring board recommended termination of the placebo arm given the beneficial effects of INH. The investigators therefore aim to follow-up these children to compare the long term impact of two different INH and CTX preventive regimens (daily versus thrice weekly) on morbidity, mortality, adherence and incidence of adverse reactions. The investigators also aim to investigate the efficacy, safety and tolerability of INH compared with placebo for prevention of TB in children receiving HAART as the benefit in this group is unknown.

Detailed Description
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Isoniazid
* Drug: Cotrimoxazole
* Drug: isoniazid
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 8 Weeks
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isoniazid preventive therapy<br>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. | Drug: Isoniazid<br>* isoniazid 10mg/kg orally, daily, for study period<br>Drug: Cotrimoxazole<br>* Cotrimoxazole given 3 times a week or daily, orally, for study period<br>Drug: isoniazid<br>* Isoniazid, 10mg/kg daily for study period<br>|
| Placebo Comparator: Placebo<br>HIV infected children living in a high TB prevalence area receive placebo once daily | Drug: Cotrimoxazole<br>* Cotrimoxazole given 3 times a week or daily, orally, for study period<br>Other: placebo<br>* Placebo tablet identicle in appearance to intervention: isoniazid table<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TB incidence |  | Jan 2003 to July 2011 | 
| Mortality |  | Jan 2003 to July 2011 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| intercurrent infections |  | Jan 2003 to July 2011 | 
| adherence |  | Jan 2003 to July 2011 | 
| adverse events |  | Jan 2003 to July 2011 | 
| antimicrobial resistance |  | Jan 2003 to July 2011 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, Child, HIV, prophylaxis, mortality