Clinical trial NCT00330304: Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
Keywords: Tuberculosis
Child
HIV
prophylaxis
mortality
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: University of Stellenbosch
name: Medical Research Council
name: Rockefeller Foundation
First posted: 2006-05-26
Enrollment: 450
Sex: ALL
Minimum age (years): 8
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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: 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

1. 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
2. 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
3. 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.

Eligibility criteria: 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

Primary outcomes:
measure: TB incidence
timeFrame: Jan 2003 to July 2011
measure: Mortality
timeFrame: Jan 2003 to July 2011
Secondary outcomes:
measure: intercurrent infections
timeFrame: Jan 2003 to July 2011
measure: adherence
timeFrame: Jan 2003 to July 2011
measure: adverse events
timeFrame: Jan 2003 to July 2011
measure: antimicrobial resistance
timeFrame: Jan 2003 to July 2011
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Red Cross Childrens Hospital
state: Western Cape
city: Cape Town
country: South Africa
facility: Tygerberg Hospital
state: Western Cape
Study officials:
affiliation: University of Cape Town
name: Heather J Zar, MD PHd
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Stellenbosch
name: Mark Cotton, Md PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amlabu V, Mulligan C, Jele N, Evans A, Gray D, Zar HJ, McIlleron H, Smith P. Isoniazid/acetylisoniazid urine concentrations: markers of adherence to isoniazid preventive therapy in children. Int J Tuberc Lung Dis. 2014 May;18(5):528-30. doi: 10.5588/ijtld.13.0730.
citation: Gray DM, Workman LJ, Lombard CJ, Jennings T, Innes S, Grobbelaar CJ, Cotton MF, Zar HJ. Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study. Int J Tuberc Lung Dis. 2014 Mar;18(3):322-7. doi: 10.5588/ijtld.13.0354.
citation: Frigati LJ, Kranzer K, Cotton MF, Schaaf HS, Lombard CJ, Zar HJ. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax. 2011 Jun;66(6):496-501. doi: 10.1136/thx.2010.156752. Epub 2011 Apr 2.
citation: le Roux SM, Cotton MF, Golub JE, le Roux DM, Workman L, Zar HJ. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Med. 2009 Nov 3;7:67. doi: 10.1186/1741-7015-7-67.
citation: Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.