Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Isoniazid; Drug: Cotrimoxazole; Other: placebo; Drug: isoniazid

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.

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa
      • Tygerberg Hospital
    • Cape Town, Western Cape, South Africa, 7700
      • Red Cross Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Isoniazid; isoniazid 10mg/kg orally, daily, for study period; Drug: Cotrimoxazole; Cotrimoxazole given 3 times a week or daily, orally, 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Cape Town
• Collaborators: Medical Research Council; University of Stellenbosch; Rockefeller Foundation
• Investigators: Principal Investigator: Heather J Zar, MD PHd, University of Cape Town; Principal Investigator: Mark Cotton, Md PhD, University of Stellenbosch

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Int J Tuberc Lung Dis. 2014 Jun;18(6):754.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2003
• Primary Completion (Actual): November 15, 2011
• Study Completion (Actual): November 15, 2011

Study Registration Dates

• First Submitted: May 24, 2006
• First Submitted That Met QC Criteria: May 24, 2006
• First Posted (Estimate): May 26, 2006

Study Record Updates

• Last Update Posted (Actual): April 22, 2019
• Last Update Submitted That Met QC Criteria: April 18, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Child; HIV; prophylaxis; Tuberculosis; mortality
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Antimalarials; Anti-Infective Agents, Urinary; Renal Agents; Fatty Acid Synthesis Inhibitors; Trimethoprim, Sulfamethoxazole Drug Combination; Isoniazid
• Other Study ID Numbers: 299/2005