Impact of Malnutrition on Pharmacokinetic of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in TB-HIV Co-infected Children (TB-Speed TB-PK)

Institut National de la Santé Et de la Recherche Médicale, France85 enrolled

Overview

TB-Speed TB-PK is a cross-sectional PK study of anti-TB treatment nested in the TB-Speed HIV and TB-Speed SAM studies aiming at assessing the impact of malnutrition on PK of rifampicin, isoniazid, pyrazinamide, and ethambutol in TB-HIV co-infected children in Uganda and Zambia.

Tuberculosis can worsen malnutrition and in turn malnutrition increases the risk of TB. HIV infection is prevalent in children with TB and SAM and is often associated with poor outcomes when present. TB alone is the leading cause of death of among HIV-infected children worldwide accounting for a third of all the death in this group. In 2010, the WHO recommended increased dose for rifampicin (+50%), isoniazid (+100%), and pyrazinamide (+33%) based on PK data showing that plasma drug concentrations in children using standard adult dosages did not reach target levels. In children that are TB/HIV co-infected, drug-drug interactions between anti-TB drugs and antiretroviral drugs are of concern. The investigators hypothesize that HIV-infection and SAM, each one on its own, may have an impact on TB drugs concentrations. Furthermore, SAM is frequent in children with HIV, and may affect the metabolism of anti-TB drugs and consequently result in low serum concentration. TB-Speed TB-PK is a cross-sectional PK study of anti-TB treatment nested in the TB-Speed HIV and TB-Speed SAM studies aiming at assessing the impact of malnutrition on PK of rifampicin, isoniazid, pyrazinamide, and ethambutol in TB-HIV co-infected children. It will be implemented in Uganda and Zambia. Children will also be enrolled from routine care for TB outside of the TB- Speed HIV and TB-Speed SAM studies.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Tuberculosis Pulmonary

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 5 Years

Medical Language ↔ Plain English

INCLUSION CRITERIA: * Gr1. HIV-infected children with SAM * Age 6 months to 5 years * Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion * HIV-infection * SAM as defined by WHO at the time of starting TB treatment * Weight-for-height z-score (WHZ) \< -3 SD, * OR MUAC \<11.5 cm or * OR presence of bilateral pitting oedema of nutritional origin * Ability to take drugs orally during the planned PK day * Signed informed consent from parents or guardian * Gr2. HIV-infected children without SAM * Age 6 months to 5 years * Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion * HIV-infection * Absence of SAM as defined by WHO at the time of starting TB treatment * Weight-for-height z-score (WHZ) \> -3 SD, * AND MUAC \>11.5 cm or * AND absence of bilateral pitting oedema of nutritional origin * Ability to take drugs orally during the planned PK day * Signed informed consent from parents or guardian * Gr3. HIV-negative children with SAM * Age 6 months to 5 years * Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion * HIV-negative * SAM as defined by WHO at the time of starting TB treatment * Weight-for-height z-score (WHZ) \< -3 SD, * OR MUAC \<11.5 cm or * OR presence of bilateral pitting oedema of nutritional origin * Ability to take drugs orally during the planned PK day * Signed informed consent from parents or guardian * Gr4. HIV-negative children without SAM * Age 6 months to 5 years * Diagnosed with TB and first line TB treatment to be initiated or started less than 4 weeks prior to inclusion * HIV-negative * Absence of SAM as defined by WHO at the time of starting TB treatment * Weight-for-height z-score (WHZ) \> -3 SD, * AND MUAC \>11.5 cm or * AND absence of bilateral pitting oedema of nutritional origin * Ability to take drugs orally during the planned PK day * Signed informed consent from parents or guardian NON INCLUSION CRITERIA: * Very ill or moribund children unable to take drugs orally or requiring nasogastric drug intake * Severe anaemia (Hb \< 6 g/dl), * Severe renal impairment (DAIDS grade 3 and above) * Severe hepatic impairment (DAIDS grade 3 and above) * Children on second line TB drugs

Locations (4)

Mulago National Referral Hospital

Kampala, Uganda

Mbarara Regional Hospital

Mbarara, Uganda

The University Teaching Hospital

Lusaka, Zambia

Arthur Davison Children Hospital

Ndola, Zambia

Outcomes

Primary Outcomes

Effect of SAM on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB

Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol peak concentration (Cmax)

Time frame: 6 months

Effect of SAM on minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB

Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol minimum concentration (Cmin or C trough)

Time frame: 6 months

Effect of SAM on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB

Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol exposure (Area Under the Curve - AUC)

Time frame: 6 months

Secondary Outcomes

Effect of HIV-infection and antiretroviral treatment on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM

Cmax of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection

Time frame: 6 months

Effect of HIV-infection and antiretroviral treatment on Minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM

Cmin of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection

Time frame: 6 months

Effect of HIV-infection and antiretroviral treatment on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM

AUC of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection

Data from ClinicalTrials.gov

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