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

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Pulmonary

Detailed Description

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 (Actual): 85

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Mulago National Referral Hospital
  • Mbarara, Uganda
    • Mbarara Regional Hospital
• Zambia
  • Lusaka, Zambia
    • The University Teaching Hospital
  • Ndola, Zambia
    • Arthur Davison Children Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 5 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Intensive PK of rifampicin, isoniazid, pyrazinamide, and ethambutol will be performed between 2 to 4 weeks of TB treatment in the following 4 groups of children receiving first-line anti-TB treatment:

• Group (Gr) 1. HIV-infected with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV+/SAM+)
• Gr2. HIV-infected without SAM (none of the 3 criteria above) (HIV+/SAM-)
• Gr3. HIV-negative with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV-/SAM+)
• Gr4. HIV-negative without SAM (none of the 3 criteria above) (HIV-/SAM-)

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Group 1.HIV+/SAM+; Group 1. HIV-infected with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV+/SAM+)
Group 2. HIV+/SAM-; Group 2. HIV-infected without SAM (none of the 3 criteria above) (HIV+/SAM-)
Group 3. HIV-/SAM+; Group 3. HIV-negative with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV-/SAM+)
Group 4. HIV-/SAM-; Group 4. HIV-negative without SAM (none of the 3 criteria above) (HIV-/SAM-)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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)	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)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	6 months
WHO-based dosages will achieve rifampicin, isoniazid, pyrazinamide, and ethambutol drug concentrations above the target therapeutic concentrations in HIV-TB co-infected children with and without SAM	Proportion of children with AUC24 and Cmax above the recommended threshold for Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol	6 months
Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on CL/F of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	CL/F(Apparent total clearance of the drug from plasma) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on V/F of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	V/F (Apparent volume of distribution after administration) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Effect of personnal parameters (nutritional parameters, HIV-infection, antiretroviral treatment, age, liver enzymes and NAT2 status) on Ka of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB	Ka (Absorption rate constant) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.	6 months
Relationship between all-cause mortality in children with TB and SAM, and Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best Cmax plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Relationship between all-cause mortality in children with TB and SAM, and the minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best Cmin plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Relationship between all-cause mortality in children with TB and SAM, and Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.	Define the best AUC plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.	6 months
Rifampicin protein binding in relation with malnutrition and albuminemia	Proportion of protein bound rifampicin in children with SAM and association with albuminemia	6 months

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: National Agency for Research on AIDS and Viral Hepatitis (ANRS)

Publications and helpful links

Helpful Links

• TB-Speed project official website

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Actual): March 22, 2022
• Study Completion (Actual): March 22, 2023

Study Registration Dates

• First Submitted: June 30, 2021
• First Submitted That Met QC Criteria: July 12, 2021
• First Posted (Actual): July 22, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 21, 2025
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; Pharmacodynamics; Severe acute malnutrition; Childhood tuberculosis
• Additional Relevant MeSH Terms: Nutrition Disorders; Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Malnutrition; Tuberculosis
• Other Study ID Numbers: C20-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No