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

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04972903

Collaborator

National Agency for Research on AIDS and Viral Hepatitis (ANRS) (Other)

Enrollment

Locations

Anticipated Duration (Months)

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
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 Design

Study Type:

Observational

Anticipated Enrollment :

80 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Anticipated Study Start Date :

Aug 1, 2021

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
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-)

Outcome Measures

Primary Outcome Measures

Effect of SAM on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB [6 months]
Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol peak concentration (Cmax)
Effect of SAM on minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB [6 months]
Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol minimum concentration (Cmin or C trough)
Effect of SAM on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB [6 months]
Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol exposure (Area Under the Curve - AUC)

Secondary Outcome Measures

Effect of HIV-infection and antiretroviral treatment on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM [6 months]
Cmax of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection
Effect of HIV-infection and antiretroviral treatment on Minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM [6 months]
Cmin of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection
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 [6 months]
AUC of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol in children with HIV infection on or off ART and children without HIV infection
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 [6 months]
Proportion of children with AUC24 and Cmax above the recommended threshold for Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol
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 [6 months]
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.
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 [6 months]
V/F (Apparent volume of distribution after administration) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.
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 [6 months]
Ka (Absorption rate constant) after oral administration of rifampicin, isoniazid, pyrazinamide, and ethambutol in HIV-infected children with TB.
Relationship between all-cause mortality in children with TB and SAM, and Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol. [6 months]
Define the best Cmax plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.
Relationship between all-cause mortality in children with TB and SAM, and the minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol. [6 months]
Define the best Cmin plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.
Relationship between all-cause mortality in children with TB and SAM, and Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol. [6 months]
Define the best AUC plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment sucess.
Rifampicin protein binding in relation with malnutrition and albuminemia [6 months]
Proportion of protein bound rifampicin in children with SAM and association with albuminemia

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 5 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Contacts and Locations

Locations

	Site	City	Country
1	Mulago National Referral Hospital	Kampala	Uganda
2	Mbarara Regional Hospital	Mbarara	Uganda
3	The University Teaching Hospital	Lusaka	Zambia
4	Arthur Davison Children Hospital	Ndola	Zambia