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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Tuberculosis, Pulmonary

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1.HIV+/SAM+<br>Group 1. HIV-infected with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV+/SAM+) | |
| Group 2. HIV+/SAM-<br>Group 2. HIV-infected without SAM (none of the 3 criteria above) (HIV+/SAM-) | |
| Group 3. HIV-/SAM+<br>Group 3. HIV-negative with SAM (WHZ<-3SD or edematous malnutrition or MUAC <115) (HIV-/SAM+) | |
| Group 4. HIV-/SAM-<br>Group 4. HIV-negative without SAM (none of the 3 criteria above) (HIV-/SAM-) | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Childhood tuberculosis, Severe acute malnutrition, HIV, Pharmacokinetics, Pharmacodynamics