Clinical trial NCT04972903: Impact of Malnutrition on Pharmacokinetic of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in TB-HIV Co-infected Children (TB-Speed TB-PK)
Official title: Impact of Malnutrition on Pharmacokinetic of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in TB-HIV Co-infected Children
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis
Pulmonary
Keywords: HIV
Childhood tuberculosis
Severe acute malnutrition
Pharmacokinetics
Pharmacodynamics
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: National Agency for Research on AIDS and Viral Hepatitis (ANRS)
First posted: 2021-07-22
Enrollment: 85
Sex: ALL
Minimum age (years): 6
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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-)

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect of SAM on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB
timeFrame: 6 months
measure: Effect of SAM on minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB
timeFrame: 6 months
measure: Effect of SAM on Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB
timeFrame: 6 months
Secondary outcomes:
measure: Effect of HIV-infection and antiretroviral treatment on Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM
timeFrame: 6 months
measure: Effect of HIV-infection and antiretroviral treatment on Minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol in children with TB and SAM
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Relationship between all-cause mortality in children with TB and SAM, and Peak plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.
timeFrame: 6 months
measure: Relationship between all-cause mortality in children with TB and SAM, and the minimum plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.
timeFrame: 6 months
measure: Relationship between all-cause mortality in children with TB and SAM, and Area Under the Curve plasma concentration of rifampicin, isoniazid, pyrazinamide, and ethambutol.
timeFrame: 6 months
measure: Rifampicin protein binding in relation with malnutrition and albuminemia
timeFrame: 6 months
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Mulago National Referral Hospital
city: Mbarara
country: Uganda
facility: Mbarara Regional Hospital
city: Lusaka
country: Zambia
facility: The University Teaching Hospital
city: Ndola
country: Zambia
facility: Arthur Davison Children Hospital
Study officials:
References: