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Validatie van een algoritme voor de behandeling van tuberculose bij met hiv geïnfecteerde kinderen

21 september 2026 bijgewerkt door: Institut National de la Santé Et de la Recherche Médicale, France

TB-Speed HIV is a prospective multicentre management study evaluating the safety and feasibility of the recently proposed PAANTHER TB treatment decision algorithm for HIV-infected children with presumptive TB. It will be conducted in four countries with high and very high TB (Tuberculosis) incidence (Côte d'Ivoire, Uganda, Mozambique, and Zambia) which have not participated in the study that developed the PAANTHER algorithm.

Studie Overzicht

Toestand

Voltooid

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

The ANRS 12229 PAANTHER 01 (Pediatric Asian African Network for Tuberculosis and HIV Research) study, which enrolled 438 HIV-infected children of median age 7.3 (IQR: 3.3 - 9.7) years with presumptive TB in four countries (Burkina Faso, Cameroon, Cambodia, Vietnam) from 2011 to 2014, aimed at developing a diagnostic prediction score and algorithm for TB treatment decision in HIV-infected children. This was the first study developing a TB diagnostic score exclusively in HIV-infected children, using methods recommended for diagnostic prediction models. Based on microbiological, clinical and radiological features, the best scoring system obtained had a sensitivity of 88.6% and specificity of 61.2% when Xpert MTB/RIF was included in the algorithm. The investigators showed previously that mortality is high in children with both confirmed and unconfirmed TB and that initiation of anti-TB treatment, that occurred at a median time of 7 (IQR: 5 - 11) days in the study, led to delayed ART initiation, which is associated to significantly increased mortality. The score, based on easily collected clinical features, chest radiographic features, Xpert MTB/RIF results, and abdominal ultrasonography, could enable same-day TB treatment decision. Abdominal ultrasonography has shown promise for the diagnosis of TB in both HIV-infected adults and children. In the PAANTHER study, it detected abdominal lymphadenopathy in 50% of culture confirmed TB cases and 35% of all confirmed and unconfirmed cases, with a specificity of 85%.

Developed in tertiary research-experienced health facilities, the PAANTHER score could enable standardized treatment decision in HIV-infected children with presumptive TB, and could be recommended for extensive use in secondary and primary healthcare settings where most of these children are seeking care. However, external validation studies are now needed to assess the predictive performance of the PAANTHER diagnostic score on independent datasets.

The PAANTHER TB treatment decision algorithm will be used for a TB treatment decision by site clinicians in all children enrolled in the study. Validation of the algorithm will be performed by evaluating the safety of withholding TB treatment in children not initiated on treatment as per the PAANTHER TB treatment decision algorithm. The safety of this strategy will be carefully assessed through review of safety reports every 4 to 6 months during study conduct by the safety sub-committee of the SAB.

Occurrence of algorithm failures in terms of missed TB cases (TB cases subsequently detected among untreated cases, i.e. false negatives) and cases with unlikely TB among those initiated on TB treatment as per the algorithm (cases not secondarily validated as confirmed or unconfirmed TB cases by the expert committee, i.e. false positives) will enable to estimate the negative and positive predictive values of the algorithm.

A centralized international Expert Committee will clinically review and validate TB diagnosis in children. This will enable assessment of the added value of new markers (MLR and CRP) and, if need be, to propose a new version of the score based on an optimised predicted probability.

The TB-Speed HIV study will be implemented in 7 tertiary healthcare level hospitals in capital cities of Côte d'Ivoire, Uganda, Mozambique, and Zambia. A total of 550 HIV-infected children (aged < 15 years) with clinically suspected TB (presumptive TB) will be enrolled, using standard entry criteria. The inclusion period will last until all sites have reached the expected number of children enrolled.

Studietype

Ingrijpend

Inschrijving (Werkelijk)

278

Fase

  • Niet toepasbaar

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

  • Ivoorkust
      • Abidjan, Ivoorkust
        • Cocody University Teaching Hospital
      • Abidjan, Ivoorkust
        • Treichville University Teaching Hospital
  • Mozambique
      • Maputo, Mozambique
        • José Macamo General Hospital
      • Maputo, Mozambique
        • Maputo Central Hospital
  • Oeganda
      • Mbarara, Oeganda
        • Mbarara Regional Hospital
  • Zambia
      • Lusaka, Zambia
        • Lusaka University Teaching Hospital
      • Ndola, Zambia
        • Arthur Davidson Children Hospital

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

1 maand tot 14 jaar (Kind)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

Inclusion Criteria:

  1. Children aged 1 month to 14 years

  2. Documented HIV-infection (i.e., confirmed before entry into the study)

  3. Presumptive TB based on at least one criteria among the following:

    1. Persistent cough for more than 2 weeks
    2. Persistent fever for more than 2 weeks
    3. Recent failure to thrive (documented clear deviation from a previous growth trajectory in the last 3 months or Z score weight/age < 2)
    4. Failure of broad spectrum antibiotics for treatment of pneumonia
    5. Suggestive CXR features

    OR

    History of contact with a TB case and any of the symptoms listed under point 3 with a shorter duration (< 2 weeks)

  4. Informed consent signed by parent/guardian

Exclusion Criteria:

Ongoing TB treatment or history of intake of anti-TB drugs in the last 3 months (isoniazid alone or rifampin/isoniazid for preventive therapy is not an exclusion criteria)

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Diagnostisch
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: HIV-infected children with presumptive TB

Recruitment will be performed at entry in HIV outpatient/inpatient centres of participating hospitals, as well as during the follow up of HIV-infected children on ART. Children will be first pre-screened for TB by attending clinicians and nurses in the context of routine care based on WHO criteria, i.e. with any one of the following symptoms: poor weight gain, fever, current cough and contact with a TB case. If not routinely performed, this pre-screening step will be reinforced and a screening logbook will be set up (if not already in place) to collect aggregated data on the eligibility criteria assessment process. Children pre-screened positive for TB will be further subjected to the study selection criteria by the study nurses.
Ander: External validation of the PAANTHER TB treatment decision algorithm

The PAANTHER algorithm will be used for a TB treatment decision by site clinicians in all children enrolled in the study. The PAANTHER algorithm and prediction score was designed as a guiding tool for empirical TB treatment decision in HIV-infected children with presumptive TB. The proposed score includes:

  • history of contact
  • suggestive TB symptoms
  • tachycardia
  • chest radiography
  • abdominal ultrasound
  • Xpert MTB/RIF Ultra.

A score of >100 is highly predictive of TB. In children with a score >100, anti-TB treatment will be initiated immediately. In children with a score of <100, TB treatment will not be initiated except in those with severe/life-threatening conditions for whom TB treatment decision could be made at the discretion of the site clinician. TB could be definitely ruled out after further assessment and decision made as to what treatment the children should receive in accordance with existing national protocols, along with clinical follow-up.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Proportion of missed TB cases
Tijdsspanne: 6 months

Proportion of missed TB cases (false negative cases) in children not initiated on treatment as per the PAANTHER TB treatment decision algorithm
6 months

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Haalbaarheid van het PAANTHER tbc-behandelingsbeslissingsalgoritme (b): Tijd tot definitieve tbc-behandelingsbeslissing
Tijdsspanne: 6 maanden
6 maanden
Incidentie van sterfte
Tijdsspanne: 6 maanden
6 maanden
Tijd tot ART-initiatie bij ART-naïeve kinderen
Tijdsspanne: 6 maanden
6 maanden
Uitkomsten tbc-behandeling (b): tbc-symptomen verdwijnen bij kinderen die tbc-behandeling ondergaan
Tijdsspanne: 6 maanden
6 maanden
Feasibility of the PAANTHER TB treatment decision algorithm (a): Proportion of children with presumptive TB having completed the algorithm.
Tijdsspanne: 6 months

The algorithm will be considered completed if a decision to initiate TB treatment has been taken at any step of the algorithm or if TB has been excluded after systematic evaluation, and all steps planned in the algorithm have been implemented.
6 months
Proportion of HIV-infected children with unlikely TB among those initiated on treatment as per the PAANTHER TB treatment decision algorithm
Tijdsspanne: 6 months

Proportion of cases considered as unlikely TB by the Expert Committee in those initiated on treatment as per the PAANTHER TB treatment decision algorithm (false positive)
6 months
Incidence of morbidity
Tijdsspanne: 6 months

Incidence of morbidity defined as drug-induced toxicity (ART and TB treatment-related), opportunistic infections, and IRIS, with or without TB treatment
6 months
CD4 (absolute count and %) gain
Tijdsspanne: 6 months

Immunologic evolution at 6 months after enrolment defined as CD4 cells gain (absolute count and %)
6 months
TB treatment outcomes (a): Weight gain at 6 months (absolute value and percentage of body weight)
Tijdsspanne: 6 months

TB treatment outcome in HIV-infected children initiated on treatment as per the PAANTHER TB treatment decision algorithm defined by weight gain at 6 months (absolute value and percentage of body weight)
6 months
Feasibility of IPT initiation (a): Time to IPT initiation
Tijdsspanne: 6 months

Time to Isoniazid Preventive Therapy (IPT) initiation in HIV-infected children not initiated on treatment as per the PAANTHER TB treatment decision algorithm (a)
6 months
Feasibility of IPT initiation (b): Proportion of children initiated on IPT
Tijdsspanne: 6 months

Proportion of children initiated on IPT in HIV-infected children not initiated on treatment as per the PAANTHER TB treatment decision algorithm (b)
6 months
Performance of the Monocyte-to-Lymphocyte Ratio and the C-reactive protein and their potential added value in the PAANTHER score and algorithm to detect TB
Tijdsspanne: 6 months

Discrimination (area under the receiver-operating-characteristic curves [AUROC]) and calibration measures of the PAANTHER prediction model including or not MLR and CRP, against the TB composite reference standard as defined by the Expert Committee
6 months
Proportion of NPAs (or sputum) and stool samples with mycobacterium tuberculosis (MTB) detected using Ultra
Tijdsspanne: 6 months

Diagnostic performance of Ultra performed on one NPA and one stool sample against mycobacterial culture performed on standard samples in HIV-infected children
6 months
Proportion of children with NPA and stool samples collected as per study protocol
Tijdsspanne: 6 months

Feasibility of NPA and stool samples collection in HIV-infected children defined as the proportion of children with NPA and stool samples collected as per study protocol
6 months
Proportion of NPA-related adverse events (AEs)
Tijdsspanne: 6 months

Safety of NPA collection defined as proportion of AEs (vomiting, nose bleeding, low oxygen saturation, respiratory distress) occurring during NPA
6 months
Discomfort/pain/distress experienced by the child during NPA as assessed by the child
Tijdsspanne: Within 3 days of inclusion

Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the child using the Wong-Baker face scale (in a subset of children).

Scale range: 0 (no hurt) - 5 (hurts worst)
Within 3 days of inclusion
Discomfort/pain/distress experienced by the child during NPA as assessed by the parents
Tijdsspanne: Within 3 days of inclusion

Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the parents using the visual analog scale (in a subset of children).

Scale range: 0 (no pain) - 10 (pain as bad as it could possibly be)
Within 3 days of inclusion
Discomfort/pain/distress experienced by the child during NPA as assessed by the nurse
Tijdsspanne: Within 3 days of inclusion

Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the nurses using the "Face Legs Activity Cry Consolability" behavioral pain scale (in a subset of children).

Total score range: 0 (relaxed and comfortable) - 10 (severe discomfort/pain). Each item of the FLACC scale - Face, Legs, Activity, Cry, Consolability - has 3 possible quotes: 0 or 1 or 2, with a precise description provided to help with the rating. The total score is obtained by adding individual item scores.
Within 3 days of inclusion
Sensitivity
Tijdsspanne: 6 months

false negative rate, i.e. negative predictive value, and corresponding sensitivity of the PAANTHER algorithm in the different subgroups in terms of age, CD4 counts, nutritional statuses, and timings of ART initiation (on/off ART)
6 months
Positivity
Tijdsspanne: 6 months

false positiverate, i.e. Positive predictive value, and corresponding positivity of the PAANTHER algorithm in the different subgroups in terms of age, CD4 counts, nutritional statuses, and timings of ART initiation (on/off ART)
6 months

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Incremental cost-effectiveness ratio (ICER)
Tijdsspanne: 33 months

Incremental cost-effectiveness ratio (ICER)
33 months

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Medewerkers

UNITAID

Onderzoekers

  • Hoofdonderzoeker: Olivier Marcy, MD, PhD, University of Bordeaux, France
  • Hoofdonderzoeker: Eric Wobudeya, MD, PhD, MU-JHU Care Ltd, Kampala, Uganda
  • Hoofdonderzoeker: Maryline Bonnet, MD, PhD, Institut de Recherche pour le Développemnt (IRD) Montpellier, France

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Nuttige links

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

2 oktober 2019

Primaire voltooiing (Werkelijk)

20 juni 2022

Studie voltooiing (Werkelijk)

20 juni 2022

Studieregistratiedata

Eerst ingediend

1 oktober 2019

Eerst ingediend dat voldeed aan de QC-criteria

7 oktober 2019

Eerst geplaatst (Werkelijk)

9 oktober 2019

Updates van studierecords

Laatste update geplaatst (Werkelijk)

24 september 2026

Laatste update ingediend die voldeed aan QC-criteria

21 september 2026

Laatst geverifieerd

1 februari 2025

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • C18-27

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Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

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