Clinical trial NCT04121026: Validation of a Tuberculosis Treatment Decision Algorithm in HIV-infected Children (TB-Speed HIV)
Official title: Validation of a Tuberculosis Treatment Decision Algorithm in HIV-infected Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Tuberculosis
HIV
Keywords: Tuberculosis
Diagnosis
HIV
Child
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: UNITAID
First posted: 2019-10-09
Enrollment: 278
Sex: ALL
Minimum age (years): 1
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: DIAGNOSTIC

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Proportion of missed TB cases
timeFrame: 6 months
Secondary outcomes:
measure: Feasibility of the PAANTHER TB treatment decision algorithm (a): Proportion of children with presumptive TB having completed the algorithm.
timeFrame: 6 months
measure: Feasibility of the PAANTHER TB treatment decision algorithm (b): Time to final TB treatment decision
timeFrame: 6 months
measure: Proportion of HIV-infected children with unlikely TB among those initiated on treatment as per the PAANTHER TB treatment decision algorithm
timeFrame: 6 months
measure: Incidence of morbidity
timeFrame: 6 months
measure: Incidence of mortality
timeFrame: 6 months
measure: Time to ART initiation in ART-naïve children
timeFrame: 6 months
measure: CD4 (absolute count and %) gain
timeFrame: 6 months
measure: TB treatment outcomes (a): Weight gain at 6 months (absolute value and percentage of body weight)
timeFrame: 6 months
measure: TB treatment outcomes (b): TB symptoms resolution in children on TB treatment
timeFrame: 6 months
measure: Feasibility of IPT initiation (a): Time to IPT initiation
timeFrame: 6 months
measure: Feasibility of IPT initiation (b): Proportion of children initiated on IPT
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Proportion of NPAs (or sputum) and stool samples with mycobacterium tuberculosis (MTB) detected using Ultra
timeFrame: 6 months
measure: Proportion of children with NPA and stool samples collected as per study protocol
timeFrame: 6 months
measure: Proportion of NPA-related adverse events (AEs)
timeFrame: 6 months
measure: Discomfort/pain/distress experienced by the child during NPA as assessed by the child
timeFrame: Within 3 days of inclusion
measure: Discomfort/pain/distress experienced by the child during NPA as assessed by the parents
timeFrame: Within 3 days of inclusion
measure: Discomfort/pain/distress experienced by the child during NPA as assessed by the nurse
timeFrame: Within 3 days of inclusion
measure: Sensitivity
timeFrame: 6 months
measure: Positivity
timeFrame: 6 months
Other outcomes:
measure: Incremental cost-effectiveness ratio (ICER)
timeFrame: 33 months
Locations:
city: Abidjan
country: Côte D'Ivoire
facility: Cocody University Teaching Hospital
city: Abidjan
country: Côte D'Ivoire
facility: Treichville University Teaching Hospital
city: Maputo
country: Mozambique
facility: José Macamo General Hospital
city: Maputo
country: Mozambique
facility: Maputo Central Hospital
city: Mbarara
country: Uganda
facility: Mbarara Regional Hospital
city: Lusaka
country: Zambia
facility: Lusaka University Teaching Hospital
city: Ndola
country: Zambia
facility: Arthur Davidson Children Hospital
Study officials:
affiliation: University of Bordeaux, France
name: Olivier Marcy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Recherche pour le Développemnt (IRD) Montpellier, France
name: Maryline Bonnet, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: MU-JHU Care Ltd, Kampala, Uganda
name: Eric Wobudeya, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: