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Cochrane Database of Systematic Reviews

Isoniazida para la prevención de la tuberculosis en niños con infección por VIH

Información

DOI:
https://doi.org/10.1002/14651858.CD006418.pub3Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 29 agosto 2017see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:

  1. Grupo Cochrane de Enfermedades infecciosas

Clasificada:
  1. Actualizada

    All studies incorporated from most recent search

    All eligible published studies found in the last search (17 Feb, 2017) were included

    Evaluada: 12 April 2019

Copyright:
  1. Copyright © 2017 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
  2. This is an open access article under the terms of the Creative Commons Attribution‐Non‐Commercial Licence, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Autores

  • Moleen Zunza

    Correspondencia a: Centre for Evidence‐based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    [email protected]

  • Diane M Gray

    Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa

  • Taryn Young

    Centre for Evidence‐based Health Care, Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa

  • Mark Cotton

    Children's Infectious Diseases Clinical Research, Tygerberg Children's Hospital, Tygerberg, South Africa

  • Heather J Zar

    Department of Paediatrics and Child Health, Red Cross Children's Hospital and MRC Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa

Contributions of authors

  • DG was the lead author for the first version of the review.

  • DG and HZ conducted the search and scrutinized identified studies for eligibility.

  • DG and TY assessed the methodological quality of included studies.

  • All authors critically reviewed the manuscript before submission (initial review).

  • MZ was the lead author of the review update.

  • MZ and TY screened the search results and assessed potential studies for eligibility.

  • MZ and a research assistant assessed the methodological quality of included studies.

  • DG, MC, and HZ critically reviewed the manuscript for content (review update). All authors approved the final version of the review.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • HIV/AIDS mentoring programme, South African Cochrane Centre, South Africa.

  • Cochrane Child Health Field Bursary, Canada.

  • Department for International Development, UK. Research Programme Grant, UK.

    Grant: 5242

Declarations of interest

MZ: MZ is supported by the Effective Health Care Research Consortium funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The views expressed in this publication do not necessarily reflect UK government policy.

DG: Author of an included study

TY: TY is supported by the Effective Health Care Research Consortium funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The views expressed in this publication do not necessarily reflect UK government policy.

MC: Author of an included study

HZ: Author of an included study

To avoid potential bias, authors who were investigators on included studies did not do data extraction and methodological quality assessment of included studies.

Acknowledgements

We thank Paul Garner, Co‐ordinating Editor of the Cochrane Infectious Diseases Group (CIDG), for his guidance. We thank Olatunji Adetokunboh (OA) who assisted with data extraction and assessment of risk of bias.

Moleen Zunza and Taryn Young are partly supported by the Effective Health Care Research Consortium. This Consortium and the CIDG editorial base are funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The views expressed in this publication do not necessarily reflect UK government policy.

Version history

Published

Title

Stage

Authors

Version

2017 Aug 29

Isoniazid for preventing tuberculosis in HIV‐infected children

Review

Moleen Zunza, Diane M Gray, Taryn Young, Mark Cotton, Heather J Zar

https://doi.org/10.1002/14651858.CD006418.pub3

2009 Jan 21

Impact of tuberculosis preventive therapy on tuberculosis and mortality in HIV‐infected children

Review

Diane M Gray, Taryn Young, Mark Cotton, Heather Zar

https://doi.org/10.1002/14651858.CD006418.pub2

2007 Jan 24

The impact of tuberculosis preventive therapy on tuberculosis and mortality in HIV‐infected children

Protocol

Di Gray, Heather Zar, Mark Cotton

https://doi.org/10.1002/14651858.CD006418

Differences between protocol and review

This is an update of the 2009 version Gray 2009b of this review. Gray 2009b included one completed and two ongoing RCTs. The latter two RCTs are complete and now included in the update. An updated search identified no other studies. The methods now include the latest Cochrane risk of bias assessment tool, GRADE and Summary of findings tables. Findings are stratified into HIV positive children on ART and not on ART. Moleen Zunza joined the author team.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Child; Humans;

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Figuras y tablas -
Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
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Figure 3

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

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Forest plot of comparison: 1 Isoniazid prophylaxis versus placebo, outcome: 1.1 Active TB, HIV‐positive children on ART.
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Isoniazid prophylaxis versus placebo, outcome: 1.1 Active TB, HIV‐positive children on ART.

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Forest plot of comparison: 1 Isoniazid prophylaxis versus placebo, outcome: 1.2 Death, HIV‐positive children on ART.
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Figure 5

Forest plot of comparison: 1 Isoniazid prophylaxis versus placebo, outcome: 1.2 Death, HIV‐positive children on ART.

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Comparison 1 Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART), Outcome 1 Active TB.
Figuras y tablas -
Analysis 1.1

Comparison 1 Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART), Outcome 1 Active TB.

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Comparison 1 Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART), Outcome 2 Death.
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Analysis 1.2

Comparison 1 Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART), Outcome 2 Death.

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Summary of findings for the main comparison. Isoniazid prophylaxis compared to placebo for HIV‐positive children not on antiretroviral therapy (ART)

Isoniazid prophylaxis compared to placebo for HIV‐positive children not on antiretroviral therapy (ART)

Patient or population: HIV‐positive children not taking ART
Settings: any setting
Intervention: isoniazid prophylaxis daily or three times weekly
Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Certainty of the evidence
(GRADE)

Comment

Assumed risk

Corresponding risk

Placebo

Isoniazid prophylaxis

Active TB

10 per 100

3 per 100

(1 to 9)

HR 0.31

(95% CI 0.11 to 0.87)

240

(1 trial)

⊕⊕⊝⊝
low1,2,3,4,5

due to serious indirectness and imprecision

Isoniazid prophylaxis may reduce active TB

Death

17 per 100

8 per 100

(8 per 17)

HR 0.46

(95% CI 0.22 to 0.95)

240

(1 trial)

⊕⊕⊝⊝
low1,2,3,4,5

due to serious indirectness and imprecision

Isoniazid prophylaxis may reduce death

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; RR: risk ratio; HR: hazard ratio.

GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

1No serious risk of bias: this trial was at low risk of selection bias, and adequately blinded study participants and personnel. However, the study was stopped early on the recommendation of the data safety monitoring board after only 277 of the planned 432 were enrolled. Not downgraded.
2No serious inconsistency: a single trial.
3Downgraded by 1 for serious indirectness: this single trial is from a single setting in South Africa. Broad generalization of this result to other settings is difficult given the variation in isoniazid resistance worldwide.
4Downgraded by 1 for serious imprecision: there were very few events in this trial and as such the finding is fragile. The original paper reports the result using a hazard ratio and the result reached standard levels of statistical significance.
5We reported the study authors' data.

Figuras y tablas -
Summary of findings for the main comparison. Isoniazid prophylaxis compared to placebo for HIV‐positive children not on antiretroviral therapy (ART)
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Summary of findings 2. Isoniazid prophylaxis compared to placebo for HIV‐positive children on antiretroviral therapy (ART)

Isoniazid prophylaxis compared to placebo for HIV‐positive children on antiretroviral therapy (ART)

Patient or population: HIV‐positive children on ART
Settings: any setting
Intervention: isoniazid prophylaxis daily or three times weekly
Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Isoniazid prophylaxis

Active TB

13 per 100

9 per 100
(7 to 15)

RR 0.76
(0.50 to 1.14)

737
(3 trials)

⊕⊝⊝⊝
very low1,2,3,4

due to serious indirectness and imprecision

We don't know if Isoniazid prophylaxis reduce active TB

Death

4 per 100

6 per 100
(3 to 11)

RR 1.45

(0.78 to 2.72)

737
(3 trials)

⊕⊝⊝⊝
very low1,2,3,5

due to serious indirectness and imprecision

We don't know if Isoniazid prophylaxis reduce death

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

1No serious risk of bias: trials were at low risk of selection bias. Both studies adequately blinded study participants and personnel.
2No serious inconsistency: statistical heterogeneity was low.
3Downgraded by 1 for serious indirectness: all trials were conducted in South Africa. Given the variation in isoniazid resistance globally it is difficult to generalize this result to all settings.
4Downgraded by 2 for serious imprecision: to confidently detect a 25% relative reduction in active TB would require a sample size of nearly 3000 participants. This meta‐analysis is therefore underpowered, and the 95% CI includes both appreciable benefit and no effect.
5Downgraded by 2 for serious imprecision: there were few events and the 95% CI includes both appreciable harm and no effect.

Figuras y tablas -
Summary of findings 2. Isoniazid prophylaxis compared to placebo for HIV‐positive children on antiretroviral therapy (ART)
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Table 1. Number of children with adverse events and number of adverse events (of grade 3 or higher) in HIV‐positive children on antiretroviral therapy (ART) and not on ART, by study

Number of children with adverse events

Number of adverse events

Zar 2007

Madhi 2011

Gray 2014

Children not on ART

Children on ART

Children on ART

Children on ART

Isoniazid prophylaxis group

N = 91

Placebo group

N = 91

Isoniazid prophylaxis group

N = 41

Placebo group

N = 40

Isoniazid prophylaxis group

N = 273

Placebo group

N = 274

Isoniazid prophylaxis group

N= 85

Placebo group

N = 82

Clinical adverse events

Peripheral neuropathy

Not reported

Not reported

Not reported

Not reported

3

2

Not reported

Not reported

Other clinical adverse events

Not reported

Not reported

Not reported

Not reported

14

23

1

1

Laboratory adverse events

Haematological (neutropenia, thrombocytopenia, anaemia)

5

6

0

0

10

9

Not reported

Not reported

Liver enzyme abnormalities

0

2

0

0

12

12

3

1

Other laboratory adverse events

Not reported

Not reported

0

0

Not reported

Not reported

Not reported

Not reported

Abbreviations: ART: antiretroviral therapy; N: number of participants.
Figuras y tablas -
Table 1. Number of children with adverse events and number of adverse events (of grade 3 or higher) in HIV‐positive children on antiretroviral therapy (ART) and not on ART, by study
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Table 2. Optimal information size calculations

Outcome

Assumed risk

Source

Clinically important relative reduction

Sample size required1,2

Active TB

46/366 (13%)

Analysis 1.1

25%

2990

Death

15/366 (4%)

Analysis 1.2

50%

2282

1We based all calculations on: 2‐sided tests, with a ratio of 1:1, power of 0.8, and confidence level of 0.05.
2We performed all calculations using: sealedenvelope.com/power/binary‐superiority

Figuras y tablas -
Table 2. Optimal information size calculations
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Comparison 1. Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Active TB Show forest plot

3

737

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.50, 1.14]

2 Death Show forest plot

3

737

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.78, 2.72]
Figuras y tablas -
Comparison 1. Isoniazid prophylaxis versus placebo for HIV‐positive children on antiretroviral therapy (ART)
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