Isoniazid for preventing tuberculosis in HIV‐infected children

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

doi:10.1002/14651858.CD006418.pub3

Scolaris Content Display Scolaris Content Display

Contenido relacionado

Ir a:

Revisiones y protocolos relacionados
Respuestas clínicas Cochrane
Guías
Temas

Revisiones y protocolos relacionados

Respuestas clínicas Cochrane

Topics

Temas

Figure 1

Study flow diagram.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 2

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 3

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 4

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 5

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.1

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

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)	⊕⊕⊝⊝ low^1,2,3,4,5 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)	⊕⊕⊝⊝ low^1,2,3,4,5 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.

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

Ir a la tabla de la revisión

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 low^1,2,3,4 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 low^1,2,3,5 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.

Summary of findings 2. Isoniazid prophylaxis compared to placebo for HIV‐positive children on antiretroviral therapy (ART)

Ir a la tabla de la revisión

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.

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

Ir a la tabla de la revisión

Table 2. Optimal information size calculations

Outcome	Assumed risk	Source	Clinically important relative reduction	Sample size required^1,2
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

Table 2. Optimal information size calculations

Ir a la tabla de la revisión

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]

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

Ir a la tabla de la revisión

The Cochrane Library

Scolaris Language Selector Scolaris Language Selector

Idioma de la Revisión Cochrane

Idioma de la web

Scolaris Content Language Banner Portlet Scolaris Content Language Banner Portlet