Isoniazid for preventing tuberculosis in HIV-infected children: Cochrane systematic review

Abstract

Background

Tuberculosis (TB) is an important cause of illness and death in HIV-positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV-negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV-positive children.

Objectives

To summarise the effects of TB preventive treatment versus placebo in HIV-positive children with no known TB contact on active TB, death, and reported adverse events.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017.

Selection criteria

We included trials of HIV-positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo.

Data collection and analysis

Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE.

Main results

We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow-up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART).

In HIV-positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported.

In HIV-positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups.

Authors' conclusions

Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV-positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected. .

Author(s)

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

Summary

Isoniazid prophylaxis for preventing active tuberculosis and death in HIV-positive children

What was the aim of this review?

To summarise the effects of isoniazid prophylaxis on TB, death, and adverse effects in HIV-positive children.

Key messages

In areas of high tuberculosis endemicity, isoniazid prophylaxis prevents active TB and death in HIV-positive children who are not on ART.

We conducted a review to assess the effect of TB medication on active TB or death and its safety in HIV-positive children.

What was studied in the review?

TB is a common cause of severe lung disease and death in HIV-positive children. Childhood TB is common in poor countries, especially those with a coexisting burden of HIV/AIDS disease. HIV-positive children have a higher risk of developing TB than HIV-negative children. Isoniazid prevents TB in HIV-positive adults and is currently used in children who are at high risk of developing TB disease after exposure to someone with TB. However, there is limited information on the effect of isoniazid medication in reducing active TB or death if given to HIV-positive children without known TB contact.

We searched for studies up to 17 February 2017, and found three studies published between 2007 and 2014 that addressed the effect of isoniazid medication compared to no medication on active TB and death in 991 HIV-positive children, below the age of 13 years. Most of the children were on antiretroviral therapy (ART) and the studies were conducted in South Africa and Botswana. The median length of follow-up ranged from 5.7 to 34 months.

What are the main results of the review?

In HIV-positive children not taking ART, isoniazid medication reduced the number of children developing active TB by 69% (low certainty evidence), and death by 54% (low certainty evidence).

One trial was conducted in HIV-positive children taking ART, and this did not detect any benefit or harm of isoniazid (very low certainty evidence).

The number of children with adverse effects were similar in children receiving isoniazid medication as the control group in both children on ART and not on ART.

How up to date is the review?

The review authors searched for studies published up to February 2017.

Reviewer's Conclusions

Implications for practice

Isoniazid prophylaxis may reduce active tuberculosis (TB) disease and death in HIV-positive children not on antiretroviral therapy (ART). The WHO 2013 guidelines recommend ART for all HIV-positive children, which has to be started soon after diagnosis (WHO 2013). However, many children have delayed access to ART and coverage is not universal in most sub-Saharan settings, suggesting that any child awaiting ART in a high TB prevalence area, should have isoniazid prophylaxis until the child is virally suppressed and immune reconstituted. Baseline risk of HIV-positive children on ART, benefits and harms should be considered when making treatment decisions.

Implications for research

The risk of TB is substantially higher in HIV-positive children on ART compared to HIV-negative children from the same community. In Madhi 2011, children on ART had a higher rate of TB disease, 121 cases per 1000 child-years than HIV-negative children, 41 per 1000 child-years. Adequately powered trials assessing the impact of TB preventive therapy in HIV-positive children on ART are required. A target sample size of 848 HIV-positive children on ART will be required to have an 80% chance of detecting a 43% relative reduction, as significant at the 5% level, in the intervention group assuming a 14% baseline risk in active TB disease outcome. Trials that assess the long-term effects of TB prophylaxis are also needed to better assess the length of benefit in different settings. The three included trials investigated isoniazid prophylaxis versus placebo. There are no data on the efficacy of other TB preventive treatment regimens. Studies in adults included multiple-drug combination preventive treatment (Akolo 2010). However adverse events leading to discontinuation of treatment were more common for multiple-drug therapy, as opposed to isoniazid treatment alone (Akolo 2010).

Although most cases of definite TB in the included studies were sensitive to isoniazid prophylaxis, long-term data on the impact of isoniazid prophylaxis on Mycobacterium tuberculosis sensitivity are needed.

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TY - ELEC T1 - Isoniazid for preventing tuberculosis in HIV-infected children: Cochrane systematic review ID - 433243 BT - Cochrane Abstracts UR - https://evidence.unboundmedicine.com/evidence/view/Cochrane/433243/all/Isoniazid_for_preventing_tuberculosis_in_HIV_infected_children:_Cochrane_systematic_review DB - Evidence Central DP - Unbound Medicine ER -