INT J TUBERC LUNG DIS 18(3):322–327 © 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0354
Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study D. M. Gray,* L. J. Workman,* C. J. Lombard,† T. Jennings,* S. Innes,‡ C. J. Grobbelaar,§ M. F. Cotton,‡ H. J. Zar* * Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, † Biostatistics Unit, Medical Research Council, Cape Town, ‡ Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, § Anova Health Institute, TC Newman Hospital, Paarl, South Africa SUMMARY SETTING:
Tuberculosis (TB) is a common cause of mortality and morbidity in children infected with the human immunodeficiency virus (HIV). Data on isoniazid preventive therapy (IPT) efficacy in HIV-infected children receiving antiretroviral therapy (ART) are inconclusive. O B J E C T I V E : To assess the efficacy, tolerability and safety of isoniazid (INH) in HIV-infected children on ART. D E S I G N : A pilot randomised controlled study of INH was undertaken in HIV-infected children on ART. The primary outcome measure was TB disease or death. R E S U LT S : A total of 167 children were randomised to receive INH (n = 85) or placebo (n = 82), and followed for a median of 34 months (interquartile range [IQR]
24–52). The median age was 35 months (IQR 15–65). There was one death in a child on INH and none in the placebo group. Eleven (6.6%) cases of TB occurred, 4 (5%) in the INH and 7 (9%) in the placebo group. Among the TB cases, 5 were culture confirmed—2 in the INH group and 3 in the placebo group, all susceptible to INH. Severe adverse events occurred rarely (n = 6; 2%). C O N C L U S I O N : IPT is safe and well tolerated in HIVinfected children on concomitant ART. This study supports the need for a larger study to assess efficacy in HIV-infected children living in TB-endemic areas. K E Y W O R D S : TB; prophylaxis; ART; IPT
TUBERCULOSIS (TB) and the human immunodeficiency virus (HIV) are dual epidemics in southern Africa. Of 2.5 million children living with HIV, 2.3 million live in sub-Saharan Africa.1,2 Africa accounts for 26% of the global TB burden and 82% of TB cases among people living with HIV.2 TB contributes to acute and chronic respiratory disease, and is a leading cause of death amongst HIVinfected children in TB endemic areas.3–5 The diagnosis of TB may be particularly difficult in HIV-infected children.6,7 Drug interactions, adverse events and immune reconstitution during TB treatment or on initiation of combination antiretroviral therapy (ART) complicate the management of co-infected children. The prevention of TB in children is therefore of major importance to public health. ART reduces TB risk and improves outcomes in HIV-infected adults8 and children in high TB prevalence areas.9–11 However, TB incidence remains substantially higher in HIV-infected compared to noninfected infants and children.12 Isoniazid (INH) preventive therapy (IPT) significantly reduces tuberculous infection and TB disease in non-HIV-infected adults and children exposed to a
TB smear-positive household contact.13 TB preventive therapy for 36 months reduces the risk of TB in purified protein derivative (PPD) positive HIV-infected adults by 74%.14 In children, however, the data are less clear. A randomised placebo-controlled trial of INH prophylaxis in HIV-infected children in the preART era reduced all-cause mortality by >50% and TB by 70% in HIV-infected children on either daily or thrice-weekly INH.15 All children were changed to open-label INH and enrolment continued onto daily or thrice-weekly INH. In a cohort analysis, IPT offered additional protection against TB in children on ART.16 However, HIV-infected infants receiving ART and with no previous exposure to TB received no protection from INH in a placebo-controlled trial.12 IPT offers additional protection against TB disease in HIV-infected adults on ART,8,14 and is currently recommended by the World Health Organization for all adults and children living with HIV in TB-endemic areas.2 In a recent randomised controlled trial in adults on ART, IPT reduced the hazard of acquiring TB by 47% compared to placebo.17 This pilot study aimed to assess the efficacy, tolerability and safety of IPT compared to placebo in
Correspondence to: Diane Gray, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, Klipfontein Road, Rondebosch 7700, Cape Town, South Africa. e-mail: [email protected] Article submitted 16 May 2013. Final version accepted 24 October 2013.
IPT in HIV-infected children
HIV-infected children on ART living in a high TB prevalence area to provide preliminary data for a randomised study.
METHODS A prospective double-blind randomised placebocontrolled trial comparing INH versus placebo was conducted in HIV-infected children on ART attending two hospitals and one community clinic in Cape Town, South Africa. Enrolment occurred between May 2005 and October 2009, with follow-up until November 2011. Participants Participants were HIV-infected children aged >8 weeks who had been on ART for >2 months. Inclusion criteria were weight >2.5 kg, informed consent from a parent or legal guardian, residence in the area with access to transport and >90% adherence to ART. Children were excluded if they had chronic diarrhoea, were currently being treated with INH prophylaxis or had had exposure to a TB contact, had a history of INH hypersensitivity, had severe anaemia (haemoglobin
Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study D. M. Gray,* L. J. Workman,* C. J. Lombard,† T. Jennings,* S. Innes,‡ C. J. Grobbelaar,§ M. F. Cotton,‡ H. J. Zar* * Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, † Biostatistics Unit, Medical Research Council, Cape Town, ‡ Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, § Anova Health Institute, TC Newman Hospital, Paarl, South Africa SUMMARY SETTING:
Tuberculosis (TB) is a common cause of mortality and morbidity in children infected with the human immunodeficiency virus (HIV). Data on isoniazid preventive therapy (IPT) efficacy in HIV-infected children receiving antiretroviral therapy (ART) are inconclusive. O B J E C T I V E : To assess the efficacy, tolerability and safety of isoniazid (INH) in HIV-infected children on ART. D E S I G N : A pilot randomised controlled study of INH was undertaken in HIV-infected children on ART. The primary outcome measure was TB disease or death. R E S U LT S : A total of 167 children were randomised to receive INH (n = 85) or placebo (n = 82), and followed for a median of 34 months (interquartile range [IQR]
24–52). The median age was 35 months (IQR 15–65). There was one death in a child on INH and none in the placebo group. Eleven (6.6%) cases of TB occurred, 4 (5%) in the INH and 7 (9%) in the placebo group. Among the TB cases, 5 were culture confirmed—2 in the INH group and 3 in the placebo group, all susceptible to INH. Severe adverse events occurred rarely (n = 6; 2%). C O N C L U S I O N : IPT is safe and well tolerated in HIVinfected children on concomitant ART. This study supports the need for a larger study to assess efficacy in HIV-infected children living in TB-endemic areas. K E Y W O R D S : TB; prophylaxis; ART; IPT
TUBERCULOSIS (TB) and the human immunodeficiency virus (HIV) are dual epidemics in southern Africa. Of 2.5 million children living with HIV, 2.3 million live in sub-Saharan Africa.1,2 Africa accounts for 26% of the global TB burden and 82% of TB cases among people living with HIV.2 TB contributes to acute and chronic respiratory disease, and is a leading cause of death amongst HIVinfected children in TB endemic areas.3–5 The diagnosis of TB may be particularly difficult in HIV-infected children.6,7 Drug interactions, adverse events and immune reconstitution during TB treatment or on initiation of combination antiretroviral therapy (ART) complicate the management of co-infected children. The prevention of TB in children is therefore of major importance to public health. ART reduces TB risk and improves outcomes in HIV-infected adults8 and children in high TB prevalence areas.9–11 However, TB incidence remains substantially higher in HIV-infected compared to noninfected infants and children.12 Isoniazid (INH) preventive therapy (IPT) significantly reduces tuberculous infection and TB disease in non-HIV-infected adults and children exposed to a
TB smear-positive household contact.13 TB preventive therapy for 36 months reduces the risk of TB in purified protein derivative (PPD) positive HIV-infected adults by 74%.14 In children, however, the data are less clear. A randomised placebo-controlled trial of INH prophylaxis in HIV-infected children in the preART era reduced all-cause mortality by >50% and TB by 70% in HIV-infected children on either daily or thrice-weekly INH.15 All children were changed to open-label INH and enrolment continued onto daily or thrice-weekly INH. In a cohort analysis, IPT offered additional protection against TB in children on ART.16 However, HIV-infected infants receiving ART and with no previous exposure to TB received no protection from INH in a placebo-controlled trial.12 IPT offers additional protection against TB disease in HIV-infected adults on ART,8,14 and is currently recommended by the World Health Organization for all adults and children living with HIV in TB-endemic areas.2 In a recent randomised controlled trial in adults on ART, IPT reduced the hazard of acquiring TB by 47% compared to placebo.17 This pilot study aimed to assess the efficacy, tolerability and safety of IPT compared to placebo in
Correspondence to: Diane Gray, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, Klipfontein Road, Rondebosch 7700, Cape Town, South Africa. e-mail: [email protected] Article submitted 16 May 2013. Final version accepted 24 October 2013.
IPT in HIV-infected children
HIV-infected children on ART living in a high TB prevalence area to provide preliminary data for a randomised study.
METHODS A prospective double-blind randomised placebocontrolled trial comparing INH versus placebo was conducted in HIV-infected children on ART attending two hospitals and one community clinic in Cape Town, South Africa. Enrolment occurred between May 2005 and October 2009, with follow-up until November 2011. Participants Participants were HIV-infected children aged >8 weeks who had been on ART for >2 months. Inclusion criteria were weight >2.5 kg, informed consent from a parent or legal guardian, residence in the area with access to transport and >90% adherence to ART. Children were excluded if they had chronic diarrhoea, were currently being treated with INH prophylaxis or had had exposure to a TB contact, had a history of INH hypersensitivity, had severe anaemia (haemoglobin
