Effect on mortality and virological response of delaying antiretroviral therapy initiation in children receiving tuberculosis treatment

Department of Epidemiology, University of North Carolina at Chapel Hill, USA. <>
AIDS (London, England) (Impact Factor: 5.55). 06/2010; 24(9):1341-9. DOI: 10.1097/QAD.0b013e328339e576
Source: PubMed


To estimate the effect of delaying antiretroviral treatment (ART) for 15, 30, or 60 days after tuberculosis (TB) treatment initiation on mortality and virological suppression.
Cohort of 573 ART-naive HIV-infected children initiated on TB treatment at an outpatient clinic in South Africa between April 2004 and March 2008.
Hazard ratios for mortality and viral suppression were estimated using marginal structural models and multivariate Cox models, respectively.
During follow-up (median 9.64 months), 37 HIV-infected children died after a median of 62 days of TB treatment. ART was initiated in 461 children at a median of 17 days after TB treatment initiation, 415 (90%) achieved viral suppression. The hazard ratios of death for initiating ART more than 15, more than 30, or more than 60 days of TB treatment compared with initiating within 15, 30 and 60 days, respectively, were 0.82 (95% CI: 0.48, 1.41), 0.86 (95% CI: 0.46, 1.60), and 1.32 (95% CI: 0.55, 3.16). Hazard ratios for analysis restricted to severely immunosuppressed children were: 0.92 (95% CI: 0.51, 1.63), 1.08 (95% CI: 0.56, 2.08), and 2.23 (95% CI: 0.85, 5.80), respectively. Hazard ratios for viral suppression were 0.98 (95% CI: 0.76, 1.26), 0.95, (95% CI: 0.73, 1.23), 0.84 (95% CI: 0.61, 1.15), respectively and did not change with restriction to children severely immunosuppressed.
In this observational study, we found that delaying ART for 2 months or more in children diagnosed with TB may be associated with poorer virological response and increased mortality, particularly in children with severe immunosuppression. These findings should be confirmed in a randomized controlled trial.

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    • "The recommendations are extrapolated from adult trials, which showed that mortality is decreased in severely immunocompromised patients with CD4 <50 cells/mm3 with early start of ART [60-62]. A paediatric retrospective study from Johannesburg, South Africa, in children, most of whom were severely immunocompromised, showed that delaying ART for longer than 8 weeks was associated with increased mortality and worse virologic outcome [63]. The data from adult studies suggest that delayed ART in patients with no or mild immunocompromise was not associated with worse outcomes [60-62]. "
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    ABSTRACT: HIV is the top and tuberculosis is the second leading cause of death from infectious disease worldwide, with an estimated 8.7 million incident cases of tuberculosis and 2.5 million new HIV infections annually. The World Health Organization estimates that HIV prevalence among children with tuberculosis, in countries with moderate to high prevalence, ranges from 10 to 60%. The mechanisms promoting susceptibility of people with HIV to tuberculosis disease are incompletely understood, being likely caused by multifactorial processes. Paediatric tuberculosis and HIV have overlapping clinical manifestations, which could lead to missed or late diagnosis. Although every effort should be made to obtain a microbiologically-confirmed diagnosis in children with tuberculosis, in reality this may only be achieved in a minority, reflecting their paucibacillary nature and the difficulties in obtain samples. Rapid polymerase chain reaction tests, such as Xpert MTB/RIF assay, are increasingly used in children. The use of less or non invasive methods of sample collection, such as naso-pharyngeal aspirates and stool samples for a polymerase chain reaction-based diagnostic test tests and mycobacterial cultures is promising technique in HIV negative and HIV positive children. Anti-tuberculosis treatment should be started immediately at diagnosis with a four drug regimen, irrespective of the disease severity. Moreover, tuberculosis disease in an HIV infected child is considered to be a clinical indication for initiation of antiretroviral treatment. The World Health Organization recommends starting antiretroviral treatment in children as soon as anti-tuberculosis treatment is tolerated and within 2- 8 weeks after initiating it. The treatment of choice depends on the child’s age and availability of age-appropriate formulations, and potential drug interactions and resistance. Treatment of multi-drug resistant tuberculosis in HIV-infected children follows same principles as for HIV uninfected children. There are conflicting results on effectiveness of isoniazid preventive therapy in reducing incidence of tuberculosis disease in children with HIV. Conclusion Data on HIV/TB co-infection in children are still lacking. There are on-going large clinical trials on the prevention and treatment of TB/HIV infection in children that hopefully will help to guide an evidence-based clinical practice in both resource-rich and resource-limited settings.
    Full-text · Article · Jan 2014 · BMC Infectious Diseases
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    • "This finding is consistent with a study done in USA and ten European countries and South Africa which showed that most of the deaths occurred in the first 6 months following ART initiation [14-16]. Children in WHO clinical stage IV and with severe immunodeficiency had a significant risk of early death at 3 or 6 months [17-19]. This indicated that early HIV diagnosis and early antiretroviral therapy might not be well adopted as recommend which could have reduced early infant mortality by 76% in this study [20,21]. "
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    ABSTRACT: The introduction of antiretroviral therapy in 1996 improved the longevity and wellbeing of peoples living with HIV in the industrialized world including children. This survival benefit of antiretroviral therapy (ART) in reducing HIV related deaths has been well studied in the developed world. In resource-poor settings, where such treatment was started recently, there is inadequate information about impact of ART on the survival of patients especially in children. So, this study aims to investigate predictors of mortality of children on ART. Therefore, the objective of this study was to identify predictors of mortality among children on HAART. A retrospective cohort study was conducted on 432 children who initiated antiretroviral therapy from June 2006 to June 2011 at pediatrics ART clinic in Mekelle Hospital, Northern-Ethiopia. Data were extracted from electronic and paper based medical records database and analyzed using Kaplan Meier survival and Cox proportional hazard model to identify independent predictors of children's mortality on ART. The total time contributed by the study participants were 14,235 child-months with median follow up of 36 months. The mortality rate of this cohort was 1.40 deaths per 1000 child-months or 16.85 deaths per 1000 child-years. Age less than 18 months [ Adj.HR (95% CI) = (4.39(1.15-17.41)], CD4 percentage <10 [Adj.HR (95% CI) = 2.98(1.12-7.94)], WHO clinical stage (III&IV) [Adj.HR (95% CI) = 4.457(1.01-19.66)], chronic diarrhea[Adj.HR (95% CI) = 4.637(1.50-14.31)] and hemoglobin < 8 g/dl[Adj.HR (95% CI) = 3.77(1.29-10.98)] all at baseline were significantly and independently associated with survival of children on ART. Mortality of children on ART was low and factors that affect mortality of children on ART were age less than 18 months, lower CD4 percentage, advanced WHO clinical stage (III&IV), presence of chronic diarrhea and lower hemoglobin level all at baseline. The high early mortality rate would support the value of an earlier treatment start before development of signs of immunodeficiency syndrome despite the method of HIV diagnosis and WHO stage.
    Full-text · Article · Nov 2013 · BMC Public Health
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    • "The most recent WHO guidelines recommend initiation of HAART as soon as tuberculosis therapy is tolerated, ideally as early as 2 weeks and no later than 8 weeks subsequent to initiation of TB treatment, regardless of clinical stage and degree of immunosuppression [79]. However, studies on the optimal timing of HAART initiation among children with TB have been limited to observational reports, although a recent such study suggested a trend towards decreased mortality and higher rates of virological suppression with earlier HAART initiation in this age group [80]. Extrapolation of findings from adult studies to the pediatric population may not be possible given potential differences in pharmacokinetics and pharmacodynamics as well as challenges in definitive pediatric TB diagnosis. "
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    ABSTRACT: The convergent human immunodeficiency virus (HIV) and tuberculosis (TB) pandemics continue to collectively exact significant morbidity and mortality worldwide. Highly active antiretroviral therapy (HAART) has been a critical component in combating the scourge of these two conditions as both a preemptive and therapeutic modality. However, concomitant administration of antiretroviral and antituberculous therapies poses significant challenges, including cumulative drug toxicities, drug-drug interactions, high pill burden, and the immune reconstitution inflammatory syndrome (IRIS), thus complicating the management of coinfected individuals. This paper will review data from recent studies regarding the optimal timing of HAART initiation relative to TB treatment, with the ultimate goal of improving coinfection-related morbidity and mortality while mitigating toxicity resulting from concurrent treatment of both infections.
    Full-text · Article · Jan 2011 · Clinical and Developmental Immunology
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