When is the best time to start antiretroviral therapy in children 2 to 5 years old who have HIV infection?

Antiretroviral combination therapy (cART) has been shown to be effective in slowing down the progression of AIDS and in reducing HIV-related illnesses and death. In infants and children who are diagnosed with HIV infection and are below two years of age the World Health Organization (WHO) recommends that cART should be started immediately. In children aged 2 to 5 years the WHO 2010 recommendations stated that treatment should be started when the body’s defence system has started to weaken (as indicated by a decline in a child’s CD4 cell count) or complications have occurred. This systematic review was undertaken to help inform the 2013 WHO guidelines which aimed to revise the recommendations of when to start therapy in 2 to 5 years old children. The authors identified two randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART in HIV-positive children aged 1 to 12 years in Thailand or Cambodia. Additional analyses of 122 children enrolled in the two studies at ages 2 to 5 years were made available for this review. A cohort study from South Africa in HIV-positive children (median age 3.5 years) starting tuberculosis treatment and ART was also included. Results showed that we still lack enough evidence to determine whether early or late initiation of cART is best in children aged 2 to 5 years. The authors recognized the lack of evidence but highlighted the potential value of simplifying WHO recommendations to start cART in all children below five years with the goal of providing programmatic advantage to treatment programmes in resource-limited settings.

Authors' conclusions: 

This systematic review shows that there is insufficient evidence from clinical trials in support of either early or CD4-guided initiation of ART in HIV-infected children aged 2 to 5 years. Programmatic issues such as the retention in care of children in ART programmes in resource-limited settings will need to be considered when formulating WHO 2013 recommendations.  

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Background: 

The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children. Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic thresholds or the clinical condition for all infants (less than one years of age) and children under the age of two years. For children aged two to five years current WHO guidelines recommend (based on low quality evidence) that clinical and immunological thresholds be used to identify those who need to start cART (advanced clinical stage or CD4 counts ≤ 750 cells/mm3 or per cent CD4 ≤ 25%). This Cochrane review will inform the current available evidence regarding the optimal time for treatment initiation in children aged two to five years with the goal of informing the revision of WHO 2013 recommendations on when to initiate cART in children.

Objectives: 

To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-infected children aged 2 to 5 years.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the AEGIS conference database, specific relevant conferences, www.clinicaltrials.gov, the World Health Organization International Clinical Trials Registry platform and reference lists of articles. The date of the most recent search was 30 September 2012.

Selection criteria: 

Randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART, and prospective cohort studies which followed children from enrolment to start of cART and on cART.

Data collection and analysis: 

Two review authors considered studies for inclusion in the review, assessed the risk of bias, and extracted data on the primary outcome of death from all causes and several secondary outcomes, including incidence of CDC category C and B clinical events and per cent CD4 cells (CD4%) at study end. For RCTs we calculated relative risks (RR) or mean differences with 95% confidence intervals (95% CI). For cohort data, we extracted relative risks with 95% CI from adjusted analyses. We combined results from RCTs using a random effects model and examined statistical heterogeneity.

Main results: 

Two RCTs in HIV-positive children aged 1 to 12 years were identified. One trial was the pilot study for the larger second trial and both compared initiation of cART regardless of clinical-immunological conditions with deferred initiation until per cent CD4 dropped to <15%. The two trials were conducted in Thailand, and Thailand and Cambodia, respectively. Unpublished analyses of the 122 children enrolled at ages 2 to 5 years were included in this review. There was one death in the immediate cART group and no deaths in the deferred group (RR 2.9; 95% CI 0.12 to 68.9). In the subgroup analysis of children aged 24 to 59 months, there was one CDC C event in each group (RR 0.96; 95% CI 0.06 to 14.87) and 8 and 11 CDC B events in the immediate and deferred groups respectively (RR 0.95; 95% CI 0.24 to 3.73). In this subgroup, the mean difference in CD4 per cent at study end was 5.9% (95% CI 2.7 to 9.1). One cohort study from South Africa, which compared the effect of delaying cART for up to 60 days in 573 HIV-positive children starting tuberculosis treatment (median age 3.5 years), was also included. The adjusted hazard ratios for the effect on mortality of delaying ART for more than 60 days was 1.32 (95% CI 0.55 to 3.16).

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