Momento óptimo para el comienzo del tratamiento antirretroviral (TAR) en niños entre dos y cinco años de edad con infección por el VIH sin tratamiento previo
Resumen
Antecedentes
El uso de tratamiento antirretroviral de combinación (TARc) con tres medicamentos antirretrovirales de al menos dos clases de fármacos es el tratamiento estándar actual para la infección por VIH en adultos y niños. Las guías actuales de la Organización Mundial de la Salud (OMS) para el tratamiento antirretroviral recomiendan el tratamiento temprano independientemente de los umbrales inmunológicos o de la condición clínica de todos los lactantes (menores de un año de edad) y niños menores de dos años de edad. En los niños entre dos a cinco años de edad las guías actuales de la OMS recomiendan (según pruebas de baja calidad) que se utilicen los umbrales clínicos e inmunológicos para identificar a los pacientes que necesiten comenzar con el TARc (estadio clínico avanzado o recuentos de CD4 ≤ 750 células/mm3 o porcentaje de CD4 ≤ 25%). Esta revisión Cochrane informará las pruebas disponibles actuales con respecto al momento óptimo para comenzar el tratamiento en niños entre dos y cinco años de edad con el objetivo de informar la revisión de las recomendaciones de la OMS de 2013 sobre cuándo iniciar el TARc en niños.
Objetivos
Evaluar las pruebas del momento óptimo para comenzar el TARc en niños entre dos y cinco años de edad con infección por el VIH sin tratamiento previo.
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE, EMBASE, la AEGIS conference database, conferencias relevantes específicas, www.clinicaltrials.gov, la International Clinical Trials Registry platform de la Organización Mundial de la Salud y las listas de referencias de artículos. La fecha de búsqueda más reciente fue 30 de septiembre de 2012.
Criterios de selección
Ensayos controlados aleatorios (ECA) que compararon el comienzo inmediato con el comienzo tardío del TARc, y estudios de cohortes prospectivos que siguieron a los niños desde el reclutamiento al comienzo del TARc y durante dicho tratamiento.
Obtención y análisis de los datos
Dos revisores consideraron los estudios para inclusión en la revisión, evaluaron el riesgo de sesgo y extrajeron los datos sobre el resultado primario mortalidad por todas las causas y varios resultados secundarios, incluida la incidencia de eventos clínicos de categoría C y B del CDC y el porcentaje de células CD4 (CD4%) al final del estudio. En los ECA se calcularon los riesgos relativos (RR) o las diferencias de medias con intervalos de confianza del 95% (IC del 95%). En los datos de cohortes se extrajeron los riesgos relativos con IC del 95% a partir de los análisis ajustados. Los resultados de los ECA se combinaron con un modelo de efectos aleatorios y se examinó la heterogeneidad estadística.
Resultados principales
Se identificaron dos ECA en niños con infección por el VIH entre uno y 12 años de edad. Un ensayo fue el estudio piloto del segundo ensayo más grande y ambos compararon el comienzo del TARc independientemente de las condiciones clínicas e inmunológicas, con un comienzo tardío hasta que el porcentaje de CD4 descendió a < 15%. Los dos ensayos se realizaron en Tailandia, y en Tailandia y Camboya, respectivamente. En esta revisión se incluyeron los análisis no publicados de los 122 niños entre dos y cinco años de edad que se reclutaron. Hubo una muerte en el grupo con TARc inmediato y ninguna en el grupo tardío (CR 2,9; IC del 95%: 0,12 a 68,9). En el análisis de subgrupos de los niños con edades entre 24 y 59 meses hubo un evento C del CDC en cada grupo (CR 0,96; IC del 95%: 0,06 a 14,87) y ocho y 11 eventos B del CDC en el grupo inmediato y tardío respectivamente (CR 0,95; IC del 95%: 0,24 a 3,73). En este subgrupo la diferencia de medias en el porcentaje de CD4 al final del estudio fue 5,9% (IC del 95%: 2,7 a 9,1). También se incluyó un estudio de cohortes de Sudáfrica que comparó el efecto de retrasar el TARc hasta 60 días en 573 niños con infección por el VIH que comenzaron el tratamiento contra la tuberculosis (mediana de la edad 3,5 años). El cociente de riesgos instantáneo ajustado para el efecto sobre la mortalidad del TARc tardío por más de 60 días fue 1,32 (IC del 95%: 0,55 a 3,16).
Conclusiones de los autores
Esta revisión sistemática indica que no hay pruebas suficientes a partir de ensayos clínicos para apoyar el comienzo temprano o guiado por el CD4 del TARc en niños con infección por el VIH de entre dos y cinco años de edad. Las cuestiones programáticas, como que los niños reciben atención en programas de TARc en contextos de recursos limitados deberán considerarse cuando se formulen las recomendaciones 2013 de la OMS.
PICO
Resumen en términos sencillos
¿Cuándo es el mejor momento para comenzar el tratamiento antirretroviral en los niños entre dos y cinco años de edad que presentan infección por el VIH?
El tratamiento antirretroviral combinado (TARc) ha mostrado ser efectivo para desacelerar la progresión del SIDA y disminuir el número de enfermos y de muertes relacionadas con el VIH. En los lactantes y niños menores de dos años de edad con diagnóstico de infección por el VIH, la Organización Mundial de la Salud (OMS) recomienda comenzar de inmediato el TARc. En los niños entre dos y cinco años de edad las recomendaciones 2010 de la OMS señalaron que el tratamiento se debe comenzar cuando el sistema de defensa del cuerpo comienza a debilitarse (según se indica por una disminución en el recuento de células CD4 del niño) o cuando ocurrieron complicaciones. Esta revisión sistemática se realizó para ayudar a informar las guías 2013 de la OMS que tienen como objetivo revisar las recomendaciones de cuándo comenzar el tratamiento en niños entre dos y cinco años de edad. Los revisores identificaron dos ensayos controlados aleatorios (ECA) que compararon el comienzo inmediato con tardío del TARc en niños con infección por el VIH entre uno y 12 años de edad en Tailandia o Camboya. Los análisis adicionales de 122 niños reclutados en los dos estudios con edades entre dos y cinco años estuvieron disponibles para esta revisión. Además, se incluyó un estudio de cohortes de Sudáfrica en niños con infección por el VIH (mediana de la edad 3,5 años) que comenzaron el tratamiento contra la tuberculosis y el TARc. Los resultados indicaron que todavía no hay pruebas suficientes para determinar si el comienzo temprano o tardío del TARc es mejor en niños entre dos y cinco años de edad. Los revisores reconocieron la falta de pruebas pero destacaron el valor potencial de simplificar las recomendaciones de la OMS para comenzar el TARc en todos los niños menores de cinco años de edad con el objetivo de proporcionar una ventaja programática a los programas de tratamiento en contextos de recursos limitados.
Authors' conclusions
Summary of findings
| IMMEDIATE initiation of cART compared to DEFERRED initiation of cART for HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged one to 12 years old | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| DEFERRED initiation of cART | IMMEDIATE initiation of cART | |||||
| Death | 0 per 1000 | 0 per 1000 | RR 3 | 343 | ⊕⊝⊝⊝ | |
| CDC Category C disease (number of children) | 12 per 1000 | 18 per 1000 | RR 1.5 | 343 | ⊕⊝⊝⊝ | |
| CDC Category B disease (numbers of children) Peto Odds Ratio | 189 per 1000 | 141 per 1000 | OR 0.7 | 343 | ⊕⊝⊝⊝ | |
| Proportion of children on ART with HIV‐RNA < 50 copies/ml (Copy) | 815 per 1000 | 783 per 1000 | RR 0.96 | 238 | ⊕⊕⊝⊝ | |
| Weight gain per year in kg | The mean weight gain per year in kg in the intervention groups was | 300 | ⊕⊕⊝⊝ | |||
| Height gain per year in cm | The mean height gain per year in cm in the intervention groups was | 300 | ⊕⊕⊝⊝ | |||
| Standardized score on Beery VMI at 144 weeks | The mean standardized score on Beery VMI at 144 weeks in the intervention groups was | 272 | ⊕⊕⊝⊝ | |||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| DEFERRED initiation of cART | ||||||
| 1 As the trials were open‐label neither participants nor caregivers were blinded. However outcome assessors were blinded in the PREDICT trial. Attrition was low in both trials. Information on the randomisation procedure was lacking in Ananworanich 2008. However, given that this trial is relatively small, we judged the overall risk of bias to be low for the two trials together. | ||||||
| SUBGROUP ANALYSIS: IMMEDIATE initiation of cART compared to DEFERRED initiation of cART in HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT) | |||||
| Death | 0 per 1000 | 0 per 1000 | RR 2.88 | 122 | ⊕⊝⊝⊝ | |
| CDC Category C disease (number of children) | 16 per 1000 | 15 per 1000 | RR 0.96 | 122 | ⊕⊝⊝⊝ | |
| CDC Category B disease (numbers of children) Peto Odds Ratio | 239 per 1000 | 167 per 1000 | OR 0.64 | 94 | ⊕⊝⊝⊝ | |
| Proportion of children on ART with HIV‐RNA < 50 copies/ml | 789 per 1000 | 876 per 1000 | RR 1.11 | 67 | ⊕⊝⊝⊝ | |
| Mean weight gain per year in kg | The mean weight gain per year in kg in the intervention groups was | 94 | ⊕⊝⊝⊝ | |||
| Mean height gain per year in cm | The mean height gain per year in cm in the intervention groups was | 94 | ⊕⊝⊝⊝ | |||
| Mean standardized score on Beery VMI at 144 weeks | The mean standardized score on Beery VMI at 144 weeks in the intervention groups was | 82 | ⊕⊝⊝⊝ | |||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 This is a subgroup analysis within each of the Ananworanich 2009 and PREDICT 2012 trials. Randomisation was not conducted within the sub‐group. For Ananworanich 2008, the proportion of children aged 24 to 59 months in the IMMEDIATE group was 46% (11/24) and in the DEFERRED group it was 89% (17/19). This differential could introduce selection bias. | ||||||
Background
Description of the condition
The World Health Organization (WHO) estimated that in 2011 there were 2.5 million (2.24 to 2.8 million) people who became newly infected with HIV (UNAIDS 2012). Of these, an estimated 330 000 [200 000–270 000] were children less than 15 years old. This is a 24% decrease in global figures since 2009 and can largely be attributed to the expansion in access to services for preventing mother‐to‐child transmission of HIV, the primary route of HIV acquisition in children.
Sub‐Saharan Africa is disproportionately represented in the epidemic with 69% of the global total of people living with HIV (UNAIDS 2012). An estimated 90% of the world’s children living with HIV live in sub‐Saharan Africa. At the end of 2011, 54% of the 14.2 million people (adults and children) in need of treatment in low‐ and middle‐income countries were receiving antiretroviral therapy (UNAIDS 2012). However, in sub‐Saharan Africa, antiretroviral therapy coverage of children in the region is far below the global average, at just 28% (25 ‐ 31%).
Description of the intervention
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 (WHO 2010b). While the availability of cART has changed the course of paediatric HIV infection with a notable reduction in mortality observed over long‐term follow‐up (Patel 2008), late initiation of cART and poor retention in care remain significant challenges in resource‐limited settings (Fenner 2010). Determining the optimal timing to initiate cART in children is challenging for several reasons. As children grow, the organs involved in drug metabolism mature. As a result, the pharmacokinetic environment is dynamic and treatment needs to be adjusted according to age and weight (Heidari 2012). If malnutrition is present or treatment for co‐infections such as tuberculosis or malaria is required, the pharmacokinetics of drugs may be further altered (Heidari 2012). Markers of disease progression, such as the CD4 count, are unreliable in young children limiting disease monitoring (Prendergast 2012). Given that treatment is life‐long, the risk of drug resistance is prolonged and the potential for long‐term toxicity exists (Heidari 2012). Determining the optimal time to initiate cART in children is therefore critical.
Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic or clinical thresholds for all infants (less than one year of age) and children under the age of two years (WHO 2010b). The decision to initiate early treatment in infants was based on the evidence provided by the Children with HIV Early Antiretroviral Therapy trial (CHER) (Violari 2008) and supported by a Cochrane review (Penazzato 2012). The subsequent extension of this guideline to children under the age of two years was developed with the goal of improving retention and based on the high risk of disease progression and death and the poor predictive value of immunological markers in this age group (Prendergast 2012).
For children aged 24 to 59 months (two to five years) current WHO guidelines recommend that clinical and immunological thresholds be used to identify those children aged 24 to 59 months who need to start cART (WHO 2010b). Specifically, treatment should be initiated for all HIV‐infected children with WHO HIV clinical stages 3 and 4, irrespective of CD4 count. In children aged 24 to 59 months (2 to 5 years in age), cART should be initiated when CD4 counts <= 750 cells/mm3 or %CD4 <= 25%, irrespective of the WHO clinical stage. These recommendations are acknowledged to be based on low or very low quality evidence.
Why it is important to do this review
The World Health Organization (WHO) Antiretroviral Therapy Guideline is the main normative cART tool at global level and is used by regional and national programme managers to develop national treatment guidelines. The first guideline was produced in 2002 (WHO 2002), then revised in 2003 (WHO 2003). In 2006, and then again in 2010, separate sets of recommendations – one for adults and adolescents (WHO 2006a; WHO 2010a) and another for children (WHO 2006b; WHO 2010b) ‐ were published as two guideline documents. In 2011, WHO/UNAIDS established a new initiative,Treatment 2.0, that advocates for the development and expanded use of more simplified, less toxic drug regimens, with high barriers to drug resistance, that require minimal clinical monitoring while maintaining therapeutic efficacy (WHO 2011b). Treatment 2.0 aims to expand access to treatment and applies equally to both adults and children. In this context, revising WHO recommendations will require re‐examining the evidence for when to start cART in infants and children. While a completed Cochrane review has focused on the effectiveness of cART in children aged under two years (Penazzato 2012), this Cochrane review will inform the revision of the WHO antiretroviral therapy guidelines specifically for when to initiate cART in children aged two to five years old.
Objectives
To assess the evidence for the optimal time to initiate cART in treatment‐naive, HIV‐infected children aged 24 to 59 months (2 to 5 years old).
Methods
Criteria for considering studies for this review
Types of studies
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Randomised controlled trials (RCTs)
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Prospective cohort studies which followed children from enrolment to start of cARTand for at least a median of one year on cART
Non‐comparative cohort studies in which children are all commenced on cART at enrolment regardless of clinical‐immunological condition were excluded.
Types of participants
Children with confirmed HIV infection (HIV PCR‐positive if diagnosed at age<18 months or HIV ELISA‐positive if diagnosed after 18 months of age) aged between 24 and 59 months (two to five years in age) who are treatment‐naïve (except for exposure to drugs to prevent mother‐to‐child transmission) at commencement of the study.
Studies which included the above age group within a larger age range were included. We contacted trial authors to obtain the specific age range 24 to 59 months.
Studies in children with tuberculosis and other opportunistic illnesses were included.
Studies focused only on infants (less than one year in age) were excluded. These are included in another Cochrane review (Penazzato 2012).
For RCTs, at study entry, children must not have fulfilled guideline criteria for starting antiretroviral treatment recommended at the time of the study.
Types of interventions
Studies which compare initiating triple cART at different thresholds.
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In RCTs, the intervention group must have initiated triple cART irrespective of clinical stage or CD4 count (immediate initiation). The control group must have initiated cART using clinical and immunological criteria to determine the time for initiation (deferred initiation) as recommended at the time of the study.
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In cohort studies, children starting triple cART at different CD4 percent or CD4 counts must have been compared. Analysis must have included adjustment for time‐dependent confounding and lead‐time bias specifically to evaluate the effect of timing of cART initiation on outcomes.
Types of outcome measures
Primary outcomes
Mortality (all‐cause)
Secondary outcomes
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Clinical occurrence of new HIV‐related events (death or AIDS‐defining illness)
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Time to event of new HIV‐related events (death or AIDS‐defining illness)
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Immunological response (change in mean or median CD4+ cell count (mean or median relative change (percent) or mean or median absolute change, compared with baseline, and standard deviation or range as appropriate)
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Adherence
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Loss‐to‐follow‐up
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Virologic response (proportion of patients achieving and maintaining an undetectable viral load, as defined by the investigators; change in HIV‐RNA levels (mean relative change (percent) or mean absolute change, compared with baseline, and standard deviations)
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HIV drug resistance
Adverse events
Severe adverse events were reported. If classified according to grade 1 to 4 of the Adverse Event Toxicity Scale, we reported grade 3 and 4 events. Using this scale, grade 1 and 2 denote mild to moderate symptoms, grade 3 denote serious symptoms and grade 4 denote life‐threatening events requiring significant clinical intervention. Grade 5 denotes death (DAIDS 2009).
Search methods for identification of studies
See: HIV/AIDS Collaborative Review Group search strategy. The search aimed to be comprehensive and included published and unpublished studies and was not limited to any language.
Electronic searches
We developed the search strategy with the assistance of the HIV/AIDS Review Group Trials Search Co‐ordinator. We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant randomised controlled trials and cohort studies regardless of language or publication status (published, unpublished, in press, and in progress). Full details of the Cochrane HIV/AIDS Review Group methods and the journals hand‐searched are published in the section on Collaborative Review Groups inThe Cochrane Library.
For the RCT search, we combined the RCT strategy developed by The Cochrane Collaboration and detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) in combination with terms specific to initiation of antiretroviral therapy and children. The search was iterative and a number of trial searches were run first as there are no database‐specific terms for 'initiation' of treatment and so we used many free text terms. This increased the yield and hence the search sensitivity but reduced the precision.
As there are no validated search strategies for cohort studies, our strategy was informed by the cohort strategy developed by BMJ Clinical Evidence (http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html).
We searched the following databases:
1. Journal databases
For RCT Identification:
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Medline via Pubmed ‐ see search strategy conducted on 27 June 2012 in Appendix 1
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EmBase ‐ see search strategy conducted on 27 June 2012 in Appendix 2
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Cochrane Central Register of Controlled Trials (CENTRAL) ‐ see search strategy conducted on 27 June 2012 in Appendix 3
For cohort identification:
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Medline via Pubmed ‐ see search strategy conducted on 11 September 2012 in Appendix 4
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EmBase ‐ see search strategy conducted on 11 September 2012 in Appendix 5
2. Conference databases:
We searched the AEGIS database (www.aegis.org) on 24 July 2012. www.aegis.org contained abstracts from the following major related conferences: 1st‐5th International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment and Prevention (2001‐2009); 10th‐17th International AIDS Conference (IAC) (1994‐2008); 1st‐16th Conference of Retrovirus and Opportunistic Infections (CROI) (1994‐2009); US National HIV Prevention Conference; 7th‐14th British HIV Association (2001‐2008); and 8th‐9th European AIDS Clinical Society Conference (2001, 2003).
AEGIS does not allow for multiple search strings and so, in order to search the database effectively, a separate search was done for relevant terms combined with the term [random*] to identify relevant trials:
ANTIRETROVIRAL* AND RANDOM* AND (child* OR infant* OR toddler* OR pediatric* OR paediatric*)
The more recent conferences (up to 2012) were covered by searching the conference web‐sites of the International AIDS Society, the International AIDS Conference and the CROI. The abstracts of the 1st, 2nd, 3rd and 4th International Workshop on HIV Pediatrics were hand‐searched in Reviews in Antiviral Therapy & Infectious Diseases where they are published following the conference.
3. Ongoing trials:
To identify ongoing RCTs we searched ClinicalTrials.gov (http://clinicaltrials.gov/) on 9 July 2012 and the World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) on 12 July 2012.
Searching other resources
We also checked the reference lists of all studies identified by the above methods and examined any systematic reviews, meta‐analyses, or guidelines we identified during the search process for references.
We were in close contact with individual researchers working in the field, and policymakers based in inter‐governmental organizations including the World Health Organization (WHO) and UNAIDS.
We did not conduct hand‐searching of specific journals other than those searched by the Cochrane HIV/AIDS Review Group and already included in CENTRAL.
Data collection and analysis
Selection of studies
For the RCT search of journal databases, NS and ME read the titles, abstracts and descriptor terms of all downloaded material from the electronic searches to identify potentially eligible reports. Full text articles were be obtained for all citations identified as potentially eligible and NS and ME independently inspected these to establish the relevance of the article according to the pre‐specified criteria. Where there was any uncertainty as to the eligibility of the record, we obtained the full article.
NS and ME independently applied the inclusion criteria, and any differences arising were resolved by discussions with the third reviewer, MD. Studies were reviewed for relevance based on study design, types of participants, exposures and outcome measures.
For the additional cohort search of journal databases, NS read the titles, abstracts and descriptor terms of all downloaded material from the electronic searches to identify potentially eligible reports. After identification of potentially eligible articles, ME checked these and any uncertainty was discussed and resolved by discussions with the third review author, MD.
For all conference abstract searching, NS read the titles, abstracts and descriptor terms of all downloaded material and manually hand‐searched conference abstract books when it was not possible to search the web‐site effectively. NS contacted authors of abstracts to confirm whether the study had been published and/or whether a final report was available. Abstracts which described studies already identified in the electronic searches were linked to these.
Data extraction and management
NS independently extracted data into a standardised data extraction form. ME checked the data extraction independently. The following characteristics were extracted from each included study.
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Administrative details: Trial or study identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited;
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Details of the study: Study design; type, duration and completeness of follow‐up; country and location of study (e.g. higher‐income vs. lower‐income country); informed consent and ethics approval;
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Details of participants: Setting, numbers, relevant baseline characteristics including CD4 count and viral load;age range;
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Details of intervention: CD4 count and age at which treatment was initiated; drug combinations; additional co‐interventions; and
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Details of outcomes: Mortality; HIV‐related morbidity; HIV‐RNA viral load measurements and proposed levels for suppression, as defined by the authors; clinical disease progression; CD4+ cell counts; adverse events and toxicity.
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Details of the analysis: For RCTs, details of the type of analysis (intention‐to‐treat or per protocol); for cohort studies, details of the type of adjustment performed in the analysis.
Assessment of risk of bias in included studies
For both RCTs and cohort studies, NS and ME independently examined the components of each included study for risk of bias using a standard form. This includes information on the sequence generation, allocation concealment, blinding (participants, personnel and outcome assessor), incomplete outcome data, selective outcome reporting and other sources of bias. The methodological components of the trials were assessed and classified as at a high, low or unclear risk of bias as per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Where differences arose, these were resolved by discussions with the third reviewer, MD.
Sequence generation
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Adequate: investigators described a random component in the sequence generation process such as the use of random number table, coin tossing, cards or envelops shuffling etc
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Inadequate: investigators described a non‐random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number
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Unclear: insufficient information to permit judgment of the sequence generation process
Allocation concealment
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Adequate: participants and the investigators enrolling participants cannot foresee assignment, e.g. central allocation; or sequentially numbered, opaque, sealed envelopes.
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Inadequate: participants and investigators enrolling participants can foresee upcoming assignment, e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or nonopaque or not sequentially numbered
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Unclear: insufficient information to permit judgment of the allocation concealment or the method not described
Blinding
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Adequate: blinding of the participants, key study personnel and outcome assessor, and unlikely that the blinding could have been broken. Or lack of blinding unlikely to introduce bias. No blinding in the situation where non‐blinding is not likely to introduce bias.
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Inadequate: no blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding
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Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding
Incomplete outcome data
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Adequate: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups
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Inadequate: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data
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Unclear: insufficient reporting of attrition or exclusions
Selective Reporting
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Adequate: a protocol is available which clearly states the primary outcome as the same as in the final trial report
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Inadequate: the primary outcome differs between the protocol and final trial report
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Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present
Control of time‐dependent confounding (cohort studies only)
The use of standard regression models for the analysis of cohort studies with time‐updated measurements may result in biased estimates of treatment effects if time‐dependent confounders are present (Robins 2000). In cohorts of HIV‐infected patients CD4 cell percentage or CD4 cell counts are measured regularly to assess the patients' eligibility for cART and, once on cART, to monitor therapy. CD4 count is a time‐dependent confounder because it predicts both future cART and outcome, and is influenced by past antiretroviral therapy. In other words, CD4 count is on the causal pathway between treatment and the outcome.
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Adequate: appropriate methods were used to control for time‐dependent confounding (e.g. marginal structural models)
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Inadequate: there was no control for time‐dependent confounding
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Unclear: insufficient reporting to determine whether there was control for time‐dependent confounding
Other forms of bias
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Adequate: there is no evidence of bias from other sources
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Inadequate: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design)
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Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias
Measures of treatment effect
Data analysis was conducted using (RevMan) version 5.1.7.
For RCT data, outcome measures for dichotomous data (e.g. death, virological suppression) were calculated as relative risks with 95% confidence intervals. For continuous data (e.g. CD4+ cell counts, HIV‐RNA viral loads) we calculated the mean difference and standard deviation where means were reported. Where medians and ranges were reported, we extracted the data directly from the report.
For cohort data, we reported on the adjusted analysis using the estimate of effect reported in the study. Where the adjusted estimate of effect was reported with 95% Confidence Intervals (CI), we calculated the Standard Error in order to enter the data into RevMan, using the following formula for ratio measures:
lower limit = ln(lower confidence limit given for HR)
upper limit = ln(upper confidence limit given for HR)
intervention effect estimate = lnHR
SE = (upper limit – lower limit) / 3.92
Unit of analysis issues
We did not anticipate cluster or cross‐over trials, with the potential for unit of analysis issues, being conducted to investigate this question.
Dealing with missing data
Where data was missing or required clarification, we contacted study authors to request additional data. Should this not have been possible, we would have stated explicitly where calculations were based on assumptions regarding missing data.
In trials which included participants from within a larger age range, we contacted study authors to obtain the specific age range 24 to 59 months.
Assessment of heterogeneity
Where RCTs were found to be methodologically or clinically comparable, we pooled trial results in a meta‐analysis. As we anticipated the presence of statistical heterogeneity we combined the data using the random effects model throughout.
Only one cohort study was included in the review, so it was not applicable to assess heterogeneity. In future updates of this review, where cohort studies are found to be methodologically or clinically comparable, we will pool the results in a meta‐analysis using the generic inverse variance function in RevMan to allow adjusted data to be used in the analysis. As we anticipate heterogeneity due to the likelihood of different analytical techniques and different adjusted variables, we will combine studies using the random effects model.
For the RCT meta‐analyses, we formally tested for statistical heterogeneity using the Chi‐square test for statistical homogeneity with a 10% level of significance as the cut‐off. The amount of any statistical heterogeneity was quantified using the I² statistic (Higgins 2002).
Where studies do not have combinable outcomes, we provide the data in a narrative form.
Data synthesis
For meta‐analysis of RCTs, we combined the results and calculated the overall relative risk and 95% confidence intervals using the Mantel‐Haenszel random‐effects model. For continuous data, we combined the mean differences to calculate a weighted mean difference and standard deviation, using the inverse‐variance random‐effects model. Peto fixed‐effects models were used in sensitivity analyses. If time‐to‐event data is available in future updates, we will combine the hazard ratios reported in the RCTs using the inverse‐variance random‐effects model.
For cohort studies in future updates, we will combine the adjusted estimates of effects using the inverse‐variance random‐effects model.
Subgroup analysis and investigation of heterogeneity
We anticipated statistical heterogeneity due to differences between studies conducted in resource‐constrained compared with resource‐rich settings, and planned to present the results according to these sub‐groups should this have been necessary.
We performed subgroup analyses restricted to children less than 5 years old who had a CD4 above 25% to best inform the current (2012) WHO guideline processes.
Sensitivity analysis
For RCTs, we planned to explore the effect of study quality on the results by excluding those studies where allocation concealment was unclear or inadequate from the meta‐analysis and assessing the effect of this on the overall results. For cohort studies we planned to examine the effect of adjustments for confounding and in particular confounding by indication.
We also conducted meta‐analyses using the Peto Odds Ratio in addition to the RR for those comparisons where the event rate was extremely low.
GRADE assessment
GradePro 2008 was used to create Summary of Findings and Evidence Profile tables. GradePro software was developed as part of a larger initiative led by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADE offers a system for rating quality of evidence in systematic reviews and guidelines and grading strength of recommendations in guidelines (Guyatt 2011). Use of GradePro within a Cochrane systematic review facilitates the process of presenting and grading evidence transparently (http://ims.cochrane.org/revman/other‐resources/gradepro/about‐gradepro).
In determining the level of evidence for each outcome, both the efficacy results and the assessment of the risk of bias was integrated into a final assessment of the level of evidence and full details of the decision was provided in footnotes.
Results
Description of studies
Results of the search
Electronic databases
1. Journal databases
RCT studies
Using the RCT string, the PUBMED search yielded 914 records, the EMBASE search yielded 616 records and the CENTRAL search yielded 127 records. After deduplication using ProCite software, we screened 1475 records of which 54 were identified as potentially eligible RCTs or cohort studies and the full texts were obtained. See Figure 1.
Study flow diagram of database yields using the RCT string
Cohort studies
Using the additional cohort string, the PUBMED search yielded 130 records, and the EMBASE search yielded 950 records. These were de‐duplicated electronically using EndNote reference management software, and 33 duplicate records were removed prior to manual checking of the remaining 1047 records. No studies in addition to those already selected for full text review in the RCT string search, were identified.
2. Conference databases
The www.aegis.com conference database search yielded 170 records of which 9 abstracts were selected for further assessment.
We also searched the conference web‐sites for the following specific conferences using a broad term 'child':
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International AIDS Society 2009: 305 records identified of which 16 were selected for further assessment
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International AIDS Society 2011:513 records identified of which 15 were selected for further assessment
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International AIDS Conference 2012: 115 records identified of which three were selected for further assessment; all relevant sessions reviewed and no additional relevant records identified
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CROI 2011: 69 records identified of which four were selected for further assessment
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CROI 2012: 85 records identified of which four were selected for further assessment
NS identified one study (Munyagwa 2012) from the conference searches which was published after the date the electronic journal database search. This study was excluded after an eligibility assessment of the full text. No other studies identified in the conference searching were in addition to those studies already reviewed in the electronic database searches, or contained data which was relevant to this review after complete data sets were obtained. We contacted a total of five abstract authors to confirm whether their abstracts contained the same data as that reported in publications.
3. Trials Registries
We searched ClinicalTrials.gov (http://clinicaltrials.gov/) on 9 July 2012 and retrieved 300 records of which 9 studies were selected for further assessment.
We also searched the World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) on 12 July 2012 and retrieved 12 records of which one study was selected for further assessment.
None of the 21 studies assessed met our inclusion criteria. in future updates we will capture the details of studies meeting our inclusion criteria under Characteristics of ongoing studies.
Searching other resources
To supplement the electronic searching for conference databases, we searched the following books of conference abstracts manually during August and September 2012:
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CROI 2009: 2 records were identified for further assessment
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CROI 2010: 2 records were identified for further assessment
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1st International Workshop on HIV Pediatrics (157 abstracts in total): 13 records identified for further assessment
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2nd International Workshop on HIV Pediatrics (123 abstracts in total); 10 records identified for further assessment
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3rd International Workshop on HIV Pediatrics (186 abstracts in total): 10 records identified for further assessment
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4th International Workshop on HIV Pediatrics (200 abstracts in total); 5 records identified for further assessment
Through discussions with experts in the field and prior discussions at conferences, we were aware of the PREDICT 2012 trial which was published during the conduct of this review. This study was reported in several of the above abstracts which we selected for further assessment. No additional eligible studies were identified in this way.
Included studies
RCTs
Following detailed eligibility assessment, two RCTs were identified as eligible (Ananworanich 2008; PREDICT 2012) from the database searches. Additional searches of conferences and the trials registries identified further abstracts which referred to these trials, but no additional RCTs were identified in this way.
Details of the included studies are reported in the table Characteristics of included studies.
In summary, two RCTs have evaluated the timing of initiating cART in HIV‐positive children aged 1 to 12 years, with CD4% between 15 and 24%, and no CDC clinical stage C disease. cART was initiated immediately on enrolment (IMMEDIATE group) or deferred until the CD4% dropped to < 15% (DEFERRED group). The first trial (Ananworanich 2008) commenced in December 2001 and was designed as a small feasibility study prior to the conduct of the larger trial which commenced in March 2006 (PREDICT 2012). Both trials were conducted in south‐east Asia: Ananworanich 2008 was conducted in Thailand with a sample size of 43 and PREDICT 2012 was conducted in Thailand and Cambodia with a sample size of 300.
Of note, no trials have been conducted only in the specific age group this review covers, viz. 24 to 59 months. In the Ananworanich 2008 trial, the median age of participants was 4.8 years (IQR: 2.7 to 6.6) and in the PREDICT 2012 trial, 59% (88/150) and 55% (83/150) of children were aged 1 to 6 years in the IMIMEDIATE and DEFERRED group respectively.
Cohorts
Following detailed eligibility assessment, several cohort studies were selected for further assessment of the full‐text. After discussions between the co‐authors, only one cohort study was deemed eligible (Yotebieng 2010). See the details of the study in the table Characteristics of included studies.
This study was an observational cohort of prospectively collected routine data of children infected with tuberculosis (TB) and compared the timing of initiation of cART using the number of days since TB treatment was initiated, rather than based on CD4 cell count or percentage. The cohort study commenced in April 2004 and took place in a paediatric clinic attached to a tertiary hospital in Soweto, South Africa.
The study included 573 children aged 1 to 15 years with a median age of 3.5 years (IQR: 1.4 ‐ 6.8). The median length of follow‐up was 9.6 months (IQR: 1.9 to 23.1) which was less than the median follow‐up of one year stipulated in our review criteria for study eligibility. However, after discussion among the co‐authors, we determined that given the paucity of data on ART initiation in TB populations, we would include the study in the current review.
Excluded studies
After assessing the full‐text articles 51 studies were excluded for the reasons detailed in Figure 1.
Risk of bias in included studies
The detail of the risk of bias are presented in the Characteristics of included studies and the graphical summary of the risk of bias is represented in Figure 2; Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
RCTs
In Ananworanich 2008 we were unable to assess the risk of bias in the randomisation and allocation procedures due to a lack of reporting and judged the risk of bias as unclear. We judged the risk of bias due to selection bias as low for the PREDICT 2012 trial as the random sequence was generated by a computer and allocation was done centrally.
Cohort
As Yotebieng 2010 is a cohort study, allocation was not done randomly. The study is therefore at high risk of selection bias but it was analysed in a way that will have reduced bias (mimicking a randomised trial ‐ see other sources of bias below).
Blinding
RCTs
Both trials were open‐label and thus neither participants and their caregivers nor personnel were blinded, potentially introducing a high risk of performance bias.
In the Ananworanich 2008 trial we were not able to determine whether outcomes were assessed in a blinded manner and we rated the risk of bias as unclear. In PREDICT 2012, the primary outcomes were assessed by an independent committee blinded to allocation and the risk of detection bias was low.
Cohort
The personnel and caregivers were not blinded to whether the children were receiving cART or not and we judged the risk of performance bias as high.
Although the authors do not report on blinding for the two primary outcomes of death and virological suppression (in those patients receiving cART) or on how death was confirmed, we judged the lack of blinding as unlikely to result in a high risk of detection bias given the nature of these outcomes
Incomplete outcome data
RCTs
Both trials had high follow‐up rates (≤ 10%) and risk of attrition bias was low.
Cohort
The overall loss to follow‐up was 13% and the study used time‐to‐event analysis to address this. The authors also report that the children lost to follow‐up did not differ from those remaining in care in any of the baseline characteristics or timing of ART initiation and we judged the risk of bias to be low.
Selective reporting
RCTs
We were able to compare the protocol in www.clinicaltrials.gov with the PREDICT 2012 report and no selective reporting was noted with a low risk of bias. We were not able to identify the protocol for Ananworanich 2008 and rated the risk of bias as unclear.
Cohort
We were not able to compare the protocol with the results and rated the risk of bias as unclear.
Other potential sources of bias
RCTs
We did not identify other potential sources of bias in either trial.
Cohort
For cohort studies we assessed whether the analysis had appropriately controlled for time‐dependent confounding. In the Yotebieng 2010 cohort the authors made use of inverse probability‐of‐treatment and censoring (IPTC) weighting of marginal structural models, an appropriate statistical analysis to control for time‐dependent confounding, which mimics a randomised trial. We rated the risk as low.
Effects of interventions
See: Summary of findings for the main comparison IMMEDIATE initiation of cART compared to DEFERRED initiation of cART for HIV‐positive, treatment‐naive children aged one to 12 years old; Summary of findings 2 Subgroup analysis: IMMEDIATE initiation of cART compared to DEFERRED initiation of cART for HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old)
We present the outcomes as these were reported in the study reports and include any additional outcomes where these were not included in our outcomes list in the protocol. As the two trials were conducted in similar populations we did not consider clinical or methodological heterogeneity as barriers to meta‐analysis. Therefore we have combined the results from both trials in meta‐analyses using the random effects model where possible. Where indicated, we conducted further sensitivity analyses using different analytical models. We report the results from our RevMan calculations and provide narrative results where it was not possible to extract the data for further analysis e.g. where adjusted analyses were conducted or where medians were reported.
The authors of both trials provided unpublished age‐specific data for the 24 to 59 month age group for outcomes determined to be most critical for guideline development, and we present these results as a post hoc subgroup analysis and report on this in the text.
For the results from the cohort study, we present the adjusted and weighted results and not the crude results due to the inherent confounding present in unadjusted analyses.
Mortality
In the PREDICT 2012 trial, one death was observed in the IMMEDIATE group . Due to the low number of events the results are unlikely to be meaningful (see Analysis 1.1). This death was in the IMMEDIATE group in the 24 to 59 month age group. See Analysis 2.1.
In the Yotebieng 2010 cohort study, death was compared in three different time periods: 1) cART initiation after 15 days following TB treatment compared with within 15 days; 2) cART initiation after 30 days (1 month) following TB treatment compared with within 30 days (1 month); and 3) cART initiation after 60 days following TB treatment compared within 60 days.
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More than 15 days vs less than 15 days:
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The authors calculated a weighted HR accounting for time‐dependent level of immuno‐suppression, viral load, weight‐for‐age Z score and age at TB treatment initiation. The reported weighted HR was 0.82 (95% CI: 0.48, 1.41). See Analysis 3.1. (note that the calculated 95% CI in RevMan differs very slightly from the 95% CI reported by the authors).
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More than 30 days vs less than 30 days:
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The authors calculated a weighted HR of 0.86 (95% CI: 0.46, 1.60). Weighting accounted for time‐dependent level of immuno‐suppression, viral load, weight‐for‐age Z score and age at TB treatment initiation. See Analysis 3.1 (note that the calculated 95% CI in RevMan differs very slightly from the reported 95% CI).
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More than 60 days vs less than 60 days:
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The authors calculated a weighted HR of 1.32 (95% CI: 0.55, 3.16). Weighting accounted for time‐dependent level of immuno‐suppression, viral load, weight‐for‐age Z score and age at TB treatment initiation. See Analysis 3.1 (note that the calculated 95% CI in RevMan differs very slightly from the reported 95% CI).
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From Analysis 3.1 a dose‐response gradient can be observed in the increasing HR values. This indicates that deferring cART initiation to later than 15 days after commencing TB treatment was protective against death but this effect was reduced at 30 days. Deferred initiation became potentially harmful if cART was deferred beyond 60 days. None of these HR were statistically significantly different from 1.
NOTE: The denominators in Analysis 3.1 vary with each cut‐off time period due to censoring (the authors provide an example of a child whose follow‐up ended 25 days after TB initiation and prior to cART who would be classified for the 15 days cut‐off but not for the 30 or 60 day cut‐off periods).
Morbidity
AIDS‐free survival
In the PREDICT 2012 trial, the authors report an intention‐to‐treat analysis of AIDS‐free survival rates for all children at week 144 using the Kaplan‐Meier product limit method and the IMMEDIATE group as the reference group. At week 144 AIDS‐free survival rates in intention to treat analysis were 98.7% (95%CI: 94.7, 99.7%) in the DEFERRED group and 97.9% (95% CI: 93.7, 99.3%) in the IMMEDIATE group (Log rank p=0.6). In per protocol analysis, AIDS‐free survival rates at week 144 were 98.7% (95% CI: 94.7, 99.7%) in the DEFERRED group and 98.6% (95% CI 94.5‐99.6%) in the IMMEDIATE group (Log rank p=0.96).
CDC category C disease
No children in the Ananworanich 2008 trial developed CDC Category C disease. In the PREDICT 2012 trial three children in the IMMEDIATE group developed CDC Category C disease (Pneumocystis jiroveci pneumonia (1); Pneumonia/Sepsis leading to death (1); Disseminated Penicilliosis (1)) and two children developed Category C disease in the DEFERRED group (Oesaphageal Candidiasis (1); Extrapulmonary Tuberculosis (1)). We calculated the relative risk (RR) in RevMan (See Analysis 1.2). The RR was 1.50 (95% CI: 0.25, 8.85; p = 0.65). The authors report CDC category C events incidence as 4.9 per 1000 person‐years of follow‐up (PYFU) in the DEFERRED group and 7.6 per 1000 PYFU in the IMMEDIATE group (unadjusted hazard ratio (HR) = 0.7 (95%CI: 0.1, 3.9; p=0.6) and HR adjusted for age and gender = 0.8 (95%CI: 0.1, 4.6; p=0.8).
In the subgroup analysis of the 24 to 59 month age group in the PREDICT 2012 trial, the RR was 0.96 (95% CI: 0.06, 14.87; p = 0.98). See Analysis 2.2.
CDC Category B disease
We combined the data from both trials for children in all age groups using the random effects model. The RR was 1.42 (95% CI: 0.14, 14.28; p = 0.77; see Analysis 1.3). We categorised the pulmonary TB observed in the Ananworanich 2008 trial as CDC Category B disease. The results show that there was a greater likelihood of CDC Category B diseases in the IMMEDIATE group than in the DEFERRED group but that this was not statistically significant. However, statistical heterogeneity was present (Chi² = 2.84, df = 1; p = 0.09) with the I² = 65% indicating that there was substantial heterogeneity not explained by chance.
We conducted a sensitivity analysis and re‐analysed the data using the Peto Odds Ratio (POR) because it is the recommended approach for uncommon events, particularly when there are trials with zero events as in the Ananworanich 2008 trial. The POR was 0.70 (95% CI: 0.39, 1.24; p = 0.22; see Analysis 1.4). Note that the weighting for Ananworanich 2008 changes from 33.5% to 7.8% in this analysis. These results indicate that the odds of developing CDC Category B events was 0.7 times lower in the IMMEDIATE group than in the DEFERRED group. However, heterogeneity was present (Chi² = 5.22, df = 1; p = 0.02) with an I² = 81%.
The high level of heterogeneity would suggest that these results should not be combined in a meta‐analysis, although the second analysis which down‐weights the Ananworanich 2008 trial is probably more appropriate. The authors of PREDICT 2012 report that CDC class B incidence was 110 (95%CI: 80, 147) events per 1000 PYFU in the DEFERRED group and 88 (95%CI: 61,122) events per 1000 PYFU in the IMMEDIATE group (incidence rate ratio (IRR) = 1.25; 95% CI: 0.8, 1.9; p = 0.3). Therefore, early treatment of 45 children for a year rather than deferring treatment until CD4 falls to below 15% would prevent 1 CDC category B event. This result is more consistent with that of Analysis 1.4 (note the reference or control group is the IMMEDIATE group in the results reported from the PREDICT 2012 trial, and in Analysis 1.4 the reference group is the DEFERRED group).
In the meta‐analysis of the subgroups of 24 to 59 month age groups, we performed the identical sensitivity analysis to that reported above. The result was similar to that of all age groups (POR = 0.76; 95% CI: 0.29, 2.02; p = 0.59). See Analysis 2.4.
Pulmonary TB
The incidence of pulmonary TB was low in both trials. We combined the results for children of all age groups in a random effects meta‐analysis (see Analysis 1.5). The risk of developing pulmonary TB was greater in the IMMEDIATE group than the DEFERRED group but the difference was not statistically significant (RR = 3.21, 95% CI: 0.52, 19.89; p = 0.21). Heterogeneity was minimal (Chi² = 0.99, df = 1; p = 0.32); with an I² = 0% indicating no important statistical heterogeneity.
Given the low number of events we again conducted a sensitivity analysis using the Peto Odds Ratio and found similar results (POR: 3.49, 95% CI: 0.67, 18.13; p = 0.14) with likely unimportant heterogeneity (Chi² = 1.20, df = 1; p = 0.27; I² = 17%). The authors of the Ananworanich 2008 trial report that the four TB events were not considered to be the result of immune reconstitution syndromes due to the large gap between ART initiation and TB diagnosis (median time of 60 weeks with range 48 to 72 weeks). All four children responded well to anti‐TB treatment.
In the meta‐analysis of the subgroups of 24 to 59 month age groups, one case of pulmonary TB was observed in each group (RR = 1.19; 95% CI: 0.19, 7.27; p = 0.85) with low heterogeneity (Chi² = 1.36, df = 1; p = 0.24; I² = 26%).
Median time before development of CDC B or C events
Both trials reported on the median time before development of either CDC B or C events for children of all age groups. In the Ananworanich 2008 trial, events developed in the IMMEDIATE group after a median of 60 (IQR: 48 ‐ 72) weeks and no events developed in the DEFERRED group. In the PREDICT 2012 trial, events developed after a median of 9 (IQR: 4 ‐ 30) weeks since enrolment in the IMMEDIATE group compared with a median of 57 (IQR: 34 ‐ 101) weeks in the DEFERRED group.
Virological and immunological response
Virological suppression
1. Proportion of children on cART with HIV‐RNA < 50 copies/ml
Both trials provided data on the proportion of children of all age groups on cART with HIV‐RNA < 50 copies/ml, but the PREDICT 2012 trial restricted analyses to children on first‐line cART for at least 48 weeks whereas this was not the case in the Ananworanich 2008 trial so we cannot be certain that the time periods are identical. We combined the data in a random effects meta‐analysis (RR = 0.96; (95% CI: 0.84, 1.09; p = 0.52; see Analysis 1.7). From these data it is evident that the probability of a viral load < 50 copies/ml was similar in the IMMEDIATE group and the DEFERRED group. There was no statistical heterogeneity (Chi² = 0.29, df = 1; p = 0.59; I² = 0%).
In the subgroup analysis of the 24 to 59 month age group in the PREDICT 2012 trial, the results were similar to that for all age groups (RR = 1.11; 95%CI: 0.86, 1.43; p = 0.43).
2. Proportion of children on cART with HIV‐RNA < 400 copies/ml
The Yotebieng 2010 cohort study assessed virologic suppression in 70% (324/461) of children who initiated cART and who had at least one viral load measurement after cART initiation. The results were analysed in the same three time‐periods as for mortality.
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More than 15 days vs less than 15 days:
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The authors calculated an adjusted HR which accounted for baseline differences. The reported adjusted HR was 0.98 (95% CI: 0.76, 1.26; see Analysis 3.2).
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More than 30 days vs less than 30 days:
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The authors calculated a HR adjusted for baseline differences of 0.95 (95% CI: 0.73, 1.23; see Analysis 3.2).
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More than 60 days vs less than 60 days:
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The authors calculated an adjusted HR of 0.84 (95% CI: 0.61, 1.15; see Analysis 3.2).
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As for the analysis of death (see Analysis 3.1) we noted a dose‐response gradient in the hazard ratios for virologic suppression: children were less likely to achieve virologic suppression for each increment in deferred time to cART initiation, however, none of the HRs were statistically significantly different from 1.
Median viral load at study end
The authors of the Ananworanich 2008 trial report on the median viral load at the end of the study (median of 134 weeks follow‐up) for children of all age groups. In the IMMEDIATE group, there was a statistically significantly lower median viral load of 1.7 log10 copies/ml (IQR 1.7 – 2.5) compared with the DEFERRED group viral load of 3.1 log10 copies/ml (IQR 1.7 – 4.5; p = 0.039). The median change in viral load at study end was ‐2.8 log10 copies/ml (IQR ‐3.4 to ‐1.9) in the IMMEDIATE group compared with ‐1.8 log10 copies/ml (IQR: ‐3.2 to ‐0.3). The p value for this difference was p = 0.079.
Median CD4% at study end
For children of all age groups, the authors of Ananworanich 2008 reported that at the end of the study (median of 134 weeks follow‐up), the median CD4% in the IMMEDIATE group was statistically significantly higher at 31% (IQR: 24 ‐ 39) compared with the DEFERRED group of median CD4% 23% (IQR: 17 ‐ 31; p = 0.032). The median CD4% change was 13.5% (IQR: 4 ‐ 18) in the IMMEDIATE group compared with 3% (IQR: ‐2 to 13) in the DEFERRED group (p = 0.012).
Mean CD4% and change in CD4% at week 144
In the PREDICT 2012 trial, the authors report a mean CD4% at week 144 of 33.2% (SD: 6.4) in the IMMEDIATE group compared with a mean CD4% of 24.8% (SD: 7.4) in the DEFERRED group for children of all age groups. We calculated the mean difference (see Analysis 1.9) as 8.40% (95% CI: 6.83, 9.97; p < 0.00001). At the end of the study the mean CD4% in the IMMEDIATE group was thus higher than in the DEFERRED group. The authors also conducted a Kaplan‐Meier analysis to determine the probability of achieving CD4% ≥30% at week 96. The probability was 0.83 (95% CI 0.77‐0.89) in the IMMEDIATE group and 0.74 (95% CI 0.62‐0.84) in the DEFERRED group (p < 0.001) indicating that the children in the IMMEDIATE group were more likely to achieve CD4% ≥30% at week 96. In the subgroup analysis of the 24 to 59 month age group in the PREDICT 2012 trial, the mean CD4% at the end of the trial was 5.9% higher in the IMMEDIATE group than in the DEFERRED group (95%CI: 2.74, 9.06; p = 0.0003; see Analysis 2.7).
Proportion of children with CD4% <15% at study end
In Ananworanich 2008 no children in the IMMEDIATE group had a CD4% <15% at study end and three children did in the DEFERRED group ‐ all of whom had less than four week of cART. In PREDICT 2012, using the Last Observation Carried Forwards (LOCF) approach, one child in the IMMEDIATE group and nine children in the DEFERRED group had a CD4% <15% at study end (unpublished data). The meta‐analysis of the combined data showed that fewer children in the IMMEDIATE group had CD4% <15% at study end compared with in the DEFERRED group (RR = 0.11; 95% CI: 0.02, 0.60; p = 0.01). There was no statistical heterogeneity (see Analysis 1.10). In the 24 to 59 month age group, the proportion of children with CD4% <15% in the IMMEDIATE group was lower than that in the DEFERRED group but the results were less precise and no longer statistically significant (RR = 0.40; 95% CI: 0.06, 2.52; p = 0.33, see Analysis 2.8).
Growth parameters
Weight
In the PREDICT 2012 trial, for all age groups, the mean weight gain per year was 2.2kg (SD: 1.1) in the IMMEDIATE group and 2.1kg (SD: 1.2) in the DEFERRED group, for a mean difference of 0.1kg (95% CI: ‐0.16, 0.36; p = 0.45; see Analysis 1.11). Median weight‐for‐age z scores at study end were available for all children in both trials. In the Ananworanich 2008 trial, the score in the IMMEDIATE group was ‐1.1 (IQR: ‐1.5 to ‐0.8) and in the DEFERRED group the score was ‐1.0 (IQR: ‐1.7 to 0.2). In the PREDICT 2012 trial, the score was ‐1.27 (IQR: ‐1.78 to ‐0.39) in the IMMEDIATE group and ‐1.40 (IQR: ‐1.99 to ‐0.89) in the DEFERRED group. These scores indicate that growth was compromised in both groups in both trials (see Analysis 1.12). The change in median weight‐for‐age z score was calculated in PREDICT 2012. In the IMMEDIATE group, the change in median score was 0.26 (IQR: ‐2.00 to ‐0.75) which was a greater gain in weight than the median change in score of 0.04 (IQR: ‐0.28 to 0.34) in the DEFERRED group (p = 0.02 for difference). In a multivariate model, the authors found that the effect of group allocation remained significant (p = 0.01) after adjusting for baseline CD4% (< 20% and ≥ 20%), age (< 5 years and ≥ 5 years), haemoglobin level, and HIV RNA level. In the analysis of the 24 to 59 month age group in the PREDICT 2012 trial, weight gain was similar in the IMMEDIATE and DEFERRED groups, with a mean difference of ‐ 0.03kg (95% CI: ‐0.25, 0.19; p = 0.79, see Analysis 2.9).
Height
In the PREDICT 2012 trial, for all ages, the mean height gain per year was 5.4cm (SD: 1.4) in the IMMEDIATE group and 4.9cm (SD: 1.2) in the DEFERRED group, for a mean difference of 0.50cm (95% CI: 0.20, 0.80; p = 0.0009); see Analysis 1.13). Median height‐for‐age z scores at study end were available in both trials. In the Ananworanich 2008 trial, the score in the IMMEDIATE group was ‐1.4 (IQR: ‐2.0 to ‐0.8) and in the DEFERRED group the score was ‐0.8 (IQR: ‐1.3 to ‐0.4). In the PREDICT 2012 trial, the score was ‐1.50 (IQR: ‐2.35 to ‐0.54) in the IMMEDIATE group and ‐1.73 (IQR: ‐2.42 to ‐0.95) in the DEFERRED group. These scores indicate that height was compromised in both groups in both trials (see Analysis 1.14). The change in median height‐for‐age z score was calculated in the PREDICT 2012 trial. In the IMMEDIATE group, the change in median score was 0.25 (IQR: ‐0.21 to ‐0.69) in the IMMEDIATE group and the median change in score was ‐0.02 (IQR: ‐0.40 to 0.34) in the DEFERRED group (p = 0.004 for difference). The children in the IMMEDIATE group thus gained more height than those in the DEFERRED group. In an adjusted analysis, the authors found that the effect of group allocation remained significant (p = 0.002) after adjusting for baseline CD4% (< 20% and ≥ 20%), age (< 5 years and ≥ 5 years), haemoglobin level, and HIV RNA level. In the analysis of the 24 to 59 month age group in PREDICT 2012, mean height gain was slightly greater in the IMMEDIATE group compared to the DEFERRED group, with a mean difference of 0.3cm (95%CI: ‐0.28, 0.88; p = 0.31; see Analysis 2.10).
Neurological parameters
In the PREDICT 2012 trial, the neurodevelopment sub‐study was phased in after the main study had started and baseline Beery Visual Motor Integration assessment was only performed in 71 children. The mean baseline scores for children of all age groups in the IMMEDIATE and DEFERRED groups were 81.5 (SD: 17.2) and 87.1 (SD: 14.4) respectively. There was no statistically significant difference between the groups at study end (week 144). The mean difference was ‐1.40 (95% CI: ‐4.70, 1.90; p = 0.41; see Analysis 1.15). The authors report that for the 71 children who had a baseline assessment, the mean difference in Beery standard score change from baseline from week 0 to 144 between IMMEDIATE and DEFERRED arms was –4·37 (–12·00 to 3·26; p =0·26). In the subgroup analysis, the Beery Visual Motor Integration score was available for 42 and 40 of the children aged 24 to 59 months in the IMMEDIATE and DEFERRED group respectively. Again, there was no statistically significant difference between the groups at study end. The mean difference was 2.3 (95% CI: ‐4.37, 8.97; p = 0.50; see Analysis 2.11).
Adverse events
The Ananworanich 2008 trial reported on the proportion of children of all age groups with adverse events, but did not provide data on the severity of the events. All children in the DEFERRED group and 92% of those in the IMMEDIATE group experienced an adverse event (RR = 0.92; 95% CI: 0.80, 1.07; p = 0.29). Both trials reported on the proportion of children of all age groups with adverse events related to cART. Children in the IMMEDIATE group were more likely to develop cART‐related adverse events than those in the DEFERRED group but this was not statistically significant (RR = 1.87; 95% CI: 0.77, 4.51; p = 0.17) and there was little statistical heterogeneity (Chi² = 0.96, df = 1; p = 0.33; I² = 0%). The proportion of children in the 24 to 59 month age group in the PREDICT 2012 trial with ART‐related Grade 3 or 4 events was lower in the IMMEDIATE group than in the DEFERRED group (RR = 0.48; 95%CI: 0.04, 5.11; p = 0.54; see Analysis 2.12).
GRADE ASSESSMENTS
GRADE assessments were conducted for all outcomes where data was available to enter into GRADEPro. For the Summary of Findings tables we selected seven outcomes per comparison based on what is most important to patients.
Overall, the quality of evidence observed in the two trials was low or very low. For evidence for initiation of cART in all age groups, we down‐graded the evidence for indirectness (as the age group was not specific to the population group of interest) and for serious or very serious imprecision. The PREDICT 2012 trial was well‐conducted with the sample size planned to be powered for the primary outcome of AIDS‐free survival; however, due to the low number of events and slow disease progression, the study was ultimately under‐powered to adequately assess this outcome. Note that we did not create a Summary of Findings Table for the outcome of AIDS‐free survival. For all other outcomes, the sample size was considered small and for most outcomes the event rate was extremely small, leading to imprecision in the results. This remained when combined with the data from the Ananworanich 2008 trial as the trial added only 43 children to the total. See summary of findings Table for the main comparison.
For the post hoc subgroup analysis of ages 24 to 59 months, we did not downgrade for indirectness as the population was specific to the question of this review. However, as this was a post hoc analysis, the risk of selection bias resulted in downgrading for risk of bias. We continued to downgrade for very serious imprecision due to the small sample size, the low event rate and wide confidence intervals. See summary of findings Table 2.
For the evidence arising from the observational study (Yotebieng 2010), the quality of evidence was rated as very low for all outcomes. We downgraded for risk of bias due to a residual risk of selection bias: we cannot be certain that the IPTC weighting of marginal structural models removed all bias. As the study included children aged one to 15 years we downgraded for indirectness. Due to the low number of events, we downgraded for serious imprecision.
Using the GRADE approach, we are very uncertain of the effect estimates overall.
Discussion
Summary of main results
Our review identified limited evidence from two small randomised controlled trials evaluating the effects of initiating cART in children aged one to 12 years immediately at CD4% between 15 and 25%, compared with deferring cART until pre‐defined immunological and clinical thresholds. No differences in outcomes were noted between the randomised groups.
We identified a single cohort study which compared delaying cART in HIV‐infected children co‐infected with TB with initiating cART soon after commencing TB treatment. Delaying cART initiation to later than 15 days after commencing TB treatment was protective against death but this effect was reduced at 30 days, and potentially harmful if cART was deferred beyond 60 days.
None of the studies exclusively included children within the specific focus age of two to five years.
Overall completeness and applicability of evidence
The trials included in this review did not evaluate the effects of immediate or deferred initiation of cART in children aged two to five years, but in the broader age group of one to 12 years. Although we were able to obtain age‐specific data from the two trials, the evidence generated from these post hoc sub‐group analyses is less robust given that randomisation did not take place within the age‐specific sub‐group. Stronger evidence would be gained from replicating trials within the specific age group, but it is unlikely that new trials will assess this in future. Antiretroviral treatment has been indicated for all HIV‐positive infants and children less than two years of age since 2010 (WHO 2010b). As cART becomes increasingly available across the world, identification and recruitment into trials of children aged two or more may no longer be feasible.
The evidence generated from the two trials and the single included cohort study arise from resource‐constrained settings affected by the HIV/AIDS epidemic (Thailand, Cambodia and South Africa). The participants in the trials are therefore likely to be representative of HIV‐infected children living in poverty. However, the children and their carers were from urban settings and in this respect the results may not be generalizable to those children and their carers living in impoverished rural areas.
Quality of the evidence
The quality of the methodological conduct for the larger PREDICT 2012 trial was judged to be high and the risk of bias was likely to be low to moderate for both trials overall. However, when using the GRADE approach to assess the overall quality of the evidence generated in the review, the quality of the evidence was rated as low or very low. This was due to the indirectness of the included population and the marked imprecision present in the results. Imprecision was driven largely by the small sample size and low event rates. The sample size of the PREDICT 2012 trial was powered for the primary outcome of AIDS‐free survival; however, due to the low number of events and slow disease progression, the study was ultimately under‐powered to adequately assess this and this reduced the quality of the evidence.
In the Yotebieng 2010 cohort study, close attention was paid to confounding and the authors addressed this via weighted adjusted analyses which included adjusting for time‐dependent level of immuno‐suppression, viral load, weight‐for‐age Z score and age at TB treatment initiation. Despite this, the quality of evidence generated by a single cohort study was appraised in GRADE as providing very low evidence due to selection bias (lack of randomisation), indirectness and imprecision.
Potential biases in the review process
Possible selection biases in the review process were minimised by using a comprehensive search strategy to identify studies and, wherever possible, independently selecting and appraising the studies. In addition to searching journal and conference electronic databases, we conducted hand‐searching of several important conference abstract books, including the International Workshop on HIV Pediatrics and recent relevant conferences not yet included in the electronic databases. We contacted several authors of conference abstracts to confirm whether the data in their abstract corresponded to subsequent journal articles or to assess whether the reported data was eligible for inclusion in this review. it is unlikely that important trials have been missed given the high‐profile nature of the topic and the close partnership established with agencies and organizations working in this area.
Data extraction was done independently by one author and then checked by a second author. Ideally all data extraction should be conducted independently by two authors; however, this was not feasible given the time constraints of the rapid review process. The results were presented at a WHO Guidelines Committee Meeting in December 2012 providing a further check of the data by experts and investigators familiar with the data, thereby reducing any potential measurement bias introduced by a single author conducting data extraction.
We conducted several sensitivity analyses using different statistical models and estimates of effect. This was especially important to do for several of the analyses which were limited by small denominators and few events (Higgins 2009). Conducting sensitivity analyses allowed us to interrogate the data closely and consider the robustness of the findings.
Agreements and disagreements with other studies or reviews
We were unable to identify any other studies or reviews addressing the question of when to start cART in children aged 24 to 59 months. Lewis et al monitored 127 children enrolled in the Paediatric European Network for the Treatment of AIDS 5 and found that initiation of cART at higher CD4 counts may improve long term immune reconstitution and may potentially reduce the so‐called 'non‐AIDS' morbidity developed as a result of immune activation without causing harm or significantly increasing drug‐related toxicity (Lewis 2011).
Study flow diagram of database yields using the RCT string
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 1 Death.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 2 CDC Category C disease (number of children).
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 3 CDC Category B disease (numbers of children) Relative Risk.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 4 CDC Category B disease (numbers of children) Peto Odds Ratio.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 5 Pulmonary TB (clinically diagnosed).
| Study | IMMEDIATE (time on ART before events) | DEFERRED (time from enrolment to events) |
| Ananworanich 2008 | 60 (IQR: 48 ‐ 72) weeks | Nil |
| PREDICT 2012 | 9 (IQR: 4 ‐ 30) weeks | 57 (IQR: 34 ‐ 101) weeks |
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 6 Median time before development of CDC B or C event.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 7 Proportion of children on ART with HIV‐RNA < 50 copies/ml.
| Study | IMMEDIATE | DEFERRED | P value |
| Ananworanich 2008 | Median (IQR): 31 (24 ‐ 39) | Median (IQR): 23 (17 ‐ 31) | 0.032 |
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 8 Median CD4% at study end.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 9 Mean CD4% at week 144.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 10 Proportion of children with CD4% < 15% at study end.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 11 Mean weight gain per year in kg.
| Study | IMMEDIATE | DEFERRED |
| Ananworanich 2008 | ‐1.1 (IQR: ‐1.5 to ‐0.8) | ‐1.0 (IQR: ‐1.7 to 0.2) |
| PREDICT 2012 | ‐1.27 (IQR: ‐1.78 to ‐.0.39) | ‐1.40 (IQR: ‐1.99 to ‐0.89) |
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 12 Median weight‐for‐age Z score at study end (134 ‐ 144 weeks).
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 13 Mean height gain per year in cm.
| Study | IMMEDIATE | DEFERRED |
| Ananworanich 2008 | ‐1.4 (IQR: ‐2.0 to ‐0.8) | ‐0.8 (IQR: ‐1.3 to ‐0.4) |
| PREDICT 2012 | ‐1.50 (IQR: ‐2.35 to ‐.0.54) | ‐1.73 (IQR: ‐2.42 to ‐0.95) |
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 14 Median height‐for‐age Z score at study end (134 ‐ 144 weeks).
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 15 Mean standardized score on Beery VMI at 144 weeks.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 16 Proportion of children with adverse events.
Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 17 Proportion of children with ART‐related adverse events.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 1 Death.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 2 CDC Category C disease (number of children).
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 3 CDC Category B disease (numbers of children) Relative Risk.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 4 CDC Category B disease (numbers of children) Peto Odds Ratio.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 5 Pulmonary TB (clinically diagnosed).
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 6 Proportion of children on ART with HIV‐RNA < 50 copies/ml.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 7 Mean CD4% at week 144.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 8 Proportion of children with CD4% < 15% at study end.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 9 Mean weight gain per year in kg.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 10 Mean height gain per year in cm.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 11 Mean standardized score on Beery VMI at 144 weeks.
Comparison 2 SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT), Outcome 12 Proportion of children with ART‐related Grade 3 or 4 adverse events.
Comparison 3 ADJUSTED/WEIGHTED EARLY vs DEFERRED initiation of ART in children with TB and HIV, Outcome 1 Death.
Comparison 3 ADJUSTED/WEIGHTED EARLY vs DEFERRED initiation of ART in children with TB and HIV, Outcome 2 Virologic suppression.
| IMMEDIATE initiation of cART compared to DEFERRED initiation of cART for HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged one to 12 years old | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| DEFERRED initiation of cART | IMMEDIATE initiation of cART | |||||
| Death | 0 per 1000 | 0 per 1000 | RR 3 | 343 | ⊕⊝⊝⊝ | |
| CDC Category C disease (number of children) | 12 per 1000 | 18 per 1000 | RR 1.5 | 343 | ⊕⊝⊝⊝ | |
| CDC Category B disease (numbers of children) Peto Odds Ratio | 189 per 1000 | 141 per 1000 | OR 0.7 | 343 | ⊕⊝⊝⊝ | |
| Proportion of children on ART with HIV‐RNA < 50 copies/ml (Copy) | 815 per 1000 | 783 per 1000 | RR 0.96 | 238 | ⊕⊕⊝⊝ | |
| Weight gain per year in kg | The mean weight gain per year in kg in the intervention groups was | 300 | ⊕⊕⊝⊝ | |||
| Height gain per year in cm | The mean height gain per year in cm in the intervention groups was | 300 | ⊕⊕⊝⊝ | |||
| Standardized score on Beery VMI at 144 weeks | The mean standardized score on Beery VMI at 144 weeks in the intervention groups was | 272 | ⊕⊕⊝⊝ | |||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| DEFERRED initiation of cART | ||||||
| 1 As the trials were open‐label neither participants nor caregivers were blinded. However outcome assessors were blinded in the PREDICT trial. Attrition was low in both trials. Information on the randomisation procedure was lacking in Ananworanich 2008. However, given that this trial is relatively small, we judged the overall risk of bias to be low for the two trials together. | ||||||
| SUBGROUP ANALYSIS: IMMEDIATE initiation of cART compared to DEFERRED initiation of cART in HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Patient or population: HIV‐positive, treatment‐naive children aged 24 to 59 months (2 to 5 years old) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT) | |||||
| Death | 0 per 1000 | 0 per 1000 | RR 2.88 | 122 | ⊕⊝⊝⊝ | |
| CDC Category C disease (number of children) | 16 per 1000 | 15 per 1000 | RR 0.96 | 122 | ⊕⊝⊝⊝ | |
| CDC Category B disease (numbers of children) Peto Odds Ratio | 239 per 1000 | 167 per 1000 | OR 0.64 | 94 | ⊕⊝⊝⊝ | |
| Proportion of children on ART with HIV‐RNA < 50 copies/ml | 789 per 1000 | 876 per 1000 | RR 1.11 | 67 | ⊕⊝⊝⊝ | |
| Mean weight gain per year in kg | The mean weight gain per year in kg in the intervention groups was | 94 | ⊕⊝⊝⊝ | |||
| Mean height gain per year in cm | The mean height gain per year in cm in the intervention groups was | 94 | ⊕⊝⊝⊝ | |||
| Mean standardized score on Beery VMI at 144 weeks | The mean standardized score on Beery VMI at 144 weeks in the intervention groups was | 82 | ⊕⊝⊝⊝ | |||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 This is a subgroup analysis within each of the Ananworanich 2009 and PREDICT 2012 trials. Randomisation was not conducted within the sub‐group. For Ananworanich 2008, the proportion of children aged 24 to 59 months in the IMMEDIATE group was 46% (11/24) and in the DEFERRED group it was 89% (17/19). This differential could introduce selection bias. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Death Show forest plot | 2 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.12, 73.06] |
| 2 CDC Category C disease (number of children) Show forest plot | 2 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 1.5 [0.25, 8.85] |
| 3 CDC Category B disease (numbers of children) Relative Risk Show forest plot | 2 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 1.42 [0.14, 14.28] |
| 4 CDC Category B disease (numbers of children) Peto Odds Ratio Show forest plot | 2 | 343 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.70 [0.39, 1.24] |
| 5 Pulmonary TB (clinically diagnosed) Show forest plot | 2 | 343 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.21 [0.52, 19.89] |
| 6 Median time before development of CDC B or C event Show forest plot | Other data | No numeric data | ||
| 7 Proportion of children on ART with HIV‐RNA < 50 copies/ml Show forest plot | 2 | 238 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.84, 1.09] |
| 8 Median CD4% at study end Show forest plot | Other data | No numeric data | ||
| 9 Mean CD4% at week 144 Show forest plot | 1 | 300 | Mean Difference (IV, Random, 95% CI) | 8.40 [6.83, 9.97] |
| 10 Proportion of children with CD4% < 15% at study end Show forest plot | 2 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.02, 0.60] |
| 11 Mean weight gain per year in kg Show forest plot | 1 | 299 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.16, 0.36] |
| 12 Median weight‐for‐age Z score at study end (134 ‐ 144 weeks) Show forest plot | Other data | No numeric data | ||
| 13 Mean height gain per year in cm Show forest plot | 1 | 300 | Mean Difference (IV, Fixed, 95% CI) | 0.5 [0.20, 0.80] |
| 14 Median height‐for‐age Z score at study end (134 ‐ 144 weeks) Show forest plot | Other data | No numeric data | ||
| 15 Mean standardized score on Beery VMI at 144 weeks Show forest plot | 1 | 272 | Mean Difference (IV, Fixed, 95% CI) | ‐1.40 [‐4.70, 1.90] |
| 16 Proportion of children with adverse events Show forest plot | 1 | 43 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.80, 1.07] |
| 17 Proportion of children with ART‐related adverse events Show forest plot | 2 | 343 | Risk Ratio (M‐H, Random, 95% CI) | 1.87 [0.77, 4.51] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Death Show forest plot | 2 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 2.88 [0.12, 68.88] |
| 2 CDC Category C disease (number of children) Show forest plot | 2 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.06, 14.87] |
| 3 CDC Category B disease (numbers of children) Relative Risk Show forest plot | 2 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.24, 3.73] |
| 4 CDC Category B disease (numbers of children) Peto Odds Ratio Show forest plot | 2 | 122 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.76 [0.29, 2.02] |
| 5 Pulmonary TB (clinically diagnosed) Show forest plot | 2 | 122 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.19, 7.27] |
| 6 Proportion of children on ART with HIV‐RNA < 50 copies/ml Show forest plot | 1 | 67 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.86, 1.43] |
| 7 Mean CD4% at week 144 Show forest plot | 1 | 94 | Mean Difference (IV, Random, 95% CI) | 5.90 [2.74, 9.06] |
| 8 Proportion of children with CD4% < 15% at study end Show forest plot | 2 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.06, 2.52] |
| 9 Mean weight gain per year in kg Show forest plot | 1 | 94 | Mean Difference (IV, Fixed, 95% CI) | ‐0.03 [‐0.25, 0.19] |
| 10 Mean height gain per year in cm Show forest plot | 1 | 94 | Mean Difference (IV, Fixed, 95% CI) | 0.30 [‐0.28, 0.88] |
| 11 Mean standardized score on Beery VMI at 144 weeks Show forest plot | 1 | 82 | Mean Difference (IV, Fixed, 95% CI) | 2.30 [‐4.37, 8.97] |
| 12 Proportion of children with ART‐related Grade 3 or 4 adverse events Show forest plot | 1 | 94 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.04, 5.11] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Death Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 1.1 > 15 DAYS vs =< 15 DAYS | 1 | 501 | Hazard Ratio (Fixed, 95% CI) | 0.82 [0.52, 1.31] |
| 1.2 > 30 DAYS vs =< 30 DAYS | 1 | 494 | Hazard Ratio (Fixed, 95% CI) | 0.86 [0.49, 1.52] |
| 1.3 > 60 DAYS vs =< 60 DAYS | 1 | 489 | Hazard Ratio (Fixed, 95% CI) | 1.32 [0.36, 4.87] |
| 2 Virologic suppression Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 2.1 > 15 DAYS vs =< 15 DAYS | 1 | 324 | Hazard Ratio (Fixed, 95% CI) | 0.98 [0.76, 1.26] |
| 2.2 > 30 DAYS vs =< 30 DAYS | 1 | 324 | Hazard Ratio (Fixed, 95% CI) | 0.95 [0.74, 1.22] |
| 2.3 > 60 DAYS vs =< 60 DAYS | 1 | 324 | Hazard Ratio (Fixed, 95% CI) | 0.84 [0.64, 1.10] |
