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Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old

  1. Nandi Siegfried1,2,*,
  2. Mary-Ann Davies3,
  3. Martina Penazzato4,5,
  4. Lulu M Muhe4,
  5. Matthias Egger6

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 10 OCT 2013

Assessed as up-to-date: 24 MAY 2013

DOI: 10.1002/14651858.CD010309.pub2


How to Cite

Siegfried N, Davies MA, Penazzato M, Muhe LM, Egger M. Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010309. DOI: 10.1002/14651858.CD010309.pub2.

Author Information

  1. 1

    University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, South Africa

  2. 2

    University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California, USA

  3. 3

    School of Public Health and Family Medicine, Centre for Infectious Disease Epidemiology and Research (CIDER), Cape Town, South Africa

  4. 4

    World Health Organization, Geneva, Switzerland

  5. 5

    MRC Clinical Trials Unit, London, UK

  6. 6

    Institute of Social and Preventive Medicine, Institute of Social Medicine, Bern, Switzerland

*Nandi Siegfried, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. nandi.siegfried@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 10 OCT 2013

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Characteristics of included studies [ordered by study ID]
Ananworanich 2008

MethodsSTUDY TYPE:

  • Randomised controlled trial


COUNTRY:

  • Thailand


SETTING:

  • Research clinical sites: The HIV Netherlands Australia Thailand Research Collaboration/Chulalongkorn University in Bangkok and the Khon Kaen University in Northeast Thailand


DURATION OF RECRUITMENT:

  • Dec 2001 - Mar 2003 (Bangkok); Oct 2002 - Mar 2003 (Khon Kaen)


DURATION OF TRIAL:

  • 3 years and 3 months. Completed March 2005


FOLLOW-UP:

  • Length of follow-up was 108 weeks.
  • Children were followed monthly for the first three months and then every three months.
  • At baseline, CD4 was tested by flow cytometry and CBC and alanine transferase (ALT) were tested.
  • At every visit, CD4, Complete Blood Count and ALT were tested.
  • At every 24 week visit, viral load (Roche Amplicor Ultrasensitive assay), fasting lipids and glucose were tested.
  • Median duration of follow-up from randomization: 134 (IQR: 123 - 154) weeks


This trial was a pilot study was conducted to explore the feasibility and HIV disease outcome of the immediate versus deferred strategy as ground work for the PREDICT trial (PREDICT 2012).


ParticipantsINCLUSION CRITERIA:

  • Children aged one to 12 years old, with HIV infection, with CDC clinical stage A or B and who had never received ART other than zidovudine as part of PMTCT.


EXCLUSION CRITERIA:

  • Children younger than one year.
  • Children with CDC C or CD4 < 15%
  • Children without symptoms or with normal CD4 (> 25%)


Number of participants randomised: 43

  • Median age at randomization: IMMEDIATE group: 5.2 (IQR: 2.4 - 8.0) years; DEFERRED group: 4.4 (IQR: 2.7 - 5.8) years
  • Gender distribution (Male: Female) (n, %): IMMEDIATE group:10:14 (42: 58); DEFERRED group: 7: 12 (37: 63)
  • Median weight for age z-scores (WAZ) (IQR): IMMEDIATE group: -1.0 (-1.5 - 0.4); DEFERRED group: -0.1 (-1.5 - 0.3)
  • Median height for age z-scores (WAZ) (IQR): IMMEDIATE group: -1.7 (-2.0 - 0.9); DEFERRED group: -0.8 (-1.7 - 0.1)
  • Median percent CD4 count (%; IQR): IMMEDIATE group: 19 (16 - 22); DEFERRED group: 20 (17 - 22)
  • Median CD4 count (cells/mm3; IQR): IMMEDIATE group: 649 (509 - 834); DEFERRED group: 615 (544 - 818)


All characteristics and baseline data did not differ between the two groups except median triglyceride at 48 weeks. This was statistically significantly higher in the DEFERRED group (98; IQR: 70 - 148) compared with the IMMEDIATE group (69: IQR: 54 - 88)(p = 0.016).


InterventionsINTERVENTION: IMMEDIATE GROUP

  • Participants were started on ART immediately at study entry.


CONTROL: DEFERRED GROUP

  • Participants were started on ART when CD4 fell to < 15% in those with baseline CD4 20 - 24% or CD4 dropped by 25% in those with baseline CD4 15 - 19%. A repeat confirmatory CD4 was done immediately if CD4 fell below ART initiation threshold.


ART comprised standard doses of generic individual zidovudine, lamivudine and nevirapine according to the Thai Government Pharmaceutical Organization guidelines.

COMPLIANCE:

No formal means of assessing compliance is reported.

CO-INTERVENTIONS:

Cotrimoxazole was started immediately with the first decrease of CD4 below 15% and was continued for at least three months until two consecutive CD4 were above 15%.


OutcomesPRIMARY OUTCOMES:

  • Recruitment rate
  • Adherence to randomized group
  • Retention in the study


SECONDARY OUTCOMES:

  • Proportion (%) children with CDC C or with CD4 < 15%
  • Growth
  • Median CD4%
  • Median Viral load
  • ART savings (reduced time on ART)
  • ART-related Adverse Events (measured using the 1994 Adult and Pediatric Grading Tables of the Division of AIDS, NIH (DAIDS 1994)


NotesETHICS

Institutional Review Board at Chulalongkorn and Khon Kaen Universities.

INFORMED CONSENT:

All caregivers gave signed informed consent.

FUNDING

Not specifically reported. The Thai Government Pharmaceutical Organization provided anti-retrovirals.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskThis was an open-label trial so personnel and caregivers were not blinded, potentially introducing performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIn the IMMEDIATE group, attrition was 1/24 (4.2%) and in the DEFERRED group, attrition was 2/19 (10.5%). We judged this to be low risk.

Selective reporting (reporting bias)Low riskWe were not able to identify a registered protocol for the trial to compare registered and reported outcomes. However, given that the trial was designed as a feasibility study with recruitment rate, adherence and retention as primary outcomes rather than measures of efficacy, we judged the risk of selective reporting to be low.

Control of time-dependent confounding COHORT ONLYLow riskNot applicable due to the nature of randomisation which eliminates the need to control for confounding.

Other biasUnclear riskThe trial was conducted to ascertain the feasibility of the larger PREDICT 2012 trial and was intentionally not powered to evaluate efficacy. We did not identify other sources of bias.

PREDICT 2012

MethodsSTUDY TYPE:

  • Randomised controlled trial


COUNTRY:

  • Thailand
  • Cambodia


SETTING:

  • Nine tertiary referral hospitals and research sites of the Comprehensive International Program for Research in IADS (CIPRA) - Thailand and Cambodia Network


DURATION OF RECRUITMENT:

  • Mar 2006 - Sep 2008


DURATION OF TRIAL:

  • 5 years and 3 months. Trial completed in May 2011


FOLLOW-UP:

  • Length of follow-up was 144 weeks.
  • Children in the IMMEDIATE group were followed at weeks 2, 4, 8, 12 and then every 12 weeks thereafter; children in the DEFERRED group were followed at weeks 8, 12 and every 12 weeks thereafter
  • At baseline, all children were evaluated clinically, and complete blood count, CD4% and count, serum electrolytes and alanine aminotransferase (ALT) were performed
  • At every follow-up visit, clinical evaluation was done including an assessment for toxicity or HIV-related events
  • At every 12 week visit, complete blood count, CD4% and count, serum electrolytes and Alanine Transferase (ALT) were performed
  • At every 24 week visit, plasma HIV RNA (viral load) and Beery Visual Motor Integration (VMI) tests were conducted
  • 96% of children completed 144 weeks of follow-up.


ParticipantsINCLUSION CRITERIA:

  • Children aged one to 12 years old, with HIV infection (defined as positive HIV DNA PCR or RNA PCR twice among children between 12 and 18 months, or with positive HIV antibody test among children aged > 18 months)
  • CD4% 15 - 24%
  • No history of AIDS illness (CDC C events)
  • Never received ART other than for prevention of MTCT


EXCLUSION CRITERIA:

  • Children younger than one year
  • Active AIDS-defining illness
  • Use of immunosuppressive drugs
  • Use of immuno-modulators within 30 days prior to study entry
  • Abnormal laboratory results:
    • Absolute neutrophil count < 750 cells/mm3
    • Haemoglobin < 7.5 g/dL
    • Platelet count < 50,000/mm3
    • ALT > 4 times upper limit of normal (ULN)


Number of participants randomised: 300

Baseline data:

  • Median age at randomization (IQR): IMMEDIATE group: 6.4 (IQR: 3.6 - 8.0) years; DEFERRED group: 6.5 (IQR: 4.2 - 8.7) years
  • Number and % in age groups (n (%)):
    • 1 - 3 years: IMMEDIATE group: 45 (30); DEFERRED group: 33 (22)
    • 4 - 6 years: IMMEDIATE group: 43 (29); DEFERRED group: 50 (33)
    • 7 - 9 years: IMMEDIATE group: 44 (30); DEFERRED group: 49 (33)
    • 10 - 12 years: IMMEDIATE group: 17 (11); DEFERRED group: 18 (12)
  • Gender distribution (Male: Female) (n, %): IMMEDIATE group:77: 72 (48; 52); DEFERRED group: 54:96 (36: 64)
  • Median weight for age z-scores (WAZ) (IQR): IMMEDIATE group: -1.3 (-2.0 to -0.8); DEFERRED group: -1.3 (-2.0 to -0.8)
  • Median height for age z-scores (WAZ) (IQR): IMMEDIATE group: -1.6 (-2.5 to -0.8); DEFERRED group: -1.7 (-2.6 to -0.9)
  • Median percent CD4 count (%; IQR): IMMEDIATE group: 19 (16 - 22); DEFERRED group: 20 (17 - 23)
  • Median CD4 count (cells/mm3; IQR): IMMEDIATE group: 620 (425 - 851); DEFERRED group: 619 (466 - 847)


Baseline characteristics were similar between the two groups except for gender. There was a significantly greater proportion of females in the deferred arm (p value not reported).


InterventionsINTERVENTION: IMMEDIATE GROUP

  • Participants were started on ART immediately at study entry


CONTROL: DEFERRED GROUP

  • Participants were started on ART during the trial if
    • Development of CDC category C events OR
    • Confirmed CD4% decline to < 15% prior to December 2008 for all children OR
    • Confirmed CD4% decline to < 20% in children aged 1 to 3 years from December 2008*


*The change in the immunologic criteria was due to a change in World Health Organization and national treatment guidelines. Recruitment was completed in September 2008 prior to implementing the change.

First-line ART comprised:

  • Zidovudine, lamivudine and nevirapine
  • A protease inhibitor (lopinavir/ritonavir or nelfinavir) was substituted for nevirapine in children with prior exposure to nevirapine (nelfinavir was not used after September 2007)
  • Abacavir was substituted for zidovudine in cases of grade 3 or 4 hematologic toxicity
  • Efavirenz or a protease inhibitor was substituted for nevirapine in children with nevirapine- hypersensitivity depending on the severity
  • Children also requiring anti-tuberculosis treatment received zidovudine, lamivudine and abacavir


Second-line ART:

  • ART treatment failure was defined as HIV RNA >1000 copies/ml after ≥6 months of treatment
  • ART selection was based on genotypic resistance testing.


COMPLIANCE:

Adherence questionnaires and pill counts were used to assess adherence. Good adherence (defined as average adherence by pill count of > 95% while receiving study drug) was reported in 88% of the IMMEDIATE and 90% of the DEFERRED group.

CO-INTERVENTIONS:

Cotrimoxazole was started immediately with the first decrease of CD4 below 15% and was continued for at least six months until two consecutive CD4 were above 15%.


OutcomesPRIMARY OUTCOMES:

  • CDC Category C event-free (AIDS-fee) survival at week 144


SECONDARY OUTCOMES:

  • CDC Category B events
  • Beery VM standard score
  • Hospitalization rates
  • CD4% changes
  • Growth changes
  • Cumulative proportion of children with virologic failure
  • ART-related Adverse Events (measured using the 2004 Adult and Pediatric Grading Tables of the Division of AIDS, NIH.


NotesETHICS

Institutional Review Board permission obtained at all sites.

INFORMED CONSENT:

All caregivers gave written informed consent.

FUNDING

Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development (NICHD) and National Institute of Mental Health (NIMH), US National Institutes of Health (NIH).

Antiretroviral drugs were provided by ViiV Healthcare/GlaxoSmithKline (zidovudine, lamivudine and abacavir), Boehringer-Ingelheim (nevirapine), Merck (efavirenz), Abbott (lopinavir/ritonavir) and Roche (nelfinavir).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation program using SAS 9.1. The randomisation employed minimization by research site and history of nevirapine exposure.

Allocation concealment (selection bias)Low riskThe process was done centrally at a trial coordinating centre in Bangkok and assignment was communicated to the site investigator via fax.

Blinding of participants and personnel (performance bias)
All outcomes
High riskCaregivers and personnel were not blinded as the study was open-label. This may introduce performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAn independent committee blinded to assignment, CD4 and ART status, reviewed outcomes of CDC category B and C endpoints and hospitalizations. Other outcomes may have been susceptible to detection bias but we judged this to be of low risk.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIn the IMMEDIATE group, 7/150 (4.6%) were lost-to-follow-up and in the DEFERRED group, 3/150 (2%) were lost-to-follow-up. This represents a low attrition rate.

Selective reporting (reporting bias)Low riskWe compared the trial report with the entry for NCT00234091 on www.clinicaltrials.gov. There was no selective reporting.

Control of time-dependent confounding COHORT ONLYLow riskNot applicable due to the nature of randomisation which eliminates the need to control for confounding.

Other biasLow riskThe trial was funded by government organizations. The drugs were supplied by pharmaceutical companies which had no role in the study design, analysis or manuscript preparation. The trial was not stopped early. For these reasons we judged the risk of bias to be low for other forms of bias.

Yotebieng 2010

MethodsSTUDY TYPE:

  • Observational cohort study using prospectively routinely collected data


COUNTRY:

  • South Africa


SETTING:

  • Harriet Shezi Children's Clinic, an outpatient paediatric clinic at Chris Hani Baragwanath Hospital in Soweto (tertiary facility)


DURATION OF RECRUITMENT:

  • Apr 2004 - Mar 2008


DURATION OF TRIAL:

  • 4 years. Completed on 31 March 2008 or at last visit before 31 March 2008 by administrative censoring


FOLLOW-UP:

  • Median length of follow-up 9.6 months (IQR: 1.9 - 23.1 months)
  • Children were followed after one month, then at three months and then every three months or as clinically indicated
  • At baseline, laboratory investigations (CD4 cell count and viral load) were conducted
  • At every 6 monthly visit, CD4 and viral load were conducted on when indicated


ParticipantsINCLUSION CRITERIA:

  • Children (age defined as younger than 15 years old and assumed to be excluding infants (less than one years old)), with HIV infection, with tuberculosis (TB) infection diagnosed by clinical grounds including:
    • Failure to thrive
    • Prolonged (more than 2 weeks) cough
    • Suspicious chest radiograph
    • With or without positive contact history
    • Bacteriological confirmation was attempted in older children who could produce sputum samples
  • TB treatment must have been initiated prior to ART initiation


EXCLUSION CRITERIA:

  • Children already on TB treatment at first visit in the clinic


Number of participants eligible for inclusion: 573

  • Median age of all children at baseline (age in years; IQR): 3.5 years (1.4 - 6.8)
  • Gender distribution (Male: Female) (n, %): Not reported
  • Median weight for age z-scores of all children at baseline (WAZ) (IQR): -2.3 (-3.6 to -1.3)
  • Median height for age z-scores of all children at baseline (WAZ) (IQR): Not reported
  • Median percent CD4 count of all children at baseline (%; IQR): 11.9% (6.6 - 18.3)
  • Median viral load for all children at baseline (log copies/ml; IQR): 5.2 (4.5 - 5.9)


Characteristics and baseline data were compared between those who initiated ART and those who did not initiate ART and between those who initiated ART within one month from enrolment and those who initiated ART equal to or greater than one month from enrolment. As the comparison this review is focused on is timing on ART initiation, the baseline results are presented for those who initiated ART within one month (n = 288) and greater or equal to one month (n = 206) below:

  • Median age of children at TB treatment initiation (age in years; IQR): ART INITIATED < 1 MONTH: 3.5 years (1.4 - 7.1); ART INITIATED ≥ 1 MONTH: 3.5 (1.4 - 6.7)
  • Median weight for age z-scores of children: (WAZ) (IQR): ART INITIATED < 1 MONTH: -2.71 (-4.11 to 1.60); ART INITIATED ≥ 1 MONTH: -1.92 (-2.92 to -0.83)
  • Median percent CD4 count of children (%; IQR): ART INITIATED < 1 MONTH 8.0 (4.6 - 13.6): ART INITIATED ≥ 1 MONTH: 15.0 (9.8-21.2)
  • Median CD4 cell count of children (count/microL; IQR): ART INITIATED < 1 MONTH 273 (98 - 604): ART INITIATED ≥ 1 MONTH: 533 (238 - 868)
  • Median viral load for children (log copies/ml; IQR): ART INITIATED < 1 MONTH: 5.3 (4.6 - 6.0); ART INITIATED ≥ 1 MONTH: 5.2 (4.5 - 5.8)
  • Median time from TB to ART initiation (days; IQR): ART INITIATED < 1 MONTH: 4 (0 - 14); ART INITIATED ≥ 1 MONTH: 59 (42 - 130)


The baseline difference between the groups was statistically significant for CD4 cell count, CD4 cell percentage, WAZ, and time from TB to ART initiation.

The authors report that the distribution of baseline characteristics was similar to that of the above for 15 and 60 day cut-offs. The actual data is not reported.


InterventionsINTERVENTION: ART INITIATED < 1 MONTH

ART was initiated in children within one month of enrolment

CONTROL: ART INITIATED ≥ 1 MONTH

ART was initiated in children after one month or more of enrolment

The authors also consider the data in 15-day and 60-day cut-offs.

First-line ART regimen at the time, according to South African National Guidlines. comprised stavudine, lamivudine, and ritonavir-boosted lopinavir for children three years or younger; or stavudine, lamivudine and efavirenz for those over three years and over 10kg of weight. Double doses of ritonavir were given during anti-TB treatment.

CO-INTERVENTIONS:

All children were receiving TB treatment which comprised a combination of rifampicin, isoniazid, and pyrazinamide for the initial two months followed by rifampicin and isoniazid for the remaining four months.


OutcomesPRIMARY OUTCOMES:

  • Survival (time from TB treatment initiation to death)
  • Time to viral suppression (time from ART initiation to date of first viral load measure below 400 HIV RNA copies/ml)


NotesETHICS

Not reported. Routine data collection

INFORMED CONSENT:

Not reported.

FUNDING

US National Institutes of Health (NIH) Fogarty grant: DHHS/NIH/FIC 5 D43 TW01039-08 AIDS International Training and Research Program at the University of North Carolina (UNC) at Chapel Hill. Additional support from the UNC Center of Global Initiative and the American International Health Alliance.

Antiretroviral drugs were provided by ViiV Healthcare/GlaxoSmithKline (zidovudine, lamivudine and abacavir), Boehringer-Ingelheim (nevirapine), Merck (efavirenz), Abbott (lopinavir/ritonavir) and Roche (nelfinavir).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskThe groups were not randomised as this was a cohort study.

Allocation concealment (selection bias)High riskThe groups were not randomised as this was a cohort study.

Blinding of participants and personnel (performance bias)
All outcomes
High riskAs the personnel determined when to initiate ART, blinding was not possible and performance bias may be present.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe authors do not report if the assessment was blinded. However as the outcomes are death and viral load lack of blinding is unlikely to be a major source of bias.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe overall loss to follow-up was 13% (75/573) overall with 38 lost prior to ART initiation and 37 while on ART. The authors report that those children lost to follow-up did not differ to those in care in any of the baseline characteristics or timing of ART initiation.

Selective reporting (reporting bias)Unclear riskNo protocol was obtained for this study and there is no report of ethical clearance. As it is based on analysis of routinely collected data there is a risk of selective reporting of those outcomes which were found to be significant or noteworthy in preference over other outcomes. However, given that the outcomes of death and viral suppression are of primary interest to the research question, we did not rate the risk as high but as unclear.

Control of time-dependent confounding COHORT ONLYLow riskThe 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.

Other biasLow riskThe authors state that the funding sources had no role in the design and conduct of this study.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Edmonds 2009The analysis estimated the effect of ART versus no ART on the incidence of TB (rather than the effect of starting ART earlier or later).

Edmonds 2011The analysis estimated the effect of ART versus no ART on the incidence of TB (rather than the effect of starting ART earlier or later).

Munyagwa 2012This analysis compared ART versus no ART and was not appropriately adjusted for (it did not consider time-dependent confounding).

Musoke 2010This study analyzed growth trajectories and immunological and virological response of children starting ART. There were no morbidity/mortality endpoints and no appropriate comparisons of starting early versus starting late.

Patel 2008 aThe analysis did not include mortality and morbidity data and estimated the effect of ART versus no ART (rather than the effect of starting earlier or later.)

Patel 2008 bIn this study the analysis estimated the effect of ART versus no ART (rather than the effect of starting ART earlier or later).

 
Comparison 1. IMMEDIATE versus DEFERRED initiation of ART all ages (RCT)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death2343Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 73.06]

 2 CDC Category C disease (number of children)2343Risk Ratio (M-H, Random, 95% CI)1.5 [0.25, 8.85]

 3 CDC Category B disease (numbers of children) Relative Risk2343Risk Ratio (M-H, Random, 95% CI)1.42 [0.14, 14.28]

 4 CDC Category B disease (numbers of children) Peto Odds Ratio2343Peto Odds Ratio (Peto, Fixed, 95% CI)0.70 [0.39, 1.24]

 5 Pulmonary TB (clinically diagnosed)2343Risk Ratio (M-H, Fixed, 95% CI)3.21 [0.52, 19.89]

 6 Median time before development of CDC B or C eventOther dataNo numeric data

 7 Proportion of children on ART with HIV-RNA < 50 copies/ml2238Risk Ratio (M-H, Random, 95% CI)0.96 [0.84, 1.09]

 8 Median CD4% at study endOther dataNo numeric data

 9 Mean CD4% at week 1441300Mean Difference (IV, Random, 95% CI)8.40 [6.83, 9.97]

 10 Proportion of children with CD4% < 15% at study end2343Risk Ratio (M-H, Random, 95% CI)0.11 [0.02, 0.60]

 11 Mean weight gain per year in kg1299Mean Difference (IV, Fixed, 95% CI)0.10 [-0.16, 0.36]

 12 Median weight-for-age Z score at study end (134 - 144 weeks)Other dataNo numeric data

 13 Mean height gain per year in cm1300Mean Difference (IV, Fixed, 95% CI)0.5 [0.20, 0.80]

 14 Median height-for-age Z score at study end (134 - 144 weeks)Other dataNo numeric data

 15 Mean standardized score on Beery VMI at 144 weeks1272Mean Difference (IV, Fixed, 95% CI)-1.40 [-4.70, 1.90]

 16 Proportion of children with adverse events143Risk Ratio (M-H, Random, 95% CI)0.92 [0.80, 1.07]

 17 Proportion of children with ART-related adverse events2343Risk Ratio (M-H, Random, 95% CI)1.87 [0.77, 4.51]

 
Analysis 1.6 Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 6 Median time before development of CDC B or C event.
Median time before development of CDC B or C event

StudyIMMEDIATE (time on ART before events)DEFERRED (time from enrolment to events)

Ananworanich 200860 (IQR: 48 - 72) weeksNil

PREDICT 20129 (IQR: 4 - 30) weeks57 (IQR: 34 - 101) weeks

 
Analysis 1.8 Comparison 1 IMMEDIATE versus DEFERRED initiation of ART all ages (RCT), Outcome 8 Median CD4% at study end.
Median CD4% at study end

StudyIMMEDIATEDEFERREDP value

Ananworanich 2008Median (IQR): 31 (24 - 39)Median (IQR): 23 (17 - 31)0.032

 
Analysis 1.12 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).
Median weight-for-age Z score at study end (134 - 144 weeks)

StudyIMMEDIATEDEFERRED

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)

 
Analysis 1.14 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).
Median height-for-age Z score at study end (134 - 144 weeks)

StudyIMMEDIATEDEFERRED

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 2. SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death2122Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 68.88]

 2 CDC Category C disease (number of children)2122Risk Ratio (M-H, Random, 95% CI)0.96 [0.06, 14.87]

 3 CDC Category B disease (numbers of children) Relative Risk2122Risk Ratio (M-H, Random, 95% CI)0.95 [0.24, 3.73]

 4 CDC Category B disease (numbers of children) Peto Odds Ratio2122Peto Odds Ratio (Peto, Fixed, 95% CI)0.76 [0.29, 2.02]

 5 Pulmonary TB (clinically diagnosed)2122Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.19, 7.27]

 6 Proportion of children on ART with HIV-RNA < 50 copies/ml167Risk Ratio (M-H, Random, 95% CI)1.11 [0.86, 1.43]

 7 Mean CD4% at week 144194Mean Difference (IV, Random, 95% CI)5.90 [2.74, 9.06]

 8 Proportion of children with CD4% < 15% at study end2122Risk Ratio (M-H, Random, 95% CI)0.40 [0.06, 2.52]

 9 Mean weight gain per year in kg194Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.25, 0.19]

 10 Mean height gain per year in cm194Mean Difference (IV, Fixed, 95% CI)0.30 [-0.28, 0.88]

 11 Mean standardized score on Beery VMI at 144 weeks182Mean Difference (IV, Fixed, 95% CI)2.30 [-4.37, 8.97]

 12 Proportion of children with ART-related Grade 3 or 4 adverse events194Risk Ratio (M-H, Random, 95% CI)0.48 [0.04, 5.11]

 
Comparison 3. ADJUSTED/WEIGHTED EARLY vs DEFERRED initiation of ART in children with TB and HIV

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death1Hazard Ratio (Fixed, 95% CI)Subtotals only

    1.1 > 15 DAYS vs =< 15 DAYS
1501Hazard Ratio (Fixed, 95% CI)0.82 [0.52, 1.31]

    1.2 > 30 DAYS vs =< 30 DAYS
1494Hazard Ratio (Fixed, 95% CI)0.86 [0.49, 1.52]

    1.3 > 60 DAYS vs =< 60 DAYS
1489Hazard Ratio (Fixed, 95% CI)1.32 [0.36, 4.87]

 2 Virologic suppression1Hazard Ratio (Fixed, 95% CI)Subtotals only

    2.1 > 15 DAYS vs =< 15 DAYS
1324Hazard Ratio (Fixed, 95% CI)0.98 [0.76, 1.26]

    2.2 > 30 DAYS vs =< 30 DAYS
1324Hazard Ratio (Fixed, 95% CI)0.95 [0.74, 1.22]

    2.3 > 60 DAYS vs =< 60 DAYS
1324Hazard Ratio (Fixed, 95% CI)0.84 [0.64, 1.10]

 
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

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
Settings: Thailand and Cambodia
Intervention: IMMEDIATE initiation of cART
Comparison: DEFERRED initiation of cART

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

DEFERRED initiation of cARTIMMEDIATE initiation of cART

Death0 per 10000 per 1000
(0 to 0)
RR 3
(0.12 to 73.06)
343
(2 studies)
⊕⊝⊝⊝
very low1,2,3

CDC Category C disease (number of children)
Follow-up: 144 weeks
12 per 100018 per 1000
(3 to 105)
RR 1.5
(0.25 to 8.85)
343
(2 studies)
⊕⊝⊝⊝
very low1,2,4

CDC Category B disease (numbers of children) Peto Odds Ratio189 per 1000141 per 1000
(83 to 225)
OR 0.7
(0.39 to 1.24)
343
(2 studies)
⊕⊝⊝⊝
very low1,2,4,5

Proportion of children on ART with HIV-RNA < 50 copies/ml (Copy)815 per 1000783 per 1000
(685 to 889)
RR 0.96
(0.84 to 1.09)
238
(2 studies)
⊕⊕⊝⊝
low1,2,4

Weight gain per year in kgThe mean weight gain per year in kg in the intervention groups was
0.1 higher
(0.16 lower to 0.36 higher)
300
(1 study)
⊕⊕⊝⊝
low1,2,6,7

Height gain per year in cmThe mean height gain per year in cm in the intervention groups was
0.5 higher
(0.2 to 0.8 higher)
300
(1 study)
⊕⊕⊝⊝
low1,2,6,7

Standardized score on Beery VMI at 144 weeksThe mean standardized score on Beery VMI at 144 weeks in the intervention groups was
1.4 lower
(4.7 lower to 1.9 higher)
272
(1 study)
⊕⊕⊝⊝
low1,2,6,7

*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).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;


Patient or population:

HIV-positive, treatment-naive children aged 24 to 59 months (2 to 5 years old)
Settings: Thailand and Cambodia
Intervention: IMMEDIATE initiation of cART
Comparison: DEFERRED initiation of cART

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding 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.
2 The age group included in the trials ranged from one year to 12 years old and did not focus on the specific population focus of this review: ages 24 to 59 months.
3 The confidence interval is very large and the event rate very low. There was only one death.
4 The event rate was very low and the overall sample size is also small.
5 The trials reported conflicting results and there was substantial unexplained heterogeneity.
6 The results are from only one trial so consistency cannot be adequately gauged.
7 The sample size is less than 400 and according to the GRADE approach imprecision is present when continuous outcomes are compared in samples less than 400.
 
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)

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)
Settings: Thailand and Cambodia
Intervention: SUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlSUBGROUP ANALYSIS: IMMEDIATE versus DEFERRED initiation of ART 24 to 59 months (RCT)

Death0 per 10000 per 1000
(0 to 0)
RR 2.88
(0.12 to 68.88)
122
(2 studies)
⊕⊝⊝⊝
very low1,2

CDC Category C disease (number of children)16 per 100015 per 1000
(1 to 236)
RR 0.96
(0.06 to 14.87)
122
(2 studies)
⊕⊝⊝⊝
very low1,2

CDC Category B disease (numbers of children) Peto Odds Ratio239 per 1000167 per 1000
(70 to 355)
OR 0.64
(0.24 to 1.75)
94
(1 study)
⊕⊝⊝⊝
very low3,4

Proportion of children on ART with HIV-RNA < 50 copies/ml789 per 1000876 per 1000
(679 to 1000)
RR 1.11
(0.86 to 1.43)
67
(1 study)
⊕⊝⊝⊝
very low5,6

Mean weight gain per year in kgThe mean weight gain per year in kg in the intervention groups was
0.03 lower
(0.25 lower to 0.19 higher)
94
(1 study)
⊕⊝⊝⊝
very low3,7

Mean height gain per year in cmThe mean height gain per year in cm in the intervention groups was
0.3 higher
(0.28 lower to 0.88 higher)
94
(1 study)
⊕⊝⊝⊝
very low3,7

Mean standardized score on Beery VMI at 144 weeksThe mean standardized score on Beery VMI at 144 weeks in the intervention groups was
2.3 higher
(4.37 lower to 8.97 higher)
82
(1 study)
⊕⊝⊝⊝
very low3,7

*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).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 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.
2 The sample size of the two subgroups of age-specific data for 24 to 59 months is 122 and the event rate is very small. The confidence interval is very large.
3 Randomisation was not conducted within the sub-group. In the PREDICT trial, the proportion of the overall sample in the subgroup in the IMMEDIATE group was 32% (48/150) and in the DEFERRED group it was 31% (46/150). Although this is balanced, we cannot exclude the possibility of selection bias as this analysis was conducted post hoc.
4 The sample size of the subgroup of age-specific data for 24 to 59 months in the PREDICT 2012 trial is 94 and the event rate is very small. The confidence interval is large.
5 Randomisation was not conducted within the sub-group. In the PREDICT trial, the proportion of the overall sample in the subgroup in the IMMEDIATE group was 32% (48/150) and in the DEFERRED group it was 31% (46/150). In this comparison (children on ART with HIV-RNA < copies/ml) only those children on ART in the DEFERRED group (19/150) were included so the proportions are very imbalanced.
6 The sample size of the two subgroups of age-specific data for 24 to 59 months is small (N = 67). Imprecision is likely to be present.
7 The sample size is very small. In the GRADE system, imprecision is likely to be present when continuous outcomes are compared in samples less than 400.