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. Author manuscript; available in PMC: 2014 Oct 10.
Published in final edited form as: Cochrane Database Syst Rev. 2013 Oct 10;10:CD010309. doi: 10.1002/14651858.CD010309.pub2

Table 1.

Characteristics of included studies [ordered by study ID]

Ananworanich 2008
Methods STUDY 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).
Participants INCLUSION 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)
Interventions INTERVENTION: 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 nevi-rapine 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%
Outcomes PRIMARY 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)

Notes ETHICS
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
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Not reported
Allocation concealment (selection bias) Unclear risk Not reported
Blinding of participants and personnel (performance bias)
All outcomes		 High risk This 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 risk Not reported
Incomplete outcome data (attrition bias)
All outcomes		 Unclear risk In 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 risk We 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 ONLY		 Low risk Not applicable due to the nature of randomisation which eliminates the need to control for confounding
Other bias Unclear risk The 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
Methods STUDY 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.

Participants INCLUSION 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)
Interventions INTERVENTION: 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%
Outcomes PRIMARY 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.

Notes ETHICS
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
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias) Low risk Computer-generated randomisation program using SAS 9.1. The randomisation employed minimization by research site and history of nevirapine exposure
Allocation concealment (selection bias) Low risk The 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 risk Caregivers 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 risk An 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 risk In 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 risk We compared the trial report with the entry for NCT00234091 on www.clinicaltrials.gov. There was no selective reporting
Control of time-dependent confounding
COHORT ONLY		 Low risk Not applicable due to the nature of randomisation which eliminates the need to control for confounding
Other bias Low risk The 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
Methods STUDY 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

Participants INCLUSION 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
Interventions INTERVENTION: 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
Outcomes PRIMARY 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)
Notes ETHICS
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
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias) High risk The groups were not randomised as this was a cohort study.
Allocation concealment (selection bias) High risk The groups were not randomised as this was a cohort study.
Blinding of participants and personnel (performance bias)
All outcomes		 High risk As 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 risk The 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 risk The 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 risk No 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 ONLY		 Low risk 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
Other bias Low risk The authors state that the funding sources had no role in the design and conduct of this study