DURATION OF RECRUITMENT:
DURATION OF TRIAL:
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.
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
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
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|
CONTROL: DEFERRED GROUP
*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
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.
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%.
CDC Category B events
Beery VM standard score
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.
Institutional Review Board permission obtained at all sites.
All caregivers gave written informed consent.
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) |
|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) |
|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) |
|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.|