ARROW: Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa

Sponsor

Medical Research Council (Other)

Overall Status

Completed

CT.gov ID

NCT02028676

Collaborator

Department for International Development, United Kingdom (Other), ViiV Healthcare (Industry), GlaxoSmithKline (Industry)

1,206

Enrollment

Locations

Arms

Duration (Months)

301.5

Patients Per Site

4.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART):

Whether clinically driven monitoring (CDM) will have a similar outcome in terms of disease progression or death as routine laboratory and clinical monitoring (LCM) for toxicity (haematology/biochemistry) and efficacy (CD4)?
Whether induction with four drugs from two ART classes followed by maintenance with three drugs after 36 weeks be more effective than a continuous non-nucleoside reverse transcriptase inhibitors (NNRTI)-based triple drug regimen in terms of CD4 and clinical outcome?

Two secondary objectives were to determine

Whether changing from twice daily lamivudine+abacavir to once daily lamivudine+abacavir after 48 weeks on ART will have a similar outcome in terms of virological suppression and will result in improvements in adherence to ART?
Whether stopping daily cotrimoxazole prophylaxis in children over 3 years of age who have been on ART for at least 96 weeks has a similar outcome in terms of hospitalisation or death as continuing daily cotrimoxazole?

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus	Other: Clinically Driven Monitoring (CDM) Other: Laboratory plus Clinical Monitoring (LCM) Drug: Arm A: ABC+3TC+NNRTI Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance Drug: Once-daily ABC+3TC Drug: Twice-daily ABC+3TC Drug: Continued cotrimoxazole prophylaxis Other: Stopped cotrimoxazole prophylaxis	Phase 4

Detailed Description

The ARROW (AntiRetroviral Research fOr Watoto) protocol describes an open-label randomised trial primarily evaluating two strategic approaches for management of antiretroviral therapy (ART) in 1200 symptomatic HIV-infected infants and children initiating ART following WHO guidelines in Uganda and Zimbabwe. The first strategy compares clinically driven monitoring (CDM) with laboratory plus clinical monitoring (LCM). In both groups, tests for toxicity (standard haematology and biochemistry panels) and efficacy (lymphocyte subsets including CD4 count) will be done every 12 weeks. In LCM, all results will be returned for patient management. In CDM, physicians may request results from routine haematology/biochemistry panels if needed for clinical management, but results will not be returned routinely, and lymphocyte subsets will never be returned. Extra laboratory tests may be requested outside of the scheduled visits at any time in either group (except for lymphocyte subsets in CDM). The second strategy compares a continuous WHO-recommended first-line ART three-drug two-class regimen, comprising two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) plus one Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), with induction with four drugs (two classes) for 36 weeks followed by maintenance with three drugs. After at least 36 and 96 weeks on ART respectively, two further randomisations will assess simplification strategies which could improve long-term ART adherence (i) once versus twice daily lamivudine+abacavir NRTI drugs (ii) stopping versus continuing daily cotrimoxazole prophylaxis.

Study Design

Study Type:

Interventional

Actual Enrollment :

1206 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa

Study Start Date :

Mar 1, 2007

Actual Primary Completion Date :

Mar 1, 2012

Actual Study Completion Date :

Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Clinically Driven Monitoring (CDM)	Other: Clinically Driven Monitoring (CDM) Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Active Comparator: Laboratory plus Clinical Monitoring (LCM)	Other: Laboratory plus Clinical Monitoring (LCM) Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Active Comparator: Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.	Drug: Arm A: ABC+3TC+NNRTI Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age. Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva
Experimental: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.	Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age. Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva
Experimental: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO.	Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age. Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva
Experimental: Once-daily ABC+3TC ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO	Drug: Once-daily ABC+3TC Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Active Comparator: Twice-daily ABC+3TC ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO	Drug: Twice-daily ABC+3TC Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Active Comparator: Continued cotrimoxazole prophylaxis Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole	Drug: Continued cotrimoxazole prophylaxis Other Names: trimethoprim+sulfamethoxazole
Experimental: Stopped cotrimoxazole prophylaxis Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.	Other: Stopped cotrimoxazole prophylaxis

Outcome Measures

Primary Outcome Measures

LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation [Baseline, 72 weeks]
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation [Baseline, 144 weeks]
Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation [48 weeks]
Number of participants with HIV RNA viral load <80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of <80 copies/ml was used to indicate suppression.
Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV, Judged Definitely/Probably or Uncertain Whether Related to Lamivudine or Abacavir [Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Cotrimoxazole: New Hospitalisation or Death [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods

Secondary Outcome Measures

LCM vs CDM, Induction ART: All-cause Mortality [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants who died from any cause, to be analysed using time-to-event methods
Induction ART: New WHO Stage 4 Event or Death [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new or recurrent WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: Weight-for-age Z-score [Baseline and a median of 4 years (maximum 5 years)]
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
LCM vs CDM, Induction ART: Height-for-age Z-score [Baseline and a median of 4 years (maximum 5 years)]
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score [Baseline and a median of 4 years (maximum 5 years)]
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
LCM vs CDM: Change From Baseline in CD4% to Week 72 [Baseline, week 72]
LCM vs CDM: Change From Baseline in CD4% to Week 144 [Baseline, week 144]
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 [Baseline, week 72]
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 [Baseline, week 144]
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline [72 weeks]
Number of participants with HIV RNA viral load <80 copies/ml 72 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline [144 weeks]
Number of participants with HIV RNA viral load <80 copies/ml 144 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants stopping their first-line regimen for clinical/immunological failure, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new grade 3 or 4 adverse event definitely/probably or uncertainly related to ART, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new serious adverse events not solely related to HIV, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: New ART-modifying Adverse Event [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Number of participants with a new ART-modifying adverse event, to be analysed using time-to-event methods
LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) [Median 4 years (from randomization to 16 March 2012; maximum 5 years)]
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation [96 weeks]
Number of participants with HIV RNA viral load <80 copies/ml at 96 weeks. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48 [Randomisation to once vs twice daily, week 48]
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72 [Baseline, week 72]
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96 [Randomisation to once vs twice daily, week 96]
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48 [Randomisation to once vs twice daily, week 48]
Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 [Baseline, week 72]
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 [Randomisation to once vs twice daily, week 96]
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality [Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]
Number of participants who died, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death [Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death [Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score [Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Age-adjusted change in height-for-age Z-score over all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score [Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score [Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV [Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 48 Weeks [48 weeks after randomization to once- versus twice-daily]
Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 48 weeks.
Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 96 Weeks [96 weeks after randomization to once- versus twice-daily]
Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 96 weeks.
Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) [Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Cotrimoxazole: New Clinical and Diagnostic Positive Malaria [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new clinical and diagnostic positive malaria, to be analysed using time-to-event methods. Diagnostic positive by either microscopy (thick film) or rapid diagnostic test (RDT)
Cotrimoxazole: New Severe Pneumonia [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new severe pneumonia, to be analysed using time-to-event methods
Cotrimoxazole: New WHO Stage 3 or 4 Event or Death [Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new WHO stage 3 severe recurrent pneumonia or diarrhoea, to be analysed using time-to-event methods
Cotrimoxazole: New WHO Stage 4 Event or Death [Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Cotrimoxazole: All-cause Mortality [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants who died, to be analysed using time-to-event methods
Cotrimoxazole: Weight-for-age Z-score [Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Cotrimoxazole: Height-for-age Z-score [Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Age-adjusted change in height-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Cotrimoxazole: Body Mass Index-for-age Z-score [Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Cotrimoxazole: Change From Baseline in CD4% to Week 72 [Baseline, week 72]
Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72 [Baseline, week 72]
Estimated in those >5 years at randomization to stop vs continue, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV [Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) [Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]
Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Months to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

For initial randomisation to CDM vs LCM, and to ART induction strategy:

Inclusion Criteria:

Children should have an adult carer in the household who is either:

participating in the DART trial OR
being treated with ART OR
HIV positive but not yet needing treatment but with access to a treatment programme when ART is required OR
HIV negative. Children of DART participants should have first priority on any available remaining slots to enter ARROW.

Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
Participants must have a confirmed documented diagnosis of HIV-1 infection:
For children aged under 18 months: two separate peripheral blood specimens from different days, both results being positive with HIV-DNA polymerase chain reaction (PCR).
For children aged 18 months or over: antibody positive serology by ELISA test (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test (performed in series) both on the same sample. Any child previously tested at another clinic should have a repeat test at an ARROW screening laboratory to confirm their status.
Age 3 months to 17 years (13-17 years to be capped at 10%)
ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:

WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or count
WHO paediatric clinical stage III disease:
<12 months: treat all
12 months: treat all children irrespective of the CD4 percent or count; however, in children aged > 12 months with tuberculosis, lymphocytic interstitial pneumonia (LIP), oral hairy leukoplakia (OHP) or thrombocytopenia (low platelet count treat) be guided by CD4 cell assays (see below).
WHO paediatric clinical stage II or I disease: treat guided by CD4 percent or count
CD4%<25% for infants <12 months;
CD4%<20% for children 1-<3 years;
CD4% <15% for children 3-<5years;
CD4% <15% for children > 5years (consideration should also be taken of the CD4 count. A CD4 count <200 cells/mm3 can be used to guide starting ART and CD4 should generally be <350 cells/mm3.)

Exclusion Criteria:

Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre)
Likelihood of poor adherence
Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an acute infection. Children with chronic lung disease, including recurrent respiratory infections, are eligible. Children with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART (see 4 below)
In receipt of medication contraindicated by ART

children under three years of age receiving anti-tuberculosis therapy should not be enrolled (as they will have to receive nevirapine).
on chemotherapy for malignancy

Laboratory abnormalities which are a contra-indication for the child to start ART (haemoglobin <8.5g/dL; neutrophils <0.50x109/L; aspartate transaminase (AST) or alanine transaminase (ALT) >5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine >1.9 x ULN).

N.B. causes of anaemia, such as concurrent bacterial infection, malaria, helminthiasis and/or malnutrition should be investigated, and treatment for anaemia and its causes commenced prior to re-screening for eligibility.

Being pregnant or breast-feeding an infant
Perinatal exposure to nevirapine (either through prevention of mother-to-child transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only

Eligibility criteria for the secondary randomisation to once vs twice daily lamivudine+abacavir Inclusion criteria

Participating in ARROW
On ART for at least 36 weeks
Currently taking lamivudine+abacavir twice daily as part of their ART regimen and expected to stay on these two drugs for at least the next 12 weeks
Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to once or twice daily lamivudine+abacavir

Exclusion criteria

Likely to switch to second-line therapy in the next 12 weeks

Eligibility criteria for the secondary randomisation to stop or continue cotrimoxazole prophylaxis randomisation Inclusion criteria

Participating in ARROW
Aged at least 3 years
Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART allowing for any interruptions in ART
Currently prescribed daily cotrimoxazole as primary prophylaxis
Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to stop or continue daily cotrimoxazole prophylaxis
If living in a malaria endemic area, has an insecticide treated bednet and prepared to use this for the child.

Exclusion criteria

Previous diagnosis of Pneumocystis jiroveci pneumonia (cotrimoxazole is secondary prophylaxis and should not be discontinued)

Contacts and Locations

Locations

	Site	City	Country
1	MRC /UVRI Uganda Research Unit on AIDS	Entebbe	Uganda
2	Joint Clinical Research Centre	Kampala	Uganda
3	Baylor College of Medicine Children's Foundation	Mulago	Uganda
4	University of Zimbabwe Medical School	Harare	Zimbabwe

Sponsors and Collaborators

Medical Research Council
Department for International Development, United Kingdom
ViiV Healthcare
GlaxoSmithKline

Investigators

Principal Investigator: Diana M Gibb, MD, Medical Research Council
Principal Investigator: Peter Mugyenyi, PhD, Joint Clinical Research Centre, Kampala, Uganda
Principal Investigator: Kusum Nathoo, PhD, University of Zimbabwe, Harare, Zimbabwe
Principal Investigator: Adeodata Kekitiinwa, MD, Baylor College of Medicine Children's Foundation, Mulago, Uganda
Principal Investigator: Paula Munderi, MBChB, MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
Principal Investigator: Victor Musiime, PhD, Joint Clinical Research Centre, Kampala, Uganda
Principal Investigator: Mutsa F Bwakura-Dangarembizi, MBChB, University of Zimbabwe, Harare, Zimbabwe
Principal Investigator: Philippa Musoke, PhD, Baylor College of Medicine Children's Foundation, Mulago, Uganda
Principal Investigator: Sabrina Bakeera-Kitaka, MBChB, Baylor College of Medicine Children's Foundation, Mulago, Uganda
Principal Investigator: Patricia Nahirya-Ntege, MBChB, MRC/UVRI and LSHTM Uganda Research Unit

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

main ARROW trial webpage

Publications

None provided.

Responsible Party:

Diana M Gibb, Professor of Epidemiology, Medical Research Council

ClinicalTrials.gov Identifier:

NCT02028676

Other Study ID Numbers:

G0300400
24791884
G0300400

First Posted:

Jan 7, 2014

Last Update Posted:

Jun 6, 2014

Last Verified:

Jun 1, 2014

Keywords provided by Diana M Gibb, Professor of Epidemiology, Medical Research Council

HIV

Africa

children

antiretroviral therapy

laboratory monitoring

toxicity

CD4

induction maintenance

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome

Lamivudine, zidovudine drug combination

Trimethoprim

Sulfamethoxazole

Trimethoprim, Sulfamethoxazole Drug Combination

Study Results

Participant Flow

Recruitment Details	All recruited children (n=1206) were randomly assigned to CDM vs LCM and the three different induction ART strategies at enrolment (3/2007-11/2008). This was a factorial randomisation meaning that the children were effectively randomized into 6 parallel groups. Baseline characteristics are presented below separately for each initial randomization.
Pre-assignment Detail	There were two additional nested substudy randomizations after initial trial enrolment (see inclusion/exclusion criteria for eligibility). From 8/2009 to 6/2010, eligible children were randomized to once vs twice daily abacavir+lamivudine. From 9/2009 to 2/2011, eligible children were randomized to stop vs continue cotrimoxazole prophylaxis.

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance	Once-daily ABC+3TC	Twice-daily ABC+3TC	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Clinically Driven Monitoring (CDM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Laboratory plus Clinical Monitoring (LCM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm A: ABC+3TC+NNRTI: Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO Once-daily ABC+3TC	ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO Twice-daily ABC+3TC	Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole Continued cotrimoxazole prophylaxis	Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis. Stopped cotrimoxazole prophylaxis
Period Title: Initial Enrolment: CDM vs LCM
STARTED	606	600	0	0	0	0	0	0	0
COMPLETED	606	600	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Initial Enrolment: CDM vs LCM
STARTED	0	0	397	404	405	0	0	0	0
COMPLETED	0	0	397	404	405	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Initial Enrolment: CDM vs LCM
STARTED	0	0	0	0	0	336	333	0	0
COMPLETED	0	0	0	0	0	336	333	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Initial Enrolment: CDM vs LCM
STARTED	0	0	0	0	0	0	0	376	382
COMPLETED	0	0	0	0	0	0	0	376	382
NOT COMPLETED	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance	Once-daily ABC+3TC	Twice-daily ABC+3TC	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis	Total
Arm/Group Description	Clinically Driven Monitoring (CDM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Laboratory plus Clinical Monitoring (LCM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm A: ABC+3TC+NNRTI: Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO Once-daily ABC+3TC	ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO Twice-daily ABC+3TC	Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole Continued cotrimoxazole prophylaxis	Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis. Stopped cotrimoxazole prophylaxis	Total of all reporting groups
Overall Participants	606	600	397	404	405	336	333	376	382	3839
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	5.9	6.0	NA	NA	NA	NA	NA	NA	NA	6.0
Age, Customized (participants) [Number]
< 3 years	197 32.5%	173 28.8%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
3 years or older	409 67.5%	427 71.2%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Sex: Female, Male (Count of Participants)
Female	308 50.8%	302 50.3%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Male	298 49.2%	298 49.7%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Region of Enrollment (participants) [Number]
Uganda	405 66.8%	401 66.8%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Zimbabwe	201 33.2%	199 33.2%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Age, continuous: Period 2 (trial enrollment, induction ART) (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	NA	NA	6.1	6.2	5.7	NA	NA	NA	NA	6.0
Age, continuous: Period 3 (randomization to once vs twice daily ABC+3TC) (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	NA	NA	NA	NA	NA	5.9	5.1	NA	NA	5.5
Age, continuous: Period 4 (randomization to stop versus continue cotrimoxazole) (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	NA	NA	NA	NA	NA	NA	NA	7.5	8.3	7.9
Age, categorical: Period 2 (trial enrollment, induction ART) (participants) [Number]
<3 years	NA NaN	NA NaN	121 30.5%	117 29%	132 32.6%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
3 years or older	NA NaN	NA NaN	276 69.5%	287 71%	273 67.4%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Age, categorical: Period 3 (randomization to once vs twice daily ABC+3TC) (participants) [Number]
<3 years	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	36 10.7%	38 11.4%	NA NaN	NA NaN	NA NaN
3 years and older	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	300 89.3%	295 88.6%	NA NaN	NA NaN	NA NaN
Age, categorical: Period 4 (randomization to stop versus continue cotrimoxazole) (participants) [Number]
<3 years	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	0 0%	0 0%	NA NaN
3 years and older	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	376 100%	382 100%	NA NaN
Gender, Male/Female: Period 2 (trial enrollment, induction ART) (participants) [Number]
Female	NA NaN	NA NaN	204 51.4%	197 48.8%	209 51.6%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Male	NA NaN	NA NaN	193 48.6%	207 51.2%	196 48.4%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Gender, Male/Female: Period 3 (randomization to once vs twice daily ABC+3TC) (participants) [Number]
Female	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	173 51.5%	172 51.7%	NA NaN	NA NaN	NA NaN
Male	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	163 48.5%	161 48.3%	NA NaN	NA NaN	NA NaN
Gender, Male/Female: Period 4 (randomization to stop versus continue cotrimoxazole) (participants) [Number]
Female	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	195 51.9%	203 53.1%	NA NaN
Male	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	181 48.1%	179 46.9%	NA NaN
Region of Enrollment: Period 2 (trial enrollment, induction ART) (participants) [Number]
Uganda	NA NaN	NA NaN	266 67%	268 66.3%	272 67.2%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Zimbabwe	NA NaN	NA NaN	131 33%	136 33.7%	133 32.8%	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN
Region of Enrollment: Period 3 (randomization to once vs twice daily ABC+3TC) (participants) [Number]
Uganda	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	249 74.1%	246 73.9%	NA NaN	NA NaN	NA NaN
Zimbabwe	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	87 25.9%	87 26.1%	NA NaN	NA NaN	NA NaN
Region of Enrollment: Period 4 (randomization to stop versus continue cotrimoxazole) (participants) [Number]
Uganda	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	283 75.3%	286 74.9%	NA NaN
Zimbabwe	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	NA NaN	93 24.7%	96 25.1%	NA NaN
CD4 T cell percentage (percentage of total lymphocytes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of total lymphocytes]	12.5	12.0	NA	NA	NA	NA	NA	NA	NA	12.0
CD4 T cell percentage: Period 2 (trial enrollment, induction ART) (percentage of total lymphocytes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of total lymphocytes]	NA	NA	11.7	12.0	12.5	NA	NA	NA	NA	12.0
CD4 T cell percentage: Period 3 (randomization to once vs twice daily ABC+3TC) (percentage of total lymphocytes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of total lymphocytes]	NA	NA	NA	NA	NA	33.0	33.0	NA	NA	33.0
CD4 T cell percentage: Period 4 (randomization to stop versus continue cotrimoxazole) (percentage of total lymphocytes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of total lymphocytes]	NA	NA	NA	NA	NA	NA	NA	33.0	32.0	33.0
Duration of antiretroviral therapy: Period 3 (randomization to once vs twice daily ABC+3TC) (years) [Median (Full Range) ]
Median (Full Range) [years]	NA	NA	NA	NA	NA	1.8	1.8	NA	NA	1.8
Duration of antiretroviral therapy: Period 4 (randomization to stop versus continue cotrimoxazole) (years) [Median (Full Range) ]
Median (Full Range) [years]	NA	NA	NA	NA	NA	NA	NA	2.1	2.1	2.1
Weight-for-age Z-score: Period 1 (trial enrollment, CDM vs LCM) (Z-score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Z-score]	-2.3	-2.2	NA	NA	NA	NA	NA	NA	NA	-2.2
Weight-for-age Z-score: Period 2 (trial enrollment, induction ART) (Z-score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Z-score]	NA	NA	-2.3	-2.2	-2.2	NA	NA	NA	NA	-2.2
Weight-for-age Z-score: Period 3 (randomization to once vs twice daily ABC+3TC) (Z-score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Z-score]	NA	NA	NA	NA	NA	-1.4	-1.3	NA	NA	-1.4
Weight-for-age Z-score: Period 4 (randomization to stop versus continue cotrimoxazole) (Z-score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Z-score]	NA	NA	NA	NA	NA	NA	NA	-1.3	-1.3	-1.3

Outcome Measures

1. Primary Outcome

Title	LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
Description	Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
All randomized participants (time-to-event)

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Measure Participants	606	600
Number [participants]	47 7.8%	39 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Upper 95% confidence interval for the hazard ratio was 1.64, see other analysis for this endpoint for details

Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95% 0.73 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments	Assumptions: control group (LCM) event rate 3% per year rates are reduced to 2% per year in the best of the induction-maintenance arms leading to an overall rate of progression to new WHO stage 4 or death of 2.5% recruitment is over 1.5 years and follow-up for a minimum further 3.5 years. cumulative loss to follow-up is 10% at 5 years. See below for rest of sample size as this box is not big enough.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	With assumptions detailed above, >90% power and one-sided alpha=0.05, 1160 children would be required to exclude an increase in progression rate of 1.6% from 2.5% to 4.1% per year in the CDM arm (upper 95% confidence limit of LCM: CDM hazard ratio 1.64).

Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Comparison of poisson rates
	Comments	Statistical analysis plan specified that p-value was to be calculated from the log-rank test, so not provided for the risk difference

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95% -0.47 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is CDM minus LCM

2. Primary Outcome

Title	LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Description	Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Measure Participants	606	600
Number [participants]	283 46.7%	282 47%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.83 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

3. Primary Outcome

Title	Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Description
Time Frame	Baseline, 72 weeks

Outcome Measure Data

Analysis Population Description
All participants alive at 72 weeks with CD4 measured (completeness in those in follow-up was 96.6%).

Arm/Group Title	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age
Measure Participants	374	388	374
Mean (Standard Error) [percentage of total lymphocytes]	16.4 (0.45)	17.1 (0.43)	17.3 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments	Assuming a standard deviation for the change in CD4 percentage from baseline to 72 weeks of 10% (slightly higher than that observed in the PENTA 5 trial) 1200 children would provide at least 80% power to detect a difference in change in CD4% from baseline of more than 2.5% across the 3 groups (F-test with 2-sided alpha=0.05) assuming 20% missing data (loss to follow-up during the first year plus failure to attend the week 72 visit/missing sample).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Regression, Linear
	Comments	Global test with 2df, adjusted for randomization stratification factors

4. Primary Outcome

Title	Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Description
Time Frame	Baseline, 144 weeks

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4% (95% completeness)

Arm/Group Title	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age
Measure Participants	371	387	378
Mean (Standard Error) [percentage of total lymphocytes]	19.8 (0.44)	19.6 (0.49)	19.2 (0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Regression, Linear
	Comments	Global test with 2df, adjusted for randomization stratification factors

5. Primary Outcome

Title	Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Description	Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age
Measure Participants	397	404	405
Number [participants]	157 25.9%	190 31.7%	218 54.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95% 1.07 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is Arm B vs A

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.58
	Confidence Interval	(2-Sided) 95% 1.29 to 1.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
Description	Number of participants with HIV RNA viral load <80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of <80 copies/ml was used to indicate suppression.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description
All randomized participants with VL result from stored plasma specimen (available for 661/669, 99%, randomized participants)

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	330	331
Number [participants]	236 38.9%	242 40.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	631 children would be required to exclude a 12% lower suppression rate in the once daily group with at least 90% power and two-sided alpha=0.05 (lower 95% confidence limit of difference between once and twice daily -12%, the non-inferiority margin). 630 children retains at least 80% (rather than 90%) power to exclude a 10% (rather than 12%) lower suppression rate in the once daily group with one-sided alpha=0.05 (lower 90% confidence limit of difference between once and twice daily -10%).

Statistical Test of Hypothesis	p-Value	0.65
	Comments
	Method	Chi-squared
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95% -8.4 to 5.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in suppression <80 copies/ml in once-daily minus twice-daily

7. Primary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV, Judged Definitely/Probably or Uncertain Whether Related to Lamivudine or Abacavir
Description	Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Time Frame	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	1 0.2%	0 0%

8. Primary Outcome

Title	Cotrimoxazole: New Hospitalisation or Death
Description	Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	48 7.9%	72 12%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments	Assumptions 5% of children receiving daily cotrimoxazole prophylaxis have a new hospitalisation or death per year recruitment starts 1 July 2009 with 10% children (those already on ART for >96 weeks) entering immediately, and then the remaining children recruited over the following 15 months as they reach 96 weeks on ART. Follow-up is until March 2012. cumulative loss to follow-up at March 2012 is 10%. See below for further details as box is not big enough
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	With assumptions above, at least 80% power and one-sided alpha=0.05, 947 children would be required in the stop/continue cotrimoxazole prophylaxis comparison to exclude an increase in hospitalisation/death rate of 3% from 5% to 8% per year in the stop cotrimoxazole arm (upper 95% confidence limit of stop:continue hazard ratio 1.6).

Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95% 1.14 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments	Assumptions 5% of children receiving daily cotrimoxazole prophylaxis have a new hospitalisation or death per year recruitment starts 1 July 2009 with 10% children (those already on ART for >96 weeks) entering immediately, and then the remaining children recruited over the following 15 months as they reach 96 weeks on ART. Follow-up is until March 2012. cumulative loss to follow-up at March 2012 is 10%. See below for further details as box is not big enough.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	With assumptions above, at least 80% power and one-sided alpha=0.05, 947 children would be required in the stop/continue cotrimoxazole prophylaxis comparison to exclude an increase in hospitalisation/death rate of 3% from 5% to 8% per year in the stop cotrimoxazole arm (upper 95% confidence limit of stop:continue hazard ratio 1.6).

Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Poisson regression for risk difference
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 95% 0.8 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Risk difference is stop vs continue.

9. Primary Outcome

Title	Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Description	Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	55 9.1%	64 10.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95% 0.83 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue.

10. Secondary Outcome

Title	LCM vs CDM, Induction ART: All-cause Mortality
Description	Number of participants who died from any cause, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	25 4.1%	29 4.8%	20 5%	14 3.5%	20 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95% 0.49 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95% 0.33 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.52 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

11. Secondary Outcome

Title	Induction ART: New WHO Stage 4 Event or Death
Description	Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age
Measure Participants	397	404	405
Number [participants]	30 5%	28 4.7%	28 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.53 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95% 0.54 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

12. Secondary Outcome

Title	LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death
Description	Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	77 12.7%	73 12.2%	73 18.4%	61 15.1%	54 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.73 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.55 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% 0.54 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

13. Secondary Outcome

Title	LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death
Description	Number of participants with a new or recurrent WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	91 15%	79 13.2%	64 16.1%	53 13.1%	53 13.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95% 0.82 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.34
	Comments	Global test with 2df, adjusted for randomization stratification factors
	Method	Log Rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.54 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.56 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

14. Secondary Outcome

Title	LCM vs CDM, Induction ART: Weight-for-age Z-score
Description	Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 4 years (maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Mean (Standard Deviation) [age-adjusted z-score]	0.76 (1.05)	0.78 (1.01)	0.72 (0.95)	0.79 (1.00)	0.80 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

15. Secondary Outcome

Title	LCM vs CDM, Induction ART: Height-for-age Z-score
Description	Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 4 years (maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Mean (Standard Deviation) [age-adjusted z-score]	0.36 (0.65)	0.43 (0.66)	0.40 (0.67)	0.40 (0.65)	0.38 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

16. Secondary Outcome

Title	LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score
Description	Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 4 years (maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Mean (Standard Deviation) [age-adjusted z-score]	0.65 (1.28)	0.61 (1.20)	0.56 (1.11)	0.64 (1.21)	0.69 (1.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

17. Secondary Outcome

Title	LCM vs CDM: Change From Baseline in CD4% to Week 72
Description
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4% (97% completeness)

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Measure Participants	577	563
Mean (Standard Error) [percentage of total lymphocytes]	17.2 (0.36)	16.7 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

18. Secondary Outcome

Title	LCM vs CDM: Change From Baseline in CD4% to Week 144
Description
Time Frame	Baseline, week 144

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4% (95% completeness)

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Measure Participants	579	557
Mean (Standard Error) [percentage of total lymphocytes]	19.7 (0.38)	19.4 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

19. Secondary Outcome

Title	LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72
Description	Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	326	325	208	231	212
Mean (Standard Error) [absolute cells per mm3]	408 (22.2)	385 (19.8)	402 (24.7)	447 (28.5)	336 (22.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Regression, Linear
	Comments	Global test with 2df, adjusted for randomization stratification factors

20. Secondary Outcome

Title	LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144
Description	Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Time Frame	Baseline, week 144

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	326	320	201	231	214
Mean (Standard Error) [absolute cells per mm3]	418 (20.8)	420 (22.5)	446 (25.3)	450 (28.9)	360 (24.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Regression, Linear
	Comments	Global test with 2df, adjusted for randomization stratification factors

21. Secondary Outcome

Title	CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline
Description	Number of participants with HIV RNA viral load <80 copies/ml 72 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Time Frame	72 weeks

Outcome Measure Data

Analysis Population Description
Viral loads were assayed retrospectively in a random subset of children

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	98	102	73	85	42
Number [participants]	76 12.5%	78 13%	56 14.1%	72 17.8%	26 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Chi-squared
	Comments

22. Secondary Outcome

Title	CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline
Description	Number of participants with HIV RNA viral load <80 copies/ml 144 weeks after baseline. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Time Frame	144 weeks

Outcome Measure Data

Analysis Population Description
Viral load was assayed retrospectively at week 144 on a random subset of participants, plus all those aged <5 years at enrolment

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	284	266	168	180	203
Number [participants]	192 31.7%	193 32.2%	127 32%	135 33.4%	124 30.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

23. Secondary Outcome

Title	LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure
Description	Number of participants stopping their first-line regimen for clinical/immunological failure, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Measure Participants	606	600
Number [participants]	28 4.6%	35 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.48 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

24. Secondary Outcome

Title	LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART
Description	Number of participants with a new grade 3 or 4 adverse event definitely/probably or uncertainly related to ART, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	30 5%	42 7%	14 3.5%	30 7.4%	28 6.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.672
	Confidence Interval	(2-Sided) 95% 0.420 to 1.075
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.16
	Confidence Interval	(2-Sided) 95% 1.15 to 4.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95% 1.05 to 3.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

25. Secondary Outcome

Title	LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV
Description	Number of participants with a new serious adverse events not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	147 24.3%	117 19.5%	87 21.9%	82 20.3%	95 23.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95% 1.02 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95% 0.68 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95% 0.81 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

26. Secondary Outcome

Title	LCM vs CDM, Induction ART: New ART-modifying Adverse Event
Description	Number of participants with a new ART-modifying adverse event, to be analysed using time-to-event methods
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Number [participants]	31 5.1%	32 5.3%	8 2%	30 7.4%	25 6.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.58 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is CDM vs LCM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments	Global test with 2df, adjusted for randomization stratification factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.80
	Confidence Interval	(2-Sided) 95% 1.74 to 8.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm B vs A

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Regression, Cox
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.09
	Confidence Interval	(2-Sided) 95% 1.39 to 6.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Arm C vs A

27. Secondary Outcome

Title	LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Description	Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Time Frame	Median 4 years (from randomization to 16 March 2012; maximum 5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Clinically Driven Monitoring (CDM)	Laboratory Plus Clinical Monitoring (LCM)	Arm A: ABC+3TC+NNRTI	Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
Arm/Group Description	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.	Other Names: ZDV: zidovudine, azidothymidine, Retrovir ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ZDV+3TC co-formulated: Combivir ABC+3TC co-formulated: Kivexa ZDV+ABC+3TC co-formulated: Trizivir NVP: nevirapine, Viramune EFV: efavirenz, Sustiva Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
Measure Participants	606	600	397	404	405
Mean (Standard Deviation) [% of visits reporting missed pills]	8.5 (11.1)	9.4 (12.4)	8.3 (10.8)	9.5 (11.8)	9.1 (12.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance, Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance, Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

28. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation
Description	Number of participants with HIV RNA viral load <80 copies/ml at 96 weeks. Threshold for suppression <80 copies/ml as samples had to be diluted due to low volumes.
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description
All participants with viral load assayed in stored specimens (98% of those randomized)

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	331	326
Number [participants]	230 38%	234 39%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Chi-squared
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95% -9.3 to 4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48
Description
Time Frame	Randomisation to once vs twice daily, week 48

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4%

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	331
Mean (Standard Deviation) [percentage of total lymphocytes]	0.9 (6.1)	1.3 (5.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95% -1.2 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

30. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72
Description
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4%

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	332	325
Mean (Standard Deviation) [percentage of total lymphocytes]	1.9 (6.3)	1.9 (5.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95% -0.9 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

31. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96
Description
Time Frame	Randomisation to once vs twice daily, week 96

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4%

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	306	304
Mean (Standard Deviation) [percentage of lymphocytes]	1.6 (7.0)	2.5 (6.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95% -1.9 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

32. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48
Description	Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Time Frame	Randomisation to once vs twice daily, week 48

Outcome Measure Data

Analysis Population Description
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	193	170
Mean (Standard Deviation) [cells per mm3]	3 (348)	-3 (301)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8
	Confidence Interval	(2-Sided) 95% -60 to 76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

33. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72
Description	All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	190	165
Mean (Standard Deviation) [cells per mm3]	-6 (350)	27 (316)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-33
	Confidence Interval	(2-Sided) 95% -104 to 38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

34. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96
Description	All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
Time Frame	Randomisation to once vs twice daily, week 96

Outcome Measure Data

Analysis Population Description
All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	171	149
Mean (Standard Deviation) [cells per mm3]	-26 (445)	60 (737)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-87
	Confidence Interval	(2-Sided) 95% -220 to 46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is once-daily minus twice-daily

35. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality
Description	Number of participants who died, to be analysed using time-to-event methods
Time Frame	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	1 0.2%	4 0.7%

36. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death
Description	Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	3 0.5%	7 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.11 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is once-daily vs twice-daily

37. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death
Description	Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	9 1.5%	12 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95% 0.31 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is once-daily vs twice-daily

38. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score
Description	Age-adjusted change in height-for-age Z-score over all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Mean (Standard Deviation) [age-adjusted z-score]	0.28 (0.36)	0.32 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

39. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score
Description	Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Mean (Standard Deviation) [age-adjusted z-score]	0.01 (0.35)	-0.00 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

40. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score
Description	Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Mean (Standard Deviation) [age-adjusted z-score]	-0.29 (0.49)	-0.35 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Generalised estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

41. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Description	Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	57 9.4%	54 9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95% 0.72 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is once-daily vs twice-daily

42. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV
Description	Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Number [participants]	30 5%	37 6.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.48 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is once-daily vs twice-daily

43. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 48 Weeks
Description	Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 48 weeks.
Time Frame	48 weeks after randomization to once- versus twice-daily

Outcome Measure Data

Analysis Population Description
All participants completing the questionnaire

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	330
Number [participants]	32 5.3%	29 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Chi-squared
	Comments

44. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 96 Weeks
Description	Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 96 weeks.
Time Frame	96 weeks after randomization to once- versus twice-daily

Outcome Measure Data

Analysis Population Description
All participants completing the questionnaire

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	311	309
Number [participants]	26 4.3%	25 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	Chi-squared
	Comments

45. Secondary Outcome

Title	Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Description	Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Time Frame	Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Once-daily ABC+3TC	Twice-daily ABC+3TC
Arm/Group Description	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa	Other Names: ABC: abacavir: Ziagen 3TC: lamivudine: Epivir ABC+3TC co-formulated: Kivexa
Measure Participants	336	333
Mean (Standard Deviation) [% of visits reporting missed pills]	8 (12)	8 (12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Generalized estimating equations
	Comments	Generalised estimating equation with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

46. Secondary Outcome

Title	Cotrimoxazole: New Clinical and Diagnostic Positive Malaria
Description	Number of participants with a new clinical and diagnostic positive malaria, to be analysed using time-to-event methods. Diagnostic positive by either microscopy (thick film) or rapid diagnostic test (RDT)
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	39 6.4%	77 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95% 1.50 to 3.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

47. Secondary Outcome

Title	Cotrimoxazole: New Severe Pneumonia
Description	Number of participants with a new severe pneumonia, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	7 1.2%	10 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95% 0.56 to 3.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

48. Secondary Outcome

Title	Cotrimoxazole: New WHO Stage 3 or 4 Event or Death
Description	Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	8 1.3%	19 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.40
	Confidence Interval	(2-Sided) 95% 1.05 to 5.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

49. Secondary Outcome

Title	Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea
Description	Number of participants with a new WHO stage 3 severe recurrent pneumonia or diarrhoea, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	1 0.2%	4 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.98
	Confidence Interval	(2-Sided) 95% 0.44 to 35.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

50. Secondary Outcome

Title	Cotrimoxazole: New WHO Stage 4 Event or Death
Description	Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods
Time Frame	Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	4 0.7%	7 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.80
	Confidence Interval	(2-Sided) 95% 0.53 to 6.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

51. Secondary Outcome

Title	Cotrimoxazole: All-cause Mortality
Description	Number of participants who died, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	3 0.5%	2 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95% 0.12 to 4.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

52. Secondary Outcome

Title	Cotrimoxazole: Weight-for-age Z-score
Description	Age-adjusted change in weight-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Mean (Standard Deviation) [age-adjusted z-score]	-0.01 (0.37)	-0.05 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Generalised estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

53. Secondary Outcome

Title	Cotrimoxazole: Height-for-age Z-score
Description	Age-adjusted change in height-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Mean (Standard Deviation) [age-adjusted z-score]	0.22 (0.33)	0.19 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Generalised estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

54. Secondary Outcome

Title	Cotrimoxazole: Body Mass Index-for-age Z-score
Description	Age-adjusted change in body mass index-for-age Z-score at all 12-weekly visits attended over the whole follow-up, no specific timepoint prespecified. Mean and SD are time-averaged area under the change curve calculated using the trapezoidal rule. Z-scores calculated using UK norms which cover the full age range of children (Cole, T. J., J. V. Freeman, and M. A. Preece. 1998. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Statistics in Medicine 17(4): 407-29).
Time Frame	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Mean (Standard Deviation) [age-adjusted z-score]	-0.24 (0.54)	-0.28 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Generalised estimating equations
	Comments	Generalised estimating equations with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

55. Secondary Outcome

Title	Cotrimoxazole: Change From Baseline in CD4% to Week 72
Description
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants alive in follow-up with CD4%

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	360	360
Mean (Standard Deviation) [percentage of total lymphocytes]	1.7 (5.5)	1.1 (5.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -1.4 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is stop minus continue

56. Secondary Outcome

Title	Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72
Description	Estimated in those >5 years at randomization to stop vs continue, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.)
Time Frame	Baseline, week 72

Outcome Measure Data

Analysis Population Description
All participants aged >5 years at randomization to stop versus continue alive in follow-up with CD4 measured

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	253	254
Mean (Standard Deviation) [cells per mm3]	7 (310)	-2 (303)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Regression, Linear
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11
	Confidence Interval	(2-Sided) 95% -65 to 42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is stop minus continue

57. Secondary Outcome

Title	Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV
Description	Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods
Time Frame	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Number [participants]	32 5.3%	48 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Log Rank
	Comments	Adjusted for randomization stratification factors

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95% 1.02 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is stop vs continue

58. Secondary Outcome

Title	Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
Description	Binary outcome measure: missed any doses of ART in the last 4 weeks by self-report. Mean calculated across all 12-weekly visits attended over the whole follow-up (no specific timepoint prespecified), giving the percentage of visits attended where the carer/participant reported missing any pills in the last 4 weeks.
Time Frame	Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Continued Cotrimoxazole Prophylaxis	Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Other Names: trimethoprim+sulfamethoxazole
Measure Participants	376	382
Mean (Standard Deviation) [% of visits reporting missed pills]	9 (13)	8 (13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clinically Driven Monitoring (CDM), Laboratory Plus Clinical Monitoring (LCM)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.21
	Comments	Adjusted for randomization stratification factors
	Method	Generalised estimating equation
	Comments	Generalised estimating equation with independent correlation structure and robust standard errors, calculated over all post-randomization visit weeks

Adverse Events

	Clinically Driven Monitoring (CDM)		Laboratory Plus Clinical Monitoring (LCM)		Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI		Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance		Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance		Once-daily ABC+3TC		Twice-daily ABC+3TC		Continued Cotrimoxazole Prophylaxis		Stopped Cotrimoxazole Prophylaxis
Time Frame	LCM vs CDM and induction-maintenance: median 4 years (maximum 5 years); for randomizations; once vs twice daily: median 2 years (maximum 2.6 years); cotrimoxazole: median 2 years (maximum 2.5 years)
Adverse Event Reporting Description	Children were reviewed by a doctor at every scheduled doctor visit, as well as additional visits, and prompts on the doctor follow-up CRF asked about new/worsening/resolved Serious Adverse Events and Grade 3 or 4 Adverse Events.

Arm/Group Title	Clinically Driven Monitoring (CDM)		Laboratory Plus Clinical Monitoring (LCM)		Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI		Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance		Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance		Once-daily ABC+3TC		Twice-daily ABC+3TC		Continued Cotrimoxazole Prophylaxis		Stopped Cotrimoxazole Prophylaxis
Arm/Group Description	Clinically Driven Monitoring (CDM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.		Laboratory plus Clinical Monitoring (LCM): Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.		ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO non-nucleoside reverse transcriptase inhibitor (NNRTI): either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm A: ABC+3TC+NNRTI: Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.		ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus NNRTI subsequently. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.		ZDV [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO NNRTI: either nevirapine or efavirenz based on availability (provided by national ART programmes in Uganda/Zimbabwe). Nevirapine syrup or tablet dosed twice-daily according to weight-bands following WHO. Efavirenz tablets dosed once-daily according to weight-bands following WHO. Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance: Children initiated ART using an induction-maintenance approach, starting with open-label four-drug lamivudine, abacavir, NNRTI, plus zidovudine for 36 weeks, then open-label lamivudine, abacavir, plus zidovudine subsequently (triple NRTI maintenance). The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.		ABC [abacavir]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed once-daily according to weight-bands following WHO Once-daily ABC+3TC		ABC [abacavir]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC [lamivudine]: syrup or tablet, dosed twice-daily according to weight-bands following WHO Twice-daily ABC+3TC		Once-daily doses 5-<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole >=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole Continued cotrimoxazole prophylaxis		Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis. Stopped cotrimoxazole prophylaxis
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Clinically Driven Monitoring (CDM)		Laboratory Plus Clinical Monitoring (LCM)		Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI		Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance		Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance		Once-daily ABC+3TC		Twice-daily ABC+3TC		Continued Cotrimoxazole Prophylaxis		Stopped Cotrimoxazole Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/606 (24.3%)		117/600 (19.5%)		87/397 (21.9%)		92/404 (22.8%)		95/405 (23.5%)		30/336 (8.9%)		37/333 (11.1%)		32/376 (8.5%)		48/382 (12.6%)
Blood and lymphatic system disorders
Clinical Anaemia	17/606 (2.8%)	18	12/600 (2%)	12	6/397 (1.5%)	6	10/404 (2.5%)	11	13/405 (3.2%)	13	3/336 (0.9%)	3	0/333 (0%)	0	0/376 (0%)	0	4/382 (1%)	4
Neutropenia	2/606 (0.3%)	2	3/600 (0.5%)	3	0/397 (0%)	0	2/404 (0.5%)	2	3/405 (0.7%)	3	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Pancytopenia	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	0/404 (0%)	0	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Pneumococcal septicaemia	2/606 (0.3%)	2	0/600 (0%)	0	1/397 (0.3%)	1	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Cardiac disorders
Hypertension	2/606 (0.3%)	2	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Endocrine disorders
Hyperthyroidism	0/606 (0%)	0	1/600 (0.2%)	1	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	0/336 (0%)	0	1/333 (0.3%)	1	0/376 (0%)	0	1/382 (0.3%)	1
Gastrointestinal disorders
Acute diarrhoea	10/606 (1.7%)	10	6/600 (1%)	6	4/397 (1%)	4	7/404 (1.7%)	7	5/405 (1.2%)	5	2/336 (0.6%)	2	1/333 (0.3%)	1	3/376 (0.8%)	3	1/382 (0.3%)	1
Gasteroenteritis	3/606 (0.5%)	3	2/600 (0.3%)	2	1/397 (0.3%)	1	3/404 (0.7%)	3	1/405 (0.2%)	1	0/336 (0%)	0	1/333 (0.3%)	1	1/376 (0.3%)	1	1/382 (0.3%)	1
Vomiting	1/606 (0.2%)	1	0/600 (0%)	0	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	0/336 (0%)	0	1/333 (0.3%)	1	0/376 (0%)	0	1/382 (0.3%)	1
Chronic diarrhoea	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	0/404 (0%)	0	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Hepatobiliary disorders
Acute hepatitis	1/606 (0.2%)	1	3/600 (0.5%)	3	2/397 (0.5%)	2	2/404 (0.5%)	2	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	1/376 (0.3%)	1	0/382 (0%)	0
Infections and infestations
Measles	7/606 (1.2%)	7	4/600 (0.7%)	4	0/397 (0%)	0	5/404 (1.2%)	5	6/405 (1.5%)	6	1/336 (0.3%)	1	3/333 (0.9%)	3	1/376 (0.3%)	1	3/382 (0.8%)	3
Malaria	78/606 (12.9%)	113	49/600 (8.2%)	65	48/397 (12.1%)	69	38/404 (9.4%)	54	41/405 (10.1%)	55	19/336 (5.7%)	27	26/333 (7.8%)	33	16/376 (4.3%)	19	34/382 (8.9%)	47
Septicaemia/bacteremia (presumptive)	5/606 (0.8%)	5	5/600 (0.8%)	6	4/397 (1%)	5	4/404 (1%)	4	2/405 (0.5%)	2	2/336 (0.6%)	2	1/333 (0.3%)	1	2/376 (0.5%)	2	2/382 (0.5%)	2
Febrile convulsions	0/606 (0%)	0	1/600 (0.2%)	1	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Investigations
Raised liver enzymes	0/606 (0%)	0	1/600 (0.2%)	1	0/397 (0%)	0	0/404 (0%)	0	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Metabolism and nutrition disorders
Kwashiorkor	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Malnutrition	1/606 (0.2%)	1	0/600 (0%)	0	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Musculoskeletal and connective tissue disorders
Bone fracture	5/606 (0.8%)	5	4/600 (0.7%)	4	2/397 (0.5%)	2	4/404 (1%)	4	3/405 (0.7%)	3	0/336 (0%)	0	1/333 (0.3%)	1	0/376 (0%)	0	0/382 (0%)	0
Trauma	4/606 (0.7%)	4	4/600 (0.7%)	4	3/397 (0.8%)	3	2/404 (0.5%)	2	3/405 (0.7%)	3	2/336 (0.6%)	2	1/333 (0.3%)	1	3/376 (0.8%)	3	1/382 (0.3%)	1
Arthralgia/arthritis	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	0/404 (0%)	0	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Nervous system disorders
Coma	1/606 (0.2%)	1	0/600 (0%)	0	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	1/336 (0.3%)	1	0/333 (0%)	0	0/376 (0%)	0	1/382 (0.3%)	1
Death, cause unknown	2/606 (0.3%)	2	3/600 (0.5%)	3	3/397 (0.8%)	3	0/404 (0%)	0	2/405 (0.5%)	2	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Pregnancy, puerperium and perinatal conditions
Pre-eclampsia	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Psychiatric disorders
Manic psychosis	0/606 (0%)	0	1/600 (0.2%)	1	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	1/333 (0.3%)	1	0/376 (0%)	0	1/382 (0.3%)	1
Overdose	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchietasis	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	1/333 (0.3%)	1	0/376 (0%)	0	1/382 (0.3%)	1
Pneumonia	7/606 (1.2%)	7	7/600 (1.2%)	7	6/397 (1.5%)	6	3/404 (0.7%)	3	5/405 (1.2%)	5	2/336 (0.6%)	2	1/333 (0.3%)	1	2/376 (0.5%)	2	0/382 (0%)	0
Bronchospasm/asthma	1/606 (0.2%)	1	0/600 (0%)	0	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Chronic sinusitis	1/606 (0.2%)	1	0/600 (0%)	0	0/397 (0%)	0	1/404 (0.2%)	1	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Upper respiratory tract infection	1/606 (0.2%)	1	1/600 (0.2%)	1	0/397 (0%)	0	0/404 (0%)	0	2/405 (0.5%)	2	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Skin and subcutaneous tissue disorders
Hypersensitivity reaction	22/606 (3.6%)	22	19/600 (3.2%)	19	15/397 (3.8%)	15	15/404 (3.7%)	15	11/405 (2.7%)	11	0/336 (0%)	0	1/333 (0.3%)	1	2/376 (0.5%)	2	0/382 (0%)	0
Burns	0/606 (0%)	0	1/600 (0.2%)	1	1/397 (0.3%)	1	0/404 (0%)	0	0/405 (0%)	0	0/336 (0%)	0	0/333 (0%)	0	1/376 (0.3%)	1	0/382 (0%)	0
Maculopapular rash	1/606 (0.2%)	1	1/600 (0.2%)	1	0/397 (0%)	0	1/404 (0.2%)	1	1/405 (0.2%)	1	0/336 (0%)	0	0/333 (0%)	0	0/376 (0%)	0	0/382 (0%)	0
Other (Not Including Serious) Adverse Events
	Clinically Driven Monitoring (CDM)		Laboratory Plus Clinical Monitoring (LCM)		Arm A: Abacavir (ABC)+Lamivudine (3TC)+NNRTI		Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance		Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance		Once-daily ABC+3TC		Twice-daily ABC+3TC		Continued Cotrimoxazole Prophylaxis		Stopped Cotrimoxazole Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	190/606 (31.4%)		198/600 (33%)		96/397 (24.2%)		124/404 (30.7%)		168/405 (41.5%)		33/336 (9.8%)		26/333 (7.8%)		37/376 (9.8%)		26/382 (6.8%)
Infections and infestations
Anaemia with no clinical symptoms	29/606 (4.8%)	32	37/600 (6.2%)	41	20/397 (5%)	22	22/404 (5.4%)	26	24/405 (5.9%)	25	3/336 (0.9%)	3	5/333 (1.5%)	7	5/376 (1.3%)	5	5/382 (1.3%)	5
Investigations
Neutropenia with no clinical symptoms	151/606 (24.9%)	211	160/600 (26.7%)	206	69/397 (17.4%)	92	105/404 (26%)	138	137/405 (33.8%)	187	22/336 (6.5%)	27	15/333 (4.5%)	16	26/376 (6.9%)	28	18/382 (4.7%)	23
Thrombocytopenia with no clinical symptoms	32/606 (5.3%)	44	21/600 (3.5%)	29	19/397 (4.8%)	24	12/404 (3%)	14	22/405 (5.4%)	35	9/336 (2.7%)	15	7/333 (2.1%)	7	10/376 (2.7%)	14	6/382 (1.6%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	Professor Ann Sarah Walker
Organization	Medical Research Council
Phone	+44 20 7670 4726
Email	rmjlasw@ucl.ac.uk

Responsible Party:

Diana M Gibb, Professor of Epidemiology, Medical Research Council

ClinicalTrials.gov Identifier:

NCT02028676

Other Study ID Numbers:

G0300400
24791884
G0300400

First Posted:

Jan 7, 2014

Last Update Posted:

Jun 6, 2014

Last Verified:

Jun 1, 2014