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

Study Overview
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Brief Summary
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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?

Detailed Description
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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.

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

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clinically Driven Monitoring (CDM)<br> | Other: Clinically Driven Monitoring (CDM)<br>* 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.<br>|
| Active Comparator: Laboratory plus Clinical Monitoring (LCM)<br> | Other: Laboratory plus Clinical Monitoring (LCM)<br>* 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.<br>|
| Active Comparator: Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI<br>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<br>* 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.<br>* Other names: EFV: efavirenz, Sustiva;|
| Experimental: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance<br>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<br>* 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.<br>* Other names: EFV: efavirenz, Sustiva;|
| Experimental: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance<br>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<br>* 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.<br>* Other names: EFV: efavirenz, Sustiva;|
| Experimental: Once-daily ABC+3TC<br>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<br> <br> * Other names: ABC+3TC co-formulated: Kivexa;|
| Active Comparator: Twice-daily ABC+3TC<br>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<br> <br> * Other names: ABC+3TC co-formulated: Kivexa;|
| Active Comparator: Continued cotrimoxazole prophylaxis<br>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<br> <br> * Other names: trimethoprim+sulfamethoxazole;|
| Experimental: Stopped cotrimoxazole prophylaxis<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death | Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 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 | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| 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 | 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 | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation | 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. | 48 weeks | 
| 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 | 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 | Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Cotrimoxazole: New Hospitalisation or Death | Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 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 | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LCM vs CDM, Induction ART: All-cause Mortality | Number of participants who died from any cause, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| Induction ART: New WHO Stage 4 Event or Death | Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | Number of participants with a new or recurrent WHO stage 3 or 4 event or death, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: Weight-for-age Z-score | 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). | Baseline and a median of 4 years (maximum 5 years) | 
| LCM vs CDM, Induction ART: Height-for-age Z-score | 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). | Baseline and a median of 4 years (maximum 5 years) | 
| LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 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). | Baseline and a median of 4 years (maximum 5 years) | 
| 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 | Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.) | Baseline, week 72 | 
| LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to 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.) | Baseline, week 144 | 
| CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 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. | 72 weeks | 
| CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 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. | 144 weeks | 
| LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure | Number of participants stopping their first-line regimen for clinical/immunological failure, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 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 | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | Number of participants with a new serious adverse events not solely related to HIV, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: New ART-modifying Adverse Event | Number of participants with a new ART-modifying adverse event, to be analysed using time-to-event methods | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 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. | Median 4 years (from randomization to 16 March 2012; maximum 5 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation | 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. | 96 weeks | 
| 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 | Estimated in those >5 years at enrolment, in whom absolute CD4 is meaningful. (In uninfected children, CD4 decreases with age during early childhood.) | Randomisation to once vs twice daily, week 48 | 
| Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 | All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured | Baseline, week 72 | 
| Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 | All participants aged >5 years at randomization to once versus twice daily alive in follow-up with CD4 measured | Randomisation to once vs twice daily, week 96 | 
| Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality | Number of participants who died, to be analysed using time-to-event methods | Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death | Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods | Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death | Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods | Median 2 years (from randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score | 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). | Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score | 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). | Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score | 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). | Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 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 | Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV | Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods | Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| 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 | Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 48 weeks. | 48 weeks after randomization to once- versus twice-daily | 
| 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 | Number of participants reporting missing any doses of ART in the last 4 weeks by self-report at 96 weeks. | 96 weeks after randomization to once- versus twice-daily | 
| Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 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. | Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years) | 
| Cotrimoxazole: New Clinical and Diagnostic Positive Malaria | 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) | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: New Severe Pneumonia | Number of participants with a new severe pneumonia, to be analysed using time-to-event methods | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: New WHO Stage 3 or 4 Event or Death | Number of participants with a new WHO stage 3 or 4 event or death, to be analysed using time-to-event methods | Median 2 years (from randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea | Number of participants with a new WHO stage 3 severe recurrent pneumonia or diarrhoea, to be analysed using time-to-event methods | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: New WHO Stage 4 Event or Death | Number of participants with a new WHO stage 4 event or death, to be analysed using time-to-event methods | Median 2 years (from randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: All-cause Mortality | Number of participants who died, to be analysed using time-to-event methods | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: Weight-for-age Z-score | 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). | Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: Height-for-age Z-score | 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). | Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: Body Mass Index-for-age Z-score | 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). | Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: Change From Baseline in CD4% to Week 72 |  | Baseline, week 72 | 
| Cotrimoxazole: Change From Baseline in Absolute CD4 to 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.) | Baseline, week 72 | 
| Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV | Number of participants with a new serious adverse event not solely related to HIV, to be analysed using time-to-event methods | Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 
| Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 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. | Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Africa, children, antiretroviral therapy, laboratory monitoring, toxicity, CD4, induction maintenance, cotrimoxazole, prophylaxis, abacavir, lamivudine, once daily