Human Immunodeficiency Virus
Conditions
Keywords
HIV, Africa, children, antiretroviral therapy, laboratory monitoring, toxicity, CD4, induction maintenance, cotrimoxazole, prophylaxis, abacavir, lamivudine, once daily
Brief summary
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART): 1. 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)? 2. 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 3. 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? 4. 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
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.
Interventions
OTHERClinically 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.
OTHERLaboratory 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.
DRUGArm 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.
DRUGArm 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.
DRUGArm 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.
DRUGOnce-daily ABC+3TC
DRUGTwice-daily ABC+3TC
DRUGContinued cotrimoxazole prophylaxis
OTHERStopped cotrimoxazole prophylaxis
Sponsors
Department for International Development, United Kingdom
ViiV Healthcare
GlaxoSmithKline
Medical Research Council
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
For initial randomisation to CDM vs LCM, and to ART induction strategy: Inclusion Criteria: 1. 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. 2. 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. 3. Participants must have a confirmed documented diagnosis of HIV-1 infection: 1. 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). 2. 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. 4. Age 3 months to 17 years (13-17 years to be capped at 10%) 5. ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission). 6. 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
1. Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre) 2. Likelihood of poor adherence 3. 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) 4. 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 5. 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. 6. Being pregnant or breast-feeding an infant 7. 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 1. Participating in ARROW 2. On ART for at least 36 weeks 3. 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 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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 |
| 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: 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. |
| 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. |
| 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 | — |
Countries
Uganda, Zimbabwe
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Clinically Driven Monitoring (CDM) 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. | 606 |
| Laboratory Plus Clinical Monitoring (LCM) 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. | 600 |
| 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.
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. | 397 |
| 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.
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. | 404 |
| 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.
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. | 405 |
| 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
Once-daily ABC+3TC | 336 |
| 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
Twice-daily ABC+3TC | 333 |
| 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
Continued cotrimoxazole prophylaxis | 376 |
| 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.
Stopped cotrimoxazole prophylaxis | 382 |
| Total | 3,839 |
Baseline characteristics
| Characteristic | Total | 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 | Clinically Driven Monitoring (CDM) | Once-daily ABC+3TC | Twice-daily ABC+3TC | Continued Cotrimoxazole Prophylaxis | Stopped Cotrimoxazole Prophylaxis |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, categorical: Period 2 (trial enrollment, induction ART) <3 years | NA participants | NA participants | 121 participants | 117 participants | 132 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Age, categorical: Period 2 (trial enrollment, induction ART) 3 years or older | NA participants | NA participants | 276 participants | 287 participants | 273 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Age, categorical: Period 3 (randomization to once vs twice daily ABC+3TC) <3 years | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 36 participants | 38 participants | NA participants | NA participants |
| Age, categorical: Period 3 (randomization to once vs twice daily ABC+3TC) 3 years and older | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 300 participants | 295 participants | NA participants | NA participants |
| Age, categorical: Period 4 (randomization to stop versus continue cotrimoxazole) <3 years | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 0 participants | 0 participants |
| Age, categorical: Period 4 (randomization to stop versus continue cotrimoxazole) 3 years and older | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 376 participants | 382 participants |
| Age, Continuous | 6.0 years | 6.0 years | NA years | NA years | NA years | 5.9 years | NA years | NA years | NA years | NA years |
| Age, continuous: Period 2 (trial enrollment, induction ART) | 6.0 years | NA years | 6.1 years | 6.2 years | 5.7 years | NA years | NA years | NA years | NA years | NA years |
| Age, continuous: Period 3 (randomization to once vs twice daily ABC+3TC) | 5.5 years | NA years | NA years | NA years | NA years | NA years | 5.9 years | 5.1 years | NA years | NA years |
| Age, continuous: Period 4 (randomization to stop versus continue cotrimoxazole) | 7.9 years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | 7.5 years | 8.3 years |
| Age, Customized < 3 years | NA participants | 173 participants | NA participants | NA participants | NA participants | 197 participants | NA participants | NA participants | NA participants | NA participants |
| Age, Customized 3 years or older | NA participants | 427 participants | NA participants | NA participants | NA participants | 409 participants | NA participants | NA participants | NA participants | NA participants |
| CD4 T cell percentage | 12.0 percentage of total lymphocytes | 12.0 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | 12.5 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes |
| CD4 T cell percentage: Period 2 (trial enrollment, induction ART) | 12.0 percentage of total lymphocytes | NA percentage of total lymphocytes | 11.7 percentage of total lymphocytes | 12.0 percentage of total lymphocytes | 12.5 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes |
| CD4 T cell percentage: Period 3 (randomization to once vs twice daily ABC+3TC) | 33.0 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | 33.0 percentage of total lymphocytes | 33.0 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes |
| CD4 T cell percentage: Period 4 (randomization to stop versus continue cotrimoxazole) | 33.0 percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | NA percentage of total lymphocytes | 33.0 percentage of total lymphocytes | 32.0 percentage of total lymphocytes |
| Duration of antiretroviral therapy: Period 3 (randomization to once vs twice daily ABC+3TC) | 1.8 years | NA years | NA years | NA years | NA years | NA years | 1.8 years | 1.8 years | NA years | NA years |
| Duration of antiretroviral therapy: Period 4 (randomization to stop versus continue cotrimoxazole) | 2.1 years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | 2.1 years | 2.1 years |
| Gender, Male/Female: Period 2 (trial enrollment, induction ART) Female | NA participants | NA participants | 204 participants | 197 participants | 209 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Gender, Male/Female: Period 2 (trial enrollment, induction ART) Male | NA participants | NA participants | 193 participants | 207 participants | 196 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Gender, Male/Female: Period 3 (randomization to once vs twice daily ABC+3TC) Female | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 173 participants | 172 participants | NA participants | NA participants |
| Gender, Male/Female: Period 3 (randomization to once vs twice daily ABC+3TC) Male | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 163 participants | 161 participants | NA participants | NA participants |
| Gender, Male/Female: Period 4 (randomization to stop versus continue cotrimoxazole) Female | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 195 participants | 203 participants |
| Gender, Male/Female: Period 4 (randomization to stop versus continue cotrimoxazole) Male | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 181 participants | 179 participants |
| Region of Enrollment Uganda | NA participants | 401 participants | NA participants | NA participants | NA participants | 405 participants | NA participants | NA participants | NA participants | NA participants |
| Region of Enrollment Zimbabwe | NA participants | 199 participants | NA participants | NA participants | NA participants | 201 participants | NA participants | NA participants | NA participants | NA participants |
| Region of Enrollment: Period 2 (trial enrollment, induction ART) Uganda | NA participants | NA participants | 266 participants | 268 participants | 272 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Region of Enrollment: Period 2 (trial enrollment, induction ART) Zimbabwe | NA participants | NA participants | 131 participants | 136 participants | 133 participants | NA participants | NA participants | NA participants | NA participants | NA participants |
| Region of Enrollment: Period 3 (randomization to once vs twice daily ABC+3TC) Uganda | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 249 participants | 246 participants | NA participants | NA participants |
| Region of Enrollment: Period 3 (randomization to once vs twice daily ABC+3TC) Zimbabwe | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 87 participants | 87 participants | NA participants | NA participants |
| Region of Enrollment: Period 4 (randomization to stop versus continue cotrimoxazole) Uganda | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 283 participants | 286 participants |
| Region of Enrollment: Period 4 (randomization to stop versus continue cotrimoxazole) Zimbabwe | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | NA participants | 93 participants | 96 participants |
| Sex: Female, Male Female | NA Participants | 302 Participants | NA Participants | NA Participants | NA Participants | 308 Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Sex: Female, Male Male | NA Participants | 298 Participants | NA Participants | NA Participants | NA Participants | 298 Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Weight-for-age Z-score: Period 1 (trial enrollment, CDM vs LCM) | -2.2 Z-score | -2.2 Z-score | NA Z-score | NA Z-score | NA Z-score | -2.3 Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score |
| Weight-for-age Z-score: Period 2 (trial enrollment, induction ART) | -2.2 Z-score | NA Z-score | -2.3 Z-score | -2.2 Z-score | -2.2 Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score |
| Weight-for-age Z-score: Period 3 (randomization to once vs twice daily ABC+3TC) | -1.4 Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | -1.4 Z-score | -1.3 Z-score | NA Z-score | NA Z-score |
| Weight-for-age Z-score: Period 4 (randomization to stop versus continue cotrimoxazole) | -1.3 Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | NA Z-score | -1.3 Z-score | -1.3 Z-score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 190 / 606 | 198 / 600 | 96 / 397 | 124 / 404 | 168 / 405 | 33 / 336 | 26 / 333 | 37 / 376 | 26 / 382 |
| serious Total, serious adverse events | 147 / 606 | 117 / 600 | 87 / 397 | 92 / 404 | 95 / 405 | 30 / 336 | 37 / 333 | 32 / 376 | 48 / 382 |
Outcome results
Primary
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
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 55 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 64 participants |
p-value: 0.3395% CI: [0.83, 1.72]Log Rank
Primary
Cotrimoxazole: New Hospitalisation or Death
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New Hospitalisation or Death | 48 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New Hospitalisation or Death | 72 participants |
Comparison: 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 enoughp-value: 0.00795% CI: [1.14, 2.37]Log Rank
Comparison: 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.p-value: 0.00695% CI: [0.8, 7.2]Poisson regression for risk difference
Primary
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Time frame: Baseline, 72 weeks
Population: All participants alive at 72 weeks with CD4 measured (completeness in those in follow-up was 96.6%).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation | 16.4 percentage of total lymphocytes | Standard Error 0.45 |
| Laboratory Plus Clinical Monitoring (LCM) | Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation | 17.1 percentage of total lymphocytes | Standard Error 0.43 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation | 17.3 percentage of total lymphocytes | Standard Error 0.41 |
Comparison: 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).p-value: 0.33Regression, Linear
Primary
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Time frame: Baseline, 144 weeks
Population: All participants alive in follow-up with CD4% (95% completeness)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation | 19.8 percentage of total lymphocytes | Standard Error 0.44 |
| Laboratory Plus Clinical Monitoring (LCM) | Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation | 19.6 percentage of total lymphocytes | Standard Error 0.49 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation | 19.2 percentage of total lymphocytes | Standard Error 0.46 |
p-value: 0.69Regression, Linear
Primary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 157 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 190 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 218 participants |
p-value: 0.0001Log Rank
p-value: 0.0195% CI: [1.07, 1.63]Regression, Cox
p-value: <0.00195% CI: [1.29, 1.94]Regression, Cox
Primary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Population: All randomized participants (time-to-event)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death | 47 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death | 39 participants |
p-value: 0.5995% CI: [0.73, 1.73]Log Rank
Comparison: 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.p-value: 0.4395% CI: [-0.47, 1.12]Comparison of poisson rates
Primary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 283 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 282 participants |
p-value: 0.8395% CI: [0.83, 1.16]Log Rank
Primary
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
Time frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | 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 | 1 participants |
| Laboratory Plus Clinical Monitoring (LCM) | 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 | 0 participants |
Primary
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.
Time frame: 48 weeks
Population: All randomized participants with VL result from stored plasma specimen (available for 661/669, 99%, randomized participants)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation | 236 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation | 242 participants |
p-value: 0.6595% CI: [-8.4, 5.2]Chi-squared
Secondary
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.
Time frame: 144 weeks
Population: Viral load was assayed retrospectively at week 144 on a random subset of participants, plus all those aged \<5 years at enrolment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 192 participants |
| Laboratory Plus Clinical Monitoring (LCM) | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 193 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 127 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 135 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline | 124 participants |
p-value: 0.2Chi-squared
p-value: 0.002Chi-squared
Secondary
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.
Time frame: 72 weeks
Population: Viral loads were assayed retrospectively in a random subset of children
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 76 participants |
| Laboratory Plus Clinical Monitoring (LCM) | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 78 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 56 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 72 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline | 26 participants |
p-value: 0.86Chi-squared
p-value: 0.02Chi-squared
Secondary
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.
Time frame: Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 9 % of visits reporting missed pills | Standard Deviation 13 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 8 % of visits reporting missed pills | Standard Deviation 13 |
p-value: 0.21Generalised estimating equation
Secondary
Cotrimoxazole: All-cause Mortality
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: All-cause Mortality | 3 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: All-cause Mortality | 2 participants |
p-value: 0.6895% CI: [0.12, 4.15]Log Rank
Secondary
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).
Time frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Body Mass Index-for-age Z-score | -0.24 age-adjusted z-score | Standard Deviation 0.54 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Body Mass Index-for-age Z-score | -0.28 age-adjusted z-score | Standard Deviation 0.45 |
p-value: 0.34Generalised estimating equations
Secondary
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.)
Time frame: Baseline, week 72
Population: All participants aged \>5 years at randomization to stop versus continue alive in follow-up with CD4 measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72 | 7 cells per mm3 | Standard Deviation 310 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72 | -2 cells per mm3 | Standard Deviation 303 |
p-value: 0.6895% CI: [-65, 42]Regression, Linear
Secondary
Cotrimoxazole: Change From Baseline in CD4% to Week 72
Time frame: Baseline, week 72
Population: All participants alive in follow-up with CD4%
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Change From Baseline in CD4% to Week 72 | 1.7 percentage of total lymphocytes | Standard Deviation 5.5 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Change From Baseline in CD4% to Week 72 | 1.1 percentage of total lymphocytes | Standard Deviation 5.7 |
p-value: 0.1395% CI: [-1.4, 0.2]Regression, Linear
Secondary
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).
Time frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Height-for-age Z-score | 0.22 age-adjusted z-score | Standard Deviation 0.33 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Height-for-age Z-score | 0.19 age-adjusted z-score | Standard Deviation 0.35 |
p-value: 0.19Generalised estimating equations
Secondary
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)
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New Clinical and Diagnostic Positive Malaria | 39 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New Clinical and Diagnostic Positive Malaria | 77 participants |
p-value: <0.00195% CI: [1.5, 3.25]Log Rank
Secondary
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
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV | 32 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV | 48 participants |
p-value: 0.0495% CI: [1.02, 2.5]Log Rank
Secondary
Cotrimoxazole: New Severe Pneumonia
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New Severe Pneumonia | 7 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New Severe Pneumonia | 10 participants |
p-value: 0.4495% CI: [0.56, 3.85]Log Rank
Secondary
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
Time frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New WHO Stage 3 or 4 Event or Death | 8 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New WHO Stage 3 or 4 Event or Death | 19 participants |
p-value: 0.0395% CI: [1.05, 5.48]Log Rank
Secondary
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
Time frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea | 1 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea | 4 participants |
p-value: 0.1895% CI: [0.44, 35.7]Log Rank
Secondary
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
Time frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: New WHO Stage 4 Event or Death | 4 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: New WHO Stage 4 Event or Death | 7 participants |
p-value: 0.3495% CI: [0.53, 6.17]Log Rank
Secondary
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).
Time frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Cotrimoxazole: Weight-for-age Z-score | -0.01 age-adjusted z-score | Standard Deviation 0.37 |
| Laboratory Plus Clinical Monitoring (LCM) | Cotrimoxazole: Weight-for-age Z-score | -0.05 age-adjusted z-score | Standard Deviation 0.34 |
p-value: 0.07Generalised estimating equations
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Induction ART: New WHO Stage 4 Event or Death | 30 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Induction ART: New WHO Stage 4 Event or Death | 28 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | Induction ART: New WHO Stage 4 Event or Death | 28 participants |
p-value: 0.89Log Rank
p-value: 0.6495% CI: [0.53, 1.48]Regression, Cox
p-value: 0.7195% CI: [0.54, 1.52]Regression, Cox
Secondary
LCM vs CDM: Change From Baseline in CD4% to Week 144
Time frame: Baseline, week 144
Population: All participants alive in follow-up with CD4% (95% completeness)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM: Change From Baseline in CD4% to Week 144 | 19.7 percentage of total lymphocytes | Standard Error 0.38 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM: Change From Baseline in CD4% to Week 144 | 19.4 percentage of total lymphocytes | Standard Error 0.38 |
p-value: 0.7Regression, Linear
Secondary
LCM vs CDM: Change From Baseline in CD4% to Week 72
Time frame: Baseline, week 72
Population: All participants alive in follow-up with CD4% (97% completeness)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM: Change From Baseline in CD4% to Week 72 | 17.2 percentage of total lymphocytes | Standard Error 0.36 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM: Change From Baseline in CD4% to Week 72 | 16.7 percentage of total lymphocytes | Standard Error 0.35 |
p-value: 0.45Regression, Linear
Secondary
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.
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 8.5 % of visits reporting missed pills | Standard Deviation 11.1 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 9.4 % of visits reporting missed pills | Standard Deviation 12.4 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 8.3 % of visits reporting missed pills | Standard Deviation 10.8 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 9.5 % of visits reporting missed pills | Standard Deviation 11.8 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 9.1 % of visits reporting missed pills | Standard Deviation 12.7 |
p-value: 0.53Generalized estimating equations
p-value: 0.46Generalized estimating equations
Secondary
LCM vs CDM, Induction ART: All-cause Mortality
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: All-cause Mortality | 25 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: All-cause Mortality | 29 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: All-cause Mortality | 20 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: All-cause Mortality | 14 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: All-cause Mortality | 20 participants |
p-value: 0.4595% CI: [0.49, 1.44]Log Rank
p-value: 0.43Log Rank
p-value: 0.2395% CI: [0.33, 1.31]Regression, Cox
p-value: 0.9395% CI: [0.52, 1.81]Regression, Cox
Secondary
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).
Time frame: Baseline and a median of 4 years (maximum 5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 0.65 age-adjusted z-score | Standard Deviation 1.28 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 0.61 age-adjusted z-score | Standard Deviation 1.2 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 0.56 age-adjusted z-score | Standard Deviation 1.11 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 0.64 age-adjusted z-score | Standard Deviation 1.21 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score | 0.69 age-adjusted z-score | Standard Deviation 1.39 |
p-value: 0.64Generalized estimating equations
p-value: 0.3Generalized estimating equations
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure | 28 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure | 35 participants |
p-value: 0.2295% CI: [0.48, 1.29]Log Rank
Secondary
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.)
Time frame: Baseline, week 144
Population: All participants alive in follow-up with CD4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 | 418 absolute cells per mm3 | Standard Error 20.8 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 | 420 absolute cells per mm3 | Standard Error 22.5 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 | 446 absolute cells per mm3 | Standard Error 25.3 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 | 450 absolute cells per mm3 | Standard Error 28.9 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 | 360 absolute cells per mm3 | Standard Error 24 |
p-value: 0.81Regression, Linear
p-value: 0.03Regression, Linear
Secondary
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.)
Time frame: Baseline, week 72
Population: All participants alive in follow-up with CD4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 | 408 absolute cells per mm3 | Standard Error 22.2 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 | 385 absolute cells per mm3 | Standard Error 19.8 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 | 402 absolute cells per mm3 | Standard Error 24.7 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 | 447 absolute cells per mm3 | Standard Error 28.5 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 | 336 absolute cells per mm3 | Standard Error 22.5 |
p-value: 0.59Regression, Linear
p-value: 0.01Regression, Linear
Secondary
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).
Time frame: Baseline and a median of 4 years (maximum 5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Height-for-age Z-score | 0.36 age-adjusted z-score | Standard Deviation 0.65 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Height-for-age Z-score | 0.43 age-adjusted z-score | Standard Deviation 0.66 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Height-for-age Z-score | 0.40 age-adjusted z-score | Standard Deviation 0.67 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Height-for-age Z-score | 0.40 age-adjusted z-score | Standard Deviation 0.65 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Height-for-age Z-score | 0.38 age-adjusted z-score | Standard Deviation 0.64 |
p-value: 0.07Generalized estimating equations
p-value: 0.9Generalized estimating equations
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: New ART-modifying Adverse Event | 31 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: New ART-modifying Adverse Event | 32 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New ART-modifying Adverse Event | 8 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: New ART-modifying Adverse Event | 30 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New ART-modifying Adverse Event | 25 participants |
p-value: 0.8495% CI: [0.58, 1.56]Log Rank
p-value: 0.002Log Rank
p-value: 0.00195% CI: [1.74, 8.29]Regression, Cox
p-value: 0.00695% CI: [1.39, 6.85]Regression, Cox
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 30 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 42 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 14 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 30 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART | 28 participants |
p-value: 0.0995% CI: [0.42, 1.075]Log Rank
p-value: 0.04Log Rank
p-value: 0.01795% CI: [1.15, 4.08]Regression, Cox
p-value: 0.03495% CI: [1.05, 3.8]Regression, Cox
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | 91 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | 79 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | 64 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | 53 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death | 53 participants |
p-value: 0.5295% CI: [0.82, 1.49]Log Rank
p-value: 0.34Log Rank
p-value: 0.1995% CI: [0.54, 1.13]Regression, Cox
p-value: 0.2595% CI: [0.56, 1.16]Regression, Cox
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | 147 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | 117 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | 87 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | 82 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV | 95 participants |
p-value: 0.0495% CI: [1.02, 1.66]Log Rank
p-value: 0.53Log Rank
p-value: 0.695% CI: [0.68, 1.25]Regression, Cox
p-value: 0.5695% CI: [0.81, 1.46]Regression, Cox
Secondary
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
Time frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | 77 participants |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | 73 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | 73 participants |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | 61 participants |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death | 54 participants |
p-value: 0.9895% CI: [0.73, 1.38]Log Rank
p-value: 0.44Log Rank
p-value: 0.395% CI: [0.55, 1.2]Regression, Cox
p-value: 0.2495% CI: [0.54, 1.17]Regression, Cox
Secondary
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).
Time frame: Baseline and a median of 4 years (maximum 5 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | LCM vs CDM, Induction ART: Weight-for-age Z-score | 0.76 age-adjusted z-score | Standard Deviation 1.05 |
| Laboratory Plus Clinical Monitoring (LCM) | LCM vs CDM, Induction ART: Weight-for-age Z-score | 0.78 age-adjusted z-score | Standard Deviation 1.01 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Weight-for-age Z-score | 0.72 age-adjusted z-score | Standard Deviation 0.95 |
| Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI Maintenance | LCM vs CDM, Induction ART: Weight-for-age Z-score | 0.79 age-adjusted z-score | Standard Deviation 1 |
| Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC Maintenance | LCM vs CDM, Induction ART: Weight-for-age Z-score | 0.80 age-adjusted z-score | Standard Deviation 1.13 |
p-value: 0.71Generalized estimating equations
p-value: 0.58Generalized estimating equations
Secondary
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.
Time frame: Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 8 % of visits reporting missed pills | Standard Deviation 12 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) | 8 % of visits reporting missed pills | Standard Deviation 12 |
p-value: 0.93Generalized estimating equations
Secondary
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.
Time frame: 48 weeks after randomization to once- versus twice-daily
Population: All participants completing the questionnaire
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | 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 | 32 participants |
| Laboratory Plus Clinical Monitoring (LCM) | 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 | 29 participants |
p-value: 0.74Chi-squared
Secondary
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.
Time frame: 96 weeks after randomization to once- versus twice-daily
Population: All participants completing the questionnaire
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | 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 | 26 participants |
| Laboratory Plus Clinical Monitoring (LCM) | 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 | 25 participants |
p-value: 0.9Chi-squared
Secondary
Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality | 1 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality | 4 participants |
Secondary
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).
Time frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score | -0.29 age-adjusted z-score | Standard Deviation 0.49 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score | -0.35 age-adjusted z-score | Standard Deviation 0.57 |
p-value: 0.08Generalised estimating equations
Secondary
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.)
Time frame: Randomisation to once vs twice daily, week 48
Population: All participants aged \>5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48 | 3 cells per mm3 | Standard Deviation 348 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48 | -3 cells per mm3 | Standard Deviation 301 |
p-value: 0.8295% CI: [-60, 76]Regression, Linear
Secondary
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
Time frame: Baseline, week 72
Population: All participants aged \>5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 | -6 cells per mm3 | Standard Deviation 350 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 | 27 cells per mm3 | Standard Deviation 316 |
p-value: 0.3695% CI: [-104, 38]Regression, Linear
Secondary
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
Time frame: Randomisation to once vs twice daily, week 96
Population: All participants aged \>5 years at randomization to once versus twice daily alive in follow-up with CD4 measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 | -26 cells per mm3 | Standard Deviation 445 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 | 60 cells per mm3 | Standard Deviation 737 |
p-value: 0.295% CI: [-220, 46]Regression, Linear
Secondary
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48
Time frame: Randomisation to once vs twice daily, week 48
Population: All participants alive in follow-up with CD4%
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48 | 0.9 percentage of total lymphocytes | Standard Deviation 6.1 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48 | 1.3 percentage of total lymphocytes | Standard Deviation 5.4 |
p-value: 0.3995% CI: [-1.2, 0.5]Regression, Linear
Secondary
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72
Time frame: Baseline, week 72
Population: All participants alive in follow-up with CD4%
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72 | 1.9 percentage of total lymphocytes | Standard Deviation 6.3 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72 | 1.9 percentage of total lymphocytes | Standard Deviation 5.3 |
p-value: 0.9895% CI: [-0.9, 0.9]Regression, Linear
Secondary
Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96
Time frame: Randomisation to once vs twice daily, week 96
Population: All participants alive in follow-up with CD4%
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96 | 1.6 percentage of lymphocytes | Standard Deviation 7 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96 | 2.5 percentage of lymphocytes | Standard Deviation 6.3 |
p-value: 0.1295% CI: [-1.9, 0.2]Regression, Linear
Secondary
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).
Time frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score | 0.28 age-adjusted z-score | Standard Deviation 0.36 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score | 0.32 age-adjusted z-score | Standard Deviation 0.45 |
p-value: 0.16Generalized estimating equations
Secondary
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
Time frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 57 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV | 54 participants |
p-value: 0.8295% CI: [0.72, 1.52]Log Rank
Secondary
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
Time frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV | 30 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV | 37 participants |
p-value: 0.3195% CI: [0.48, 1.27]Log Rank
Secondary
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
Time frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death | 9 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death | 12 participants |
p-value: 0.5195% CI: [0.31, 1.77]Log Rank
Secondary
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
Time frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death | 3 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death | 7 participants |
p-value: 0.295% CI: [0.11, 1.64]Log Rank
Secondary
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.
Time frame: 96 weeks
Population: All participants with viral load assayed in stored specimens (98% of those randomized)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation | 230 participants |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation | 234 participants |
p-value: 0.5295% CI: [-9.3, 4.7]Chi-squared
Secondary
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).
Time frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinically Driven Monitoring (CDM) | Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score | 0.01 age-adjusted z-score | Standard Deviation 0.35 |
| Laboratory Plus Clinical Monitoring (LCM) | Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score | -0.00 age-adjusted z-score | Standard Deviation 0.37 |
p-value: 0.54Generalized estimating equations