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

Human Immunodeficiency Virus Clinical Trial

— ARROW  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02028676
• Other study ID #: G0300400
• Secondary ID: 24791884G0300400
• Status: Completed
• Phase: Phase 4
• First received: December 31, 2013
• Last updated: June 4, 2014
• Start date: March 2007
• Est. completion date: June 2012

Study information

• Verified date: June 2014
• Source: Medical Research Council
• Contact: n/a
• Is FDA regulated: No
• Health authority: Uganda: National Council for Science and TechnologyUganda: National Drug AuthorityZimbabwe: Medical Research Council
• Study type: Interventional

Clinical Trial 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?

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1206
• Est. completion date: June 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Months to 17 Years

Eligibility

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

Exclusion criteria

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

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

1. Participating in ARROW

2. Aged at least 3 years

3. Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART allowing for any interruptions in ART

4. Currently prescribed daily cotrimoxazole as primary prophylaxis

5. Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to stop or continue daily cotrimoxazole prophylaxis

6. If living in a malaria endemic area, has an insecticide treated bednet and prepared to use this for the child.

Exclusion criteria

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes

Intervention

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

Drug:
• Arm A: ABC+3TC+NNRTI
Children received a standard WHO-recommended regimen of open-label lamivudine, abacavir, plus NNRTI continuously. The NNRTI (nevirapine or efavirenz) was chosen by clinicians according to local availability and age.
• 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.
• 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.
• Once-daily ABC+3TC

• Twice-daily ABC+3TC

• Continued cotrimoxazole prophylaxis

Other:
• Stopped cotrimoxazole prophylaxis

Locations

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

Sponsors (4)

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

Countries where clinical trial is conducted

Uganda,  Zimbabwe, 

References & Publications (2)

ARROW Trial team, Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P, Nahirya-Ntege P, Bakeera-Kitaka S, Thomason M, Bwakura-Dangarembizi M, Musiime V, Munderi P, Naidoo-James B, Vhembo T, Tumusiime C, Katuramu R, Crawley J, Prendergast AJ, Musoke P, Walker AS, G — View Citation

Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, Nahirya-Ntege P, Keishanyu R, Nathoo K, Spyer MJ, Kekitiinwa A, Lutaakome J, Mhute T, Kasirye P, Munderi P, Musiime V, Gibb DM, Walker AS, Prendergast AJ; Antiretroviral Research for Watoto (ARROW) Tria — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	Yes
Primary	Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation		Baseline, 72 weeks	No
Primary	Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation		Baseline, 144 weeks	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	Yes
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.	48 weeks	No
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	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	Yes
Primary	Cotrimoxazole: New Hospitalisation or Death	Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	Yes
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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).	Baseline and a median of 4 years (maximum 5 years)	No
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).	Baseline and a median of 4 years (maximum 5 years)	No
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).	Baseline and a median of 4 years (maximum 5 years)	No
Secondary	LCM vs CDM: Change From Baseline in CD4% to Week 72		Baseline, week 72	No
Secondary	LCM vs CDM: Change From Baseline in CD4% to Week 144		Baseline, week 144	No
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.)	Baseline, week 72	No
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.)	Baseline, week 144	No
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.	72 weeks	No
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.	144 weeks	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	Yes
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	Yes
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	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	Yes
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.	Median 4 years (from randomization to 16 March 2012; maximum 5 years)	No
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.	96 weeks	No
Secondary	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48		Randomisation to once vs twice daily, week 48	No
Secondary	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72		Baseline, week 72	No
Secondary	Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96		Randomisation to once vs twice daily, week 96	No
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.)	Randomisation to once vs twice daily, week 48	No
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	Baseline, week 72	No
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	Randomisation to once vs twice daily, week 96	No
Secondary	Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality	Number of participants who died, to be analysed using time-to-event methods	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)	No
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	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)	No
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	Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)	No
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).	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	No
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).	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	No
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).	Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	No
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	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	Yes
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	Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	Yes
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.	48 weeks after randomization to once- versus twice-daily	No
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.	96 weeks after randomization to once- versus twice-daily	No
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.	Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)	No
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)	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
Secondary	Cotrimoxazole: New Severe Pneumonia	Number of participants with a new severe pneumonia, to be analysed using time-to-event methods	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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	Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)	No
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	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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	Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)	No
Secondary	Cotrimoxazole: All-cause Mortality	Number of participants who died, to be analysed using time-to-event methods	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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).	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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).	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
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).	Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No
Secondary	Cotrimoxazole: Change From Baseline in CD4% to Week 72		Baseline, week 72	No
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.)	Baseline, week 72	No
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	Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	Yes
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.	Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)	No

External Links

•   main ARROW trial webpage