Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa
ARROW
A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa
2 other identifiers
interventional
1,206
2 countries
4
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?
- 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?
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_4
Started Mar 2007
Longer than P75 for phase_4
4 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
March 1, 2007
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 1, 2012
CompletedStudy Completion
Last participant's last visit for all outcomes
June 1, 2012
CompletedFirst Submitted
Initial submission to the registry
December 31, 2013
CompletedFirst Posted
Study publicly available on registry
January 7, 2014
CompletedResults Posted
Study results publicly available
June 6, 2014
CompletedJune 6, 2014
June 1, 2014
5 years
December 31, 2013
January 15, 2014
June 4, 2014
Conditions
Keywords
Outcome Measures
Primary Outcomes (9)
LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Baseline, 72 weeks
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Baseline, 144 weeks
Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
Number of participants with HIV RNA viral load \<80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of \<80 copies/ml was used to indicate suppression.
48 weeks
Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV, Judged Definitely/Probably or Uncertain Whether Related to Lamivudine or Abacavir
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Cotrimoxazole: New Hospitalisation or Death
Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Secondary Outcomes (49)
LCM vs CDM, Induction ART: All-cause Mortality
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Induction ART: New WHO Stage 4 Event or Death
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death
Median 4 years (from randomization to 16 March 2012; maximum 5 years)
LCM vs CDM, Induction ART: Weight-for-age Z-score
Baseline and a median of 4 years (maximum 5 years)
- +44 more secondary outcomes
Study Arms (9)
Clinically Driven Monitoring (CDM)
EXPERIMENTALLaboratory plus Clinical Monitoring (LCM)
ACTIVE COMPARATORArm A: abacavir (ABC)+lamivudine (3TC)+NNRTI
ACTIVE COMPARATORABC \[abacavir\]: 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 B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance
EXPERIMENTALZDV \[abacavir\]: 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
EXPERIMENTALZDV \[abacavir\]: 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.
Once-daily ABC+3TC
EXPERIMENTALABC \[abacavir\]: 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
Twice-daily ABC+3TC
ACTIVE COMPARATORABC \[abacavir\]: 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
Continued cotrimoxazole prophylaxis
ACTIVE COMPARATOROnce-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
Stopped cotrimoxazole prophylaxis
EXPERIMENTALChildren had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.
Interventions
Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. Screening results were used to assess eligibility. All subsequent results at and after randomisation were only returned if requested for clinical management (authorised by centre project leaders); haemoglobin results at week 8 were automatically returned on the basis of early anaemia in a previous adult trial as were grade 4 laboratory toxicities (protocol safety criteria). Total lymphocytes and CD4 tests were never returned for CDM participants, but for all children other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
Participants were examined by a doctor and had routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), biochemistry tests (bilirubin, urea, creatinine, aspartate aminotransferase, alanine aminotransferase) at screening, randomisation (lymphocytes only), weeks 4, 8, and 12, then every 12 weeks. All results were returned to physicians for patient management. Other investigations (including tests from the routine panels) could be requested and concomitant drugs prescribed, as clinically indicated at extra patient-initiated or scheduled visits.
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.
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.
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.
Eligibility Criteria
You may qualify if:
- Children should have an adult carer in the household who is either:
- participating in the DART trial OR
- being treated with ART OR
- HIV positive but not yet needing treatment but with access to a treatment programme when ART is required OR
- HIV negative. Children of DART participants should have first priority on any available remaining slots to enter ARROW.
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
- Participants must have a confirmed documented diagnosis of HIV-1 infection:
- For children aged under 18 months: two separate peripheral blood specimens from different days, both results being positive with HIV-DNA polymerase chain reaction (PCR).
- For children aged 18 months or over: antibody positive serology by ELISA test (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test (performed in series) both on the same sample. Any child previously tested at another clinic should have a repeat test at an ARROW screening laboratory to confirm their status.
- Age 3 months to 17 years (13-17 years to be capped at 10%)
- ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
- Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:
- WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or count
- WHO paediatric clinical stage III disease:
- \<12 months: treat all
- +6 more criteria
You may not qualify if:
- Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre)
- Likelihood of poor adherence
- Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an acute infection. Children with chronic lung disease, including recurrent respiratory infections, are eligible. Children with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART (see 4 below)
- In receipt of medication contraindicated by ART
- children under three years of age receiving anti-tuberculosis therapy should not be enrolled (as they will have to receive nevirapine).
- on chemotherapy for malignancy
- Laboratory abnormalities which are a contra-indication for the child to start ART (haemoglobin \<8.5g/dL; neutrophils \<0.50x109/L; aspartate transaminase (AST) or alanine transaminase (ALT) \>5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine \>1.9 x ULN).
- N.B. causes of anaemia, such as concurrent bacterial infection, malaria, helminthiasis and/or malnutrition should be investigated, and treatment for anaemia and its causes commenced prior to re-screening for eligibility.
- Being pregnant or breast-feeding an infant
- Perinatal exposure to nevirapine (either through prevention of mother-to-child transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only
- Participating in ARROW
- On ART for at least 36 weeks
- Currently taking lamivudine+abacavir twice daily as part of their ART regimen and expected to stay on these two drugs for at least the next 12 weeks
- Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to once or twice daily lamivudine+abacavir
- Likely to switch to second-line therapy in the next 12 weeks
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Medical Research Councillead
- Department for International Development, United Kingdomcollaborator
- ViiV Healthcarecollaborator
- GlaxoSmithKlinecollaborator
Study Sites (4)
MRC /UVRI Uganda Research Unit on AIDS
Entebbe, Uganda
Joint Clinical Research Centre
Kampala, Uganda
Baylor College of Medicine Children's Foundation
Mulago, Uganda
University of Zimbabwe Medical School
Harare, Zimbabwe
Related Publications (3)
ARROW Trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013 Apr 20;381(9875):1391-1403. doi: 10.1016/S0140-6736(12)62198-9. Epub 2013 Mar 7.
PMID: 23473847RESULTBwakura-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. A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. N Engl J Med. 2014 Jan 2;370(1):41-53. doi: 10.1056/NEJMoa1214901.
PMID: 24382064RESULTMusiime V, Kasirye P, Naidoo-James B, Nahirya-Ntege P, Mhute T, Cook A, Mugarura L, Munjoma M, Thoofer NK, Ndashimye E, Nankya I, Spyer MJ, Thomason MJ, Snowden W, Gibb DM, Walker AS; ARROW Trial Team. Once vs twice-daily abacavir and lamivudine in African children. AIDS. 2016 Jul 17;30(11):1761-70. doi: 10.1097/QAD.0000000000001116.
PMID: 27064996DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Professor Ann Sarah Walker
- Organization
- Medical Research Council
Study Officials
- PRINCIPAL INVESTIGATOR
Diana M Gibb, MD
Medical Research Council
- PRINCIPAL INVESTIGATOR
Peter Mugyenyi, PhD
Joint Clinical Research Centre, Kampala, Uganda
- PRINCIPAL INVESTIGATOR
Kusum Nathoo, PhD
University of Zimbabwe, Harare, Zimbabwe
- PRINCIPAL INVESTIGATOR
Adeodata Kekitiinwa, MD
Baylor College of Medicine Children's Foundation, Mulago, Uganda
- PRINCIPAL INVESTIGATOR
Paula Munderi, MBChB
MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
- PRINCIPAL INVESTIGATOR
Victor Musiime, PhD
Joint Clinical Research Centre, Kampala, Uganda
- PRINCIPAL INVESTIGATOR
Mutsa F Bwakura-Dangarembizi, MBChB
University of Zimbabwe, Harare, Zimbabwe
- PRINCIPAL INVESTIGATOR
Philippa Musoke, PhD
Baylor College of Medicine Children's Foundation, Mulago, Uganda
- PRINCIPAL INVESTIGATOR
Sabrina Bakeera-Kitaka, MBChB
Baylor College of Medicine Children's Foundation, Mulago, Uganda
- PRINCIPAL INVESTIGATOR
Patricia Nahirya-Ntege, MBChB
MRC/UVRI and LSHTM Uganda Research Unit
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 4
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- FACTORIAL
- Sponsor Type
- OTHER GOV
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor of Epidemiology
Study Record Dates
First Submitted
December 31, 2013
First Posted
January 7, 2014
Study Start
March 1, 2007
Primary Completion
March 1, 2012
Study Completion
June 1, 2012
Last Updated
June 6, 2014
Results First Posted
June 6, 2014
Record last verified: 2014-06