Phase 4 N=1,206 Randomized Treatment

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

Human Immunodeficiency Virus

Bottom Line

View on ClinicalTrials.gov: NCT02028676 ↗

Enrolled (actual)

1,206

Serious AEs

17.8%

Results posted

Jun 2014

Primary outcome: Primary: LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death — 47; 39 participants — p=0.59

Study Design & Population

Study type: Interventional
Phase: Phase 4
Interventions: Clinically Driven Monitoring (CDM) (Other); Laboratory plus Clinical Monitoring (LCM) (Other); Arm A: ABC+3TC+NNRTI (Drug); Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance (Drug); Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance (Drug); Once-daily ABC+3TC (Drug); Twice-daily ABC+3TC (Drug); Continued cotrimoxazole prophylaxis (Drug); Stopped cotrimoxazole prophylaxis (Other)
Age: Pediatric · 0+ yrs
Sex: All
Sponsor: Medical Research Council
Primary completion: Mar 2012

Outcome Measures

Outcome	Result	p-value
PRIMARY LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death	47; 39	0.59
PRIMARY LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV	283; 282	0.83
PRIMARY Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation	16.4; 17.1; 17.3	0.33
PRIMARY Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation	19.8; 19.6; 19.2	0.69
PRIMARY Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV	157; 190; 218	0.0001 sig
PRIMARY Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation	236; 242	0.65
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	1; 0	—
PRIMARY Cotrimoxazole: New Hospitalisation or Death	48; 72	0.007 sig
PRIMARY Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV	55; 64	0.33
SECONDARY LCM vs CDM, Induction ART: All-cause Mortality	25; 29; 20; 14; 20	0.45
SECONDARY Induction ART: New WHO Stage 4 Event or Death	30; 28; 28	0.89
SECONDARY LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death	77; 73; 73; 61; 54	0.98
SECONDARY LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death	91; 79; 64; 53; 53	0.52
SECONDARY LCM vs CDM, Induction ART: Weight-for-age Z-score	0.76; 0.78; 0.72; 0.79; 0.80	0.71
SECONDARY LCM vs CDM, Induction ART: Height-for-age Z-score	0.36; 0.43; 0.40; 0.40; 0.38	0.07
SECONDARY LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score	0.65; 0.61; 0.56; 0.64; 0.69	0.64
SECONDARY LCM vs CDM: Change From Baseline in CD4% to Week 72	17.2; 16.7	0.45
SECONDARY LCM vs CDM: Change From Baseline in CD4% to Week 144	19.7; 19.4	0.70
SECONDARY LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72	408; 385; 402; 447; 336	0.59
SECONDARY LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144	418; 420; 446; 450; 360	0.81
SECONDARY CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline	76; 78; 56; 72; 26	0.86
SECONDARY CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline	192; 193; 127; 135; 124	0.20
SECONDARY LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure	28; 35	0.22
SECONDARY LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART	30; 42; 14; 30; 28	0.09
SECONDARY LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV	147; 117; 87; 82; 95	0.04 sig
SECONDARY LCM vs CDM, Induction ART: New ART-modifying Adverse Event	31; 32; 8; 30; 25	0.84
SECONDARY LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)	8.5; 9.4; 8.3; 9.5; 9.1	0.53
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation	230; 234	0.52
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48	0.9; 1.3	0.39
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72	1.9; 1.9	0.98
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96	1.6; 2.5	0.12
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48	3; -3	0.82
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72	-6; 27	0.36
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96	-26; 60	0.20
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality	1; 4	—
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death	3; 7	0.20
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death	9; 12	0.51
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score	0.28; 0.32	0.16
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score	0.01; -0.00	0.54
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score	-0.29; -0.35	0.08
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV	57; 54	0.82
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV	30; 37	0.31
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	32; 29	0.74
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	26; 25	0.90
SECONDARY Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)	8; 8	0.93
SECONDARY Cotrimoxazole: New Clinical and Diagnostic Positive Malaria	39; 77	<0.001 sig
SECONDARY Cotrimoxazole: New Severe Pneumonia	7; 10	0.44
SECONDARY Cotrimoxazole: New WHO Stage 3 or 4 Event or Death	8; 19	0.03 sig
SECONDARY Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea	1; 4	0.18
SECONDARY Cotrimoxazole: New WHO Stage 4 Event or Death	4; 7	0.34
SECONDARY Cotrimoxazole: All-cause Mortality	3; 2	0.68
SECONDARY Cotrimoxazole: Weight-for-age Z-score	-0.01; -0.05	0.07
SECONDARY Cotrimoxazole: Height-for-age Z-score	0.22; 0.19	0.19
SECONDARY Cotrimoxazole: Body Mass Index-for-age Z-score	-0.24; -0.28	0.34
SECONDARY Cotrimoxazole: Change From Baseline in CD4% to Week 72	1.7; 1.1	0.13
SECONDARY Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72	7; -2	0.68
SECONDARY Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV	32; 48	0.04 sig
SECONDARY Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)	9; 8	0.21

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?

Eligibility Criteria

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

Inclusion Criteria

Children should have an adult carer in the household who is either:
participating in the DART trial OR
being treated with ART OR
HIV positive but not yet needing treatment but with access to a treatment programme when ART is required OR
HIV negative. Children of DART participants should have first priority on any available remaining slots to enter ARROW.
Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
Participants must have a confirmed documented diagnosis of HIV-1 infection:
For children aged under 18 months: two separate peripheral blood specimens from different days, both results being positive with HIV-DNA polymerase chain reaction (PCR).
For children aged 18 months or over: antibody positive serology by ELISA test (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test (performed in series) both on the same sample. Any child previously tested at another clinic should have a repeat test at an ARROW screening laboratory to confirm their status.
Age 3 months to 17 years (13-17 years to be capped at 10%)
ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:
WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or count
WHO paediatric clinical stage III disease:
12 months: treat all 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% 5years (consideration should also be taken of the CD4 count. A CD4 count 5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine >1.9 x ULN).

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

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

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

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

Exclusion criteria

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

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

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

Exclusion criteria

Previous di

View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT02028676). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.