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

• Register: ClinicalTrials.gov
• Last refreshed on: 19 October 2017
• Main ID: NCT02028676
• Date of registration: 31/12/2013
• Prospective Registration: No
• Primary sponsor: Medical Research Council
• Public title: Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa ARROW
• Scientific 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
• Date of first enrolment: March 2007
• Target sample size: 1206
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02028676
• Study type: Interventional
• Phase: Phase 4

Countries of recruitment

Uganda, Zimbabwe

Contacts

• Name: Adeodata Kekitiinwa, MD
• Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda

• Name: Patricia Nahirya-Ntege, MBChB
• Affiliation: MRC/UVRI Uganda Research Unit on Aids

• Name: Kusum Nathoo, PhD
• Affiliation: University of Zimbabwe, Harare, Zimbabwe

• Name: Mutsa F Bwakura-Dangarembizi, MBChB
• Affiliation: University of Zimbabwe, Harare, Zimbabwe

• Name: Diana M Gibb, MD
• Affiliation: Medical Research Council

• Name: Philippa Musoke, PhD
• Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda

• Name: Peter Mugyenyi, PhD
• Affiliation: Joint Clinical Research Centre, Kampala, Uganda

• Name: Victor Musiime, PhD
• Affiliation: Joint Clinical Research Centre, Kampala, Uganda

• Name: Sabrina Bakeera-Kitaka, MBChB
• Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda

• Name: Paula Munderi, MBChB
• Affiliation: MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda

Key inclusion & exclusion 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

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)



Age minimum: 3 Months
Age maximum: 17 Years
Gender: All

Health Condition(s) or Problem(s) studied

Human Immunodeficiency Virus

Intervention(s)

Drug: Continued cotrimoxazole prophylaxis

Drug: Once-daily ABC+3TC

Drug: Arm A: ABC+3TC+NNRTI

Other: Laboratory plus Clinical Monitoring (LCM)

Other: Stopped cotrimoxazole prophylaxis

Other: Clinically Driven Monitoring (CDM)

Drug: Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance

Drug: Twice-daily ABC+3TC

Drug: Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance

Primary Outcome(s)

Cotrimoxazole: New Hospitalisation or Death [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

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 [Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation [Time Frame: Baseline, 144 weeks]

Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation [Time Frame: Baseline, 72 weeks]

Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation [Time Frame: 48 weeks]

Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

Secondary Outcome(s)

LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 [Time Frame: Baseline, week 144]

LCM vs CDM, Induction ART: Height-for-age Z-score [Time Frame: Baseline and a median of 4 years (maximum 5 years)]

LCM vs CDM, Induction ART: New ART-modifying Adverse Event [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

LCM vs CDM: Change From Baseline in CD4% to Week 72 [Time Frame: Baseline, week 72]

Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (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)]

Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score [Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

Cotrimoxazole: Body Mass Index-for-age Z-score [Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Cotrimoxazole: New Severe Pneumonia [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Cotrimoxazole: Weight-for-age Z-score [Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline [Time Frame: 72 weeks]

Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (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)]

Cotrimoxazole: All-cause Mortality [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Cotrimoxazole: Change From Baseline in CD4% to Week 72 [Time Frame: Baseline, week 72]

Cotrimoxazole: New WHO Stage 4 Event or Death [Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV [Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72 [Time Frame: Baseline, week 72]

Induction ART: New WHO Stage 4 Event or Death [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline [Time Frame: 144 weeks]

Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Cotrimoxazole: New WHO Stage 3 or 4 Event or Death [Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)]

LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Cotrimoxazole: Height-for-age Z-score [Time Frame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

LCM vs CDM, Induction ART: All-cause Mortality [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 [Time Frame: Randomisation to once vs twice daily, week 96]

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 [Time Frame: 48 weeks after randomization to once- versus twice-daily]

Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death [Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]

Cotrimoxazole: New Clinical and Diagnostic Positive Malaria [Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72 [Time Frame: Baseline, week 72]

Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death [Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]

LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 [Time Frame: Baseline, week 72]

LCM vs CDM, Induction ART: Weight-for-age Z-score [Time Frame: Baseline and a median of 4 years (maximum 5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 96 Weeks [Time Frame: 96 weeks after randomization to once- versus twice-daily]

LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death [Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48 [Time Frame: Randomisation to once vs twice daily, week 48]

LCM vs CDM: Change From Baseline in CD4% to Week 144 [Time Frame: Baseline, week 144]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48 [Time Frame: Randomisation to once vs twice daily, week 48]

Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation [Time Frame: 96 weeks]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96 [Time Frame: Randomisation to once vs twice daily, week 96]

Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 [Time Frame: Baseline, week 72]

Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV [Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score [Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score [Time Frame: Baseline and a median of 4 years (maximum 5 years)]

Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality [Time Frame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)]

Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score [Time Frame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)]

Secondary ID(s)

24791884

G0300400

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

ViiV Healthcare

Department for International Development, United Kingdom

GlaxoSmithKline

Results

• Results available: Yes
• Date Posted: 06/06/2014
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02028676