Clinical trial NCT02028676: Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Human Immunodeficiency Virus
Keywords: HIV
Africa
children
antiretroviral therapy
laboratory monitoring
toxicity
CD4
induction maintenance
cotrimoxazole
prophylaxis
abacavir
lamivudine
once daily
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
Collaborators: name: Department for International Development, United Kingdom
name: ViiV Healthcare
name: GlaxoSmithKline
First posted: 2014-01-07
Enrollment: 1206
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility 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)

Primary outcomes:
measure: LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
timeFrame: Baseline, 72 weeks
measure: Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
timeFrame: Baseline, 144 weeks
measure: Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
timeFrame: 48 weeks
measure: 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
timeFrame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Cotrimoxazole: New Hospitalisation or Death
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Secondary outcomes:
measure: LCM vs CDM, Induction ART: All-cause Mortality
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: Induction ART: New WHO Stage 4 Event or Death
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: Weight-for-age Z-score
timeFrame: Baseline and a median of 4 years (maximum 5 years)
measure: LCM vs CDM, Induction ART: Height-for-age Z-score
timeFrame: Baseline and a median of 4 years (maximum 5 years)
measure: LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score
timeFrame: Baseline and a median of 4 years (maximum 5 years)
measure: LCM vs CDM: Change From Baseline in CD4% to Week 72
timeFrame: Baseline, week 72
measure: LCM vs CDM: Change From Baseline in CD4% to Week 144
timeFrame: Baseline, week 144
measure: LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72
timeFrame: Baseline, week 72
measure: LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144
timeFrame: Baseline, week 144
measure: CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline
timeFrame: 72 weeks
measure: CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline
timeFrame: 144 weeks
measure: LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: New ART-modifying Adverse Event
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
timeFrame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation
timeFrame: 96 weeks
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48
timeFrame: Randomisation to once vs twice daily, week 48
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72
timeFrame: Baseline, week 72
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96
timeFrame: Randomisation to once vs twice daily, week 96
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48
timeFrame: Randomisation to once vs twice daily, week 48
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72
timeFrame: Baseline, week 72
measure: Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96
timeFrame: Randomisation to once vs twice daily, week 96
measure: Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality
timeFrame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death
timeFrame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death
timeFrame: Median 2 years (from randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score
timeFrame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score
timeFrame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score
timeFrame: Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
timeFrame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV
timeFrame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: 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
timeFrame: 48 weeks after randomization to once- versus twice-daily
measure: 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
timeFrame: 96 weeks after randomization to once- versus twice-daily
measure: Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
timeFrame: Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
measure: Cotrimoxazole: New Clinical and Diagnostic Positive Malaria
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: New Severe Pneumonia
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: New WHO Stage 3 or 4 Event or Death
timeFrame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: New WHO Stage 4 Event or Death
timeFrame: Median 2 years (from randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: All-cause Mortality
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: Weight-for-age Z-score
timeFrame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: Height-for-age Z-score
timeFrame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: Body Mass Index-for-age Z-score
timeFrame: Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: Change From Baseline in CD4% to Week 72
timeFrame: Baseline, week 72
measure: Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72
timeFrame: Baseline, week 72
measure: Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV
timeFrame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
measure: Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
timeFrame: Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Other outcomes:
Locations:
city: Entebbe
country: Uganda
facility: MRC /UVRI Uganda Research Unit on AIDS
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre
city: Mulago
country: Uganda
facility: Baylor College of Medicine Children's Foundation
city: Harare
country: Zimbabwe
facility: University of Zimbabwe Medical School
Study officials:
affiliation: Medical Research Council
name: Diana M Gibb, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Joint Clinical Research Centre, Kampala, Uganda
name: Peter Mugyenyi, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Zimbabwe, Harare, Zimbabwe
name: Kusum Nathoo, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda
name: Adeodata Kekitiinwa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
name: Paula Munderi, MBChB
role: PRINCIPAL_INVESTIGATOR
affiliation: Joint Clinical Research Centre, Kampala, Uganda
name: Victor Musiime, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Zimbabwe, Harare, Zimbabwe
name: Mutsa F Bwakura-Dangarembizi, MBChB
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda
name: Philippa Musoke, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda
name: Sabrina Bakeera-Kitaka, MBChB
role: PRINCIPAL_INVESTIGATOR
affiliation: MRC/UVRI and LSHTM Uganda Research Unit
name: Patricia Nahirya-Ntege, MBChB
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. 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.
citation: Musiime 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.