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

NCT ID: NCT02028676

Last Updated: 2014-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1206 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-03-31
• Study Completion Date: 2012-06-30

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.

Conditions

Human Immunodeficiency Virus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Clinically Driven Monitoring (CDM)

Group Type: EXPERIMENTAL

Clinically Driven Monitoring (CDM)

Intervention Type: OTHER

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)

Group Type: ACTIVE_COMPARATOR

Laboratory plus Clinical Monitoring (LCM)

Intervention Type: OTHER

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.

Arm A: abacavir (ABC)+lamivudine (3TC)+NNRTI

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 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.

Group Type: ACTIVE_COMPARATOR

Arm A: ABC+3TC+NNRTI

Intervention Type: DRUG

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

ZDV \[abacavir\]: 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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

ZDV \[abacavir\]: 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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

ABC \[abacavir\]: 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

Group Type: EXPERIMENTAL

Once-daily ABC+3TC

Intervention Type: DRUG

Twice-daily ABC+3TC

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

Group Type: ACTIVE_COMPARATOR

Twice-daily ABC+3TC

Intervention Type: DRUG

Continued cotrimoxazole prophylaxis

Once-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

Group Type: ACTIVE_COMPARATOR

Continued cotrimoxazole prophylaxis

Intervention Type: DRUG

Stopped cotrimoxazole prophylaxis

Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.

Group Type: EXPERIMENTAL

Stopped cotrimoxazole prophylaxis

Intervention Type: OTHER

Interventions

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.

Intervention Type: OTHER

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.

Intervention Type: OTHER

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Once-daily ABC+3TC

Intervention Type: DRUG

Twice-daily ABC+3TC

Intervention Type: DRUG

Continued cotrimoxazole prophylaxis

Intervention Type: DRUG

Stopped cotrimoxazole prophylaxis

Intervention Type: OTHER

Other Intervention Names

ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ZDV: zidovudine, azidothymidine, Retrovir; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ZDV+3TC co-formulated: Combivir; ABC+3TC co-formulated: Kivexa; ZDV+ABC+3TC co-formulated: Trizivir; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ZDV: zidovudine, azidothymidine, Retrovir; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ZDV+3TC co-formulated: Combivir; ABC+3TC co-formulated: Kivexa; ZDV+ABC+3TC co-formulated: Trizivir; NVP: nevirapine, Viramune; EFV: efavirenz, Sustiva; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; ABC: abacavir: Ziagen; 3TC: lamivudine: Epivir; ABC+3TC co-formulated: Kivexa; trimethoprim+sulfamethoxazole

Eligibility Criteria

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.)

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

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

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

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

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

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Department for International Development, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

ViiV Healthcare

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

Medical Research Council

OTHER_GOV

Sponsor Role: lead

Responsible Party

Diana M Gibb

Professor of Epidemiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Diana M Gibb, MD

Role: PRINCIPAL_INVESTIGATOR

Medical Research Council

Peter Mugyenyi, PhD

Role: PRINCIPAL_INVESTIGATOR

Joint Clinical Research Centre, Kampala, Uganda

Kusum Nathoo, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Zimbabwe, Harare, Zimbabwe

Adeodata Kekitiinwa, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine Children's Foundation, Mulago, Uganda

Paula Munderi, MBChB

Role: PRINCIPAL_INVESTIGATOR

MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda

Victor Musiime, PhD

Role: PRINCIPAL_INVESTIGATOR

Joint Clinical Research Centre, Kampala, Uganda

Mutsa F Bwakura-Dangarembizi, MBChB

Role: PRINCIPAL_INVESTIGATOR

University of Zimbabwe, Harare, Zimbabwe

Philippa Musoke, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine Children's Foundation, Mulago, Uganda

Sabrina Bakeera-Kitaka, MBChB

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine Children's Foundation, Mulago, Uganda

Patricia Nahirya-Ntege, MBChB

Role: PRINCIPAL_INVESTIGATOR

MRC/UVRI and LSHTM Uganda Research Unit

Locations

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

Countries

Uganda; Zimbabwe

References

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.

Reference Type: RESULT

PMID: 23473847 (View on PubMed)

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.

Reference Type: RESULT

PMID: 24382064 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27064996 (View on PubMed)

Related Links

http://www.arrowtrial.org/

main ARROW trial webpage

Other Identifiers

24791884

Identifier Type: REGISTRY

Identifier Source: secondary_id

G0300400

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

G0300400

Identifier Type: -

Identifier Source: org_study_id