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

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?

Conditions

• Human Immunodeficiency Virus

Interventions

OTHER

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.

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.

DRUG

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.

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.

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.

DRUG

Once-daily ABC+3TC

DRUG

Twice-daily ABC+3TC

DRUG

Continued cotrimoxazole prophylaxis

OTHER

Stopped cotrimoxazole prophylaxis

Sponsors & Collaborators

• Department for International Development, United Kingdom

  collaborator OTHER_GOV

• ViiV Healthcare

  collaborator INDUSTRY

• GlaxoSmithKline

  collaborator INDUSTRY

• Medical Research Council

  lead OTHER_GOV

Principal Investigators

• Diana M Gibb, MD · Medical Research Council

• Peter Mugyenyi, PhD · Joint Clinical Research Centre, Kampala, Uganda

• Kusum Nathoo, PhD · University of Zimbabwe, Harare, Zimbabwe

• Adeodata Kekitiinwa, MD · Baylor College of Medicine Children's Foundation, Mulago, Uganda

• Paula Munderi, MBChB · MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda

• Victor Musiime, PhD · Joint Clinical Research Centre, Kampala, Uganda

• Mutsa F Bwakura-Dangarembizi, MBChB · University of Zimbabwe, Harare, Zimbabwe

• Philippa Musoke, PhD · Baylor College of Medicine Children's Foundation, Mulago, Uganda

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

• Patricia Nahirya-Ntege, MBChB · MRC/UVRI and LSHTM Uganda Research Unit

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

FACTORIAL

Eligibility

Min Age

3 Months

Max Age

17 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2007-03-31

Primary Completion

2012-03-31

Completion

2012-06-30

Countries

• Uganda
• Zimbabwe

Study Locations