HIV Care Research Programme / ARROW trial

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

The treatment of HIV infection with anti-retroviral therapy (ART) has the potential to greatly improve the immune status of children and adults. In industrialised countries, ART provided is supported by routine laboratory tests to monitor whether the treatment is effective and safe. In Africa, routine laboratory support is usually not available and/or too expensive. As a result, ART in children is often managed based on clinical check-ups rather than with the help of laboratory data. Whilst the recently completed DART trial has shown that clinical driven monitoring is safe in adults, and that routine laboratory monitoring for toxicity is not required, these results cannot directly be applied to children without further research into the effectiveness and safety of this approach. The ARROW trial, conducted in about 1200 children in Uganda and Zimbabwe, is trying to address this question. The trial has also the aim to investigate whether ART is more effective if children receive the standard treatment with 3 different drugs plus a 4th drug during the first 9 months of treatment, or just a continuous therapy with 3 drugs only. Different combinations of the 4 drugs are explored.

Technical Summary

The ARROW trial (Antiretroviral Research for Watoto) is A randomised multi-site trial of monitoring practice and induction maintenance drug regimens in the management of antiretroviral therapy (ART) in children in Africa. The Objectives are (1) to compare, in terms of HIV disease progression or death, routine laboratory monitoring (LCM) and clinically driven monitoring of ART (CDM); (2) to compare, in terms of long term effectiveness (immunological and clinical outcomes) 36 week induction of therapy with 4 ART drugs followed by maintenance using 3 drugs with a standard continuous triple drug ART regimen; (3) to address through separate sub-studies: the pharmacokinetics of antiretroviral drugs in children; the acceptability of and adherence to different antiretroviral drug formulations; the impact of malnutrition and nutritional supplementation; immune reconstitution syndromes in children; immunological and virological outcomes of ART in African children; metabolic complications of long term ART; and the cost benefits of the monitoring and induction maintenance approaches to ART in children. The design is an open, parallel group, randomised controlled clinical endpoint trial with a total duration of 5 years. At treatment initiation 1210 children (189 at MRC/UVRI Entebbe) were randomised 1:1 to the CDM or LCM monitoring strategy and to one of the following three 1st line ART regimens: Arm A (standard): NNRTI + ABC +3TC continuously Arm B (induction - maintenance): NNRTI + ZDV + ABC + 3TC for 36 weeks, then NNRTI + ABC +3TC Arm C (induction - maintenance): NNRTI + ZDV + ABC + 3TC for 36 weeks, then ZDV + ABC + 3TC Enrolment into the trial began in March 2007 and was completed in November 2008. Results of the ARROW trial are expected in late 2012. The trial is funded by the MRC, UK and the Department for International Development (UK). GlaxoSmithKline Ltd supply the drugs for the trial.

Publications

10 25 50
 
Description Uganda Ministry of Health - HIV Clinical Care Commitee
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact Development and revision of National antiretroviral therapy guidelines based on data from a research cohort in Uganda
 
Description WHO Guidelines on Antiretroviral therapy in resource limited settings
Geographic Reach Africa 
Policy Influence Type Participation in advisory committee
Impact Novel data on adverse events of specific antiretroviral drugs in an African population
 
Description Partnership with the Infectious Diseases Institute, Kampala 
Organisation Makerere University College of Health Sciences
Department The Infectious Diseases Institute, Kampala
Country Uganda 
Sector Academic/University 
PI Contribution Contribution to scientific seminars and training activities.
Collaborator Contribution Joint activities to implement a common clinical trial protocol. Joint scientific seminar and training activities
Impact Ongoing research and training collaboration and capacity to jointly implement future clinical studies in HIV care
 
Description Partnershipt iwth The Joint Clinical Research Centre, Kampala 
Organisation Joint Clinical Research Center, Kampala
Country Uganda 
Sector Academic/University 
PI Contribution Joint clinical study protocol implementation activities, including collaboration in virology and basic scince research activities.
Collaborator Contribution Intersite collaboration on implementing the DART clinical study protocol. Provision of diagnostic laboratory services not available at MRC Entebbe Provision of post trial Antiretroviral therapy for DART study participants
Impact Established relationship and processes for future joint clinical studies in HIV care
 
Description Support from DfID 
Organisation Government of the UK
Department Department for International Development (DfID)
Country United Kingdom 
Sector Public 
PI Contribution Implentation of funded clinical trial protocol as per agreement, regular communication regarding progress and products of research, acknowledgement of organisational support at every dissemination forum.
Collaborator Contribution Support in dissemination of research findings to Health Policy stakeholders
Impact Health policy relevant clinical research results which are being disseminated to nationall and international health policy stakeholders
 
Description Presentation of Results to Uganda National ART Guidelines Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact A one day workshop where data generated in the ocuntry that are relevant for our national guideline revision. DART study results were a major contribution to the scientific data discussed by the national advisory panel.

DART study results will influence guidance on monitoring of ART in our next revision of the National guidelines
Year(s) Of Engagement Activity 2010,2012
 
Description Uganda National Council of Science and Technology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact National consultative meeting of research and medicines regulators to discuss ethical appropriateness of further trials on cotrimoxazole prophylaxis among HIV infected patients on antiretroviral therapy. We provided data on effect of Cotrimoxazole on haematologic parameters of untreated HIV infected adults.

A call was made for further studies evaluating continued prophylactic treatment with Cotrimoxazole for HIV infected patients on antiretroviral therapy
Year(s) Of Engagement Activity 2008