A randomised trial of monitoring practice and treatment interruptions in the management of antiretroviral therapy in HIV

Lead Research Organisation: Medical Research Council
Department Name: UNLISTED

Abstract

Most poor countries with many HIV-infected people, such as those in sub-Saharan Africa, are adopting the WHO ?public health approach? for providing anti-HIV (antiretroviral) drugs. This uses simple approaches to treatment that can be delivered by health care workers under supervision of non-specialist clinicians, supported by basic laboratory tests, available. Doctors in specialist hospitals support clinical teams and problem cases are referred to them for expert management. Without this simplified approach, with the severe shortage of doctors and HIV specialists, scaling up anti-HIV drugs provision to meet the needs of HIV-infected people would be impossible.

However, even simple laboratory tests need significant infrastructure (laboratories, reagents, electricity) and trained personnel. Costs of laboratory tests can be as high as costs of the drugs, and are not feasible in large areas of Africa. Finding out whether or not anti-HIV drugs can be given safely and effectively without the intensive routine laboratory testing provided in industrialised countries is of significant relevance to clinical management of HIV-infected people in the developing world. Many anti-HIV drug treatment programmes are struggling to staff and develop laboratory services - if clinical monitoring only (i.e. with no tests) and laboratory monitoring (with tests) have similar clinical outcomes, then emphasis should be given to support and training for quality clinical services, rather than providing laboratory tests. If HIV disease progresses significantly faster when patients receive anti-HIV drugs without regular tests, then provision of anti-HIV drugs must be accompanied by new resources to strengthen and deliver a basic laboratory service.

This proposal describes an extension to an ongoing clinical trial addressing this and other key issues surrounding management of anti-HIV drugs in resource-limited settings. The reason the trial needs an extension is because disease progression is occurring much less frequently than originally anticipated when the trial was started. This is surprising - but is very good news for anti-HIV programmes in Africa and other resource-limited settings, and for trial participants. However, it also means that longer follow-up is needed to meet the trial?s primary objective of evaluating the relative risks and benefits of giving anti-HIV drugs with and without regular laboratory monitoring tests. Given the potentially huge numbers of HIV-infected people in developing countries, for whom the results of this trial will have a direct impact, we believe it is critical to have longer follow-up of DART patients in order to address these questions as originally planned.

Technical Summary

DART is an open randomised trial evaluating two strategic approaches for ART management in previously untreated symptomatic HIV-infected adults with CD4 cell counts under 200 cells/mm3 initiating ART in three clinical centres in Africa (2 in Uganda and 1 in Zimbabwe). The first strategy compares clinical monitoring only (CMO) with laboratory plus clinical monitoring (LCM) for efficacy (CD4 cell counts) and toxicity (haematology and biochemistry). The second approach compares structured treatment interruptions (STI) (12 weeks on, 12 weeks off ART) with continuous ART in patients who achieve CD4 cell counts over 300 cells/mm3 after 48 weeks on continuous ART. All patients receive triple-drug antiretroviral therapy, with three different regimens being used first-line, one being the standard WHO recommended 2NRTI+NNRTI. The primary endpoint for both comparisons is development of a new WHO stage 4 event (like AIDS) or death, and the trial is designed to demonstrate equivalence between each pair of randomised strategies. 3300 patients were enrolled into the CMO/LCM comparison, and 800 into the STI comparison. Retention and follow-up have been excellent. Substudies including the blinded NORA (Nevirapine OR Abacavir) randomised substudy trial, and a virology substudy are included; high quality DART data are also extremely valuable for addressing numerous epidemiological questions surrounding the optimal use of ART in resource-limited settings.

Although the approved DART protocol was a 5 calendar year trial (2003-2007), initial MRC funding was for four years in the first instance (because of the application process at the time). Further, over the last year it has become apparent that the rate for the primary endpoint - progression to new WHO stage 4 event or death - is considerably lower than predicted (approx 10% rather than 15% annually). This is surprising - but is very good news for ART programmes in Africa and other resource-limited settings, and for DART participants. However, this lower progression rate reduces the power of the trial. Therefore this proposal describes an extension requested for the DART sites supported by the MRC (MRC Entebbe, MRC CTU and Imperial College) in order to close the funding gap for DART for 2006/2007 and extend the trial for one additional calendar year (2008) to maintain power according to the original trial design. Similar proposals are being developed for partner funders of DART.

Publications

10 25 50

 
Description Uganda/Zimbabwe Ministries of Health
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact Contribution from DART co-PIs has shaped national HIV/AIDS policy.
 
Guideline Title Antiretroviral therapy for HIV Infection in Adults and Adolescents: recommendations for a public health approach 2006
Description WHO 2006 guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact In 2006 guidelines, DART was referenced in three areas (primary randomisation was still ongoing): development of anaemia on zidovudine-based regimens, virological response to 3NRTI first-line, and high incidence of early mortality on ART
URL http://www.who.int/hiv/pub/arv/adult/en/
 
Description WHO 2010 Guidelines Committees
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact WHO guidelines set the standard for HIV treatment in resource-limited settings
 
Description Alexander Fleming Dissemination Scheme
Amount £29,983 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 12/2010
 
Description DFID
Amount £1,896,304 (GBP)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start 05/2011 
End 10/2014
 
Description Abbott 
Organisation Abbott
Country Spain 
Sector Private 
PI Contribution The research team ran the trial: Abbott contributed drugs and funding for specific substudies.
Collaborator Contribution Provided second-line drugs for the trial and some funding for second-line substudies.
Impact Abbott provided second-line drugs for the trial, without drugs there would have been no publications.
Start Year 2006
 
Description Boehringer Ingelheim 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution The research team ran the trial: BI contributed drugs.
Collaborator Contribution Provided drugs for the trial
Impact BI provided first-line drugs for the trial, without which there would have been no publications.
 
Description Bucconi University, Milan, Italy 
Organisation Bocconi University
Department Health Economics
Country Italy 
Sector Academic/University 
PI Contribution Collected data to inform the cost-effectiveness analysis. Have commented extensively on draft manuscripts.
Collaborator Contribution Supported health economist who moved from University of Liverpool during 2010. Will provide a Research Assistant to help write up primary costing papers from the health economics analysis during 2011.
Impact Final cost-effectiveness paper about to be submitted to NEJM. This collaboration is multi-disciplinary involving health economists from Bucconi, and statisticians and clinicians from the DART team.
Start Year 2010
 
Description DFID 
Organisation Government of the UK
Department Department for International Development (DfID)
Country United Kingdom 
Sector Public 
PI Contribution Dfid have co-funded a number of trials (and substudies) and projects we have coordinated including DART, ARROW, REALITY trials and Lablite project
Collaborator Contribution DART TRial: DFID contributed funding for additional drugs and the cost-effectiveness evaluation ARROW Trial: co-funding, Young Lives Project; economic substudies LAblite Project is funded by DfID
Impact DART trial: Without DFID support there would have been no publications, and no cost-effectiveness analysis. DFID also funded the Policy Briefing document, a four page glossy summarising the trial results for policymakers and governments. ARROW trial (including winning 2014 BMJ Paper of the year which was submitted by DfID)
Start Year 2006
 
Description Gilead Sciences 
Organisation Gilead Sciences, Inc.
Department Gilead
Country United Kingdom 
Sector Private 
PI Contribution The research team ran the trial: Gilead contributed drugs and funding for specific substudies.
Collaborator Contribution Provided drugs for the trial
Impact Gilead provided first-line drugs for the trial, without which there would have been no publications. They also provided specific funding for PMID 18444867, 18839777 and for the current PENTA 17 (SMILE) elvitegravir trial
 
Description GlaxoSmithKline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The research team ran the trial: GSK contributed drugs and funding for specific substudies.
Collaborator Contribution GSK provided drugs for the trial.
Impact GSK provided first-line drugs for the trial, without which there would have been no publications. They also provided specific funding for PMID 16791013, 19938977, 20136661
 
Description Rockfeller 
Organisation Rockefeller Foundation
Country United States 
Sector Private 
PI Contribution The research team ran the trial: Rockefeller supported research costs in 2 of the 4 clinical centres and also supported a full time post throughout the duration of the trial at the MRC Clinical Trials Unit.
Impact Without Rockefeller support for the trial which there would have been no publications.
 
Description University of Liverpool 
Organisation University of Liverpool
Department Department of Public Health and Policy
Country United Kingdom 
Sector Academic/University 
PI Contribution Research team ran the trial providing underlying data for cost effectiveness analysis
Collaborator Contribution Supported health economist
Impact Cost effectiveness analysis - oral presentation at the International AIDS Society conference, Cape Town July 2009 Publication in PLos One
Start Year 2006
 
Description University of Liverpool - PK 
Organisation University of Liverpool
Department Department of Molecular and Clinical Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Research team ran the trial; wrote substudy protocol, recruited trial participants into additional PK substudies, and jointly drafted manuscript
Collaborator Contribution In kind contribution running drug assays for pharmacokinetic studies
Impact Manuscript under review with AAC so not listed, but oral presentation by Ugandan co-PI at the 9th International Congress on HIV and Drug Therapy in HIV Infection, November 2008.
Start Year 2007
 
Title Development of AntiRetroviral Therapy in Africa (DART) 
Description 4 RANDOMISATIONS 1) monitoring for efficacy & toxicity in African adults on antiretroviral therapy 2) antiretroviral interruptions 3 & 4) second line therapy strategies 
Type Management of Diseases and Conditions
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Closed
Clinical Trial? Yes
Impact Impact on management of ART roll out in Africa, influenced WHO guidelines 2010 and 2013. 
URL http://www.controlled-trials.com/ISRCTN13968779
 
Description British Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The DART film and information about the trial were featured in a British Science Festival event "the Truth about Trials", led by MRC and Birmingham University. Press papers produced for the event and distriubuted widely.

The event led to the request for an interview with the Naked Scientists which is published online as a podcast and widely distributed through partner websites, facebook, twitter and the Naked Scientists.
Year(s) Of Engagement Activity 2010
 
Description DART Film (2) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact The DART film has continued to be used since reporting in 2009. It has been shown on BBC World Internationally and on the Research Channel in the United States. It has also been featured on TV in Uganda, Botswana, Kenya, Malawi, Zambia, Tanzania, Nigeria. It will be particularly featured over World AIDS Day (1st December 2010).

The film is also used widely as an educational resource for secondary / high schools in UK and the US. It is featured in a number of teaching programmes at Medical School level (Imperial and UCL).

In addition it has been used as a way of engageing with policy makers, academics and medical practitioners in International Forums such as CROI, IAS, World Aids and other international meetings. Trial sites are provided with copies for their own promotional and advicasy purposes.

The film is a well regarded and powerful tool for dissemination and engagement. This has helped recognition of the trials relevance and important results. It has also stimulated debate about the use of such media in the process of using research to inform public opinion and policy.
Year(s) Of Engagement Activity 2010,2011
 
Description DART Film 2 - Policy Recommendations 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact A short 10 minute film outlining policy recommendations arising from DART was produced and uploaded to the MRC hosted youtube channel. It was advertised via link from partner organisations and from news stories, and from other sites such as EfA and i-base. It is featured on Facebook and twitter.

Alongside the 2 minute film uploaded to youtube alongside results of the trial in 2009 this marks a significant presence online. With wide search terms and raising popularity the films are now suggested viewing to youtube users (over 2000 views of the peices combined).
Year(s) Of Engagement Activity 2010,2011
 
Description DART film (1) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact A film describing the DART trial, narrated by a trial participant, was produced - shown on BBC World as a 20 min short, and produced on DVD as a longer film with chapters and is being widely distributed both to disseminate trial results and also for education about research, why it is done, what it means.

During 2010-11, the film has had colour correction work to bring it to broadcast standard. It has been re-packaged as a DVD containg two versions of the film (26.5 minutes and 52.5 minutes) and a number of discrete chapters which can be embedded to websites or used in presentations. These DVDs are available in both PAL (African and European format, broadly speaking) and NTSC (US format).

The DART film has been provided on broadcast quality tape and shown on:

BBC World (International, repeatedly shown over a period of 7 days, late 2009)
Botswana TV (date to be confirmed, tape provided November 2010)
Kingdom TV, Nigeria (date to be confirmed, tape provided November 2010)
Kenya Broadcasting Corporation (date to be confirmed, tape provided November 2010)
Uganda Broadcasting Corporation (on several occasions since November 2009)
Ugandan Wavah Broadcasting Service (on several occasions since early 2009)
United States of America 'The Research Channel' (September 2010)
University of Washington (United States, September 2010, and podcasting)
Television Malawi (date to be confirmed, tape provided November 2010)
Zambia Broadcasting Corporation (date to be confirmed, tape provided November 2010)

The film has also sparked debate on various blogs.

The film has been extremely well received and noted in public as a highly innovative way to disseminate trial information.

Tom Gibb, who made the film was nominated and shortlisted for the British Medical Journal Health Communicator of the Year Award, for his work on the DART films. Inevitably this led to further exposure for the film and DART results, but it was also a deserved recognition of the success of the films.
Year(s) Of Engagement Activity 2009,2010,2011
 
Description DART participants meetings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Each DART centre held a participants day/celebration after the results were presented internationally in July 2009 to feedback the results of the trial to participants. Presentations were done by junior doctors. These participants days were also held annually during the trial.

Participants were very appreciative of being told results early in the dissemination process. Throughout the trial, regular meetings with participants enabled researchers to become aware of concerns and issues before these developed into major problems.
Year(s) Of Engagement Activity 2009
 
Description DART policy brief 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact An A3 (folded, so 4 A4 pages) glossy policy briefing document has been produced summarising the key trial findings and aimed at health policymakers.

The policy brief was launched by DFID on 9 December 2009, the day the primary manuscript was published, so not enough time to identify impact yet.
Year(s) Of Engagement Activity 2009
 
Description DART presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Presentation of main DART results to health professionals at seminars, national meetings etc, has occurred in Uganda, Zimbabwe and the UK

DART was awarded best research in 2009 at the Zimbabwe Institute of Continued Health Education annual meeting, and a junior DART doctor was awarded best Presenter.
Year(s) Of Engagement Activity 2009
 
Description Debating Matters 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact DART was used in a debating topic in the National Debating Matters annual debating competition. PI Diana Gibb acted as judge in a heat and the finals.

Wide dissemination of the DART trial and issues around performing clinical research in Africa accross secondary pupils in the UK.
Year(s) Of Engagement Activity 2010
 
Description Lancet Paper of the Year 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact The DART main results paper was nominated for the Lancet Paper of the Year - a competition which considers entrants not just from Lancet publications but all journals worldwide. In a public vote, the paper was voted runner-up.

This gave the paper huge exposure and was considered a significant accolade. It also resulted in a number of press releases.
Year(s) Of Engagement Activity 2009
 
Description Online Presence 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The DART website is widely used and referred - a google link search completed on 24 November 2010 confirmed 5150 infomedia websites which provide a link to the website.

DART is a widely known trial and information about the trial is used internationally.
Year(s) Of Engagement Activity 2009,2010,2011
 
Description Radio, Television and Magazine Interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact A significant number of interviews have been given by the trial team in response to requests from the media. These include over 9 radio interviews / podcasts, over 10 magazine or newspaper articles and at least 6 television interviews worldwide.

High impact activities by the trial investigators result in wider interest in the trial results accross academic, non-academic communities, including policymakers and the general public.
Year(s) Of Engagement Activity 2009,2010