HIV Care Research Programme / DART Trial

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

Abstract

Effective antiretroviral drugs have been available for some time to treat HIV infection. ART can drastically reduce HIV in the blood and the tissue and reinstall the competence of the bodys immune response, so that patients with advanced HIV disease become free of symptoms and can lead a normal life at least for many years. In industrialised countries, ART is delivered through intensive follow-up by physicians and involves regular sophisticated laboratory investigations, in order to monitor treatment effectiveness and detect possible side effects of ART.|Most African countries have plans (and meanwhile some funding) for the stepwise introduction of ART delivery services. However, in developing countries, and in rural Africa in particular, the number of highly trained health personnel is small, good laboratory support is often non-existent outside of major cities, funds are limited, and most patients live in rural areas or smaller towns and cannot afford long distance travel. Millions of patients are in need of treatment. A key question is therefore whether simplified but effective ART delivery strategies can be developed for the use by district hospitals and rural health centres in Africa.|Another important question is whether it is possible to interrupt ART at certain intervals in order to reduce the frequency of ART related adverse effects and to save drugs (thus making the available drugs accessible to additional patients), without endangering treatment effectiveness or increasing the risk for drug resistance. Research is therefore needed to identify safe strategies for planned (structured) treatment interruptions. |The DART trial, conducted at research centres in Entebbe, Kampala and Harare, is performed to answer these important questions. It is coordinated by the MRC Clinical Trials Unit and the Imperial College in London. Since 2003, more than 3000 consenting study participants have been enrolled to the study and randomised to different ART delivery strategies. The study will continue until 2008.|The term randomisation implies that after the provision of detailed information, consenting study participants are allocated to one of different treatment groups, whereby the allocation occurs by chance, e.g. based on random numbers generated by a computer. This procedure is the recognised gold standard for studies that investigate the effectiveness of new health interventions, and is the only way to avoid the influence of factors that may otherwise lead to bias or confounding which may invalidate research results.|Whilst results of the trial will only become available after its completion in 2008, interim analyses conducted under the supervision of the trials independent Data Safety and Monitoring Board have so far shown that the drug schemes in use have generally led to excellent suppression of the virus in the blood of the majority of the participants and to a drastic improvement of health and a massive reduction in HIV related death rates.|Early in 2006, at one of the regular interim analyses conducted by the studys independent Data Safety and Monitoring Board, it became apparent that comparatively more clinical adverse events had occurred in the structured treatment interruptions (STI) group than in the continuous treatment group of the study. These adverse events were mostly cases of oesophageal candidiasis, and there was no excess mortality in the STI arm as compared to the CT arm. The comparison between STI and continuous ART has been discontinued, and all patients who had been randomised to STI have been moved to continuous ART. The question whether under certain circumstances STI are feasible and effective remains unanswered, and further research in other patient groups is required.

Technical Summary

Purpose: The DART Trial is an open-label randomised controlled trial to evaluate different strategies for the management and monitoring of antiretroviral therapy (ART) in Africa. It involves two main randomizations and several substudies. The first randomization compares the effectiveness of clinical monitoring only (CMO) with laboratory plus clinical monitoring (LCM). A second randomization was performed to compare the effectiveness of structured treatment interruptions (STI) with continuous ART. The careful evaluation of these management strategies will answer the important question whether simplified but effective ART delivery approaches can be found that will allow to deliver ART to the millions of patients in Africa who live outside of major cities where only few specialised staff and no sophisticated laboratory support are available. Methods: Main DART trial: (i) Adults (18 years and above) with HIV infection, a CD4 cell count of <200 cells/mm3 and no prior ART were eligible for enrolment. Patients were randomised at enrolment to either the CMO or the LCM arm. (ii) The second randomisation included all patients who had been on ART continuously for 48 weeks or 72 weeks, who had attained a CD4 cell count of >300 cells/ mm3 and who had no record of a serious HIV related infection in the preceding 12 weeks. These patients were randomised to continuous ART or to cycles of STI (12 weeks on /12 weeks off ART). The initial ART regimen in patients on the main DART trial at the Entebbe site comprises zidovudine, lamivudine and tenofovir. Substitutions of individual antiretroviral drugs, within the same class, are made when required for toxicity and a second line treatment regimen is available in the event of documented treatment failure. Follow up monitoring with haematologic tests, tests of liver function, tests of renal function and CD4 counts is performed every 12 weeks. Patients are monitored monthly when drugs are also refilled. Results of investigations in the CMO arm are not returned to clinicians unless indicative of a grade 4 adverse event or unless explicitly requested by clinicians to aid patient management. CD4 counts in the CMO arm are monitored independently by a subgroup of the Data Safety and Monitoring Committee (DSMC). Primary end-points for the trial include progression to new WHO stage 4 disease or death and any serious adverse event which is not HIV-related. An end point review committee with an independent chair regularly reviews and confirms all trial end points as they occur. The randomisation to compare the effectiveness of structured treatment interruptions (STI) with continuous ART has been discontinued in 2006 following a recommendation by the DSMC, as it became obvious that the STI schedule was associated with an increase in disease progression compared to continued treatment. All patients in the STI group were changed to continous ART. Substudies: These include e.g. research of the toxicity of abacavir compared with nevirapine, both in combination with zidovudine + lamivudine, as first-line ART; further investigations of the perceived health related quality of life of patients on ART to identify important needs that go beyond the mere biomedical aspects of ART; investigations of the effect of ART on the sexual behaviour of study participants; studies of the pharmacokinetics of certain drugs; virological studies to explore the effectiveness of the treatment schemes used; research on viral resistance to certain types of drugs; or studies of the effects of different ART management strategies on the immune system. Study sites and coordination: The trial is conducted at 3 sites: Entebbe (MRC/UVRI Uganda Research Unit on AIDS), Kampala (Joint Clinical Research Centre) and Harare (University of Zimbabwe); with funding from MRC, DFID and the Rockefeller Foundation. The Entebbe site works in close collaboration with The AIDS Support Organisation (TASO). The study clinic in Entebbe is situated at the pre

Publications

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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 Uganda Ministry of Health National Working Group on Antiretroviral Drug Resistance
Geographic Reach Africa 
Policy Influence Type Participation in advisory committee
Impact Participation of PI in leadership of national project to monitor and prevent the emergence of resistance to antiretroviral drugs
 
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 Entebbe District Hospital 
Organisation Entebbe District Hospital
Country Uganda 
Sector Hospitals 
PI Contribution Creation of infrastructure for effective antiretroviral therapy including establishment of antiretroviral therapy clinic and joint training and consultation
Collaborator Contribution Entebbe hopsital provided MRC with clinical research clinic premises under a memorandum of understanding. MRC clinical tudy participants have conviniente access to the hospital's admission facility, radiological and surgical services.
Impact Inproved HIV patient care services for the Entebbe community
 
Description Partnership with Imperial College London 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Logistic support and central coordination of clinical trial and grant management activities
Collaborator Contribution Logistic Support and coordination services in grant and clinical trial management
Impact Established capacity for central support of multicentre international HIV studies.
 
Description Partnership with The AIDS Support Organisation (TASO), Entebbe Branch 
Organisation The AIDS Support Organization (TASO)
Country Uganda 
Sector Charity/Non Profit 
PI Contribution Joint provision of HIV clinical care services. Joint development, consultation, training on antiretroviral therapy provision
Collaborator Contribution Source of research participants from the organisations' membership. Contribution of pyschosocial support services to research participants. Contribution of community outreach networks for dissemination of research information and research results
Impact Acceptance and imbedding of MRC research teams and projects in the community. Facilitated communication with community members on MRC clinical research objectives and results
 
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 Partnership with the University of Zimbabwe Clinical Research Centre, Harare 
Organisation University of Zimbabwe
Department University of Zimbabwe Clinical Research Centre
Country Zimbabwe 
Sector Academic/University 
PI Contribution Scientific exchange, joint training activities, joint research managemnet activities
Collaborator Contribution Implementation of a common clinical trial protocol
Impact Established clinical trial partnership able to implement joint clinical research activities in the future
 
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 Director's Lecture at London School of Hygeine and Tropical Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Aproximately 50 postgraduate students of public helath and epidemiolgy at the London School of Hygeine and Tropical Medicine attended the talk on DART results and implications for ART policy in Africa. The results sparked a fair amount of interest, questions and discussion.

A couple of students expressed interest in collaborating with our study group an their research projects.
Year(s) Of Engagement Activity 2010
 
Description Dissemination of study results study participants 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact All study participants invited to a meeting where results of study were presented and questions on outcomes answered

Patients feel proud to have been partners in this trial whose results will influence access to and quality of treatment for others affected by HIV/AIDS
Year(s) Of Engagement Activity 2009
 
Description Policy briefing document on DART study results 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact A policy briefing document presenting the study results for an audinece of health policy makers; published in December 2009

The impact remains to be seen
Year(s) Of Engagement Activity 2009
 
Description Presentation of DART study results to Staff at DfID headquarters 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation of DART study results and history of the study to staff in Research and Policy Departments of DfID, Glasgow and London.

Well receievd, since DfID were major funders of the study. There is interest in follow on support for a study to implement the ART monitoirng startegy tested in DART
Year(s) Of Engagement Activity 2010
 
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 The Story of DART - a film 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A film from patients perspective on having HIV infection and participating in a clinical trial. The results were also briefly featured. Broadcast on National Television channels and on the BBC

Raised the profile of the study and gave it a human face. Extended the reach of the study results.
Year(s) Of Engagement Activity 2009
 
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
 
Description WHO workshop on Pharmacovigilance of antiretroviral medicines 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact One week workshop attended by ART programme managers and Drug regulatory officials from 8 African countries and Ukraine. Taught sessions on clinical toxicity of antiretroviral medicines drew on published data from the DART study and utilised available illustrative patient case hisotories.

Audience appreciated learning from examples and data that have been accumulated in an African treatment population. There is a clear motivation to set up systems to monitor the long term toxicities of antiretroviral medicines in Africa since overall therapeutic experience with these medicines remains limited.
Year(s) Of Engagement Activity 2009