Development of AntiRetroviral Therapy in Africa - A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa
A trial to learn more about how useful routine laboratory tests are when using anti-HIV drugs
What was this study about?
DART was a clinical trial about the best ways to manage anti-HIV therapy in the public health access programmes being rolled-out in Africa and other resource-limited settings. It was designed to address two main questions:
- Can doctors prescribe anti-HIV drugs without doing regular routine laboratory tests, and instead rely on clinical assessments they can make themselves and only do tests when needed? (Laboratories are scarce in some parts of Africa, and the tests can be very expensive. How much of the money for access programmes should be spent on doctors, nurses and drugs and how much on laboratories, technicians and tests?)
- Is taking anti-HIV drugs some of the time as effective as taking them continuously?
In order to answer question 1, all participants had laboratory safety tests carried out every 3 months. But doctors were not routinely given the results for one group of patients. Instead they had to rely more on clinical observations when managing these patients. Where the doctors felt there was a specific clinical need they could ask for any relevant laboratory tests. In order to minimise any unnecessary risks to participants in this group, the routine test results were always sent to doctors if they suggested there may have been a serious problem, in case the problems had not been identified clinically. Additionally, only the group getting regular routine tests received CD4 counts every 3 months, the other group never received CD4 counts.
CD4 counts are used to indicate how well the immune system is working and are often used to identify when anti-HIV drugs are no longer working so well. To answer question 2 above, patients who responded well to initial treatment were randomly assigned to either keep taking their anti-HIV drugs all the time, or to move on to cycles of 12 weeks on and 12 weeks off drugs.
DART was the largest trial of its kind in Africa, and one of the first HIV trials to take place in more than one African country and in a number of different clinics. It was run by researchers in Uganda and Zimbabwe, collaborating with Imperial College London and the MRC Clinical Trials Unit.
What difference did this study make?
DART showed that doing laboratory tests routinely to monitor ART toxicity and side effects makes no difference to patient outcomes over an average of five years; and is also very costly.
Providing CD4 testing of patients on ART to monitor the ongoing effectiveness of first line ART had no benefit during the first 2 years on ART. After the second year, 3-monthly CD4 tests resulted in a small but significant reduction in death (3 percentage points), largely as a result of switching to second-line ART; but was also a costly intervention.
DART had exceptional levels of participation with only 7% loss-to-follow-up over 5 years. Survival was 88% at 5 years, and this is among the best reported from any trial, ART programme or study in Africa. This shows the dramatic impact ART has; historical comparisons show that as few as 10% of people with HIV infection would be alive after 5 years without ART.
The cost-effectiveness analysis showed that use of routine laboratory testing, as used in DART in Uganda and Zimbabwe, is not cost-effective. Priority should be given to widening access to first- and second-line drugs to treat HIV infection.
DART provided evidence that ART can be safely and successfully delivered without expensive routine blood tests; this opens up the possibility for ART to be delivered locally by suitably trained and supervised healthcare workers, and has led to the Lablite project. Lablite is working closely alongside Ministries of Health in Malawi, Zimbabwe and Uganda, with the overall aim of evaluating strategies to roll-out ART to smaller rural health centers, nearer to where people live.
DART evidence has widened the debate around routine monitoring of treatment for HIV in resource-limited settings and continues to feed into the World Health Organization (WHO) guidelines processes. The trial also built research capacity in Africa; many of the investigators are now considered to be leading researchers in the HIV field, and their trial clinics are considered national centres of excellence.
Type of study
Who funded the study?
Medical Research Council, DFID, Rockefeller Foundation. Antiretroviral drugs donated by Gilead Sciences, GlaxoSmithKline, Boehringer-Ingelheim and Abbott Labs. Gilead, GlaxoSmithKline and Abbott have also provided some funding for some substudies of DART.
When did it take place?
This trial recruited people between 2003 and 2004. Participants were treated, cared for and followed through to the end of 2008, with phased and managed transition to national treatment programmes in 2009.
Where did it take place?
In Uganda and Zimbabwe.
Who was included?
DART recruited 3,320 people with advanced HIV disease or AIDS.