Trial summary

DART is a six year clinical trial of anti-HIV therapy in 3300 patients with advanced HIV or AIDS in Uganda and Zimbabwe. The trial aimed to investigate two main questions: can anti-HIV drugs be given in the absence of routine laboratory tests, relying on clinical assessments instead; and can anti-HIV drugs be given intermittently rather than continuously to provide a similar level of benefit to patients but with less toxicity.

To address the first question all patients had laboratory tests carried out to monitor drug toxicity but half of them, selected at random, did not have their results returned to their doctors throughout the trial. This meant that clinical examination alone was used to make health management decisions. For all patients however, doctors were able to request the results of laboratory tests for drug side effects if there was a concern that clinical assessment alone was not sufficient to make a decision. In addition, all laboratory test results that were considered to show severe drug toxicity (grade 4) were always returned to doctors.

For the second question, patients who responded well to initial therapy were randomly assigned to either stay on continuous therapy or move on to structured treatment interruption (STI): cycles of 12 weeks on and 12 weeks off drugs. STI patients were moved to continuous therapy in March 2006. See ‘Structured Treatment Interruptions (STIs) in DART’ page.

The outcome of the trial was assessed in terms of the development of new AIDS-defining illnesses or death. These events were compared across the different groups.

All data was reviewed periodically by the Data and Safety Monitoring Committee (DSMC) to ensure that it was safe to carry on with the trial. The DSMC would recommend the trial should stop early if there is a difference between study arms indicating that one strategy was worse than another.

Trial Protocol

The DART protocol describes an open-label randomised trial evaluating two strategic approaches for management of antiretroviral therapy (ART) in symptomatic HIV infected adults in Africa. The first strategy compares clinically driven monitoring (CDM) with laboratory plus clinical monitoring (LCM). The second approach compares structured treatment interruptions (STIs) of 12 weeks on and 12 weeks off ART with continuous ART in patients who achieve CD4 cell counts ≥ 300 cells/mm³ after 48 or 72 weeks on continuous ART. HIV infects CD4 cells and the number of these cells present in the body generally gives a good indication of disease progression.

Eligible patients had symptomatic HIV disease (World Health Organisation symptomatic HIV stage 2, 3 or 4) and CD4 cell counts <200 cells/mm³, no prior ART and no clinical or laboratory abnormalities contra-indicating start of ART. 3316 patients were enrolled by October 2004 into the CDM versus LCM comparison from three African sites, two in Uganda and one in Zimbabwe, and were followed for four to six years. In both the CDM and LCM arms, patients had regular haematology and biochemistry tests performed but the results were not returned to clinicians caring for patients in the CDM arm unless indicative of a grade 4 adverse event. In both arms a doctor could request laboratory tests if they had any clinical concerns about a patient and these results were returned to the doctor in all cases. CD4 counts were performed both in the CDM and LCM arms with results not returned to physicians in the CDM arm.

The second randomised trial opened after a non-randomised pilot study of 100 patients assigned to STIs had been completed and the DSMC and Trial Steering Committees had assessed this data. Following the pilot STI study, it was expected that around 600 patients would achieve CD4 = 300 cells/mm³ by 48 or 72 weeks after trial entry and would undergo a second randomisation to STI or to continuous ART. During the pilot study and during the first phase of the STI randomisation, all patients in both the CDM and LCM arms underwent monthly CD4 cell monitoring. These results were reviewed regularly by a subgroup of the Trial Steering Committee. In March 2006, following review by the DSMC, the STI randomisation was terminated and all patients in the STI arm were transferred to continuous therapy. Further details can be found on the ‘Structured Treatment Interruptions (STIs) in DART’ page.

As first-line treatment, all patients received a triple combination of ART. Patients were prescribed zidovudine (ZDV) and lamivudine (3TC) in combination (Combivir) as the backbone of their treatment. For their third drug, 2,469 patients received tenofovir (TDF) and 247 patients received nevirapine (NVP). In addition, 600 patients were co-enrolled with additional, separate consent to a double blind 24-week comparison of the safety of abacavir (ABC) versus nevirapine (NVP) as the third drug for first-line therapy. These patients continued to receive ABC or NVP, respectively, after the blinded period finished. For intolerance or toxicity of any individual drug, another ART drug from the same class was substituted.

The primary efficacy endpoint for first-line ART treatment was progression to a new WHO HIV stage 4 disease or death. The decision to change to second-line ART was based on clinical criteria alone for the CDM arm and on clinical plus CD4 count criteria for the LCM arm. The second-line ART combination used was dependant on the first-line regimen received. Patients who failed the second-line regimen were offered the best combination available.

DART was a six year trial. Recruitment into the trial took place over two years for the first randomisation to the CDM and LCM monitoring strategies, with follow-up until the end of 2008. Participants will be transferred into national and other ART programmes throughout 2009. For the second randomisation to STIs or continuous ART, recruitment took place during the second and third years of the trial.

DART is a collaboration between the University of Zimbabwe, Harare, Zimbabwe; the Medical Research Council and Uganda Virus Research Institute (MRC/UVRI), Entebbe, Uganda; the Joint Clinical Research Center (JCRC), Kampala, Uganda; Mulago Hospital – Academic Alliance -Infectious Diseases Institute, Kampala, Uganda; the MRC Clinical Trials Unit, London, UK; and Imperial College London, London, UK.

Funding was provided by the UK Medical Research Council (MRC), the UK Government’s Department for International Development (DFID) and the Rockefeller Foundation.

Antiretroviral drugs were provided by GlaxoSmithKline, Gilead and Boehringer-Ingelheim.