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

ISRCTN	ISRCTN13968779
DOI	https://doi.org/10.1186/ISRCTN13968779
Protocol serial number	G0000068
Sponsor	Medical Research Council (MRC) (UK)
Funders	Medical Research Council (UK), Department for International Development, Rockefeller Foundation (USA), Antiretroviral drugs donated by Gilead (USA), GlaxoSmithKline (UK), Boehringer-Ingelheim (Germany)

Submission date: 18/10/2000
Registration date: 18/10/2000
Last edited: 27/02/2017

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=12

Contact information

Prof Janet Darbyshire
Scientific

MRC Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom

Phone	+44 (0)20 7670 4780
Email	dart@ctu.mrc.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	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
Study acronym	DART
Study objectives	To compare, in terms of clinical HIV disease progression or death: 1. Clinical monitoring only (CMO) versus routine regular laboratory and clinical monitoring (LCM) 2. Structured Treatment Interruptions (STIs: 12 weeks on, 12 weeks off therapy) versus continuous ART, initiated if the CD4 count has increased to 200 cells/mm3 or above (after 24 or 48 weeks on ART) [updated June 2006 from 300 cells/mm3 or above (after 48 or 72 weeks on ART)] The hypothesis is that CMO will result in similar outcomes to LCM, and that ART administered as pulse therapy (STI) will result in similar outcomes to continuous ART, in terms of progression of clinical HIV disease or death. STI Pilot Study Objectives: The initial non-randomised pilot study of STIs will inform on the safety of the 12 weeks on, 12 weeks off STI strategy and only after the completion of this substudy will the second randomisation commence. Abacavir Safety Substudy Nevirapine OR Abacavir (NORA) Substudy Objectives: This randomised sub-study of 600 patients will address issues of safe administration of Abacavir in resource poor settings and will compare the safety of Abacavir with that of Nevirapine when used in combination with Combivir.
Ethics approval(s)	Protocol approved in Uganda, Zimbabwe and United Kingdom
Health condition(s) or problem(s) studied	Human Immunodeficiency Virus (HIV), Acquired Immunodeficiency Syndrome (AIDS)
Intervention	Randomisation to Clinical Monitoring Only (CMO) or Laboratory and Clinical Monitoring (LCM): 3300 patients will be randomised to CMO or LCM over a period of 1-2 years. Randomisation will be stratified by CD4 count (0-99, 100-199) clinical site and by third drug (Tenofovir DF, Nevirapine or NORA substudy). Structured Treatment Interruptions (STI): Because there were no data on STI in the African setting, where patients are likely to have low CD4 cell counts before starting ART, a non-randomised pilot study of the first 100 patients eligible for the STI randomisation was undertaken. Following the successful completion of this pilot a randomisation to STI or continuous antiretroviral therapy (ART) was opened to patients when they reached 52 or 76 weeks of DART if they had a CD4 count of ≥300 at week 48 or 72. NORA substudy: A randomised, double-blind, phase II (substudy) trial to evaluate the toxicity of Abacavir compared with Nevirapine, both in combination with Ziduvudine + Lamivudine (Combivir), as first-line antiretroviral therapy in patients participating in the DART trial.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)
Primary outcome measure(s)	1. Efficacy: Progression to a new WHO stage 4 HIV event or death 2. Safety: Any serious adverse event, which is not HIV related
Key secondary outcome measure(s)	1. Progression to a new or recurrent WHO stage 4 HIV event or death 2. Progression to a new WHO stage 4 HIV event or death from 6 weeks after randomisation 3. Progression to a new or recurrent WHO stage 4 HIV event or death from 6 weeks after randomisation 4. Any grade 3 or 4 adverse events 5. Number and class of anti-HIV drugs received by 3 years 6. Time to cessation of first-line regimen for failure 7. Adherence as measured by questionnaire and pill counts 8. CD4 count at 3 years (provided that it is at least 2 months after restarting ART for those in the STI group) 9. HIV RNA viral load (performed retrospectively) at 3 years (providing that it is at least 2 months after restarting ART for those in the STI group) 10. HIV resistance profiles at 3 years in those with detectable viral load (providing that it is at least 2 months after restarting ART for those in the STI group)
Completion date	31/12/2007

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	3300
Key inclusion criteria	1. Documentation of HIV-1 infection: antibody positive serology by enzyme-linked immunosorbent assay (ELISA) test (confirmed by licensed second ELISA or Western Blot) 2. Age ≥18 years 3. Symptomatic WHO stage 2, 3 or 4 HIV disease and CD4 <200 cells/mm3 4. ART naïve (except for ART use during pregnancy for the prevention of mother-to-child HIV transmission) 5. Agreement and documented informed consent to be randomised to CMO or LCM and to STI or continuous ART, if eligible 6. Life expectancy of at least 3 months
Key exclusion criteria	1. Cannot or unlikely to attend regularly (e.g. usual residence too far from Study Centre) 2. Likelihood of poor compliance 3. Presence of acute infection (e.g. malaria, acute hepatitis, pneumococcal pneumonia, non-typhoid salmonella septicaemia, cryptococcal meningitis). Patients may be admitted after recovery of an acute infection. Patients with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART. Patients starting ART whilst on anti-tuberculosis therapy after the intensive phase will not receive NVP, nor will they be randomised into the NORA substudy. 4. On chemotherapy for malignancy 5. Laboratory abnormalities which are a contraindication for the patient to start ART (e.g. haemoglobin <8 g/dl, total white blood cell count [WBC] <0.75 x 10^9/l, aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >5 x the upper limit of normal [ULN], grade 3 renal dysfunction - creatinine >360 µmol/l and/or urea >5 x ULN) 6. Pregnancy or breastfeeding
Date of first enrolment	15/01/2003
Date of final enrolment	28/10/2004

Locations

Countries of recruitment

United Kingdom
England
Uganda
Zimbabwe

Study participating centre

MRC Clinical Trials Unit

London
NW1 2DA
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results of pharmacokinetic sub-study	30/03/2007		Yes	No
Results article	results on interupted versus continous therapy	11/01/2008		Yes	No
Results article	results on demographics of poor adherence	01/08/2008		Yes	No
Results article	results on routine versus laboratory monitoring	09/01/2010		Yes	No
Results article	results of observational analysis	10/04/2010		Yes	No
Results article	results on pregnancy and infant outcomes	01/04/2012		Yes	No
Results article	secondary analysis results	02/10/2013		Yes	No
Results article	retrospective analysis results	13/03/2014		Yes	No
Results article	retrospective analysis results	21/02/2017		Yes	No
Other publications	publication on prevalence, incidence and predictors of severe anaemia	01/06/2006		Yes	No
Other publications	publication on virological response	26/06/2006		Yes	No
Other publications	cost -effectiveness of routine versus laboratory monitoring	01/04/2012		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

27/02/2017: Publication reference added.