Contact information

Type

Scientific

Primary contact

Prof Janet Darbyshire

ORCID ID

Contact details

MRC Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom
+44 (0)20 7670 4780
dart@ctu.mrc.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

G0000068

Study information

Scientific title

Acronym

DART

Study hypothesis

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

Protocol approved in Uganda, Zimbabwe and United Kingdom

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Patient information can be found at: http://www.ctu.mrc.ac.uk/dart/faq.asp

Condition

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 Specified

Drug names

Antiretroviral therapy

Primary outcome measures

1. Efficacy: Progression to a new WHO stage 4 HIV event or death
2. Safety: Any serious adverse event, which is not HIV related

Secondary outcome measures

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)

Overall trial start date

15/01/2003

Overall trial end date

31/12/2007

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

3300 (recruitment completed 28 October 2004)

Participant 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 breast-feeding

Recruitment start date

15/01/2003

Recruitment end date

31/12/2007

Locations

Countries of recruitment

Uganda, Zimbabwe

Trial participating centre

MRC Clinical Trials Unit
London
NW1 2DA
United Kingdom

Sponsor information

Organisation

Medical Research Council (MRC) (UK)

Sponsor details

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

Sponsor type

Research council

Website

http://www.ctu.mrc.ac.uk/

Funders

Funder type

Government

Funder name

Medical Research Council (UK)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

UK Department for International Development (DFID)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Rockefeller Foundation (USA)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United States of America

Funder name

Antiretroviral drugs donated by Gilead (USA), GlaxoSmithKline (UK), Boehringer-Ingelheim (Germany)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2006 publication on virological response in http://www.ncbi.nlm.nih.gov/pubmed/16791013
2. 2006 publication on prevalence, incidence and predictors of severe anaemia in http://www.ncbi.nlm.nih.gov/pubmed/17310818
3. 2007 results of pharmacokinetic sub-study in http://www.ncbi.nlm.nih.gov/pubmed/17413694
4. 2008 results on interupted versus continous therapy in http://www.ncbi.nlm.nih.gov/pubmed/18097226
5. 2008 results on demographics of poor adherence in http://www.ncbi.nlm.nih.gov/pubmed/18614918
6. 2009 results on routine versus laboratory monitoring in http://www.ncbi.nlm.nih.gov/pubmed/20004464
7. 2010 results of observational analysis in http://www.ncbi.nlm.nih.gov/pubmed/20347483
8. 2012 cost -effectiveness of routine versus laboratory monitoring in http://www.ncbi.nlm.nih.gov/pubmed/22545079
9. 2012 results on pregnancy and infant outcomes in http://www.ncbi.nlm.nih.gov/pubmed/22615543
10. 2013 secondary analysis results in http://www.ncbi.nlm.nih.gov/pubmed/24098434
11. 2014 retrospective analysis results in http://www.ncbi.nlm.nih.gov/pubmed/24625508

Publication citations

  1. Publication on virological response

    Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa., AIDS, 2006, 20, 10, 1391-1399, doi: 10.1097/01.aids.0000233572.59522.45.

  2. Results on routine versus laboratory monitoring

    , Mugyenyi P, Walker AS, Hakim J, Munderi P, Gibb DM, Kityo C, Reid A, Grosskurth H, Darbyshire JH, Ssali F, Bray D, Katabira E, Babiker AG, Gilks CF, Grosskurth H, Munderi P, Kabuye G, Nsibambi D, Kasirye R, Zalwango E, Nakazibwe M, Kikaire B, Nassuna G, Massa R, Fadhiru K, Namyalo M, Zalwango A, Generous L, Khauka P, Rutikarayo N, Nakahima W, Mugisha A, Todd J, Levin J, Muyingo S, Ruberantwari A, Kaleebu P, Yirrell D, Ndembi N, Lyagoba F, Hughes P, Aber M, Lara AM, Foster S, Amurwon J, Wakholi BN, Whitworth J, Wangati K, Amuron B, Kajungu D, Nakiyingi J, Omony W, Fadhiru K, Nsibambi D, Khauka P, Mugyenyi P, Kityo C, Ssali F, Tumukunde D, Otim T, Kabanda J, Musana H, Akao J, Kyomugisha H, Byamukama A, Sabiiti J, Komugyena J, Wavamunno P, Mukiibi S, Drasiku A, Byaruhanga R, Labeja O, Katundu P, Tugume S, Awio P, Namazzi A, Bakeinyaga GT, Katabira H, Abaine D, Tukamushaba J, Anywar W, Ojiambo W, Angweng E, Murungi S, Haguma W, Atwiine S, Kigozi J, Namale L, Mukose A, Mulindwa G, Atwiine D, Muhwezi A, Nimwesiga E, Barungi G, Takubwa J, Murungi S, Mwebesa D, Kagina G, Mulindwa M, Ahimbisibwe F, Mwesigwa P, Akuma S, Zawedde C, Nyiraguhirwa D, Tumusiime C, Bagaya L, Namara W, Kigozi J, Karungi J, Kankunda R, Enzama R, Latif A, Hakim J, Robertson V, Reid A, Chidziva E, Bulaya-Tembo R, Musoro G, Taziwa F, Chimbetete C, Chakonza L, Mawora A, Muvirimi C, Tinago G, Svovanapasis P, Simango M, Chirema O, Machingura J, Mutsai S, Phiri M, Bafana T, Chirara M, Muchabaiwa L, Muzambi M, Mutowo J, Chivhunga T, Chigwedere E, Pascoe M, Warambwa C, Zengeza E, Mapinge F, Makota S, Jamu A, Ngorima N, Chirairo H, Chitsungo S, Chimanzi J, Maweni C, Warara R, Matongo M, Mudzingwa S, Jangano M, Moyo K, Vere L, Mdege N, Machingura I, Katabira E, Ronald A, Kambungu A, Lutwama F, Mambule I, Nanfuka A, Walusimbi J, Nabankema E, Nalumenya R, Namuli T, Kulume R, Namata I, Nyachwo L, Florence A, Kusiima A, Lubwama E, Nairuba R, Oketta F, Buluma E, Waita R, Ojiambo H, Sadik F, Wanyama J, Nabongo P, Oyugi J, Sematala F, Muganzi A, Twijukye C, Byakwaga H, Ochai R, Muhweezi D, Coutinho A, Etukoit B, Gilks C, Boocock K, Puddephatt C, Grundy C, Bohannon J, Winogron D, Gibb DM, Burke A, Bray D, Babiker A, Walker AS, Wilkes H, Rauchenberger M, Sheehan S, Spencer-Drake C, Taylor K, Spyer M, Ferrier A, Naidoo B, Dunn D, Goodall R, Darbyshire JH, Peto L, Nanfuka R, Mufuka-Kapuya C, Kaleebu P, Pillay D, Robertson V, Yirrell D, Tugume S, Chirara M, Katundu P, Ndembi N, Lyagoba F, Dunn D, Goodall R, McCormick A, Lara AM, Foster S, Amurwon J, Wakholi BN, Kigozi J, Muchabaiwa L, Muzambi M, Weller I, Babiker A, Bahendeka S, Bassett M, Wapakhabulo AC, Darbyshire JH, Gazzard B, Gilks C, Grosskurth H, Hakim J, Latif A, Mapuchere C, Mugurungi O, Mugyenyi P, Burke C, Jones S, Newland C, Pearce G, Rahim S, Rooney J, Smith M, Snowden W, Steens JM, Breckenridge A, McLaren A, Hill C, Matenga J, Pozniak A, Serwadda D, Peto T, Palfreeman A, Borok M, Katabira E, Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial., Lancet, 2010, 375, 9709, 123-131, doi: 10.1016/S0140-6736(09)62067-5.

  3. Results of observational analysis

    Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, Reid A, Katabira E, Grosskurth H, Mugyenyi P, Hakim J, Darbyshire JH, Gibb DM, Babiker AG, Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort., Lancet, 2010, 375, 9722, 1278-1286, doi: 10.1016/S0140-6736(10)60057-8.

  4. Results on pregnancy and infant outcomes

    Gibb DM, Kizito H, Russell EC, Chidziva E, Zalwango E, Nalumenya R, Spyer M, Tumukunde D, Nathoo K, Munderi P, Kyomugisha H, Hakim J, Grosskurth H, Gilks CF, Walker AS, Musoke P, , Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial., PLoS Med., 2012, 9, 5, e1001217, doi: 10.1371/journal.pmed.1001217.

  5. Secondary analysis results

    Parikh SM, Obuku EA, Walker SA, Semeere AS, Auerbach BJ, Hakim JG, Mayanja-Kizza H, Mugyenyi PN, Salata RA, Kityo CM, , Clinical differences between younger and older adults with HIV/AIDS starting antiretroviral therapy in Uganda and Zimbabwe: a secondary analysis of the DART trial., PLoS ONE, 2013, 8, 10, e76158, doi: 10.1371/journal.pone.0076158.

  6. Retrospective analysis results

    Kityo C, Gibb DM, Gilks CF, Goodall RL, Mambule I, Kaleebu P, Pillay D, Kasirye R, Mugyenyi P, Walker AS, Dunn DT, , High level of viral suppression and low switch rate to second-line antiretroviral therapy among HIV-infected adult patients followed over five years: retrospective analysis of the DART trial., PLoS ONE, 2014, 9, 3, e90772, doi: 10.1371/journal.pone.0090772.

  7. Ssali F, Stöhr W, Munderi P, Reid A, Walker AS, Gibb DM, Mugyenyi P, Kityo C, Grosskurth H, Hakim J, Byakwaga H, Katabira E, Darbyshire JH, Gilks CF, , Prevalence, incidence and predictors of severe anaemia with zidovudine-containing regimens in African adults with HIV infection within the DART trial., Antivir. Ther. (Lond.), 2006, 11, 6, 741-749.

  8. Kikaire B, Khoo S, Walker AS, Ssali F, Munderi P, Namale L, Reid A, Gibb DM, Mugyenyi P, Grosskurth H, , Nevirapine clearance from plasma in African adults stopping therapy: a pharmacokinetic substudy., AIDS, 2007, 21, 6, 733-737, doi: 10.1097/QAD.0b013e3280121801.

  9. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts < 200 cells/microl., AIDS, 2008, 22, 2, 237-247, doi: 10.1097/QAD.0b013e3282f2d760.

  10. Muyingo SK, Walker AS, Reid A, Munderi P, Gibb DM, Ssali F, Levin J, Katabira E, Gilks C, Todd J, , Patterns of individual and population-level adherence to antiretroviral therapy and risk factors for poor adherence in the first year of the DART trial in Uganda and Zimbabwe., J. Acquir. Immune Defic. Syndr., 2008, 48, 4, 468-475, doi: 10.1097/QAI.0b013e31817dc3fd.

  11. Medina Lara A, Kigozi J, Amurwon J, Muchabaiwa L, Nyanzi Wakaholi B, Mujica Mota RE, Walker AS, Kasirye R, Ssali F, Reid A, Grosskurth H, Babiker AG, Kityo C, Katabira E, Munderi P, Mugyenyi P, Hakim J, Darbyshire J, Gibb DM, Gilks CF, , Cost effectiveness analysis of clinically driven versus routine laboratory monitoring of antiretroviral therapy in Uganda and Zimbabwe., PLoS ONE, 2012, 7, 4, e33672, doi: 10.1371/journal.pone.0033672.

Editorial Notes