A RANDOMIZED CONTROL TRIAL OF MONITORING PRACTICE AND STRUCTURED TREATMENT INTERRUPTIONS IN THE MANA

1
A RANDOMIZED CONTROL TRIAL OF MONITORING PRACTICE
AND STRUCTURED TREATMENT INTERRUPTIONS IN THE
MANAGEMENT OF ANTIRETROVIRAL THERAPY IN
AFRICAAN OVERVIEW OF DART TRIAL

• Dr DAVID NSIBAMBI DR RONALD KASIRYE
• On behalf DART trial team.

2
Development of AntiRetroviral Therapy In
Africa DART
Joint Clinical Research Centre, Kampala,
Uganda Academic Alliance, Mulago Hospital,
Uganda
MRC/Uganda Virus Research Institute Programme on
AIDS, Entebbe, Uganda TASO, Uganda
MRC CTU Imperial College
University of Zimbabwe, Harare, Zimbabwe
GSK Gilead Boehringer-Ingelheim
DFID, UK
Rockefeller Foundation
MRC, UK
3
Aim and Objectives

• To evaluate strategies for the management of ART
  in Africa.

• to compare routine Laboratory and Clinical
  Monitoring (LCM) versus Clinical Monitoring Only
  (CMO)
• in those with CD4 count increases to above 300
  cells/mm3 after 48 or 72 weeks on ART
• to compare Continuous Therapy (CT) versus
  Structured Treatment Interruption (STI)
• STI 12 weeks on ART, 12 weeks off ART

4
DART Trial Schema
WHO 2, 3 or 4 CD4lt200 cells/mm3 no
contra-indications to antiretroviral therapy
1st randomisation
LCM n1650
CMO n1650
CD4 gt300 cells/mm3 continue LCM/CMO randomise to
STI or continuous
CD4lt300 at 48/72 weeks
CD4lt300 at 48/72 weeks
STI (n300)
Continuous CT (n300)
2nd randomisation
follow-up 3-5 years in CMO/LCM 2-3.5 years in
STI/continuous ART
5
Endpoints - Primary

• Efficacy Progression to a new HIV stage 4 event
  or death
• Safety Any serious adverse event which is not
  HIV-related

6
Endpoints - Secondary

• progression to new or recurrent WHO stage 4 event
  or death
• Grade 3 or 4 adverse events
• time to cessation of first-line regimen for
  failure
• adherence as measured by questionnaire and pill
  counts
• CD4 count at 3 years
• HIV RNA viral load at 3 years (retrospective)
• HIV resistance profiles at 3 years

7
Inclusion criteria

• confirmed HIV-1 antibody positive
• age 18 years or over
• WHO stage 2, 3 or 4 and CD4 lt200 cells/mm3
• previously untreated with ARVs
• except for ART use for the prevention of
  mother-to-child HIV transmission
• written informed consent
• agreement to be randomised to CT or STI if
  eligible
• life expectancy at least 3 months

8
Exclusion criteria

• cannot / unlikely to attend regular follow-up
• presence of acute infection
• patients may be admitted to the trial after
  resolution of acute phase illness
• on chemotherapy for malignancy
• laboratory abnormalities contraindicating ART
• e.g. Haemoglobin lt8g/dl
• e.g. AST or ALT gt5-fold the upper limit of normal
• pregnancy or breast-feeding

9
First line ART regimens

• 
  patient numbers
• ZDV / 3TC / TDF 2460 (76)
• all 3 sites
• ZDV / 3TC / NVP 246 (8)
• Harare site only
• ZDV / 3TC / bABC or bNVP 539 (17)
• JCRC and Entebbe sites

10
Recruitment

• Recruitment period January 2003 15 October 2005
• 3269 patients across the three sites
• 1018 MRC - Entebbe
• 1000 JCRC Kampala
• 301 Academic Alliance Mulago
• 950 Harare
• 65 Females 35 Males
• Median age 37.6 with 65 below lt 30 years

11
Baseline characteristics
12
Change in CD4 from enrolment
13
Viral suppression at week 24 in a subgroup of
DART participants
Mean log drop
3.70
3.67
3.95
Percentage
NOTE 8 values lt100 or lt400 due to insufficient
sample volume are conservatively counted as
?50c/ml (3)
14
Acknowledgments

• We thank all the patients and staff from all the
  centres participating in the DART trial.
• Virology Committee P Kaleebu, D Pillay, V
  Robertson, D Yirrell, P Mugyenyi, C Kityo, J
  Hakim, H Grosskurth, J Darbyshire
• Joint Clinical Research Centre, Kampala, Uganda
  P Mugyenyi, C Kityo, D Tumukunde, F Ssali, D
  Atwine, G Mulindwa, G Kabuye, R Byaruhanga, T
  Bakeimyaga-Grace, H Katabira, E Nimwesiga, G
  Barungi, S Atwiine, F Ahimbisibwe, S Tugume, T
  Otim, J Takubwa, M Mulindwa, S Murungi, J
  Tukamushaba, D Muebesa, H Kyomugisha, J Kagina, L
  Namale.
• University of Zimbabwe, Harare, Zimbabwe A
  Latif, J Hakim, V Robertson, A Reid, A Jamu, S
  Makota, G Musoro, N Ngorima, M Pascoe, F Taziwa,
  L Chakonza, E Chidziva, H Chirairo, S Chitsungo,
  F Mapinge, A Mawora, C Muvirimi, G Tinago, J
  Chimanzi, J Machingura, C Maweni, S Mutsai, R
  Warara, M Matongo, N Mdege, S Mudzingwa, M
  Jangano, I Machingura, K Moyo, L Vere, E
  Chigwedere, M Phiri.
• MRC Programme on AIDS/Uganda Virus Research
  Institute, Entebbe, Uganda H Grosskurth, P
  Munderi, K Wangati, D Kajungu, B Amuron, D
  Nsibambi R Kasirye, E Zalwango, M Nakazibwe, B
  Kikaire, G Nassuna, R Massa, K Fadhiru, M
  Namyalo, A Zalwango, L Generous, P Khauka, N
  Rutikarayo, W Nakahima, A Mugisha J Nakiyingi, P
  Hughes.
• Academic Alliance, Mulago Hospital, Uganda E
  Katabira, J Oyugi, A Ronald, A Kambungu, J
  Martin, R Nalumenya, R Nairubi, E Bulume, M
  Teopista, C Twijukye, F Sematala, H Byakwaga.
• The AIDS Support Organisation (TASO), Uganda A
  Coutinho, B Etukoit.
• Imperial College C Gilks, L Colquhoun, K
  Boocock, C Puddephatt
• MRC Clinical Trials Unit J Darbyshire, DM Gibb,
  A Burke, D Bray, A Babiker, AS Walker, H Wilkes,
  M Rauchenberger, S Sheehan, C OBrien
• Trial Steering Committee I Weller (Chair), A
  Babiker (Trial Statistician), S Bahendeka, M
  Bassett, A Chogo Wapakhabulo, J Darbyshire, B
  Gazzard, C Gilks, H Grosskurth, J Hakim, A Latif,
  E Loeliger (observer), M Imperiale (observer), O
  Mugurungi, P Mugyenyi, P Naidoo (observer), M
  Palmer (observer), J Rooney (observer), J-M
  Steens (observer)
• GlaxoSmithKline donated first-line drugs for DART
  and provided funding for this virology substudy.
  Gilead and Boehringer-Ingelheim also donated
  first-line drugs.
• Funding DART is funded by the UK Medical
  Research Council, the UK Department for
  International Development (DFID), and the
  Rockefeller Foundation.

15
(No Transcript)