Determination of the underlying cause of death in three multicenter international HIV clinical trials.
OBJECTIVE
Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials.


METHODS
Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated.


RESULTS
Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached.


CONCLUSIONS
ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.
Lifson
Alan R
AR
University of Minnesota, Minneapolis, Minnesota 55454-1015, USA. lifso001@umn.edu
Belloso
Waldo H
WH
Carey
Cate
C
Davey
Richard T
RT
Duprez
Daniel
D
El-Sadr
Wafaa M
WM
Gatell
Jose M
JM
Gey
Daniela C
DC
Hoy
Jennifer F
JF
Krum
Eric A
EA
Nelson
Ray
R
Nixon
Daniel E
DE
Paton
Nick
N
Pedersen
Court
C
Perez
George
G
Price
Richard W
RW
Prineas
Ronald J
RJ
Rhame
Frank S
FS
Sampson
James
J
Worley
John
J
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D044966:Anti-Retroviral Agents; D002423:Cause of Death; D002986:Clinical Trials as Topic; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic
D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents