A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen.
OBJECTIVE
Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure.


METHODS
Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels<500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs>200 copies/mL) and treatment discontinuation.


RESULTS
At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P=.77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P=.22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms.


CONCLUSIONS
The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.
Division of Infectious Diseases, Columbia University, New York, New York 10032, USA. smh48@columbia.edu
Scott M
SM
Hammer
Heather
H
Ribaudo
Roland
R
Bassett
John W
JW
Mellors
Lisa M
LM
Demeter
Robert W
RW
Coombs
Judith
J
Currier
Gene D
GD
Morse
John G
JG
Gerber
Ana I
AI
Martinez
William
W
Spreen
Margaret A
MA
Fischl
Kathleen E
KE
Squires
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000592:standards; D018791:CD4 Lymphocyte Count; D015224:Dideoxynucleosides / Q000494:pharmacology* / Q000592:standards; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010919:Placebos; D017211:Treatment Failure; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D019469:Indinavir; D010919:Placebos; D015215:Zidovudine; D000099227:Abacavir
AIDS. 2004 May 21;18(8):1147-58
15166530
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193-7
9371822
J Virol. 1999 Nov;73(11):9404-12
10516049
J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):33-7
14707789
N Engl J Med. 1999 May 27;340(21):1605-13
10341272
Lancet. 2008 Apr 26;371(9622):1417-26
18387667
J Acquir Immune Defic Syndr. 2005 Apr 15;38(5):627-8
15793377
Antimicrob Agents Chemother. 2003 Jun;47(6):1929-35
12760869
Science. 2009 Mar 6;323(5919):1304-7
19265012
N Engl J Med. 2002 Jun 27;346(26):2039-46
12087139
Virology. 2003 Sep 30;314(2):617-29
14554089
N Engl J Med. 1997 Sep 11;337(11):725-33
9287227
J Infect Dis. 2003 Sep 1;188(5):625-34
12934177
Science. 1997 Nov 14;278(5341):1291-5
9360926
QJM. 2007 Feb;100(2):97-105
17277317
Lancet. 2006 Jul 22;368(9532):287-98
16860698
N Engl J Med. 2003 Dec 11;349(24):2293-303
14668455
J Virol. 2003 Oct;77(20):11212-9
14512569
AIDS. 2007 Apr 23;21(7):813-23
17415036
Antivir Ther. 2000 Jun;5(2):91-4
10971861
J Virol. 2006 Jul;80(13):6441-57
16775332
AIDS. 2010 Oct 23;24(16):2451-60
20827162
PLoS One. 2010 Feb 23;5(2):e9390
20186346
J Acquir Immune Defic Syndr. 2009 May 1;51(1):20-8
19282778
Ann Intern Med. 2003 Sep 2;139(5 Pt 1):313-20
12965939
Ann Intern Med. 2001 Dec 4;135(11):954-64
11730396
J Antimicrob Chemother. 2004 Jul;54(1):6-9
15163657
AIDS Res Hum Retroviruses. 2007 Mar;23(3):381-90
17411371
Science. 1997 Nov 14;278(5341):1295-300
9360927
PLoS Pathog. 2007 Apr;3(4):e46
17411338
JAMA. 2006 Aug 16;296(7):769-81
16905783
JAMA. 2010 Jul 21;304(3):321-33
20639566
Nat Med. 2010 Apr;16(4):460-5
20228817
PLoS Med. 2010 Aug 10;7(8):
20711481
HIV Med. 2001 Jan;2(1):27-34
11737373
J Urol. 1998 Mar;159(3):820-5; discussion 825-6
9474159
Clin Infect Dis. 2010 Mar 15;50(6):912-9
20156060
N Engl J Med. 2003 Dec 11;349(24):2304-15
14668456