Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial.
BACKGROUND
Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge.


OBJECTIVE
To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen.


METHODS
Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks.


METHODS
Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.


METHODS
A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL.


METHODS
Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil.


METHODS
Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility.


RESULTS
Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03).


CONCLUSIONS
In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.
Hammer
Scott M
SM
Division of Infectious Diseases, Department of Medicien, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA. smh48@columbia.edu
Vaida
Florin
F
Bennett
Kara K
KK
Holohan
Mary K
MK
Sheiner
Lewis
L
Eron
Joseph J
JJ
Wheat
Lawrence Joseph
LJ
Mitsuyasu
Ronald T
RT
Gulick
Roy M
RM
Valentine
Fred T
FT
Aberg
Judith A
JA
Rogers
Michael D
MD
Karol
Cheryl N
CN
Saah
Alfred J
AJ
Lewis
Ronald H
RH
Bessen
Laura J
LJ
Brosgart
Carol
C
DeGruttola
Victor
V
Mellors
John W
JW
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D018791:CD4 Lymphocyte Count; D002219:Carbamates; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000493:pharmacokinetics / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D019888:Nelfinavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D063065:Organophosphonates; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D016016:Proportional Hazards Models; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019258:Saquinavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D017211:Treatment Failure; D019562:Viral Load; D000099227:Abacavir
D000225:Adenine; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002219:Carbamates; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D005663:Furans; D017320:HIV Protease Inhibitors; D019469:Indinavir; D019888:Nelfinavir; D063065:Organophosphonates; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019258:Saquinavir; D013449:Sulfonamides; D000099227:Abacavir; C095108:amprenavir; C098320:efavirenz; C106812:adefovir dipivoxil