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Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure
A Randomized Trial
Scott M. Hammer, MD;
Florin Vaida, PhD;
Kara K. Bennett, MS;
Mary K. Holohan, BA;
Lewis Sheiner, MD;
Joseph J. Eron, MD;
Lawrence Joseph Wheat, MD;
Ronald T. Mitsuyasu, MD;
Roy M. Gulick, MD;
Fred T. Valentine, MD;
Judith A. Aberg, MD;
Michael D. Rogers, PhD;
Cheryl N. Karol, PhD;
Alfred J. Saah, MD, MPH;
Ronald H. Lewis, MD;
Laura J. Bessen, MD;
Carol Brosgart, MD;
Victor DeGruttola, PhD;
John W. Mellors, MD;
for the AIDS Clinical Trials Group 398 Study Team
JAMA. 2002;288:169-180.
Context 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.
Design 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.
Setting Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical
Trials Units in the United States.
Participants 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.
Intervention 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.
Main Outcome Measures 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
( 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.
Author Affiliations: Department of Medicine,
Columbia University College of Physicians and Surgeons, New York, NY (Dr Hammer);
Department of Biostatistics, Statistical and Data Analysis Center, Harvard
School of Public Health, Boston, Mass (Drs Vaida and DeGruttola, and Ms Bennett);
AIDS Clinical Trial Group Operations Center, Silver Spring, Md (Ms Holohan);
Department of Laboratory Medicine (Dr Sheiner) and Department of Medicine
(Dr Aberg), University of California, San Francisco; Department of Medicine,
University of North Carolina, Chapel Hill (Dr Eron); Department of Medicine,
Indiana University, Bloomington (Dr Wheat); Department of Medicine, University
of California, Los Angeles (Dr Mitsuyasu); Department of Medicine, Weill Medical
College of Cornell University, New York, NY (Dr Gulick); Department of Medicine,
New York University, New York (Dr Valentine); Department of Medicine, University
of Pittsburgh, Pa (Dr Mellors); GlaxoSmithKline, Research Triangle Park, NC
(Dr Rogers); Hoffman-LaRoche, Nutley, NJ (Dr Karol); Merck Research Laboratories,
Blue Bell, Pa (Dr Saah); Agouron Pharmaceuticals, La Jolla, Calif (Dr Lewis);
DuPont Pharmaceuticals, Wilmington, Del (Dr Bessen); and Gilead Sciences,
Foster City, Calif (Dr Brosgart). Dr Bessen is now at Bristol-Myers Squibb.
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