 |
|
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.
RELATED ARTICLES
Time Trends in Primary HIV-1 Drug Resistance Among Recently Infected Persons
Robert M. Grant, Frederick M. Hecht, Maria Warmerdam, Lea Liu, Teri Liegler, Christos J. Petropoulos, Nicholas S. Hellmann, Margaret Chesney, Michael P. Busch, and James O. Kahn
JAMA. 2002;288(2):181-188.
ABSTRACT
| FULL TEXT
Emerging Resistance to Nonnucleoside Reverse Transcriptase Inhibitors: A Warning and a Challenge
Joel D. Trachtenberg and Merle A. Sande
JAMA. 2002;288(2):239-241.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Pharmacokinetics and short-term efficacy of a double-boosted protease inhibitor regimen in treatment-naive HIV-1-infected adults
van der Lugt et al.
J Antimicrob Chemother 2008;61:1145-1153.
ABSTRACT
| FULL TEXT
Hidden Markov models for settings with interval-censored transition times and uncertain time origin: application to HIV genetic analyses
Healy and Degruttola
Biostatistics 2007;8:438-452.
ABSTRACT
| FULL TEXT
Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration
Stocker et al.
J Antimicrob Chemother 2007;59:560-564.
ABSTRACT
| FULL TEXT
Dose Separation Does Not Overcome the Pharmacokinetic Interaction between Fosamprenavir and Lopinavir/Ritonavir.
Corbett et al.
Antimicrob. Agents Chemother. 2006;50:2756-2761.
ABSTRACT
| FULL TEXT
Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection
Hazra et al.
Pediatrics 2005;116:e846-e854.
ABSTRACT
| FULL TEXT
Sensitive Phenotypic Detection of Minor Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Variants
Nissley et al.
J. Clin. Microbiol. 2005;43:5696-5704.
ABSTRACT
| FULL TEXT
Amprenavir and Efavirenz Pharmacokinetics before and after the Addition of Nelfinavir, Indinavir, Ritonavir, or Saquinavir in Seronegative Individuals
Morse et al.
Antimicrob. Agents Chemother. 2005;49:3373-3381.
ABSTRACT
| FULL TEXT
Mechanism-Based Inactivation of CYP3A by HIV Protease Inhibitors
Ernest et al.
J. Pharmacol. Exp. Ther. 2005;312:583-591.
ABSTRACT
| FULL TEXT
Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis
Palmer et al.
J. Clin. Microbiol. 2005;43:406-413.
ABSTRACT
| FULL TEXT
Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement
Ioannidis et al.
ANN INTERN MED 2004;141:781-788.
ABSTRACT
| FULL TEXT
Clinical perspective of fusion inhibitors for treatment of HIV
Rockstroh and Mauss
J Antimicrob Chemother 2004;53:700-702.
ABSTRACT
| FULL TEXT
Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates
Bulgheroni et al.
J Antimicrob Chemother 2004;53:464-468.
ABSTRACT
| FULL TEXT
Efficacy of Enfuvirtide in Patients Infected with Drug-Resistant HIV-1 in Europe and Australia
Lazzarin et al.
NEJM 2003;348:2186-2195.
ABSTRACT
| FULL TEXT
Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398
Pfister et al.
Antimicrob. Agents Chemother. 2003;47:130-137.
ABSTRACT
| FULL TEXT
Virologic Outcomes of Complex Drug Regimens for Human Immunodeficiency Virus
Carr et al.
JAMA 2002;288:2405-2406.
FULL TEXT
Emerging Resistance to Nonnucleoside Reverse Transcriptase Inhibitors: A Warning and a Challenge
Trachtenberg and Sande
JAMA 2002;288:239-241.
FULL TEXT
|
