 |
|
Efficacy and Safety of Adefovir Dipivoxil With Antiretroviral Therapy
A Randomized Controlled Trial
James Kahn, MD;
Stephen Lagakos, PhD;
Michael Wulfsohn, MD, PhD;
Deborah Cherng, MS;
Michael Miller, PhD;
Julie Cherrington, PhD;
David Hardy, MD;
Gildon Beall, MD;
Richard Cooper, MD;
Robert Murphy, MD;
Nesli Basgoz, MD;
Edmund Ng, PhD;
Steven Deeks, MD;
Dean Winslow, MD;
John J. Toole, MD, PhD;
Dion Coakley, PharmD;
for the GS-408 Study Team
JAMA. 1999;282:2305-2312.
Context Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration.
Objective To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy.
Design Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997.
Setting Thirty-three US HIV treatment centers.
Participants Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 109/L were randomized.
Intervention Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study.
Main Outcome Measures Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir.
Results Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti–HIV effects with adefovir (P .01 vs placebo group).
Conclusions This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.
Author Affiliations: Positive Health Program University of California San Francisco, San Francisco General Hospital, San Francisco (Drs Kahn and Deeks); Gilead Sciences Inc, Foster City (Drs Wulfsohn, Miller, Cherrington, Winslow, Toole, and Coakley); Pacific Oak Research, Beverly Hills (Dr Hardy); Harbor University of California Los Angeles Medical Center, Torrance (Dr Beall); Kraus Medical Partners, Los Angeles (Dr Cooper), Calif; School of Public Health, Harvard University (Drs Lagakos and Ng and Ms Cherng), and Massachusetts General Hospital (Dr Basgoz), Boston, Mass; and Northwestern University Medical School, Chicago, Ill (Dr Murphy).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
Adefovir for the Treatment of HIV Infection: If Not Now, When?
John W. Mellors
JAMA. 1999;282(24):2355-2356.
EXTRACT
| FULL TEXT
December 22/29, 1999
JAMA. 1999;282(24):2419-2420.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Renal Function in Tenofovir-Exposed and Tenofovir-Unexposed Patients Receiving Highly Active Antiretroviral Therapy in the HIV Outpatient Study
Young et al.
J Int Assoc Physicians AIDS Care (Chic Ill) 2007;6:178-187.
ABSTRACT
Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analogue Drug Cytotoxicity and Tissue Distribution
Takenaka et al.
Cancer Res. 2007;67:6965-6972.
ABSTRACT
| FULL TEXT
Progress in the treatment of chronic hepatitis B: long-term experience with adefovir dipivoxil
Delaney
J Antimicrob Chemother 2007;59:827-832.
ABSTRACT
| FULL TEXT
Functional Involvement of Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in the Renal Elimination of the Antiviral Drugs Adefovir and Tenofovir
Imaoka et al.
Mol. Pharmacol. 2007;71:619-627.
ABSTRACT
| FULL TEXT
Intracellular Metabolism and In Vitro Activity of Tenofovir against Hepatitis B Virus.
Delaney et al.
Antimicrob. Agents Chemother. 2006;50:2471-2477.
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
Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques
Van Rompay et al.
Antimicrob. Agents Chemother. 2004;48:1469-1487.
ABSTRACT
| FULL TEXT
Molecular Mechanisms of Tenofovir Resistance Conferred by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing a Diserine Insertion after Residue 69 and Multiple Thymidine Analog-Associated Mutations
White et al.
Antimicrob. Agents Chemother. 2004;48:992-1003.
ABSTRACT
| FULL TEXT
The renal tolerance of low-dose adefovir dipivoxil by lamivudine-resistant individuals co-infected with hepatitis B and HIV
Hannon et al.
Nephrol Dial Transplant 2004;19:386-390.
ABSTRACT
| FULL TEXT
Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections
De Clercq
Clin. Microbiol. Rev. 2003;16:569-596.
ABSTRACT
| FULL TEXT
Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial
Squires et al.
ANN INTERN MED 2003;139:313-320.
ABSTRACT
| FULL TEXT
Role of Baseline Human Immunodeficiency Virus Genotype as a Predictor of Viral Response to Tenofovir in Heavily Pretreated Patients
Barrios et al.
J. Clin. Microbiol. 2003;41:4421-4423.
ABSTRACT
| FULL TEXT
Pivalate-Generating Prodrugs and Carnitine Homeostasis in Man
Brass
Pharmacol. Rev. 2002;54:589-598.
ABSTRACT
| FULL TEXT
Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus
Ono-Nita et al.
Antimicrob. Agents Chemother. 2002;46:2602-2605.
ABSTRACT
| FULL TEXT
Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure: A Randomized Trial
Hammer et al.
JAMA 2002;288:169-180.
ABSTRACT
| FULL TEXT
Human Immunodeficiency Virus (HIV) Type 1 Reverse Transcriptase Resistance Mutations in Hepatitis B Virus (HBV)-HIV-Coinfected Patients Treated for HBV Chronic Infection Once Daily with 10 Milligrams of Adefovir Dipivoxil Combined with Lamivudine
Delaugerre et al.
Antimicrob. Agents Chemother. 2002;46:1586-1588.
ABSTRACT
| FULL TEXT
What Role for Adefovir?
AIDS Clin Care 2001;2001:4-4.
FULL TEXT
The organic anion transporter family: from physiology to ontogeny and the clinic
Sweet et al.
Am. J. Physiol. Renal Physiol. 2001;281:F197-F205.
ABSTRACT
| FULL TEXT
Cross-Resistance Testing of Antihepadnaviral Compounds Using Novel Recombinant Baculoviruses Which Encode Drug-Resistant Strains of Hepatitis B Virus
Delaney et al.
Antimicrob. Agents Chemother. 2001;45:1705-1713.
ABSTRACT
| FULL TEXT
Mitochondrial toxicity and HIV therapy
White
Sex. Transm. Infect. 2001;77:158-173.
ABSTRACT
| FULL TEXT
Effectiveness of Remune
Glidden et al.
CVI 2001;8:468-469.
FULL TEXT
Breaking the Camel's Back: Multicenter Clinical Trials and Local Institutional Review Boards
Burman et al.
ANN INTERN MED 2001;134:152-157.
ABSTRACT
| FULL TEXT
Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1
Mulato et al.
J. Pharmacol. Exp. Ther. 2000;295:10-15.
ABSTRACT
| FULL TEXT
Chronic Hepatitis B Virus Infection: Treatment Strategies for the Next Millennium
Malik and Lee
ANN INTERN MED 2000;132:723-731.
ABSTRACT
| FULL TEXT
Adefovir Disappoints
AIDS Clin Care 2000;2000:6-6.
FULL TEXT
Adefovir for the Treatment of HIV Infection: If Not Now, When?
Mellors
JAMA 1999;282:2355-2356.
FULL TEXT
|
