Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial.
BACKGROUND
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.


METHODS
Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997.


METHODS
Thirty-three US HIV treatment centers.


METHODS
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 10(9)/L were randomized.


METHODS
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.


METHODS
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< or =.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.
Kahn
J
J
Positive Health Program University of California San Francisco, San Francisco General Hospital, 94110, USA. jkahn@php.ucsf.edu
Lagakos
S
S
Wulfsohn
M
M
Cherng
D
D
Miller
M
M
Cherrington
J
J
Hardy
D
D
Beall
G
G
Cooper
R
R
Murphy
R
R
Basgoz
N
N
Ng
E
E
Deeks
S
S
Winslow
D
D
Toole
J J
JJ
Coakley
D
D
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D019562:Viral Load; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D000225:Adenine; C106812:adefovir dipivoxil