Maintenance of indinavir by dose adjustment in HIV-1-infected patients with indinavir-related toxicity.
OBJECTIVE
Treatment with indinavir/ritonavir (IDV/RTV) is very effective but hampered by frequent development of IDV-associated adverse events (mainly nephrotoxicity and skin changes). We tested whether dose reduction of IDV guided by therapeutic drug monitoring resulted in improved tolerability without compromising antiviral efficacy.


METHODS
HIV-infected patients with any IDV/RTV regimen who suffer from IDV-related adverse events were included. Viral load had to be adequately controlled for at least 2 months prior to inclusion. Dose reduction from 800 mg to 600 or 400 mg IDV b.i.d. followed a specified protocol. IDV-related toxicity and IDV plasma concentrations were monitored for 24 weeks. IDV concentrations were quantified with a validated high performance liquid chromatography method.


RESULTS
Twenty patients were included. Reasons for inclusion were: skin abnormalities 11, nephrotoxicity five, metabolic disturbances three, and hypertension one. IDV dose could be lowered to 400 mg b.i.d. in 13, to 600 mg b.i.d. in two patients. Five patients discontinued the treatment. Overall tolerability improved with respect to incidence and severity of adverse events. Median trough concentrations decreased from 1.02 mg/l (range 0.08-7.1) at baseline to 0.48 mg/l (0.11-1.4) after 24 weeks (p = 0.03) and remained above the critical threshold of 0.1 mg/l at any time after dose reduction. There was no change of CD4 cell counts or viral suppression. There were no significant changes in other laboratory parameters (creatinine, bilirubin, triglycerides, cholesterol, blood count, and urinalysis).


CONCLUSIONS
Dose reduction of IDV improved tolerability of IDV-containing highly active antiretroviral treatment (HAART). Sufficient IDV trough concentrations were maintained in all patients as was virologic control.
Wasmuth
J-C
JC
Department of Medicine I, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany. j-c.wasmuth@uni-bonn.de
Lambertz
I
I
Voigt
E
E
Vogel
M
M
Hoffmann
C
C
Burger
D
D
Rockstroh
J K
JK
D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005858:Germany; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D019469:Indinavir / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced; D008875:Middle Aged; D011446:Prospective Studies; D019438:Ritonavir / Q000008:administration & dosage*; D012720:Severity of Illness Index; D012871:Skin Diseases / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
D017320:HIV Protease Inhibitors; D019469:Indinavir; D019438:Ritonavir
HIV Med. 2002 Oct;3(4):277-82
12444946
AIDS. 1999 Mar 11;13(4):473-8
10197375
Antivir Ther. 2005;10(8):911-6
16430196
J Chromatogr B Biomed Sci Appl. 1999 Apr 30;727(1-2):139-49
10360433
AIDS. 1998 Dec 24;12(18):F249-54
9875572
J Acquir Immune Defic Syndr. 2001 Sep 1;28(1):9-13
11579271
AIDS. 2003 Jan 24;17(2):209-14
12545081
AIDS. 2000 Jun 16;14(9):1181-5
10894282
Antivir Ther. 2003 Aug;8(4):309-14
14518700
Antivir Ther. 2003 Dec;8(6):603-9
14760894
Clin Pharmacol Ther. 2002 Jan;71(1):57-67
11823758
Antivir Ther. 2004 Apr;9(2):213-20
15134183
J Antimicrob Chemother. 2003 May;51(5):1231-8
12668574
HIV Med. 2005 Jan;6(1):1-6
15670245
Clin Infect Dis. 2000 Jun;30 Suppl 2:S151-9
10860900
J Antimicrob Chemother. 2006 Jun;57(6):1161-7
16595641
Antivir Ther. 2005;10(2):301-7
15865224
Clin Pharmacokinet. 1998 Oct;35(4):275-91
9812178
Curr Opin Infect Dis. 2002 Feb;15(1):17-22
11964901
Ann Pharmacother. 2001 Nov;35(11):1391-5
11724090
Clin Nephrol. 2000 Oct;54(4):261-70
11076101
J Infect Dis. 2003 Sep 1;188(5):635-42
12934178