Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir.
OBJECTIVE
To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.


METHODS
Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.


METHODS
The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.


RESULTS
The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.


CONCLUSIONS
Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.
Sulkowski
Mark S
MS
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. msulkows@jhmi.edu
Mehta
Shruti H
SH
Chaisson
Richard E
RE
Thomas
David L
DL
Moore
Richard D
RD
D017088:AIDS-Related Opportunistic Infections / Q000276:immunology; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006505:Hepatitis / Q000276:immunology; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D061466:Lopinavir; D008297:Male; D019888:Nelfinavir / Q000627:therapeutic use; D011446:Prospective Studies; D011744:Pyrimidinones / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D019438:Ritonavir / Q000627:therapeutic use*; D019258:Saquinavir / Q000627:therapeutic use; D016896:Treatment Outcome
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir