This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (411)  • Contact me when this article is cited  Related Content  • Related letter  • Related article  • Similar articles in JAMA  Topic Collections  • HIV/AIDS  • Viral Infections  • Liver/ Biliary Tract/ Pancreatic Diseases  • Alert me on articles by topic

Mark S. Sulkowski, MD; David L. Thomas, MD, MPH; Richard E. Chaisson, MD; Richard D. Moore, MD

JAMA. 2000;283:74-80.

Context  Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus.

Objectives  To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.

Design  Prospective cohort study.

Setting  University-based urban HIV clinic.

Patients  A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively.

Main Outcome Measure  Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy.

Results  Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9%-44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir (6.8%; 95% CI, 3.0%-13.1%). Although chronic viral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10⁹/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.

Conclusions  Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus.

Author Affiliations: Divisions of Infectious Diseases (Drs Sulkowski, Thomas, and Chaisson) and General Internal Medicine (Dr Moore), Departments of Medicine (Drs Sulkowski, Thomas, Chaisson, and Moore) and Epidemiology (Drs Thomas, Chaisson, and Moore), Johns Hopkins University Schools of Medicine (Drs Sulkowski, Thomas, Chaisson, and Moore) and Hygiene and Public Health (Drs Thomas, Chaisson, and Moore), Baltimore, Md.

RELATED LETTER

Elevated Liver Enzymes Following Initiation of Antiretroviral Therapy
Maria Velasco, Carlos Guijarro, Mark S. Sulkowski, David L. Thomas, Richard E. Chaisson, and Richard D. Moore
JAMA. 2000;283(19):2526-2527.
EXTRACT | FULL TEXT  

RELATED ARTICLE

January 5, 2000
JAMA. 2000;283(1):137-138.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: effect of hepatitis virus co-infection and pre-existing fibrosis
Macias et al.
J Antimicrob Chemother 2009;63:178-183.
ABSTRACT | FULL TEXT  

Cellular Accumulation of Cholyl-Glycylamido-Fluorescein in Sandwich-Cultured Rat Hepatocytes: Kinetic Characterization, Transport Mechanisms, and Effect of Human Immunodeficiency Virus Protease Inhibitors
Ye et al.
Drug Metab. Dispos. 2008;36:1315-1321.
ABSTRACT | FULL TEXT  

Gastrointestinal complications of HIV infection: changing priorities in the HAART era
Wilcox and Saag
Gut 2008;57:861-870.
ABSTRACT | FULL TEXT  

Hydroxyurea induced acute elevations in liver function tests
Hallam and Kolesar
J Oncol Pharm Pract 2008;14:61-63.
ABSTRACT  

Prolongation and quality of life for HIV-infected adults treated with highly active antiretroviral therapy (HAART): a balancing act
Burgoyne and Tan
J Antimicrob Chemother 2008;61:469-473.
ABSTRACT | FULL TEXT  

Influence of Alternative Thresholds for Initiating HIV Treatment on Quality-Adjusted Life Expectancy: A Decision Model
Braithwaite et al.
ANN INTERN MED 2008;148:178-185.
ABSTRACT | FULL TEXT  

Amprenavir and ritonavir plasma concentrations in HIV-infected patients treated with fosamprenavir/ritonavir with various degrees of liver impairment
Seminari et al.
J Antimicrob Chemother 2007;60:831-836.
ABSTRACT | FULL TEXT  

Hepatotoxicity During Nevirapine-Based Fixed-Dose Combination Antiretroviral Therapy in Kampala, Uganda
Hahn et al.
J Int Assoc Physicians AIDS Care (Chic Ill) 2007;6:83-86.
ABSTRACT  

Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors
Rivero et al.
J Antimicrob Chemother 2007;59:342-346.
ABSTRACT | FULL TEXT  

Low-level liver enzyme elevations during HAART are not associated with liver fibrosis progression among HIV/HCV-coinfected patients
Vergara et al.
J Antimicrob Chemother 2007;59:87-91.
ABSTRACT | FULL TEXT  

Ritonavir, Saquinavir, and Efavirenz, but Not Nevirapine, Inhibit Bile Acid Transport in Human and Rat Hepatocytes
McRae et al.
J. Pharmacol. Exp. Ther. 2006;318:1068-1075.
ABSTRACT | FULL TEXT  

Liver-Related Deaths in Persons Infected With the Human Immunodeficiency Virus: The D:A:D Study.
The Data Collection on Adverse Events of Anti-HIV
Arch Intern Med 2006;166:1632-1641.
ABSTRACT | FULL TEXT  

Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C
Mira et al.
J Antimicrob Chemother 2006;58:140-146.
ABSTRACT | FULL TEXT  

Treatment of Hepatitis C in HIV-Coinfected Patients
Hughes and Shafran
The Annals of Pharmacotherapy 2006;40:479-489.
ABSTRACT | FULL TEXT  

Management of HIV Infection in Persons Co-infected With Hepatitis
Boston and Slish
Journal of Pharmacy Practice 2005;18:295-309.
ABSTRACT  

Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients
Canta et al.
J Antimicrob Chemother 2005;55:280-281.
FULL TEXT  

Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected Patients: A Randomized Controlled Trial
Carrat et al.
JAMA 2004;292:2839-2848.
ABSTRACT | FULL TEXT  

Impact of highly active antiretroviral therapy on incidence and management of human immunodeficiency virus-related opportunistic infections
Hung and Chang
J Antimicrob Chemother 2004;54:849-853.
ABSTRACT | FULL TEXT  

HIV Infection, Hepatitis C Infection, and HAART: Hard Clinical Choices
Kottilil et al.
JAMA 2004;292:243-250.
ABSTRACT | FULL TEXT  

Interaction between HIV-1 and HCV infections: towards a new entity?
Winnock et al.
J Antimicrob Chemother 2004;53:936-946.
ABSTRACT | FULL TEXT  

Adverse effects of antiretroviral therapy for HIV infection
Montessori et al.
CMAJ 2004;170:229-238.
ABSTRACT | FULL TEXT  

Long-term virological outcome and resistance mutations at virological rebound in HIV-infected adults on protease inhibitor-sparing highly active antiretroviral therapy
de la Rosa et al.
J Antimicrob Chemother 2004;53:95-101.
ABSTRACT | FULL TEXT  

Clinical Vignette in Antiretroviral Therapy: Jaundice
Zell
J Int Assoc Physicians AIDS Care (Chic Ill) 2003;2:133-139.
 

Overcoming the False Dichotomy of Curative vs Palliative Care for Late-Stage HIV/AIDS: "Let Me Live the Way I Want to Live, Until I Can't"
Selwyn and Forstein
JAMA 2003;290:806-814.
ABSTRACT | FULL TEXT  

Key Clinical, Ethical, and Policy Issues in the Evaluation of the Safety and Effectiveness of Solid Organ Transplantation in HIV-Infected Patients
Roland et al.
Arch Intern Med 2003;163:1773-1778.
FULL TEXT  

Chronic HCV Infection in HIV-Positive Patients: A New Challenge
Fuster and Clotet
J Int Assoc Physicians AIDS Care (Chic Ill) 2003;2:56-58.
 

Hepatitis C in the HIV-Infected Person
Sulkowski and Thomas
ANN INTERN MED 2003;138:197-207.
ABSTRACT | FULL TEXT  

HIV viral suppression in the era of antiretroviral therapy
Thaker and Snow
Postgrad. Med. J. 2003;79:36-42.
ABSTRACT | FULL TEXT  

Treatment for Hepatitis C Virus in Human Immunodeficiency Virus-Infected Patients: Clinical Benefits and Cost-effectiveness
Kuehne et al.
Arch Intern Med 2002;162:2545-2556.
ABSTRACT | FULL TEXT  

Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection
Abrescia et al.
J Antimicrob Chemother 2002;50:763-765.
FULL TEXT  

Coinfection With Hepatitis Viruses and Outcome of Initial Antiretroviral Regimens in Previously Naive HIV-Infected Subjects
De Luca et al.
Arch Intern Med 2002;162:2125-2132.
ABSTRACT | FULL TEXT  

Hepatitis C and HIV-1 coinfection
Mohsen et al.
Gut 2002;51:601-608.
ABSTRACT | FULL TEXT  

Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents: The Panel on Clinical Practices for Treatment of HIV
Dybul et al.
ANN INTERN MED 2002;137:381-433.
ABSTRACT | FULL TEXT  

Guidelines for Preventing Opportunistic Infections among HIV-Infected Persons--2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America
Masur et al.
ANN INTERN MED 2002;137:435-478.
ABSTRACT | FULL TEXT  

Hepatitis C and Progression of HIV Disease
Sulkowski et al.
JAMA 2002;288:199-206.
ABSTRACT | FULL TEXT  

Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel
Yeni et al.
JAMA 2002;288:222-235.
ABSTRACT | FULL TEXT  

Does Hepatitis C Virus Infection Increase the Risk of HIV Disease Progression?
Rossi et al.
JAMA 2002;288:241-243.
FULL TEXT  

Reciprocal Interaction of Human Immunodeficiency Virus and Hepatitis C Virus Infections
Nelson and Thomas
CVI 2001;8:867-870.
FULL TEXT  

Hepatitis C virus RNA dynamics during antiretroviral therapy
Bruno et al.
Blood 2001;97:3318-3319.
FULL TEXT  

Hepatitis C in Patients With Human Immunodeficiency Virus Infection: Diagnosis, Natural History, Meta-analysis of Sexual and Vertical Transmission, and Therapeutic Issues
Bonacini and Puoti
Arch Intern Med 2000;160:3365-3373.
ABSTRACT | FULL TEXT  

Elevated Liver Enzymes Following Initiation of Antiretroviral Therapy
Velasco et al.
JAMA 2000;283:2526-2527.
FULL TEXT  

Hepatotoxicity from Antiretroviral Drugs
AIDS Clin Care 2000;2000:5-5.
FULL TEXT  

Liver Damage from Antiretroviral Medications
JWatch General 2000;2000:3-3.
FULL TEXT