Antiretroviral Drugs and Liver Injury

[Guest guest]

From AIDS

Antiretroviral Drugs and Liver Injury

Posted 01/09/2008

Soriano; Massimo Puoti; Pilar -Gasc¨®; Juergen K Rockstroh; Yves

Benhamou; Pablo Barreiro; Barbara McGovern

Introduction

Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity,

mortality and treatment discontinuation in HIV-infected patients.[1] Prevention

and management of ARLI have emerged as major issues among HIV-infected patients

in the era of HAART.[2] Virtually every licensed antiretroviral medication has

been associated with liver enzyme elevations, although certain drugs may cause

liver injury more frequently than others. In addition, certain comorbidities,

such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose

patients to ARLI.[3] Several major mechanisms of ARLI have been described,

including metabolic host-mediated injury, hypersensitivity reactions,

mitochondrial toxicity, and immune reconstitution phenomena. The management of

ARLI should be based on its clinical severity and underlying pathogenic

mechanism. Herein, we propose use of a universal standard for defining liver

injury to enable comparisons between future studies. Novel mechanisms for

hepatotoxicity are also discussed along with preventive measures to avoid the

onset of ARLI.

Definition of Antiretroviral Drug -related Liver Injury

ARLI is defined by elevations in liver enzymes in serum, with alanine

aminotransferase (ALT) characteristically greater than aspartate

aminotransferase (AST). To date, there has been broad variability in the

criteria used in clinical studies to categorize the severity of hepatotoxicity.

Some studies have utilized ALT parameters as minimal as two times the upper

limits of normal[4] while others have employed an absolute threshold (e.g.,> 100

IU/ml), regardless of baseline liver function tests.[5] The clinical relevance

of these elevations is uncertain.

More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading

scheme against the patient's baseline serum aminotransferase concentrations. For

example, in patients with a normal pretherapy ALT or AST, hepatic injury is

graded as moderate or severe based on a 5-fold or 10-fold increase in

aminotransferases, respectively.[6] In patients with abnormal liver enzymes

prior to therapy, a> 3.5-fold or a 5-fold increase in ALT or AST is considered

indicative of moderate or severe hepatotoxicity, respectively.[7]

Liver function test abnormalities require careful interpretation. On the one

hand, some drugs (e.g., nevirapine and less frequently efavirenz) increase

¦Ã-glutamyl transpeptidase serum levels. This laboratory result is often

misinterpreted as a marker of liver damage, when isolated elevation of this

enzyme actually reflects enzyme induction. Similarly, hyperbilirubinaemia alone

should not be equated with liver injury, since indirect hyperbilirubinaemia may

be related to medications, such as indinavir or atazanavir[8-10]; this risk is

increased in patients with underlying Gilbert's syndrome, a genetic disorder

(Figure 1). On the other hand, drug-induced liver injury that is associated with

an elevated direct bilirubin and clinical jaundice portends a poor clinical

outcome. A cholestatic profile should only be considered when there is an

associated increase in serum alkaline phosphatase as well as bilirubin.

Elevated aminotransferases also need to be interpreted within their clinical

context. For example, increased liver enzymes in a patient with chronic HBV

infection do not necessarily imply drug injury but may reflect HBV-related

hepatic flares, which often occur during the natural course of the disease.

Clinical Relevance

With the widespread use of HAART and the availability of new antiretroviral

medications, ARLI has gained prominent attention owing to its negative impact on

clinical outcomes. Drug-associated hepatotoxicity also creates an economic

burden on already strained medical budgets, since additional visits and hospital

admissions are often required for appropriate patient care and management.[1]

Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV

suppression.

The severity of ARLI may range from the absence of symptoms to liver

decompensation, and the outcome can range from spontaneous resolution to liver

failure and death.[11,12] In one study, severe hepatotoxicity with acute hepatic

necrosis was recognized in 2% of HIV-infected patients dying from liver disease.

Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART,

the most common grade 4 adverse events were liver related; this risk was

increased in patients with underlying chronic viral hepatitis.[13]

Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most

ALT elevations resolve spontaneously, as described for many other medications,

probably through a process called 'adaptation'.[14] However, in a minority,

drug-induced liver injury can be overt and have serious consequences. Therefore,

it is critically important for the clinician to understand risk factors

associated with poor outcomes and the pathogenic mechanisms of disease.

FULL TEXT:http://www.medscape.com/viewarticle/568415?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

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[Guest guest]

From AIDS

Antiretroviral Drugs and Liver Injury

Posted 01/09/2008

Soriano; Massimo Puoti; Pilar -Gasc¨®; Juergen K Rockstroh; Yves

Benhamou; Pablo Barreiro; Barbara McGovern

Introduction

Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity,

mortality and treatment discontinuation in HIV-infected patients.[1] Prevention

and management of ARLI have emerged as major issues among HIV-infected patients

in the era of HAART.[2] Virtually every licensed antiretroviral medication has

been associated with liver enzyme elevations, although certain drugs may cause

liver injury more frequently than others. In addition, certain comorbidities,

such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose

patients to ARLI.[3] Several major mechanisms of ARLI have been described,

including metabolic host-mediated injury, hypersensitivity reactions,

mitochondrial toxicity, and immune reconstitution phenomena. The management of

ARLI should be based on its clinical severity and underlying pathogenic

mechanism. Herein, we propose use of a universal standard for defining liver

injury to enable comparisons between future studies. Novel mechanisms for

hepatotoxicity are also discussed along with preventive measures to avoid the

onset of ARLI.

Definition of Antiretroviral Drug -related Liver Injury

ARLI is defined by elevations in liver enzymes in serum, with alanine

aminotransferase (ALT) characteristically greater than aspartate

aminotransferase (AST). To date, there has been broad variability in the

criteria used in clinical studies to categorize the severity of hepatotoxicity.

Some studies have utilized ALT parameters as minimal as two times the upper

limits of normal[4] while others have employed an absolute threshold (e.g.,> 100

IU/ml), regardless of baseline liver function tests.[5] The clinical relevance

of these elevations is uncertain.

More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading

scheme against the patient's baseline serum aminotransferase concentrations. For

example, in patients with a normal pretherapy ALT or AST, hepatic injury is

graded as moderate or severe based on a 5-fold or 10-fold increase in

aminotransferases, respectively.[6] In patients with abnormal liver enzymes

prior to therapy, a> 3.5-fold or a 5-fold increase in ALT or AST is considered

indicative of moderate or severe hepatotoxicity, respectively.[7]

Liver function test abnormalities require careful interpretation. On the one

hand, some drugs (e.g., nevirapine and less frequently efavirenz) increase

¦Ã-glutamyl transpeptidase serum levels. This laboratory result is often

misinterpreted as a marker of liver damage, when isolated elevation of this

enzyme actually reflects enzyme induction. Similarly, hyperbilirubinaemia alone

should not be equated with liver injury, since indirect hyperbilirubinaemia may

be related to medications, such as indinavir or atazanavir[8-10]; this risk is

increased in patients with underlying Gilbert's syndrome, a genetic disorder

(Figure 1). On the other hand, drug-induced liver injury that is associated with

an elevated direct bilirubin and clinical jaundice portends a poor clinical

outcome. A cholestatic profile should only be considered when there is an

associated increase in serum alkaline phosphatase as well as bilirubin.

Elevated aminotransferases also need to be interpreted within their clinical

context. For example, increased liver enzymes in a patient with chronic HBV

infection do not necessarily imply drug injury but may reflect HBV-related

hepatic flares, which often occur during the natural course of the disease.

Clinical Relevance

With the widespread use of HAART and the availability of new antiretroviral

medications, ARLI has gained prominent attention owing to its negative impact on

clinical outcomes. Drug-associated hepatotoxicity also creates an economic

burden on already strained medical budgets, since additional visits and hospital

admissions are often required for appropriate patient care and management.[1]

Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV

suppression.

The severity of ARLI may range from the absence of symptoms to liver

decompensation, and the outcome can range from spontaneous resolution to liver

failure and death.[11,12] In one study, severe hepatotoxicity with acute hepatic

necrosis was recognized in 2% of HIV-infected patients dying from liver disease.

Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART,

the most common grade 4 adverse events were liver related; this risk was

increased in patients with underlying chronic viral hepatitis.[13]

Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most

ALT elevations resolve spontaneously, as described for many other medications,

probably through a process called 'adaptation'.[14] However, in a minority,

drug-induced liver injury can be overt and have serious consequences. Therefore,

it is critically important for the clinician to understand risk factors

associated with poor outcomes and the pathogenic mechanisms of disease.

FULL TEXT:http://www.medscape.com/viewarticle/568415?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008

[Guest guest]

From AIDS

Antiretroviral Drugs and Liver Injury

Posted 01/09/2008

Soriano; Massimo Puoti; Pilar -Gasc¨®; Juergen K Rockstroh; Yves

Benhamou; Pablo Barreiro; Barbara McGovern

Introduction

Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity,

mortality and treatment discontinuation in HIV-infected patients.[1] Prevention

and management of ARLI have emerged as major issues among HIV-infected patients

in the era of HAART.[2] Virtually every licensed antiretroviral medication has

been associated with liver enzyme elevations, although certain drugs may cause

liver injury more frequently than others. In addition, certain comorbidities,

such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose

patients to ARLI.[3] Several major mechanisms of ARLI have been described,

including metabolic host-mediated injury, hypersensitivity reactions,

mitochondrial toxicity, and immune reconstitution phenomena. The management of

ARLI should be based on its clinical severity and underlying pathogenic

mechanism. Herein, we propose use of a universal standard for defining liver

injury to enable comparisons between future studies. Novel mechanisms for

hepatotoxicity are also discussed along with preventive measures to avoid the

onset of ARLI.

Definition of Antiretroviral Drug -related Liver Injury

ARLI is defined by elevations in liver enzymes in serum, with alanine

aminotransferase (ALT) characteristically greater than aspartate

aminotransferase (AST). To date, there has been broad variability in the

criteria used in clinical studies to categorize the severity of hepatotoxicity.

Some studies have utilized ALT parameters as minimal as two times the upper

limits of normal[4] while others have employed an absolute threshold (e.g.,> 100

IU/ml), regardless of baseline liver function tests.[5] The clinical relevance

of these elevations is uncertain.

More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading

scheme against the patient's baseline serum aminotransferase concentrations. For

example, in patients with a normal pretherapy ALT or AST, hepatic injury is

graded as moderate or severe based on a 5-fold or 10-fold increase in

aminotransferases, respectively.[6] In patients with abnormal liver enzymes

prior to therapy, a> 3.5-fold or a 5-fold increase in ALT or AST is considered

indicative of moderate or severe hepatotoxicity, respectively.[7]

Liver function test abnormalities require careful interpretation. On the one

hand, some drugs (e.g., nevirapine and less frequently efavirenz) increase

¦Ã-glutamyl transpeptidase serum levels. This laboratory result is often

misinterpreted as a marker of liver damage, when isolated elevation of this

enzyme actually reflects enzyme induction. Similarly, hyperbilirubinaemia alone

should not be equated with liver injury, since indirect hyperbilirubinaemia may

be related to medications, such as indinavir or atazanavir[8-10]; this risk is

increased in patients with underlying Gilbert's syndrome, a genetic disorder

(Figure 1). On the other hand, drug-induced liver injury that is associated with

an elevated direct bilirubin and clinical jaundice portends a poor clinical

outcome. A cholestatic profile should only be considered when there is an

associated increase in serum alkaline phosphatase as well as bilirubin.

Elevated aminotransferases also need to be interpreted within their clinical

context. For example, increased liver enzymes in a patient with chronic HBV

infection do not necessarily imply drug injury but may reflect HBV-related

hepatic flares, which often occur during the natural course of the disease.

Clinical Relevance

With the widespread use of HAART and the availability of new antiretroviral

medications, ARLI has gained prominent attention owing to its negative impact on

clinical outcomes. Drug-associated hepatotoxicity also creates an economic

burden on already strained medical budgets, since additional visits and hospital

admissions are often required for appropriate patient care and management.[1]

Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV

suppression.

The severity of ARLI may range from the absence of symptoms to liver

decompensation, and the outcome can range from spontaneous resolution to liver

failure and death.[11,12] In one study, severe hepatotoxicity with acute hepatic

necrosis was recognized in 2% of HIV-infected patients dying from liver disease.

Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART,

the most common grade 4 adverse events were liver related; this risk was

increased in patients with underlying chronic viral hepatitis.[13]

Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most

ALT elevations resolve spontaneously, as described for many other medications,

probably through a process called 'adaptation'.[14] However, in a minority,

drug-induced liver injury can be overt and have serious consequences. Therefore,

it is critically important for the clinician to understand risk factors

associated with poor outcomes and the pathogenic mechanisms of disease.

FULL TEXT:http://www.medscape.com/viewarticle/568415?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008

[Guest guest]

From AIDS

Antiretroviral Drugs and Liver Injury

Posted 01/09/2008

Soriano; Massimo Puoti; Pilar -Gasc¨®; Juergen K Rockstroh; Yves

Benhamou; Pablo Barreiro; Barbara McGovern

Introduction

Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity,

mortality and treatment discontinuation in HIV-infected patients.[1] Prevention

and management of ARLI have emerged as major issues among HIV-infected patients

in the era of HAART.[2] Virtually every licensed antiretroviral medication has

been associated with liver enzyme elevations, although certain drugs may cause

liver injury more frequently than others. In addition, certain comorbidities,

such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose

patients to ARLI.[3] Several major mechanisms of ARLI have been described,

including metabolic host-mediated injury, hypersensitivity reactions,

mitochondrial toxicity, and immune reconstitution phenomena. The management of

ARLI should be based on its clinical severity and underlying pathogenic

mechanism. Herein, we propose use of a universal standard for defining liver

injury to enable comparisons between future studies. Novel mechanisms for

hepatotoxicity are also discussed along with preventive measures to avoid the

onset of ARLI.

Definition of Antiretroviral Drug -related Liver Injury

ARLI is defined by elevations in liver enzymes in serum, with alanine

aminotransferase (ALT) characteristically greater than aspartate

aminotransferase (AST). To date, there has been broad variability in the

criteria used in clinical studies to categorize the severity of hepatotoxicity.

Some studies have utilized ALT parameters as minimal as two times the upper

limits of normal[4] while others have employed an absolute threshold (e.g.,> 100

IU/ml), regardless of baseline liver function tests.[5] The clinical relevance

of these elevations is uncertain.

More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading

scheme against the patient's baseline serum aminotransferase concentrations. For

example, in patients with a normal pretherapy ALT or AST, hepatic injury is

graded as moderate or severe based on a 5-fold or 10-fold increase in

aminotransferases, respectively.[6] In patients with abnormal liver enzymes

prior to therapy, a> 3.5-fold or a 5-fold increase in ALT or AST is considered

indicative of moderate or severe hepatotoxicity, respectively.[7]

Liver function test abnormalities require careful interpretation. On the one

hand, some drugs (e.g., nevirapine and less frequently efavirenz) increase

¦Ã-glutamyl transpeptidase serum levels. This laboratory result is often

misinterpreted as a marker of liver damage, when isolated elevation of this

enzyme actually reflects enzyme induction. Similarly, hyperbilirubinaemia alone

should not be equated with liver injury, since indirect hyperbilirubinaemia may

be related to medications, such as indinavir or atazanavir[8-10]; this risk is

increased in patients with underlying Gilbert's syndrome, a genetic disorder

(Figure 1). On the other hand, drug-induced liver injury that is associated with

an elevated direct bilirubin and clinical jaundice portends a poor clinical

outcome. A cholestatic profile should only be considered when there is an

associated increase in serum alkaline phosphatase as well as bilirubin.

Elevated aminotransferases also need to be interpreted within their clinical

context. For example, increased liver enzymes in a patient with chronic HBV

infection do not necessarily imply drug injury but may reflect HBV-related

hepatic flares, which often occur during the natural course of the disease.

Clinical Relevance

With the widespread use of HAART and the availability of new antiretroviral

medications, ARLI has gained prominent attention owing to its negative impact on

clinical outcomes. Drug-associated hepatotoxicity also creates an economic

burden on already strained medical budgets, since additional visits and hospital

admissions are often required for appropriate patient care and management.[1]

Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV

suppression.

The severity of ARLI may range from the absence of symptoms to liver

decompensation, and the outcome can range from spontaneous resolution to liver

failure and death.[11,12] In one study, severe hepatotoxicity with acute hepatic

necrosis was recognized in 2% of HIV-infected patients dying from liver disease.

Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART,

the most common grade 4 adverse events were liver related; this risk was

increased in patients with underlying chronic viral hepatitis.[13]

Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most

ALT elevations resolve spontaneously, as described for many other medications,

probably through a process called 'adaptation'.[14] However, in a minority,

drug-induced liver injury can be overt and have serious consequences. Therefore,

it is critically important for the clinician to understand risk factors

associated with poor outcomes and the pathogenic mechanisms of disease.

FULL TEXT:http://www.medscape.com/viewarticle/568415?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008