Leonard B. Seeff, MD Hepatology Consultant, Retired

Transcription

1 Leonard B. Seeff, MD Hepatology Consultant, Retired

2 Subjects with Active Liver Disease Need Special Observation Leonard B. Seeff, MD Hepatology Consultant, Retired DILI Conference XIV March 2014 Predicting Serious Drug-Induced Liver Injury

3 Introduction Lacking a specific diagnostic test for drug-induced liver injury (dili), its presence continues to depend on identifying raised levels of the non-specific serum enzymes, ALT or Alk P, temporally related to receipt of a drug or herbal product without other identifiable cause for the abnormality The elevation is considered worth investigating if the ALT level is found to be 3x or 5x, or the Alk P 2x, the upper limit of normal (ULN) The manufacturer generally establishes the ULN although each laboratory may define its own level

4 Background: Upper Limits of Normal for ALT The ULN is set for each laboratory by screening a large local population believed to be healthy and then selecting as a reference number the mean value +2 standard deviations Commonly, 40 U/L has been used as the ALT ULN but is clearly not a valid measure of normality or health ALT values have been found to differ by age, gender, race; metabolic factors as BMI, glucose, cholesterol, triglycerides; and by recognized or unrecognized chronic hepatitis, eg., hepatitis C, fatty liver diseases

5 Background: Validity of ULN for ALT Thus, what is referred to as the ULN is not necessarily indicative of normal health In 2002, Prati et al reported that the real ULN for ALT was actually 30 U/L for males and 19 U/L for females, since which many other investigators worldwide have also found normal ALT levels to be far lower than 40 U/L and to clearly differ by gender. Indeed, liver disease progression has been reported even with high normal ALT levels, i.e U/L Prati D, et al, Updated definition of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:1-10

6 Problems Regarding the ULN for ALT Therefore, the baseline ULN of ALT against which a subsequent increase in ALT during treatment might signal impending dili remains somewhat problematic but is generally accepted as the ULN value set by the manufacturer or the laboratory There is a problem, however, when the baseline ALT level is clearly abnormal or when it is not known as is commonly the case in the routine clinical setting

7 Where May DILI Occur? Dili, although rare, occurs both in pre-marketing clinical trials and in general clinical practice In the former, it is customary to routinely screen study subjects for serum enzymes and other causes of liver injury and to exclude them from the trial if the ALT is raised and/or other causes for the liver injury are identified In clinical practice, when dili is suspected from receipt of approved drugs or herbals, baseline serum enzyme levels are commonly not known and other liver disease remain to be excluded

8 Evaluation and Causality Assessment In either situation, if there is suspicion of existing or impending dili, meticulous evaluation must be performed to determine the cause of the liver injury This involves the systematic assembly of historical, clinical, biochemical, serological, radiological and, occasionally, histological data regarding the injury Causality assessment for dili can then be performed using one of two methods: analysis by careful clinical judgment ( expert opinion ) or the use of RUCAM

9 A New Paradigm The advent of highly effective direct acting antiviral drugs for hepatitis C has ushered in a new era in which drug therapy is being administered deliberately to persons with existing liver disease who have already raised serum enzymes prior to starting treatment Antiviral drugs are being used also to treat patients with chronic hepatitis B and abnormal liver chemistries In addition, persons with any type of chronic liver disease (chronic hepatitis B and C, NASH, etc) may receive treatment for non liver-related reasons

10 Guidelines for Monitoring DILI The FDA has guidelines for monitoring patients in clinical trials for potential dili but they are restricted to study enrollees with normal baseline liver-related tests Guidelines have not been developed for monitoring individuals who enter trials with already existing liver test abnormalities Guidance for Industry: Drug-induced Liver Injury: Premarketing Clinical Evaluation. July 2009

11 Dilemma How does one establish possible dili based on increased ALT values during treatment when the affected persons already have raised levels even before starting drug therapy? Are evaluation and causality assessment for dili the same for patients with hepatitis C being treated with antiviral therapy as they are for patients with any chronic liver disease and raised serum enzymes (including hepatitis C) who are receiving non-antiviral drug treatment? Are RUCAM and Expert Opinion equally useful when baseline ALT values are abnormal?

12 Evaluating DILI when Baseline ALT Values are Abnormal Evaluating potential dili when baseline ALT values are abnormal differs somewhat between those being treated with direct acting antivirals (DAAs) for chronic hepatitis C and those with pre-existing chronic liver disease of any cause receiving non-antiviral drug therapy

13 Impact of Antiviral Therapy for Patients with Chronic Hepatitis C Patients with chronic hepatitis C listed for treatment begin with high viral titers and abnormal ALT values Most contemporary direct acting antiviral treatments last for 12 weeks and are highly effective, leading to complete loss of detectable virus and normalization of ALT within days to a couple of weeks Treatment then continues for the full course but ALT may rise again as antiviral therapy is completed due either to viral breakthrough (re-appearance of HCV RNA) or a new liver disease, including possible dili

14 Outcomes of Antiviral Therapy For Patients with Chronic Hepatitis C If the ALT returns to normal on treatment but then increases again during continued treatment, accompanied by reappearance of HCV RNA, the diagnosis is almost certainly viral breakthrough and not dili If, on the other hand, the HCV RNA remains undetectable but the ALT increases again, another liver disease, including dili, is likely and needs full evaluation to determine cause

15 Trigger to Consider Possible Dili in Persons with Hepatitis C Treated with Antiviral Drugs? Since treatment with DAAs almost invariably causes complete loss of HCV RNA and return of the ALT to normal levels, suspicion of possible impending dili as treatment continues should now be triggered by the ALT increased to 3x that of the new normalized baseline values, and not the original abnormal baseline ALT value

16 Causality Assessment for Dili In Hepatitis C Treatment With Antiviral Drugs Thereafter, evaluation for possible dili proceeds in routine fashion, namely exclusion of other known causes of liver disease if not already done; assessing possible implication of accompanying drugs or herbals, if relevant; continued monitoring of liver-related tests (ALT, AST, Alk P, TBil), discontinuing suspected responsible medication if concern for advancing liver disease, and assessment for evidence of improvement of liver disease (de-challenge)

17 What Causality Assessment Tool Should Be Used When Baseline ALT Levels Abnormal? RUCAM not designed to assess dili causality when the baseline ALT value is abnormal Some items needed in RUCAM scoring are unavailable in pre-marketing clinical trials - liver injury signature of new drug based on past experience - alcoholism and pregnancy excludes enrollment -re-challenge precluded in clinical trials Therefore, prefer Expert Opinion approach

18 Trigger to Consider Possible Dili in Persons with Chronic Liver Disease Treated with Non- Antiviral Medications? Treatment of persons with CLD and chronically increased ALT values with non-antiviral medications does not lower the levels regardless of their extent of abnormality However, what remains undefined is the level of subsequent increase in the ALT value and the comparator baseline ALT level that should constitute a warning of possible developing dili

19 Trigger to Consider Possible Dili in Persons with Chronic Liver Disease Treated with Non-Antiviral Medications The following values are proposed: Baseline ALT value: Because the definitive ULN is disputed, the baseline comparator should be the individual patient s own abnormal ALT level measured prior to and at start of drug treatment Treatment ALT eliciting concern: If baseline ALT <100 U/L, trigger should be a 3-fold increase in ALT If baseline ALT >100 U/L, trigger should be a 2-fold increase in ALT

20 Causality Assessment for DILI in Persons with Chronic Liver Disease Treated with Non-Antiviral Medications Thereafter, evaluation for possible dili proceeds in routine fashion, namely exclusion of other known causes of liver disease if not already done; assessing possible implication of accompanying drugs or herbals, if relevant; continued monitoring of liver-related tests (ALT, AST, Alk P, TBil), discontinuing suspected responsible medication if concern for advancing liver disease, and assessment for evidence of improvement of liver disease (de-challenge)

21 Summary The trigger for considering dili in persons with chronic hepatitis C treated with antiviral drugs that leads to undetectable HCV RNA and return to normal of the ALT is a subsequent increase in ALT 3x that of the nadir normalized ALT while antiviral treatment continues Additional information required is the level of detection of HCV RNA when the ALT normalizes and again when it increases by 3-fold Thereafter, routine causality assessment procedures are performed to support the diagnosis of dili

22 Summary, contd. The trigger for considering dili in persons with any cause of chronic liver disease and persistently abnormal ALT levels who are receiving treatment with non-antiviral drugs is a subsequent increase in the ALT level to at least 2 to 3x that of the individual s own baseline abnormal ALT value, depending upon whether it is < or >100 U/L Thereafter, routine causality assessment procedures are performed to support the diagnosis of dili

23 Conclusion Performing causality assessment for possible dili in persons who have raised ALT levels when treatment is initiated or who have known chronic liver disease does not diverge from the approach normally utilized in assessing causality among persons with normal ALT levels The only difference is in what constitutes the trigger for considering the possibility that dili might be developing and what baseline ALT value should be used