Can rechallenge be done safely after mild or moderate drug‐induced liver injury?
Authors: John R. Senior
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Drug‐induced liver injury (DILI) in human subjects participating in clinical trials is uncommon1 or rare, the more serious the rarer. New drugs in development are first tested in animals to find compounds that predictably cause hepatocellular chemical injury, but the great variability of human responses2 accounting for most of the rare serious DILI must be investigated by clinical trials in subjects or patients as much as possible such as those intended to be treated after the drug is approved. If hepatocellular injury, detected by rise in serum alanine aminotransferase (ALT) activity is found in subjects participating in a clinical trial, study sponsors may stop test drug3 administration if a serum ALT activity is greater than 5 times the upper limit of the normal range (×ULN) or if >3×ULN along with >2×ULN total bilirubin (TBL) concentration. If no cause other than the experimental drug is found, the finding probably may be considered as drug induced, termed4 "Hy's Law," reflecting the lifelong observation of the late Hyman Zimmerman that drug‐induced hepatocellular jaundice is a potentially life‐threatening event. Because resuming administration of the causative drug may lead to rapid and worse injury, it has been widely believed that it is too dangerous to rechallenge by resuming drug administration.5 This approach has reduced U.S. Food and Drug Administration (FDA) approvals8 of new drugs that subsequently had to be withdrawn from the market. But has this practice gone too far, been too conservative,9 led to discarding possibly useful new drugs unnecessarily? The vast majority of drug‐induced ALT elevations are transient and reversible even if drug administration is continued, because hepatocytes are remarkably able to adapt and develop tolerance to new chemicals. However, data on negative rechallenge are not usually gathered. Focus only on positive rechallenge responses may skew assessments toward dangers and may be overconservative. There is no question that positive rechallenge effects must be very promptly evaluated to be sure that worsening does not occur, with development of whole liver functional impairment, for which drug administration must be stopped immediately. Liver injury may be detected in several ways, such as by: (1) abnormalities found on routine laboratory tests; 2) observations noticed by the investigator; or 3) symptoms reported by the patient. It is not feasible to measure ALT daily, or even weekly, for detecting injury to hepatocytes as a screening or routine test in hundreds or thousands of subjects. However, reporting of symptoms, such as fatigue, anorexia, nausea, vomiting, or jaundice, could be done daily at minimal cost and should be investigated at once. Trial subjects and investigators should be educated to be alert for them, and to inform the site immediately, for confirming whether a problem exists and for testing to determine the rapidity and direction of the time course of changes and for seeking the likely causative diagnosis. An essential first step is to determine how severe the injury is and whether it is progressing or regressing, by immediate testing by serial measurements. Serum ALT activity is useful for detecting hepatocytic injury, but not for indicating severity of whole‐liver impairment, which is better assessed by measuring a true function of the liver, by measuring TBL concentration that reflects the ability of the organ to clear plasma of bilirubin, or by a protein synthetic function such as prothrombin time (or its international normalized ratio, INR). Whole‐liver functions depend not so much on how many hepatocytes are injured, but on how many remain uninjured and still able to carry out the work of the organ. Elevations of ALT activity are better interpreted as indicating urgency to repeat the test to show whether liver injury is progressing or subsiding. Time is very critical, and dysfunction must be detected before it becomes irreversible. Protocol‐based rules and schedules for monitoring set long in advance may cause delays, especially if distant standard central laboratories are used. Therefore, physicians conducting clinical trials must quickly obtain additional clinical information from local laboratories that return immediate results so that they can diagnose the likely cause and act promptly. Because of the variable responses that may occur when individuals are treated with new drugs, preclinical models of standardized human cells to replicate them cannot be relied upon to predict what may occur in humans, all of whom are idiosyncratic, meaning that they differ from one another in one way or others, particularly with respect to how they respond to new chemicals or drugs. Only by observing how real patients or subjects actually respond can this be determined, both for beneficial and adverse effects. Hepatotoxicity caused by drugs is usually rare, especially if serious, and may not be detected in limited numbers of trial subjects. But discovery of elevated ALT values using protocol schedules may not represent the true onset time of liver cell injury, which may already be far advanced, subsiding, or past when first found. Clinical differential diagnosis cannot yet be reduced to a simple algorithm, but requires medical diagnostic skills learned by physicians over many years of experience. If a trial investigator is not well informed about liver diseases, consultants should be called at once to assist in making a probable diagnosis and in managing the patient. If the liver injury is found to be regressing or is past, or if another cause than the drug is likely, restarting the drug may be considered and done cautiously and carefully, with close observation of the effects by daily or twice‐weekly ALT and TBL testing. Rechallenge Effects: Consider Both Negative and Positive Results It was learned decades ago that rechallenge of a patient who showed initial liver injury caused by a drug sometimes led to explosively rapid, more severe injury and even fatal dysfunction. This has resulted in a blanket condemnation of rechallenge as too dangerous6 to be allowed. A positive rechallenge response has been considered the most powerful finding for confirming the diagnosis of DILI. However, data on negative or lack of response after rechallenge are almost nil, so liver adaptation cannot be well assessed. Subclinical hepatoxicity may be occurring in the real world more often than is known, with inadvertent rechallenge. That actually occurred in the study10 of 218 male patients exposed to tuberculosis and who received prophylactic isoniazid alone daily for 1 year, had serum drawn monthly, but frozen and analyzed retrospectively. Of them, 20% showed mild liver injury and 3 actually showed evidence that today would fulfill diagnostic criteria as Hy's Law cases, but all recovered despite continuing isoniazid treatment. Nevertheless, subjects so diagnosed should be watched especially closely, as should any showing sensitivity or immunological effects, if they are to be rechallenged at all, and only if the beneficial effects of the new drug justify the risk. Focus only on positive rechallenge while ignoring the vastly greater number of negative rechallenge results may create misleading conclusions, and prevents learning about how to recognize which subjects might be rechallenged safely. It is strongly emphasized that these arguments pertain only to controlled clinical trials, where close follow‐up and complete reporting are required to be done and reported. From this, we may someday learn whether and how it might be done safely in medical practice after approval of new drugs. This editorial is aimed at stimulating discussion of this admittedly controversial issue, at least provoking consideration of gathering more complete information during clinical trials, toward eventual understanding and developing consensus, as well as developing future guidelines for how it can be done safely.