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Challenges in Reintroducing Tuberculosis Medications after Hepatotoxicity
Department of Medicine, Pulmonary Center, Boston University School of Medicine
(See the article by Sharma et al, on pages 833–839.)
The potential for medications to cause hepatotoxicity has troubled clinicians treating tuberculosis (TB) for decades. Consequently, treatment-limiting biochemical thresholds and symptom screens have been used to forestall the development of severe TB drug–induced liver injury (TBDILI). If treatment has been interrupted because of suspected hepatotoxicity, diagnostic studies are undertaken, and a period of time for hepatic biochemical normalization ensues. The clinician then rechallenges the patient with all or some of the drugs used in the initial regimen. These steps can take more than a month and require additional clinic visits with repeated clinical and biochemical monitoring. During this time, the patient may be treated with sub-optimal, alternative regimens. The time required to achieve negative sputum acid-fast bacillus culture results may be prolonged for patients under these circumstances. Unfortunately, there is little evidence other than expert opinion to guide the re-introduction of TB medications following a hepatotoxic event.
Received 1 December 2009; accepted 2 December 2009; electronically published 15 February 2010. Reprints or correspondence: Dr Jussi Saukkonen, Dept of Medicine, Pulmonary Center, Boston University School of Medicine, 80 E Concord St, R-304, Boston, MA 02118 (email@example.com). Clinical Infectious Diseases 2010; 50:840–842 2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5006-0007$15.00 DOI: 10.1086/650577
The prospective study by Sharma et al  in this issue of Clinical Infectious Diseases assesses 3 strategies for rechallenge with TB medication after a hepatotoxic event. Of the 273 patients who were initially identiﬁed as having experienced TB medication–related hepatotoxicity, 58 patients who were pregnant, had a history of alcoholism or chronic liver disease, were taking concomitant hepatotoxic medication, or had human immunodeﬁciency virus infection were excluded. Four of these patients had died before rechallenge (3 due to liver failure and 1 due to progressive tuberculosis). Altogether, 175 patients with normalized liver biochemistry test results were randomized to either simultaneous rechallenge or one of 2 sequential rechallenge regimens, each lasting at least 2 weeks and including isoniazid, rifampin, and pyrazinamide. There are several possible hypotheses underpinning such rechallenge. The initial hepatotoxic event could have been the result of hepatic adaptation (ie, transaminase elevation that reﬂects mild, nonprogressive injury to hepatocyte cell membranes and organelles) [2, 3]; could have been unrelated to any of the TB medications; or could have been the result of 1 or more of the TB medications causing true, potentially progressive TB-DILI. In the ﬁrst 2 instances, it is likely that all TB medications would be tolerated with rechallenge. In the third instance, it is a mat-
ter of identifying which TB drug caused the problem, either through actual rechallenge with all of the drugs that had been used initially or through successful reintroduction of all but 1 of the initial TB medications, which is then presumed to be the hepatotoxic agent. In practice, the clinician tries to determine whether alanine aminotransferase (ALT) level and/ or total bilirubin increase to the same level as that achieved during the initial hepatotoxic event; to identify a particular drug as being hepatotoxic and to avoid it; and most critically, to ﬁnd a regimen that the patient can tolerate. The authors found that there was no difference in the rate of recurrent hepatotoxicity among patients who underwent simultaneous challenge (13.8%) or sequential challenges (10.2% and 8.6%). These rates were substantially lower than the 24% reported by Tahaoglu et al , perhaps because of differences in study populations, such as the exclusion of those patients at high risk for hepatotoxicity from the study by Sharma et al . It should be noted that, for patients who had simultaneous rechallenge and then developed recurrent hepatotoxicity, it would not be clear which drug caused the hepatotoxicity. An advantage of sequential rechallenge is greater ease in determining which drug is hepatotoxic. If the recurrent hepatotoxicity rate can be as much as 24%, this may provide sufﬁcient impetus for se-
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quential rechallenge to avoid the uncertainty of simultaneous challenges. What factors could account for the lack of difference among the 3 different strategies? The outcomes of the rechallenge data ultimately rest with the population selected for the study. Speciﬁcally, how many patients who reached treatmentlimiting thresholds experienced true TBDILI, and how many experienced hepatic adaptation or an unrelated hepatic event? A stringent deﬁnition of TB-DILI can be used to assess the study population. Dr Hyman Zimmerman reported decades ago that drug-induced hepatocellular injury associated with jaundice is associated with a mortality rate of at least 10% (“Hy’s Law”) . A Hy’s Law case is now thought of as occurring in a patient with an ALT elevation 13 times the upper limit of normal (ULN) and with a bilirubin level 12 times the ULN [6, 7]. In this study, 43% of the patients experienced jaundice, the majority with hepatotoxicity symptoms and transaminase elevation. The maximum mean total bilirubin levels ranged from 2.14 to 2.88 mg/dL. Although there were certainly patients with Hy’s Law cases included in the population, the majority of the patients in this study did not reach the deﬁnition of a Hy’s Law case of TBDILI. Most of the patients did reach recommended thresholds for interrupting treatment because of suspected hepatotoxicity , which are not entirely synonymous with the thresholds for TB-DILI. These thresholds select for a broader group of patients, including those who may be experiencing hepatic adaptation; have coincidental gastrointestinal symptoms unrelated to the liver; have newly developed viral hepatitis; have another liver or biliary tract disease; or have hepatotoxicity related to other medications, drugs, or alcohol. In the study by Sharma et al , those patients with confounding features were excluded from subsequent rechallenge, including those who died of liver failure. Because treatment-limiting thresh-
olds, (rather than a stringent, Hy’s Law– type deﬁnition) were used as entry criteria, it is possible that some patients without true TB-DILI were included. However, it would be premature to use the Hy’s Law deﬁnition as the sole criterion to interrupt treatment at this time. How many of the study patients could have had hepatic adaptation or indeterminate unrelated hepatic events? It is likely that this was considerably less than the 57% of patients who did not have jaundice in the study. The authors did include patients who experienced an elevation in transaminase levels 13 times the ULN on 3 separate occasions. Without symptoms or bilirubin elevation, these patients may very well have had hepatic adaptation. The authors do not explicitly refer to these individuals as having symptoms of hepatotoxicity, but state that only 6.9% of the entire study population had asymptomatic treatment-limiting transaminase elevation. Whether the symptoms experienced by patients are actually attributable to hepatotoxicity is sometimes debated, because nonspeciﬁc gastrointestinal symptoms may occur with coincidental lowgrade transaminase elevation. Another inclusion criterion was a single elevation 15 times the ULN of either aspartate aminotransferase (AST) or ALT levels. Although historically AST level has been used in the TB literature as a marker of hepatotoxicity, it is not as speciﬁc as ALT level for liver injury  and may lead to the inclusion of patients who did not experience TB-DILI. It appears that these groups with transaminase elevation were distributed evenly across the study arms, but they could have diluted the proportion of patients with true TB-DILI, as well as any differences among the study arms. It appears that the majority of the patients included in this study reached reasonable thresholds for treatment interruption because of suspected TB drug hepatotoxicity, and it is likely that many of them had true TB-DILI. Viewed from a practical standpoint, this study assesses management
strategies for patients who had treatment interrupted because of concern for evolving hepatotoxicity rather than because of established hepatotoxicity. There are several potential reasons why the different strategies did not differ in outcome. The rechallenge strategy likely would be immaterial if many of the initial hepatotoxic events were actually hepatic adaptation or unrelated to TB medication. Another possible explanation would be that compliance with daily dosing of medication was suboptimal, because only 14.3% of the patients were receiving Directly Observed Treatment Short-Course therapy. Noncompliance could have reduced recurrent hepatotoxicity rates but would likely have led to clinically detectable adverse treatment outcomes. Because 3 months of follow-up biochemical testing was done once patients were stabilized on their new regimens, it is possible that some hepatotoxicity cases were missed, albeit relatively few. The American Thoracic Society recommendations  for rechallenge do not advocate adding pyrazinamide to the regimen if the initial hepatotoxic event was severe and isoniazid and rifampin were tolerated. Leaving out pyrazinamide may reduce the incidence of recurrent hepatotoxicity and reduce the time required to establish a new stable regimen by 1 week but still prolong overall therapy from 6 to 9 months. Lastly, it is possible that excluding patients with preexisting liver disease or who were at greater risk for hepatotoxicity would have yielded different results. The study by Sharma et al  is important in providing prospective rechallenge data from a relatively large cohort of patients who have reached treatmentlimiting thresholds for hepatotoxicity. This study does move us forward a step in our thinking regarding how to manage these patients, but it raises some issues for consideration. First, these data need to be conﬁrmed in studies with diverse populations before they can be generalized. Second, some important patients at high risk
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for hepatotoxicity were excluded from this study. Third, it is not entirely evident from the sample size of this study how patients with more-severe hepatic injury, such as those with Hy’s Law cases, would respond to different rechallenge strategies. This study, if conﬁrmed by others, could potentially challenge some treatment-limiting thresholds for suspected hepatotoxicity that are currently used. We do need better methods and rules for discriminating between true TB-DILI and hepatic adaptation. Optimally, treatment-limiting thresholds should have greater speciﬁcity for TB-DILI and still allow clinicians to prevent severe progressive drug-induced liver injury at an earlier stage.
Potential conﬂicts of interest. J.S.: no conﬂicts.
1. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment–induced hepatotoxicity. Clin Infect Dis 2010; 50:833–839 (in this issue). 2. Chitturi S, Farrell G. Drug-induced liver disease. In: Schiff E, Sorrell M, Maddrey W, eds. Schiff’s diseases of the liver. Vol I. 10th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2007:935–936. 3. Saukkonen JJ, Cohn DL, Jasmer RM, et al; American Thoracic Society (ATS). Hepatotoxicity of antituberculosis therapy subcommittee: an ofﬁcial ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174(8):935–952.
4. Tahaoglu K, Atac G, Sevim T, et al. The man¸ agement of anti-tuberculosis drug induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5: 65–69. 5. Zimmerman HJ. The spectrum of hepatotoxicity. (Kober Lecture). Perspect Biol Med 1968; 12(1):135–161. 6. US Food and Drug Administration. Guidance for industry drug-induced liver injury: premarketing clinical evaluation. http://www.fda .gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/default.htm. Accessed 3 February 2010. 7. Watkins P, Bloom J, Hunt C. Biomarkers of acute idiosyncratic hepatocellular injury (AIHI) within clinical trials. In: Olson S, Robinson S, Gifﬁn R, eds. Accelerating the development of biomarkers for drug safety: workshop summary. Forum on Drug Discovery, Development, and Translation; Institute of Medicine. Washington, DC: National Academies Press, 2009:42–48.
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