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Challenges in ATT Reintroduction

Challenges in ATT Reintroduction

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Published by: Rhea Derije on Jun 22, 2011
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CID 2010:50 (15 March)
Challenges in Reintroducing Tuberculosis Medicationsafter Hepatotoxicity 
Jussi Saukkonen
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 causehe-patotoxicity has troubled clinicians treat-ing tuberculosis (TB) for decades. Con-sequently, treatment-limiting biochemicalthresholds and symptom screens havebeen used to forestall the development of severe TB drug–induced liver injury (TB-DILI). If treatment has been interruptedbecause of suspected hepatotoxicity, di-agnostic studies are undertaken, and a pe-riod of time for hepatic biochemical nor-malization ensues. The clinician thenrechallenges the patient with all or someof the drugs used in the initial regimen.These steps can take more than a monthand require additional clinic visitswithre-peated clinical and biochemical monitor-ing. During this time, the patient may betreated with sub-optimal, alternative reg-imens. The time required to achieve neg-ative sputum acid-fast bacillus culture re-sults may be prolonged for patients underthese circumstances. Unfortunately, thereis little evidence other than expertopinionto guide the re-introduction of TB med-ications following a hepatotoxic event.
Received 1 December 2009; accepted 2 December 2009;electronically published 15 February 2010.Reprints or correspondence: Dr Jussi Saukkonen, Dept ofMedicine, Pulmonary Center, Boston University School ofMedicine, 80 E Concord St, R-304, Boston, MA 02118(jsaukk@bu.edu).
Clinical Infectious Diseases 2010;50:840–842
2010 by the Infectious Diseases Society of America. Allrights reserved.1058-4838/2010/5006-0007$15.00DOI: 10.1086/650577
The prospective study by Sharma et al[1] in this issue of 
Clinical Infectious Dis-eases 
assesses 3 strategies for rechallengewith TB medication after a hepatotoxicevent. Of the 273 patients who were ini-tially identified as having experienced TBmedication–related hepatotoxicity, 58 pa-tients who were pregnant, had a history ofalcoholismorchronicliverdisease,weretaking concomitant hepatotoxic medica-tion, or had human immunodeficiencyvi-rus infection were excluded. Four of thesepatientshaddiedbeforerechallenge(3dueto liver failure and 1 due to progressivetuberculosis). Altogether, 175 patientswith normalizedliverbiochemistrytestre-sults were randomized to either simulta-neous rechallenge or one of 2 sequentialrechallenge regimens, each lasting at least2 weeks and including isoniazid, rifampin,and pyrazinamide.There are several possible hypothesesunderpinning such rechallenge.Theinitialhepatotoxic event could have been the re-sult of hepatic adaptation (ie, transami-nase elevation that reflects mild, nonpro-gressive injury to hepatocyte cell mem-branes and organelles) [2, 3]; could havebeen unrelated to any of the TB medica-tions; or could have been the result of 1or more of the TB medications causingtrue, potentially progressive TB-DILI. Inthe first 2 instances, it is likely that all TBmedications would be tolerated with re-challenge. In the third instance,itisamat-ter of identifying which TB drug causedthe problem, either through actual re-challenge with all of the drugs that hadbeen used initially or through successfulreintroduction of all but 1 of the initialTB medications, which is then presumedto be the hepatotoxic agent. In practice,the clinician tries to determine whetheralanine aminotransferase (ALT) level and/or total bilirubin increase to thesamelevelas that achieved during the initial hepa-totoxic event; to identify a particular drugas being hepatotoxic and to avoid it; andmost critically, to find a regimen that thepatient can tolerate.The authors found that there was nodifference in the rate of recurrent hepa-totoxicity among patients who underwentsimultaneous challenge (13.8%) or se-quential challenges (10.2% and 8.6%).These rates were substantially lower thanthe 24% reported by Tahaoglu et al [4],perhaps because of differences in study populations,suchastheexclusionofthosepatients at high risk for hepatotoxicity from the study by Sharma et al [1]. Itshould be noted that,forpatientswhohadsimultaneous rechallenge and then devel-oped recurrent hepatotoxicity, it wouldnot be clear which drug caused the he-patotoxicity. An advantage of sequentialrechallenge is greater ease in determiningwhich drug is hepatotoxic. If the recurrenthepatotoxicityratecanbeasmuchas24%,this may provide sufficient impetus forse-
CID 2010:50 (15 March)
quential rechallenge to avoid the uncer-tainty of simultaneous challenges.What factors could account for the lackof difference among the 3 different strat-egies? The outcomes of the rechallengedata ultimately rest with the populationselected for the study. Specifically, howmany patients who reached treatment-limiting thresholds experienced true TB-DILI, and how many experienced hepaticadaptation or an unrelated hepatic event?A stringent definition of TB-DILI can beused to assess the study population. DrHymanZimmermanreporteddecadesagothat drug-induced hepatocellular injury associated with jaundice is associated witha mortality rate of at least 10% (“Hy’sLaw”) [5].AHy’s Lawcaseisnowthoughtof as occurring in a patient with an ALTelevation
3 times the upper limit of nor-mal (ULN) and with a bilirubin level
2times the ULN [6, 7]. In this study, 43%of the patients experienced jaundice, themajority with hepatotoxicity symptomsand transaminase elevation. The maxi-mum mean total bilirubin levels rangedfrom 2.14 to 2.88 mg/dL. Although therewerecertainlypatientswithHy’sLawcasesincluded in the population, the majority of the patients in this study did not reachthe definition of a Hy’s Law case of TB-DILI.Most of the patients did reach recom-mended thresholds for interrupting treat-ment because of suspected hepatotoxicity [3], which are not entirely synonymouswith the thresholds for TB-DILI. Thesethresholds select for a broader group of patients, including those who may be ex-periencing hepatic adaptation; have co-incidental gastrointestinal symptoms un-related to the liver; have newly developedviral hepatitis; have anotherliverorbiliary tract disease; or have hepatotoxicity re-lated to other medications, drugs, or al-cohol. In the study by Sharma et al [1],those patients with confounding featureswere excluded from subsequent rechal-lenge, including those who died of liverfailure.Becausetreatment-limitingthresh-olds, (rather than a stringent, Hy’s Law–typedefinition)wereusedasentrycriteria,it is possible that some patients withouttrue TB-DILI were included. However, itwould be premature to use the Hy’s Lawdefinition as the sole criterion to interrupttreatment at this time.How many of the study patients couldhave had hepatic adaptation or indeter-minateunrelatedhepaticevents?Itislikely that this was considerably less than the57%ofpatientswhodidnothavejaundicein the study. The authors did include pa-tients who experienced an elevation intransaminase levels
3 times the ULN on3 separate occasions. Without symptomsor bilirubin elevation, these patients may verywellhavehadhepaticadaptation.Theauthors do not explicitly refer to these in-dividuals as having symptoms of hepa-totoxicity, but state that only 6.9% of theentirestudypopulationhadasymptomatictreatment-limiting transaminase eleva-tion. Whether the symptoms experiencedby patients are actually attributable to he-patotoxicity is sometimes debated, be-cause nonspecific gastrointestinal symp-toms may occur with coincidental low-grade transaminase elevation. Another in-clusion criterion was a single elevation
5times the ULN of either aspartate ami-notransferase (AST) or ALT levels. Al-though historically AST level has beenused in the TB literature as a marker of hepatotoxicity, it is not as specific as ALTlevel for liver injury [3] and may lead tothe inclusion of patients who did not ex-perience TB-DILI. It appears that thesegroups with transaminase elevation weredistributed evenly across the study arms,buttheycouldhavedilutedtheproportionof patients with true TB-DILI, as well asany differences among the study arms. Itappears that the majority of the patientsincluded in this study reached reasonablethresholds for treatment interruption be-cause of suspectedTBdrughepatotoxicity,and it is likely that many of them had trueTB-DILI. Viewed from a practical stand-point, this study assesses managementstrategies for patients who had treatmentinterrupted because of concern for evolv-ing hepatotoxicity rather than because of established hepatotoxicity.There are several potential reasons why the different strategies did not differ inoutcome. The rechallenge strategy likely would be immaterial if many of the initialhepatotoxic events were actually hepaticadaptation or unrelated to TBmedication.Another possible explanation would bethat compliance with daily dosingofmed-ication was suboptimal, because onl14.3% of the patients were receiving Di-rectly Observed Treatment Short-Coursetherapy. Noncompliance could have re-duced recurrent hepatotoxicity rates butwould likely have led to clinically detect-able adverse treatment outcomes. Because3 monthsof follow-upbiochemicaltestingwas done once patients were stabilized ontheirnewregimens,itispossiblethatsomehepatotoxicity cases were missed, albeitrelatively few. The American Thoracic So-ciety recommendations[3]forrechallengedo not advocate adding pyrazinamide tothe regimen if the initialhepatotoxiceventwas severe and isoniazid and rifampinwere tolerated. Leaving out pyrazinamidemay reduce the incidence of recurrent he-patotoxicity and reduce the time requiredtoestablishanewstableregimenby1weekbut still prolong overall therapy from 6 to9 months. Lastly, it is possible that ex-cluding patients with preexisting liver dis-ease or who were at greater risk for he-patotoxicity would have yielded differentresults.The study by Sharma et al [1] is im-portant in providing prospective rechal-lenge data from a relatively large cohortof patients who have reached treatment-limiting thresholds for hepatotoxicity.This study does move us forward a stepin our thinking regarding how to managethese patients, but it raises some issues forconsideration. First, these data need to beconfirmed in studies with diverse popu-lationsbefore theycanbegeneralized.Sec-ond, some important patients at high risk

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how to reintroduce att in att induce hepatitis..........
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