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  Safety of Treatment of Latent Tuberculosis Infection inCompensated Cirrhotic Patients During TransplantCandidacy Period  Alex W. Jahng, 1 Thao Tran,  2 Lanchi Bui, 3 and James L. Joyner  4,5 Background. Treatmentoflatenttuberculosisinfectionwithisoniazid(INH)orrifampin(RIF)iscontroversialinlivertransplant candidates due to potential hepatotoxicity. In this study, treatment of latent tuberculosis during transplantcandidacy period is explored, and relevant literature is reviewed. Methods.  Liver transplant candidates with latent tuberculosis infection by positive tuberculin skin test (  5 mm) wereprospectively enrolled and treated with 9 months of INH or 4 months of RIF, and were monitored monthly for theirliver enzyme profiles, adverse effects, compliance, and completion rate. Results.  Four of nine patients with INH had asymptomatic, mild elevations of aspartate aminotransferase (AST) oralanine aminotransferase (ALT) versus none of five patients in the RIF group. Two cases of elevations were attributedtoINH.TwoothercaseswereattributedtoalcoholismoractivechronichepatitisBvirusinfection.Onlyonepatientinthe INH group experienced symptoms possibly attributed to INH hepatotoxicity. Compliance was 100% per patientreporting.Completionrateswere79%forINHand100%forRIF.Nofulminanthepaticfailureordeathwasobserved. Conclusion.  Treatment of latent tuberculosis in liver transplant patients during their candidacy with INH or RIFappears to be a safe, viable option, if carefully monitored for adverse effects and liver enzymes. Keywords:  Treatment of latent infection, Latent tuberculosis, Liver transplant, Isoniazid, Rifampin. (Transplantation  2007;83: 1557–1562) T he incidence of tuberculosis (TB) ranges from 0.9% to2.3% in liver transplant patients and is a significantsource of mortality and morbidity despite treatment ( 1–6  ).GuidelinesoftheAmericanThoracicSociety(ATS),theCen-ters for Disease Control and Prevention (CDC), and the In-fectious Diseases Society of America (IDSA) advocate the useof isoniazid (INH) or rifampin (RIF) for all transplant pa-tients with positive tuberculin skin test and suspected latenttuberculosis infection. However, due to the hepatotoxicity inherent in both drugs, controversy exists with respect totheir use in liver transplant candidates ( 7  ,  8 ).Transplant centers take individualized approaches tothe treatment of latent infection in patients undergoing livertransplantation( 9  , 10  ).Forinstitutionsthatoptfortreatmentof latent tuberculosis, the timing of initiation with respect tothe transplantation is controversial. Treatment of latent tu-berculosis may be done during the candidacy period or aftertransplant.Someinstitutionsforgotreatmentoflatenttuber-culosis in favor of surveillance and then treat as necessary forincident active TB infection.ThesafetyoftreatmentoflatenttuberculosisduringthelivertransplantcandidacyperiodwithINHorRIFisexploredin this study. We report our experience with 14 patients pro-spectively followed and review relevant literature regardingdifferent approaches to treatment of latent tuberculosis inliver transplant patients. METHODS This was a prospective, observational study conductedat the University of California, Irvine, Medical Center from2003 to 2006. Patient Population Patients with end-stage liver disease 18 years of age orgreater with positive tuberculin skin test (  5 mm) were en-rolled. Demographic information including ethnicity, age,sex, comorbid diseases, etiology of liver failure, and concur-rent medications was obtained. Model of End-stage LiverDisease (MELD) scores and Child-Pugh scores were calcu-lated at the initiation of treatment of latent tuberculosis. Pa-tients were excluded from the study if they did not have aprospect for liver transplant within 2 years. Typically, thesewere patients with a good quality of life suffering no stigmataof end-stage liver disease. In these patients, the risk/benefitratiooftreatmentoflatenttuberculosiswasnotfeltsufficientto warrant treatment of latent tuberculosis. Patients withprior treatment of latent tuberculosis or active TB were alsoexcluded. Patients were also excluded if there was clinical orlaboratoryevidenceofactivedecompensateddisease.Becauseof this the study is biased toward patients with compensatedcirrhosis who are expected to undergo transplantation in thenear future. Methods The patients were treated with either 300 mg of INHdaily along with 25–50 mg of vitamin B6 for 9 months or 600mgofRIFdailyfor4months.Basedonitsproventrackrecord 1 School of Medicine, University of California, Irvine, Irvine, CA. 2 Department of Pharmacy Services, Kaiser Permanente Fontana MedicalCenter, Fontana, CA. 3 Division of Transplantation and Department of Pharmacy Services, Uni-versity of California, Irvine, Orange, CA. 4 Department of Medicine, Hospitalist Division and Division of InfectiousDiseases, University of California, Irvine, Medical Center, Orange, CA. 5 Address correspondence to: James Joyner, M.D., Building 58, Room 103,UCI Medical Center, 101 The City Drive South, Orange, CA 92868.E-mail: jjoynermd@gmail.comReceived 3 October 2006. Revision requested 6 March 2007.Accepted 14 March 2007.Copyright © 2007 by Lippincott Williams & WilkinsISSN 0041-1337/07/8312-1557DOI: 10.1097/  Transplantation  ã Volume 83, Number 12, June 27, 2007  1557  for treatment of latent tuberculosis, INH was the primary choice. RIF was used if the patient had a prior adverse reac-tiontoINHorifthetransplantwasverylikelytooccurinlessthan 9 months. Patients were followed with a monthly clinicvisit until the completion of therapy. Monthly laboratory tests included aspartate aminotransferase (AST), alanineaminotransferase (ALT), total bilirubin, and internationalnormalization ratio (INR). When liver function tests werefound to be more than twice baseline (calculated as meanenzyme values over the 10 months period preceding treat-ment of latent tuberculosis as available) and the patient wasasymptomatic, treatment was continued and follow-up labo-ratorytesting was repeated atthe soonestpossible time.If theelevations persisted upon repeat testing or if the patient hadclinically significant signs or symptoms of hepatotoxicity (nausea,vomiting,abdominalpain,increasedicterusorjaun-dice),treatmentoflatenttuberculosiswasstopped.Ifelevatedliver function tests persisted despite cessation of treatment of latent tuberculosis, appropriate investigation into othercauses was initiated. The protocol was approved by the Uni-versity of California Irvine Medical Center Institutional Re-view Board. Outcome Measures Primary outcome was drug-induced hepatotoxicity.INH or RIF induced hepatotoxicity was presumed if the en-zyme levels returned to the patient’s baseline with the with-drawal of drugs, and other causes of enzyme elevation wereexcluded, including exacerbation of existing liver disease.Secondaryoutcomewasthecompletionoftreatmentoflatenttuberculosis. RESULTS Fourteen liver transplant candidates were enrolled intotreatment of latent tuberculosis during the study period. Pa-tientcharacteristicsaresummarizedinTable1.Themeanagewas53(range:41–68)yearsandthemeanMELDscorewas15(range: 6–23). Excepting one patient in the INH group withclass C liver disease by Child-Pugh score ( 10  ), all the otherpatients were with either class A or B liver disease. The etiol-ogyoftheliverdiseasewashepatitisCvirus(HCV)in54%(8of 14) of the patients, with or without prior alcoholism, andhepatitis B virus (HBV) in 21% (3 of 14) of the patients. Onepatient had alcoholic liver disease, one had primary biliary cirrhosis (PBC), and one had cryptogenic cirrhosis. All theHBV patients were negative for E antigen reactivity and pos-itive for S antigen reactivity. The most common comorbiddisease was diabetes, present in 36% (5 of 14). Renal failure/insufficiency was present in 21% (3 of 14) of the patients.Hepatocellularcarcinomawaspresentin21%(3of14)ofthepatients.The baseline liver enzymes levels are summarized inTable 2, calculated as described in the Methods. The baselineAST and ALT levels were elevated over the upper limits of normalin62%(8of13)ofthepatients,withmeansof57IU/L(range: 23–124) and 52 IU/L (range: 19–97), respectively.The baseline AST and ALT levels were not significantly dif-ferent between the INH and the RIF groups.During the course of treatment four of nine patients inthe INH group developed elevated AST or ALT over theirbaseline. On the other hand, none of five patients in the RIFgroup had elevations in liver enzyme above baseline. This issummarized in Table 2. Patient 5 had AST elevation twicebaseline with no corresponding ALT elevation at treatmentmonth 8. Patient 8 had AST elevations less than three timesthe baseline at treatment months 3 and 7 without corre-sponding ALT elevations. Both patients’ transaminase eleva-tions were asymptomatic, spontaneously resolved despitecontinuedINH,andwerepresumptivelyattributedtonaturalfluctuation of ongoing liver inflammation, laboratory vari-ance, or transient INH induced hepatotoxicity. Patient 2 hadasymptomatic, mild elevations of both AST and ALT to lessthan two times the baseline that peaked at the treatmentmonth 8. At this time, the patient was diagnosed with schizo- TABLE 1.  Demographic and baseline hepatic function parameters for the 14 liver transplant candidates Patient Age Sex TreatmentUnderlying disease MELDChild-Pugh score(class)Total bilirubin(mg/dL) INR 1 42 F INH HCV 18 8 (B) 1.8 2.12 59 M INH HCV 13 6 (A) 1.9 1.43 40 M INH HCV 23 6 (A) 0.8 1.34 54 F INH HCV 6 6 (A) 0.5 1.05 42 M INH HBV 15 5 (A) 0.7 1.16 68 M INH HBV 11 5 (A) 1.3 1.27 51 M INH HCV 8 6 (A) 1.2 1.08 41 F INH HCV 20 7 (B) 0.6 1.09 45 M INH Cryptogenic 23 10 (C) 4.9 2.010 67 M RIF HBV 9 5 (A) 1.0 1.111 62 M RIF Alcoholism 15 6 (A) 1.1 1.112 64 F RIF HCV 8 5 (A) 0.8 1.113 52 F RIF PBC 6 6 (A) 1.4 0.914 59 M RIF HCV 13 5 (A) 1.8 1.5 HBV,hepatitisvirusB;HCV,hepatitisvirusC;INH,isoniazid;INR,internationalnormalizedratioforprothrombintime;MELD,ModelofEnd-stageLiverDisease score; PBC, primary biliary cirrhosis; RIF, rifampin. 1558  Transplantation  ã Volume 83, Number 12, June 27, 2007  phrenia and professed to covert daily alcohol use. INH wasdiscontinued at this time because of concurrent alcoholabuse, and because the patient was no longer a transplantcandidate. Patient 6 had asymptomatic AST and ALT eleva-tions greater than three times the baseline with onset at treat-ment month 6. This was correlated linearly over time with amarkedincreaseinHBVviralload.INHwasdiscontinued8.5months into treatment due to concerns about continued usein the face of concurrent transaminase elevation. Histransaminase elevations subsequently remained elevated un-til antiviral therapy directed against HBV was adjusted andhisviralloadsubsequentlydeclined.Insummary,onlytwoof the nine patients receiving INH had transaminase elevationwhichcouldbeattributedtoINHalone.Inbothcasesthiswastransientandmild,andinneithercasewastreatmentoflatenttuberculosis discontinued.In the INH group, patient 3 suffered mild and transientright upper quadrant abdominal pain, although without con-currentelevationsinASTorALT.NoneofthepatientsintheRIFgroup developed symptoms. Compliance per patient self-reporting was 100% in both groups. Patient 3 discontinuedtreatment of latent tuberculosis after 1 month, not understand-ing that 9 months of treatment was necessary. This patient sub-sequently reinitiated treatment of latent tuberculosis andcompleted 9 months in an uninterrupted fashion. Completionrate was 78% in the INH group, but as mentioned above, dis-continuationwasalwaysforreasonsunrelatedtotheINHitself.Completionratewas100%intheRIFgroup.Althoughcomple-tion of treatment of latent infection was not required for trans-plantation,alloftheenrolledpatientsdidcompletetheirtherapy before transplantation. None of the patients suffered fulminanthepatic failure or death secondary to INH or RIF, and all thepatientsarefreefromactiveTBtodate. DISCUSSION Current guidelines recommend treatment of latent tu-berculosisforallpatientswithlatenttuberculosisinfection( 7  , 8 ).NinemonthsofINHisthetherapyofchoicefortreatmentof latent tuberculosis, and has been demonstrated to reducethe incidence of active infection in compliant, immunocom-petent patients by as much as 90% ( 8 ,  11 ). RIF is used as analternative agent when organism resistance or patient intol-erance to INH is suspected, and its recommendation is basedlargelyonasingleclinicaltrialcarriedoutinsilicosispatients.Inthisstudy,theefficacyofthreemonthsofRIFinpreventingactive TB was 63% ( 7  ,  8 ,  12 ,  13 ).For transplant patients treatment of latent tuberculosisisrecommendedbasedontheobservationthatthereishigherincidence of active TB than in the general population, andthat reactivation of latent tuberculosis infection is the mostcommonroutetoanactiveinfection( 1–6  ).Inthelivertrans-plant patients, the safety of treatment of latent tuberculosis isquestioned secondary to inherent hepatotoxicity present inboth INH and RIF. The frequency of treatment of latenttuberculosis-relatedhepatotoxicityinthepatientswitheitherend-stage liver disease or liver transplantation has not beenstudiedinlargeclinicaltrials.Inthegeneralpopulation,mild,transient transaminase elevation during treatment with INHoccurs in 10% to 20% of patients (usually   100 IU/L). Half or more of these cases are observed within the first twomonths of therapy ( 14 , 15 ). Severe hepatotoxicity is observedin only one to three cases per one thousand, sometimes leadingto fulminant hepatic failure that requires liver transplantation( 16–19  ). The risk factors for INH hepatotoxicity are age, sex,concurrentliverdisease,diabetes,alcoholuse,intravenousdruguse, and the use of substances that are either hepatotoxic or areinducersofcytochromeP450( 8 , 18–27  ).Thefrequencyofhep-atotoxicitywithRIFasmonotherapyappearstobelessthanthatofINHinthegeneralpopulation(  28 ,  29  ).Ontheotherhand,theriskofhepatotoxicitycanbedramaticwhenRIFiscoupledwithotherhepatotoxicdrugssuchaspyrazinamide(PZA);thePZA-RIF combination for treatment of latent tuberculosis was with-drawnfromtheCDCrecommendationssecondarytoincreasedmortality( 30  ).Therearethreegeneralapproachestolatenttuberculo-sis infection in the liver transplant candidate which vary be- TABLE 2.  Summary of AST and ALT levels during treatment and categorization Patient TreatmentMean baselineAST (IU/L)Mean baselineALT (IU/L)Peak treatmentAST (IU/L)Peak treatmentALT (IU/L)Month onset attransaminase elevation 1 INH 116 95 145 104 NA2 INH 124 94 207 131 73 INH 23 19 25 18 NA4 INH 55 81 60 71 NA5 INH 41 48 92 73 86 INH 44 46 162 254 67 INH 47 47 49 53 NA8 INH 38 28 91 57 79 INH 35 24 47 33 NA10 RIF 32 35 29 27 NA11 RIF 40 28 38 17 NA12 RIF 33 37 45 55 NA13 RIF 128 97 163 108 NA14 RIF 42 47 49 56 NA ALT, alanine aminotransferase; AST, aspartate amino transferse; INH, isoniazid; NA, not applicable/no significant elevation over baseline; RIF, rifampin. © 2007 Lippincott Williams & Wilkins  1559 Jahng et al.  tween individual transplant centers. Treatment of latenttuberculosis may be given during the candidacy period orafter the transplantation. Alternatively, treatment of latenttuberculosis may be forgone in favor of active surveillanceand treatment of incident TB as necessary.Currently, treatment of latent tuberculosis is mostcommonly utilized posttransplant. The advantage of post-transplanttreatmentisthattheexposureofthefailinglivertohepatotoxic drugs is avoided. On the other hand, posttrans-plant treatment of latent tuberculosis exposes the newly transplanted liver to drugs that are hepatotoxic. In the post-transplant scenario, it becomes very difficult to distinguishdrug-induced hepatotoxicity from other common entitiessuch as acute rejection and opportunistic infections. Thusconcerns about rejection or infection may lead to frequentbiopsies in cases of simple drug-induced hepatotoxicity, andconcerns about hepatotoxicity may lead to frequent discon-tinuation of treatment of latent tuberculosis in cases of rejec-tion or infection. In the posttransplant scenario, there ispotential for drug interactions that may lead directly to acuteorgan rejection. RIF, and to lesser degree INH, increase themetabolism of antirejection medications such as cyclospor-ine,tacrolimus,andcorticosteroidsviatheinductionofcyto-chrome P450 pathway ( 3 ,  31 ,  32 ).Onlytwostudieshaveevaluatedthesafetyofposttrans-plant treatment of latent tuberculosis. In a study by Schlugeret al., three of the six patients who received INH alone devel-oped mild, transient transaminase elevations, and were allcorrelated to acute rejection or HCV ( 33 ). Benito et al.showed that 48% (11 of 24) of the patients taking INH dem-onstrated liver dysfunction as assessed by transaminase ele-vation and/or liver biopsy ( 34 ). Seven cases were related toacute rejection or hepatitis virus, and in two of these patientsINH had to be discontinued prematurely.Some transplant centers avoid treatment of latent tuber-culosis entirely and opt for surveillance of active tuberculosis.Since most liver transplant patients with latent tuberculosisinfection will not develop active TB this avoids unnecessary ex-posure to potentially hepatotoxic agents. Unfortunately, themortality rate of active TB in transplant patients ranges from21%to33%inthepublishedstudies( 1 , 3 , 33 )Thisiscoupledtohigherincidenceofconversionoflatenttoactiveinfectionwhencompared to immunocompetent patients ( 1–6  ). Conventionaltreatmentof active TB infectionemploys amulti-drugregimentwith INH, RIF and PZA, all which have varying potentials tocause hepatotoxicity and drug interactions thus raising issuesmore complex than those mentioned above in posttransplanttreatmentoflatenttuberculosis( 35 ).There appears to be a higher incidence of hepatotoxic-ity with conventional therapy of active TB in the liver trans-plant recipients than in the general population. Use of multi-drug TB therapy after transplantation has also beenassociated with allograft rejection. Meyer et al. reported that100%(sixofsix)oflivertransplantpatientsundergoingtreat-mentofactiveTBwithconventionaldrugregimendevelopedhepatotoxicity,with50%demonstratingacuterejection( 36  ).In a study by Aguado et al., 50% (12 of 24) of liver transplantpatients treated with a multi-drug regimen for active TB de-veloped hepatotoxicity, with half of them being severe ( 1 ).Although not limited to liver patients, the authors went onfurther to demonstrate that the majority of organ rejectioncases were secondary to interaction between RIF and cyclo-sporin. Schluger et al. demonstrated 100% (five of five) hep-atotoxicity in liver transplant patients when treated withcombination of RIF and INH. Three cases were associatedwith HCV reinfection or acute rejection ( 37  ). Higgins et al.demonstrated 40% (two of five) hepatotoxicity with conven-tional therapy ( 38 ). Singh et al. in a literature review showedliverdysfunctionrequiringdiscontinuationoftreatmentwithconventional regiment for active TB occurred in 41% of pa-tients, many of them associated with cofactors such as acuterejection ( 3 ).Because of the issues mentioned above, when treatingactive TB in the posttransplant scenario, some authorsadvocatethecompletereplacementoffirst-lineTBdrugswithsecond-line agents such as fluoroquinolones or ethambutol,while other authors recommend continuation of INH as themain back bone of therapy with the addition of the second-line drugs ( 10  ,  36  ). Meyers et al. have shown that continuedtherapy with ethambutol and fluoroquinolones is effective inliver transplant patients who show hepatotoxicity to the con-ventional drug regimen ( 36  ). Similarly, in those patients whoare transplanted secondary to fulminant hepatic failure fromeither conventional therapy or treatment of latent tuberculo-sis, successful continuation of treatment with second-line TBdrugshasbeenreported( 16  , 17  , 39  , 40  ).Itmustbenotedthatthe efficacy of second-line regiments is yet to be proven inlarge scale clinical trials, and as mentioned previously, evenfirst-line agent therapy for active TB on the posttransplantscenario is associated with high morbidity.Pretransplant treatment of latent tuberculosis duringthe candidacy period avoids many of the issues associatedwith posttransplant treatments. Issues of acute rejection anddrug interactions are replaced by concern of burdening theend-stage liver. In the only other study of treatment of latenttuberculosis during the candidacy period, Singh et al. dem-onstrated that none of the 18 patients had hepatotoxicity toINH. All patients were able to complete therapy without ad-verse events ( 41 ).Our study adds to the previous work done by Singh etal. with a unique observation in regards to the role of RIF intreatment of latent tuberculosis. In this current study, theobserved 22% (two of nine) incidence of mild liver dysfunc-tion attributed to INH alone compares favorably with thegeneralpopulationincidence.Twopatientshadtobediscon-tinued from INH, but the events were primarily related toissuesotherthanINH.Nopatientsdevelopedfulminantliverfailureordeath.ThislowrateofINH-inducedhepatotoxicity occursdespitethefactthatourstudypatientsdisplaymultiplerisk factors for drug induced hepatotoxicity, including theburden of chronic liver disease and age. Particular to ourpresent study, 79% (11 of 14) of the patients had either HCVor HBV, and no HBV patient had E antigen reactivity. It isnotable that recent data involving patients with HBV (E an-tigen negative) or HCV with latent tuberculosis infectionshowed that the incidence of hepatoxicity to INH was notdifferent from the general population ( 42–44 ).Our results differ slightly from the study by Singh et al.who noted no transaminase elevations during treatment of latenttuberculosiswithINH( 41 ),andthisisaccountedforby different methodologies utilized in each study. Singh et al.onlymonitoredALT,whereasthepresentstudyalsoincluded 1560  Transplantation  ã Volume 83, Number 12, June 27, 2007

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