Hepatotoxicity of Antitubercular Drugs

C H A P T E R

27 Hepatotoxicity of Antitubercular Drugs Sumita Verma1 and Neil Kaplowitz2 1

Brighton and Sussex Medical School, Brighton, United Kingdom, 2University of Southern California, Los Angeles, California, USA O U T L I N E

Introduction

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Incidence of Hepatotoxicity

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Mechanism of Hepatotoxicity

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Hepatotoxicity of Individual Drugs Isoniazid Rifampicin Pyrazinamide

488 488 488 489

Hepatotoxicity with Multidrug Antitubercular Therapy Risk Factors for Antitubercular Therapy Hepatotoxicity Acetylator Status and CYP2E1 Polymorphisms Age Drug Dose Alcohol Use Enzyme Inducers Other Than Rifampicin Gender Race or Ethnicity Other Genetic Factors Malnutrition

489 490 490 491 491 492 492 492 493 493 493

Underlying Chronic Liver Disease Including Coinfection with Hepatitis B and C HIV Infection

493 494

Clinical, Biochemical, and Histological Features

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Management, Including Referral for Liver Transplant

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Alternative Therapy for Underlying Tuberculosis and Reintroduction of Antitubercular Therapy

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Antitubercular Therapy in Patients with Underlying Liver Disease

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Hepatotoxicity of Antitubercular Therapy in Liver Transplant Recipients

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Recommendations for Monitoring Patients While on ATT Monotherapy with Isoniazid for Latent Tuberculosis Infection For Patients on Multidrug Regimens

alanine aminotransferase aspartate aminotransferase antitubercular therapy Mycobacterium tuberculosis p-aminosalicylate

Drug-Induced Liver Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-387817-5.00027-3

498 499

Conclusions

499

References

500

INTRODUCTION

A B B R E V I AT I O N S ALT AST ATT MTB PAS

498

Tuberculosis is a major public health concern in developing countries. Nearly one third of the world’s population is infected and this disease kills almost 3 million people per year, second only to HIV/AIDS. In the mid-1980s, there was a resurgence of outbreaks

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© 2013 Elsevier Inc. All rights reserved.

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27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

in developed countries like the United States, largely due to the human immunodeficiency virus (HIV) epidemic, the development of drug-resistant strains, and the continued immigration from endemic areas. Since 1953, when the Centers for Disease Control and Prevention (CDC) initiated public health surveillance for tuberculosis in the United States, the tuberculosis case rate has declined almost 10-fold from 53 cases per 100,000 to 5.1 per 100,000 in 2003. During 1993
2003, the incidence of tuberculosis in the United States decreased by 444% and is now occurring at a historic low level. Nonetheless, there were still 14,874 new cases of tuberculosis in 2003, indicating that this infection remains a major public health problem in developed countries like the United States [1,2]. The first specific drug for tuberculosis became available in 1944 when the American microbiologist Selman Abraham Waksman discovered streptomycin. This was followed by the development of p-aminosalicylate (PAS; 1949), isoniazid (1952), pyrazinamide (1954), ethambutol (1962), and rifampicin (1963). Of the four most commonly used first-line drugs for tuberculosis (isoniazid, rifampicin, pyrazinamide, and ethambutol), three are potentially hepatotoxic (isoniazid, rifampicin, and pyrazinamide). Table 27-1 lists the antitubercular drugs being used in the United States and Table 27-2 indicates the recommended treatment schedules [3]. Though streptomycin is as efficacious as ethambutol, because of the increasing frequency of resistance to this drug, it is no longer considered first-line therapy. In those with latent tuberculosis infection (LTBI; Table 27-2), rifampicin and pyrazinamide for 2 months had been considered for those for which long-term compliance was an issue [3]. However this latter regimen is associated with an increased risk of severe hepatotoxicity [4.5% discontinued therapy because they either developed serum aspartate aminotransferase (AST) levels over five times the upper limit of normal (ULN) or symptoms of hepatitis] and is now not routinely TABLE 27-1 States

Antitubercular Drugs Being Used in the United

First-Line Drugs

Second-Line Drugs

Ethambutol Isoniazid Pyrazinamide Rifabutina Rifampicin Rifapentine

Amikacina Capreomycin Cycloserine Ethionamide Gatifloxacina Levofloxacina Moxifloxacina p-Aminosalicylic acid Streptomycin

a

Not approved by the US Food and Drug Administration for the treatment of tuberculosis in the United States. Adapted, with permission, from the American Thoracic Society Guidelines [3].

recommended by either the CDC or the American Thoracic Society (ATS) [2,4]. More recently, based on evidence from three randomized trials on treatment of LTBI [5
7], the CDC has recommended a combination of isoniazid-rifapentine given weekly for 12 weeks as a directly observed therapy (DOT). This combination is suitable in healthy patients aged over 12 years, including those who are HIV-positive, as long as there is no concomitant use of antiretroviral therapy (ART) [8]. In the largest trial, compared to 9 months of isoniazid, 12 weeks of isoniazid-rifapentine therapy was associated with a lower cumulative rate of development of tuberculosis (0.19% versus 0.43%), better completion rates (82% versus 69%, P , 0.001), and a lower risk of hepatotoxicity (0.4% versus 2.7%, P , 0.001) [7]. It must be emphasized, however, that rifapentine has not been approved by the US Food and Drug Administration (FDA) for treatment of tuberculosis and therefore its use is off label. Due to an increased risk of hepatotoxicity from isoniazid with older age, treatment for LTBI with isoniazid had been restricted to those ,35 years of age [3,9] but its use has recently been broadened by the CDC to any age. Nevertheless, many health authorities (e.g., Los Angeles County TB Control) tend to treat those over age 35 who have been in the United States less than 5 years as well as all with a high risk for reactivation. In the first few years after the introduction of isoniazid, only sporadic cases of hepatotoxicity were noted and these were often attributed to concurrent viral infections or other drugs such as PAS [10
12]. In 1959, Berte et al. reported an excellent hepatic safety profile of isoniazid with no cases of hepatitis occurring in 513 treated patients [12]. Subsequently, in 1963, the ATS recommended that 1 year of isoniazid prophylaxis should be offered to all tuberculin-positive patients irrespective of age or duration of tuberculin positivity [13]. Concerns regarding isoniazid hepatotoxicity were first brought to attention in 1969 (17 years after isoniazid was introduced!) by Scharer et al., who observed liver test abnormalities in 10.3% of their cohort receiving isoniazid [14]. This failed to attract attention until 1971, when Garibaldi et al. retrospectively analyzed data on 2,321 subjects receiving isoniazid prophylaxis (following an outbreak on Capitol Hill). They reported clinical hepatitis in 19 (0.81%), of whom 13 developed overt jaundice with two deaths (0.08%), although mortality among those with hepatitis was 2/19 (10%) [15]. This unsettling data prompted the US Public Health Service (USPHS) to initiate a large prospective multicenter surveillance study to determine the incidence of isoniazid-related hepatotoxicity. This involved 13,838 persons in 21 participating health departments. In this study, probable isoniazid-related hepatitis was defined as AST .250 Karmen units or AST ,250 Karmen units but with alanine aminotransferase (ALT) . AST,

III. HEPATOTOXICITY OF SPECIFIC DRUGS

INCIDENCE OF HEPATOTOXICITY

TABLE 27-2

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Recommended Antitubercular Therapy Schedule for Tuberculosis

Clinical Situation

Drug Therapy

Active tuberculosis: initial phase

Isoniazid 1 rifampicin 1 pyrazinamide 1 ethambutola for 2 months

Active tuberculosis: continuation phaseb

Isoniazid 1 rifampicin for 4 months for most patients Isoniazid 1 rifampicin for 7 months if: • cavitary tuberculosis with positive sputum after 2 months therapy • initial phase did not include pyrazinamide (if underlying liver disease) Isoniazid for 9 months Rifampicin with or without isoniazid for 4 months Isoniazid 1 rifapentine weekly for 12 weeks (DOT).c Managed in a similar fashion, although in the continuation phase isoniazid-rifampicin is recommended either daily (in a non-HIV patient) or at least thrice weekly; remember the drug interactions between rifampicin and antiretroviral agents

Latent tuberculosis infection

Tuberculosis in a patient with HIV

DOT, directly observed therapy. a If and when drug susceptibility results are known and the organism in not isoniazid resistant, then ethambutol need not be added to the initial phase. In children, as visual acuity cannot always be accurately monitored, ethambutol is not recommended unless there is strong clinical suspicion of infection being caused by isoniazid-resistant organisms or if the child has adult-type tuberculosis (upper lobe cavitation). b The continuation phase may be given daily or twice/thrice weekly by DOT. c Recent recommendation by the Centers for Disease Control and Prevention [8]. Adapted, with permission, from the American Thoracic Society Guidelines [3].

negative HBV serology, and no other apparent cause of hepatitis. Possible hepatitis was defined as AST ,250 Karmen units or AST .250 Karmen units in the presence of other causes of liver disease or AST . 250 Karmen units, but lacking other biochemical tests. The overall incidence of hepatitis was 1.25% (a total of 174 probable and possible cases), with most occurring within the first 3 months of treatment. The hepatitis risk increased dramatically with age, being 0%, 0.3%, 1.2%, and 2.3% among those aged ,20, 20
34, 35
49, and 50
64 years, respectively. Alcohol consumption appeared to more than double the rate of isoniazid hepatitis, with daily alcohol consumption increasing the rate more than four times [16]. Overall, there were eight deaths (0.06%) due to acute liver failure (ALF), of which seven occurred in the Baltimore area. Black females accounted for five of the eight deaths [16]. The unexpectedly high mortality resulted in termination of the study. Both Garibaldi et al.’s study [15] and the one commissioned by USPHS [16] finally brought to attention the hepatotoxic potential of isoniazid.

INCIDENCE OF HEPATOTOXICITY The use of multiple drug regimens, varying definitions of drug-induced liver injury (DILI), different study populations (as regards gender, ethnicity, alcohol consumption, and coinfection with other viruses), along with variable monitoring, makes it difficult to be certain of the precise incidence of antitubercular therapy (ATT)-induced hepatotoxicity. In fact, very few studies have followed the World Health Organization guidelines, in which DILI is classified as mild (serum aminotransferases ,5 3 ULN), moderate

(serum aminotransferases 5
10 3 ULN), and severe (serum aminotransferases .10 3 ULN) [17]. Another contentious issue is that in some studies, other causes of liver injury, specifically viral hepatitis, have not always been diligently excluded [18,19]. In addition, the occurrence of DILI with ATT appears to be higher in developing (8
10%) [20] than in developed (4%) countries [21], probably due to a higher prevalence of viral hepatitis and malnutrition [18,22,23], although genetic factors cannot be excluded. Even if we account for these factors, identification of DILI cases remains problematic and highlights the need for prospective surveillance networks [24]. Despite these limitations, the incidence of hepatotoxicity associated with multidrug regimens and isoniazid monotherapy is best illustrated in an excellent meta-analysis performed by Steele et al. [10], which included 34 studies published between 1966 and 1989 (22 in adults and 12 in children). Only clinical trials or surveys of public health departments in which strict hepatitis criteria were stated (elevated bilirubin, clinical manifestations of hepatitis in conjunction with AST .1,000 U/L) were included. The incidence of hepatitis was: isoniazid alone, 0.6% (82/38,257); with multidrug regimens containing isoniazid without rifampicin, 1.6% (33/2,053); with regimens containing rifampicin and not isoniazid, 1.1% (14/1,264); and with regimens containing both isoniazid and rifampicin 2.5% (156/6,105) [10]. The overall incidence of hepatotoxicity in regimens containing isoniazid-rifampicin was significantly higher than in those that had isoniazid without rifampicin (P 5 0.04) or rifampicin without isoniazid (P 5 0.008). However, the incidence of clinical hepatitis was similar in regimens that contained isoniazid without rifampicin or rifampicin without isoniazid

III. HEPATOTOXICITY OF SPECIFIC DRUGS

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27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

(P 5 0.87). In children, the incidence of hepatitis in the isoniazid alone group was 0.2%; in multidrug isoniazid regimens without rifampicin it was 1%; and in the isoniazid-rifampicin group it was 6.9%. Thus, in both adults and children, hepatitis with ATT was significantly higher with regimens that contained both isoniazid and rifampicin, rather than when these drugs were used separately [10]. However, due to a lack of data, the authors were unable to stratify the incidence of hepatitis according to age, severity of underlying illness, and alcohol consumption [10]. Since the phenotype of toxicity from isoniazid and rifampicin are different, based on the published data, it is difficult to draw conclusions as to whether the effects of the two drugs are additive or synergistic, although our view is that the combination is synergistic with regard to hepatocellular injury phenotype. A British study published a few years later involving 1,317 persons reported the incidence of hepatitis as follows: isoniazid 0.3%, rifampicin 1.4%, and pyrazinamide 1.25% [25]. However, since pyrazinamide was utilized for only 2 months and isoniazid and rifampicin were used for 6 months or longer, the hepatitis rate per treatment month was three times higher with pyrazinamide compared to rifampicin, and five times higher than for isoniazid. This suggests that pyrazinamide probably has the most hepatotoxic potential of all the antitubercular drugs [26].

nature of isoniazid toxicity might reflect the unique features of isoniazid metabolism, which, along with response to injury, could dictate who will develop subclinical or overt toxicity. Thus, toxicity does not need to exhibit a relation to dose or blood level concentrations, as the toxicity occurs at normal levels when a downstream toxic pathway is favored. Figure 27-1 illustrates the metabolism of isoniazid. It is first acetylated into acetylisoniazid [by the polymorphic N-acetyltransferase 2 (NAT2)], which is then hydrolyzed into acetylhydrazine and isonicotinic acid. Acetylhydrazine can then be further acetylated (again by NAT2) to a stable metabolite, diacetylhydrazine, or hydrolyzed (by an amidase) to hydrazine. A small proportion of isoniazid is directly hydrolyzed by the amidase to isonicotinic acid and hydrazine (Fig. 27-1; utilization of this pathway is greater in slow acetylators) [31,32]. Hydrazine can therefore be generated directly by hydrolysis of isoniazid or indirectly by hydrolysis of acetylhydrazine, both sources involving the activity of the amidase [32]. Hydrazine is a known hepatotoxin in animal models [33,34] and the most plausible mechanistic animal model of isoniazid toxicity involves the conversion to hydrazine. It is unclear if the hydrazine involved in Isoniazid O

C

Acetylisoniazid O

NH-NH2

C

1

MECHANISM OF HEPATOTOXICITY The pathogenesis of isoniazid hepatotoxicity is not fully understood. Although clearly idiosyncratic, the issue of mechanism is unresolved. Drug hypersensitivity has been considered unlikely because of the variable and often prolonged time lag between exposure to the drug and onset of symptoms, and also because most patients can be rechallenged with isoniazid without recurrence of the hepatotoxicity [27]. Absence of fever, eosinophilia, and rash also argue against a hypersensitivity phenomenon. However, in rare cases there is evidence of an allergic phenomenon in the form of prominent eosinophils on liver biopsy and development of hepatotoxicity on rechallenge [28,29]. On the other hand, rat hepatocytes maintained in gel entrapment culture are susceptible to isoniazid-induced killing accompanied by glutathione (GSH) depletion and protection with use of N-acetylcysteine (NAC) or cytochrome P450 2E1 (CYP2E1) inhibition [30]. Owing to the lack of allergic features, a direct toxic effect of the drug or its metabolite has been widely held to be more relevant. Both overt and subclinical hepatotoxicity is not related to serum isoniazid or acetylhydrazine concentrations. However, the idiosyncratic

O

NH-NH-C-CH3

N

2

N Isonicotinic acid O

C

OH

2

N NH2-NH2 Hydrazine

1 2

O NH2-NH-C-CH3 Acetylhydrazine 1 O

O

CH3-C-NH-NH-C-CH-CH3 Diacetylhydrazine

3 Toxic metabolite 1. N acetyl transferase (NAT) 2. Amidase 3. CYP reductase vs. CYP (not clear which)

FIGURE 27-1

Metabolism of isoniazid. CYP, cytochrome P450. Reprinted with permission from Sarich et al. [32].

III. HEPATOTOXICITY OF SPECIFIC DRUGS

MECHANISM OF HEPATOTOXICITY

toxicity is derived directly from isoniazid or from N-acetylhydrazine. Hydrazine appears to undergo conversion by NADPH-cytochrome P450 reductase (P450R) to a nitrogen-centered radical or by CYP to a carbon-centered radical [35
37]. Irrespective of the uncertain identity of the ultimate toxic species and the relative roles of CYP versus reductase in its formation, strong support exists for the hydrazine as the proximate toxin. CYP2E1 increases hydrazine-induced hepatotoxicity in rats [38]. The most reliable animal model of isoniazid toxicity is the rabbit given repeated doses over 2 days; hepatic necrosis develops [32,39]. Plasma hydrazine, but not acetylhydrazine or isoniazid, levels correlate with necrosis. Phenobarbitone pretreatment increases toxicity, suggesting the possible potentiation of isoniazid hepatotoxicity with induction of CYP enzymes [34,39]. In the rabbit model, inhibition of the amidase by bis-p-nitrophenyl phosphate (BNPP), protects against necrosis and steatosis (Fig. 27-2) [32]. Also, tocopherol or cimetidine protects in this model [40]. GSH depletion is modest in this model and does not correlate with the toxicity; therefore, there is no evidence of a role for GSHinduced detoxification of the toxic metabolite [32]. Furthermore, the toxicity of isoniazid in a rat hepatocyte suspension is blocked by inhibiting hydrazine formation with BNPP [41]. Using an up-to-date omic approach to assess the effects of hydrazine in rats has provided some insights; for example, upregulation of HSPA5 mRNA [translated to 78 kDa glucose-regulated protein (GRP78)] and downregulation of GSH, superoxide dismutase, and genes related to lipid transport. Most of these changes were confirmed at the level of protein expression. Metabolite profiling (nuclear magnetic resonance of serum) revealed alterations in lipid and glucose metabolism [42]. However, it is not certain if these omic profiles reflect pathways leading to injury or a response to injury. The recent examples of drug-associated hepatotoxicity associated with HLA (histocompatibility antigen) markers, even in the absence of systemic allergic features and with phenotypes quite similar to isoniazid, have led to a reappraisal of the possible role of 300 250

240 ± 81

ALT

200 150 62.8 ± 24

100 50 0

24.9 ± 2.3 Control

INH

INH + BNPP

FIGURE 27-2 Effect of amidase inhibitor on serum alanine aminotransferase levels. ALT, alanine aminotransferase; BNPP, bis-pnitrophenyl phosphate; INH, isoniazid. Adapted from [32].

487

the immune system [43]. The delayed nature of the isoniazid injury, adaptation in most individuals, and negative rechallenge are now recognized to occur commonly in presumed immune-mediated idiosyncratic DILI (IDILI). The adaptation and negative rechallenge could be due to the development of immune tolerance. Certainly, an immune-mediated injury from a drug may be determined by the exposure to a toxic metabolite (adduct formation) or a level of mild stress (danger) induced by the metabolite, which then favors the development of an adaptive immune response. Interestingly, isoniazid treatment is also associated with the development of drug-induced lupus [44]. In addition, one study found an association with HLA markers and antitubercular hepatotoxicity [45]. Furthermore, some evidence suggests that isoniazid may be directly oxidized by CYP to a reactive metabolite, which could be the hapten for an immune response [43]; either hydrazine (directly from isoniazid or from acetylhydrazine) or an oxidation product of isoniazid could serve as a hapten. Although we have favored metabolic idiosyncrasy in the past, the arguments raised by Uetrecht and colleagues in favor of an immune mechanism [43] and the mounting evidence with other examples of IDILI with a similar phenotype to isoniazid hepatotoxicity (e.g., lapatinib, lumiracoxib, and ximelagatran) are compelling by their striking HLA associations in favor of immune mechanisms. At present, this is an unresolved issue and the results of genetic studies of cohorts of isoniazid-treated patients currently under way are greatly anticipated and may resolve this uncertainty. Rifampicin is metabolized in the liver, mainly by deacetylation followed by glucuronidation, and is excreted in large concentrations in the bile as desacetyl rifampicin [46]. The mechanisms underlying rifampicin hepatotoxicity are also unclear. An allergic reaction is a possibility but is probably responsible for only 1
3% of the cases [47]. Rifampicin does transiently increase serum bilirubin (mostly unconjugated), but this is related to competitive inhibition of bilirubin uptake or excretion at the level of the hepatocyte membrane and is not indicative of hepatotoxicity [48,49]. This effect is more prominent in children and may contribute to the increased incidence of jaundice in children compared with adults [10]. It is, however, well established that combined isoniazid-rifampicin is associated with a greater risk of hepatotoxicity than either drug alone. During isoniazid metabolism, reactive toxic metabolites are produced by oxidation of hydrazine by the microsomal CYP enzymes. Since rifampicin induces the microsomal enzymes, it could theoretically result in increased production of this toxic metabolite. This would account for the enhanced and more rapid hepatotoxicity when

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27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

rifampicin is coadministered with isoniazid. Although this attractive and plausible hypothesis was first postulated in the early 1990s, it remains to be confirmed [50
52]. In addition, rifampicin also induces the metabolism of isoniazid by amidase (especially in slow acetylators), resulting in increased direct formation of hydrazine [43
55]. It is nonetheless uncertain whether the hepatotoxicity of the isoniazid-rifampicin combination is additive or synergistic. It should also be recognized that a rifampicin-mediated increase in a toxic moiety, e.g., hydrazine, is not inconsistent with an immune mechanism, as the likelihood of an immune response may depend on the toxic moiety reaching a certain threshold of adduct and/or danger to elicit an immune response The mechanism responsible for pyrazinamide hepatotoxicity also remains to be elucidated. Lack of hypersensitivity signs and symptoms argue against an allergic phenomenon. It may be a direct toxic effect of the drug, as prolonged duration of therapy and higher doses increase the risk of hepatotoxicity [50,56]. At present, there are no data to support a deleterious effect of rifampicin on pyrazinamide, as pyrazinamide is not metabolized by the CYP system but by both a microsomal deaminase and xanthine oxidase (XO) and rifampicin does not appear to enhance any of these enzymes [50]. Nonetheless, the combination of rifampicinpyrazinamide is associated with an increased risk of severe hepatotoxicity in the treatment of LTBI and is no longer recommended [2,4].

HEPATOTOXICITY OF INDIVIDUAL DRUGS Isoniazid This first-line tuberculosis drug shows bactericidal activity against both extra- and intracellular organisms [50]. Earlier studies by Garibaldi et al. [15] and data from surveillance programs [16] suggest that approximately 10% of subjects who receive isoniazid monotherapy develop abnormal serum aminotransferases (usually ,3 3 ULN). In most of these cases, the subjects report no symptoms and discontinuation of therapy is not warranted. Only about 1% of patients on isoniazid monotherapy develop the more serious form of hepatotoxicity—overt hepatitis. Two recent American studies corroborated this and reported that serum aminotransferase elevation of .5 3 ULN occurred in 0.3
0.56% of cases [57,58]. Isoniazidrelated hepatitis occurs mostly within the first 3 months, although it can occur as early as 1 week after drug initiation (Fig. 27-3). In contrast to those with asymptomatic serum aminotransferase elevations, patients with

35 30 25

Incidence of hepatotoxicity (%)

20 15 10 5 0

1

2

3

4

5

6

7

8

9

10 11 12

Months of therapy

FIGURE 27-3 Incidence of isoniazid hepatotoxicity depending on duration of therapy. Adapted from [16].

hepatitis are symptomatic, with anorexia, nausea, vomiting, abdominal pain, and jaundice. The significance of these symptoms occurring while on ATT cannot be overemphasized. It is therefore mandatory that treating physicians educate and regularly question patients on ATT about gastrointestinal symptoms. Other characteristic features of severe hepatitis include significant elevations in serum aminotransferases (.10 3 ULN). Jaundice is a sign of poor prognosis, as it is associated with a high mortality (10%). Of those patients with clinical hepatitis (symptomatic and/or jaundiced), about 5
10% (0.05
0.1% of patients treated overall) may develop a fulminant course characterized by coagulopathy and hepatic encephalopathy, for which an urgent referral to a liver transplant unit is necessary [3,51,59
62]. Overall death rates with isoniazid toxicity are 14.0 per 100,000 persons (0.014%) who started preventive therapy and between 23.2 and 57.9 in every 100,000 persons (0.023
0.057%) who completed therapy [16,60]. However, pooled results of published studies in which patients received isoniazid chemoprophylaxis and were monitored according to the ATS guidelines revealed a much lower mortality: overall 0.0009% (2 out of 202,497) and in those older than 35 years 0.002% (1 out of 43,334) [63]. Factors associated with mortality after isoniazid therapy include increasing age, female gender, delayed onset of hepatitis (2 months or more after treatment initiation), continuing isoniazid use after the onset of symptoms, and serum bilirubin .350 μmol/L (.17 3 ULN) [14,51,60
62,64].

Rifampicin This drug is also bactericidal against intra- and extracellular organisms. It is difficult to be sure of the

III. HEPATOTOXICITY OF SPECIFIC DRUGS

HEPATOTOXICITY WITH MULTIDRUG ANTITUBERCULAR THERAPY

exact hepatotoxic potential of rifampicin as it is often used as part of a multidrug regimen. However, rifampicin monotherapy therapy for 4 months is an acceptable alternative regimen for the treatment of LTBI [65]. There remains no doubt about the hepatotoxic potential of this drug, although it appears to be less likely than isoniazid monotherapy to result in DILI. A study from an American public health tuberculosis clinic reported a low incidence of rifampicininduced hepatotoxicity (AST/ALT of .5 3 ULN or .3 3 ULN with symptoms) during treatment of LTBI (1.95%, 95% CI, 0
4.33%). Of the four patients who developed liver injury, three had elevated serum aminotransferases at baseline [66]. However a 40% dropout rate in this study make the data difficult to interpret. In a recent randomized controlled trial among predominantly non-HIV-infected individuals, 4 months of rifampicin therapy was not only better tolerated than 9 months of isoniazid but was also associated with a lower incidence of serious adverse events leading to discontinuation of therapy (3.8% versus 0.7%) [67]. A meta-analysis involving approximately 3,500 subjects showed that noncompletion of therapy with 4 months of rifampicin was 8.8% to 28.4% compared to 24.1% to 47.4% among the isoniazid group. Grade 3
4 hepatotoxicity was also significantly lower with rifampicin [0
0.7% versus 1.4
5.2%; relative risk (RR), 0.12; 95% CI, 0.05
0.30] [68]. The dosing schedule may be important, as use of daily versus twice-weekly rifampicin therapy (in patients who received both isoniazid and rifampicin) resulted in a higher incidence of hepatotoxicity in the former (21% versus 5%) [20]. Liver injury due to rifampicin may result in a cholestatic liver panel [elevated bilirubin and alkaline phosphatase (ALP)]. This contrasts with the hepatitis-like liver injury (elevated serum aminotransferases) seen with isoniazid [50,69].

Pyrazinamide Pyrazinamide is only active against intracellular organisms. Liver injury is the most common and serious side effect of pyrazinamide treatment, generally resulting in a hepatitis-like liver injury similar to isoniazid; fever, arthralgia, skin rashes, and eosinophilia are usually absent. After its introduction in 1954, pyrazinamide was used in high doses (40
50 mg/kg) and asymptomatic elevation of serum aminotransferases and symptomatic hepatitis were observed in 20% and 10% of patients, respectively [50,70]. Fatal fulminant hepatitis was also reported, resulting in the drug being abandoned as first-line therapy for tuberculosis. More recently, pyrazinamide was reintroduced as first-line therapy (as the incidence of tuberculosis

489

increased) to overcome problems related to resistant strains. However, the current trend is to use a lower dose (30 mg/kg) for a shorter duration (2 months) [50]. There is very little data on incidence of hepatotoxicity with pyrazinamide monotherapy. In most cases where hepatotoxicity is reported, pyrazinamide has been used as part of a multidrug regimen. There is some evidence to suggest that addition of pyrazinamide to isoniazid-rifampicin increases the risk of hepatotoxicity. In a case-control study of 60 patients who had evidence of ATT-induced liver injury, the use of pyrazinamide was more frequent in the hepatitis group (70% versus 42%) [71]. In a recent Chinese study, the RR (95% CI) of hepatotoxicity for regimens incorporating pyrazinamide relative to non-pyrazinamide regimens was 2.8 (1.4
5.9) [72]. Durand et al. studied 18 patients with fulminant or subfulminant liver failure due to ATT, of whom nine had received pyrazinamide (at 30 mg/kg). Those in the non-pyrazinamide group developed liver failure, usually within 2 weeks of drug initiation, with a good overall prognosis (spontaneous survival in eight out of nine). In the pyrazinamide group, two patterns were seen: one of an onset within 15 days (similar to the non-pyrazinamide group) with a good prognosis; and a second in which liver failure occurred later (18
244 days after initiation) and was associated with a dismal prognosis (overall survival of two out of nine) [56]. Continuation of pyrazinamide after the first manifestation of hepatitis increased the risk of a fatal outcome [3,56]. Use of rifampicin-pyrazinamide for LTBI is also associated with a higher incidence of hepatotoxicity compared to isoniazid alone (see the next section) and this regimen is no longer recommended [4]. However, Snider et al. did not find an increased risk of hepatotoxicity with the addition of pyrazinamide to the ATT regimen [73]. A recent meta-analysis also showed that the risk of pyrazinamide-induced hepatotoxicity was not dose related and not different when used as mono- or combination therapy [74]. Despite these conflicting results, our opinion is that the use of pyrazinamide does increase the risk of hepatotoxicity over and above that caused by isoniazid and rifampicin.

HEPATOTOXICITY WITH MULTIDRUG ANTITUBERCULAR THERAPY As Steele et al. demonstrated in their meta-analysis, the incidence of hepatotoxicity is significantly higher in patients who receive combination therapy than those who receive these drugs individually [10]. The incidence of hepatotoxicity varies from 3% to 4% in the United States and United Kingdom, respectively, to approximately 11% in countries like India [21,73,75].

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However, it is difficult to accurately assess the contribution of each individual drug or whether this toxicity is additive or synergistic. Increased serum aminotransferases are seen in approximately 10% of those that receive isoniazid monotherapy, but this is increased to 20% if rifampicin is added; in addition, the hepatitis occurs sooner (after 2 rather than 4 weeks) [10,51,52,76]. Use of a daily and twice-weekly rifampicin-pyrazinamide combination for treatment of LTBI is also associated with an increased risk of severe hepatotoxicity [4,77]. From January 2000 to June 2002, the CDC monitored data on hepatotoxicity associated with rifampicin-pyrazinamide, which were reported to the CDC until June 2003. For surveillance purposes, severe liver injury was defined as leading to hospitalization or death. Of the total of 7,737 patients who started rifampicin-pyrazinamide for LTBI, 5,980 (77%) received daily doses and 1,757 received twice-weekly doses. A total of 204 (2.6%) patients discontinued therapy because of AST .5 3 ULN. An additional 146 (1.9%) patients stopped therapy because of symptoms of hepatitis. There were 48 (0.6%) cases of severe liver injury, of whom 11 (23%) died [4]. In two clinical trials in nonHIV persons, significant hepatotoxicity (AST/ALT .5 3 ULN) ranged from 10% to 35% in patients receiving therapy with rifampicin-pyrazinamide for 2 months and was significantly higher than that observed in the group receiving isoniazid monotherapy (2.5% and 2.8%, respectively) [78,79]. This was corroborated in a meta-analysis of different regimens for LTBI among HIV-infected subjects, where the isoniazid regimen was less likely to be stopped because of adverse events (RR, 0.63; 95% CI, 0.48
0.84) compared to rifampicinpyrazinamide combination therapy [80]. In view of this current evidence, rifampicin-pyrazinamide combination is no longer recommended as treatment for LTBI [4]. Finally, use of pyrazinamide in combination with isoniazid-rifampicin is also associated with a higher incidence of hepatic adverse effects, as mentioned above [56,71]. It is uncertain whether the hepatotoxic potential of isoniazid and pyrazinamide is affected by coadministration of ethambutol and streptomycin [76].

RISK FACTORS FOR ANTITUBERCULAR THERAPY HEPATOTOXICITY Acetylator Status and CYP2E1 Polymorphisms The acetyltransferase NAT2 plays an important role in the metabolism of isoniazid. About 60% of Caucasians and blacks and 20% of Asians (Chinese and Japanese) are slow acetylators [81]. Some regard slow acetylators to be at increased risk of isoniazid hepatotoxicity, especially if isoniazid is used with

rifampicin [20]. Others have reported DILI more often in fast acetylators [82,83]. However, two studies subsequently showed no impact of acetylator status on the risk of developing hepatotoxicity [75,84]. This included a study from South India by Gurumurty et al. with approximately 3,000 patients who received various isoniazid-containing regimens [84]. A more recent study from Switzerland corroborated these findings and reported no significant influence of NAT2 polymorphism on the risk of isoniazid-induced hepatitis or elevated liver enzymes [85]. There could be a number of reasons for these discrepant results. First, it may be that, although fast acetylators form acetylhydrazine more rapidly than slow acetylators, they also tend to inactive at this precursor of the reactive metabolite more quickly into the stable metabolite, diacetylhydrazine [50]. Second, it may be a reflection of the different genotype distribution among the Asian and the European populations. Third, some researchers phenotyped (rather than genotyped) acetylator status, and this can be influenced by many extrinsic factors. Finally, it could be related to drug-drug pharmacokinetic and pharmacodynamic interactions, as rifampicin is known to reduce NAT2 activity and isoniazid is known to have a biphasic effect on CYP2E1 [85]. To determine more accurately whether acetylator status affects the risk of hepatotoxicity, Huang et al. genotyped NAT2 in over 200 patients on ATT. They observed slow acetylators to be at an increased risk of hepatotoxicity after multidrug ATT (26% versus 11%). In addition, once the slow acetylators developed hepatotoxicity, they were prone to develop more serious hepatic injury than were the rapid acetylators [86]. A more recent study from Taiwan (in which 140 patients were treated with multidrug ATT) confirmed these results. Slow acetylators defined by NAT2 genotypes [NAT2*7 (rs1799931)] had a higher risk of hepatotoxicity (ALT .2 3 ULN) than rapid acetylators (51.2% versus 25.2%; P 5 0.0026), with an odds ratio (OR) of 3.98 (95% CI, 1.72
9.25) [87]. Pyrazinamide coadministrationinduced hepatitis was also associated with NAT2 acetylator status [87]. In one of the largest such studies in tuberculosis contacts in British Columbia (n 5 170; 43.5% Caucasian and 34.8% Asian), no single genetic variant of NAT2 and CYP2E1 showed significant association with isoniazid-induced hepatotoxicity, although there was a trend across rapid, intermediate, and slow acetylator groups [88]. Thus, although a genetic polymorphism of NAT2 (slow acetylators) may be a modest risk factor for isoniazid toxicity, it cannot alone account for the idiosyncratic nature of this problem. The high frequency of slow acetylator status precludes the use of genotyping for making decisions regarding the use of isoniazid.

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During the metabolism of isoniazid, CYP2E1 may play an important role in the oxidation of hydrazine to toxic metabolites. This enzyme exhibits genetic polymorphisms in intron 6 and its three genotypes are classified as c1/c1 (wild type), c1/c2, and c2/c2 [89]. NAT2 and CYP2E1 polymorphisms may act synergistically. Huang et al. genotyped CYP2E1 and NAT2 status in 318 patients receiving multidrug ATT and observed that the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status [90]. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype was an independent risk factor for hepatotoxicity [90]. The mutant c2/c2 genotype (25% of Asian population) was somewhat protective. Basal CYP2E1 activity is unaffected by this polymorphism and its functional significance is unclear, although the CYP2E1 activity (phenotype) was less inhibited by isoniazid in c1/c1 patients. It is also possible that this gene is in linkage disequilibrium with other genes. A study in a pediatric population also showed an association between multidrug ATT-induced hepatotoxicity and CYP2E1 genotype [91]. A recent meta-analysis that included five studies on NAT2 polymorphisms and four on CYP2E1 reported a modest increase in the risk of ATT-induced hepatotoxicity with the NAT2 homozygous variant genotype and CYP2E1 homozygous wild genotype [OR (95% CI) of 1.93 (0.81
4.62) and 2.2 (1.06
4.66), respectively] [92]. Age It is well established that isoniazid hepatotoxicity is related to age and is very uncommon below the age of 20 years [16,24,93]. A Danish study observed that patients .60 years of age were significantly more likely to have abnormal serum aminotransferases after administration of isoniazid and rifampicin compared to their younger counterparts [93]. A recent report from the USPHS on isoniazid monotherapy using AST monitoring ( . 5 3 ULN) revealed an age-dependent risk of hepatotoxicity of 0.44% for ages 25
34, 0.85% for ages 35
49, and 2.08% for ages $ 50 years [57]. In a study of isoniazid treatment of LTBI involving more than 11,000 patients in Seattle, symptomatic serum aminotransferase elevation varied from 0% if ,14 years to 28% if .65 years of age [94]. In a similar study from Tennessee, AST .5 3 ULN occurred in 0.44% of subjects ,35 years and 2.08% of subjects .49 years [57]. Finally, in a systematic review that included seven studies and 115 cases of hepatotoxicity, the incidence of hepatotoxicity with isoniazid and rifampicin for LTBI treatment was as follows : age .35years, 1.7% (95% CI, 1.4
2.2); and age ,35 years, 0.2% (95% CI, 0.1
0.3) [95]. It should be noted that the association of hepatotoxicity with age has also been observed when

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isoniazid is used in combination with other hepatotoxic tuberculosis drugs [56]. However, a recent cluster-randomized study from South Africa reported that clinical hepatotoxicity with community-wide isoniazid preventative therapy was not associated with age, sex, weight, or concurrent ART, but was associated with alcohol consumption [96]. In this trial, the incidence of hepatotoxicity was 0.04% (3 out of 7,763) in those ,35 years of age compared to 0.07% (14 out of 16,404) in those .35 years of age. Due to the low incidence of hepatic adverse events, and the fact that over two-thirds of the participants were ,45 years of age, the results of this study must be interpreted with caution. Mortality due to isoniazid-induced liver injury is also age dependent, as Snider et al. observed in their review of 177 isoniazid-related deaths: 60.8% of the deaths occurred in those . 50 years of age, in contrast to 9.2% in those ,20 years of age [60]. A recent study from India (the largest prospective study on ATT and ALF; n 5 70) also found nonsurvivors to be older than survivors (mean age 34.8 6 16.8 versus 28.8 6 12.9), although the differences did not reach statistical significance [62]. In children, age may have less of an impact, and a recent pediatric study reported no statistical difference in the incidence of overall isoniazidrelated toxicity in groups aged ,5 years, 5
10 years, and .10 years [97]. The reasons why age affects DILI phenotypes are unclear but may include clearance of certain CYP3A substrates, impaired renal function, production of more reactive metabolites in the elderly, or exaggerated immune responses to these metabolites [98] Drug Dose Even though it is traditionally accepted that IDILI is not dose dependent, idiosyncratic drug reactions are unusual if patients receive drug doses less than 10 mg/day [99]. Recent data from two pharmaceutical databases also showed that serious DILI (liver failure or the need for a liver transplant) and death were more likely to occur with increasing daily drug doses ( . 50 mg) [100]. The Spanish Hepatotoxicity Registry corroborated this; 77% of their cohort with DILI received .50 mg/day [101]. Regarding the question of whether isoniazid hepatotoxicity is dose dependent, in two large studies, this did not appear to be the case [83,102]. However in another series, 9 out of 18 patients who developed fulminant liver failure after multidrug ATT regimens had received isoniazid at higher (10 mg/kg) than the maximum recommended dose (5 mg/kg) [56]. Pessayre et al. also reported 6 patients with fulminant hepatitis who had received isoniazid in doses in the range of 9.5
19 mg/kg [76]. Therefore, it appears that mild variations from the recommended dose of

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isoniazid (5 mg/kg) may not increase the risk of hepatotoxicity, but increasing the dosage to around 10 mg/kg or greater may incur a higher risk [50]. With rifampicin, accidental overdose has resulted in serious liver injury [103]. Regarding pyrazinamide, the earlier tendency to use the drug at higher doses (40
50 mg/kg) was associated with a high risk of asymptomatic elevation of serum aminotransferases and symptomatic hepatitis (20% and 10%, respectively) [50,70]. Alcohol Use It has been suggested that alcohol abusers are more likely to develop hepatotoxicity with both multidrug antitubercular regimens and isoniazid monotherapy [104]. Pande et al. observed a high alcohol intake in 19.8% of those with ATT hepatotoxicity compared to 4.9% of controls [23]. The association between alcohol excess and ATT is not surprising as first, alcohol dependent patients may be GSH depleted (although there is no evidence that GSH detoxifies the reactive metabolite of isoniazid) and, second, chronic alcohol abuse induces the CYP2E1 enzyme, which could further enhance the formation of the toxic metabolite [50]. A recent study from South Africa found that daily alcohol use rather than age was more likely to be associated with hepatotoxicity with isoniazid monotherapy [96]. However, some studies, including prospective registries, have shown that alcoholics are not at a greater risk of hepatotoxicity from ATT or isoniazid monotherapy [57,93,104,105]. Enzyme Inducers Other than Rifampicin There are a number of drugs that induce hepatic CYP enzymes, thus increasing the risk of hepatotoxicity with isoniazid. Fulminant hepatic failure has been reported in patients who initiated therapy with isoniazid and rifampicin after receiving general anesthesia with halothane [76]. It has been reported that induction of CYP2E1 by isoniazid increases the risk of acetaminophen (paracetamol) toxicity and ALF has been observed in patients on ATT who were prescribed therapeutic doses of acetaminophen (,4 g/day) [106
108]. In the series of Nolan et al., all three patients were receiving multidrug ATT, including rifampicin, which is also a known inducer of the microsomal enzymes [106]. Crippin et al.’s case report involved a 21-year-old Asian female who had initiated isoniazid chemoprophylaxis 6 months previously (with a normal liver panel at 5 months) and, after ingesting only 3.25 g of acetaminophen, developed ALF (AST, .20,000 IU/L; bilirubin, 159 μM; prothrombin time, 26 s). Treatment with NAC was commenced and a referral initiated for a liver transplant evaluation, but she improved clinically and biochemically over the next week [107]. Murphy et al. reported on

acetaminophen-induced hepatotoxicity after ingestion of 11.5 g by a patient being treated with 300 mg isoniazid daily [108]. Thus, when hepatotoxicity develops in a patient receiving isoniazid, careful assessment of acetaminophen use is critical. Accurate attribution of cause (isoniazid versus acetaminophen) may be very challenging. Towering serum aminotransferases (.3,000 IU/L) may be a clue pointing to acetaminophen. The employment of a test for serum acetaminophen-protein adducts shows promise as a means of verifying the role of acetaminophen [109]. We recommend that patients receiving isoniazid should limit acetaminophen to 2 g/day or less, similar to the recommendation for alcoholics. Gender Women, especially if pregnant or elderly, appear to be at increased risk of developing ATT-related hepatotoxicity [110,111]. This is a nearly universal observation in DILI. In a prospective study on 603 patients with DILI (of whom 38 had received ATT), men and women were equally represented (51% and 49%), with men more likely to be older and develop cholestasis and women being younger with a propensity for hepatitic injury. However, the development of ALF and/or the need for liver transplant was significantly higher in women [101]. A prospective trial of the Drug-Induced Liver Injury Network corroborated this and showed a greater number of women with hepatocellular DILI than men (65% versus 35%; P , 0.05) [112]. Snider et al., in their review of 177 isoniazid-associated deaths, reported a higher prevalence of women (69%), with 38% of deaths occurring in the postpartum period [60]. In a large series of pregnant women, the incidence of isoniazid-induced hepatitis and death were twofold and fourfold higher, respectively, compared to nonpregnant women [110]. In two recent studies (one from India and another French), approximately 70% of the patients with ATT-induced ALF were women [61,62], and in the Indian study 10% were pregnant as well [61,62]. This apparent increased risk of hepatotoxicity and associated morbidity/mortality in women could be related to multiple factors: that a larger number of women than men were being treated; that women were more compliant and had better follow-up, especially during pregnancy; or possibly due to genderrelated variations in drug metabolism. However, in a series of 20 isoniazid-related deaths reported from California, 80% were women (of whom 25% were postpartum), and, even taking into account the fact that more women than men received isoniazid, the difference in mortality was still striking [113]. Thus, it appears that the increased isoniazid-related morbidity/mortality in women is real and not spurious. It is therefore recommended that women who

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require isoniazid should be closely monitored and, if pregnant, should receive isoniazid based on their prepregnancy body weight in order to minimize risk of overdose [50]. Race or Ethnicity Blacks appear to be at particularly high risk of hepatotoxicity from ATT [16,51]. This was further corroborated by the French study, in which 64% of patients with ATT-induced ALF were black [61]. In a review of probable and possible isoniazid-related deaths (n 5 62), 49 (79%) were non-Hispanic black (50%) and Hispanic (29%) [114]. A study in patients with HIV also suggested that non-white race/ethnicity is associated with increased risk of hepatotoxicity [115]. Other Genetic Factors Other genetic factors that have been studied include the HLA II (encoding histocompatibility antigen class II) alleles. In a study from North India, Sharma et al. observed that absence of HLA-DQA1*0102 (adjusted OR, 4.0) or the presence of HLA-DQB1*0201 (adjusted OR, 1.9) were independent risk factors for ATTinduced liver injury [116]. Malnutrition In studies from India, a higher incidence of isoniazid-rifampicin hepatotoxicity has been reported in malnourished patients [23,117]. In the study by Singhla et al., a midarm circumference of ,20 cm and albumin of ,3.5 g/dL were independent predictors of ATT-induced DILI. Drug-metabolizing processes in the liver, including acetylation or GSH detoxification, are altered under conditions of protein energy malnutrition. In fact, a significant decrease in isoniazid metabolism has been observed in kwashiorkor [118]. Another reason that poor nutritional status may be a risk factor for ATT hepatotoxicity is the tendency for such patients to receive higher doses of the drug on a body weight basis [71]. In fact, a study from the Netherlands reported that weight loss during ATT (of 2 kg or more) was the most important risk factor for DILI, necessitating interruption of antitubercular drugs [119]. Underlying Chronic Liver Disease Including Coinfection with Hepatitis B and C Gronhagen-Riska et al. observed that approximately 50% of patients who developed moderate increases in serum aminotransferases (.150 IU/L) after isoniazidrifampicin therapy had a history of either alcohol excess or underlying chronic liver disease [111]; this was corroborated by Kopanoff et al. [16]. There is also a case series of three patients with primary biliary cirrhosis who initiated rifampicin as an antipruritic agent. All developed significant hepatitis and impairment of

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synthetic function within 2 months of the initiation of therapy, necessitating liver transplantation in one patient [120]. In liver disease, metabolism of both isoniazid and rifampicin is impaired, resulting in increased serum elimination half-life [46]. Acocelia et al. observed that there were no pharmacokinetic interactions between isoniazid and rifampicin in patients with cirrhosis but that both drugs had prolonged half-lives [121]. These data indicate that these drugs should be used with caution in patients with moderate to severe liver disease [46,121]. The presence of chronic hepatitis B virus (HBV) infection appears to increase the risk for ATT hepatotoxicity. Following isoniazid-rifampicin therapy, Wu et al. observed higher peak ALT (1,353 IU/L versus 885 IU/L), bilirubin (18.1 mg/dL versus 4.4 mg/dL), and incidence of fulminant/sub-ALF/mortality (47% versus 4%) in patients who were HBV carriers versus noncarriers. The carriers (who were all HBcIgM negative) also developed the hepatotoxicity after a significantly longer duration of therapy (110 days versus 52 days) [122]. A study in Chinese patients with chronic HBV infection (of whom 26% were HBeAg positive) found a higher prevalence (26.3% versus 8.8%) of DILI (serum aminotransferases .1.5 3 ULN or .1.5 3 baseline) and more severe histological injury in carriers compared to noncarriers, even after excluding those with elevated pretreatment serum aminotransferases and periportal interface hepatitis (a direct HBV effect) [123]. Another interesting observation in this and Wu et al.’s study [122] was that episodes of hepatotoxicity were preceded by increased HBV DNA levels. This raises the issue of whether to use prophylactic antiviral agents prior to the introduction of ATT in patients with chronic HBV infection, but begs the question of whether the toxicity is really due to ATT or to HBV reactivation/flare due to ATT (since fewer untreated HBV controls had spontaneous hepatitis). The underlying mechanism(s) remains unclear but may be related to ATT-induced immune reconstitution. In a more recent and the largest such study from Korea, Lee et al. report on 110 inactive hepatitis B surface antigen (HBsAg) carriers who were treated with isoniazid, rifampicin, ethambutol, and/or pyrazinamide. All had normal pretreatment serum aminotransferases, were HBeAg negative and HBeAb positive, and had ,105 copies/mL of HBV DNA. Thirty-five percent of HBV carriers versus 20% of controls developed an increase in serum aminotransferases (P 5 0.01). Moderate to severe hepatotoxicity (serum aminotransferases .5 3 ULN) also occurred more frequently in the carriers (8% versus 2%; P 5 0.05), although ATT could be safely reintroduced in over 50% of the carriers [22]. Unfortunately, HBV DNA levels were not available in this study. In contrast, chemoprophylaxis with isoniazid in young HBV

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carriers (,35 years of age) does not appear to be associated with increased risk of hepatotoxicity [124]. Coinfection with hepatitis C virus (HCV) and HIV may also increase the risk of ATT hepatitis [125
127]. A study from Taiwan showed that during standard ATT therapy in 295 patients with active tuberculosis, 25 (8.5%) developed hepatitis, of whom 7 (28%) had a positive HCV serology and three (12%) had a positive HBV serology. Multivariate analysis showed that HCV but not HBV infection was an independent predictor of ATT-induced hepatitis (OR, 3.42; 95% CI, 1.14
10.35; P 5 0.03). More worrisome was the fact that mortality was significantly higher in those that developed hepatitis (32% versus 7%; OR, 6.22; 95% CI, 2.0
17.6; P 5 0.001). Unfortunately, HCV RNA and HBV DNA were unavailable in this study [125]. Ungo et al. also showed that the relative risk of ATT hepatotoxicity in patients being treated for tuberculosis was fivefold and fourfold, respectively, in the presence of HCV or HIV [126]; the risk was .14-fold increased if both viruses were present. In four of these patients (who had had recurrence of DILI upon rechallenge with ATT), liver biopsy findings revealed active inflammation that could be attributed at least in part to HCV. They were treated with interferon and, once the liver panel improved, were able to undergo reintroduction of ATT without reoccurrence of liver injury [128]. However not all studies have reported an increased risk of ATT-induced hepatotoxicity in the presence of HCV infection. A Korean study in fact observed no difference in risk of liver injury with ATT (defined as ALT .120 IU/L) in HCV-positive and HCV-negative patients with tuberculosis (4% versus 13%), but again data on HCV RNA was unavailable. ATT could be safely reintroduced in about 40% of HCV-positive patients [128]. Therefore, as with HBV coinfection, the interpretation of liver injury with chronic HCV remains a murky area; is it the ATT, reactivation/flare of the virus, or improved immune system due to control of the tuberculosis infection leading to attack on the virus? There is no certain answer at present and perhaps all are true. Such patients can therefore present a diagnostic dilemma (DILI versus viral reactivation) and sometimes the only diagnostic test will be to treat the underlying virus before reinitiating ATT. However, as observed with chronic HBV infection, the use of isoniazid monotherapy as chemoprophylaxis is not associated with an increased risk of hepatotoxicity in presence of chronic HCV infection [129,130]. What about ATT in patients with underlying cirrhosis due to chronic viral hepatitis? In a study from Korea, in 37 patients with cirrhosis (about 50% had cirrhosis due to HBV and 50% were Child-Pugh class B/C), the risk of hepatotoxicity with isoniazid- and

rifampicin-based ATT was higher in those with cirrhosis compared to a control group without cirrhosis (27% versus 10%; P 5 0.079) [131]. HIV Infection The risk of tuberculosis is higher in immunosuppressed patients and increases with the degree of immunosuppression [132]. Hence, the threshold to initiate ATT and/or isoniazid monotherapy for LTBI may be lower. Ung et al. [126] reported that in the presence of HIV, the use of ATT was associated with a fourfold increased risk of ALT elevation to 120 IU/L or total bilirubin to at least 1.5 mg/dL [126]. Another recent retrospective study from the United Kingdom also found that during treatment of active tuberculosis, HIV infection (but not concurrent use of ART) significantly increased the risk of hepatotoxicity (AST/ALT .3 3 ULN; 35% versus 7%; P 5 0.006) [133]. About 27% of the HIV cohort developed hepatotoxicity compared to 12% among the non-HIV group. However, an earlier study from the United Kingdom reported a similar incidence of grade III
IV hepatotoxicity in patients with and without HIV (13%) [134]. Therefore, despite the conflicting results, the presence of HIV should be regarded as a risk factor for DILI with ATT and regular liver function test (LFT) monitoring is recommended. Use of isoniazid monotherapy in adult and pediatric patients with HIV, however, does not appear to be associated with an increased risk of DILI, irrespective of the presence or absence of ATT [96,135].

CLINICAL, BIOCHEMICAL, AND HISTOLOGICAL FEATURES About 20% of patients develop mild abnormal serum aminotransferases with multidrug ATT, and more serious hepatotoxicity (AST/ALT .5 3 ULN) occurs in up to 4% [21]. Common symptoms include fatigue, anorexia, nausea, jaundice, and right upper quadrant pain. Symptoms precede jaundice and liver failure by only a few days. Symptoms are a reliable indicator of hepatotoxicity when present, but their absence does not negate the possibility of DILI. In a study of 72 consecutive patients with ATT-induced hepatitis from India, 61% presented with jaundice, 39% experienced nausea, vomiting, and abdominal discomfort, and only 1.3% (1/72) reported a skin rash or fever; 12 (15%) developed fulminant/ALF, of whom 75% died [75]. It is therefore of paramount importance that patients on ATT be regularly questioned about gastrointestinal symptoms, as continuing drug use in the presence of existing liver damage can worsen liver injury and ultimately prognosis. However, we

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recommend ALT monitoring of all patients receiving multidrug regimens (see below). Hepatotoxicity with isoniazid monotherapy usually develops within the first few months of therapy, with the peak incidence being 2 months after initiation of treatment (Fig. 27-3). With multiple drug ATT (isoniazid, rifampicin, and pyrazinamide), two patterns of hepatotoxicity can be recognized. The first is characterized by elevated serum aminotransferases, occurring within the first 2 weeks and probably related to rifampicin-induced hepatotoxicity of isoniazid. This short interval between drug initiation and hepatotoxicity is associated with a relatively good prognosis, even in the presence of fulminant hepatic failure. The second pattern consists of hepatotoxicity that occurs more than 4 weeks after starting ATT. As discussed above, this is associated with a poorer prognosis. Most cases of late hepatotoxicity appear to be associated with concomitant use of pyrazinamide. However, this classification of ATT-induced hepatotoxicity into an early and late type is not absolute, and it is imperative that all ATT is suspended in the presence of moderate to severe liver injury [50,56]. ATT-induced hepatotoxicity is generally characterized by a hepatitis-like profile, with elevated serum aminotransferases (usually ,1,000 IU/L). If the aminotransferase level is ,5 3 ULN, then the hepatotoxicity is considered mild; 5
10 3 ULN is considered moderate; and .10 3 ULN is considered severe [17]. The clinical pattern, however, can be a mixed one, with evidence of increased bilirubin (as high as .10 3 ULN) and ALP. However, disproportionate elevations of bilirubin or ALP may be more indicative of rifampicin hepatotoxicity [17,26,69]. Patients with underlying liver disease can develop more marked abnormalities in the liver panel [111]. In an earlier study from California reporting on 20 isoniazid-related deaths (from 1973 to 1986), aminotransferases and bilirubin as high as 3,685 IU/L and 46 mg/dL, respectively, were observed (60% had AST . ALT). However, in 12 of the 19 cases for which information was available, the patients had an underlying liver disease or were receiving other potentially hepatotoxic drugs or enzyme inducers; this included two or three with possible alcohol-related liver disease, two who were given anesthesia containing barbiturates while on isoniazid, one or two who used therapeutic doses of acetaminophen, and one who was on long-term tetracycline [113]. Clinically and biochemically, it can be difficult to distinguish ATT hepatotoxicity from acute viral hepatitis, and there have been reports of acute viral hepatitis being misdiagnosed as ATT hepatotoxicity [18,19]. Therefore, the demonstration of negative viral serologies is essential before diagnosing DILI. It is also important to exclude other hepatotoxins (e.g., acetaminophen) and

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biliary tract disease by performing an ultrasound examination of the liver and gallbladder. With regard to histology, ATT-induced hepatotoxicity is characterized by focal necrosis and/or confluent necrosis and portal inflammation [76,123]. Histological changes were more marked in the 20 fatal cases reported from California, with 39% and 61% showing histological evidence of submassive and massive hepatic necrosis, respectively, although, as indicated above, other hepatotoxins may have been involved [113]. In a recent French study, histology was available in 13 out of 14 patients with ATT-induced ALF and showed confluent necrosis in 11, with no evidence of chronic hepatitis. Only four patients had noncaseating granulomas [61]. Severe cases of ATT-induced liver injury can develop fulminant or sub-ALF, characterized by hepatic encephalopathy and coagulopathy. Ascites is usually absent, as are features of drug hypersensitivity (fever, drug rash, eosinophilia). ALF due to ATT is rare and accounts for 2.8
5.7% of all causes of ALF [61,62]. The Indian study (which allowed us to assess the natural history of ALF due to ATT as liver transplantation was not available) showed a dismal prognosis, with 23% spontaneous survival [58]. In the French study, 50% of patients experienced spontaneous survival and about 40% underwent liver transplantation [61].

MANAGEMENT, INCLUDING REFERRAL FOR LIVER TRANSPLANT Approximately 20% of patients treated with a standard four-drug regimen will develop asymptomatic elevations in aminotransferases [10]. As long as the serum aminotransferases are less than 5 3 ULN (in the absence of symptoms), there is no need to stop therapy, though patients need to be monitored frequently (see below). However, if aminotransferases .5 3 ULN in the absence of symptoms or .3 3 ULN in the presence of symptoms, most hepatologists recommend that ATT should be stopped immediately, and we strongly concur [136]. Development of jaundice and or an increasing international normalized ratio (INR) are also a cause for concern. Continuation of therapy in the presence of these clinical and biochemical features of toxicity has been associated with a poorer prognosis [51,56,75]. After cessation of therapy, most patients will develop spontaneous resolution of the biochemical abnormalities, after which ATT can be cautiously recommenced. However, a small proportion may develop worsening jaundice, confusion, and a coagulopathy. If this unfortunate course of events does occur, it is recommended that the patient be referred

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to a center where expertise is available for liver transplant. A recent study from the US Acute Liver Failure Study Group indicated that intravenous NAC improved transplant-free survival in patients with non-acetaminophen-induced ALF. Maximal benefit was seen in those with early (grade 1
2) rather than late (grade 3
4) hepatic encephalopathy [137]. Another small study from Iran also reported a lower incidence of hepatotoxicity (AST/ALT .5 3 ULN) in the group that received NAC (37.5% versus 0%). However, the follow-up period was very short (2 weeks), thus precluding any firm conclusions [138]. The most widely used criteria to list patients for liver transplant after DILI are those that have been developed by Kings College, London [139]. Russo et al. analyzed data from United Network for Organ Sharing (UNOS), and observed that between 1990 and 2002, 15% (n 5 370) of liver transplants performed for ALF were due to drug-induced hepatotoxicity. Of the 270 subjects in whom complete data were available, a single drug was implicated in 258 (96%), with the remainder having multidrug-associated DILI. Acetaminophen was the most common drug responsible (46%), followed by isoniazid (17.5%), propylthiouracil (9.5%), phenytoin (7.3%), and valproate (7.3%) [140]. According to a more recent retrospective study of patients from the UNOS Registry (1987
2006), 0.07% of liver transplants for ALF were due to ATT (50 out of 73,977): 48 were caused by isoniazid alone and 2 were due to the combination of isoniazid, pyrazinamide, and rifampicin [141]. These data indicate that isoniazid remains a very important and common cause of ALF in the United States. As already stated, there does appear to be a female preponderance in patients with ATT-induced ALF. In the study by Russo et al., of the 24 cases of isoniazid-induced liver failure, 67% were women and 33% were African American (compared to only 10% African Americans in the acetaminophen group) [140]. The recent Indian [62] and French studies [61] corroborated this, as 70% of ATT-induced ALF cases were women.

ALTERNATIVE THERAPY FOR UNDERLYING TUBERCULOSIS AND REINTRODUCTION OF ANTITUBERCULAR THERAPY Depending on the urgency of the need for ATT, it may be reasonable to wait for the liver tests to improve before a rechallenge. However, if that is not an option, then there will be a need to use regimens with no or minimal hepatotoxic potential. Such a combination might include streptomycin, ethambutol, a fluoroquinolone, and another second-line oral drug. However,

there are no data on choice, duration, or clinical effectiveness of such therapy. Expert opinion indicates that such a regimen needs to be continued for approximately 18
24 months in case the original ATT regimen cannot be reintroduced. Once the aminotransferases return to ,2 3 ULN (or, in those with underlying liver disease, serum aminotransferases return to baseline levels), the original ATT can be slowly reinstituted. Because rifampicin is much less likely to cause hepatotoxicity compared to isoniazid and pyrazinamide and is the most effective agent, it should be started first [3,10,142]. It can be started at doses of 75 mg/day, increased to 300 mg/day after 2
3 days, and then to 450 mg/day (,50 kg) or 600 mg/day ( . 50 kg) after a further 2
3 days. If the liver panel remains normal, isoniazid can be reinstituted (starting with a low dose of 50 mg, increasing after every 2
3 days to 300 mg), and after one more week pyrazinamide can be restarted [starting at 250 mg, increasing to 1,000 mg after 2
3 days and then to 1,500 mg (,50 kg) or 2,000 mg ( . 50 kg)]. If symptoms recur or serum aminotransferases again become abnormal, the last drug should be stopped. If isoniazid and rifampicin are well tolerated and the hepatotoxicity was severe, then pyrazinamide should be the presumed offending agent and not restarted. In such a situation, it may be necessary to extend the usual 6-month therapy with isoniazidrifampicin to 9 months [3]. Singh et al. could safely reintroduce therapy with isoniazid and rifampicin (in appropriate doses calculated according to body weight) in 35 out of 41 patients, with 6 (15%) redeveloping liver injury. Of these 6, successful reintroduction was possible in 3 at the second attempt [75]. In a recent randomized controlled trial from India, 175 patients with ATT-induced DILI were retreated with ATT in one of the following arms: isoniazid, rifampicin, pyrazinamide, maximum dose from day 1; rifampicin, isoniazid, and pyrazinamide introduced sequentially at full dose; and isoniazid, rifampicin, and pyrazinamide introduced sequentially in escalating doses. The incidence of DILI was no different in the three arms (13.8%, 10.2%, and 8.6%, respectively) [143]. However, in this study the initial DILI was not severe (mean bilirubin ,3 3 ULN and mean ALT ,500 IU/L) and therefore results may be difficult to extrapolate to more challenging scenarios. In fact, if the original DILI is severe enough to cause ALF and/or the need for a liver transplant, reintroduction of first-line ATT cannot be justified and alternative drugs need serious consideration [61]. Hence, though standard ATT can be reintroduced safely in the vast majority, there does remain a risk of recurrence of severe hepatitis. However, most experts agree that rechallenge should be attempted, since nonisoniazid-rifampicin ATT regimens are problematic

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due to uncertainty regarding duration of therapy and clinical efficacy, and the development of resistance [144]. It is unclear why hepatitis does not occur in the majority after rechallenge. One reason may be their improved general condition, as these patients had received ATT for some time, with a possible reduction in bacterial load. Another could be that the phased reintroduction may have reduced the hepatotoxic potential [144], thus promoting an adaptive protective mechanism. Finally, as noted above, immune tolerance may have developed. We would recommend, however, that the original ATT should not be reintroduced in the following clinical setting: (1) if the liver injury was a life-threatening event (jaundice along with INR .1.5 3 ULN and/or encephalopathy) or (2) in patients with moderately severe underlying liver disease (Child-Pugh class B/C cirrhosis).

ANTITUBERCULAR THERAPY IN PATIENTS WITH UNDERLYING LIVER DISEASE Treatment of tuberculosis in patients with unstable or advanced liver disease is problematic for a number of reasons. First, the likelihood of developing hepatotoxicity may be greater (especially in the presence of HBV and HCV coinfection). Second, due to the poor hepatic reserve, the liver injury may more readily become life-threatening. Third, it may be impossible to differentiate symptoms of ATT hepatotoxicity from that of the underlying liver disease, and, finally, tuberculosis may itself cause abnormalities in the liver tests [3]. Because of the effectiveness of first-line ATTs, these remain the drugs of choice in patients with wellcompensated underlying liver disease. However, these patients need close monitoring (see below). The following regimens can be used [3], although there have been no firm recommendations as to the choice: 1. Although the frequency of pyrazinamide hepatitis is less than that of isoniazid, it may be more severe; thus, one could utilize isoniazid, rifampicin, and ethambutol for 2 months followed by isoniazidrifampicin for an additional 7 months. In our opinion, this is probably a reasonable approach when chronic liver disease is well compensated (Child-Pugh class A). 2. For those with more advanced disease (Child-Pugh class B or C), or even compensated cirrhosis, only one potentially hepatotoxic drug is retained, usually rifampicin, with the addition of cycloserine, ethambutol, fluoroquinolone, and injectable agents.

497

The duration of such therapy should be 12
18 months 3. As an alternative to (2) in those with severe liver disease, it may be best to avoid all hepatotoxic agents. The regimen recommended is streptomycin, ethambutol, a fluoroquinolone, and another secondline oral drug, and total duration of therapy needs to be extended to 18
24 months. Overall, we recommend avoiding pyrazinamide in patients with underlying liver disease and avoiding isoniazid if chronic liver disease is clinically severe, but would not argue with a judgment toward isoniazid if chronic liver disease is well compensated. Close monitoring of ALT is recommended.

HEPATOTOXICITY OF ANTITUBERCULAR THERAPY IN LIVER TRANSPLANT RECIPIENTS Tuberculosis is a significant opportunistic infection in immunosuppressed transplant recipients, with earlier studies showing a 36
74-fold higher risk for these patients than for the general population [99]. More recent data suggest an 18-fold increased risk of active tuberculosis and a 4-fold increase in the case fatality rate [145]. The prevalence after liver transplant varies from 0.9% to 2.3%, but may be as high as 15% in areas of high endemicity [145,146]. Approximately 50% of these patients develop disseminated tuberculosis and extrapulmonary involvement is common [145,147]. Mortality from tuberculosis in liver transplant recipients ranges from 6.7% to 33% [145
149]. Because of the immunosuppressed state of most transplant candidates, it is recommended that those with a tuberculin skin test (TST) of .5 mm or recent conversion should receive chemoprophylaxis with isoniazid. Those with a negative result should have a second TST in 1
3 weeks [150]. Despite this, owing to the increased risk of cutaneous anergy in such a cohort, the potential to underdiagnose LTBI remains high. There are limited data comparing TST and interferon gamma (IFN-γ) release assays in transplant candidates, and no gold standard exists to support the use of one over the other [151]. A recent American study found both TST and IFN-γ release assays to demonstrate similar rates of detecting LTBI, although IFN-γ release assays were associated with a moderate rate of indeterminate results [152] Concerns about hepatotoxicity during isoniazid chemoprophylaxis have prompted experts to recommend not treating LTBI in the immediate post-liver transplant period, but instead delaying therapy until LFTs have stabilized [153]. This is despite the immediate

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27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

post-liver transplant period also being the time of maximal immunosuppression. In fact, in such a clinical situation it may be difficult to differentiate isoniazid hepatotoxicity from other causes of abnormal liver tests such as rejection. However, liver biopsies have suggested the latter to be a more likely diagnosis [147,154]. Overall, hepatotoxicity requiring discontinuation of therapy occurs in 25
41% of liver transplant recipients, and this exceeds the rate of isoniazid hepatotoxicity in renal (2.5%) and heart or lung (4.5%) transplant recipients [146,147,154]. A recent American study found that the use of isoniazid for LTBI early after liver transplant (mean, 0.67 months) was poorly tolerated (discontinued in .50%) but, despite that, none of the patients developed tuberculosis reactivation, with a mean follow-up of 33 months [152]. A recent meta-analysis also showed that isoniazid LTBI treatment was associated with reduced tuberculosis reactivation in liver transplant recipients (0.0% versus 8.2%; P 5 0.02), with isoniazid-related hepatotoxicity occurring in 6% of the patients [145]. An alternative approach may be to use isoniazid chemoprophylaxis in the pretransplant period, thereby eliminating diagnostic confusion with graft rejection and reducing the likelihood of premature discontinuation. Obviously, this can be problematic in patients with decompensated cirrhosis. Nevertheless, this would also avoid drug interactions between ATT and immunosuppressive agents, which could potentially impact graft survival [154]. A recent study from California reported the safe use of either 9 months of isoniazid or 4 months of rifampicin in the treatment of LTBI in 14 liver transplant candidates [155]. In liver transplant recipients with active tuberculosis, the use of first-line multidrug antitubercular regimens can be problematic because of concerns regarding hepatotoxicity. In a recent meta-analysis reviewing 139 liver transplant patients, 86 had received a standard ATT regimen (ethambutol, isoniazid, pyrazinamide, and rifampicin), 24/86 (28%) presented with hepatotoxicity of whom 22 had received isoniazid along with either rifampicin or rifabutin [145]. The short-term mortality in this study was 31%. Surviving patients were more likely to have received three or more drugs and to have been diagnosed within a month of symptoms, and were less likely to have multiorgan disease or to have suffered episodes of acute rejection [145]. Another challenge in the management of tuberculosis in patients with liver transplants is the use of rifampicin, which can significantly decrease serum levels of calcineurin and mTOR inhibitors and alter corticosteroid metabolism [146,149]. Meyers et al. describe the outcome in 9 liver transplant recipients with tuberculosis (of whom 78% had disseminated disease) who received ATT (ethambutol, isoniazid, pyrazinamide, and rifampicin).

Overall, during induction therapy, histological features consistent with isoniazid/drug-induced hepatotoxicity developed in .80%, with 50% showing additional features of rejection. These patients were not rechallenged with the original ATT; instead, continuation therapy was provided by ETM and ofloxacin [156]. In a recent French study, all 5 patients who underwent liver transplantation and received rifampicin had an acute cellular rejection [61]. A meta-analysis corroborated this: approximately 40% of patients who received rifampicin needed dose adjustment of their immunosuppression [145]. There is a suggestion that assessment of NAT2 and CYP2E1 genotypes can quantify risk of isoniazid toxicity after liver transplant [157]. However, this is not a practical approach and it may be best to avoid rifampicin altogether in the post-liver transplant setting.

RECOMMENDATIONS FOR MONITORING PATIENTS WHILE ON ATT Monitoring patients on isoniazid monotherapy or multidrug ATT has remained controversial [3,50,144,158], and we offer our opinion here.

Monotherapy with Isoniazid for Latent Tuberculosis Infection 1. If the patient is ,35 years old, monthly interrogation for symptoms at time of drug refill. The patient should be educated to stop isoniazid if symptoms develop. ALT monitoring is unnecessary, as the need for hospitalization for symptomatic hepatitis is ,1 in every 10,000. This is a widely accepted approach. 2. If the patient is .35 years old, we recommend adding monthly ALT monitoring with the usual stopping rules (ALT . 5 3 ULN or ALT . 3 3 ULN with symptoms). If ALT .3 3 ULN without symptoms, weekly ALT monitoring is needed until resolution or worsening (discontinue therapy). We acknowledge that this is more likely to be an acceptable strategy to hepatologists than to infectious disease specialists but, in view of increased risks with increasing age, it maximizes patient safety. 3. If patients have underlying hepatitis B or C and/or HIV, monthly monitoring of serum ALT. 4. For liver transplant candidates who need treatment for LTBI, it may be best to initiate therapy with isoniazid in the pretransplant period with close

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CONCLUSIONS

(2 weekly) monitoring of the liver panel, whether initiated pre- or post-liver transplant.

For Patients on Multidrug Regimens 1. It is useful to do a baseline evaluation of the liver panel in all patients prior to initiation of ATT. At the onset, the patients and their care providers must be clearly educated about the hepatotoxic potential of ATT and given clear instructions to watch for symptoms such as nausea, vomiting, abdominal pain, and jaundice. At the first sign of these symptoms, patients must be instructed to immediately discontinue therapy and seek urgent medical attention. 2. ATT should be prescribed in conjunction with either a respiratory or infectious disease specialist. 3. Alcohol abuse should be actively discouraged while ATT is being continued. 4. In those with no underlying liver disease and no risk factors for ATT hepatotoxicity, it is reasonable to write an initial prescription for 1 month. We would recommend monitoring the liver panel every 2 weeks for the first 8 weeks, and then every 4 weeks until the completion of therapy. If the serum aminotransferases are elevated to ,2 3 ULN, it would be reasonable to continue to monitor the liver panel as above, i.e., at 4-weekly intervals. If the aminotransferases are .2 3 ULN but ,5 3 ULN, then ATT can be continued as long as there are no symptoms. These patients need liver panel monitoring every week and then bimonthly until the aminotransferases stabilize. However, it is essential that treatment be stopped if: a. serum aminotransferases increase to .5 3 ULN in the absence of symptoms b. serum aminotransferases increase to .3 3 ULN in the presence of symptoms c. serum bilirubin increases to .1.5 3 ULN (along with ALT of .3 3 ULN) or prothrombin time increases to .1.5 3 ULN, irrespective of the presence or absence of symptoms. An isolated increase in unconjugated or conjugated serum bilirubin is usually a benign and transient phenomenon related to interference with bilirubin excretion by rifampicin. Conjugated hyperbilirubinemia accompanied by increased ALT (irrespective of the absence or presence of symptoms), however, mandates cessation of all ATT. Conjugated bilirubin can be defined as .35% direct (total of .1.5 3 ULN) or bilirubinuria. The ATT can be restarted once bilirubin returns to normal and serum aminotransferases return to ,2 3 ULN. Mild

unconjugated or conjugated hyperbilirubinemia without elevated liver enzymes can be caused by rifampicin inhibition of transport: this is transient and should be watched closely but does not necessitate discontinuation. Owing to insufficient evidence, no firm recommendations can be made for those that develop an isolated or predominant increase in serum ALP. 5. Those with underlying liver disease or risk factors for ATT hepatotoxicity should receive no more than a 2 weeks0 supply of drugs initially and liver tests should be monitored at 2-weekly intervals until the end of therapy. 6. In those with baseline liver test abnormalities, we recommend continuing therapy until serum aminotransferases increase to more than twice baseline and/or jaundice or other symptoms develop. If this occurs, ATT should be stopped and the liver panel monitored at weekly and then at 2-weekly intervals. The drugs can be cautiously reintroduced once the serum aminotransferases approach baseline. 7. Treatment of tuberculosis in a liver transplant recipient is a complex situation and needs to be individualized. Most of these patients do not tolerate a full duration of first-line antitubercular drugs. It may be reasonable to initiate such therapy for the induction phase only and then convert to safer second-line drugs for the continuation phase. The liver panel needs to be monitored every 1
2 weeks.

CONCLUSIONS Tuberculosis remains an important cause of death worldwide from a single infectious agent. Three of the first-line drugs for tuberculosis, while being highly effective antitubercular agents, are potentially hepatotoxic. With isoniazid monotherapy, about 10% develop asymptomatic elevations in serum aminotransferases with ,1% developing more serious liver injury. With multiple drug regimens, up to 4% (higher in developing countries) may develop overt hepatitis. After acetaminophen, isoniazid is the second most common cause of drug-induced ALF in the United States. Once patients develop jaundice, the mortality is high (10%). Therefore, the decision to initiate isoniazid monotherapy or multidrug ATT must be made judiciously and under close supervision, especially in those with risk factors for ATT hepatotoxicity. It is imperative that patients be made aware of the danger symptoms of hepatotoxicity and instructed to stop all medication if such signs and symptoms develop. Initial prescriptions for combination ATT should be written for only

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2
4 weeks and close monitoring of the liver panel is indicated throughout the duration of the therapy. Due to the hepatotoxic potential of standard ATT and drug resistance, about 20% of patients with tuberculosis do not receive the best possible treatment. Therefore new, safer drugs are urgently needed.

References [1] CDC. Trends in tuberculosis—United States 1998
2003. MMWR 2004;53:209
14. [2] American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169
1227. [3] Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society/Centers for Disease Control and prevention/Infectious Diseases Society. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603
62. [4] Centers for Disease Control and Prevention/American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States. 2003. MMWR Morb Mortal Wkly Rep Aug 8 2003;52(31):735
739. [5] Schechter M, Zajdenverg R, Falco G, Barnes GL, Faulhaber JC, Coberly JS, et al. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med 2006;173:922
6. [6] Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011;365:11
20. [7] Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Consortium PREVENT TB study team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155
66. [8] Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Dec 9 2011;60:1650
3. [9] Preventive therapy of tuberculosis infection. Am Rev Respir Dis 1974;110:371
4 [10] Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465
71. [11] Randolph H, Joseph S. Toxic hepatitis with jaundice occurring in a patient treated with isoniazid. JAMA 1953;152:38
40. [12] Berte SJ, Dewlett HJ. Isoniazid and para-aminosalicylic acid toxicity in 513 cases: a study including high doses of INH and gastrointestinal intolerance to PAS. Dis Chest 1959 Aug;36:146
51. [13] American Thoracic Society. Chemoprophylaxis for the prevention of tuberculosis; a statement by an ad-hoc committee. Am Rev Respir Dis 1965;96:558
60. [14] Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969;71:1113
20. [15] Garibaldi RA, Drusin RE, Ferebee SH, Gregg MB. Isoniazidassociated hepatitis. Report of an outbreak. Am Rev Respir Dis 1972;106:357
65. [16] Kopanoff DE, Snider Jr DE, Caras GJ. Isoniazid-related hepatitis: a U.S. public health service cooperative surveillance study. Am Rev Respir Dis 1978;117:991
1001.

[17] World Health Organization Collaborating Center for International Drug Monitoring. Adverse drug reaction terminology (ART), 1979. http://www.WHO-UMC.org [accessed 1.12.06]. [18] Sarda P, Sharma SK, Mohan A, Makharia G, Jayaswal A, Pandey RM, et al. Role of acute viral hepatitis as a confounding factor in antituberculosis treatment induced hepatotoxicity. Indian J Med Res 2009;129:64
7. [19] Davern TJ, Chalasani N, Fontana RJ, Hayashi PH, Protiva P, Kleiner DE, et al. Drug-Induced liver injury network (DILIN). Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology 2011 Aug 16; 41(5):1665
72. [20] Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P, Santha T, Sivasubramanian S, et al. Hepatic toxicity in South Indian patients during treatment of tuberculosis with shortcourse regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99
108. [21] British Thoracic Association. A controlled trial of six month chemotherapy in pulmonary tuberculosis. first report: results during chemotherapy. Br J Dis Chest 1981;75:141
53. [22] Lee BH, Koh WJ, Choi MS, Suh GY, Chung MP, Kim H, et al. Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy. Chest 2005;127:1304
11. [23] Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a casecontrol study. Thorax 1996;51:132
6. [24] Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol 2007;102:2437
43. [25] Ormerod LP. Analysis of frequency of drug reactions to antituberculosis drugs. Thorax 1994;45:403
8. [26] Ormerod LP. Hepatotoxicity of antituberculosis drugs. Thorax 1996;51:111
3. [27] Maddrey WC. Isoniazid-induced liver disease. Semin Liver Dis 1981;1:129
33. [28] Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites. Clin Pharmacol Ther 1975;18:70
9. [29] Maddrey WC, Boitnott JK. Isoniazid hepatitis. Ann Intern Med 1973;79:1
12. [30] Shen C, Zhang H, Zhang G, Meng Q. Isoniazid induced hepatotoxicity of gel entrapment culture. Tox Lett 2006;167:66
74. [31] Timbrell JA, Mitchell JR, Snodgrass WR, Nelson SD. Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo. J Pharmacol Exp Ther 1980;213:364
9. [32] Sarich TC, Adams SP, Petricca G, Wright JM. Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor. J Pharmacol Exp Ther 1999;289:695
702. [33] Patrick RL, Black KC. Pathology and toxicity of repeated doses of hydrazine and 1,1-dimethylhydrazine in monkeys and rats. Ind Med Surg 1965;34:430
5. [34] Sarich TC, Zhou T, Adams SP, Bain AI, Wall RA, Wright JM. A model of isoniazid-induced hepatotoxicity in rabbits. J Pharmacol Toxicol Methods 1995;34:109
16. [35] Sarich TC, Adams SP, Wright JM. The role of L-thyroxine and hepatic reductase activity in isoniazid-induced hepatotoxicity in rabbits. Pharmacol Res 1998;38:199
207. [36] Sinha BK. Activation of hydrazine derivatives to free radicals in the perfused rat liver: a pin trapping study. Biochimica et Biophysica Acta 1987;924:261
9. [37] Sinha BK, Motten AG. Oxidative metabolism of hydrazine. Evidence for nitrogen centered radicals formations. Biochem Biophys Res Commun 1982;105:1044
51.

III. HEPATOTOXICITY OF SPECIFIC DRUGS

501

REFERENCES

[38] Yue J, Peng RX, Yang J, Kong R, Liu J. CYP2E1 mediated isoniazid-induced hepatotoxicity in rats. Acta Pharmacol Sin 2004;25:699
704. [39] Sarich TC, Youssefi M, Zhou T, Adams SP, Walls RA, Wright JM. The role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch Toxicol 1996;70:835
40. [40] Tayal V, Kalra BS, Agarwal S, Kharana N, Gupta V. Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits. Ind J Exp Biol 2007;45:1031
6. [41] Tafazoli S, Mashaegi M, O’Brien PJ. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model. Tox Appl Pharm 2008;229:94
101. [42] Kleno TG, Kiehr D, Baunsgaard D, Sidelmann UG. Combination of “omics” data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in rats and to identify potential biomarkers. Biomarkers 2004;9:116
38. [43] Metushi IG, Lai P, Shu X, Nakagawa T, Uetrecht JP. A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clin Pharm Therap 2011;89:911
4. [44] Salazar-Paramo M, Rubin RL. Garcia-De La Torre I. Systemic lupus erythematous induced by isoniazid. Ann Rheum 1992;51:1085
7. [45] Sharma SK, Balmurugan A, Saha PK, et al. Evaluations of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:919
20. [46] McConnell JB, Powell-Jackson PR, Davis M, Williams R. Use of liver function tests as predictors of rifampicin metabolism in cirrhosis. Q J Med 1981;50:77
82. [47] De Jong M, Mulder RJ. Drugs used in the treatment of tuberculosis and leprosy. In: Dukes MUG, editor. Meyler’s side effects of drugs, vol. 1. Oxford: Excerpta Medica; 1977. p. 676
89. [48] Cohn HD. Clinical studies with a new rifamycin derivative. J Clin Pharmacol J New Drugs 1969;9:118
25. [49] Kenwright S, Levi AJ. Sites of competition in the selective hepatic uptake of rifamycin-SV, flavaspidic acid, bilirubin, and bromsulphthalein. Gut 1974;15:220
6. [50] Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J. Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf 1996;15:394
405. [51] Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975;69:289
302. [52] Gronhagen-Riska C, Hellstrom PE, Froseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis. Am Rev Respir Dis 1978;118:461
6. [53] Sarma GR, Immanuel C, Kailasam S, Narayana AS, Venkatesan P. Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin. Am Rev Respir Dis 1986;133:1072
5. [54] Dickinson DS, Bailey WC, Hirschowitz BI. The effect of acetylation status on isoniazid (INH) hepatitis. Am Rev Respir Dis 1977;115:395. [55] Weber WW, Hein DW, Litwin A, Lower Jr GM. Relationship of acetylator status to isoniazid toxicity, lupus erythematosus, and bladder cancer. Fed Proc 1983;42:3086
97. [56] Durand F, Bernuau J, Pessayre D, Samuel D, Belaiche J, Degott C, et al. Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid. Hepatol 1995;21:929
32. [57] Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis

[58]

[59]

[60]

[61]

[62]

[63] [64] [65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

infection: a 7-year evaluation from a public health tuberculosis clinic. Chest 2005;128:116
23. LoBue PA, Moser KS. Isoniazid- and rifampin-resistant tuberculosis in San Diego County, California, United States, 1993
2002. Int J Tuberc Lung Dis 2005;9:501
6. Mitchell JR, Zimmerman HJ, Ishak KG, Thorgeirsson UP, Timbrell JA, Snodgrass WR, et al. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med 1976;84:181
92. Snider Jr DE, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992;145 (2 Pt 1):494
7. Ichai P, Saliba F, Antoun F, Azoulay D, Sebagh M, Antonini TM, et al. Acute liver failure due to antitubercular therapy: strategy for antitubercular treatment before and after liver transplantation. Liver Transpl 2010;16:1136
46. Kumar R, Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, et al. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. Hepatol 2010;51:1665
74. Salpeter SR. Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis. West J Med 1993;159:560
4. Farrell GC. Drug-induced liver disease. Edinburgh: Churchill Livingstone; 1994. American Thoracic Society. Centers for Disease Control and Prevention and Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221
47. Fountain FF, Tolley EA, Jacobs AR, Self TH. Rifampin hepatotoxicity associated with treatment of latent tuberculosis infection. Am J Med Sci 2009;337:317
20. Menzies D, Long R, Trajman A, Dion MJ, Yang J, Al Jahdali H, et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med 2008;149:689
97. Ziakas PD, Mylonakis E. 4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity. Clin Infect Dis 2009;49:1883
9. Alford RH. Antimycobacterial agents. In: Mandell GL, Douglas RJ, Benett JE, editors. Principles and practices of infectious diseases. 3rd ed. New York: Churchill Livingstone; 1990. p. 350
61. McDermott W, Ormond L, Muschenheim C, Deuschle K, McCune Jr RM, Tompsett R. Pyrazinamide-isoniazid in tuberculosis. Am Rev Tuberc 1954;69:319
33. Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. Postgrad Med J 1995;71:359
62. Chang KC, Leung CC, Yew WW, Lau TY, Tam CM. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med 2008;177:1391
6. Snider Jr DE, Long MW, Cross FS, Farer LS. Six-months isoniazid-rifampin therapy for pulmonary tuberculosis. Report of a United States Public Health Service cooperative trial. Am Rev Respir Dis 1984;129:573
9. Pasipanodya JG, Gumbo T. Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used. Antimicrob Agents Chemother 2010;54:2847
54. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol 1996;22:211
4.

III. HEPATOTOXICITY OF SPECIFIC DRUGS

502

27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

[76] Pessayre D, Bentata M, Degott C, Nouel O, Miguet JP, Rueff B, et al. Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology 1977;72:284
9. [77] McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest 2003;123:102
6. [78] Tortajada C, Martı´nez-Lacasa J, Sa´nchez F, Jime´nez-Fuentes A, De Souza ML, Tuberculosis Prevention Working Group, et al. Is the combination of pyrazinamide plus rifampicin safe for treating latent tuberculosis infection in persons not infected by the human immunodeficiency virus? Int J Tuberc Lung Dis 2005;9:276
81. [79] Leung CC, Law WS, Chang KC, Tam CM, Yew WW, Chan CK, et al. Initial experience on rifampin and pyrazinamide vs isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong. Chest 2003;124:2112
8. [80] Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010;(1):CD000171. [81] Ellard GA. Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis. Clin Pharmacol Ther 1976;19:610
25. [82] Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites. Clin Pharmacol Ther 1975;18:70
9. [83] Yamamoto T, Suou T, Hirayama C. Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatol 1986;6:295
8. [84] Gurumurthy P, Krishnamurthy MS, Nazareth O, Parthasarathy R, Sarma GR, Somasundaram PR, et al. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984;129:58
61. [85] Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006;62:423
9. [86] Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatol 2002;35:883
9. [87] Lee SW, Chung LS, Huang HH, Chuang TY, Liou YH, Wu LS. NAT2 and CYP2E1 polymorphisms and susceptibility to firstline anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis 2010;14:622
6. [88] Yamada S, Tang M, Richardson K, Halaschek-Wiener J, Chan M, Cook VJ, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics 2009;10:1433
45. [89] Stephens EA, Taylor JA, Kaplan N, Yang CH, Hsieh LL, Lucier GW, et al. Ethnic variations in the CYP2E1 gene:polymorphism analysis of 695 African-Americans, EuropeanAmericans and Taiwanese. Pharmacogenetics 1994;4:185
92. [90] Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatol 2003;37:924
30. [91] Roy B, Ghosh SK, Sutradhar D, Sikdar N, Mazumder S, Barman S. Predisposition of antituberculosis drug induced hepatotoxicity by cytochrome P450 2E1 genotype and haplotype in pediatric patients. J Gastroenterol Hepatol 2006; 21:784
6.

[92] Sun F, Chen Y, Xiang Y, Zhan S. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis druginduced liver injury: a meta-analysis. Int J Tuberc Lung Dis 2008;12:994
1002. [93] Dossing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996;77:335
40. [94] Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999;281:1014
8. [95] Kunst H, Khan KS. Age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review. Int J Tuberc Lung Dis 2010;14:1374
81. [96] Grant AD, Mngadi KT, van Halsema CL, Luttig MM, Fielding KL, Churchyard GJ. Adverse events with isoniazid preventive therapy: experience from a large trial. AIDS 2010;24(Suppl. 5): S29
36. [97] Devrim I, Olukman O, Can D, Dizdarer C. Risk factors for isoniazid hepatotoxicity in children with latent TB and TB: difference from adults. Chest 2010;137:737
8. [98] Chalasani N, Bjo¨rnsson E. Risk factors for idiosyncratic druginduced liver injury. Gastroenterology 2010;138:2246
59. [99] Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007;47:513
39. [100] Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatol 2008;47:2003
9. [101] Lucena MI, Andrade RJ, Kaplowitz N, Garcı´a-Cortes M, Ferna´ndez MC, Spanish Group for the Study of Drug-Induced Liver Disease, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatol 2009;49:2001
9. [102] Mitchell JR, Long MW, Thorgeirsson UP, Jollow DJ. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy. Chest 1975;68: 181
90. [103] Rothwell DL, Richmond DE. Hepatorenal failure with selfinitiated intermittent rifampicin therapy. Br Med J 1974; 2:481
2. [104] Cross FS, Long MW, Banner AS, Snider Jr. DE. Rifampinisoniazid therapy of alcoholic and nonalcoholic tuberculous patients in a U.S. Public Health Service cooperative therapy trial. Am Rev Respir Dis 1980;122:349
53. [105] Andrade RJ, Lucena MI, Kaplowitz N, Garcı´a-Munoz ¸ B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatol 2006;44:1581
8. [106] Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 1994;105:408
11. [107] Crippin JS. Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J Gastroenterol 1993;88:590
2. [108] Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990;111:799
800. [109] James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009;37:1779
84. [110] Franks AL, Binkin NJ, Snider Jr DE, Rokaw WM, Becker S. Isoniazid hepatitis among pregnant and postpartum Hispanic patients. Public Health Rep 1989;104:151
5.

III. HEPATOTOXICITY OF SPECIFIC DRUGS

REFERENCES

[111] Gronhagen-Riska C, Hellstrom PE, Froseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis. Am Rev Respir Dis 1978;118:461
6. [112] Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Drug induced liver injury network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924
34. [113] Moulding TS, Redeker AG, Kanel GC. Twenty isoniazid deaths in one state. Am Rev Respir Dis 1989;140:700
5. [114] Millard PS, Wilcosky TC, Reade-Christopher SJ, Weber DJ. Isoniazid-related fatal hepatitis. West J Med 1996;164:486
91. [115] Gordin FM, Cohn DL, Matts JP, Chaisson RE, O’Brien RJ. Terry Beirn Community Programs for Clinical Research on AIDS; Adult AIDS Clinical Trials Group; Centers for Disease Control and Prevention. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? Clin Infect Dis 2004;39:561
5. [116] Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916
9. [117] Singla R, Sharma SK, Mohan A, Makharia G, Sreenivas V, Jha B, et al. Evaluation of risk factors for antituberculosis treatment induced hepatotoxicity. Indian J Med Res 2010;132:81
6. [118] Buchanan N, Eyberg C, Davis MD. Isoniazid pharmacokinetics in kwashiorkor. S Afr Med J 1979;56:299
300. [119] Warmelink I, ten Hacken NH, van der Werf TS, van Altena R. Weight loss during tuberculosis treatment is an important risk factor for drug-induced hepatotoxicity. Br J Nutr 2011;105:400
8. [120] Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut 2002;50:436
9. [121] Acocella G, Bonollo L, Garimoldi M, Mainardi M, Tenconi LT, Nicolis FB. Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 1972;13:47
53. [122] Wu JC, Lee SD, Yeh PF, Chan CY, Wang YJ, Huang YS, et al. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers. Gastroenterology 1990;98:502
4. [123] Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201
6. [124] McGlynn KA, Lustbader ED, Sharrar RG, Murphy EC, London WT. Isoniazid prophylaxis in hepatitis B carriers. Am Rev Respir Dis 1986;134:666
8. [125] Chien JY, Huang RM, Wang JY, Ruan SY, Chien YJ, Yu CJ, et al. Hepatitis C virus infection increases hepatitis risk during anti-tuberculosis treatment. Int J Tuberc Lung Dis 2010;14: 616
21. [126] Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998;157:1871
6. [127] Ferna´ndez-Villar A, Sopen˜a B, Garcı´a J, Gimena B, Ulloa F, Botana M, et al. Hepatitis C virus RNA in serum as a risk factor for isoniazid hepatotoxicity. Infection 2007;35:295
7. [128] Kwon YS, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ. Hepatitis C virus infection and hepatotoxicity during antituberculosis chemotherapy. Chest 2007;131:803
8.

503

[129] Fernandez-Villar A, Sopena B, Vazquez R, Ulloa F, Fluiters E, Mosteiro M, et al. Isoniazid hepatotoxicity among drug users: the role of hepatitis C. Clin Infect Dis 2003;36:293
8. [130] Bliven EE, Podewils LJ. The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection. Int J Tuberc Lung Dis 2009;13:1054
60. [131] Cho YJ, Lee SM, Yoo CG, Kim YW, Han SK, Shim YS, et al. Clinical characteristics of tuberculosis in patients with liver cirrhosis. Respirology 2007;12:401
5. [132] Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science 2003;301:1535
7. [133] Walker NF, Kliner M, Turner D, Bhagani S, Cropley I, Hopkins S, et al. Hepatotoxicity and antituberculosis therapy: time to revise UK guidance? Thorax 2009;64:918. [134] Breen RA, Miller RF, Gorsuch T, Smith CJ, Schwenk A, Holmes W, et al. Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax 2006;61:791
4. [135] Gray D, Nuttall J, Lombard C, Davies MA, Workman L, Apolles P, et al. Low rates of hepatotoxicity in HIV-infected children on anti-retroviral therapy with and without isoniazid prophylaxis. J Trop Pediatr 2010;56:159
65. [136] Adams PC, Arthur MJ, Boyer TD, DeLeve LD, Di Bisceglie AM, Hall M, et al. Screening in liver disease: report of an AASLD clinical workshop. Hepatol 2004;39:1204
12. [137] Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage nonacetaminophen acute liver failure. Gastroenterology 2009;137:856
64. [138] Baniasadi S, Eftekhari P, Tabarsi P, Fahimi F, Raoufy MR, Masjedi MR, et al. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur J Gastroenterol Hepatol 2010;22:1235
8. [139] O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439
45. [140] Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10: 1018
23. [141] Mindikoglu AL, Magder LS, Regev A. Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the United Network for organ sharing database. Liver Transpl 2009;15:719
29. [142] Thompson NP, Caplin ME, Hamilton MI, Gillespie SH, Clarke SW, Burroughs AK, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995;8:1384
8. [143] Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis 2010;50: 833
9. [144] Garg PK, Tandon RK. Antituberculous agents-induced liver injury. In: Deleve L, Kaplowitz N, editors. Drug induced liver disease. New York: Marcel Dekker Inc.; 2002. p. 505
17. [145] Holty JE, Gould MK, Meinke L, Keeffe EB, Ruoss SJ. Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data. Liver Transpl 2009;15:894
906. [146] Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, Blanes M, Rufi G, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain.

III. HEPATOTOXICITY OF SPECIFIC DRUGS

504

[147]

[148]

[149]

[150]

[151] [152]

[153]

27. HEPATOTOXICITY OF ANTITUBERCULAR DRUGS

Spanish transplantation infection study group, GESITRA. Transplant 1997;63:1278
86. Singh N, Wagener MM, Gayowski T. Safety and efficacy of isoniazid chemoprophylaxis administered during liver transplant candidacy for the prevention of post transplant tuberculosis. Transplant 2002;74:892
5. Mun˜oz P, Rodrı´guez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005;40:581
7. Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical features and outcome of tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;334:106
10. Subramanian A, Dorman S. AST infectious diseases community of practice. Mycobacterium tuberculosis in solid organ transplant recipients. Am J Transplant 2009 Dec;9(Suppl. 4):S57
62. Yehia BR, Blumberg EA. Mycobacterium tuberculosis infection in liver transplantation. Liver Transpl 2010;16:1129
35. Jafri SM, Singal AG, Kaul D, Fontana RJ. Detection and management of latent tuberculosis in liver transplant patients. Liver Transpl 2011;17:306
14. Aguado JM, Torre-Cisneros J, Fortu´n J, Benito N, Meije Y, Doblas A, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of

[154]

[155]

[156]

[157]

[158]

infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009;48:1276
84. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27:1266
77. Jahng AW, Tran T, Bui L, Joyner JL. Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during transplant candidacy period. Transplantation 2007; 83:1557
62. Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 2000; 69:64
9. Barcena R, Oton E, Angeles Moreno M, Fortu´n J, GarciaGonzalez M, Moreno A, et al. Is liver transplantation advisable for isoniazid fulminant hepatitis in active extrapulmonary tuberculosis? Am J Transplant 2005;5:2796
8. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. ATS (American Thoracic Society) hepatotoxicity of antituberculosis therapy subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935
52.

III. HEPATOTOXICITY OF SPECIFIC DRUGS