Review Article Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management Vidyasagar Ramappa, Guruprasad P. Atha IIR Bomeical Fesearch Uniti Gastronlastinal and Liver Diseases, Nottingham University Hospitals NHS Trust, Univesity of Nottingham, ‘Nottingham, UK Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequen tial events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical ‘observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority ofthe studies are retrospective with varied case definitions and sample sizes. Investigations on genetic susceptibility to hepatotoxicity have so far focused on for~ mation and accumulation reactive metabolite as well as factors that contribute to cellular antioxidant defense ‘mechanisms and the environment which can modulate the threshold for hepatocyte death secondary to oxidative stress. Recent advances in pharmacogenetics have promised the development of refined algorithms including ‘drug, host and environmental risk factors thatallow better tailoring of medications based on accurate estimates of risk-benefit ratio, Future investigations exploring the pathogenesis of hepatotoxicity should be performed us ing human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY applications. (J Cun Exr Heravor. 2013;3:37-49) erculosis (TB) remains a major global health | problem despite the availability of highly effica- cious treatment for decades. World Health Organization (WHO) declared TB a global public health ‘emergency in 1993, at a time when an estimated 7-8 mil- lion new cases and 1.3-1.6 million deaths occurred each year. In 2010, chere was an reported and 1.4 million deaths inciuding deaths from TB. ‘mated 8.8 million new cases “Keywords drug induced liver injury, hepatotoxicity, cuberculosis, genetic, pathogenesis ‘Revol: 129.2012; cpt 12.12.2012; Ave online: 20.12.2012 ‘Adina or corrspondene.Gurupasad P. Atha, Professor, NHS Director, [NILIR Digestive Disses Biomedical Research Unit, D Floor, South Block, ‘Qucen's Medical Centre, Notingham NG? 2UH, UK. Tel: +44 (0) 1S 924992457044; fae +4 (0) 115 9709012 Ema gorupeasadathal@nortingham ack Aborvistion THs aberculosis; WHO: World Health Organization; DILL NAT2*7 > NAT2*6 > NAT2*S alleles: In cheir first study involving genotyping acetyla- tor starus in 224 subjects on anti-TB cherapy, Huang, et al found that patients possessing NAT2 genotypes ass0- ciated with slow acetylation hada fourfold risk of Figure 1 Pathways involved in the metabo of soriazi, Journal of Cinical and Experimental Hepatology | March 2013 | Vol 3 | No.2. | 37-49) 9HEPATOTOXICITY RELATED TO ANTITUBERCULOSIS DRUGS developing INH-induced hepatotoxicity*® and_ recent meta-analysis of 14 studies involving 474 cases and 1446 controls have drawn similar conclusions with an odds ratio of 46 for slow acetylators.” In addition, slow acerylators were prone t0 develop more severe hepatotoxicity than rapid acecylators. Those with NA72%6/6 and NAT2"6/7 ge- notypes had a significantly higher risk than other geno- types. The same group investigated whether genetic polymorphism of CYP2E1 influenced susceptibility co anti-TB drug induced hepatorosicity. During the admi tration of INH, CYP2E1 activity is inhibited. Under this hibitory effect of INH, subjects who were homozygous for CYP2EI cl allele (wild type) had higher enzyme activity compared those with one or more CYP2EI @2 allele." A study including 318 subjects on anti-TB therapy showed that subjects with C¥P2E1 cl/c1 were 2.5 times more likely to develop hepatotoxicity when compared with the other genotypes. The risk of hepatotoxicity increased 7-fold ‘when C¥P2EI c1/cl was combined with slow-acetylator sta- tus. A similar study looking at 218 patients receiving ATT by Bose et al in India examined the role of the NAT? and CYP2EI (promoter and intron 6 region) polymorphisms in ATT hepatotoxicity. There was a higher prevalence of NAT255/*7 and NAT2%6/*7 genotypes (slow-acetylator) genotypes in anti-TB DILI group. CYPZEI ¢l/el were pres- encin both DILI and non-DILI groups, however CYP2EI C/ Dor C/C genotypes 3 times more likely co develop ant-TB DILL. The same study also demonstrated that slow- acetylator status (NAT2 gene polymorphism) and the CYP2EI C/D or C/C genotype together showed a higher fre- quency in DILL” Glutathione plays an important protective role as an in- tracellular free radical scavenger by conjugating with toxic reactive metabolites that are generated from biotransfor- mation of drugs and xenobiotics. Sulfhydryl (SH) conjuga- tion of the metabolites facilitates their elimination from the body, and so reduces the potential for toxicity. Defi- ciency in GST activity, because of homozygous null muta- tions at GSTMI and GSTTI loci, modulate susceptibility co drug- and xenobiotic-induced hepatotoxicity. In a_case control seudy involving 33 eases and equal number of con- trols Roy et al examined the frequency of GSTMI and GST null mutations and noted GSTMI null mutations twice as common in the cases with anti-TB DILL" In an- other seudy involving Caueasian patients, anti-TB DIL was 2.6 cimes more likely in those with GSTTY mull muta- tions."" The dara so far suggest chat INH hepatotoxicity is, caused by the reactive metabolites. A recent review on mechanism of INH hepatotoxicity highlights the role of immune mediated idiosyncrasy as a mechanism that is ex- plained by the adaptive responses of liver to INH and het- cerogeneity of clinical picture of INH hepatotoxicity.” Rifampicin: Rifampicin is well absorbed from the stomach, and metabolized in the liver by desacerylation co 40 RAMAPPA & AITHAL desacetyl rifampicin’“* and a separate pathway of hydrolysis produces 3-formyl rifampicin.*°** Desacetyl rifampicin is more polar than the parenc compound, and mierobiologically active. This metabolite accounts for the majority of che antibacterial activity in the bile. Rifampicin is almost equally excreted in the bile and urine. These metabolites are non-toxic. Rifampicin is asso- ciated with hepatocellular pattern of ILI" and more often ic potentiates the hepatotoxicity of other anti-TB drugs." The xeno sensing pregnane X receptor (PXR) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that can be acti- vated bya variety of drugs including rifampicin. Activated PXR binds co response elements in the promoters and up- regulates the transcription of phase I and II drug metabo- lizing enzymes such as cytochrome P450 (CYPs and gluta- thione S-transferases (GSTs), and transporters (involved in phase Il), Rifampicin is a potent inducer of several meta- bolic enzyme pathways in particular cytochrome P4SO (CYP3A4) system via the hepatocyte PXR This activation of the CYP3A4 leads to increased metabolism of isoniazid yielding toxic metabolites thus explains the potentiating effect of rifampicin in anti-TB drug induced hepatotoxicity. Rifampicin also induces isoniazid hydro- lases, leading to increased hydrazine production especially in slow acetylators thus increasing the toxicity when used in combination with isoniazid." Processes that are in- volved in the excretion and elimination of the drag metab- olite are grouped as phase Il of drug_ disposition Transporter ABCBI is responsible for the transport of ‘many anti-retroviral and anti-TB deugs including rifampi- cin and ethambutol. ABCBI 3435T variant allele is reported to lower expression level and protein folding thereby alter- ing che structure of substrate binding sites to and de- creased transport activity.*' In a study involving patients on treatment with a combination of anti-TB and anti- retroviral therapy (ART), the proportion of those homozy- gous for ABCBI 343STT genotype was 3-fold higher in those who developed DILL. Rifampicin occasionally in- terferes with bilirubin uptake and results in cransient un- conjugated — hyperbilirubinemia hepatocyte damage. However more commonly, it does contribute to conjugated hyperbilirubinemia by interfering with the bil- irubin excretion by inhibiting che bile salt exporter pump (BSEP) without Pyrazinamide: Pyrazinamide is a nicotinic acid devivative. It is deamidated to pyrazinoic acid. This is further oxidized by xanthine oxidase to S-hydroxy pyrazinoic acid. °°*” The metabolites are excreted via the kidneys. The half-life of pyrazinamide is longer than isoniazid and rifampicin; it is prolonged even further in the presence of underlying liver disease and when used wich other drugs that inhibit xanthine oxidase such as allopurinol. The toxieity of pyra- Zinamide is both dose dependent with a higher dose at 40- (© 2022, ASLJOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY 50 mg/kg being associated with a greater frequency of hepatotoxicity chan the doses used in current regimens, (25-35 mg/kg). In murine models, pyrazinamide inhibited ‘CyPAS0™ activity and NAD" levels were altered in associ ation with free radical species mediated hepatocoxicity. Fluoroquinolones: Fluoroquinolones have been used as second line agents in the context of multi-drug resistant ‘TB and in the events of hepatotoxicity due to first line agents. Quinolones are either metabolized in the liver (as with ciprofloxacin) or are excreted unchanged by the kid- rneys (as with levofloxacin). With an exception of trovaflox- acin which is now withdrawn, fluoroquinolone induced hepatotoxicity is very rare and identifiable only through large-scale studies or worldwide pharmacovigilance report- ing Isolated eases of significant hepatotoxicity have been reported with ciprofloxacin,*! levofloxacin," gatifloxa- cin" The mechanism of hepatotoxicity is thought co be due co hypersensitivity reaction often associated with peripheral eosinophilia and fever. Introduction of fluoroquinolones didn't cause additional hepatotoxicity ‘when used in patients wich hepatitis induced by first line anti-TB drugs.“ In patients with pre-existent liver disease, use of ofloxacin has been Found to be safe and effective. ‘Host Related Risk Factors Although several risk factors have been associated with hepatotoxicity, robust conclusions can't be drawn due to marked variations in study design, cohort size and case def initions. Age ‘Age has been associated with an increased risk of DILL. In ‘one study including $19 patients on standard ant-TB medications, age over 60 years was associated with a 3.5 fold risk of DILL? Another study including 430 patients, pyrazinamide associated adverse events including. DILI ‘was 2.6-fold higher in those over the age of 60 years.” In a cohort of over 3000 patients who were on INH mono- therapy, frequency of DILI was higher in those aged SO years of older."' The severity of INH hepatocoxicity and consequent mortality has also been reported to be higher after the age of 50." In a case-control study, patients ‘who developed DILI on anti-TB drugs were older (39 years) compared to those who did not (32 years).** In another study, the incidence of hepatotoxicity was 17% in patients below 35 years of age and 33% in age above 35 years; in a multivariate analysis, age >35 years was the only indepen- dent variable for predicting anti-TB DILL Older age is as- sociated with decreased liver blood flow, changes in the drug distribution and metabolism, thus potentially reduc- ing the effective clearance of the drugs. Contrary to these, a meta-analysis reported a higher in- idence of clinical hepatitis (6.9%) in children receiving INH and rifampicin, compared to 2.7% in adults.” How- ever, the high frequency of DILI in children was primarily derived from the inclusion of 3 small studies each with 22- 60 patients, ye reporting a very high frequency of ‘clinical hepatitis’ in 25%-52% of all patients Gender Women are more susceptible to DIL from anti-TB ther- apy"? with a reported fold risk.” Activity of CYP3A is higher in females rendering chem more suscepti- bile for hepatotoxicity.” A trend toward increased inci- dence of INH hepatotoxicity has been noted in pregnant women in che thied trimester and first three months post-partum.”> Nutritional Status Malnutrition is common in TB and associated with higher incidence of antiTB drug induced hepatotoxicity.” A recent retrospective observational study revealed that a weight loss of 2 kg or more developing within 4 weeks during TB creat- ment is highly significant independent risk factor for DILL” An adequate intake of nutrients is important for the integrity of liver metabolism and detoxification of TB drugs, as the cytochrome P4S0 enzyme system is affected by nutrient intake, fasting and malnourished states” Alcobol Intake Alcohol can induce enzymes and has potential to cause liver injury. Several studies have demonstrated that alcohol perpetuates anticTB drug induced hepatoroxicicy."*? This risk has been demonstrated even in patients receiving rifampicin for preventative therapy."*** Concomitant Infection The observation that drug hypersensitivity is more com- ‘mon in patients with concomitant viral infection has led to the suggestion that mild inflammatory reaction due to co-existent infection can often act as a ‘danger signal? which permits the development of initial events in the pathophysiological process into a full blown hepatotoxic reaction."* Whether chronic infections other than TB in- crease the risk of DILI during anti-TB therapy has been in- vestigated in several cohorts. The risk of anti-TB drug induced hepatotoxicity is higher in patients with chronic hepatitis B virus (HBV) pa- tients compared to uninfected subjects (16% vs 4.7% p<0.001) and the severity was much higher in the HBV pa- tients in this study (4.7% vs 2.5% p < 0.001). Studies also hhave shown that the severity of the hepatotoxicity is di- rectly related to vieal load at the time of initiation of anti-TB therapy.°° Similar to HBV infection, approximately 30% of all of hepatitis C virus (HCV) infected patients receiving treat- ment with anticTB drugs developed hepatotoxicity com- pared to 11% in controls with a S-fold relative risk of developing, hepatocoxicity and severity associated directly Journal of Cinical and Experimental Hepatology | March 2013 | Vol 3 | No.2. | 37-49) anHEPATOTOXICITY RELATED TO ANTITUBERCULOSIS DRUGS with the viral Load.” Concomitant HIV infection also in- «creases the risk of anti-TB drug induced hepatotoxicity sig- nificantly. This has been observed both before highly active anti-retroviral therapy (HAART) era and during HAART era. The hepatotoxicity in the pre-HAART era ranged from 4 to 15% and in the HAART era ranges from 4 co 27%."* However, there have been several confounding fac- tors such as intravenous drug use, alcoholism, viral hepati- tis, HAART therapy causing hepatotoxicity, drug-drug interactions and liver injury due to immune reconsticu- tion. Overall influence of HIV infection alone on the anti-TB therapy induced hepatotoxicity has been estimated to be 4 times higher than in controls and co-infection with HCY, increases this risk by L4-fole.®® GENETIC SUSCEPTIBILITY Anti-TB DILI remains unpredictable even when variables such as drug regimen and environmental factors are taken into account. Neither the drug related factors nor the con- ‘current risk factors adequately explain why, in the vast ma- jority of cases, hepatotoxicity occurs during the early phase of anti-TB therapy. In addition, observations such as Asian males have double the rate of isoniazid hepatitis than white males and nearly 14 times that of black males!!!” indicate that genetic susceptibility may contribute substantially 00 the developmen of hepatotoxicity. Single nucleotide polymorphisms in the genes coding, for the drug metabolizing enzymes (such as NAT2 and. ‘CYP2E1) eventually leading co an excess formation, accu- mulation of reactive metabolites or their reduced clearance (ouch as ABCCI) have been associated with increased risk of anti-TB DILI (Table 1). Natural PXR protein variants have been associated with inter-individual variability of CYPSA4 expression’ and may contribute to individuals’ RAMAPPA & AITHAL susceptibility to anti-TB DILL. Magnitude of impact of re- active metabolites can be modified by cellular response to oxidative stress that is generated. Hence, polymorphisms in the genes which influence antioxidant defense processes (such as BACHI, MAFK, GST1 and MnSOD) appear to de- {ermine one's predisposition to DILL Although protein binding of reactive metabolites may impair cellular function to cause toxicity, drug-metabolite adducts may interace with the immune system. In order for the drug-metabolite adduct to be recognized by the im- ‘mune system, they should be presented by antigen present- ing cells in conjunction with major histocompatiility complex (MHC) molecules. Consistent with this, studies from India have shown that absence of HLA-DQAI*0102 al- lele, and presence of HLA-DQBI*0201 allele were indepen- dencrisk factors for anti-TB drug induced hepatocoxicity."" PATHOPHYSIOLOGY: UNIFYING HYPOTHESIS: Development of idiosyncratic DILI isan intricate process in- volving both concurrent as well as sequential events deter- mining the direction of the pathways, degree of liver injury and its outcome (Figure 2). The key upstream events include drug specific pachways triggered by particular drugs or their metabolites. Increased formation of reactive metab- lites generally asa result of phase [metabolism or failure of dotoxification usually a function of phase II metabolism is likely to be an initiating event. The expression of these drug metabolizing, enzymes and transporters involved in the excretion and elimination of drug metabolites (phase II!) are regulated by transcription factors (nuclear hormone receptors) such as pregnane X receptor. Genetic and envi- ronmental factors that influence the expression andl activi- ties of proteins involved in phase 1, II and Ul of drug ‘Table 1 Studies that have demonstrated association of specific genotypes with ant DILI. Drug Genotype Hazard rato Cases (n) pValue 25 49 0.009 04 65 0.08 25 63 0.02 2a 66 Isoniazid™ cyraet cio Ani TB drugs and HAART? nares, +1207 "13, Isoniazid”? ns00 1/6 or G/¢ Isoniazid! 82 cosmo nuit Anti TB drugs?” BACHE C/C at 2070401 MAEK G/A or A/A at rs4720833 Anti drugs busoaas0202 or 100 02 56 ‘BACH: gone encodes transcription regulator protein BACHE (BT8 and CNC homology 1. [MAPK gene encodes small Maf basic leucine ziper protein MafK. Hazard ratio forthe any ofthe two singlerucleotide polymorphism (SNPS). 2JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY Pregnane X Receptor Transporters Phase 1,2 enzymes (ATP-binding cassetesub- (nacetyansterase 2 amily, member 1) ‘yoctreme P450 261) D-metabolites Failure of antioxidant defence (Manganese superoxiie ‘ssmulase, gathone Stranslerase, ‘rescnpton factors Bach end Mark) Modklaton of CColuar stess: reactive oxygen species pattern and = magnitude of immune response (HLA ‘aptoyees) | imate immune response | Apoptosis! necrosis ~ Bianger signal (etroné Failure of regeneration veal hepatitis FAV JS (ristone acetytransferase) intecton) | ‘Adaptive immune response Figure 2 Hypothetical model of DIL! due to anti-TS agents with potential drug and host related factors (mb) involved in the pathogeness. disposition or their regulation will determine the rate of for= mation and accumulation of reactive metabolite. ‘These reactive metabolites induce the production of ex- cessive reactive oxygen species (ROS) leading to lipid perox- idation and cell death, Cellular environment can modulate the threshold for hepatocyte death secondary to oxidative stress, Transcription factor Nuclear Factor Erythroid 2- relaced factor-2 (Nef2) regulates glutathione synehetie and detoxification enzymes. Heterodimers of Nrf2 and small Maf basic leucine zipper proteins bind co the antioxidant-responsive element in the promoters of cyto protective gene battery. Nrf2-directed endogenous antiox- idanc systems in the liver may dampen the injurious effect of reactive metabolites. On the other hand, a hetero- dimer complex of broad complex, tramtrack, briea-brac domain (BTB) and cap'n'collar type of basic region (CNC) homology 1 (Bach!) and small Maf proteins down- regulate the expression of antioxidant enzymes. Therefore, dysregulation of the activator arm (including Nef2 and small Mafs) and the repressor arm (including Bach and small Mafs) of the antioxidant pathway may contribute to the propagation of anti-TB DILL.” Reactive metabolite may induce cell stress. by over= whelming antioxidant defense or alternatively by binding to cellular enzymes, lipids or nucleic acids. Mitochondria have been considered an important target in DIL inbibi- tion of mitochondrial respiratory chain results in adeno- sine triphosphate (ATP) depletion and accumulation of reactive oxygen species (ROS). Manganese superoxide dis mutase (MnSOD) is a protein encoded by the nucleus and residing in the mitochondrial matrix where it plays key role in the detoxification of superoxide anion radicals that arise constantly during electron eransport.”' In acase- control genetic association study tha¢ included 63 pacients with antiTB DILI, those with a variant C allele (genotype ‘T/C ot C/O) of MnSOD had 2.5-fold higher tisk of hepato- {oxicity when compared with those MnSOD TT genotype.” Mitochondrial inhibition due to lack of defense against su- peroxide ultimately leads t mitochondrial permeability transition (MPT) with consequent apoptosis or necrosis dependent on presence or absence of ATP. Although variation of drug metabolism and clearance are certainly the key upstream events determining suscep- tibility co hepatotoxicity, the occurrence and extent of liver Journal of Cinical and Experimental Hepatology | March 2013 | Vol 3 | No.2. | 37-49) aHEPATOTOXICITY RELATED TO ANTITUBERCULOSIS DRUGS injury could be influenced by events downstream of initial drug metabolism. Innate immune response can promote orinhibit the inflammatory process and thereby determine the progression and severity of DILL In addition, superim- position of drug metabolizing enzymes and the immune system creates a setting wherein a reactive drug merabolite covalently binds to cellular proteins and this misleads the immune system to mount an attack against the ‘modified sel? resulting in immune mediated descruction of targeted hepatocyte.'® Association of anti-TB DILI with specific human leukocyte antigen (HLA) genotypes" implies that the susceptible individual has an immune system that ‘would more readily recognize the formed neoantigens. Fea- tures of hypersensitivity with multi-system involvement manifested by renal dysfunction, hemolytic anemia, flu like syndrome, arthralgia and rash have been reported with rifampicin.”®°* Rarely pyrazinamide also manifests as granulomatous hepatitis” with fever, eosinophilia and systemic illness. Alternatively, innate immune system may be involved through cytokines that modulate the de- _geee of hepatic inflammation secondary to toxic injury or the ability of liver to regenerate in response to hepatocyte death. In certain circumstances neither the production of reactive metabolites nor the auto-antibodies generated in response fo covalent binding of these metabolites t© pro- teins (haptenization) is sufficient to elicic and immune re~ sponse. Signal I represents the interaction between antigen presenting cell and the T-cell receptor which requires a co stimulatory trigger, a ‘danger signal (signal 2) to prime the adaptive immune system, Signal 3 represents polarizing ey- tokine environment that drives T-cells to ThI of Th2 im- mune response. The ‘danger’ signals are thought to be generated by cytokine release from inflammation associ- ated with chronic viral infections which increase the risk of anti-TB DILL" Altered cytokines environment under these circumstances may prime a genetically susceptible adaptive immune system to respond co ant-TB drug- metabolite adduct (hapten) leading to DILL The ‘danger’ signals are derived from cells that are stressed by reactive metabolite formation or released from cells dying from necrosis" In addition 10 being a second signal in the adaptive immune response, ‘danger’ signals, can also activate signaling pathways for oxidative stress. ‘Therefore, sub-clinical hepatocyte injury manifesting as asymptomatic transaminitis may itself represent the ‘dan- ger) signal indicating both an individual's vulnerability and actas.a decerminancof more significant serious DILL”? More recently, investigations have provided evidence of DILI may potentially be mediated through inhibition of a histone modification.” Histone acetylation results in an open chromatin structure enabling genes in that region to be read; this acetylation is mediated by enzymes known as histone acetyltransferases.* Authors hypothesized that histone acetyltransferase can be involved in acetylation of hydralazine derivatives including INH (on long term ad- “4 RAMAPPA & AITHAL ministration of the drug) leading to exhaustion of the en- zyme.” Considering the fundamental role histone acetylation has in activation of gene transcription, che ex- haustion of histone acetyleransferase can lead co failure of hepatocyte regeneration and hence, unrestrained pro- session of the pathogenic process leading to DILL MANAGEMENT Despite the huge global burden of TB and decades of expe- rience in the use of anti-TB medications, studies investigat- ing DILI lack scientific rigor, consistent methodology and large enough scale to generate the evidence on which ree- ‘ommendations can be based upon. Therefore, approaches to prevent, monitor and manage hepatotoxicity have been based primarily on retrospective observational studies. Recommendations from the American Thoracic Society (ATS).” the British Thoracic Society (BTS)” and more re- cently by National Insite for Clinical Excellence (NICE), UK"™ for the assessment, choice of anti-TB drug regimen, patient education, clinical monitoring and interventions in, the event of hepatotoxicity have been published. It must be noted that many of these recommendations are reliant on expert opinion only Risk Stratification Pretreatment evaluation whenever feasible should include screening for existing chronic liver disease including his- tory of excess alcohol consumption, intravenous drug abuse and nutritional assessment. Baseline evaluation should also include serology for chronic viral infections (hepatitis B, C and HIV) and appropriate assessment for underlying liver disease.””'®° Assessment of risk-benefit ratio is critical when empirical treatment for TB is being considered as these patients have been shown to have excess risk of adverse outcome,"* Individual's risk of DIL should be weighed against thac for developing active TB before opting to treat latent TB. Choice of Drugs and Regimen. There is no evidence to suggest that three times per week regimes are associated wich lower risk of hepatotoxicity than daily dosing regimens.” Guidelines from profes- sional bodies?" provide advice on the choice of drugs, combinations and duration of therapy that are considered suitable to different clinical Considerations should include the cost, affordability, access as well as efficacy and associated adverse effects. AAs isoniazid and rifampicin are highly efficacious, theie use in the treatment of latent or active TB infection is de- sirable whenever possible. However, considering that com- bination therapy increases the tisk of DILI,”’ monotherapy with either isoniazid or rifampicin is preferable for the treatment of latent TB when particular individual is at (© 2022, ASLJOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY higher risk of hepatotoxicity. In patients with unstable or advanced liver disease, ifthe serum alanine aminotransfer- ase level is more than 3 times normal at baseline, the fol- lowing regimens should be considered. The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used. Possible regimens include" ‘+ Two hepatotoxic drugs regimen (rather than the three in the standard regimen) {9 months of isoniazid and rifampicin, plus ethambu- tol — 2 months of isoniazid, rifampicin, streptomycin and ethambutol, followed by 6 months of isoniazid and rifampicin; — 6-9 months of rifampicin, pyrazinamide and etham- butol '* One hepatotoxic drug regimen: — 2 months of isoniazid, ethambutol and streptomy- cin, followed by 10 months of isoniazid and echam- butol ‘* No hepatotoxic drug regimen: in patients with advanced ithosis or portosystemic encephalopathy — 18-24 months treatment with a combination of eth- ambutol, fluoroquinolone, cycloserine and capreo- ‘mycin or aminoglycoside has been suggested as an option.!° Patient Education Patients should be educated about the importance of ad- erence to medications, follow up visits for monitoring, and symptoms of hepatotoxicity with appropriate re- minders wherever possible. In the event of symptoms that are attributable co hepatotoxicity, patients should be forewamed to stop all anti-TB medications and seek med- ical advice in the event of any symproms of hepatotoxicity and seek immediate medical advice. One report from a pro- {gramme of INH based chemoprophylaxis suggested thar regular inquiry and reporting of symptoms at monthly visits proved effective in averting serious DILI without the need for routine measurements of liver biochemistry." Patients should be advised to refrain from alcohol and co seek medical advice about any prescription or non-pre- scription medication use as chese could potentially ‘crease toxicity leading to DILL ‘Monitoring Regular clinical review of patients is helpful to monitor treatment adherence and directly observed. short-course therapy (DOTS) enhances its effectiveness. Therapeutic drug, monitoring!” !° has been shown to improve clinical response, but its use in predicting hepatotoxicit remains to be demonstrated. Within the first few weeks of initiation of anti-TB therapy, up co 20% of patients develop transient, asymptomatic elevations in ALT and as these spontaneously resolve these are thought to repre- sent ‘adapration"” rather than hepatotoxicity; potential mechanisms underlying the former phenomenon are dis cussed in the literature. The Seattle-King County Public Health Departmenc used a protocol to monitor INH ther- apy which included advising the patient at each visit to stop the medication and call the clinic if symptoms oF hep- arotoxicity occurred! With careful clinical monicoring without routine laboratory tests, che rate of hepatotoxicity in 11,141 patients was much lower (0.1%-0.15%) than pre- viously expected (1%) and there were no deaths." The ATS guidelines do not recommend routine liver biochemistry testing in those without any obvious tisk factors; but, liver biochemistry based monitoring should be considered at 2 weekly intervals in the first 2-3 months of therapy in pa- tients with risk factors for developing hepatotoxicity and in those who have abnormal baseline tests. Interventions Prompt withdrawal ofthe offending medication is the most critical intervention in the management of hepatotoxicity. However, considering the lack of specific markers that dis- ‘inguish transient self-resolving transamintis from poten- tially serious DILI, the thresholds set for discontinuation of anti-TB drugs remain pragmatic rather than evidence based. The ATS, BTS, NICEand World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease guidelines have some minor variations in the interventions for hepatotoxicity. In general, advice isto stop allanti-TB medications when elevation in ALT rea- ches 3 times ULN with symptomsattributable to hepatotox- icity or ALT level of 5 times ULN is detected. In smear positive TB cases or where discontinuation of therapy is deemed unsafe due to severity of the illness, a non- hepatotoxic anti-TB treatment such as ethambutol, fiuoro- quinolone or cyeloserine could be considered. Once withdrawn, anti-TB treatment should be withheld ideally until che liver tests normalize, or at least ALT falls below 2 times ULN. Considering that first line anti-TB drugs are highly effective and relatively inexpensive, bene s of re-challenge must outweigh its risks; it is unwise to discard these drugs from the regimen. Therefore, it is ac- ceptable to attempe reintroduction of these medica- tions." In 11%%-24% of patients, re-exposure to che same drug regimen leads to recurrence of DILI"” and positive re-challenge is nocaffected by the degree of initial injury."!° Both ATS and BTS advice restarting the anti-TB medica- tions one at a time, The WHO as well as the International Union Against Tuberculosis and Lung Disease advice re- starting all the drugs simultaneously if however, there is a second bout of hepatotoxicity after re-challenge, then the drugsare to be reintroduced consecutively. A study ran- domized 175 patients with hepatotoxicity into these 3 rein- troduction regimens and found no difference in the Journal of Cinical and Experimental Hepatology | March 2013 | Vol 3 | No.2. | 37-49) soHEPATOTOXICITY RELATED TO ANTITUBERCULOSIS DRUGS frequency of recurrent DILL" On the contrary a small randomized controlled trial of 4S patients with hepatotox- icity compared restarting of all drugs simultaneously with, sequential reintroduction regimen without pyrazinamide showed safety of the latter regimen." In the light of such controversial evidence one has co weigh the risks of severe life threatening forms of TB, need for faster sputum conversion, need for reduction in disease transmission in the community and to reduce the risk of developing rmulei-drug resistance forms against the risks of hepatotox- icity. A sequential regimen with or without pyrazinamide ‘would be suitable in those individuals who have a higher baseline prediction of hepatotoxicity as defined by their phenotype of malnutrition, low albumin, alcoholics and HIV-positive individuals." Co-administration of N-acetyl cysteine (NAC)'"? was protective against DILI in animals treated with hepatotoxic doses of INH and rifampicin. A report on benefit of oral ad- ministration of NAC (600 mg twice daily) in the prevention, of anti-TB DILI comes from an open labeled trial including (60 patients of age >60 years, in the study 37.5% developed clevation of both AST (mean 99.4) and ALT (mean 65.8) and mean bilirubin of 1.1 mg/dl within a mean duration Of 5 days of starting combination anti-TB therapy when not treated with NAC.""® In contrast, none in the group treated with NAC developed abnormalities of the liver chemistry. Iis difficult ro put the details of this study in the context of a vast amount of clinical observations de- scribed in the literature; significance of these findings and theie generalizability are unclear due co the fact, that mean age of the cohorts were 73 years and possibility that the asymptomatic transaminitis could have been tol- erance and not clinically significant DILL. Report of reduc- tion of incidence and severity of anti-TB hepatotoxicity by the use herbal formulation" warrants replication in large clinical trials in independent cohorts. yi FUTURE DEVELOPMENTS Anti-TB drug induced hepatotoxicity is a serious adverse effect and continues to be a problem worldwide. Efforts at prevention and/or early recognition of anti-TB DILI are severely hampered by limited understanding of its pathogenesis. Fucure investigations exploring the mecha- nisms underlying the pathogenesis of anti-TB DILI should bbe performed using human tissue and samples whenever possible, so that the novel findings can be translated read- ily into clinical applications. Clear and consistent pheno- typi definitions are essential firs step! in those studies seeking to identify risk factors of DILL in large cohorts of patients. Recent investigations focused on genetic suscep- tibilty to ‘idiosyncratic’ DILI have promised the develop- ment of refined algorithms including drug, host and environmental risk factors that would allow pre-emption of DILI!"® and hence allow better tailoring of medications 46 RAMAPPA & AITHAL based on accurate estimates of risk-benefic ratio. Undoubr- edly, there is an urgent need for more refined, novel, ge- netic, proteinaceous and metabolite biomarkers which will decece patients with inereased susceptibility to DILI, assist in early diagnosis and monitoring for DILI during therapy. 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