Treatment of tuberculosis in presence of hepatic and renal impairment

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1 Respirology (2008) 13 (Suppl. 3), S100 S107 doi: /j x Treatment of tuberculosis in presence of hepatic and renal impairment Kin-Sang CHAN Pulmonary Unit, Haven of Hope Hospital, Hong Kong Treatment of tuberculosis in presence of hepatic and renal impairment CHAN K-S. Respirology 2008; 13: S100 S107 Abstract: Antituberculous drugs are potentially hepatotoxic and nephrotoxic, which may complicate the treatment course, increase treatment morbidity or even be potentially fatal if not recognized early. Prediction, prevention and precaution for early liver derangement are important to minimize antituberculosis drug hepatotoxicity (ATDH). Identification of hosts at risk can predict or prevent ATDH. Genetic polymorphism of drug metabolizing enzymes (N-acetyltransferase 2, cytochrome P450 oxidase [CYP2E1], and glutathione S-transferase) are suggested as one of the key factors in determining the risk of ATDH. Vigilant clinical and biochemical monitoring are mandatory to improve outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. The clinical approach to ATDH depends on its phase of treatment and the severity of drug-induced hepatitis. Current professional guidelines suggest withholding of antituberculosis drugs when alanine aminotransferase exceeds three- or five-times the upper limit of normal. This can be followed by an interim nonhepatotoxic regime, or gradual introduction of one or two or three hepatotoxic drugs when liver function becomes normal. In the presence of renal impairment, antituberculosis drugs can be modified by manipulating the dosage or dose interval or both as follows: (1) no adjustment in dosage and dose interval; (2) increase of the dose interval without decreasing dose; (3) reduction of the dose without change in dose interval; and (4) reduction of the dose and increase of the dose interval. Key words: hepatic impairment, renal impairment, tuberculosis treatment. INTRODUCTION The treatment of tuberculosis (TB) depends on the interplay of the following triad: host, drugs and microorganisms. This article will focus on the aspect of drug host interaction. Current standard anti-tb drugs can potentially induce hepatotoxicity and nephrotoxicity, which may complicate the treatment course, increase treatment morbidity or even be potentially fatal if not recognized early. TREATMENT OF TB IN PRESENCE OF HEPATIC IMPAIRMENT Incidence of anti-tb drug hepatotoxicity (ATDH) Anti-TB drugs with greater propensity to induce hepatoxicity include isoniazid (H), rifampicin (R), pyrazinamide (Z) among the first-line drugs; and ethionamide, prothionamide and para-aminosalicylic Correspondence: K-S Chan, Pulmonary Unit, Haven of Hope Hospital. 8 Haven of Hope Road, Tseung Kwan O, Hong Kong, China. chanks@ha.org.hk acid among the second-line drugs. A meta-analysis of TB studies have shown the following incidence rates of ATDH: 1.6% for regimens contained isoniazid without rifampicin, 1.1% for regimens contained rifampicin without isoniazid, and 2.55% for regimens contained both isoniazid and rifampicin. 1 Among the various components of a short-course anti-tb drug regimen, recent studies have identified pyrazinamide as one associated with higher risk of hepatotoxicity. In a recent study performed in Canada, 2 the incidence of all major adverse events was 1.48 per 100 personmonths of exposure for pyrazinamide as compared with 0.49 for isoniazid, and 0.43 for rifampicin. In another prospective study, 45 patients who developed ATDH were randomised to either HRZE or SHRE (E, ethambutol; S, streptomycin), and the recurrence rate of hepatotoxicity was 24% versus 0% respectively (P = 0.021). 3 The incidence of ATDH with standard multidrug TB treatment has been variably reported, ranging from 2% to 28% The great variation in incidence among different studies may be contributed by differences in definition of ATDH, study population, drug regimens and risk factors. The issue of ATDH has drawn greater attention in the case of treating latent TB infection (LTBI) with rifampicin plus pyrazinamide. In a national survey performed in United States to measure rates of liver injury, hospitalisation and

2 The production of toxic metabolite of isoniazid death associated with rifampicin and pyrazinamide in treatment of LTBI in 8087 patients, per 1000 therapy developed hepatitis and seven patients died. The revised American Thoracic Society/Centers for Disease Control recommendations now state that rifampicin plus pyrazinamide should generally not be offered to persons with LTBI. 20 Pathogenesis of anti-tb drug hepatotoxicity The biochemical mechanisms and pathogenesis of ATDH are not entirely clear. Drug induced liver toxicity may result from direct toxicity of the primary compound or its metabolite, or from an immunologically mediated response affecting hepatocytes, biliary epithelial cells and/or liver vasculature. 21 It may be a dose-dependent or an idiosyncratic reaction comprising most type of drug induced liver toxicity. 21 It has been postulated that reactive metabolite has a central role in drug-induced liver injury. 22 For most drugs, the major routes of elimination involve production of metabolites that are safely secreted and represent no threat to the liver cells. Drugs may go through bioactivation via a relatively minor metabolic pathway to form reactive or toxic metabolites. In general, the liver has ability to detoxify these metabolites, allowing their safe elimination. However, under certain circumstances, the reactive metabolites can accumulate in the hepatocytes resulting in damages through a variety of mechanisms, such as covalent binding with cellular macromolecules or oxidative stress. 22 ATDH-related metabolites of isoniazid have been studied extensively. It has been proposed that in the metabolism of isoniazid, acetylation by N-acetyltransferase 2 (NAT2), oxidation by cytochrome P450 oxidase (CYP2E1) and detoxification by glutathione S-transferase (GST) might play important roles in isoniazid-induced hepatotoxicity 23 (Fig. 1). The metabolism pathways of isoniazid are summarized in Figure 2. Acetylation of isoniazid may result in the formation of acetylisoniazid, which is hydrolysed to acetyl hydrazine and subsequently diacetyl hydrazine, which is possibly nontoxic. 24 Another hypothetical pathway involves hydrolysation of isoniazid by isoniazid hydrolase to hydrazine, which is further acetylated to acetyl hydrazine. This pathway may be operationally more important in the slow acetylator phenotype. It has been demonstrated that CYP2E1-mediated oxidation of acetyl hydrazine may generate hepatotoxins such as acetyldiazene, acetylonium ion or ketene. These hepatotoxins could be detoxified by GSTs present in the liver. 25 It is suggested that isoniazid is converted to diacetyl hydrazine rapidly in rapid acetylators and excreted from the body, rendering rapid acetylators less susceptible to ATDH. In slow acetylators, less acetyl hydrazine is converted to diacetyl hydrazine, and most of the acetyl hydrazine is oxidized to toxic products by CYP2E1. 23 Approaching anti-tb drug hepatotoxicity Prediction, prevention and precaution for detecting early liver derangements are the three major strategies. Predicting anti-tb drug hepatotoxicity S101 Many risk factors associated with the development of ATHD have been reported 4 11,13 18,26,27 (Table 1). The identification of high-risk patients might alert the early detection of ATDH. Among all risk factors, advanced age is most commonly reported. 4,5,7,8,11,14,15,17,27 Patients with advanced age may be more vulnerable to ATHD due to a decreased clearance of drugs metabolized by CYP450 enzymes, changes in liver blood flow, liver size, drug binding or drug distribution with aging. Other risk factors include abnormal baseline liver function tests, 8 11 preexisting hepatitis B, 6,9,26,27 hepatitis C infection, 9,16 HIV status, 7,16 alcohol intake, 6,17 low body mass index, 9,14 use of other hepatotoxic drugs 6,10 and slow acetylator status. 14,17 Some workers also reported female gender as a risk factor, 4,5,7,13 while some showed no difference. 11,14,27 Figure 1 Reactive metabolites as playinig central role in druginduced liver injury.

3 S102 K-S Chan Figure 2 Metabolism of isoniazid and the actions of drugmetabolizing enzymes. CYP2E1, cytochrome P450 oxidase; NAT2, N-acetyltransferase 2; GST, glutathione S-transferase. Table 1 Risk factors of antituberculosis drug hepatotoxicity Author Dossing M 4 Ormerod LP 5 Tost JR 6 Yee D 7 Teleman MD 8 Fernandez-Villar A 9 Pukenyte E 10 Schaberg T 11 VanHestR 13 Huang YS 14 Sharma SK 15 Ungo JR 16 Pande JN 18 Wong WM 25 Chang KC 26 Risk factors Advanced age, female sex, extensive tuberculosis Advanced age, female sex Alcohol, hepatitis B, other hepatotoxic drugs Female sex, advanced age, HIV, Asian Advanced age, abnormal baseline LFT, female sex Abnormal baseline LFT, low body mass index, hepatitis B/C, other drugs Abnormal baseline LFT, fluconazole exposure History of hepatitis, advanced age Female sex Advanced age, low BMI, slow acetylator, CYP2E1 c1/c1 genotype Advanced age, advanced TB, low albumin, HLA-DQB1*0201 HIV, hepatitis C Advanced age, low albumin, alcohol, slow acetylator, extensive TB Hepatitis B Hepatitis B, advanced age LFT, liver function test. Genetic polymorphism of drug metabolizing enzymes and ATDH Genetic polymorphisms of drug metabolizing enzymes are suggested as one of the key factors in determining the risk of ATDH. There are three key drug metabolising enzymes regulating the metabolism of isoniazid: NAT2, CYP2E1 and GST. 23 Acetylator rate is genetically determined and it is possible to be a fast, intermediate or slow acetylator. Previously, the acetylator phenotypes of isoniazid were determined by enzymatic methods. NAT2 is genetically determined by the NAT2 locus located at chromosome 8p22. The NAT2 locus contains several single nucleotide polymorphisms (SNP) and are expressed as rapid, intermediate and slow acetylator phenotypes. Most investigators studied seven or less SNPs at the nucleotide position (np) (191[G/A], 282[C/T], 341[T/C], 481[C/T], 590[G/A], 803[A/G], 857[G/A]) at exon 2 on the NAT2 locus to determine the acetylator status of individuals. 23 Genotypes are expressed as alleles/haplotypes, such as NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*12, etc, depending on the arrangements of nucleotides (G/A, C/T, T/C, C/T, G/A, at 191, 282, 341, 481and 590 np respectively). The common allele (i.e. NAT2*4) is known as a rapid acetylator allele. Individuals carrying two rapid acetylator alleles (NAT2*4/NAT2*4 genotype) are rapid acetylators. Individuals carrying one rapid acetylator and one slow acetylator allele

4 The production of toxic metabolite of isoniazid (e.g. NAT2*4/NAT2*5 genotype) are intermediate acetylators. Individuals carrying two slow acetylator alleles (e.g. NAT2*5/NAT2*6 genotype) are slow acetylators. Individuals with slow acetylator genotypes were shown to have a higher risk of ATDH compared to fast acetylators (relative risk, 28 in a Japanese study; 28 odds ratio [OR], 3.66 in a Taiwanese study; 29 and 3.8-fold risk in a Korean study. 30 ) The CYP2E1 locus is located at chromosome 10q24.2 which also possesses a polymorphism. The common genotype CYP2E1 c1/c1 is associated with a higher CYP2E1 activity and may lead to a higher production of hepatotoxins. 23 A study showed that patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2) with an OR of The deficiency of GST activity may also increase the risk of ATDH. Studies have shown that the homozygous deletion at GSTM1 locus had an increased risk of isoniazid-induced hepatotoxicity with an OR of 2.13 in Indian patients, 32 and an OR of 2.23 in Taiwanese patients. 33 Pharmacogenetic studies of these drug metabolising enzymes may have a potential role in predicting ATDH. 23,34 Preventing anti-tb drug hepatotoxicity There are several strategies in preventing ATDH. These include: 1 Clinical assessment. A standardized format of history-taking and physical examination to look for signs of chronic liver disease may be helpful in identifying individuals who are high risk for developing ATDH Baseline blood investigations, including liver function tests 21,35,36 and viral studies for individuals at risk, 21 for example hepatitis B/HIV in high-prevalent countries, hepatitis C for individuals who inject drugs. 3 Advising patients to abstain from alcohol and to avoid concomitant administration of hepatotoxic drugs Instructing patients to immediately to stop medications in the presence of symptoms of hepatitis, for example nausea, vomiting, abdominal discomfort or unexplained fatigue. Instructing patients with symptoms to contact the clinic for further evaluation. 21,35,37 Vigilant clinical monitoring of symptoms of hepatitis is essential. 5 Regular biochemical monitoring of liver function tests in the presence of risk factors of ATDH is advised by several professional societies, 21,35,37 although there is still some controversy. 38 Early liver derangements are often asymptomatic, and regular monitoring of liver function tests may detect early changes which ultimately affect prognosis of ATDH. For patients with significant underlying liver disease or who are otherwise at risk of major hepatotoxicity, experts recommend monitoring regularly at weekly/biweekly intervals for the initial 2 months, 35,37,38 followed by more widely spaced assessments throughout the treatment course. 38 Clinical management of anti-tb drug hepatotoxicity S103 Drug-induced liver injury is ultimately a clinical diagnosis which is made by excluding other aetiological causes. 21 In patients with severe cases of ATHD or in whom alanine aminotransferase (ALT) did not recover with drug withdrawal, additional testing for other causes of hepatitis should be considered. 21 There are several patterns of drug-induced liver derangements: 1 Isolated raised bilirubin, which can be caused by rifampicin. 2 Transient mildly raised liver enzymes, which is usually caused by hepatic adaptation Hepatitis pattern, defined as ALT (expressed as multiples of upper limit of normal [ULN]) to serum alkaline phosphatase (ALP) (expressed as multiples of ULN) ratio > Cholestatic pattern, defined as ALT (expressed as multiples of ULN) to serum ALP (expressed as multiples of ULN) ratio < Mixed hepatitis and cholestatic pattern: defined as ALT (expressed as multiples of ULN) to serum ALP (expressed as multiples of ULN) ratio between 2 and The professional societies recommend cessation of all anti-tb treatment if clinical or symptomatic hepatitis develops. For asymptomatic rise in liver enzymes, the cut-off value adopted by American Thoracic Society, 21 British Thoracic Society 35 and European Respiratory Society 36 for stopping anti-tb treatment is elevation of ALT five-times the ULN. The cut-off value adopted by Hong Kong Tuberculosis Service is elevation of ALT thrice the ULN, or elevation of bilirubin twice the ULN. 37 TB specialists in Hong Kong attach more significance to a stepwise escalation of transaminase levels and a persistent elevation of bilirubin levels as indicative of hepatotoxicity. It appears that for patients who are going to develop hepatitis eventually, an elevated enzyme level thrice the ULN may easily become five-times the ULN in due course. 38 The American Thoracic Society also recommends stopping anti-tb drugs when the serum transaminase level reaches thrice the ULN in patients with symptoms suggestive of hepatitis. 21 The overall clinical approach of managing ATDH is summarized in Figure 3. After the liver enzymes return to the normal range, the strategies of rechallenge with anti-tb drugs depend on the phase of treatment or disease course, and the severity of hepatitis. When cessation of anti-tb occurs in the early phase of treatment, or when the disease is extensive, often an interim anti-tb treatment regimen will be introduced to cover the TB treatment. 38 The choice of interim regimen depends on the severity of hepatitis. In case of severe hepatitis, an interim regimen of no hepatotoxic drugs is adopted. Ofloxacin/levofloxacin appear to be a useful component of nonhepatotoxic drug regimens during the interim or even the definitive phase of treatment of TB in the presence of druginduced hepatotoxicity. 38 If the hepatitis is less severe, an interim regimen of one hepatoxic drug can be adopted. 21 Subsequently, another hepatotoxic drug is

5 S104 K-S Chan Figure 3 A proposed approach for management of antituberculosis drug-induced hepatitis. E, ethambutol; H, isoniazid; levo, levofloxacin; LFT, liver function test; O, ofloxacin; R, rifampicin; S, streptomycin. Figure 4 Treatment of tuberculosis in pre-existing liver disease. HRZ, isoniazid rifampicin pyrazinamide. introduced slowly with the careful monitoring of liver function tests. Whenever possible, it seems advisable to resume the use of both isoniazid and rifampicin so that the total duration of treatment will not be unduly long. 38 Rifampicin is recommended to be restarted first according to the guidelines of American Thoracic Society. 21 In general, resuming pyrazinamide is not advisable if reintroduction of both isoniazid and rifampicin for treating drug-susceptible disease is successful. 38 The patient is ultimately put on definitive treatment regimens as determined by patient responses to drug challenge. The regimens can contain two potential hepatotoxic drugs: isoniazid and rifampicin, one potential hepatotoxic drug: isoniazid or rifampicin or no potential hepatotoxic drugs, which are usually ofloxacin/levofloxacinbased. 21,38 In patient with pre-existing liver dysfunction, initial work-up and diagnosis is important. TB infection of the liver itself usually requires no anti-tb drug dose modification. Fatty liver is a common cause of mildly elevated liver enzymes and can be diagnosed by ultrasound. For chronic liver disease, staging of illness according to Child s criteria will affect the treatment regimen, which may vary from standard treatment to modified regimen with two or one or no hepatotoxic drugs 21 (see Fig. 4). TREATMENT OF TB IN PRESENCE OF RENAL IMPAIRMENT A drug, after administration, will eventually reach its maximum serum concentration (C max), followed by decline at a rate determined by pattern of tissue distribution, drug metabolism and drug elimination. The therapeutic effect of a drug depends on the minimum inhibitory concentration (MIC) of the targeted organism, the drug C max, or the area that is above MIC (AUC). Metabolism and elimination of drugs involves mainly the hepatic and renal routes, and dysfunction of the liver and kidneys will affect both the therapeutic level and the drug toxicity. The pharmacokinetcs of different anti-tb drugs are summarized in Table 2. 40,41 Isoniazid, rifampicin, pyrazinamide and ethionamide are predominately excreted by hepatic clearance; while ethambutol, streptomycin, amikacin and levofloxacin are mainly renally excreted. Anti-TB drugs can be modified by manipulating the dosage or dose interval or both in the presence of renal impairment: (1) no adjustment in dosage and dose interval; (2) increase of the dose interval without decreasing dose; (3) reduction of the dose without change in dose interval; and (4) reduction of the dose and increase of the dose interval. 41

6 The production of toxic metabolite of isoniazid S105 Table 2 Excretion of antituberculosis drugs 40,41 Drug Renal excretion (%) Hepatic clearance (%) Isoniazid Fast, 10; Slow, 30 Fast, 90; Slow, 70 Rifampicin Pyrazinamide 5 95 Ethambutol Streptomycin >95 0 Amikacin >95 0 Levofloxacin >70 <5 PAS Cycloserine Not known Ethionamide 5 95 Fast, fast acetylator; PAS, para-aminosalicyclic acid; Slow, slow acetylator. Figure 5 Antituberculosis drug dosage adjustment in renal impairment. INAH, isoniazid; PAS, para-aminosalicyclic acid. For drugs that are predominately excreted by hepatic clearance, little dosage or interval adjustment is required. Adjusting the dosage or interval of administration of a drug in a patient with renal impairment is necessary for those drugs likely to generate higher plasma concentrations of parent compound and/or metabolite when given at normal dosages in these patients, resulting in potential toxicity. The fourth method of dosage adjustment (reduce dose and increase dose interval) should be used when adjustment with the second method produces subtherapeutic concentrations and adjustment with the third method does not provide sufficient therapeutic cover throughout the dose interval. 41 There is evidence that the efficacy of anti-tb drugs is not dependent on prolonged maintenance of blood and tissue levels in excess of their MICs. Anti-TB therapy is equally efficacious if larger doses are given less frequently. The elected method of anti-tb dosage adjustment in patients with renal failure would be increasing the dose interval instead of reducing the dose. 41 However, exceptions to this general rule exist: ethionamide and aminosalicylic acid require adjustment of the dosage and not of the dose interval; levofloxacin and aminoglycosides require adjustment of both the dosage and dose interval. 41 The dosage adjustment of anti-tb drugs in the presence of renal impairment are summarized in Figure 5. Locally applicable prediction formulae such as the Cockcroft and Gault formula can be used to estimate glomerular filtration rate. Although pyrazinamide is primarily eliminated by hepatic metabolism, its active metabolite is excreted by the renal route. When creatinine clearance is less than 30 ml/min, a dosage of mg/kg thrice weekly is recommended. 41 The use of ethambutol in the presence of renal impairment brings particular concern because of its renal route of excretion and the risk of ocular toxicity. The major relative contraindications for ethambutol are a patient s inability to report symptoms, lack of reasonable vision for carrying out independent daily living activities, and renal impairment. 42 When renal insufficiency is the only relative contraindication, ethambutol may be used safely in a thrice-weekly regimen with isoniazid, rifampicin and pyrazinamide after appropriate dosage adjustments. 42 Various professional bodies have made different recommendations on the prescription of ethambutol in the presence of renal impairment. The British Thoracic Society recommends substantial dose reduction unless dialysis is given. 35 The American Thoracic Society prefers increase in dose interval to dose reduction because of concern over suboptimal serum concentration. Thus the American Thoracic Society recommends mg/kg thrice weekly for patients with creatinine clearance less than 30 ml/min. 43 Hong Kong TB experts recommend ethambutol to be given thrice weekly with isoniazid, rifampicin and pyrazinamide with the following dosage: mg/kg when creatinine clearance equals ml/min; mg/kg when creatinine clearance equals ml/min; and 15 mg/kg when creatinine clearance is less than 10 ml/min. 42 International experts recommend baseline assessment of visual acuity and red green colour perception for every patient before starting ethambutol. However, whether periodic testing of visual acuity and colour discrimination may facilitate early diagnosis of ocular toxicity remains uncertain. The American Thoracic Society considers these tests necessary for patients with renal insufficiency. 43 Therapeutic drug monitoring may be a useful tool in adjusting dosage in patients with renal impairment. REFERENCES 1 Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991; 99: Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I et al. Incidence of serious side effects from firstline antituberculosis drugs among patients treated for active tuberculosis. Am. J. Respir. Crit. Care Med. 2003; 167: Tahaoglu K, Atac G, Sevim T et al. The management of anti-tuberculosis drug-induced hepatotoxicity. Int. J. Tuberc. Lung Dis. 2001; 5: 65 9.

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