Lung (2014) 192:205–210 DOI 10.1007/s00408-013-9535-8

TUBERCULOSIS

Antituberculosis Treatment and Hepatotoxicity in Patients with Chronic Viral Hepatitis Yuag-Meng Liu • Yu-Jen Cheng • Yu-Lin Li Chun-Eng Liu • Wu-Huei Hsu



Received: 15 May 2013 / Accepted: 5 November 2013 / Published online: 30 November 2013 Ó Springer Science+Business Media New York 2013

Abstract Background Whether antituberculosis (anti-TB) treatment in patients with chronic viral hepatitis affects the incidence and onset time of drug-induced hepatotoxicity (DIH) is still controversial. The aim of this retrospective study was to find out whether chronic viral hepatitis affects the incidence and onset time of DIH. Methods All patients diagnosed with active TB and being treated at a tertiary referral hospital between 2002 and 2009 were identified from medical records, from which 553 patients were enrolled in the study. The incidence and onset of DIH in patients with and without chronic viral hepatitis (controls) were compared. Results The incidence of DIH was similar in patients with and without chronic hepatitis (8 % [32/392] vs. 7 % [11/ 161], P [ 0.05). The incidence of transient liver function impairment (TLI) was significantly lower in controls than in chronic hepatitis patients (2 % [9/392] vs. 12 % [20/ 161], P \ 0.001. The mean onset times of DIH in the control, hepatitis B virus (HBV), and hepatitis C virus (HCV) groups were not significantly different (40, 39, and 67 days, respectively, all P [ 0.05). The mean onset times of TLI in the control, HBV, and HCV groups were

Y.-M. Liu Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, ROC Y.-M. Liu  Y.-J. Cheng  Y.-L. Li  C.-E. Liu Department Infectious Disease, Changhua Christian Hospital, 135 Nanxiao St, Changhua, Chaghua, Taiwan, ROC W.-H. Hsu (&) Department of Internal Medicine, China Medical University Hospital, 2 Yuh-Der Road, Taichung 40447, Taiwan, ROC e-mail: [email protected]

significantly different (23, 48, and 68 days, respectively, all P \ 0.05). Conclusions Liver function impairment during anti-TB therapy in patients with chronic viral hepatitis was due to mostly TLI, with TLI occurring later than in controls. Chronic viral hepatitis had no significant effect on the incidence of DIH. Keywords Antitubercular agents  Hepatitis B virus  Hepatitis C virus  Drug-induced liver injury

Introduction Tuberculosis (TB) remains a major health concern worldwide [1]. Chemotherapies have been shown to be highly effective in treating TB; however, the effectiveness is offset by the increased incidence of drug-induced hepatotoxicity (DIH) [2]. The incidence of tuberculosis in Taiwan is 68 per 100,000 [3]. There is high prevalence of hepatitis B virus (HBV) (7.4 %) and hepatitis C virus (HCV) (5.5 %) in Taiwan [4, 5]. The male-to-female ratio is 2.3:1 and 53 % of the tuberculosis-infected patients were older than 65 years according to the Centers for Disease Control in Taiwan. Previous studies have discussed the factors that can cause an increased risk of DIH. These factors include advanced age, female gender, alcohol use, and malnutrition [6–8]. It is still a question whether the incidence of hepatotoxicity is higher in patients with chronic hepatitis virus infection than in those without infection during anti-TB treatment [9–13]. Few studies have reported about the potential association of chronic liver disease with the onset of hepatotoxicity. We report on our investigation on the

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association between chronic hepatitis and the onset time of liver function impairment during anti-TB treatment in patients with active TB.

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drug. Mild DIH was defined as 120 IU/L \ AST/ALT levels B200 IU/L, moderate DIH as 200 IU/L \ AST/ ALT levels B500 IU/L, and severe DIH as [500 IU/L. Treatment and Monitoring

Materials and Methods Study Design We retrospectively enrolled patients diagnosed with TB who were receiving anti-TB agents at the Changhua Christian Hospital, a tertiary referral hospital in central Taiwan, from January 2002 to December 2009. The study was approved by the Institutional Review Board. Information was collected by a computer-assisted search of medical records of patients diagnosed with TB. The following data were collected: age, sex, underlying diseases, concurrent use of other hepatotoxic agents, dates of prescribing and stopping anti-TB agents, regimens and doses of anti-TB agents, serology testing for HBV surface antigen (HBsAg) and HCV antibodies, serial liver function tests at baseline and during anti-TB treatment [including levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total and direct bilirubin], associated symptoms of hepatitis (including poor appetite, nausea, vomiting, fatigue, lower leg edema, abdominal discomfort, and jaundice), and treatment outcomes. Patients with abnormal baseline liver function test results and HIV infection, those who reported they are alcoholic, those who were lost to follow-up, transferred to other institutions, had stopped anti-TB treatment because an alternative diagnosis was made, and whose death was not attributable to DIH were excluded because it is difficult to define patients with an abnormal baseline liver function test who develop liver function impairment after therapy. Definitions of DIH and Transient Liver Function Impairment (TLI) The criteria used to define TLI and DIH were based on previous study recommendations [2, 11, 14–16]. TLI was diagnosed under two sets of conditions: (1) if AST/ALT levels increased above the upper limit of the normal range but resolved spontaneously despite continued anti-TB medication, and (2) if anti-TB medication was first discontinued and the patient was successfully rechallenged with the drug after the liver function test results were normal. DIH was confirmed in a patient if the liver transaminase level exceeded 120 IU/L with symptoms of acute hepatitis or it exceeded 200 IU/L with or without symptoms of acute hepatitis while the anti-TB drug treatment was stopped, and the liver transaminase level increased to [120 IU/L when the patient was rechallenged with the

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Most patients initially received daily isoniazid, rifampicin, ethambutol, and pyrazinamide in the first 2 months of treatment followed by isoniazid, rifampicin, and ethambutol in the subsequent 4 months. The recommended daily dose of an anti-TB drug in Taiwan is as follows: isoniazid 5 mg/kg, rifampicin 10 mg/kg, ethambutol 15 mg/kg, and pyrazinamide 25 mg/kg. Liver function tests were performed once every 2 weeks in the first month after the initiation of treatment and on a monthly basis thereafter. If any liver chemistry abnormalities were detected, monitoring was performed more frequently. Patients who developed increased liver transaminase levels but did not have clinical symptoms were carefully observed without discontinuation of any anti-TB agents. If the patient had symptoms of hepatitis, all possible culprit drugs were stopped. After the liver transaminase level normalized, drugs were restarted in series. If liver transaminase levels increased during a rechallenge of the therapy, the specific drug that caused the increase was discontinued. A drug was considered responsible for adverse effects if symptoms appeared with the start of taking the drug, resolved with withdrawal, and reappeared with a challenge of the same drug. Analysis Values are expressed as mean ± standard deviation or as number (percentage) in the text and tables. Differences with regard to numerical values between different groups were analyzed using Student’s t test or the Mann–Whitney U test, depending on the distribution of the data. Nominal variables were assessed using the v2 test or Fisher’s exact test. Baseline characteristics among the HBV, HCV, and control groups were analyzed by one-way analysis of variance (ANOVA) and post hoc analysis. A P value of \0.05 was considered statistically significant.

Results Baseline Characteristics A total of 553 patients were enrolled in the study. All patients were screened for HBV and HCV before anti-TB treatment began. Of these, 392 were negative for HBsAg and HCV antibody (control group), 75 were positive for HBsAg and negative for HCV antibody (HBV group), 71 were positive

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Table 1 Baseline characteristics of patients with chronic viral hepatitis and control subjects Baseline characteristics

HBV (n = 75)

HCV (n = 71)

HBV ? HCV (n = 15)

Control (n = 392)

P valuea

Age (years)

62.0 ± 15.3

69.1 ± 17.8

69.9 ± 10.9

69.1 ± 17.8

NS

Male sex

61 (81)

51 (72)

13 (87)

281 (72)

NS

Baseline AST (IU/L)

24.4 ± 6.6

22.9 ± 12.0

20.7 ± 7.2

20.7 ± 7.2

0.003

Baseline ALT (IU/L)

20.6 ± 6.8

18.8 ± 9.3

17.5 ± 7.8

17.5 ± 7.8

NS

Baseline bilirubin (mg/dL)

0.62 ± 0.28

0.64 ± 0.31

0.52 ± 0.29

0.52 ± 0.27

0.015

Baseline creatinine (mg/dL)

1.59 ± 1.33

1.43 ± 1.85

1.00 ± 0.31

1.59 ± 1.92

NS

Initial regimen HERZ

73 (97)

67 (94)

15 (100)

377 (96)

NS

HER

1 (1)

2 (3)

0

12 (3)

NS

HR

1 (1)

2 (3)

0

3 (1)

NS

Data are presented as mean ± standard error or n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HBV = HBV surface antigen positive and anti-HCV antibody negative, HCV = HBV surface antigen negative and HCV antibody positive, HBV ? HCV = both HBV surface antigen positive and anti-HCV antibody positive, HER isoniazid, ethambutol, and rifampicin, HERZ isoniazid, ethambutol, rifampicin, and pyrazinamide, HR isoniazid and rifampicin, IU international unit, NS not significant a

P value: one-way ANOVA or v2 test

for HCV antibody and negative for HBsAg (HCV group), and 15 were positive for both HBsAg and HCV antibody (HBV ? HCV group). Baseline characteristics of the HBV, HCV, HBV ? HCV, and control group patients are presented in Table 1. Age, sex, baseline renal function test results, and the initial treatment regimen were almost identical in the four groups; most patients started their anti-TB regimen with a standard four-drug combination. Of the 553 patients, 145 patients were excluded because of the following reasons: 37 had abnormal baseline liver function tests, 3 were alcohol-dependent, 7 had HIV infection, 8 were lost to follow-up, 25 were transferred to other institutions, 43 stopped anti-TB treatment because an alternative diagnosis was made, and 22 died during anti-TB treatment but their death was not attributable to DIH. Among these dropout patients, the average age was 66 years, 22 patients had HBV only, 21 patients had HCV only, 3 patients had both HBV and HCV, and 76 % were male. Their demographic distribution is similar to that of the included patients.

significant different (8 % [28/371] vs. 8 % [15/182] for DIH and 4 % (16/371) vs. 7 % (13/182) for TLI, all P [ 0.05). In the control group, women had a significantly higher chance of acquiring DIH (13 % [14/111] vs. 6 % [18/281], P = 0.043); however, this effect is not found with TLI. We did not find that age had a significant influence on DIH or TLI in the control group. The incidence of any liver function impairment was higher in patients with HBV or HCV than in those without. The incidences of elevated liver function enzyme levels during anti-TB therapy in HBV, HCV, and control groups were 19 % (14/75), 21 % (15/71), and 11 % (41/392), respectively (Table 2). Patients in the HCV and HBV groups had a significantly higher incidence of TLI during treatment than controls (all P \ 0.001). However, the incidence of DIH showed no significant differences among the three groups (7 % [5/75], 9 % [6/71], and 8 % [32/ 392], all P [ 0.05). These results are presented in detail in Table 2. Severity of Liver Function Impairment for DIH

Incidence of Liver Function Impairment Seventy-two (13 %) patients developed liver function impairment during anti-TB therapy. The incidence of DIH in women was higher but did not reach statistical significance (11 % [16/147] vs. 7 % [27/406], P [ 0.05). The incidence of TLI is similar in women and men (5 % [7/ 147] vs. 5 % [22/406], P [ 0.05). Age had no significant impact on DIH and TLI. The incidences of DIH and TLI in patients older than 65 years and those younger were not

There were no significant differences in the severity of liver function impairment in patients in the HBV, HCV, and control groups. Among the patients without chronic hepatitis B or C, mild hepatotoxicity developed in 10 patients (2.6 %), moderate hepatotoxicity in 10 (2.6 %), and severe toxicity in 11 (2.8 %). Among the 5 HBV patients with DIH, 2 (2.7 %) had mild hepatotoxicity, no patient had moderate hepatotoxicity, and 3 (4 %) had severe hepatotoxicity. Among the 6 HCV patients with

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Table 2 Incidences of hepatitis during anti-TB treatment in different patient groups Total

Any LFI

P valuea

TLI

P valuea

DIH

9 (2)

P valuea

Control

392

41 (11)

Any hepatitis

161

31 (19)

0.005

20 (12)

\0.001

11 (7)

32 (8) NS

HBV

75

14 (19)

0.043

9 (12)

\0.001

5 (7)

NS

HCV

71

15 (21)

0.011

9 (13)

\0.001

6 (9)

NS

HBV ? HCV

15

2 (13)

NS

2 (13)

NS

0

NS

Data are presented as n (%) DIH drug-induced hepatotoxicity, HBV = HBV surface antigen positive and anti-HCV antibody negative; HCV = HBV surface antigen negative and HCV antibody positive; HBV ? HCV = HBV surface antigen positive and anti-HCV antibody positive; LFI liver function impairment, NS not significant, TLI transient liver function impairment a

P value compared with the control group

Table 3 The onset of liver function impairment Control

HBV

HCV

HBV ?HCV

Any hepatitis

P valuea

*5–60

*21–97

*17–120

*15–28

*17–120

0.012

22.6 ± 22.3

47.7 ± 30.8

67.8 ± 32.8

21.5 ± 9.2

54.1 ± 29.5

B2 months

9 (100)

7 (78)

4 (44)

2 (100)

13 (65)

[2 months

0

2 (22)

5 (56)

0

7 (35)

TLI Range (days) Mean ± SD Onset time

0.05

DIH Range (days)

3–115

3–120

10–128

3–128

Mean ± SD

39.5 ± 26.6

39.4 ± 48.2

66.7 ± 44.9

54.3 ± 43.5

NS

Onset time B2 months

29 (91)

4 (80)

3 (50)

7 (64)

[2 months

3 (9)

1 (20)

3 (50)

4 (36)

0.058

DIH drug-induced hepatitis, NS not significant, TLI transient liver function impairment a P value: any hepatitis group compared with the control group

DIH, 2 (2.8 %) had mild hepatotoxicity, 2 (2.8 %) had moderate hepatotoxicity, and 2 (2.8 %) had severe hepatotoxicity. Onset of Liver Function Impairment The mean onset times of liver function impairment in patients with TLI and those with DIH were 46 ± 33 and 47 ± 29 days, respectively (P [ 0.05). The mean onset times of TLI in control, HBV, and HCV groups were significantly different (23, 48, and 68 days, respectively, all P \ 0.05; Table 3). We did not find any significant effect of the type of anti-TB medication on the time of DIH onset. In the control group, TLI developed within 1 month in 6 patients (6/9 [67 %]). In contrast, less than half of the patients in the HCV and HBV groups developed TLI during the first month of treatment. The onset times of DIH are also given in detail in Table 3. The mean onset times of DIH in control, HBV, and HCV groups were not significantly different (40, 39,

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and 67 days, respectively, all P [ 0.05). Eighty percent of HBV patients and 91 % of controls developed DIH within 2 months, and 50 % of the HCV patients developed DIH after 2 months. In patients with chronic viral hepatitis who developed liver function impairment, approximately 35 % were attributed to DIH whether the onset time of DIH was within first 2 months or not. Conversely, among patients without chronic viral hepatitis, 76 % developed liver dysfunction within 2 months due to DIH, and no patient developed TLI after 2 months. Effect of Different Types of Drug on the Onset of DIH The onset times of DIH in isoniazid-, rifampicin-, and pyrazinamide-related hepatotoxicity were 47 ± 41 days (range 3–120 days), 48 ± 33 days (range 3–128 days), and 36 ± 31 days (range 3–115 days), respectively. We did not find any significant effect of different types of anti-TB medication on the onset of DIH.

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Discussion In clinical practice it is difficult to decide whether anti-TB treatment should be continued because TLI is relatively common in patients who undergo anti-TB treatment. A newly acquired viral hepatitis or acute exacerbation of chronic hepatitis is of particular concern in areas where the disease is endemic [2, 17, 18]. Inability to recognize other causes of hepatotoxicity and unnecessary discontinuation of anti-TB medication may prolong the course of treatment, increase the possibility of treatment failure, and increase the rate of drug resistance. On the other hand, failure to find true DIH and discontinue medication promptly may be fatal [19, 20]. The mortality associated with acute liver failure is still higher at over 67 % [21–23]. We found that TLI had a significantly greater incidence in the HBsAg- or HCV antibody-positive patients (14.3 %) than in controls (2.3 %). Moreover, TLI was observed more often (14.3 %) than DIH (7.1 %) in patients with chronic viral hepatitis. Flare-up of viral hepatitis in chronic hepatitis patients and hepatic adaptations to antituberculosis medication are possible causes for these findings. Conversely, the incidences of DIH and TLI were 8.7 and 2.3 %, respectively, in patients without chronic viral hepatitis. The incidence of DIH was about the same in patients with and without chronic hepatitis (7.1 vs. 8.7 %), and had no effect on anti-TB treatment. Wang et al. [24] found that a high baseline hepatitis viral load is associated with higher odds of getting DIH and flare-up of viral hepatitis, whereas in chronic viral hepatitis patients with low or undetectable baseline viral loads, the odds are not different from those of patients without chronic hepatitis. In our study, the incidence of DIH was not increased in patients with chronic HBV or HCV; this may be due to our strict inclusion criteria. We excluded patients with abnormal baseline liver function. Based on the results of our study and Wang’s study, we infer that the chances of DIH will not increase in chronic viral hepatitis with baseline normal liver biochemistry test. According to Wang’s [24] study, the odds of DIH may increase two to three times in patients with high pretreatment hepatitis viral loads. In patients with a normal baseline liver function test and not taking any anti-TB drugs, Chien et al. [25] found that 2 % of HBV patients and 4 % of HCV patients experienced exacerbations of hepatitis in the 4-year period of observation. Taking Chien’s finding into consideration, we believe that in most chronic hepatitis patients with normal pretreatment liver function who develop DIH, their hepatitis virus remained latent. Therefore, the severity of DIH is not affected by hepatitis virus. Previous studies have reported that DIH usually occurred within the initial 2 months of therapy [26, 27]. We found that TLI occurred later in patients with chronic

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hepatitis. One possible explanation is a flare-up of the chronic hepatitis virus. A future study with detailed followup of hepatitis viral load in patients with viral hepatitis taking anti-TB medication would help to find whether this assumption is valid. We found that DIH developed more frequently in the HCV group than in the control group, more than 2 months after initiating anti-TB therapy. Therefore, we suggest that patients with HCV should have liver function tests routinely during the later period of antiTB treatment, even when DIH does not occur within first 2 months. Because this was a retrospective study, it has some limitations. First, precise information on concurrent use of other herbal medicines or so-called health foods that are commonly consumed by Taiwanese patients was not available from the medical chart review. There is no reliable evidence to support the idea that taking herbal medicine may have liver protection effects during TB treatment [28]. Indeed, some may cause liver toxicity [29]. Second, the measurement of liver function in most patients was performed on a regular biweekly or monthly basis. Therefore, the exact day of the onset of liver function impairment may be earlier than the day recorded in this study. Third, most patients who developed liver function impairment were not routinely checked for HBV and HCV viral load, hepatitis A virus IgM, and hepatitis E virus IgM, which are endemic in Taiwan [30]. Occasionally, a definite cause of hepatitis was not determined. We emphasize that the present study found some important clinical effects. First, although people with chronic hepatitis had a higher incidence of TLI during antiTB therapy, the incidence of DIH did not differ from those without chronic hepatitis. Second, physicians should take the onset of liver function impairment and whether the patient had hepatitis into consideration when deciding whether the potential hepatotoxic drug should be stopped. The time frame for development of DIH and TLI varies in the different patient groups. Based on our finding, the chance of TLI is approximately two times of that of DIH regardless of whether the onset time is within the first 2 months of the initiation of therapy in chronic viral hepatitis patients. We suggest that physicians check hepatitis viral load once liver function impairment occurs during anti-TB therapy to decide if the anti-TB drug should be stopped. In patients without chronic hepatitis, however, liver function impairment was caused mostly by DIH and physicians will have to consider discontinuing the drug, especially when liver function impairment occurs after 2 months of starting anti-TB therapy. In conclusion, we found that liver function impairment during anti-TB therapy was mostly the result of TLI in patients with chronic viral hepatitis and of DIH in patients without chronic viral hepatitis. Chronic viral hepatitis had

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no significant effect on the onset of DIH, but TLI occurred later in these patients. We suggest that clinicians should check baseline viral load in chronic viral hepatitis patients on drug therapy for tuberculosis and repeat the load test when hepatotoxicity is found during therapy to see if it is related to a flare-up of the hepatitis virus. Conflict of interest disclose.

The authors have no conflicts of interest to

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Antituberculosis treatment and hepatotoxicity in patients with chronic viral hepatitis.

Whether antituberculosis (anti-TB) treatment in patients with chronic viral hepatitis affects the incidence and onset time of drug-induced hepatotoxic...
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