Title: Antituberculosis treatment and hepatotoxicity in patients with chronic viral hepatitis
Authors:
Yuag-Meng Liu(劉元孟),Yu-Jen Cheng(鄭寓仁), Yu-Lin Li(李育霖), Chun-Eng Liu(劉尊榮), Wu-Huei Hsu(徐武輝)
Affiliations and addresses: Yuag-Meng Liu
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
Department Infectious Disease, Changhua Christian Hospital, Changhua, Taiwan, 135 Nanxiao St., Changhua City, Chaghua County, Taiwan, R.O.C
Yu-Jen Cheng, Yu-Lin Li, Chun-Eng Liu
Department Infectious Disease, Changhua Christian Hospital, Changhua, Taiwan, 135 Nanxiao St., Changhua City, Chaghua County, Taiwan, R.O.C
Wu-Huei Hsu
Department of Internal Medicine, China Medical University Hospital, 2 Yuh-Der Road, Taichung 40447, Taiwan, R.O.C
Corresponding author:
Wu-Huei Hsu M.D. 2 Yuh-Der Road, Taichung 40447, Taiwan, R.O.C Phone number: 886-4-22052121-3480
Fax number: 886-4-22038883 Email: hsuwh@mail.cmuh.org.tw
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 answer whether chronic viral hepatitis would influence 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, among which 553 patients 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 of DIH in the control, hepatitis B virus (HBV), and hepatitis C virus (HCV) groups were not significantly different (40 days, 39 days, and 67 days, respectively, all P > 0.05). The mean onset times of TLI in the control, HBV, and HCV groups were significantly different (23 days, 48 days, and 68 days, respectively, all P < 0.05).
Conclusions Liver function impairment during anti-TB therapy in patients with chronic viral hepatitis was mostly because of 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 . 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 populations . High prevalence of hepatitis B virus (HBV) (7.4%) and hepatitis C virus (HCV) (5.5%) were found in Taiwan . Male to female ratio is 2.3 to1 and 53% of the tuberculosis infected patients were older than 65 years of age according to 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 . It is still controversial whether the incidence of hepatotoxicity is higher in patients with chronic hepatitis virus infection than in those without infection during anti-TB treatment . Few studies have reported about the potential association of chronic liver disease with the onset of hepatotoxicity. We report our investigation on the association between chronic hepatitis and the onset time of liver function
impairment during anti-TB treatment in patients with active TB.
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 tests, HIV infection, 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. These patients were excluded because it is difficult to define patients 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 transient liver function impairment (TLI) and DIH were based on previous study recommendations .TLI was diagnosed under 2 sets of conditions: (1) if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels increased above the upper limit of normal range, but resolved spontaneously despite continued anti-TB medications; (2) if the drug was first discontinued and the patient was successfully re-challenged 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 exceeded 200 IU/L with or without symptoms while the anti-TB drug treatment was stopped, and the liver transaminase level increased to >120 IU/L when the patient was re-challenged with the drug. Mild DIH was defined as 120 IU/L< AST/ALT levels ≤ 200 IU/L, moderate DIH as 200 IU/L < AST/ALT levels ≤ 500 IU/L, and severe DIH as >500 IU/L.
Treatment and monitoring
Most patients initially received daily isoniazid, rifampicin, ethambutol, and pyrazinamide in the first 2 months followed by isoniazid, rifampicin, and ethambutol in the subsequent 4 months. The recommended daily dose of anti-TB drug in Taiwan is as followed: isoniazid 5mg/Kg, rifampicin 10mg/kg, ethambutol 15mg/kg,
pyrazinamide 25mg/kg. Liver function tests were performed once per 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 developing increased liver transaminase levels but without 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 liver transaminase normalization, drugs were serially restarted. If liver transaminase levels increased during a rechallenge of the therapy, the specific drug was discontinued. A drug was considered responsible for adverse effects if symptoms appeared with the start of 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 the Student t test or the Mann–Whitney U test depending on the distribution of the data. Nominal variables were assessed using the chi-square test or the Fisher exact test. Baseline characteristics among the HBV, HCV, and control groups were analyzed by 1-way 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. All patients were screened for HBV and HCV before anti-TB treatment. Of these, 392 were negative for HBsAg and HCV antibody (control group), 75 were positive for HBsAg and negative for HCV antibody (HBV group), and 71 were positive for HCV antibody and negative for HBsAg (HCV group). Fifteen patients were positive for both HBsAg and HCV antibody (HBV + HCV group). Baseline characteristics of the HBV, HCV, HBV + HCV, and control group patients are shown in Table 1. Age, sex, baseline renal function test results, and the initial treatment regimen were almost identical in the 3 groups; most patients started their anti-TB regimen with a standard 4-drug combination.
Nevertheless, 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 drop-out patients, average age is 66 years old, 22 patients had HBV only, 21 patients had HCV only, 3 patients had both HBV and HCV and 76% were man. Their
demographic distribution is similar with the included patients.
Incidence of liver function impairment
Seventy-two (13%) patients developed liver function impairment during anti-TB therapy. The incidence of DIH in woman was higher but not achieving statistic significance (11% [16/147] vs 7% [27/406], P > 0.05). The incidence of TLI is similar in woman and man (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 old and those younger had no significant differences ( 8% [28/371] vs 8% [15/182] in DIH and 4% (16/371) and 7% (13/182) in TLI, all P > 0.05). In control group, woman had a significant higher chance of acquiring DIH (13% [14/111] in woman vs 6% [18/281] in man, P = 0.043); however, this effect is not found in TLI. We did not find age had significant influence on DIH or TLI in control group.
The incidence of DIH The incidence of any liver function impairment was higher in patients with HBV or HCV than in those without; 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 or 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 3 groups (7% [5/75], 9% [6/71], and 8% [32/392], all P >
0.05). These results are shown in detail in Table 2.
Severity of liver function impairment for DIH
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 drug-induced hepatotoxicity, 2 (2.7%) had mild hepatotoxicity, no patient had moderate hepatotoxicity, and 3 (4%) had severe hepatotoxicity. Among the 6 HCV patients with DIH, 2 (2.8%) had mild hepatotoxicity, 2 (2.8%) moderate hepatotoxicity, and 2 (2.8%) 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 days and 47 ± 29 days, respectively (P > 0.05). The mean onset times of TLI in controls, HBV, and HCV were significantly different (23 days, 48 days, 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 developed TLI during the first month of treatment in the
HCV and HBV groups.
The onset times of DIH are also shown in detail in Table 3. The mean onset times of DIH in controls, HBV, and HCV groups were not significantly different (40 days, 39 days, and 67 days, respectively, all P > 0.05). Eighty percent of HBV patients and 90% of controls developed DIH within 2 months. Nevertheless, 50% of the HCV patients developed DIH after 2 months (P < 0.05).
In patients with chronic viral hepatitis who developed liver function impairment, approximately 35% are attributed to DIH whether the onset time of DIH is 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 time 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.
In clinical practice it is difficult to decide whether anti-TB treatment should be continued because TLI is relatively common in patients with 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 . 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 discontinuation of medication promptly may be fatal .The mortality with the occurrence of acute liver failure is still higher over 67% .
We found that TLI had a significantly higher 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 anti-tuberculosis 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 or without chronic hepatitis (7.1% vs. 8.7%), and had no effect on anti-TB treatment. Wang et al. found 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
carrying low or undetectable baseline viral loads the odds is not different from
patients without chronic hepatitis . In our study, the incidence of DIH is not increased in patients with chronic HBV or HCV 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 study, the odds of DIH may increase to 2 to 3 time in patients with high pretreatment hepatitis viral loads .
In patients with baseline normal liver function test ant not taking anti-tuberculosis drug, Chien found 2% in HBV patients and 4% HCV patients
experienced hepatitis exacerbations in 4 years period of observation . Take Chie’s finding into consideration, we believe 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 . We found that TLI occurred later in patients with chronic
hepatitis. One possible explanation is a flare-up of the chronic hepatitis virus. A future study with detailed follow-up of hepatitis viral load in patients with viral hepatitis taking anti-TB medication would help to find out if 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 anti-TB 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 medical chart review. There is no reliable evidence to support taking herbal medicine may have liver protection effects with TB treatment . Indeed some may cause liver toxicity . 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 . Occasionally, definite causes of hepatitis were not determined.
We emphasize that the present study found some important clinical effects. First, though people with chronic hepatitis had a higher incidence of TLI during anti-TB 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
patients had hepatitis into consideration to decide 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 that the chance of TLI is approximately two times of TLI regardless of whether the onset time is within the first 2 months of the initiation of therapy in chronic viral hepatitis patients. We suggested that
physicians check hepatitis viral load once liver function impairment occurred during anti-TB therapy to decide if anti-TB drug should be stopped. In patients without chronic hepatitis; however, liver function impairment were mostly caused by DIH and physicians shall consider discontinue drug especially when liver function impairment occurred after 2 months of initializing anti-TB therapy.
In conclusion, we found that liver function impairment during anti-TB therapy was mostly because of TLI in patients with chronic viral hepatitis, and because of DIH in patients without chronic viral hepatitis. Chronic viral hepatitis had no significant effect on the onset of DIH, but TLI occurred later in these patients. We suggested clinicians should check baseline viral load in chronic viral hepatitis patients started on the therapy of tuberculosis and repeat it when hepatotoxicity is found during therapy to see if it is related to flare up of hepatitis virus.
Financial Disclosure and Conflict of interest
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