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doi:10.1378/chest.06-2042
(Chest. 2007; 131:803-808)
© 2007 American College of Chest Physicians
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Hepatitis C Virus Infection and Hepatotoxicity During Antituberculosis Chemotherapy*

Yong Soo Kwon, MD; Won-Jung Koh, MD; Gee Young Suh, MD; Man Pyo Chung, MD; Hojoong Kim, MD, FCCP and O. Jung Kwon, MD

* From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Correspondence to: Won-Jung Koh, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135–710, Republic of Korea; e-mail: wonjung.koh{at}samsung.com

Abstract

Background: The risk of drug-induced hepatotoxicity (DIH) during treatment for tuberculosis (TB) in patients who are seropositive for the hepatitis C virus (HCV) is not clear. We evaluated whether HCV-seropositive patients are at a higher risk of DIH than control subjects during treatment for TB with standard short-course regimens.

Methods: Fifty-four HCV-seropositive patients with newly diagnosed active TB who were treated with isoniazid, rifampin, ethambutol, and/or pyrazinamide were included in the study population. Ninety-seven HCV-seronegative patients were selected as control subjects.

Results: Forty HCV-seropositive patients (74%) and 82 control subjects (85%) received an initial treatment regimen that included pyrazinamide. Twenty-two HCV-seropositive patients (41%) and 19 control subjects (20%) exhibited elevated liver enzyme levels during TB treatment, including transient elevation of transaminase. DIH, defined as a liver transaminase level ≥ 120 IU/L, occurred more frequently in HCV-seropositive patients (7 of 54 patients, 13%) than in control subjects (4 of 97 patients, 4%). Isoniazid and rifampin were reintroduced after the liver transaminase level returned to baseline in five HCV-seropositive patients exhibiting DIH, and all these retrials proved to be successful.

Conclusions: These findings suggest that treatment for TB in HCV-seropositive patients could be pursued in the usual manner, using standard short-course regimens, with the condition that monthly liver function tests are carefully performed.

Key Words: hepatitis C • toxic hepatitis • treatment • tuberculosis

Tuberculosis (TB) remains a leading health problem in both developing and developed countries.1 The modern short-course chemotherapy protocols have proven to be highly effective TB treatments.23 However, drug-induced hepatotoxicity (DIH) associated with first-line drugs such as isoniazid, rifampin, and pyrazinamide is a well-known adverse effect and may limit their use.2 Advanced age, female gender, alcohol use, malnutrition, and the presence of underlying chronic liver disease have been associated with an increased risk for DIH during treatment for TB.45678

Although chronic liver disease is known to increase the risk of DIH, the relative risks of the various etiologies of chronic liver disease, such as hepatitis virus infection, on the development of DIH remain unclear.91011 With regard to hepatitis C virus (HCV) infection, few studies have investigated whether isoniazid-associated hepatotoxicity is increased during the treatment of latent TB infection1213 or whether DIH is increased during treatment for TB with standard short-course regimens in HCV-seropositive patients.14

TB is still a serious public health problem in South Korea. Although the prevalence of smear-positive and/or culture-positive TB has decreased continuously, the incidence of active TB was as high as 73 per 100,000 population in 2005.15 In addition, it is estimated that 1.68% of middle-aged persons carry HCV antibodies in South Korea.16 The aim of this study was to determine whether HCV-seropositive patients are at a higher risk for DIH than control subjects during treatment for TB with standard short-course regimens containing isoniazid, rifampin, ethambutol, and/or pyrazinamide.

Materials and Methods

Patients and Control Subjects
All patients treated for newly diagnosed active TB at the Samsung Medical Center (Seoul, Korea) between September 1994 and June 2005 who were positive for HCV antibody and negative for hepatitis B surface antigen were identified by a computer-assisted search of medical records. One hundred thirty-six patients treated with anti-TB drugs were identified, and their medical records were retrospectively analyzed. Permission was obtained from the Institutional Review Board to review and publish patient records retrospectively.

We initially excluded HCV-seropositive patients who were unavailable for follow-up (n = 7) and those who had been transferred to their referring institutions (n = 6) after having been treated for < 3 months at our hospital. Hepatotoxicity was not detected in these 13 HCV-seropositive patients during their stay at our hospital. Other cases were excluded based on the following: an underlying malignancy that might have caused confusion with regard to the interpretation of the liver function test results due to possible liver metastasis (n = 40); initial regimens including second-line anti-TB drugs due to drug resistance to first-line drugs (n = 8) or abnormal baseline aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels ≥ 120 IU/L (n = 14); no available follow-up liver function test results (n = 2); positivity for HIV antibody (n = 1); and death not attributed to DIH (n = 4). Finally, 54 HCV-seropositive patients who received standard anti-TB medication were included in the study group. None of the HCV-seropositive patients were received concomitant antiviral therapy such as {alpha} interferon and ribavirin.

For purposes of comparison, 195 consecutive patients with newly diagnosed TB who were negative for both hepatitis B surface antigen and HCV antibody and who were treated with anti-TB drugs were also identified at the same hospital over the 6-month period between January and June of 2002.11 We initially excluded the patients who were unavailable for follow-up (n = 8) and those who had been transferred to other institutions (n = 17) after < 3 months of treatment at our hospital. Hepatotoxicity was not detected in these 25 control patients during their stay at our hospital. Patients with abnormal baseline liver transaminase levels (n = 15) and those subjects receiving initial drug regimens, including second-line anti-TB drugs (n = 18), were also excluded from the study. In addition, subjects with underlying malignancies (n = 38) and those with no available follow-up liver function test results (n = 2) were also excluded after reviewing the medical records. Finally, 97 subjects who had received standard anti-TB medication were allocated to the control group.

Definitions of DIH
The following criteria were used to define transient transaminase elevation and DIH.21417 Transient transaminase elevation was diagnosed if AST/ALT levels were increased but were still less than three times the upper normal limit (120 IU/L) and resolved spontaneously despite continued anti-TB medications. DIH was defined when liver transaminase levels were > 120 IU/L. If the AST/ALT levels were < 200 IU/L, the DIH was defined as mild. AST/ALT levels of 200 to 500 IU/L indicated moderate hepatotoxicity, and AST/ALT levels ≥ 500 IU/L were considered to indicate severe hepatotoxicity.

Treatment and Monitoring
In South Korea, a 6-month regimen consisting of 2 months of therapy with isoniazid, rifampin, ethambutol, and pyrazinamide, followed by 4 months of therapy with isoniazid, rifampin, and ethambutol has been strongly recommended by the National Tuberculosis Program.1819 Alternatively, a 9-month regimen of therapy with isoniazid, rifampin, and ethambutol can be administered.1819 Therefore, most patients at our hospital initially received daily therapy that included isoniazid (300 mg), rifampin (450 to 600 mg), ethambutol (800 to 1,200 mg), and pyrazinamide (1,500 mg). However, the decision to include pyrazinamide in the initial treatment regimen was made by clinicians on a case-by-case basis. The patients were treated at an outpatient clinic, and clinical examinations and liver chemistry tests were performed on a monthly basis after the initiation of treatment.

Treatment after the development of DIH was undertaken in the generally accepted manner.220 Patients exhibiting mild increases in liver transaminase levels, but without clinical symptoms, were carefully observed with no changes in treatment. In the case of a patient who exhibited symptoms suggesting DIH, who also showed markedly increased liver transaminase levels, it was our policy to withdraw therapy with all hepatotoxic drugs. These drugs were then replaced with nonhepatotoxic drugs, such as ethambutol, cycloserine, quinolones, and aminoglycosides. After liver transaminase normalization, the hepatotoxic drugs were serially reintroduced. Rifampin therapy was reintroduced first, at progressively increasing dosages, and then isoniazid therapy was restarted, also with gradually increasing dosages. The targeted treatment regimen usually included isoniazid, rifampin, and ethambutol, without pyrazinamide, and therapy continued for > 9 months. If symptoms recurred or liver transaminase levels increased during the reintroduction of therapy with hepatotoxic drugs, the offending drug was withdrawn, and nonhepatotoxic drug therapy was maintained.

Statistical Analysis
Values are expressed as mean ± SD or numbers and percentages. Differences with regard to numeric values between the HCV-seropositive patients and control group or between the DIH and non-DIH groups were analyzed using Student t test or the Mann-Whitney U test. Nominal variables were assessed using the {chi}2 test or Fisher exact test; p < 0.05 was considered statistically significant.

Results

Baseline Characteristics
A total of 54 HCV-seropositive patients (average age, 56.4 ± 15.7 years; 33 men [61%]) were included in the study. Table 1 shows the baseline characteristics of the 54 HCV-seropositive patients and 97 control subjects. Sex, body mass index, and infection site of TB were similar between the two groups. HCV-seropositive patients were older than control subjects, and the baseline AST and ALT levels were higher in HCV-seropositive patients (p < 0.05). Nine patients in the HCV-seropositive group had baseline AST or ALT levels ≥ 40 IU/L. However, none of these patients had AST or ALT levels ≥ 120 IU/L. Forty patients (74%) in the HCV-seropositive group and 82 patients (85%) in the control group received an initial treatment regimen that included pyrazinamide (Table 1).


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  		Table 1. Baseline Characteristics of HCV-Seropositive Patients and Control Subjects*

 
Incidence of Liver Dysfunction
Elevated liver enzyme levels during treatment for TB were observed more commonly in HCV-seropositive patients than in control subjects. Twenty-two HCV-seropositive patients (41%) and 19 control subjects (20%) exhibited elevated liver enzyme levels, including transient transaminase elevation and DIH, during treatment for TB (p = 0.005) [Table 2 ].


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  		Table 2. Liver Dysfunction in HCV-Seropositive Patients and Control Subjects During Treatment for TB*

 
The serum AST/ALT was elevated above the upper normal limit but remained below three times the upper normal limit (≥ 40 IU/L and < 120 IU/L) in 15 of 22 HCV-seropositive patients with elevated liver enzymes. In these 15 HCV-seropositive patients with a transient transaminase level elevation, asymptomatic AST/ALT elevations resolved spontaneously despite the continuation of initial TB regimens. Fifteen of the 19 control subjects with an AST/ALT elevation also showed transiently increased transaminase levels, and all patients continued with TB regimens, during which their serum AST/ALT levels normalized spontaneously.

DIH during treatment for TB occurred more frequently in HCV-seropositive patients (7 of 54 patients, 13%) than in control subjects (4 of 97 subjects, 4%), although the difference was not statistically significant (p = 0.056) [Table 2]. Four HCV-seropositive patients with DIH showed mild hepatotoxicity, and three patients exhibited moderate hepatotoxicity. Severe DIH did not occur in HCV-seropositive patients. In the control group, mild hepatotoxicity developed in two patients, and moderate-to-severe hepatotoxicity developed in another two patients with DIH. Among 11 patients who acquired DIH, including one patient with severe hepatotoxicity in the control group, HCV-seropositive patients showed slightly higher serum bilirubin levels at the time of the detection of liver injury (1.4 mg/dL vs 0.4 mg/dL), but the difference was not significant (p = 0.142).

Factors Associated With DIH During Treatment for TB
No significant differences were observed with regard to other variables, such as age, sex, body mass index, and baseline AST, ALT, and albumin levels, or the inclusion of pyrazinamide in the treatment regimens between those individuals who had or did not have DIH (Table 3 ).


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  		Table 3. Factors Associated With DIH During Treatment for TB

 
Management of DIH
Isoniazid, rifampin, ethambutol, and pyrazinamide were initially administered to all seven HCV-seropositive patients who acquired DIH during treatment for TB, with the exception of one patient who did not receive pyrazinamide. Anti-TB regimens were withheld immediately after the detection of DIH and were supplanted by nonhepatotoxic anti-TB drugs. In one patient with moderate DIH, nonhepatotoxic anti-TB drug therapy including ethambutol, cycloserine, ofloxacin, and streptomycin was maintained until the end of treatment, without the reintroduction of therapy with isoniazid and rifampin, based on the decision of an individual clinician. In another patient with mild DIH, the anti-TB drug therapy was discontinued because mild DIH was detected at the end of the treatment period. Otherwise, the other five HCV-seropositive patients were rechallenged with first-line anti-TB drugs after their AST/ALT levels returned to baseline levels. Therapy with isoniazid and rifampin without pyrazinamide was successfully reintroduced in all of these patients. No patient experienced recurrent DIH after the reintroduction of isoniazid and rifampin.

Of the four control subjects who exhibited DIH, isoniazid and rifampin without pyrazinamide were successfully readministered to two subjects after temporarily withholding the hepatotoxic drugs. In the remaining two control subjects, the reintroduction of therapy with first-line drugs was unsuccessful, and nonhepatotoxic drug therapy was subsequently instituted. No hospitalization or mortality related to DIH occurred in the HCV-seropositive or control groups.

Discussion

The prevalence of TB was reported to be higher among HCV-infected patients than among those without HCV infection.212223 However, the relationship between HCV infection and the development of DIH during treatment for TB is not well defined in the literature.121314

Sadaphal et al12 evaluated the risk of DIH in a cohort of 146 injection drug users, 95% of whom were HCV seropositive, who were treated with isoniazid for latent TB infection. In their study,12 an increase in liver transaminase values to more than three times the upper limit of normal occurred in 22% of patients, and this was within the range reported for populations with lower HCV prevalence. Fernandez-Villar et al13 also studied the risk of DIH among 415 drug users, 52% of whom were HCV seropositive, with isoniazid treatment for latent TB infection. The presence of HCV antibodies was associated with DIH, which was defined as a liver transaminase level ≥ 120 IU/L, only in univariate analysis (16 of 214 HCV-seropositive patients [7.5%] vs 4 of 201 control subjects [2%]).13 Therefore, it remains unclear as to whether HCV-seropositive patients are subject to a greater incidence of isoniazid-associated DIH during the treatment of latent TB infection. In addition, only one study14 has examined the risk of DIH in standard short-course anti-TB treatment in patients with clinical TB. Ungo et al14 investigated the association of HCV infection and the development of DIH during anti-TB treatment. DIH, which was defined as a liver transaminase level ≥ 120 IU/L, occurred more frequently in HCV-seropositive and HIV-seronegative patients (7 of 29 patients, 24%) than in HCV-seronegative and HIV-seronegative patients (3 of 55, 5%).

The present study included > 50 HCV-seropositive patients, which is a larger study population than in previous studies, and revealed that the elevation of liver enzyme levels during standard therapy for TB was more common in HCV-seropositive patients (41%) than in the control subjects (20%) and DIH occurred more frequently in HCV-seropositive patients (13%) than in control subjects (4%). However, this risk was relatively lower than that (24%)in the previous study by Ungo et al.14

In addition, the present study suggested that the reintroduction of therapy with anti-TB drugs might be safe and successful, even in HCV-seropositive patients, after recovery from DIH. Rechallenge with the drugs ostensibly responsible for the hepatotoxicity, such as isoniazid or rifampin, may constitute a burden for both the physician and patient. In our study, therapy with isoniazid and rifampin was reintroduced in five of seven HCV-seropositive patients after the resolution of their hepatotoxicity, and reintroduction was successful in all these patients. Thus, given careful monitoring, we suggest that a trial reintroduction of at least isoniazid and rifampin is feasible, even in HCV-seropositive patients.

The present study has several limitations generally inherent in retrospective analyses. For example, precise information on alcoholism or the use of potentially hepatotoxic drugs such as acetaminophen was unavailable, owing primarily to the difficulty in obtaining reliable information from a medical chart review. Second, in most patients in whom hepatotoxicity developed during treatment for TB in the present study, the evaluation of the possible aggravation of underlying viral hepatitis, such as liver biopsies, was not performed. Therefore, some HCV-seropositive patients who had been judged to have DIH in the present study may have actually faced the possibility of a natural course or progression of HCV infection. Third, testing for HCV infection was done by the third-generation enzyme-linked immunoassay from 1994 to 2003 and the chemiluminescence immunoassay from 2004 in our hospital. Confirmatory testing using the recombinant immunoblot assay or the reverse transcription-polymerase chain reaction were not routinely utilized in our patients. The evolution of the tests could have affected the sensitivity and specificity of the results. As such, some patient who were considered not to have HCV may actually have been infected and visa versa.

In summary, DIH during treatment for TB occurred more frequently in HCV-seropositive patients than in control subjects. However, the reintroduction of therapy with anti-TB drugs could be safe and successful, even in HCV-seropositive patients, after recovery from DIH. These findings suggest that treatment for TB in HCV-seropositive patients could be performed in the usual manner, using recommended short-course regimens containing isoniazid, rifampin, ethambutol, and/or pyrazinamide, under the condition that monthly liver function tests are performed.

Footnotes

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; DIH = drug-induced hepatotoxicity; HCV = hepatitis C virus; TB = tuberculosis

This work was supported by the SRC/ERC program of MOST/KOSEF (R11–2002-103).

The authors have no financial or other potential conflicts of interest to disclose.

Received for publication August 15, 2006. Accepted for publication October 24, 2006.

References

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A. Fernandez-Villar, V. Leiro, M. Botana, B. Sopena, Y. S. Kwon, and W.-J. Koh
Hepatitis C Virus Infection and Isoniazid Hepatotoxicity
Chest, August 1, 2007; 132(2): 736 - 737.
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