Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection

Abstract

Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twentyfour patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P Ͻ .001) and with HBV carriers not given anti-TB drugs (8.1%, P Ͻ .001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P ϭ .011) and had more severe liver injury compared with noncarriers (P ϭ .008). By multiple logistic regression analysis, age (P ϭ .002) and hepatitis B infection (P Ͻ .001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy. (HEPATOLOGY 2000;31:201-206.)Recently, there has been a resurgence of tuberculosis (TB) in a number of countries. 1,2 It has been estimated that approximately one third of the world' s population is infected with Mycobacterium tuberculosis. This reservoir of infected person results in 8 million new cases of TB and 2.9 million deaths annually. 1 TB and hepatitis B virus (HBV) infection are both endemic in South East Asia. In Hong Kong, the notification rate for TB was 103 persons per 100,000 population in 1996. 3 Approximately 10% of Hong Kong' s population are chronic HBV carriers. 4 Currently, the short-course program for the treatment of TB in Hong Kong begins with a 2-month course of 4 drugs, namely isoniazid, rifampicin, pyrazinamide, and ethambutol. This is followed by a continuation phase of 4 months with the 2 drugs, isoniazid and rifampicin. 3,5,6 Hepatotoxicity is the major adverse effect of isoniazid, rifampicin, and pyrazinamide. 7-10 Chronic hepatitis B 6,11,12 infection has been suggested as a possible risk factor for the development of liver dysfunction caused by anti-TB drugs. 13 However, studies of the effect of chronic hepatitis B carriage on the hepatotoxicity of anti-TB drugs have been unable to show any definite deleterious consequences. 11,14 McGlynn et al. 11 performed a retrospective analysis of isoniazid prophylaxis in 1,833 Asian patients in 1986; Hwang et al. 14 performed a prospective study in 240 Taiwanese patients in 1997. Both studies failed to identify hepatitis B infection as a risk factor for the development of liver dysfunction. None of the studies published to date have assessed the degree of liver damage by histology. There was no attempt made to differentiate between drug-induced damage and damage caused by hepatitis B viral activity. We report a prospective stu...

An Update on Drug-induced Liver Injury

“…Chronic hepatitis B and C is considered by some to enhance the risk of DILI particularly from drugs used to treat tuberculosis and HIV [73][74][75] ; however, not all studies have found a positive link between chronic B and C infection and anti-TB related DILI and highly active antiretroviral therapy related DILI. 76 Wong et al found hepatotoxicity following antituberculous drugs in 35% of HBV carriers in contrast to 9.4% non-carriers (p < 0.001).…”

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

“…55 Isoniazid monotherapy is safe in patients with HBV infection 56 while multidrug ATT is associated with significant incidence of hepatotoxicity. Multidrug therapy for tuberculosis is also associated with fulminant disease, increased mortality and later onset of hepatotoxic effects in these patients.…”

“…Multidrug therapy for tuberculosis is also associated with fulminant disease, increased mortality and later onset of hepatotoxic effects in these patients. 55,57 Amongst 110 inactive HBsAg carriers and 97 controls without HBV infection, 38 inactive HBsAg carriers (35%) and 19 control subjects (20%) developed elevated liver enzyme levels during ATT (P = 0.016). 57 A higher proportion of inactive HBsAg carriers who received ATT evidenced moderate-to-severe drug-induced hepatotoxicity when compared with the control subjects (8 vs. 2%; P = 0.05).…”

“…57 The liver injury was also more severe by histologic assessment in the hepatitis B carriers when compared to non-carriers (P = 0.008). 55 A case can be made for decreasing viral load using antiviral therapy against HBV with high-potency, high genetic barrier drugs such as entecavir and tenofovir in patients with HBV infection needing ATT to prevent the development of liver dysfunction. Hepatotoxicity related to ATT was more common in HBV positive patients who were seropositive for hepatitis B e antigen (HBeAg) than among those who were seronegative for HBeAg (relative risk [RR] = 11.38, CI = 5.49-23.59, P < 0.001).…”

“…58 Most episodes of liver dysfunction were usually preceded by an increase in HBV-DNA levels. 55 At least one case report describes that treatment with lamivudine enabled isoniazid and rifampicin treatment in a patient with pulmonary tuberculosis and hepatitis B co-infection. 59 However, more data need to be generated before a firm recommendation can be made on this issue.…”