•
•
reviews
---f~.L---_-------Toxic Hepatitis with Isoniazid and Rifampin* c','''','':.
A Meta-analysis Malcolm A. Steele, M.D.;t Raymond F. Burk, M.D.;+ and Roger M. DesPrez, M.D.§ (Cheat 1991; 99:465-71) ALT = serum alanine aminotransferase; AST = serum aspartate aminotransferase; Bill = bilirubin; EMB = ethambutol; INH = isoniazid; NSM not speci6ca11y mentioned; PAS para-aminosalicylate; PZA = pyrazinamide; RMP = rifampio; S streptomycin; TH thioacetazone
=
=
=
=
here is some, although by no means unanimous, T opinion as well as some evidence to suggest that
drug-induced hepatitis occurs with greater frequenc~ and may be more severe, when isoniazid (INH) and rifampin (RMP) are administered in combination than when INH is given alone. It has been speculated that this is due to a drug-drug interaction in which indueFor editorial comment see page 266
tion of hepatic microsomal enzymes by RMP results in production of increased concentrations of a hepatotoxic metabolic product of INH. I In this revie~ an attempt has been made to briefly summarize the recent history and developing concepts of hepatotoxicity of INH administered without RM~ of INH and RMP administered together, and to summarize the available English language published evidence concerning the incidence of this prQblem. INH-RELATED HEPATITIS; BRIEF HISTORY AND CLINICAL FEATURES During the first few years after introduction ofINH, only sporadic cases suggesting possible hepatotoxicity were noted, and jaundice developing in patients on treatment was often attributed to concurrent viral hepatitis or the toxic effects of other drugs such as . PAS.2-7 Berte and associates8 in 1959 stated that no case of hepatotoxicity was observed in 513 patients receiving INH, and such was its reputation for safety that in 1963 the American Thoracic Society recommended aU tuberculin-positive persons should receive *From the Nashville Veterans Affairs Medical Center and Vanderbilt University School of Medicine) Nashville. . t Associate Chief of Staff for Ambulatory Care; Assistant Professor of Medicine. *Chief) Division of Gastroenterology; Professor of Medicine §Chief) Medical Service; Professor of Medicine Reprint requests: Dr Steele, VA Medical Center, Nashville 372122637
a year of INH chemoprophylaxis regardless of age or the duration of tuberculin positivity. 9 In 1969, 17 years after its introduction, Scharer and Smith lo reported liver function abnormalities in 10.3 percent ofpatients receiving INH. In spite of this, however, the problem of INH-hepatitis remained generally unappreciated until 1971 when a retrospective study by Garibaldi et al ll reported clinical hepatitis in 19 of 2,321 patients (I percent) taking INH for chemoprophylaxis, 13 of whom developed overt jaundice and 2 who (0.1 percent) died. ll An ad-hoc advisory committee appointed by the Centers for Disease Control to consider the problem raised by this report concluded that there was a CCnoteworthy" risk, 0 to 10 case per 1,000 persons per year, of serious hepatotoxicity in persons taking INH.12 Because of this unsettling opinion, the United States Public Health Service (USPHS) initiated a large, prospective, multicenter surveillance study to determine the incidence ofINH-related hepatitis in 13,838 persons receiving INH for chemoprophylaxis}3 The overall rate of hepatitis was 10.3 per 1,000 (1 percent), and there were eight deaths (0.06 percent). The unexpectedly high mortality rate resulted in termination of the stud~ 14 It merits emphasis that these were cases of overt hepatitis, not simply chemical evidence of hepatic dysfunction. There has been a tendency to dismiss these findings, and, noting that seven ofeight deaths occurred in Baltimore, Comstock and Edwards l5 speculated that hepatotoxic factors other than INH might have been operative in Baltimore at that time. However, this study has not been supplanted to date by any similarly large and carefully documented experience. HEPATOTOXICITY ASSOCIATED WITH INH PLUS RMP Soon after the introduction of RM~ several reports suggested that hepatitis was more frequent and severe in patients receiving both INH and RMpl6-26 than in those receiving INH alone. Lesobre and associates l6
described 12 cases ofjaundice with four deaths among 50 patients receiving INH and RM~ although many of these had pre-existing liver disease. Lees et al l7 observed four cases among 50 patients without. known CHEST I 99 I 2 I FEBRUAR'f, 1991
485
antecedent liver disease and stated that in their experience treatment was interrupted by hepatitis more often in patients receiving INH plus RMP than in those receiving INH plus ethambutol (EMB). Lal and others 18 reported elevated transaminase levels in 18 of63 patients receiving INH and RM~ and jaundice in four. In one study, transaminase elevations were observed in up to 35 percent27 of adults taking INH plus RMP combinations, compared to 10 percent of those receiving INH alone. 10 Some reports suggested that hepatitis in IN" plus RMP combination therapy developed sooner after initiation of treatment28 than hepatitis due to IN" alone,29 with prompt and major elevations of transaminase levels and hypoprothrombinemia in some patients. In children, the difference seems to have been even more marked. A few studies of children receiving INH plus RMP combinations reported incidences of clinical hepatotoxicity as large as 25 percent, a striking Hnding in view of the rarity of hepatitis in children receiving IN" alone,13 and both drugs. 13,28,30,31-37 higher than in adults receiv~ng While many studies support the opinion that IN" plus RMP is more hepatotoxic than INH a1one,17,19,25,27,28,30,38 not all are in agreement. 23 Since administration of INH and RMP together (usually in association with other drugs) is now recommended for almost all cases of tuberculosis (TB), the issue is an important one. In order to better understand the influence of RMP on the incidence of INH-related hepatitis, a meta-analysis of clinical trials was undertaken. METHODS A Medline search of the English language literature was performed. Articles published between 1966 and December, 1989 were searched using the MESH terms "tuberculosis/drug therapy:' cchuman," and either uisoniazid" or urifampin." In addition, ccisoniazid" and urifampin" were searched as text words. The search output included 1,496 potentially relevant citations. The selection was further restricted by choosing only those articles describing clinical trials or surveys of public health departments, with data on the incidence of overt clinical hepatitis in patients receiving daily INH or RM~ Next, studies that did not systematically evaluate patients for toxic hepatitis or clearly state the criteria for diagnosing hepatitis were eliminated. These criteria included either jaundice, elevated bilirubin, or clinical manifestations of hepatitis in conjunction with AST levels ex
•
reviews
---f~.L---_-------Toxic Hepatitis with Isoniazid and Rifampin* c','''','':.
A Meta-analysis Malcolm A. Steele, M.D.;t Raymond F. Burk, M.D.;+ and Roger M. DesPrez, M.D.§ (Cheat 1991; 99:465-71) ALT = serum alanine aminotransferase; AST = serum aspartate aminotransferase; Bill = bilirubin; EMB = ethambutol; INH = isoniazid; NSM not speci6ca11y mentioned; PAS para-aminosalicylate; PZA = pyrazinamide; RMP = rifampio; S streptomycin; TH thioacetazone
=
=
=
=
here is some, although by no means unanimous, T opinion as well as some evidence to suggest that
drug-induced hepatitis occurs with greater frequenc~ and may be more severe, when isoniazid (INH) and rifampin (RMP) are administered in combination than when INH is given alone. It has been speculated that this is due to a drug-drug interaction in which indueFor editorial comment see page 266
tion of hepatic microsomal enzymes by RMP results in production of increased concentrations of a hepatotoxic metabolic product of INH. I In this revie~ an attempt has been made to briefly summarize the recent history and developing concepts of hepatotoxicity of INH administered without RM~ of INH and RMP administered together, and to summarize the available English language published evidence concerning the incidence of this prQblem. INH-RELATED HEPATITIS; BRIEF HISTORY AND CLINICAL FEATURES During the first few years after introduction ofINH, only sporadic cases suggesting possible hepatotoxicity were noted, and jaundice developing in patients on treatment was often attributed to concurrent viral hepatitis or the toxic effects of other drugs such as . PAS.2-7 Berte and associates8 in 1959 stated that no case of hepatotoxicity was observed in 513 patients receiving INH, and such was its reputation for safety that in 1963 the American Thoracic Society recommended aU tuberculin-positive persons should receive *From the Nashville Veterans Affairs Medical Center and Vanderbilt University School of Medicine) Nashville. . t Associate Chief of Staff for Ambulatory Care; Assistant Professor of Medicine. *Chief) Division of Gastroenterology; Professor of Medicine §Chief) Medical Service; Professor of Medicine Reprint requests: Dr Steele, VA Medical Center, Nashville 372122637
a year of INH chemoprophylaxis regardless of age or the duration of tuberculin positivity. 9 In 1969, 17 years after its introduction, Scharer and Smith lo reported liver function abnormalities in 10.3 percent ofpatients receiving INH. In spite of this, however, the problem of INH-hepatitis remained generally unappreciated until 1971 when a retrospective study by Garibaldi et al ll reported clinical hepatitis in 19 of 2,321 patients (I percent) taking INH for chemoprophylaxis, 13 of whom developed overt jaundice and 2 who (0.1 percent) died. ll An ad-hoc advisory committee appointed by the Centers for Disease Control to consider the problem raised by this report concluded that there was a CCnoteworthy" risk, 0 to 10 case per 1,000 persons per year, of serious hepatotoxicity in persons taking INH.12 Because of this unsettling opinion, the United States Public Health Service (USPHS) initiated a large, prospective, multicenter surveillance study to determine the incidence ofINH-related hepatitis in 13,838 persons receiving INH for chemoprophylaxis}3 The overall rate of hepatitis was 10.3 per 1,000 (1 percent), and there were eight deaths (0.06 percent). The unexpectedly high mortality rate resulted in termination of the stud~ 14 It merits emphasis that these were cases of overt hepatitis, not simply chemical evidence of hepatic dysfunction. There has been a tendency to dismiss these findings, and, noting that seven ofeight deaths occurred in Baltimore, Comstock and Edwards l5 speculated that hepatotoxic factors other than INH might have been operative in Baltimore at that time. However, this study has not been supplanted to date by any similarly large and carefully documented experience. HEPATOTOXICITY ASSOCIATED WITH INH PLUS RMP Soon after the introduction of RM~ several reports suggested that hepatitis was more frequent and severe in patients receiving both INH and RMpl6-26 than in those receiving INH alone. Lesobre and associates l6
described 12 cases ofjaundice with four deaths among 50 patients receiving INH and RM~ although many of these had pre-existing liver disease. Lees et al l7 observed four cases among 50 patients without. known CHEST I 99 I 2 I FEBRUAR'f, 1991
485
antecedent liver disease and stated that in their experience treatment was interrupted by hepatitis more often in patients receiving INH plus RMP than in those receiving INH plus ethambutol (EMB). Lal and others 18 reported elevated transaminase levels in 18 of63 patients receiving INH and RM~ and jaundice in four. In one study, transaminase elevations were observed in up to 35 percent27 of adults taking INH plus RMP combinations, compared to 10 percent of those receiving INH alone. 10 Some reports suggested that hepatitis in IN" plus RMP combination therapy developed sooner after initiation of treatment28 than hepatitis due to IN" alone,29 with prompt and major elevations of transaminase levels and hypoprothrombinemia in some patients. In children, the difference seems to have been even more marked. A few studies of children receiving INH plus RMP combinations reported incidences of clinical hepatotoxicity as large as 25 percent, a striking Hnding in view of the rarity of hepatitis in children receiving IN" alone,13 and both drugs. 13,28,30,31-37 higher than in adults receiv~ng While many studies support the opinion that IN" plus RMP is more hepatotoxic than INH a1one,17,19,25,27,28,30,38 not all are in agreement. 23 Since administration of INH and RMP together (usually in association with other drugs) is now recommended for almost all cases of tuberculosis (TB), the issue is an important one. In order to better understand the influence of RMP on the incidence of INH-related hepatitis, a meta-analysis of clinical trials was undertaken. METHODS A Medline search of the English language literature was performed. Articles published between 1966 and December, 1989 were searched using the MESH terms "tuberculosis/drug therapy:' cchuman," and either uisoniazid" or urifampin." In addition, ccisoniazid" and urifampin" were searched as text words. The search output included 1,496 potentially relevant citations. The selection was further restricted by choosing only those articles describing clinical trials or surveys of public health departments, with data on the incidence of overt clinical hepatitis in patients receiving daily INH or RM~ Next, studies that did not systematically evaluate patients for toxic hepatitis or clearly state the criteria for diagnosing hepatitis were eliminated. These criteria included either jaundice, elevated bilirubin, or clinical manifestations of hepatitis in conjunction with AST levels ex
