The hepatotoxicity rate for the 2RZ regimen in this randomized controlled trial was probably among the highest reported in literature for both immunocompromised and immunocompetent patients.4–7,11–14
As shown in Table 3
, none of the factors of HBsAg carriage, alcoholism, comorbidities, concomitant medications, body mass index, low serum albumin, baseline liver function, dosage of rifampin or pyrazinamide, or adherence to treatment could have accounted for such phenomenon. Sporadic occurrence of viral hepatitis was an unlikely explanation in the absence of common source exposure, even though viral hepatitis markers had not been checked in every case. The mean age of study subjects in this trial was probably higher than all other similar trials in the literature. It would be tempting to ascribe such a high incidence of liver dysfunction to the relatively advanced age of this study group. In a case-control study15
on the risk factors for hepatotoxicity from antituberculous drugs, only advanced age, hypoalbuminemia, high alcohol intake, slow acetylator phenotype, and extensive disease were the risk factors for the development of hepatotoxicity. In a previous study16–
of antituberculosis drug-related liver dysfunction in Hong Kong, age was found to be the only predictor of drug-related liver dysfunction after stratifying the patients according to HBsAg status. In a retrospective study17–
on tuberculosis in older people in Hong Kong, the incidence of liver dysfunction among those patients aged ≥ 65 years was found to be 17.7%, in contrast with only 9.2% among younger patients. It should be noted that, while the patients in that study were receiving treatment for active tuberculosis, some elderly patients were not administered pyrazinamide, and biochemical monitoring was not regularly performed. In a prospective study18
of isoniazid-rifampin-pyrazinamide–induced liver injury on Chinese patients in Taiwan, 26% of patients acquired antituberculous drug-induced liver injury (ALT levels greater than ULN). The incidence of drug-induced liver injury was as high as 33% in patients aged ≥ 35 years. The recent study by Jasmer et al11
on the treatment of LTBI also found that patients > 35 years old had a higher risk of grade 3 or 4 hepatotoxicity.