Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity

Clinical Infectious Diseases, Mar 2010

Background. Drug-induced hepatotoxicity (DIH) is the most common adverse drug reaction leading to interruption of antituberculosis treatment. Worldwide, different reintroduction regimens have been advocated, but no consensus guidelines are available. Reintroduction of antituberculosis drugs in patients with DIH has never been studied systematically. We aimed to compare the safety of 3 different reintroduction regimens of antituberculosis drugs in patients with antituberculosis DIH. Methods. A total of 175 patients with a diagnosis of antituberculosis DIH were randomized to receive 1 of 3 different predefined reintroduction regimens of antituberculosis drugs and were evaluated prospectively. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from day 1. In arm II, drugs were administered in a manner similar to that recommended in the American Thoracic Society guidelines for reintroduction. In arm III, drugs were administered in accordance with British Thoracic Society guidelines. Results. Nineteen patients (10.9%) had recurrence of DIH during follow-up. Eight, 6, and 5 patients had recurrence of hepatitis in arms I, II, and III, respectively (P=.69). Of all the clinical and laboratory parameters, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH on reintroduction of antituberculosis drugs (Pµ.01). Conclusions. The recurrence rate of hepatotoxicity was not significantly different between the 3 groups. According to the findings of the present study, all 3 of the potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) can be reintroduced simultaneously at full dosage safely from day 1, especially for patients with bilateral extensive pulmonary tuberculosis, to halt disease transmission or to treat patients with life-threatening tuberculosis. Trial registration. ClinicalTrials.gov identifier number: NCT00405301.

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Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity

CID Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment-Induced Hepatotoxicity Surendra K. Sharma () 0 1 Rohit Singla 0 1 Pawan Sarda 0 1 Alladi Mohan 0 1 2 Govind Makharia 0 1 Arvind Jayaswal 0 1 Vishnubhatla Sreenivas 0 1 Sarman Singh 0 1 3 0 Received 3 September 2009; accepted 2 November 2009; electronically published 15 February 2010. and Sleep Medicine, Dept of Medicine, All India Institute of Medical Sciences , Ansari Nagar, New Delhi 110029 , India 1 niazid , rifampicin, and pyrazinamide has proved to be 2 Department of Medicine, Sri Venkateswara Institute of Medical Sciences , Tirupati, Andhra Pradesh , India 3 Laboratory Medicine, All India Institute of Medical Sciences , New Delhi (See the editorial commentary by Saukkonen, on pages 840-842.) Background. Drug-induced hepatotoxicity (DIH) is the most common adverse drug reaction leading to interruption of antituberculosis treatment. Worldwide, different reintroduction regimens have been advocated, but no consensus guidelines are available. Reintroduction of antituberculosis drugs in patients with DIH has never been studied systematically. We aimed to compare the safety of 3 different reintroduction regimens of antituberculosis drugs in patients with antituberculosis DIH. Methods. A total of 175 patients with a diagnosis of antituberculosis DIH were randomized to receive 1 of 3 different predefined reintroduction regimens of antituberculosis drugs and were evaluated prospectively. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from day 1. In arm II, drugs were administered in a manner similar to that recommended in the American Thoracic Society guidelines for reintroduction. In arm III, drugs were administered in accordance with British Thoracic Society guidelines. Results. Nineteen patients (10.9%) had recurrence of DIH during follow-up. Eight, 6, and 5 patients had recurrence of hepatitis in arms I, II, and III, respectively (P p .69). Of all the clinical and laboratory parameters, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH on reintroduction of antituberculosis drugs (P ! .01). Conclusions. The recurrence rate of hepatotoxicity was not significantly different between the 3 groups. According to the findings of the present study, all 3 of the potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) can be reintroduced simultaneously at full dosage safely from day 1, especially for patients with bilateral extensive pulmonary tuberculosis, to halt disease transmission or to treat patients with life-threatening tuberculosis. Trial registration. ClinicalTrials.gov identifier number: NCT00405301. - is hepatotoxicity [1]. Anti-TB drug–induced hepatotoxicity (DIH) is associated with a mortality of 6%– 12% if these drugs are continued after the onset of symptoms [2]. The risk of hepatotoxicity is increased when the drugs are combined. The treatment of underlying TB after occurrence of hepatitis is difficult and controversial. In a limited number of published studies, different reintroduction regimens have been advocated with variable success [3– 5], but consensus guidelines for managing anti-TB DIH are yet to be developed. Reintroduction of anti-TB drugs following anti-TB DIH has never been studied systematically. With the exception of 1 small study [4], there is little empirical evidence comparing different reintroduction regimens of anti-TB drugs. The present study was designed to compare 3 different predefined regimens of reintroduction of anti-TB drugs in patients with DIH with respect to safety and risk of recurrence of hepatotoxicity. In brief, in the first reintroduction regimen (arm I), all 3 drugs were introduced together at full dosages. In the other 2 reintroduction regimens (arms II and III), the drugs were introduced sequentially, as advocated by the American Thoracic Society (ATS) and British Thoracic Society (BTS) guidelines, respectively. PATIENTS, MATERIALS, AND METHODS Patients. The study included patients with a diagnosis of DIH who attended the outpatient department or were admitted to the All India Institute of Medical Sciences Hospital (New Delhi, India) and Sri Venkateswara Institute of Medical Sciences Hospital (Tirupati, Andhra Pradesh, India). The study period was 2004–2009. We recruited 237 consecutive patients who developed clinical and/or laboratory features suggestive of DIH while receiving anti-TB treatment. Patients who met the following diagnostic criteria for DIH were enrolled: (1) an increase 5 times the upper limit of the normal levels (50 IU/L) of serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) on 1 occasion or 13 times the upper limit of normal (1150 IU/L) on 3 consecutive occasions; (2) an increase in serum total bilirubin 11.5 mg/dL; (3) any increase in serum AST and or ALT level above pretreatment values together with anorexia, nausea, vomiting, and jaundice; (4) absence of serological evidence of infection with hepatitis A, B, C, or E virus; and (5) improvement in liver function test results (serum bilirubin level !1 mg/dL; AST and ALT level !100 IU/L) after withdrawal of anti-TB drugs [6, 7]. DIH was diagnosed if criteria 1, 2, or 3 were present in combination with criteria 4 and 5. Patients of either sex who were 16–65 years of age were recruited. Patients outside this age range were excluded, because the risk of DIH increases at both extremes of age [8–13]. Written informed consent was obtained from all patients. The Institutional Ethics Committee approved the study. Data collection. The site of TB involvement, the method of establishing the diagnosis of TB, history of liver disease, history of concomitant use of other hepatotoxic drugs, and alcohol intake were recorded. The details of anti-TB drugs (nature of drugs, dosages, duration of treatment, and patient compliance) were noted. The pretreatment liver function test results (serum bilirubin level, AST level, ALT level, alkaline phosphatase [ALP] level, serum total protein, and serum albumin level) were recorded. The extent of disease as determined by examination of a chest radiograph was recorded and categorized as minimal, moderately advanced, and far advanced [14], as defined by the US National Tuberculosis Association in 1961. Patient history and family history of TB was also recorded. Nutritional status was estimated by calculating the body mass index (BMI, defined as the weight in kilograms divided by the square of height in meters) and mid-arm circumference. Time interval from initiation of anti-TB drugs to occurrence of DIH was taken as the latency period. Study design. We conducted a prospective, randomized trial to evaluate the hepatotoxic potential of 3 different predefined anti-TB drug reintroduction regimens after the occurrence of anti-TB DIH. The primary end point was recurrence of DIH, which was defined using the criteria stated above. Exclusion criteria observed were serological evidence of acute viral hepatitis, ultrasonographic evidence of chronic liver disease, human immunodeficiency virus (HIV) infection, longterm alcoholism (defined as consumption of 148 g of alcohol per day for at least 1 year [7]), concomitant consumption of other potentially hepatotoxic drugs (eg, methotrexate, phenytoin, valproate, and fluconazole), pregnancy, and failure to give written informed consent. Patients with DIH who satisfied the inclusion criteria were enrolled into the study. Treatment with the hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) was immediately stopped. Patients were administered a modified anti-TB drug regimen consisting of ethambutol, streptomycin, and 1 of the flouroquinolones. Patients were subsequently followed up at weekly intervals until clinical and biochemical parameters of acute liver injury stabilized (ie, absence of vomiting and abdominal pain, both AST and ALT levels !100 IU/L, and serum bilirubin level !1.0 mg/dL). Time interval between stopping isoniazid, rifampicin and pyrazinamide and achieving these parameters was taken as the normalization period. After stabilization of liver functions, the patients were randomized into 1 of the 3 arms with use of computer-generated random numbers, blocked in groups of 3. These numbers were kept in sealed opaque envelopes. The envelopes were in the possession of an individual who was not involved in the conduct of study. Each arm had a different reintroduction protocol for anti-TB drugs (Table 1). There was no crossover of patients between study arms. Adherence to treatment protocol was established at each visit. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at the full dosage. This strategy for reintroduction of anti-TB drugs is not recommended by any of the existing guidelines because of fear of increased hepatotoxicity. In arm II, anti-TB drugs were introduced in a manner similar to that recommended by ATS guidelines [15], and in arm III, drugs were administered in accordance with BTS guidelines [16]. Figure 1 summarizes the study. Laboratory monitoring. Tests to detect markers of acute viral hepatitis (immunoglobulin M [IgM] anti–hepatitis A virus, IgM anti–hepatitis B core antigen and/or hepatitis B surface antigen, IgM anti–hepatitis C virus antibodies, and IgM anti– Regimen H, R, and Z at maximum dosages from day 1 R at maximum dosage from day 1, H at maximum dosage from day 8, and Z at maximum dosage from day 15 H at dosage of 100 mg/day from day 1, maximum dosage from day 4; R at dosage of 150 mg/day from day 8, maximum dosage from day 11; and Z at dosage of 500 mg/day from day 15, maximum dosage from day 18 hepatitis E virus) were performed for all patients who developed features suggestive of DIH while receiving anti-TB drugs [6]. An enzyme-linked immunosorbent assay to test for HIV type 1 and type 2 was also performed. An abdominal ultrasonograph was obtained for each patient to rule out fatty liver or chronic liver disease. During reintroduction of anti-TB drugs, liver function testing was done before increasing the dosage or adding another drug to the regimen. After complete reintroduction of anti-TB drugs, regular monitoring of liver function was performed by determination of serum bilirubin level, AST level, ALT level, and serum ALP level every week for the first month, every 2 weeks during the second month, and at the end of third month. After the third month, laboratory measurement was performed when indicated. At the time of recurrence, serum samples from patients were again analyzed for markers of acute viral hepatitis. Statistical analysis. We assumed that the risk of recurrence of hepatotoxicity associated with the simultaneous reintroduction of isoniazid, rifampicin, and pyrazinamide at a full dosage (as in arm I) was 24%, as reported by Tahaoglu et al [4]. Also, we assumed that the risk of recurrence of hepatotoxicity associated with a reintroduction regimen in which isoniazid, rifampicin, and pyrazinamide were introduced sequentially in the same order in gradually escalating dosages (as in arm III) was 6.8%, as reported by Singh et al [3]. To our knowledge, no study has previously evaluated the risk of recurrence of hepatotoxicity associated with a reintroduction schedule in which rifampicin, isoniazid, and pyrazinamide are reintroduced sequentially at full dosage (as in arm II). We assumed that such a reintroduction schedule would be noninferior to the one used in arm III, and therefore, the risk of recurrence of hepatotoxicity associated with such a regimen was assumed to be 7%. To detect a difference in the risk of recurrence of hepatotoxicity with 80% power using a x2 test with a 5% level of significance, 56 subjects in each arm were required. We analyzed group mean values by means of the Student’s t test and analysis of variance (ANOVA), and the proportions were compared with use of the x2 test and Fisher’s exact test. The Bonferroni correction was applied for multiple comparisons among the 3 groups when ANOVA indicated a statistically significant difference. Associations with a P value !.05 were considered to have statistical significance. Stata, version 9.2 (StataCorp), was used for data analysis. A total of 237 patients who developed clinical and/or laboratory features suggestive of DIH while receiving anti-TB drugs were recruited. Four patients died before they could be randomized into any of the 3 arms (3 patients died due to acute liver failure, and 1 patient died due to progressive pulmonary TB leading to acute respiratory failure). A total of 58 patients were excluded for various reasons; 11 had long-term alcoholism, 5 were taking hepatotoxic drugs (chiefly phenytoin), and 17 had HIV infection. Serological evidence confirmed recent acquisition of acute viral hepatitis in 25 patients, of whom 4 (16%) had hepatitis A, 4 (16%) had hepatitis B, 3 (12%) had hepatitis C, and 14 (56%) had hepatitis E. None of the patients had multidrugresistant or extensively drug-resistant TB. The remaining 175 patients were randomized to 1 of the 3 arms after stabilization of liver functions. Of these 175 patients, 12 (6.9%) were asymptomatic and received a diagnosis on the basis of elevated transaminase levels alone. Most of the patients experienced nausea (90.2%), vomiting (65.7%), abdominal pain (28%), or jaundice (43.4%). Forty five (25.7%) had pulmonary TB, 97 (55.4%) had extrapulmonary TB, and 33 (18.9%) had disseminated or miliary TB. Only 25 (14.3%) of the patients were receiving treatment from a directly observed treatment (DOT) center, which involved thrice-weekly anti-TB treatment in accordance NOTE. Data are expressed as mean value ( standard deviation), unless otherwise indicated. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Maximum bilirubin level, mg/dL Maximum AST level, IU/L Maximum ALT level, IU/L No. (%) of patients with recurrence of DIH after reintroduction of anti-TB drugs Time period from reintroduction of anti-TB drugs to recurrence of DIH, median days (range) 14 (5– 28) 21 (14– 28)a 21 (14– 35)a NOTE. Data are mean value ( standard deviation), unless otherwise indicated. Arms I, II, and III are defined in Table 1. ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Time period was calculated from the beginning of introduction of the first drug until the occurrence of DIH. with the Revised National Tuberculosis Control Programme guidelines [17]. The remaining 150 patients (85.7%) were taking daily treatment as prescribed by their physician. Fifty-eight, 59, and 58 patients were randomized to arms I, II, and III, respectively. The median latency period was 23 days (interquartile range [IQR], 14–44 days), and the median normalization time was 18 days (IQR, 14–28 days). Table 2 and Table 3 show a comparison of the baseline characteristics of patients and the severity of DIH, respectively, among the 3 arms. Except for pretreatment serum albumin level, which was found to be significantly higher in arm I, all other parameters were similar among the 3 arms. Nineteen patients (10.9%) had recurrence of DIH during the follow-up period. None of these patients had serological evidence of acute viral hepatitis on retesting. Eight, 6, and 5 patients had recurrence of DIH in arms I, II, and III, respectively (Table 4). The maximum serum bilirubin level, AST level, and ALT level observed in each of the 3 arms was also similar (Table 4). No deaths were observed in any of the 3 arms. All the other patients were followed up with regular liver function monitoring, as described above, for a period of 3 months after experiencing successful reintroduction of all 3 hepatotoxic drugs. None of the patients reported any deviation from the prescribed treatment protocol during the follow-up period. Nineteen patients who had recurrence of DIH were compared with the remaining patients who tolerated reintroduction of anti-TB drugs with respect to clinical characteristics, baseline laboratory parameters, and severity of the first episode of hepatitis. Of the clinical and baseline laboratory parameters analyzed, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH. Patients with recurrence of DIH had mean pretreatment serum albumin levels ( standard deviation) of 3.39 0.17 g/dL, compared with 3.91 0.05 g/dL in the remaining patients who tolerated reintroduction of anti-TB drugs (P ! .01). In the present study, the severity of the first episode of DIH did not affect the risk of recurrence of DIH. DISCUSSION Hepatotoxicity is the most common adverse effect of anti-TB treatment that leads to interruption of therapy [1]. Retreatment is started only when all biochemical markers of liver injury have returned to normal levels. Although the reintroduction of isoniazid, rifampicin, and pyrazinamide therapy after hepatic injury does involve the risk of additional morbidity, the compelling rationale for doing so is grounded in the fact that nonisoniazid and non-rifampicin anti-TB treatment regimens require a longer duration of administration and lack of proof of clinical efficacy. Worldwide, different schedules for reintroduction of anti-TB drugs after hepatotoxicity has resolved have been advocated [15–18], with variable success. However, no evidence-based guidelines are available, because of the lack of prospective, randomized, controlled trials. Patients with infectious pulmonary TB—especially those with bilateral extensive pulmonary TB and a higher bacillary load—pose a threat of disease transmission in the community and require a timely reintroduction of anti-TB drugs. Furthermore, repeated recurrences of DIH may potentially predispose an individual to develop drug-resistant TB. Therefore, in this context, this topic is of considerable interest. This study is, to our knowledge, the first to compare 3 different predefined anti-TB drug reintroduction regimens in a fairly large sample population. Such a large sample size, combined with the observed exclusion criteria, would be difficult to attain, especially with the introduction of DOT as an integral part of treatment of TB in several countries (including India) where TB is endemic [19]. This is because the risk of DIH is comparatively lower among patients receiving intermittent, thrice-weekly treatment from DOT centers [20, 21]. In our study, the study team was not aware of the allocation sequence. The randomized nature of the intervention, with prospective weekly surveillance and predefined objective criteria for DIH, allowed us to compare the 3 reintroduction regimens with minimal bias. We also excluded pregnant women, individuals with long-term alcoholism, patients with chronic liver disease, and patients who were concomitantly receiving other hepatotoxic drugs. All of the above characteristics are established risk factors for DIH [15]. Also, treating TB in HIV-infected patients is a complicated matter. These patients generally require antiretroviral drugs, which are potentially hepatotoxic and are associated with multiple drug-drug interactions. Also, hepatitis in these patients may be attributable to an opportunistic infection. Therefore, to simplify matters, HIV-infected patients were excluded from the present study. Furthermore, we also investigated all patients for markers of acute viral hepatitis and carefully excluded them from the study. In the present study, the majority of patients (156 [89%] of 175) had successful reintroduction of anti-TB drugs without recurrence of DIH. This is similar to the findings of earlier studies [3–5], which observed that ∼90% of patients tolerate reintroduction of isoniazid, rifampicin, and pyrazinamide. Although the number of patients with recurrence of DIH appeared to be greater in arm I, this difference was insignificant. This observation has important implications for a country, such as India, that has a high burden of sputum-positive pulmonary TB, in which initiating isoniazid, rifampicin, and pyrazinamide simultaneously will help to achieve faster sputum conversion and reduce the risk of disease transmission. Also, this strategy has obvious merits for treating severe, life-threatening forms of TB and will theoretically reduce the risk of acquisition of drug-resistant TB. However, in accordance with the results, our study lacked sufficient power to detect a difference between the 3 arms. Therefore, there is an urgent need to plan multicenter trials in countries in which TB is endemic to address this important issue. The only other prospective clinical trial of anti-TB drug reintroduction after DIH was conducted in Turkey by Tahaoglu et al [4]. In that study, 45 patients with DIH were randomized to receive 2 different retreatment protocols. Tahaoglu et al [4] showed that the risk of developing DIH after reintroduction of anti-TB drugs was 24% in the group in which the original regimen, which included pyrazinamide, was given from day 1 during reintroduction, compared with 0% in the group in which drugs were introduced gradually in a sequential manner and in which pyrazinamide was excluded from the regimen. In our study, the risk of recurrence of hepatitis was comparatively lower when the original regimen, including pyrazinamide, was given from day 1 during reintroduction. This could be explained by ethnic differences in the 2 study populations (one in India and the other in Turkey). Also, we had excluded individuals with alcoholism and patients with HIV infection; these individuals face an increased risk of DIH [15]. Furthermore, AST and ALT levels !40 IU/L were considered to be normal by the Turkish study, in contrast with our study, in which the cut off value was 50 IU/L; this could potentially have led to an increase in the frequency of DIH diagnoses in the former study, compared with our study. Unlike Tahaoglu et al [4], we did not study a reintroduction regimen that lacked pyrazinamide. The present study also revealed pretreatment serum albumin level to be an important predictor of a second recurrence of DIH. Therefore, patients with hypoalbuminemia should be closely monitored for subsequent recurrence of DIH. Also, the nutritional status of these patients should be improved. In the present study, an increased severity of the first episode of DIH did not confer an increased risk of recurrence. This may be explained by the observation made in the present study that individuals with severe cases of DIH present late, after developing symptoms suggestive of DIH. For such patients, anti-TB dugs are modified relatively late, which further accentuates hepatotoxicity. These patients perhaps do not have an intrinsic tendency to develop more severe hepatitis per se. These findings do not support the suggestions of a very small study done at Kathmandu, Nepal [22], in which it was recommended to be more cautious in reintroducing isoniazid, rifampicin, and pyrazinamide after normalization of liver function in patients with more-severe DIH. Anti-TB DIH is a relatively common problem, especially in resource-limited settings where TB is endemic. Furthermore, acute viral hepatitis is also often endemic in these areas. Our study also shows acute viral hepatitis to be an important confounding factor in DIH [23]. After excluding individuals with alcoholism, those receiving concomitant hepatotoxic drugs, and those with HIV infection, 200 patients were observed who developed acute hepatitis while receiving anti-TB drugs. Of these patients, 25 (12.5%) had acute viral hepatitis; hepatitis E was the most common type of viral hepatitis (found in 14 [56%] of 25 patients). This observation is not surprising, given that hepatitis E virus is hyperendemic in India [24]. In the same study [23], it was shown that patients with acute viral hepatitis, compared with patients with DIH, had later onset of hepatitis, greater elevations in hepatic transaminase levels, and a longer time for normalization of liver function test results. The patient profile outlined above may guide the clinicians to suspect and look for acute viral hepatitis. Also, it must be ensured that adequate resources and good-quality laboratory services should be available to rule out acute viral hepatitis once DIH is suspected. Anti-TB DIH is a relatively common problem, adding to the morbidity and mortality among patients with TB. No evidencebased guidelines are available for management of these patients. This study provides evidence supporting the safety of introducing all 3 potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) together, which is a finding that may enable timely therapy for patients with severe disease and limit ongoing transmission of infectious TB. Acknowledgments We thank all of the patients who participated in the study and Dr Deepak Gupta, Mr Sanjeev Kumar, Mr Brijesh Jha, Mrs Rekha Sharma, Ms Deepa Dhawan, and Mrs S. Radha, for facilitating smooth conduct of the study. Potential conflicts of interest. All authors: no conflicts. 1. Schaberg T , Rebhan K , Lode H. Risk factors for side effects of isoniazidrifampicin and pyrazinamide in patients hospitalized for pulmonary tuberculosis . Eur Respir J 1996 ; 9 : 2026 - 2030 . 2. Dash LA , Comstock GW , Flynn PG . Isoniazid preventive therapy: retrospect and prospect . Am Rev Respir Dis 1980 ; 121 : 1039 - 1044 . 3. Singh J , Garg PK , Tandon RK . Hepatotoxicity due to anti-tuberculosis therapy: clinical profile and reintroduction of therapy . J Clin Gastroenterol 1996 ; 22 : 211 - 214 . 4. Tahaoglu K , Atac¸ G , Sevim T , et al. The management of anti-tuberculosis drug induced hepatotoxicity . Int J Tuberc Lung Dis 2001 ; 5 : 65 - 69 . 5. Agal S , Baijal R , Pramanik S , et al. Monitoring and management of anti-tuberculosis drug induced hepatotoxicity . J Gastroenterol Hepatol 2005 ; 20 : 1745 - 1752 . 6. Sharma SK , Balamurugan A , Saha PK , Pandey RM , Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment . Am J Respir Crit Care Med 2002 ; 166 : 916 - 919 . 7. Pande JN , Singh SPN , Khilnani GC , Khilnani S , Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study . Thorax 1996 ; 51 : 132 - 136 . 8. Ormerod LP , Horsfield N. Frequency and type of reactions to antituberculosis drugs: observations in routine treatment . Tuber Lung Dis 1996 ; 77 : 37 - 42 . 9. Yee D , Valiquette C , Pelletier M , Parisien I , Rocher I , Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis . Am J Respir Crit Care Med 2003 ; 167 : 1472 - 1477 . 10. Dossing M , Wilcke JT , Askgaard DS , Nybo B. Liver injury during antituberculosis treatment: an 11-year study . Tuber Lung Dis 1996 ; 77 : 335 - 340 . 11. Teleman MD , Chee CB , Earnest A , Wang YT . Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore . Int J Tuberc Lung Dis 2002 ; 6 : 699 - 705 . 12. Hwang SJ , Wu JC , Lee CN , et al. A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B . J Gastroenterol Hepatol 1997 ; 12 : 87 - 91 . 13. Ohkawa K , Hashiguchi M , Ohno K , et al. Risk factors for antituberculous chemotherapyinduced hepatotoxicity in Japanese pediatric patients . Clin Pharmacol Ther 2002 ; 72 : 220 - 226 . 14. National tuberculosis association of the U .S.A. Diagnostic standards and classification of tuberculosis . New York : National Tuberculosis Association , 1961 . 15. Saukkonen JJ , Cohn DL , Jasmer RM , et al on the behalf of ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: Hepatotoxicity of Antituberculosis Therapy . Am J Respir Crit Care Med 2006 ; 174 : 935 - 952 . 16. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom . Thorax 1998 ; 53 : 536 - 548 . 17. TBC India Web page. Directorate General of Health Services Ministry of Health and Family Welfare . http://www.tbcindia.org. Accessed 8 February 2010 . 18. World Health Organization (WHO). Treatment of tuberculosis: Guidelines for national programmes . 2nd ed. Geneva, Switzerland: WHO, 1997 ; 25 - 39 . 19. World Health Organization (WHO). Global tuberculosis control: surveillance, planning , financing; Geneva, Switzerland: WHO, 2007 . 20. Dhingra VK , Rajpal S , Aggarwal N , Aggarwaln JK , Shadab K , Jain SK . Adverse drug reactions observed during DOTS . J Commun Dis 2004 ; 36 : 251 . 21. Hong Kong Chest Service/British Medical Research Council. First report: Controlled trial of four thrice weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis . Lancet 1981 ; 1 : 171 - 174 . 22. Shakya R , Rao BS , Shrestha B. Management of antitubercular drugsinduced hepatotoxicity and therapy reintroduction strategy in a TB clinic of Nepal . Kathmandu Univ Med J (KUMJ) 2005 ; 3 : 45 - 49 . 23. Sarda P , Sharma SK , Mohan A , et al. Role of acute viral hepatitis as a confounding factor in antituberculosis treatment induced hepatotoxicity . Indian J Med Res 2009 ; 129 : 64 - 67 . 24. Acharya SK , Madan K , Dattagupta S , Panda SK. Viral hepatitis in India . Natl Med J India 2006 ; 19 : 203 - 217 .


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Surendra K. Sharma, Rohit Singla, Pawan Sarda, Alladi Mohan, Govind Makharia, Arvind Jayaswal, Vishnubhatla Sreenivas, Sarman Singh. Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity, Clinical Infectious Diseases, 2010, 833-839, DOI: 10.1086/650576