Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity
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 . Anti-TB drug–induced
hepatotoxicity (DIH) is associated with a mortality of 6%–
12% if these drugs are continued after the onset of
symptoms . 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 ,
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
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 , 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 ), 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 , and in arm III, drugs were administered in
accordance with BTS guidelines . 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–
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 .
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 . 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 . 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 . 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.
Hepatotoxicity is the most common adverse effect of anti-TB
treatment that leads to interruption of therapy . 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 . 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 . 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
The only other prospective clinical trial of anti-TB drug
reintroduction after DIH was conducted in Turkey by Tahaoglu
et al . In that study, 45 patients with DIH were randomized
to receive 2 different retreatment protocols. Tahaoglu et al 
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 .
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
, we did not study a reintroduction regimen that lacked
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 , in which it was recommended to be
more cautious in reintroducing isoniazid, rifampicin, and
pyrazinamide after normalization of liver function in patients with
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 . 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 . In the same
study , 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
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.
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.
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