Safety of Treatment of Latent Tuberculosis Infection in

Compensated Cirrhotic Patients During Transplant

Candidacy Period
Alex W. Jahng,1 Thao Tran,2 Lanchi Bui,3 and James L. Joyner4,5
Background. Treatment of latent tuberculosis infection with isoniazid (INH) or rifampin (RIF) is controversial in liver
transplant candidates due to potential hepatotoxicity. In this study, treatment of latent tuberculosis during transplant
candidacy period is explored, and relevant literature is reviewed.
Methods. Liver transplant candidates with latent tuberculosis infection by positive tuberculin skin test (5 mm) were
prospectively enrolled and treated with 9 months of INH or 4 months of RIF, and were monitored monthly for their
liver enzyme profiles, adverse effects, compliance, and completion rate.
Results. Four of nine patients with INH had asymptomatic, mild elevations of aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) versus none of five patients in the RIF group. Two cases of elevations were attributed
to INH. Two other cases were attributed to alcoholism or active chronic hepatitis B virus infection. Only one patient in
the INH group experienced symptoms possibly attributed to INH hepatotoxicity. Compliance was 100% per patient
reporting. Completion rates were 79% for INH and 100% for RIF. No fulminant hepatic failure or death was observed.
Conclusion. Treatment of latent tuberculosis in liver transplant patients during their candidacy with INH or RIF
appears to be a safe, viable option, if carefully monitored for adverse effects and liver enzymes.
Keywords: Treatment of latent infection, Latent tuberculosis, Liver transplant, Isoniazid, Rifampin.
(Transplantation 2007;83: 15571562)

he incidence of tuberculosis (TB) ranges from 0.9% to

2.3% in liver transplant patients and is a significant
source of mortality and morbidity despite treatment (1 6).
Guidelines of the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) advocate the use
of isoniazid (INH) or rifampin (RIF) for all transplant patients with positive tuberculin skin test and suspected latent
tuberculosis infection. However, due to the hepatotoxicity
inherent in both drugs, controversy exists with respect to
their use in liver transplant candidates (7, 8).
Transplant centers take individualized approaches to
the treatment of latent infection in patients undergoing liver
transplantation (9, 10). For institutions that opt for treatment
of latent tuberculosis, the timing of initiation with respect to
the transplantation is controversial. Treatment of latent tuberculosis may be done during the candidacy period or after
transplant. Some institutions forgo treatment of latent tuberculosis in favor of surveillance and then treat as necessary for
incident active TB infection.
The safety of treatment of latent tuberculosis during the
liver transplant candidacy period with INH or RIF is explored

School of Medicine, University of California, Irvine, Irvine, CA.

Department of Pharmacy Services, Kaiser Permanente Fontana Medical
Center, Fontana, CA.
3
Division of Transplantation and Department of Pharmacy Services, University of California, Irvine, Orange, CA.
4
Department of Medicine, Hospitalist Division and Division of Infectious
Diseases, University of California, Irvine, Medical Center, Orange, CA.
5
Address correspondence to: James Joyner, M.D., Building 58, Room 103,
UCI Medical Center, 101 The City Drive South, Orange, CA 92868.
E-mail: jjoynermd@gmail.com
Received 3 October 2006. Revision requested 6 March 2007.
Accepted 14 March 2007.
Copyright 2007 by Lippincott Williams & Wilkins
ISSN 0041-1337/07/8312-1557
DOI: 10.1097/01.tp.0000266578.45634.4f
2

Transplantation Volume 83, Number 12, June 27, 2007

in this study. We report our experience with 14 patients prospectively followed and review relevant literature regarding
different approaches to treatment of latent tuberculosis in
liver transplant patients.

METHODS
This was a prospective, observational study conducted
at the University of California, Irvine, Medical Center from
2003 to 2006.
Patient Population
Patients with end-stage liver disease 18 years of age or
greater with positive tuberculin skin test (5 mm) were enrolled. Demographic information including ethnicity, age,
sex, comorbid diseases, etiology of liver failure, and concurrent medications was obtained. Model of End-stage Liver
Disease (MELD) scores and Child-Pugh scores were calculated at the initiation of treatment of latent tuberculosis. Patients were excluded from the study if they did not have a
prospect for liver transplant within 2 years. Typically, these
were patients with a good quality of life suffering no stigmata
of end-stage liver disease. In these patients, the risk/benefit
ratio of treatment of latent tuberculosis was not felt sufficient
to warrant treatment of latent tuberculosis. Patients with
prior treatment of latent tuberculosis or active TB were also
excluded. Patients were also excluded if there was clinical or
laboratory evidence of active decompensated disease. Because
of this the study is biased toward patients with compensated
cirrhosis who are expected to undergo transplantation in the
near future.
Methods
The patients were treated with either 300 mg of INH
daily along with 2550 mg of vitamin B6 for 9 months or 600
mg of RIF daily for 4 months. Based on its proven track record

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Transplantation Volume 83, Number 12, June 27, 2007

for treatment of latent tuberculosis, INH was the primary

choice. RIF was used if the patient had a prior adverse reaction to INH or if the transplant was very likely to occur in less
than 9 months. Patients were followed with a monthly clinic
visit until the completion of therapy. Monthly laboratory
tests included aspartate aminotransferase (AST), alanine
aminotransferase (ALT), total bilirubin, and international
normalization ratio (INR). When liver function tests were
found to be more than twice baseline (calculated as mean
enzyme values over the 10 months period preceding treatment of latent tuberculosis as available) and the patient was
asymptomatic, treatment was continued and follow-up laboratory testing was repeated at the soonest possible time. If the
elevations persisted upon repeat testing or if the patient had
clinically significant signs or symptoms of hepatotoxicity
(nausea, vomiting, abdominal pain, increased icterus or jaundice), treatment of latent tuberculosis was stopped. If elevated
liver function tests persisted despite cessation of treatment of
latent tuberculosis, appropriate investigation into other
causes was initiated. The protocol was approved by the University of California Irvine Medical Center Institutional Review Board.
Outcome Measures
Primary outcome was drug-induced hepatotoxicity.
INH or RIF induced hepatotoxicity was presumed if the enzyme levels returned to the patients baseline with the withdrawal of drugs, and other causes of enzyme elevation were
excluded, including exacerbation of existing liver disease.
Secondary outcome was the completion of treatment of latent
tuberculosis.

RESULTS
Fourteen liver transplant candidates were enrolled into
treatment of latent tuberculosis during the study period. Patient characteristics are summarized in Table 1. The mean age
was 53 (range: 41 68) years and the mean MELD score was 15

(range: 6 23). Excepting one patient in the INH group with

class C liver disease by Child-Pugh score (10), all the other
patients were with either class A or B liver disease. The etiology of the liver disease was hepatitis C virus (HCV) in 54% (8
of 14) of the patients, with or without prior alcoholism, and
hepatitis B virus (HBV) in 21% (3 of 14) of the patients. One
patient had alcoholic liver disease, one had primary biliary
cirrhosis (PBC), and one had cryptogenic cirrhosis. All the
HBV patients were negative for E antigen reactivity and positive for S antigen reactivity. The most common comorbid
disease was diabetes, present in 36% (5 of 14). Renal failure/
insufficiency was present in 21% (3 of 14) of the patients.
Hepatocellular carcinoma was present in 21% (3 of 14) of the
patients.
The baseline liver enzymes levels are summarized in
Table 2, calculated as described in the Methods. The baseline
AST and ALT levels were elevated over the upper limits of
normal in 62% (8 of 13) of the patients, with means of 57 IU/L
(range: 23124) and 52 IU/L (range: 19 97), respectively.
The baseline AST and ALT levels were not significantly different between the INH and the RIF groups.
During the course of treatment four of nine patients in
the INH group developed elevated AST or ALT over their
baseline. On the other hand, none of five patients in the RIF
group had elevations in liver enzyme above baseline. This is
summarized in Table 2. Patient 5 had AST elevation twice
baseline with no corresponding ALT elevation at treatment
month 8. Patient 8 had AST elevations less than three times
the baseline at treatment months 3 and 7 without corresponding ALT elevations. Both patients transaminase elevations were asymptomatic, spontaneously resolved despite
continued INH, and were presumptively attributed to natural
fluctuation of ongoing liver inflammation, laboratory variance, or transient INH induced hepatotoxicity. Patient 2 had
asymptomatic, mild elevations of both AST and ALT to less
than two times the baseline that peaked at the treatment
month 8. At this time, the patient was diagnosed with schizo-

TABLE 1. Demographic and baseline hepatic function parameters for the 14 liver transplant candidates
Patient

Age

Sex

Treatment

Underlying
disease

MELD

Child-Pugh score
(class)

Total bilirubin
(mg/dL)

INR

1
2
3
4
5
6
7
8
9
10
11
12
13
14

42
59
40
54
42
68
51
41
45
67
62
64
52
59

F
M
M
F
M
M
M
F
M
M
M
F
F
M

INH
INH
INH
INH
INH
INH
INH
INH
INH
RIF
RIF
RIF
RIF
RIF

HCV
HCV
HCV
HCV
HBV
HBV
HCV
HCV
Cryptogenic
HBV
Alcoholism
HCV
PBC
HCV

18
13
23
6
15
11
8
20
23
9
15
8
6
13

8 (B)
6 (A)
6 (A)
6 (A)
5 (A)
5 (A)
6 (A)
7 (B)
10 (C)
5 (A)
6 (A)
5 (A)
6 (A)
5 (A)

1.8
1.9
0.8
0.5
0.7
1.3
1.2
0.6
4.9
1.0
1.1
0.8
1.4
1.8

2.1
1.4
1.3
1.0
1.1
1.2
1.0
1.0
2.0
1.1
1.1
1.1
0.9
1.5

HBV, hepatitis virus B; HCV, hepatitis virus C; INH, isoniazid; INR, international normalized ratio for prothrombin time; MELD, Model of End-stage Liver
Disease score; PBC, primary biliary cirrhosis; RIF, rifampin.

Jahng et al.

2007 Lippincott Williams & Wilkins

1559

TABLE 2. Summary of AST and ALT levels during treatment and categorization
Patient

Treatment

Mean baseline
AST (IU/L)

Mean baseline
ALT (IU/L)

Peak treatment
AST (IU/L)

Peak treatment
ALT (IU/L)

Month onset at
transaminase elevation

1
2
3
4
5
6
7
8
9
10
11
12
13
14

INH
INH
INH
INH
INH
INH
INH
INH
INH
RIF
RIF
RIF
RIF
RIF

116
124
23
55
41
44
47
38
35
32
40
33
128
42

95
94
19
81
48
46
47
28
24
35
28
37
97
47

145
207
25
60
92
162
49
91
47
29
38
45
163
49

104
131
18
71
73
254
53
57
33
27
17
55
108
56

NA
7
NA
NA
8
6
NA
7
NA
NA
NA
NA
NA
NA

ALT, alanine aminotransferase; AST, aspartate amino transferse; INH, isoniazid; NA, not applicable/no significant elevation over baseline; RIF, rifampin.

phrenia and professed to covert daily alcohol use. INH was

discontinued at this time because of concurrent alcohol
abuse, and because the patient was no longer a transplant
candidate. Patient 6 had asymptomatic AST and ALT elevations greater than three times the baseline with onset at treatment month 6. This was correlated linearly over time with a
marked increase in HBV viral load. INH was discontinued 8.5
months into treatment due to concerns about continued use
in the face of concurrent transaminase elevation. His
transaminase elevations subsequently remained elevated until antiviral therapy directed against HBV was adjusted and
his viral load subsequently declined. In summary, only two of
the nine patients receiving INH had transaminase elevation
which could be attributed to INH alone. In both cases this was
transient and mild, and in neither case was treatment of latent
tuberculosis discontinued.
In the INH group, patient 3 suffered mild and transient
right upper quadrant abdominal pain, although without concurrent elevations in AST or ALT. None of the patients in the RIF
group developed symptoms. Compliance per patient selfreporting was 100% in both groups. Patient 3 discontinued
treatment of latent tuberculosis after 1 month, not understanding that 9 months of treatment was necessary. This patient subsequently reinitiated treatment of latent tuberculosis and
completed 9 months in an uninterrupted fashion. Completion
rate was 78% in the INH group, but as mentioned above, discontinuation was always for reasons unrelated to the INH itself.
Completion rate was 100% in the RIF group. Although completion of treatment of latent infection was not required for transplantation, all of the enrolled patients did complete their therapy
before transplantation. None of the patients suffered fulminant
hepatic failure or death secondary to INH or RIF, and all the
patients are free from active TB to date.

DISCUSSION
Current guidelines recommend treatment of latent tuberculosis for all patients with latent tuberculosis infection (7,
8). Nine months of INH is the therapy of choice for treatment

of latent tuberculosis, and has been demonstrated to reduce

the incidence of active infection in compliant, immunocompetent patients by as much as 90% (8, 11). RIF is used as an
alternative agent when organism resistance or patient intolerance to INH is suspected, and its recommendation is based
largely on a single clinical trial carried out in silicosis patients.
In this study, the efficacy of three months of RIF in preventing
active TB was 63% (7, 8, 12, 13).
For transplant patients treatment of latent tuberculosis
is recommended based on the observation that there is higher
incidence of active TB than in the general population, and
that reactivation of latent tuberculosis infection is the most
common route to an active infection (1 6). In the liver transplant patients, the safety of treatment of latent tuberculosis is
questioned secondary to inherent hepatotoxicity present in
both INH and RIF. The frequency of treatment of latent
tuberculosis-related hepatotoxicity in the patients with either
end-stage liver disease or liver transplantation has not been
studied in large clinical trials. In the general population, mild,
transient transaminase elevation during treatment with INH
occurs in 10% to 20% of patients (usually 100 IU/L). Half
or more of these cases are observed within the first two
months of therapy (14,15). Severe hepatotoxicity is observed
in only one to three cases per one thousand, sometimes leading
to fulminant hepatic failure that requires liver transplantation
(16 19). The risk factors for INH hepatotoxicity are age, sex,
concurrent liver disease, diabetes, alcohol use, intravenous drug
use, and the use of substances that are either hepatotoxic or are
inducers of cytochrome P450 (8, 18 27). The frequency of hepatotoxicity with RIF as monotherapy appears to be less than that
of INH in the general population (28, 29). On the other hand, the
risk of hepatotoxicity can be dramatic when RIF is coupled with
other hepatotoxic drugs such as pyrazinamide (PZA); the PZARIF combination for treatment of latent tuberculosis was withdrawn from the CDC recommendations secondary to increased
mortality (30).
There are three general approaches to latent tuberculosis infection in the liver transplant candidate which vary be-

1560
tween individual transplant centers. Treatment of latent
tuberculosis may be given during the candidacy period or
after the transplantation. Alternatively, treatment of latent
tuberculosis may be forgone in favor of active surveillance
and treatment of incident TB as necessary.
Currently, treatment of latent tuberculosis is most
commonly utilized posttransplant. The advantage of posttransplant treatment is that the exposure of the failing liver to
hepatotoxic drugs is avoided. On the other hand, posttransplant treatment of latent tuberculosis exposes the newly
transplanted liver to drugs that are hepatotoxic. In the posttransplant scenario, it becomes very difficult to distinguish
drug-induced hepatotoxicity from other common entities
such as acute rejection and opportunistic infections. Thus
concerns about rejection or infection may lead to frequent
biopsies in cases of simple drug-induced hepatotoxicity, and
concerns about hepatotoxicity may lead to frequent discontinuation of treatment of latent tuberculosis in cases of rejection or infection. In the posttransplant scenario, there is
potential for drug interactions that may lead directly to acute
organ rejection. RIF, and to lesser degree INH, increase the
metabolism of antirejection medications such as cyclosporine, tacrolimus, and corticosteroids via the induction of cytochrome P450 pathway (3, 31, 32).
Only two studies have evaluated the safety of posttransplant treatment of latent tuberculosis. In a study by Schluger
et al., three of the six patients who received INH alone developed mild, transient transaminase elevations, and were all
correlated to acute rejection or HCV (33). Benito et al.
showed that 48% (11 of 24) of the patients taking INH demonstrated liver dysfunction as assessed by transaminase elevation and/or liver biopsy (34). Seven cases were related to
acute rejection or hepatitis virus, and in two of these patients
INH had to be discontinued prematurely.
Some transplant centers avoid treatment of latent tuberculosis entirely and opt for surveillance of active tuberculosis.
Since most liver transplant patients with latent tuberculosis
infection will not develop active TB this avoids unnecessary exposure to potentially hepatotoxic agents. Unfortunately, the
mortality rate of active TB in transplant patients ranges from
21% to 33% in the published studies (1, 3, 33) This is coupled to
higher incidence of conversion of latent to active infection when
compared to immunocompetent patients (1 6). Conventional
treatment of active TB infection employs a multi-drugregiment
with INH, RIF and PZA, all which have varying potentials to
cause hepatotoxicity and drug interactions thus raising issues
more complex than those mentioned above in posttransplant
treatment of latent tuberculosis (35).
There appears to be a higher incidence of hepatotoxicity with conventional therapy of active TB in the liver transplant recipients than in the general population. Use of
multi-drug TB therapy after transplantation has also been
associated with allograft rejection. Meyer et al. reported that
100% (six of six) of liver transplant patients undergoing treatment of active TB with conventional drug regimen developed
hepatotoxicity, with 50% demonstrating acute rejection (36).
In a study by Aguado et al., 50% (12 of 24) of liver transplant
patients treated with a multi-drug regimen for active TB developed hepatotoxicity, with half of them being severe (1).
Although not limited to liver patients, the authors went on
further to demonstrate that the majority of organ rejection

Transplantation Volume 83, Number 12, June 27, 2007

cases were secondary to interaction between RIF and cyclosporin. Schluger et al. demonstrated 100% (five of five) hepatotoxicity in liver transplant patients when treated with
combination of RIF and INH. Three cases were associated
with HCV reinfection or acute rejection (37). Higgins et al.
demonstrated 40% (two of five) hepatotoxicity with conventional therapy (38). Singh et al. in a literature review showed
liver dysfunction requiring discontinuation of treatment with
conventional regiment for active TB occurred in 41% of patients, many of them associated with cofactors such as acute
rejection (3).
Because of the issues mentioned above, when treating
active TB in the posttransplant scenario, some authors
advocate the complete replacement of first-line TB drugs with
second-line agents such as fluoroquinolones or ethambutol,
while other authors recommend continuation of INH as the
main back bone of therapy with the addition of the secondline drugs (10, 36). Meyers et al. have shown that continued
therapy with ethambutol and fluoroquinolones is effective in
liver transplant patients who show hepatotoxicity to the conventional drug regimen (36). Similarly, in those patients who
are transplanted secondary to fulminant hepatic failure from
either conventional therapy or treatment of latent tuberculosis, successful continuation of treatment with second-line TB
drugs has been reported (16, 17, 39, 40). It must be noted that
the efficacy of second-line regiments is yet to be proven in
large scale clinical trials, and as mentioned previously, even
first-line agent therapy for active TB on the posttransplant
scenario is associated with high morbidity.
Pretransplant treatment of latent tuberculosis during
the candidacy period avoids many of the issues associated
with posttransplant treatments. Issues of acute rejection and
drug interactions are replaced by concern of burdening the
end-stage liver. In the only other study of treatment of latent
tuberculosis during the candidacy period, Singh et al. demonstrated that none of the 18 patients had hepatotoxicity to
INH. All patients were able to complete therapy without adverse events (41).
Our study adds to the previous work done by Singh et
al. with a unique observation in regards to the role of RIF in
treatment of latent tuberculosis. In this current study, the
observed 22% (two of nine) incidence of mild liver dysfunction attributed to INH alone compares favorably with the
general population incidence. Two patients had to be discontinued from INH, but the events were primarily related to
issues other than INH. No patients developed fulminant liver
failure or death. This low rate of INH-induced hepatotoxicity
occurs despite the fact that our study patients display multiple
risk factors for drug induced hepatotoxicity, including the
burden of chronic liver disease and age. Particular to our
present study, 79% (11 of 14) of the patients had either HCV
or HBV, and no HBV patient had E antigen reactivity. It is
notable that recent data involving patients with HBV (E antigen negative) or HCV with latent tuberculosis infection
showed that the incidence of hepatoxicity to INH was not
different from the general population (42 44).
Our results differ slightly from the study by Singh et al.
who noted no transaminase elevations during treatment of
latent tuberculosis with INH (41), and this is accounted for by
different methodologies utilized in each study. Singh et al.
only monitored ALT, whereas the present study also included

Jahng et al.

2007 Lippincott Williams & Wilkins

AST. Using ALT elevation alone as an indicator of hepatotoxicity, we would have noted no cases of transaminase elevation.
It is interesting to note that none of the patients in the
RIF group showed transaminase elevations. This appears to
correlate with fact that monotherapy with RIF appears to be
less hepatotoxic than with INH in the general population
(28, 29). This observation is severely limited by the small
numbers in our study. The apparent lack of hepatotoxicity associated with RIF may be a biased observation due to its shorter
duration of use in treatment of latent tuberculosis. Despite the
evidence that most transaminase elevations occur within the first
2 months with INH, three of four patients in our study had
elevations that occurred after 5 months into treatment.
Limitations in our study exist. This was an uncontrolled trial with small number of cases. No biopsy was
undertaken in any of the patients with enzyme elevation. Natural fluctuations of liver enzymes in the patients with endstage liver disease may bias both the baseline calculations and
the treatment levels. Compliance to medication was measured per patient reporting, and was not assessed by more
objective measures. In addition, as mentioned in the study
design, despite the fact that all of these patients were candidates for liver transplantation, all of them were medically
stable with a relatively low MELD score. This was not an accidental bias as decompensated patients were purposefully
excluded. Such patients would be difficult to treat with INH
as any fluctuation in clinical or laboratory parameters could
potentially lead one to conclude INH-induced hepatotoxicity. Thus our study can only be generalized to relatively compensated cirrhotics preparing for transplantation.
The authors also feel it is important to disclose that our
institution lost accreditation for liver transplantation near the
end of the study period. When the liver transplant program
ceased to exist at our institution, we stopped enrolling new
patients. Patients already enrolled in the study were referred
to other nearby programs and given the choice to complete
treatment of latent infection or to stop treatment of latent
infection. The only two patients who had not finished treatment of latent infection at the time chose to continue the
course of therapy to its completion.
Despite these study limitations we feel it is important to
emphasize that 85% (12 of 14) of the patients in both the INH
and RIF groups completed treatment, and that the two patients who had to stop treatment of latent tuberculosis had
complications of existing liver disease likely unrelated to
INH. Our current study strengthens Singhs observation that
treatment of latent tuberculosis in the end-stage liver disease
patients under consideration for liver transplantation is a reasonable approach associated with good rates of completion
and low rates of significant drug-related adverse events. In
comparison to treatment of latent tuberculosis posttransplant or surveillance and treatment of active TB posttransplant, this approach offers many advantages.
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