Clin Chest Med 26 (2005) 313 – 326

Treatment of Latent Tuberculosis Infection: Challenges

and Prospects
Kelly E. Dooley, MD, MPHa, Timothy R. Sterling, MDb,*
a
Department of Medicine, Providence Portland Medical Center, 4805 NE Glissan Street, Portland, OR 97213, USA
b
Division of Infectious Diseases, Department of Medicine and Center for Health Services Research,
Vanderbilt University Medical Center, A4103 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA

It is estimated that one third of the global popu-
lation, or 2 billion people, are infected with Myco-
bacterium tuberculosis [1]. Among infected persons,
approximately 10% progress to the clinically im-
portant (and infectious) stage of active tuberculosis
over their lifetime [2,3]. The risk is higher in persons
with concomitant HIV infection (>20%), evidence of
old healed tuberculosis on chest radiograph (>20%),
or recent M. tuberculosis infection (10% to 20%) [4].
In most infected persons, the host immune response
contains the replication of M. tuberculosis and pre-
vents the development of disease [5]. Among infected
persons who develop active disease, progression
occurs either shortly after initial infection (progres-
sive primary disease) or subsequent to the initial
infection, when there is a breakdown in the host im-
mune response. A person is at greatest risk of pro-
gressing to active disease during the first 2 years
after infection with M. tuberculosis [2]. In addition
to HIV infection and recent M. tuberculosis infec-
tion, other risk factors for progression to active tu-
berculosis include silicosis, diabetes mellitus, chronic
renal failure, malnutrition, weight loss, leukemia, lym-
phoma, cancer of the head, neck, and lung, gastrec-
tomy, and jejunoileal bypass surgery [6].
Diagnosis of latent Mycobacterium tuberculosis
infection
As discussed elsewhere in this issue, the diagno-
sis of latent M. tuberculosis infection relies primarily
on the tuberculin skin test, an intradermal test that
utilizes purified protein derivative (PPD). Because
the mycobacterial proteins in PPD are not specific for
M. tuberculosis, persons infected with other myco-
bacteria (eg, environmental mycobacteria such as
M. avium intracellulare and M. bovis, the organism
in the tuberculosis vaccine bacille Calmette-Guerin)
may result in a false-positive test. Conversely, the
tuberculin skin test has low sensitivity, particularly
in immunocompromised persons. Because of these
limitations, the definition of a positive tuberculin
skin test varies according to the person’s risk of
tuberculosis infection and risk of progressing to
active disease if infected (Box 1) [6]. The different
criteria for a positive test increase its sensitivity in
high-risk persons and specificity in low-risk persons.
Indications for treatment of Mycobacterium
tuberculosis infection

All persons with evidence of latent M. tuber-

This work was supported by the National Institutes of
Allergy and Infectious Diseases K23 AI01654 (TRS).
* Corresponding author.
E-mail address: timothy.sterling@vanderbilt.edu
(T.R. Sterling).
culosis infection should be evaluated for the presence
of active disease. The evaluation should include an
assessment of the signs and symptoms of tuberculo-
sis and a chest radiograph; in persons with symptoms
or an abnormal chest radiograph, sputum for acid-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccm.2005.02.003 chestmed.theclinics.com
314 dooley
Box 1. Criteria for a positive tuberculin
skin test based on millimeters of
induration after intradermal placement of
five tuberculin units of purified protein
derivative (Mantoux technique)
5 mm induration
 HIV seropositive
 Recent contact with a culture-
confirmed tuberculosis case
 Fibrotic changes on chest
radiograph consistent with prior
tuberculosis
 Chronic immunosuppression (eg,
prednisone 15 mg/day for at
least 30 days)
10 mm induration
 Immigration from a high-
prevalence country within the last
5 years
 Injection drug use
 Residents and employees of high-
risk settings: prisons, jails, nursing
homes, and other long-term care
facilities, hospitals, residential
facilities for AIDS patients, home-
less shelters
 Mycobacteriology laboratory
personnel
 Persons at increased risk of devel-
oping active tuberculosis: those
with silicosis, diabetes mellitus,
chronic renal failure, leukemia, lym-
phoma, cancer of the head, neck or
lung, weight loss of more than
10% of ideal body weight, gas-
trectomy, jejunoileal bypass
 Children younger than 4 years old
15 mm induration
 Persons with no risk factors for
tuberculosis
From American Thoracic Society; Centers
for Disease Control and Prevention. Tar-
geted tuberculin testing and treatment
of latent tuberculosis infection. Am J
Respir Crit Care Med 2000;161(4):S234;
with permission.
& sterling
fast smear and culture should also be obtained.
Once active disease has been excluded, all persons
at increased risk of progressing to active tuberculo-
sis (see Box 1) should receive treatment for la-
tent infection.
Importance of treatment of Mycobacterium
tuberculosis infection to decrease the global
tuberculosis burden
Most cases of active tuberculosis arise from per-
sons with latent M. tuberculosis infection; treatment
of such persons is therefore necessary to achieve tu-
berculosis elimination. The focus should be on those
persons at high risk of progressing to active disease.
The strategy of targeted tuberculin skin testing among
high-risk groups and treatment of all such persons
with a positive tuberculin skin test is recommended
in the United States [6,7].
Infection with M. tuberculosis is often termed
latent because of the absence of clinical manifes-
tations, the slower replication rate of M. tuberculosis,
and the lower burden of organisms compared with
active disease [8]. Because of the relatively low
burden of organisms, treatment of latent infection
requires fewer drugs than active disease to facilitate
cure and prevent the development of drug resistance.
Use of a single antituberculosis agent is sufficient
for latent infection but not for active disease. As de-
tailed later, treatment of latent M. tuberculosis in-
fection dramatically decreases the risk of developing
active tuberculosis.
Regimens to treat Mycobacterium tuberculosis
infection
Each of the regimens available to treat latent
M. tuberculosis infection is reviewed here, with
emphasis on both the effectiveness and toxicity of
the regimens. The review is limited to studies con-
ducted in adults and published in the English peer-
reviewed literature; studies reported only in abstract
form are not included. The authors are unaware of
studies of the effectiveness of short-course therapy
conducted among children. Because the risk of
active tuberculosis is substantially higher in HIV-
seropositive persons than in HIV-seronegative per-
sons, and because the effectiveness of many regimens
has been assessed separately according to HIV sero-
status, the data are presented separately for HIV-
seropositive and HIV-seronegative persons. Toxicity
of therapy may also differ according to HIV sero-
Table 1
Randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among HIV-seronegative persons
Active TB Reduction
First author/date [reference] Randomization unit Population Follow-up Regimen n/N (%) (%)
United States Public Health Service trials
Mount, 1962 [67] Family Contacts of known active cases 4 years INH 5 mg/kg/d for 1 year 6/1463 (0.41) 54

treatment of latent tuberculosis infection

PPD+ and Placebo 12/1351 (0.89)
Ferebee, 1962 [17] Family Household contacts of new active TB 3 years INH 5 mg/kg/d for 1 year 29/12439 (0.23) 70
39 US communities, PPD+ and Placebo 97/12594 (0.77)
Ferebee, 1963 [68] Ward Mental institutions 5 years INH 5 mg/kg/d for 1 year 35/12884 (0.27) 62
PPD+ and Placebo 89/12326 (0.72)
Comstock, 1967 [69] Household Alaskan Eskimos in Bethel area 6 years INH 5 mg/kg/d for 1 year 58/3047 (1.9) 59
Most not PPD tested Placebo 141/3017 (4.67)
International trials
Chiba, 1963 [70] Household Osaka, Japan 2 years INH 5 mg/kg/d for 1 year 8/1142 (0.7) 30
Household contacts of new active TB 11/1096 (1.0)
Nyboe, 1963 [71] City blocks Suburb of Tunis City 1 year INH (very erratic pill taking) 18/7769 (0.23) 25
Placebo 25/8141 (0.31)
Egsmose, 1965 [72] Household Rural northern Kenya 4 years INH 5 – 10 mg/kg/d for 1 year (1.04) 35
PPD+ contacts of new active cases Placebo (1.6)
DelCastillo, 1965 [73] Household Philippines 2 years INH 8/97 (8.2) 41
Contacts of active cavitary TB Placebo 18/129 (14.0)
Horwitz, 1966 [74] Village Greenland villagers 6 years INH 400 mg 2 /wk for total 52 doses 238/4174 (5.7) 31
Placebo 323/3907 (8.3)
Veening, 1968 [75] Individual Royal Netherlands Navy 4 years INH 600 mg  4 mo, 400 mg  8 mo 2/133 (0.38) 96
New PPD+ after exposure to index case Placebo 12/128 (9.4)
IUAT, 1982 [9] Individual 7 European countries 5 years INH 300 mg/d for 12 weeks 76/6956 (1.1) 21
PPD+ patients with fibrotic lesions INH 300 mg/d for 24 weeks 34/6965 (0.49) 65
INH 300 mg/d for 52 weeks 24/6919 (0.35) 75
Placebo 97/6990 (1.4)
Abbreviations: INH, isoniazid; IUAT, International Union Against Tuberculosis; PPD, purified protein derivative; TB, tuberculosis.

315
316 dooley
status, so tolerability data are also presented accord-
ing to HIV serostatus. Recommended doses of
specific drugs have been published previously [6].
Isoniazid
Effectiveness
HIV-seronegative persons
Isoniazid is the best-studied regimen for the
treatment of latent M. tuberculosis infection. More
than 20 randomized, controlled trials have been con-
ducted, which together enrolled more than 100,000
persons. Most of these studies were conducted in the
1950s and 1960s and therefore enrolled only HIV-
seronegative persons. These trials are summarized
in Table 1.
Most of the studies assessed the effectiveness
of 12 months of isoniazid versus placebo. The trial
conducted by the International Union Against Tuber-
culosis (IUAT) assessed 3 versus 6 versus 12 months
of therapy and found that 6 months of isoniazid
was less effective (65%) than 12 months (75%) [9].
George Comstock [10] subsequently performed an
analysis of previously conducted clinical trials and
found that 6 months of isoniazid provided insuffi-
cient protection; 9 to 10 months of isoniazid seemed
to provide optimal protection. Based on these find-
ings, the American Thoracic Society (ATS), Centers
for Disease Control and Prevention (CDC), and In-
fectious Diseases Society of America (IDSA) guide-
lines recommend 9 months of isoniazid [6]. A
9-month regimen of isoniazid has never been com-
pared with a 6- or 12-month course of isoniazid in a
clinical trial, however.
HIV-seropositive persons
Isoniazid effectiveness has also been studied in
HIV-seropositive persons, although not as extensively
as in HIV-seronegative persons. The randomized,
controlled trials of treatment of latent M. tuberculo-
sis infection in HIV-infected persons are summarized
in Table 2, and the randomized, placebo-controlled
trials of isoniazid are summarized in Table 3. Among
tuberculin skin-test – positive persons, isoniazid is
clearly more effective than placebo in preventing tu-
berculosis; this finding has been confirmed in a meta-
analysis [11]. Isoniazid has been associated with
improved survival in some studies [12 – 14], but not
in all [11,15,16]. Although there has not been a
direct comparison of 6 versus 9 versus 12 months
of isoniazid, 6 months seems to be less effective
than 12 months. Based on the rationale used for
& sterling
HIV-seronegative persons, and to ensure uniformity
of recommendations, the ATS/CDC/IDSA guide-
lines recommend 9 months of isoniazid for HIV-
seropositive persons [6]. Although HIV-infected
persons are at increased risk of having a negative
tuberculin skin test, particularly with advanced im-
munosuppression, isoniazid is not substantially more
effective than placebo in preventing tuberculosis
in such persons, and therefore is not recommended
(Table 3) [11].
Toxicity
HIV-seronegative persons
In the initial studies of isoniazid, drug discon-
tinuation rates were low and did not differ from rates
among persons receiving placebo [17]. Subsequent
studies, however, have noted higher rates of drug
discontinuation, as summarized in Tables 4 and 5.
Few of these studies have been placebo-controlled.
Isoniazid can cause elevated hepatic transaminases
[18], but these liver function abnormalities are often
transient and are not representative of clinically
significant hepatitis. In studies in which serum trans-
aminases were monitored regularly regardless of
symptoms, 10% to 22% of participants had at least
one elevated transaminase level during the course
of therapy [19 – 25]. Rates of clinically significant
hepatitis are lower. In a surveillance study of the US
Public Health Service, 236 of 13,838 persons (1.7%)
who received isoniazid developed hepatitis. When
considering only those persons in whom the hepatitis
was probably or possibly related to isoniazid, the rate
was 174 in 13,838 (1.3%) [26]. Hepatitis risk
increased with age and concomitant alcohol con-
sumption. In another study, a 7-year survey from one
public health clinic, 11 of 11,141 patients (0.10%)
who started isoniazid developed hepatotoxicity [27].
Isoniazid-associated hepatotoxicity can be fatal,
and the risk of death increases with age. It is
estimated that the hepatotoxicity-associated case-
fatality rate per 10,000 persons initiating isoniazid
treatment is 0 for ages 20 to 34 years, 2 for ages 35 to
49 years, and 4 for ages 50 to 64 years [24,26,28,29].
Although never tested in a trial, rates of hepato-
toxicity may be lower when there is regular monitor-
ing of signs and symptoms of hepatitis [27,28]. In
the United States it is currently recommended that
patients receiving isoniazid undergo monthly clinical
assessments for adverse effects. They should also be
evaluated whenever symptoms develop. Patients
should be educated regarding the signs and symptoms
of hepatotoxicity and instructed to discontinue the
medicine and seek clinical evaluation if symptoms
Table 2
Randomized, controlled trials of treatment of latent Mycobacterium tuberculosis infection among HIV-seropositive persons
Mean
First author/date [reference] Trial type Population Regimens N follow-up Compliance/follow-up
INH versus placebo trials
Pape, 1993 [12] Randomized Haiti INH 300 mg/d for 12 months 118 33 months No loss to follow-up
Double-blind New HIV
Placebo-controlled diagnosis

treatment of latent tuberculosis infection

PPD+ or
Hawken, 1997 [76] Block-randomized Kenya INH 300 mg/d for 6 months 684 20 months 70% follow-up
Double-blind PPD+ or
Placebo-controlled
Gordin, 1997 [77] Randomized US, mostly NYC INH 300 mg/d for 6 months 517 33 months 63% completed therapy; 6% INH
Double-blind Anergic patients and 7% placebo lost to follow-up
Placebo-controlled
Fitzgerald, 2001 [78] Randomized Haiti INH 300 mg/d for 12 months 237 2.5 years 77% followed to death or
Blinding unclear PPD study end
Placebo-controlled
Multiregimen trials
Whalen, 1997 [15] Block-randomized Uganda PPD+: INH 300 mg/d for 6 months or 2018 15 months 75% urine tests and 80% – 89%
Double-blind (1) PPD+ INH 300 mg/d and RIF 600 mg/d for completed the trials
Placebo-controlled 3 months or INH 300 mg/d, RIF 600 mg/d,
and PZA 2000 mg/d for 3 months
(2) Anergic Anergic: INH 300 mg/d for 6 months 718
Mwinga, 1998 [41] Block-randomized Zambia INH 900 mg 2 /wk for 6 months or RIF 1053 1.8 years 81% placebo, 66% INH, and 75%
Double-blind 600 mg and PZA 3500 mg 2 /wk for RIF/PZA were >80% compliant
Placebo-controlled 3 months
Gordin, 2000 [36] Randomized US, Mexico, INH 300 mg/d for 12 months or RIF 600 mg 1583 37 months 80% RIF/PZA and 69% INH
Open-label Haiti, Brazil and PZA 20 mg/kg/d for 2 months completed therapy
No placebo arm PPD+
Halsey, 1998 [40] Randomized Haiti INH 600 – 800 mg 2 /wk for 6 months or 750 2.5 years 55% INH and 74% RIF/PZA had
Unmasked PPD+ RIF 450 – 600 mg and PZA 1500 – 2000 mg >80% compliance
Partly supervised 2 /wk for 2 months (weight-based)
No placebo arm
Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin.

317
318 dooley & sterling

Table 3
Results of randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among
HIV-seropositive persons
Rx n/N Control n/N 95% Confidence
First author/date [reference] (%) INH (%) placebo RR interval Reduction (%)
PPD positive
Pape, 1993 [12] 2/38 (5.2) 6/25 (24.0) 0.22 0.05, 1.00 78
Hawken, 1997 [76] 5/67 (7.5) 8/69 (11.6) 0.64 0.22, 1.87 36
Whalen, 1997 [15] 7/536 (1.3) 21/464 (4.5) 0.29 0.12, 0.67 71
PPD+ cohort
Mwinga, 1998 [41] 6/101 (5.9) 11/60 (18.3) 0.32 0.13, 0.83 68
PPD negative
Gordin, 1997 [77] 4/260 (1.5) 6/257 (2.3) 0.66 0.19, 2.31 34
Fitzgerald, 2001 [78] 6/126 (4.8) 4/111 (3.6) 1.32 0.38, 4.56 32
Hawken, 1997 [76] 11/235 (4.7) 8/224 (3.6) 1.31 0.54, 3.20 31
Pape, 1993 [12] 2/20 (10.0) 5/35 (14.3) 0.70 0.15, 3.28 30
Whalen, 1997 [15] 9/395 (2.3) 10/323 (3.1) 0.74 0.30, 1.79 26
anergic cohort
Mwinga, 1998 [41] 27/351 (7.7) 17/166 (10.2) 0.75 0.42, 1.34 25
Results are presented according to the tuberculin skin test status of study patients.
Abbreviations: INH, isoniazid; PPD, purified protein derivative; RR, relative risk.

occur. Routine laboratory monitoring is recommended Hepatitis C virus and isoniazid-associated

for persons with abnormal baseline liver function hepatotoxicity
tests, persons at increased risk of hepatotoxicity Hepatitis C virus (HCV) infection has been as-
(eg, HIV infection, liver disease, alcoholism, preg- sociated with an increased risk of hepatotoxicity
nancy), and persons who develop symptoms while among persons receiving combination antitubercu-
on therapy. [6] losis therapy for active disease, particularly HIV-
Isoniazid can also cause peripheral neuropathy, infected persons [32]. HCV infection is common in
but the risk is lower with concomitant use of vitamin injection drug users [33], who are also at high risk of
B6 (pyridoxine) [30,31]. progressing to active tuberculosis if latently infected
with M. tuberculosis. Two studies have assessed the
HIV-seropositive persons risk of isoniazid-associated hepatotoxicity in per-
The rates of isoniazid-associated toxicity requir- sons with underlying HCV. In a study of 146 injec-
ing drug discontinuation in HIV-seropositive per- tion drug users with M. tuberculosis infection and
sons are summarized in Table 5. Although the data normal baseline hepatic transaminases, 138 were
are not as extensive as in HIV-seronegative per- HCV seropositive; 32 (22%) developed hepatic trans-
sons, isoniazid is generally well tolerated in this pa- aminases levels more than three times the upper
tient population. limit of normal, and 11 (8%) required drug discon-
tinuation [34]. These rates are comparable to those
Table 4 reported in populations with lower HCV seropreva-
Toxicity of isoniazid for treatment of latent Mycobacterium lence (see preceding discussion and Table 5). In a
tuberculosis infection in HIV-seronegative patients second study of 415 drug users, of the 214 that
Toxicity requiring discontinuation were HCV-antibody – positive, 16 (7.5%) developed
First author/date of therapy hepatotoxicity (defined as drug discontinuation in
[reference] INH n/N (%) Placebo n/N (%) the setting of hepatic transaminase elevation more
than five times the upper limit of normal in the
Scharer, 1969 [18] 2/90 (2.2) No placebo arm
Byrd, 1972 [22] 16/160 (10) No placebo arm presence of symptoms or as transaminase elevation
Bailey, 1973 [79] 18/427 (7.3) No placebo arm alone on two occasions at least 1 week apart) [35].
Byrd, 1977 [80] 10/120 (8.3) 1/60 (1.7) On multivariate analysis, HCV infection was not
Byrd, 1979 [24] 64/1000 (6.4) No placebo arm independently associated with hepatotoxicity. Both
Stuart, 1999 [25] 26/83 (31.3) No placebo arm studies suggest that isoniazid is safe in persons with
Toxicity is defined as adverse events resulting in discon- HCV infection and is not associated with signifi-
tinuation of therapy. cantly higher rates of hepatotoxicity than in persons
Abbreviation: INH, isoniazid. without HCV.
 treatment of latent tuberculosis infection 319

Table 5
Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients
Toxicity requiring discontinuation of therapy 95% Confidence
First author/date [reference] INH n/N (%) Placebo n/N (%) RR interval
Pape, 1993 [12] 0/58(0) 0/60 (0) 0
Gordin, 1997 [77] 24/260 (9.2) 24/257 (9.3) 0.99 0.58, 1.69
Hawken, 1997 [76] 11/342 (3.2) 5/342 (1.5) 2.2 0.77, 6.26
Whalen, 1997 [15] PPD+ 3/536 (0.6) 1/464 (0.2) 2.60 0.27, 24.88
Anergic 0/395 0/323 0
Mwinga, 1998 [41] 26/703 (3.7) 3/350 (0.9) 4.31 1.32, 14.16
Toxicity is defined as adverse events resulting in discontinuation of therapy.
Abbreviations: INH, isoniazid; PPD, purified protein derivative; RR, relative risk.

Although the efficacy of isoniazid in preventing HIV-seropositive persons

tuberculosis exceeds 90% among persons who adhere
to therapy [9], the effectiveness of isoniazid is lower
because of low rates of adherence to the long duration
of therapy. This problem of adherence has led to the
assessment of regimens that require a shorter course
of treatment. These regimens are summarized here.
Rifampin plus pyrazinamide for 2 months
Effectiveness
The effectiveness of the 2-month rifampin plus
pyrazinamide regimen has been studied entirely in
HIV-seropositive persons. Because the risk of tuber-
culosis without treatment of latent infection is sub-
stantially higher in HIV-seropositive persons than in
HIV-seronegative persons, much smaller sample sizes
were required to study effectiveness in the former.
The results of the studies are summarized in Table 6.
In the largest of the studies, the effectiveness of daily
rifampin plus pyrazinamide for 2 months was nearly
identical to 12 months of daily isoniazid [36].

Among available short-course regimens for the Toxicity

treatment of latent M. tuberculosis infection, the
regimen with the shortest duration, and therefore
the greatest potential for improved adherence, is the
2-month regimen of rifampin plus pyrazinamide.
HIV-seronegative persons
Effectiveness of rifampin plus pyrazinamide has
not been studied in HIV-seronegative persons.
Because of high rates of hepatotoxicity in tolera-
bility studies (see later discussion), it is unlikely
that effectiveness will ever be studied in HIV-
seronegative persons.
HIV-seronegative persons
After the effectiveness and tolerability of
2 months of rifampin plus pyrazinamide were dem-
onstrated in HIV-seropositive adults, the regimen was
recommended in the United States for both HIV-
seropositive and -seronegative adults [6]. Shortly
thereafter, however, there were reports of severe
hepatotoxicity and death among persons treated with
this regimen [37,38]. When such cases continued to
be reported, the CDC began collecting retrospective
surveillance data on the number of persons treated

Table 6
Randomized, controlled trials of the effectiveness of pyrazinamide plus rifampin for the treatment of latent Mycobacterium
tuberculosis infection in HIV-seropositive persons
Control n/N 95% Confidence
First author/date [reference] Rx n/N (%) RIF/PZA (%) INH RR interval Reduction (%)
PPD positive
Gordin, 2000 [36] 28/791 (3.5) 29/792 (3.7) 0.97 0.58, 1.61 3
Halsey, 1998 [40] 19/380 (5.0) 14/370 (3.8) 1.32 0.67, 2.56 32
Mwinga, 1998 [41] 2/49 (4.1) 4/52 (7.7) 0.53 0.10, 2.77 47
PPD negative
Mwinga, 1998 [41] 13/173 (7.5) 14/178 (7.9) 0.96 0.46, 1.96 4
Results are presented according to the tuberculin skin test status of study patients.
Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin; RR, relative risk.
320 dooley & sterling

Table 7
Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients
Toxicity requiring discontinuation Hepatotoxicity requiring discontinuation
of therapy of therapy
First author/date [reference] RIF/PZA n/N (%) INH n/N (%) RR RIF/PZA n/N (%) INH n/N (%) RR
a
Bock, 2001 [58] 13/168 (7.7) No INH arm 1/168 (0.6) No INH arm
a
Chaisson, 2002 [81] 12/589 (2.0) No INH arm 10/589 (1.7) No INH arm
Jasmer, 2002 [60] 28/307 (9.1) 8/282 (2.8) 3.21 12/207 (5.8) 2/204 (1.0) 5.91
a
Lee, 2002 [82] 26/148 (17.6) No INH arm 11/148(7.4) No INH arm
a
McNeill, 2003 [83] 14/110 (12.7) 5/114 (4.4) 2.90
a
Stout, 2003 [84] 8/114 (7.0) No INH arm 6/114 (5.3) No INH arm
Van Hest, 2004 [85] 14/166 (8.4) 17/528 (3.2) 2.62 14/166 (8.4) 18/528 (3.4) 2.47
Toxicity is defined as adverse events resulting in discontinuation of therapy.
Abbreviations: INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RR, relative risk.
a
In these studies, the patient population was predominantly HIV-seronegative, with a small minority of HIV-
seropositive patients.

with this regimen so that the risk of toxicity could
be determined [39]. Data were collected for persons
initiating therapy between January 2000 and June
2002 and reported to CDC by June 6, 2003. Of the
7737 persons reported to have started rifampin plus
pyrazinamide treatment during the survey period, 204
persons developed aspartate aminotransferase con-
centrations more than five times the upper limit of
normal (2.6/100 treatment initiations), and an addi-
tional 146 patients discontinued therapy because of
symptoms of hepatitis (1.9/100 treatment initiations).
There were 48 cases of severe hepatotoxicity (de-
fined as resulting in hospitalization or death); 11 pa-
tients died. The estimated rate of death caused by
hepatotoxicity was 0.9 per 1000 treatment initiations
[39]. The estimates were limited because data were
obtained retrospectively, and the risk associated with
isoniazid was not determined concurrently. Nonethe-
less, the risk of severe hepatotoxicity and death
seemed to be approximately 10 times greater than
the risk associated with isoniazid, and it was there-
fore recommended that rifampin plus pyrazinamide
should generally not be offered for treatment of
latent tuberculosis infection [39]. The toxicity data
from clinical trials are summarized in Table 7.
HIV-seropositive persons
The regimen was very well tolerated in all of the
clinical trials conducted among HIV-seropositive
persons (Table 8) [36,40,41], even upon repeat analy-
sis specifically addressing hepatotoxicity [42]. Be-
cause of the relatively small sample sizes of the
studies, and an event rate of severe hepatotoxicity of
approximately 1 per 1000, it is possible that such
serious events were not detected in these studies. The
CDC therefore recommends that rifampin plus
pyrazinamide should generally not be offered, regard-
less of HIV serostatus [39].
Isoniazid plus rifampin for 3 months
Effectiveness
There are few studies of isoniazid plus rifampin
for the treatment of latent M. tuberculosis infection.
In the only study among HIV-seronegative adults,
the efficacy among adherent patients of 3 months of
isoniazid plus rifampin was 41% [43]. Among HIV-
seropositive adults, the regimen was 59% effective in

Table 8
Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients
Toxicity leading to discontinuation of therapy 95% Confidence
First author/date [reference] RIF/PZA n/N (%) INH n/N (%) RR interval
Halsey, 1998 [40] 0/380 (0) 0/370 (0)
Mwinga, 1998 [41] 14/351 (4.0) 12/352 (3.4) 1.17 0.55, 2.50
Gordin, 2000 [36,42] 75/791 (9.5) 48/792 (6.1) 1.56 1.09, 2.22
Narita, 2003 [86] 5/135 (3.7) 0/25 (0)
Toxicity is defined as adverse events resulting in discontinuation of therapy.
Abbreviations: INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RR, relative risk.
 treatment of latent tuberculosis infection
preventing tuberculosis [15]. Extensive programmatic
experience with the regimen among children in Great
Britain suggests its effectiveness, but there are no
clinical trial data [44]. In the United States, this
regimen is not among the recommended treatment
regimens, perhaps because of the limited available
data [6].
Toxicity
The regimen has been well tolerated, although
relatively few studies have been conducted to date.
In the study among HIV-seronegative adults, 8 of
167 persons (5%) discontinued therapy because of
adverse drug reaction [43]; the rate among HIV-
seropositive adults was 13 of 556 (2.3%) [15]. In a
pooled analysis of 6105 persons who received iso-
niazid plus rifampin, 156 (2.5%) developed hepati-
tis [45].
Rifampin for 4 months
Effectiveness
Among persons who are intolerant of isoniazid,
or among close contacts of tuberculosis cases in
which the isolate of M. tuberculosis is resistant to
isoniazid, rifampin can be used to treat latent
M. tuberculosis infection. There are, however, only
limited data from randomized clinical trials and
uncontrolled observational studies regarding the
effectiveness and tolerability of the regimen. Given
the importance of rifampin in the treatment of ac-
tive tuberculosis, it is particularly important to
exclude active disease before treating for latent
M. tuberculosis infection, because treatment of un-
diagnosed active tuberculosis with rifampin mono-
therapy will lead to rifampin resistance.
HIV-seronegative persons
The only randomized trial to evaluate the effec-
tiveness of rifampin was conducted in Hong Kong
among persons with latent M. tuberculosis infection
and silicosis. Among all persons initiating therapy,
20 of 165 (12.1%) randomly assigned to receive
rifampin for 3 months developed tuberculosis, com-
pared with 36 of 159 persons (22.6%) who received
placebo, for an effectiveness of 46% [43]. Among
persons who completed the 5-year study, rates were
17 of 103 (17%) and 34 of 99 (34%), respectively, for
321
an effectiveness of 50% [43]. In an observational
study among homeless persons with documented
tuberculin skin-test conversion during an epidemic of
tuberculosis resistant to isoniazid and streptomycin,
49 persons received rifampin. The average duration
of therapy was 6.4 months. None of the 49 persons
developed tuberculosis, compared with 6 of 71 per-
sons (8.6%) who received no therapy [46]. In a
study of 157 tuberculin skin-test – positive adolescent
close contacts of persons with isoniazid-resistant
tuberculosis, all were treated with a 6-month course
of rifampin; none developed tuberculosis during the
2-year evaluation period [47]. Although the effective-
ness of 4 months of rifampin has never been studied,
it is the currently recommended duration in the ATS/
CDC/IDSA guidelines [6].
HIV-seropositive persons
There are no studies of the effectiveness of
rifampin for the treatment of latent M. tuberculosis
infection among HIV-seropositive persons. Because
of the lack of studies, and because active disease is
more difficult to exclude in persons with HIV, one
should use rifampin in this patient population with
much caution, if at all.
Toxicity
HIV-seronegative persons
Although data on the tolerability of rifampin are
limited, it seems to be well tolerated. In the ran-
domized trial conducted in Hong Kong, 6 of 172 pa-
tients (3.5%) discontinued therapy during the study
because of adverse drug reaction. None of these
patients developed hepatotoxicity [43]. In the study
among homeless persons in Boston, 7 of 49 persons
(14%) developed adverse effects requiring discon-
tinuation of therapy, but there were no reports of
hepatotoxicity [46]. Of the 157 adolescents who
received rifampin, 18 (11.5%) interrupted therapy
temporarily, and 2 (1.3%) permanently discontinued
therapy [47]. In a recent study of persons randomly
assigned to receive either 4 months of rifampin or
9 months of isoniazid, 2 of 58 persons (3%) re-
ceiving rifampin developed adverse events requiring
permanent drug discontinuation; none developed
hepatitis [48].
HIV-seropositive persons
There are no data on the safety of this regimen in
HIV-seropositive persons.
322 dooley
Special situations
Pregnant/breastfeeding women
Pregnancy does not increase the risk of progres-
sion from latent infection to active disease. Because
of the morbidity associated with tuberculosis in the
pregnant mother and neonate, treatment of latent
M. tuberculosis infection is recommended for preg-
nant women at high risk of progression to active
disease (ie, those with recent M. tuberculosis
infection or with coinfection with M. tuberculosis
and HIV) [6]. Given the proven effectiveness of
isoniazid and its safety in pregnancy, it is the pre-
ferred regimen. Because of the low levels of iso-
niazid in breast milk, its use is not contraindicated
in breastfeeding women.
Children
The only treatment regimen that has been exten-
sively studied in children is isoniazid. Isoniazid may
be more effective in children than in adults, with a
reported effectiveness of 70% to 90% [49,50]. Be-
cause the effectiveness of short-course regimens
has not been studied in children, such regimens are
not recommended by the ATS/CDC/IDSA [6].
Contacts of persons with drug-resistant tuberculosis
If persons are infected with a strain of M. tu-
berculosis that is resistant to rifampin but suscep-
tible to isoniazid, isoniazid is effective for treatment.
For persons exposed to a case of tuberculosis resis-
tant to isoniazid, treatment with rifampin is recom-
mended, as discussed previously [6]. The optimal
treatment is unknown for persons with evidence of
latent M. tuberculosis infection who have been ex-
posed to multidrug-resistant tuberculosis (MDR-TB),
defined as resistance to at least isoniazid plus ri-
fampin. No clinical studies have assessed the effec-
tiveness of specific regimens, and such studies will
probably never be conducted because of the diffi-
culty in enrolling a sufficient sample size. Recom-
mended regimens include a fluoroquinolone plus
pyrazinamide or ethambutol plus pyrazinamide [51].
The optimal duration of these regimens is unknown,
although 6 to 12 months is recommended. They
often are poorly tolerated [52].
Tumor necrosis factor-alpha antagonists
Drugs that block the inflammatory cytokine tu-
mor necrosis factor-alpha (TNF-a), such as inflixi-
& sterling
mab, etanercept, and adalimumab, are used to treat
autoimmune diseases such as rheumatoid arthritis and
Crohn’s disease. Use of these drugs increases the risk
of progressing from latent M. tuberculosis infection
to active disease in persons with either remote or
recent M. tuberculosis infection [53 – 55]. Before
initiating the use of a TNF-a antagonist, patients
should be evaluated for latent M. tuberculosis in-
fection and, if symptomatic, for active tuberculosis. In
immunocompromised persons, induration of 5 mm
or greater is considered a positive tuberculin skin test
(see Box 1). Treatment of latent infection may be
considered in persons with an induration of less than
5 mm if epidemiologic and clinical circumstances
suggest recent M. tuberculosis infection [54,55].
Treatment for latent M. tuberculosis infection should
be initiated (and preferably completed) before start-
ing treatment with the TNF-a antagonist [55].
Difficulties and challenges of treatment of latent
Mycobacterium tuberculosis infection
Low rates of treatment initiation
Not all persons who are eligible for treatment
of latent tuberculosis infection initiate therapy. In a
study of close contacts of smear-positive pulmonary
tuberculosis cases, 95 HIV-infected persons were
eligible for treatment of latent infection; of these,
only 30 (32%) initiated therapy [56]. In another study
of close contacts of tuberculosis cases, of the
630 persons with newly documented positive tuber-
culin skin tests (all of whom were eligible for ther-
apy), treatment was recommended in 447 (71%),
and was started in only 398 (63%) [57]. Efforts must
be made to improve the use of treatment of latent
infection, particularly in those at highest risk of pro-
gression to active disease, such as HIV-infected
persons and close contacts.
Low treatment-completion rates
Among persons who start therapy, treatment-
completion rates are low. In the second study of
close contacts mentioned previously, 203 of 398 per-
sons starting therapy (51%) completed it; 203 of
630 of those eligible for therapy (32%) completed it
[57]. In a study of isoniazid treatment of latent in-
fection in an inner-city population, 84 of 409 persons
eligible for therapy (21%) completed it [58]. Low
treatment-completion rates can result in continued
transmission of M. tuberculosis and additional cases
[59]. The low completion rates may result from a lack
 treatment of latent tuberculosis infection
of understanding on the part of the patient of the
importance of treatment, the absence of symptoms
related to tuberculosis, the toxicity of the regimen,
and the prolonged duration of therapy. Even if
toxicity is relatively mild and infrequent, patients
may be less likely to tolerate adverse effects because
they do not have symptomatic tuberculosis disease.
Shorter treatment duration may improve completion
rates [36,40], but this result has not been noted
uniformly [60]. Education of the patient regarding the
importance of such therapy is extremely important.
Direct observation of treatment of latent infection can
improve adherence [61,62] but is often not feasible
for tuberculosis treatment programs because of its
high cost.
Monitoring for toxicity
As discussed previously, the potentially severe
toxicity associated with the treatment of latent
M. tuberculosis infection necessitates monitoring,
particularly in persons at increased risk for toxic-
ity. Routine monitoring for symptoms of toxicity is
recommended. Monitoring of laboratory tests (eg, he-
patic transaminases) to prevent toxicity, or at least
identify toxicity in its early stages, is a reasonable
approach in persons at high risk for toxicity, although
the utility of such a strategy (and the optimal
monitoring strategy) has never been assessed in a
clinical trial.
Logistical difficulties in implementing treatment of
latent tuberculosis infection
Treatment of latent M. tuberculosis infection has
been a cornerstone of efforts to control tuberculosis
in the United States for the past several decades. This
approach has been possible because of the relatively
low number of tuberculosis cases and available pub-
lic health resources in the United States. In areas of
the world where tuberculosis case rates are substan-
tially higher and resources are more limited, treat-
ment of latent M. tuberculosis infection is limited;
the focus in these countries is to identify and treat
cases of active tuberculosis.
Prospects for improvements in the treatment of
latent Mycobacterium tuberculosis infection
There is clearly a need for safe and effective short-
course treatment of latent M. tuberculosis infection.
Studies are underway to assess the tolerability and
effectiveness of once-weekly isoniazid plus rifapen-
323
tine for 3 months. A study assessing the tolerability
of this regimen has recently completed enrollment in
Brazil, and data analysis is underway. A compari-
son of isoniazid plus rifapentine versus the standard
regimen of daily isoniazid is underway in South
Africa and in a multinational study being conducted
by the Tuberculosis Trials Consortium of the CDC
(US Public Health Service Study 26). If effective
and well-tolerated, isoniazid plus rifapentine would
provide a relatively simple short-course regimen for
the treatment of latent tuberculosis infection, which
could improve treatment completion rates.
Data from the mouse model of tuberculosis, which
has correlated closely with human tuberculosis
[63,64], have demonstrated that moxifloxacin, a
newer fluoroquinolone, has excellent activity against
M. tuberculosis. This drug may allow shorter and
more effective treatment of active tuberculosis [65,66]
and may be effective for the treatment of latent tuber-
culosis infection. Additional studies are warranted.
The Tuberculosis Epidemiologic Studies Consor-
tium of the CDC has launched a large study of the
treatment of latent tuberculosis infection in the United
States (Task Order 13), including an assessment of
the regimens used and the factors associated with
acceptance of, adherence to, and tolerability of cur-
rent treatment regimens. A better understanding of
these factors will allow the development of in-
terventions to improve the treatment of latent
M. tuberculosis infection in the United States and
throughout the world.
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