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Treatment of Latent Tuberculosis Infection: Challenges and Prospects
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 population, or 2 billion people, are infected with Mycobacterium tuberculosis [1]. Among infected persons, approximately 10% progress to the clinically important (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 prevents the development of disease [5]. Among infected persons who develop active disease, progression occurs either shortly after initial infection (progressive primary disease) or subsequent to the initial infection, when there is a breakdown in the host immune response. A person is at greatest risk of progressing to active disease during the first 2 years after infection with M. tuberculosis [2]. In addition to HIV infection and recent M. tuberculosis infection, other risk factors for progression to active tuberculosis include silicosis, diabetes mellitus, chronic renal failure, malnutrition, weight loss, leukemia, lymphoma, cancer of the head, neck, and lung, gastrectomy, and jejunoileal bypass surgery [6].
This work was supported by the National Institutes of Allergy and Infectious Diseases K23 AI01654 (TRS). * Corresponding author. E-mail address: [email protected] (T.R. Sterling).
Diagnosis of latent Mycobacterium tuberculosis infection As discussed elsewhere in this issue, the diagnosis 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 mycobacteria (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. tuberculosis infection should be evaluated for the presence of active disease. The evaluation should include an assessment of the signs and symptoms of tuberculosis and a chest radiograph; in persons with symptoms or an abnormal chest radiograph, sputum for acid-
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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 cultureconfirmed 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 highprevalence country within the last 5 years Injection drug use Residents and employees of highrisk settings: prisons, jails, nursing homes, and other long-term care facilities, hospitals, residential facilities for AIDS patients, homeless shelters Mycobacteriology laboratory personnel Persons at increased risk of developing active tuberculosis: those with silicosis, diabetes mellitus, chronic renal failure, leukemia, lymphoma, cancer of the head, neck or lung, weight loss of more than 10% of ideal body weight, gastrectomy, 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. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4):S234; with permission.
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fast smear and culture should also be obtained. Once active disease has been excluded, all persons at increased risk of progressing to active tuberculosis (see Box 1) should receive treatment for latent infection.
Importance of treatment of Mycobacterium tuberculosis infection to decrease the global tuberculosis burden Most cases of active tuberculosis arise from persons with latent M. tuberculosis infection; treatment of such persons is therefore necessary to achieve tuberculosis 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 manifestations, 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 detailed later, treatment of latent M. tuberculosis infection 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 conducted in adults and published in the English peerreviewed 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 HIVseropositive persons than in HIV-seronegative persons, and because the effectiveness of many regimens has been assessed separately according to HIV serostatus, the data are presented separately for HIVseropositive 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 First author/date [reference]
Randomization unit
United States Public Health Service trials Mount, 1962 [67] Family Family
Ferebee, 1963 [68]
Ward
Comstock, 1967 [69]
Household
International trials Chiba, 1963 [70]
Household
Nyboe, 1963 [71]
City blocks
Egsmose, 1965 [72]
Household
DelCastillo, 1965 [73]
Household
Horwitz, 1966 [74]
Village
Veening, 1968 [75]
Individual
IUAT, 1982 [9]
Individual
Follow-up
Regimen
Contacts of known active cases PPD+ and Household contacts of new active TB 39 US communities, PPD+ and Mental institutions PPD+ and Alaskan Eskimos in Bethel area Most not PPD tested
4 years
INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo
Osaka, Japan Household contacts of new active TB Suburb of Tunis City
3 years 5 years 6 years
for 1 year for 1 year for 1 year for 1 year
2 years
INH 5 mg/kg/d for 1 year
1 year
INH (very erratic pill taking) Placebo INH 5 – 10 mg/kg/d for 1 year Placebo INH Placebo INH 400 mg 2 /wk for total 52 doses Placebo INH 600 mg 4 mo, 400 mg 8 mo Placebo INH 300 mg/d for 12 weeks INH 300 mg/d for 24 weeks INH 300 mg/d for 52 weeks Placebo
Rural northern Kenya PPD+ contacts of new active cases Philippines Contacts of active cavitary TB Greenland villagers
4 years
Royal Netherlands Navy New PPD+ after exposure to index case 7 European countries PPD+ patients with fibrotic lesions
4 years
2 years 6 years
5 years
Active TB n/N (%)
Reduction (%)
6/1463 (0.41) 12/1351 (0.89) 29/12439 (0.23) 97/12594 (0.77) 35/12884 (0.27) 89/12326 (0.72) 58/3047 (1.9) 141/3017 (4.67)
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8/1142 (0.7) 11/1096 (1.0) 18/7769 (0.23) 25/8141 (0.31) (1.04) (1.6) 8/97 (8.2) 18/129 (14.0) 238/4174 (5.7) 323/3907 (8.3) 2/133 (0.38) 12/128 (9.4) 76/6956 (1.1) 34/6965 (0.49) 24/6919 (0.35) 97/6990 (1.4)
70 62 59
30 25 35 41 31
treatment of latent tuberculosis infection
Ferebee, 1962 [17]
Population
96 21 65 75
Abbreviations: INH, isoniazid; IUAT, International Union Against Tuberculosis; PPD, purified protein derivative; TB, tuberculosis.
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status, so tolerability data are also presented according 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 conducted, which together enrolled more than 100,000 persons. Most of these studies were conducted in the 1950s and 1960s and therefore enrolled only HIVseronegative 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 Tuberculosis (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 insufficient protection; 9 to 10 months of isoniazid seemed to provide optimal protection. Based on these findings, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) guidelines recommend 9 months of isoniazid [6]. A 9-month regimen of isoniazid has never been compared 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. tuberculosis 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 tuberculosis; this finding has been confirmed in a metaanalysis [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
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HIV-seronegative persons, and to ensure uniformity of recommendations, the ATS/CDC/IDSA guidelines recommend 9 months of isoniazid for HIVseropositive persons [6]. Although HIV-infected persons are at increased risk of having a negative tuberculin skin test, particularly with advanced immunosuppression, 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 discontinuation 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 transaminases 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 consumption. 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 casefatality 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 hepatotoxicity may be lower when there is regular monitoring 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 First author/date [reference] INH versus placebo trials Pape, 1993 [12]
Gordin, 1997 [77]
Fitzgerald, 2001 [78]
Multiregimen trials Whalen, 1997 [15]
Mwinga, 1998 [41]
Gordin, 2000 [36]
Halsey, 1998 [40]
Compliance/follow-up
118
33 months
No loss to follow-up
INH 300 mg/d for 6 months
684
20 months
70% follow-up
US, mostly NYC Anergic patients
INH 300 mg/d for 6 months
517
33 months
63% completed therapy; 6% INH and 7% placebo lost to follow-up
Haiti PPD
INH 300 mg/d for 12 months
237
2.5 years
77% followed to death or study end
Uganda (1) PPD+
PPD+: INH 300 mg/d for 6 months or INH 300 mg/d and RIF 600 mg/d for 3 months or INH 300 mg/d, RIF 600 mg/d, and PZA 2000 mg/d for 3 months Anergic: INH 300 mg/d for 6 months INH 900 mg 2 /wk for 6 months or RIF 600 mg and PZA 3500 mg 2 /wk for 3 months INH 300 mg/d for 12 months or RIF 600 mg and PZA 20 mg/kg/d for 2 months
2018
15 months
75% urine tests and 80% – 89% completed the trials
718 1053
1.8 years
81% placebo, 66% INH, and 75% RIF/PZA were >80% compliant
1583
37 months
80% RIF/PZA and 69% INH completed therapy
750
2.5 years
55% INH and 74% RIF/PZA had >80% compliance
Population
Regimens
Randomized Double-blind Placebo-controlled
Haiti New HIV diagnosis PPD+ or Kenya PPD+ or
INH 300 mg/d for 12 months
Block-randomized Double-blind Placebo-controlled Randomized Double-blind Placebo-controlled Randomized Blinding unclear Placebo-controlled Block-randomized Double-blind Placebo-controlled
Block-randomized Double-blind Placebo-controlled Randomized Open-label No placebo arm Randomized Unmasked Partly supervised No placebo arm
(2) Anergic Zambia
US, Mexico, Haiti, Brazil PPD+ Haiti PPD+
INH 600 – 800 mg 2 /wk for 6 months or RIF 450 – 600 mg and PZA 1500 – 2000 mg 2 /wk for 2 months (weight-based)
N
treatment of latent tuberculosis infection
Hawken, 1997 [76]
Mean follow-up
Trial type
Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin. 317
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Table 3 Results of randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among HIV-seropositive persons First author/date [reference] PPD positive Pape, 1993 [12] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ cohort Mwinga, 1998 [41] PPD negative Gordin, 1997 [77] Fitzgerald, 2001 [78] Hawken, 1997 [76] Pape, 1993 [12] Whalen, 1997 [15] anergic cohort Mwinga, 1998 [41]
Rx n/N (%) INH
Control n/N (%) placebo
RR
95% Confidence interval
Reduction (%)
2/38 (5.2) 5/67 (7.5) 7/536 (1.3)
6/25 (24.0) 8/69 (11.6) 21/464 (4.5)
0.22 0.64 0.29
0.05, 1.00 0.22, 1.87 0.12, 0.67
78 36 71
6/101 (5.9)
11/60 (18.3)
0.32
0.13, 0.83
68
(2.3) (3.6) (3.6) (14.3) (3.1)
0.66 1.32 1.31 0.70 0.74
0.19, 0.38, 0.54, 0.15, 0.30,
34 32 31 30 26
17/166 (10.2)
0.75
0.42, 1.34
4/260 6/126 11/235 2/20 9/395
(1.5) (4.8) (4.7) (10.0) (2.3)
27/351 (7.7)
6/257 4/111 8/224 5/35 10/323
2.31 4.56 3.20 3.28 1.79
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 for persons with abnormal baseline liver function tests, persons at increased risk of hepatotoxicity (eg, HIV infection, liver disease, alcoholism, pregnancy), and persons who develop symptoms while on therapy. [6] Isoniazid can also cause peripheral neuropathy, but the risk is lower with concomitant use of vitamin B6 (pyridoxine) [30,31]. HIV-seropositive persons The rates of isoniazid-associated toxicity requiring drug discontinuation in HIV-seropositive persons are summarized in Table 5. Although the data are not as extensive as in HIV-seronegative persons, isoniazid is generally well tolerated in this patient population. Table 4 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients
First author/date [reference] Scharer, 1969 [18] Byrd, 1972 [22] Bailey, 1973 [79] Byrd, 1977 [80] Byrd, 1979 [24] Stuart, 1999 [25]
Toxicity requiring discontinuation of therapy INH n/N (%)
Placebo n/N (%)
2/90 16/160 18/427 10/120 64/1000 26/83
No placebo No placebo No placebo 1/60 (1.7) No placebo No placebo
(2.2) (10) (7.3) (8.3) (6.4) (31.3)
arm arm arm arm arm
Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviation: INH, isoniazid.
Hepatitis C virus and isoniazid-associated hepatotoxicity Hepatitis C virus (HCV) infection has been associated with an increased risk of hepatotoxicity among persons receiving combination antituberculosis therapy for active disease, particularly HIVinfected persons [32]. HCV infection is common in injection drug users [33], who are also at high risk of progressing to active tuberculosis if latently infected with M. tuberculosis. Two studies have assessed the risk of isoniazid-associated hepatotoxicity in persons with underlying HCV. In a study of 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminases, 138 were HCV seropositive; 32 (22%) developed hepatic transaminases levels more than three times the upper limit of normal, and 11 (8%) required drug discontinuation [34]. These rates are comparable to those reported in populations with lower HCV seroprevalence (see preceding discussion and Table 5). In a second study of 415 drug users, of the 214 that were HCV-antibody – positive, 16 (7.5%) developed hepatotoxicity (defined as drug discontinuation in the setting of hepatic transaminase elevation more than five times the upper limit of normal in the presence of symptoms or as transaminase elevation alone on two occasions at least 1 week apart) [35]. On multivariate analysis, HCV infection was not independently associated with hepatotoxicity. Both studies suggest that isoniazid is safe in persons with HCV infection and is not associated with significantly higher rates of hepatotoxicity than in persons without HCV.
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treatment of latent tuberculosis infection Table 5 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients Toxicity requiring discontinuation of therapy First author/date [reference]
INH n/N (%)
Placebo n/N (%)
RR
Pape, 1993 [12] Gordin, 1997 [77] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ Anergic Mwinga, 1998 [41]
0/58(0) 24/260 (9.2) 11/342 (3.2) 3/536 (0.6) 0/395 26/703 (3.7)
0/60 (0) 24/257 (9.3) 5/342 (1.5) 1/464 (0.2) 0/323 3/350 (0.9)
0 0.99 2.2 2.60 0 4.31
95% Confidence interval 0.58, 1.69 0.77, 6.26 0.27, 24.88 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 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 Among available short-course regimens for the 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 tolerability studies (see later discussion), it is unlikely that effectiveness will ever be studied in HIVseronegative persons.
HIV-seropositive persons The effectiveness of the 2-month rifampin plus pyrazinamide regimen has been studied entirely in HIV-seropositive persons. Because the risk of tuberculosis without treatment of latent infection is substantially 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]. Toxicity HIV-seronegative persons After the effectiveness and tolerability of 2 months of rifampin plus pyrazinamide were demonstrated in HIV-seropositive adults, the regimen was recommended in the United States for both HIVseropositive 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 First author/date [reference] PPD positive Gordin, 2000 [36] Halsey, 1998 [40] Mwinga, 1998 [41] PPD negative Mwinga, 1998 [41]
Rx n/N (%) RIF/PZA
Control n/N (%) INH
RR
95% Confidence interval
28/791 (3.5) 19/380 (5.0) 2/49 (4.1)
29/792 (3.7) 14/370 (3.8) 4/52 (7.7)
0.97 1.32 0.53
0.58, 1.61 0.67, 2.56 0.10, 2.77
3 32 47
13/173 (7.5)
14/178 (7.9)
0.96
0.46, 1.96
4
Reduction (%)
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.
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Table 7 Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients Toxicity requiring discontinuation of therapy First author/date [reference]
RIF/PZA n/N (%)
INH n/N (%)
a
13/168 12/589 28/307 26/148
No INH arm No INH arm 8/282 (2.8) No INH arm
Bock, 2001 [58] a Chaisson, 2002 [81] Jasmer, 2002 [60] a Lee, 2002 [82] a McNeill, 2003 [83] a Stout, 2003 [84] Van Hest, 2004 [85]
(7.7) (2.0) (9.1) (17.6)
8/114 (7.0) 14/166 (8.4)
No INH arm 17/528 (3.2)
Hepatotoxicity requiring discontinuation of therapy RR
3.21
2.62
RIF/PZA n/N (%)
INH n/N (%)
1/168 (0.6) 10/589 (1.7) 12/207 (5.8) 11/148(7.4) 14/110 (12.7) 6/114 (5.3) 14/166 (8.4)
No INH arm No INH arm 2/204 (1.0) No INH arm 5/114 (4.4) No INH arm 18/528 (3.4)
RR
5.91 2.90 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 HIVseropositive 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 concentrations more than five times the upper limit of normal (2.6/100 treatment initiations), and an additional 146 patients discontinued therapy because of symptoms of hepatitis (1.9/100 treatment initiations). There were 48 cases of severe hepatotoxicity (defined as resulting in hospitalization or death); 11 patients 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. Nonetheless, the risk of severe hepatotoxicity and death seemed to be approximately 10 times greater than the risk associated with isoniazid, and it was therefore 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 analysis specifically addressing hepatotoxicity [42]. Because 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, regardless 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 HIVseropositive 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 First author/date [reference]
RIF/PZA n/N (%)
INH n/N (%)
RR
95% Confidence interval
Halsey, 1998 [40] Mwinga, 1998 [41] Gordin, 2000 [36,42] Narita, 2003 [86]
0/380 14/351 75/791 5/135
0/370 12/352 48/792 0/25
1.17 1.56
0.55, 2.50 1.09, 2.22
(0) (4.0) (9.5) (3.7)
(0) (3.4) (6.1) (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 HIVseropositive adults was 13 of 556 (2.3%) [15]. In a pooled analysis of 6105 persons who received isoniazid plus rifampin, 156 (2.5%) developed hepatitis [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 active tuberculosis, it is particularly important to exclude active disease before treating for latent M. tuberculosis infection, because treatment of undiagnosed active tuberculosis with rifampin monotherapy will lead to rifampin resistance.
HIV-seronegative persons The only randomized trial to evaluate the effectiveness 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, compared 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
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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 persons (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 effectiveness 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 randomized trial conducted in Hong Kong, 6 of 172 patients (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 discontinuation 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%) receiving 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.
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Special situations Pregnant/breastfeeding women Pregnancy does not increase the risk of progression 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 pregnant 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 preferred regimen. Because of the low levels of isoniazid in breast milk, its use is not contraindicated in breastfeeding women.
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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 infection 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 starting treatment with the TNF-a antagonist [55].
Children The only treatment regimen that has been extensively 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]. Because 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. tuberculosis that is resistant to rifampin but susceptible to isoniazid, isoniazid is effective for treatment. For persons exposed to a case of tuberculosis resistant to isoniazid, treatment with rifampin is recommended, as discussed previously [6]. The optimal treatment is unknown for persons with evidence of latent M. tuberculosis infection who have been exposed to multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid plus rifampin. No clinical studies have assessed the effectiveness of specific regimens, and such studies will probably never be conducted because of the difficulty in enrolling a sufficient sample size. Recommended 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 tumor necrosis factor-alpha (TNF-a), such as inflixi-
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 tuberculin skin tests (all of whom were eligible for therapy), 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 progression to active disease, such as HIV-infected persons and close contacts. Low treatment-completion rates Among persons who start therapy, treatmentcompletion rates are low. In the second study of close contacts mentioned previously, 203 of 398 persons 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 infection 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 toxicity. Routine monitoring for symptoms of toxicity is recommended. Monitoring of laboratory tests (eg, hepatic 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.
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tine for 3 months. A study assessing the tolerability of this regimen has recently completed enrollment in Brazil, and data analysis is underway. A comparison 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 tuberculosis infection. Additional studies are warranted. The Tuberculosis Epidemiologic Studies Consortium 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 current treatment regimens. A better understanding of these factors will allow the development of interventions to improve the treatment of latent M. tuberculosis infection in the United States and throughout the world.
Logistical difficulties in implementing treatment of latent tuberculosis infection References 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 public health resources in the United States. In areas of the world where tuberculosis case rates are substantially higher and resources are more limited, treatment 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 shortcourse treatment of latent M. tuberculosis infection. Studies are underway to assess the tolerability and effectiveness of once-weekly isoniazid plus rifapen-
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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 population, or 2 billion people, are infected with Mycobacterium tuberculosis [1]. Among infected persons, approximately 10% progress to the clinically important (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 prevents the development of disease [5]. Among infected persons who develop active disease, progression occurs either shortly after initial infection (progressive primary disease) or subsequent to the initial infection, when there is a breakdown in the host immune response. A person is at greatest risk of progressing to active disease during the first 2 years after infection with M. tuberculosis [2]. In addition to HIV infection and recent M. tuberculosis infection, other risk factors for progression to active tuberculosis include silicosis, diabetes mellitus, chronic renal failure, malnutrition, weight loss, leukemia, lymphoma, cancer of the head, neck, and lung, gastrectomy, and jejunoileal bypass surgery [6].
This work was supported by the National Institutes of Allergy and Infectious Diseases K23 AI01654 (TRS). * Corresponding author. E-mail address: [email protected] (T.R. Sterling).
Diagnosis of latent Mycobacterium tuberculosis infection As discussed elsewhere in this issue, the diagnosis 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 mycobacteria (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. tuberculosis infection should be evaluated for the presence of active disease. The evaluation should include an assessment of the signs and symptoms of tuberculosis and a chest radiograph; in persons with symptoms or an abnormal chest radiograph, sputum for acid-
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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 cultureconfirmed 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 highprevalence country within the last 5 years Injection drug use Residents and employees of highrisk settings: prisons, jails, nursing homes, and other long-term care facilities, hospitals, residential facilities for AIDS patients, homeless shelters Mycobacteriology laboratory personnel Persons at increased risk of developing active tuberculosis: those with silicosis, diabetes mellitus, chronic renal failure, leukemia, lymphoma, cancer of the head, neck or lung, weight loss of more than 10% of ideal body weight, gastrectomy, 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. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4):S234; with permission.
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fast smear and culture should also be obtained. Once active disease has been excluded, all persons at increased risk of progressing to active tuberculosis (see Box 1) should receive treatment for latent infection.
Importance of treatment of Mycobacterium tuberculosis infection to decrease the global tuberculosis burden Most cases of active tuberculosis arise from persons with latent M. tuberculosis infection; treatment of such persons is therefore necessary to achieve tuberculosis 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 manifestations, 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 detailed later, treatment of latent M. tuberculosis infection 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 conducted in adults and published in the English peerreviewed 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 HIVseropositive persons than in HIV-seronegative persons, and because the effectiveness of many regimens has been assessed separately according to HIV serostatus, the data are presented separately for HIVseropositive 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 First author/date [reference]
Randomization unit
United States Public Health Service trials Mount, 1962 [67] Family Family
Ferebee, 1963 [68]
Ward
Comstock, 1967 [69]
Household
International trials Chiba, 1963 [70]
Household
Nyboe, 1963 [71]
City blocks
Egsmose, 1965 [72]
Household
DelCastillo, 1965 [73]
Household
Horwitz, 1966 [74]
Village
Veening, 1968 [75]
Individual
IUAT, 1982 [9]
Individual
Follow-up
Regimen
Contacts of known active cases PPD+ and Household contacts of new active TB 39 US communities, PPD+ and Mental institutions PPD+ and Alaskan Eskimos in Bethel area Most not PPD tested
4 years
INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo INH 5 mg/kg/d Placebo
Osaka, Japan Household contacts of new active TB Suburb of Tunis City
3 years 5 years 6 years
for 1 year for 1 year for 1 year for 1 year
2 years
INH 5 mg/kg/d for 1 year
1 year
INH (very erratic pill taking) Placebo INH 5 – 10 mg/kg/d for 1 year Placebo INH Placebo INH 400 mg 2 /wk for total 52 doses Placebo INH 600 mg 4 mo, 400 mg 8 mo Placebo INH 300 mg/d for 12 weeks INH 300 mg/d for 24 weeks INH 300 mg/d for 52 weeks Placebo
Rural northern Kenya PPD+ contacts of new active cases Philippines Contacts of active cavitary TB Greenland villagers
4 years
Royal Netherlands Navy New PPD+ after exposure to index case 7 European countries PPD+ patients with fibrotic lesions
4 years
2 years 6 years
5 years
Active TB n/N (%)
Reduction (%)
6/1463 (0.41) 12/1351 (0.89) 29/12439 (0.23) 97/12594 (0.77) 35/12884 (0.27) 89/12326 (0.72) 58/3047 (1.9) 141/3017 (4.67)
54
8/1142 (0.7) 11/1096 (1.0) 18/7769 (0.23) 25/8141 (0.31) (1.04) (1.6) 8/97 (8.2) 18/129 (14.0) 238/4174 (5.7) 323/3907 (8.3) 2/133 (0.38) 12/128 (9.4) 76/6956 (1.1) 34/6965 (0.49) 24/6919 (0.35) 97/6990 (1.4)
70 62 59
30 25 35 41 31
treatment of latent tuberculosis infection
Ferebee, 1962 [17]
Population
96 21 65 75
Abbreviations: INH, isoniazid; IUAT, International Union Against Tuberculosis; PPD, purified protein derivative; TB, tuberculosis.
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status, so tolerability data are also presented according 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 conducted, which together enrolled more than 100,000 persons. Most of these studies were conducted in the 1950s and 1960s and therefore enrolled only HIVseronegative 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 Tuberculosis (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 insufficient protection; 9 to 10 months of isoniazid seemed to provide optimal protection. Based on these findings, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) guidelines recommend 9 months of isoniazid [6]. A 9-month regimen of isoniazid has never been compared 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. tuberculosis 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 tuberculosis; this finding has been confirmed in a metaanalysis [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
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HIV-seronegative persons, and to ensure uniformity of recommendations, the ATS/CDC/IDSA guidelines recommend 9 months of isoniazid for HIVseropositive persons [6]. Although HIV-infected persons are at increased risk of having a negative tuberculin skin test, particularly with advanced immunosuppression, 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 discontinuation 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 transaminases 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 consumption. 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 casefatality 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 hepatotoxicity may be lower when there is regular monitoring 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 First author/date [reference] INH versus placebo trials Pape, 1993 [12]
Gordin, 1997 [77]
Fitzgerald, 2001 [78]
Multiregimen trials Whalen, 1997 [15]
Mwinga, 1998 [41]
Gordin, 2000 [36]
Halsey, 1998 [40]
Compliance/follow-up
118
33 months
No loss to follow-up
INH 300 mg/d for 6 months
684
20 months
70% follow-up
US, mostly NYC Anergic patients
INH 300 mg/d for 6 months
517
33 months
63% completed therapy; 6% INH and 7% placebo lost to follow-up
Haiti PPD
INH 300 mg/d for 12 months
237
2.5 years
77% followed to death or study end
Uganda (1) PPD+
PPD+: INH 300 mg/d for 6 months or INH 300 mg/d and RIF 600 mg/d for 3 months or INH 300 mg/d, RIF 600 mg/d, and PZA 2000 mg/d for 3 months Anergic: INH 300 mg/d for 6 months INH 900 mg 2 /wk for 6 months or RIF 600 mg and PZA 3500 mg 2 /wk for 3 months INH 300 mg/d for 12 months or RIF 600 mg and PZA 20 mg/kg/d for 2 months
2018
15 months
75% urine tests and 80% – 89% completed the trials
718 1053
1.8 years
81% placebo, 66% INH, and 75% RIF/PZA were >80% compliant
1583
37 months
80% RIF/PZA and 69% INH completed therapy
750
2.5 years
55% INH and 74% RIF/PZA had >80% compliance
Population
Regimens
Randomized Double-blind Placebo-controlled
Haiti New HIV diagnosis PPD+ or Kenya PPD+ or
INH 300 mg/d for 12 months
Block-randomized Double-blind Placebo-controlled Randomized Double-blind Placebo-controlled Randomized Blinding unclear Placebo-controlled Block-randomized Double-blind Placebo-controlled
Block-randomized Double-blind Placebo-controlled Randomized Open-label No placebo arm Randomized Unmasked Partly supervised No placebo arm
(2) Anergic Zambia
US, Mexico, Haiti, Brazil PPD+ Haiti PPD+
INH 600 – 800 mg 2 /wk for 6 months or RIF 450 – 600 mg and PZA 1500 – 2000 mg 2 /wk for 2 months (weight-based)
N
treatment of latent tuberculosis infection
Hawken, 1997 [76]
Mean follow-up
Trial type
Abbreviations: INH, isoniazid; PPD, purified protein derivative; PZA, pyrazinamide; RIF, rifampin. 317
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Table 3 Results of randomized, controlled trials of isoniazid for the treatment of latent Mycobacterium tuberculosis infection among HIV-seropositive persons First author/date [reference] PPD positive Pape, 1993 [12] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ cohort Mwinga, 1998 [41] PPD negative Gordin, 1997 [77] Fitzgerald, 2001 [78] Hawken, 1997 [76] Pape, 1993 [12] Whalen, 1997 [15] anergic cohort Mwinga, 1998 [41]
Rx n/N (%) INH
Control n/N (%) placebo
RR
95% Confidence interval
Reduction (%)
2/38 (5.2) 5/67 (7.5) 7/536 (1.3)
6/25 (24.0) 8/69 (11.6) 21/464 (4.5)
0.22 0.64 0.29
0.05, 1.00 0.22, 1.87 0.12, 0.67
78 36 71
6/101 (5.9)
11/60 (18.3)
0.32
0.13, 0.83
68
(2.3) (3.6) (3.6) (14.3) (3.1)
0.66 1.32 1.31 0.70 0.74
0.19, 0.38, 0.54, 0.15, 0.30,
34 32 31 30 26
17/166 (10.2)
0.75
0.42, 1.34
4/260 6/126 11/235 2/20 9/395
(1.5) (4.8) (4.7) (10.0) (2.3)
27/351 (7.7)
6/257 4/111 8/224 5/35 10/323
2.31 4.56 3.20 3.28 1.79
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 for persons with abnormal baseline liver function tests, persons at increased risk of hepatotoxicity (eg, HIV infection, liver disease, alcoholism, pregnancy), and persons who develop symptoms while on therapy. [6] Isoniazid can also cause peripheral neuropathy, but the risk is lower with concomitant use of vitamin B6 (pyridoxine) [30,31]. HIV-seropositive persons The rates of isoniazid-associated toxicity requiring drug discontinuation in HIV-seropositive persons are summarized in Table 5. Although the data are not as extensive as in HIV-seronegative persons, isoniazid is generally well tolerated in this patient population. Table 4 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients
First author/date [reference] Scharer, 1969 [18] Byrd, 1972 [22] Bailey, 1973 [79] Byrd, 1977 [80] Byrd, 1979 [24] Stuart, 1999 [25]
Toxicity requiring discontinuation of therapy INH n/N (%)
Placebo n/N (%)
2/90 16/160 18/427 10/120 64/1000 26/83
No placebo No placebo No placebo 1/60 (1.7) No placebo No placebo
(2.2) (10) (7.3) (8.3) (6.4) (31.3)
arm arm arm arm arm
Toxicity is defined as adverse events resulting in discontinuation of therapy. Abbreviation: INH, isoniazid.
Hepatitis C virus and isoniazid-associated hepatotoxicity Hepatitis C virus (HCV) infection has been associated with an increased risk of hepatotoxicity among persons receiving combination antituberculosis therapy for active disease, particularly HIVinfected persons [32]. HCV infection is common in injection drug users [33], who are also at high risk of progressing to active tuberculosis if latently infected with M. tuberculosis. Two studies have assessed the risk of isoniazid-associated hepatotoxicity in persons with underlying HCV. In a study of 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminases, 138 were HCV seropositive; 32 (22%) developed hepatic transaminases levels more than three times the upper limit of normal, and 11 (8%) required drug discontinuation [34]. These rates are comparable to those reported in populations with lower HCV seroprevalence (see preceding discussion and Table 5). In a second study of 415 drug users, of the 214 that were HCV-antibody – positive, 16 (7.5%) developed hepatotoxicity (defined as drug discontinuation in the setting of hepatic transaminase elevation more than five times the upper limit of normal in the presence of symptoms or as transaminase elevation alone on two occasions at least 1 week apart) [35]. On multivariate analysis, HCV infection was not independently associated with hepatotoxicity. Both studies suggest that isoniazid is safe in persons with HCV infection and is not associated with significantly higher rates of hepatotoxicity than in persons without HCV.
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treatment of latent tuberculosis infection Table 5 Toxicity of isoniazid for treatment of latent Mycobacterium tuberculosis infection in HIV-seropositive patients Toxicity requiring discontinuation of therapy First author/date [reference]
INH n/N (%)
Placebo n/N (%)
RR
Pape, 1993 [12] Gordin, 1997 [77] Hawken, 1997 [76] Whalen, 1997 [15] PPD+ Anergic Mwinga, 1998 [41]
0/58(0) 24/260 (9.2) 11/342 (3.2) 3/536 (0.6) 0/395 26/703 (3.7)
0/60 (0) 24/257 (9.3) 5/342 (1.5) 1/464 (0.2) 0/323 3/350 (0.9)
0 0.99 2.2 2.60 0 4.31
95% Confidence interval 0.58, 1.69 0.77, 6.26 0.27, 24.88 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 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 Among available short-course regimens for the 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 tolerability studies (see later discussion), it is unlikely that effectiveness will ever be studied in HIVseronegative persons.
HIV-seropositive persons The effectiveness of the 2-month rifampin plus pyrazinamide regimen has been studied entirely in HIV-seropositive persons. Because the risk of tuberculosis without treatment of latent infection is substantially 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]. Toxicity HIV-seronegative persons After the effectiveness and tolerability of 2 months of rifampin plus pyrazinamide were demonstrated in HIV-seropositive adults, the regimen was recommended in the United States for both HIVseropositive 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 First author/date [reference] PPD positive Gordin, 2000 [36] Halsey, 1998 [40] Mwinga, 1998 [41] PPD negative Mwinga, 1998 [41]
Rx n/N (%) RIF/PZA
Control n/N (%) INH
RR
95% Confidence interval
28/791 (3.5) 19/380 (5.0) 2/49 (4.1)
29/792 (3.7) 14/370 (3.8) 4/52 (7.7)
0.97 1.32 0.53
0.58, 1.61 0.67, 2.56 0.10, 2.77
3 32 47
13/173 (7.5)
14/178 (7.9)
0.96
0.46, 1.96
4
Reduction (%)
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.
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Table 7 Toxicity of rifampin plus pyrazinamide for treatment of latent Mycobacterium tuberculosis infection in HIV-seronegative patients Toxicity requiring discontinuation of therapy First author/date [reference]
RIF/PZA n/N (%)
INH n/N (%)
a
13/168 12/589 28/307 26/148
No INH arm No INH arm 8/282 (2.8) No INH arm
Bock, 2001 [58] a Chaisson, 2002 [81] Jasmer, 2002 [60] a Lee, 2002 [82] a McNeill, 2003 [83] a Stout, 2003 [84] Van Hest, 2004 [85]
(7.7) (2.0) (9.1) (17.6)
8/114 (7.0) 14/166 (8.4)
No INH arm 17/528 (3.2)
Hepatotoxicity requiring discontinuation of therapy RR
3.21
2.62
RIF/PZA n/N (%)
INH n/N (%)
1/168 (0.6) 10/589 (1.7) 12/207 (5.8) 11/148(7.4) 14/110 (12.7) 6/114 (5.3) 14/166 (8.4)
No INH arm No INH arm 2/204 (1.0) No INH arm 5/114 (4.4) No INH arm 18/528 (3.4)
RR
5.91 2.90 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 HIVseropositive 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 concentrations more than five times the upper limit of normal (2.6/100 treatment initiations), and an additional 146 patients discontinued therapy because of symptoms of hepatitis (1.9/100 treatment initiations). There were 48 cases of severe hepatotoxicity (defined as resulting in hospitalization or death); 11 patients 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. Nonetheless, the risk of severe hepatotoxicity and death seemed to be approximately 10 times greater than the risk associated with isoniazid, and it was therefore 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 analysis specifically addressing hepatotoxicity [42]. Because 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, regardless 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 HIVseropositive 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 First author/date [reference]
RIF/PZA n/N (%)
INH n/N (%)
RR
95% Confidence interval
Halsey, 1998 [40] Mwinga, 1998 [41] Gordin, 2000 [36,42] Narita, 2003 [86]
0/380 14/351 75/791 5/135
0/370 12/352 48/792 0/25
1.17 1.56
0.55, 2.50 1.09, 2.22
(0) (4.0) (9.5) (3.7)
(0) (3.4) (6.1) (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 HIVseropositive adults was 13 of 556 (2.3%) [15]. In a pooled analysis of 6105 persons who received isoniazid plus rifampin, 156 (2.5%) developed hepatitis [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 active tuberculosis, it is particularly important to exclude active disease before treating for latent M. tuberculosis infection, because treatment of undiagnosed active tuberculosis with rifampin monotherapy will lead to rifampin resistance.
HIV-seronegative persons The only randomized trial to evaluate the effectiveness 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, compared 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
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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 persons (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 effectiveness 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 randomized trial conducted in Hong Kong, 6 of 172 patients (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 discontinuation 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%) receiving 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.
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Special situations Pregnant/breastfeeding women Pregnancy does not increase the risk of progression 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 pregnant 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 preferred regimen. Because of the low levels of isoniazid in breast milk, its use is not contraindicated in breastfeeding women.
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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 infection 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 starting treatment with the TNF-a antagonist [55].
Children The only treatment regimen that has been extensively 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]. Because 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. tuberculosis that is resistant to rifampin but susceptible to isoniazid, isoniazid is effective for treatment. For persons exposed to a case of tuberculosis resistant to isoniazid, treatment with rifampin is recommended, as discussed previously [6]. The optimal treatment is unknown for persons with evidence of latent M. tuberculosis infection who have been exposed to multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid plus rifampin. No clinical studies have assessed the effectiveness of specific regimens, and such studies will probably never be conducted because of the difficulty in enrolling a sufficient sample size. Recommended 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 tumor necrosis factor-alpha (TNF-a), such as inflixi-
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 tuberculin skin tests (all of whom were eligible for therapy), 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 progression to active disease, such as HIV-infected persons and close contacts. Low treatment-completion rates Among persons who start therapy, treatmentcompletion rates are low. In the second study of close contacts mentioned previously, 203 of 398 persons 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 infection 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 toxicity. Routine monitoring for symptoms of toxicity is recommended. Monitoring of laboratory tests (eg, hepatic 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.
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tine for 3 months. A study assessing the tolerability of this regimen has recently completed enrollment in Brazil, and data analysis is underway. A comparison 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 tuberculosis infection. Additional studies are warranted. The Tuberculosis Epidemiologic Studies Consortium 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 current treatment regimens. A better understanding of these factors will allow the development of interventions to improve the treatment of latent M. tuberculosis infection in the United States and throughout the world.
Logistical difficulties in implementing treatment of latent tuberculosis infection References 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 public health resources in the United States. In areas of the world where tuberculosis case rates are substantially higher and resources are more limited, treatment 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 shortcourse treatment of latent M. tuberculosis infection. Studies are underway to assess the tolerability and effectiveness of once-weekly isoniazid plus rifapen-
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