Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. CDC indicates Centers for Disease Control and Prevention. Further details are available from the USPSTF procedure manual.106
aNineteen studies that were poor quality, ineligible, or both were excluded but used in sensitivity analyses.
Kahwati LC, Feltner C, Halpern M, Woodell CL, Boland E, Amick HR, Weber RP, Jonas DE. Primary Care Screening and Treatment for Latent Tuberculosis Infection in AdultsEvidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2016;316(9):970-983. doi:10.1001/jama.2016.10357
Five to ten percent of individuals with latent tuberculosis infection (LTBI) progress to active tuberculosis (TB) disease. Identifying and treating LTBI is a key component of the strategy for reducing the burden of TB disease.
To review the evidence about targeted screening and treatment for LTBI among adults in primary care settings to support the US Preventive Services Task Force in updating its 1996 recommendation.
MEDLINE, Cochrane Library, and trial registries, searched through August 3, 2015; references from pertinent articles; and experts. Literature surveillance was conducted through May 31, 2016.
English-language studies of LTBI screening, LTBI treatment with recommended pharmacotherapy, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of individuals for whom LTBI screening and treatment is part of public health surveillance or disease management were excluded.
Data Extraction and Synthesis
Two investigators independently reviewed abstracts and full-text articles. When at least 3 similar studies were available, random-effects meta-analysis was used to generate pooled estimates of outcomes.
Main Outcomes and Measures
Sensitivity, specificity, reliability, active TB disease, mortality, hepatotoxicity, and other harms.
The review included 72 studies (n = 51 711). No studies evaluated benefits and harms of screening compared with no screening. Pooled estimates for sensitivity of the TST at both 5-mm and 10-mm induration thresholds were 0.79 (5-mm: 95% CI, 0.69-0.89 [8 studies, n = 803]; 10 mm: 95% CI, 0.71-0.87 [11 studies; n = 988]), and those for IGRAs ranged from 0.77 to 0.90 (57 studies; n = 4378). Pooled estimates for specificity of the TST at the 10-mm and 15-mm thresholds and for IGRAs ranged from 0.95 to 0.99 (34 studies; n = 23 853). A randomized clinical trial (RCT) of 24 weeks of isoniazid in individuals with pulmonary fibrotic lesions and LTBI (n = 27 830) found a reduction in absolute risk of active TB at 5 years from 1.4% to 0.5% (relative risk [RR], 0.35 [95% CI, 0.24-0.52]) and an increase in absolute risk for hepatoxicity from 0.1% to 0.5% (RR, 4.59 [95% CI, 2.03-10.39]) for 24 weeks of daily isoniazid compared with placebo. An RCT (n = 6886) found that 3 months of once-weekly rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing active TB. The risk difference for hepatoxicity comparing isoniazid with rifampin ranged from 3% to 7%, with a pooled RR of 3.29 (95% CI, 1.72-6.28 [3 RCTs; n = 1327]).
Conclusions and Relevance
No studies evaluated the benefits and harms of screening compared with no screening. Both the TST and IGRAs are moderately sensitive and highly specific within countries with low TB burden. Treatment reduced the risk of active TB among the populations included in this review. Isoniazid is associated with higher rates of hepatotoxicity than placebo or rifampin.
Prevention of active tuberculosis (TB) by treating latent tuberculosis infection (LTBI) is a major goal of the strategy for eliminating TB.1,2Quiz Ref ID Estimating the prevalence of LTBI is challenging because there is no direct test for latent infection, but US national survey data suggest a population prevalence of 4.7% (95% CI, 3.4%-6.3%) for the overall US population and 20.5% (95% CI, 16.1%-25.8%) for the foreign-born US population, based on a positive tuberculin skin test (TST) result.3 Five percent to 10% of immunocompetent individuals with a positive TST result will develop active TB disease in their lifetime.4 In developed countries with a low prevalence of TB, LTBI screening is recommended by the World Health Organization, American Thoracic Society, Infectious Diseases Society of America, and the Centers for Disease Control and Prevention (CDC) only for high-risk groups and when treatment is feasible.5,6 Current screening tests for LTBI include the TST and interferon-gamma release assays (IGRAs). Individuals who screen positive are generally offered preventive treatment (eTable 1 in the Supplement) after active infection has been excluded.7
In 1996, the US Preventive Services Task Force (USPSTF) recommended screening with the TST for asymptomatic, high-risk individuals (A recommendation). To inform an updated recommendation, we reviewed the evidence on test accuracy and benefits and harms of screening and treatment for LTBI in settings and populations relevant to US primary care.
Detailed methods are available in the full evidence report at http://www.uspreventiveservicestaskforce.org/Page/Document/final-evidence-review157/latent-tuberculosis-infection-screening. The analytic framework and key questions that guided the review are shown in Figure 1.
PubMed/MEDLINE and the Cochrane Library were searched for English-language articles published from database inception through August 3, 2015. The search strategies for these databases are listed in the eMethods in the Supplement. ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for unpublished literature. To supplement electronic searches, the reference lists of pertinent articles and all studies suggested by reviewers or comments received during public commenting periods were reviewed. Since August 2015, ongoing surveillance has been conducted through article alerts and targeted searches of high-impact journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted on May 31, 2016, and no new studies were identified.
Two investigators independently reviewed titles, abstracts, and full-text articles using prespecified inclusion criteria for each key question (KQ) (eTable 2 in the Supplement). Disagreements about inclusion were resolved by discussion. Only studies rated as of fair or good quality were included. For the overarching question regarding direct evidence of benefits of screening (KQ1), only randomized clinical trials (RCTs) or prospective cohort studies that compared screening with no screening in primary care settings and focused on asymptomatic adults belonging to populations at increased risk for developing active TB were eligible. Primary care was broadly defined to include public health settings or specialized clinics providing primary care functions (eg, prison clinics). Studies in which more than 25% of the study population were younger than 18 years or were known to be human immunodeficiency virus (HIV) positive were excluded, unless results were stratified by these characteristics. Studies on close contacts of individuals with active TB were excluded because testing and treatment of such populations is considered a public health surveillance activity. Studies of individuals with underlying immunosuppression and for whom LTBI screening and treatment would be part of disease management were also excluded, for example, studies of individuals beginning treatment with tumor necrosis factor–alpha inhibitors. Other populations at increased risk were included, such as persons who had previously received the bacillus Calmette–Guérin (BCG) vaccination, injection drug users, persons who were homeless or residing in homeless shelters, former prisoners, persons born in or former residents of countries with high TB prevalence, persons who worked with such individuals, and persons with a documented increased risk for progression from LTBI to active TB.
For screening test accuracy and reliability (KQ2), studies assessing the TST using the Mantoux method and 3 IGRAs were included.8 Because there is no direct reference test for latent infection, we relied on studies of individuals with bacteriologically confirmed active TB conducted in any country or setting for sensitivity and on studies of healthy participants at low risk for TB and TB exposure that were conducted in countries not considered as having high TB burden for specificity.8,9 Reliability was defined as the degree to which a test provided stable and consistent results, including outcomes such as test-retest reliability, interrater reliability, and interlaboratory reliability.
To review the benefits (KQ3) and harms (KQ5) of treatment, RCTs of individuals with LTBI that compared a CDC-recommended treatment (medication, dose, and duration) with placebo, delayed treatment, no treatment, or another CDC-recommended treatment were included. For harms of treatment (KQ5), prospective cohort studies and case-control studies were also eligible. For harms associated with screening (KQ4), systematic reviews, RCTs, and prospective cohort studies reporting false-positive results leading to unnecessary testing (eg, chest radiography) or treatment, labeling, stigma, anxiety, or cellulitis were eligible.
Except for studies of screening test accuracy and reliability (KQ2), studies conducted in countries categorized as anything other than “very high” on the United Nations Human Development Index10 were excluded.
For each included study, one investigator extracted information about design, population, tests or treatments used, and outcomes (eg, sensitivity, specificity, active TB), and a second investigator reviewed for completeness and accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor, using predefined criteria developed by the USPSTF and adapted for this topic (eTable 3 in the Supplement).11 Individual study quality ratings are provided in eTables 4-7 in the Supplement.
Findings for each question are summarized in tabular and narrative form. To determine whether meta-analyses were appropriate, the number of studies available and the clinical and methodological heterogeneity of the studies following established guidance were assessed.12 To do this, the populations, similarities and differences in screening tests or treatments used, and similarities in outcomes and timing of measured outcomes, were qualitatively assessed. When at least 3 similar studies were available, quantitative synthesis was conducted with random-effects models using the inverse-variance weighted method (DerSimonian and Laird) to determine pooled estimates.12,13 Statistical heterogeneity was assessed using the I2 statistic. Results for benefits and harms of treatment (KQ3 and KQ5) were considered statistically significant if the P value was less than .05 based on 2-sided testing. All quantitative analyses were conducted using Stata version 13.1 (StataCorp).14
Sensitivity analyses for screening test accuracy (KQ2) added in 19 studies rated as poor quality to determine whether inclusion of such studies would have altered conclusions. For benefits (KQ3) and harms (KQ5) of treatment, sensitivity analyses also added 6 RCTs comparing isoniazid with placebo that were either poor quality, did not meet all of the inclusion criteria, or both, because they used a longer duration of treatment than is currently recommended (eg, they used 1 year of isoniazid15- 19 or 3 months of isoniazid20); some also used lower or higher doses than currently recommended.16,17 For RCTs to be included in sensitivity analyses, they either confirmed LTBI for participants to be eligible (eg, by enrolling only those who were TST positive), reported data for those with confirmed LTBI (eg, for the TST-positive subset of participants), or the vast majority of participants (more than 75%) were TST positive.
For all quantitative syntheses, sensitivity analyses were conducted using maximum likelihood random-effects (KQ2) or profile likelihood random-effects methods (KQs 3 and 5) because DerSimonian and Laird models may not perform well when few studies are included.21- 25 Results were essentially the same as for those using DerSimonian and Laird random-effects models, with some minor variation in width of confidence intervals for some estimates, and thus are not reported further.
Study selection included reviewing 4408 titles and abstracts and 614 full-text articles (Figure 2). Of the 72 fair- or good-quality studies that met inclusion criteria (n = 51 711), 67 were observational studies of screening test characteristics (KQ2). Five studies were RCTs focused on the benefits (KQ3) or harms (KQ5) of pharmacotherapy for LTBI. No eligible studies for KQ1 (direct evidence of screening for LTBI) or KQ4 (harms of screening) were identified.
Key Question 1. Is there direct evidence that targeted screening for LTBI in primary care settings in asymptomatic adults at increased risk for developing active TB improves quality of life or reduces active TB disease, transmission of TB, or disease specific or overall mortality?
No eligible studies were identified.
Key Question 2. What is the accuracy and reliability of the TST or IGRA (KQ2a) or sequential screening strategies (KQ2b) for screening asymptomatic adults who are at increased risk for developing active TB disease?
Quiz Ref IDNo eligible studies evaluating sequential screening strategies were identified. Fifty studies (n = 4167) related to the sensitivity of the TST or IGRA tests were identified; detailed individual study characteristics are provided in eTables 8 and 9 in the Supplement. Eight studies were conducted in high TB-burden countries,26- 33 29 were conducted in countries with intermediate TB burden,34- 62 and 10 were conducted in countries with low TB burden,63- 72 including 4 in the United States. Three multinational studies were conducted in countries with a mix of low and intermediate TB burden.73- 75 In 3 studies, fewer than 25% of the participants were BCG vaccinated.28,30,72 Thirteen studies included study populations that were between 25% and 75% vaccinated,27,29,34,36,38,39,43,56,58,59,65,70,71 and 12 studies included study populations that had more than 75% of participants vaccinated.26,32,33,40- 42,45,51,52,61,66,74 Twenty-two studies did not report the BCG vaccination prevalence in the study population.
Pooled estimates were calculated for sensitivity of the TST by induration threshold and of IGRAs by assay (Table 1). The pooled sensitivity for the TST with a 5-mm threshold was 0.79 (95% CI, 0.69-0.89; I2 = 94.6% [8 studies; n = 803]); for the 10-mm threshold, 0.79 (95% CI, 0.71-0.87; I2 = 91.4% [11 studies; n = 988]); and for 15-mm threshold, 0.52 (95% CI, 0.35-0.68, I2 = 95.5% [7 studies; n = 740]) (eFigure 1 in the Supplement). For the T-SPOT.TB IGRA, there was no difference in estimates based on whether the US Food and Drug Administration or European threshold for a positive test was used, so all studies were combined for a pooled estimate of 0.90 (95% CI, 0.87-0.93; I2 = 63.6% [16 studies; n = 984]) (eFigure 2 in the Supplement). The pooled estimate for sensitivity of the QuantiFERON TB Gold IGRA was 0.77 (95% CI, 0.74-0.81; I2 = 55.3% [17 studies; n = 1073]) and of the QuantiFERON TB Gold In-Tube IGRA was 0.80 (95% CI, 0.77-0.84; I2 = 74.3% [24 studies; n = 2321]) (eFigure 2 in the Supplement). The percentage of IGRA tests with indeterminate results ranged from 3% to 7% in studies reporting this information.
Because there was moderate to substantial statistical heterogeneity, results for all tests were stratified based on factors consistently reported across studies that could affect the accuracy of the test, including whether testing occurred after anti-TB treatment had been started, the TB burden of the country where study took place, and BCG vaccination prevalence among the study population. Detailed findings related to these analyses are in the full evidence report. For some tests, estimates for sensitivity were higher in countries with low TB burden compared with countries with intermediate or high TB burden. For example, sensitivity for the TST at the 10-mm induration threshold was 0.88 (95% CI, 0.76-0.99 [3 studies; n = 424]) in low-burden countries, compared with 0.72 in intermediate-burden countries (95% CI, 0.65-0.79 [6 studies; n = 416]).
Eighteen studies related to the specificity of the TST or IGRA tests were identified (n = 10 693); detailed individual study characteristics are provided in eTables 10 and 11 in the Supplement. Fourteen of the 18 studies evaluating specificity were conducted in countries with low TB burden (10 were in the United States).64,65,76- 87 BCG vaccination rates were more than 75% in 4 studies,40,45,58,76 less than 5% in 9 studies,64,65,77,78,80,82- 85 and not reported in 5 studies.73,79,86- 88 Pooled estimates were calculated for specificity of the TST by test threshold and of IGRAs by assay (Table 1).
The pooled specificity for the TST with a 10-mm threshold was 0.97 (95% CI, 0.96-0.99; I2 = 94.3% [9 studies; n = 9651]); for the 15-mm threshold, 0.99 (95% CI, 0.98-0.99; I2 = 91.7% [12 studies; n = 9640]); individual study estimates are provided in eFigure 3 in the Supplement. The pooled estimate for specificity was 0.95 (95% CI, 0.92-0.98; I2 = 79.1% [5 studies; n = 1810]) for the T-SPOT TB IGRA; 0.98 (95% CI, 0.90-1.0 [4 studies; n = 699]) for the QuantiFERON TB Gold IGRA; and 0.97 (95% CI, 0.94-0.99; I2 = 93.4% [4 studies; n = 2053]) for the QuantiFERON TB Gold In-Tube IGRA; individual study estimates are provided in eFigure 3 in the Supplement. The percentage of IGRA tests with indeterminate results ranged from 0% to 3% in studies reporting this information. Because of substantial heterogeneity, results were stratified based on country TB burden and BCG vaccination rates. Across all tests, specificity was substantially lower in countries with intermediate TB burden than in those with low TB burden. Although the populations of studies conducted in intermediate-burden countries also had high prevalence of BCG vaccination, the available evidence did not allow definitive conclusions about the influence of BCG vaccination on specificity estimates because BCG vaccination status was not consistently reported across studies.
Nine studies (n = 4079) were identified that assessed the reliability for at least 1 of the included screening tests.45,80,84,85,89- 93 Individual study characteristics are provided in eTable 12 in the Supplement. Overall reliability varied by test and by type of reliability outcome. Three studies (n = 1826,80 n = 1189,85 and n = 12784) measured the interrater reliability for TST results by reporting the κ statistic for agreement by TST reaction size; results ranged from 0.55 to 0.79, indicating moderate to substantial agreement between 2 observers. One study (n = 91) evaluated the interlaboratory reliability of the QuantiFERON TB Gold In-Tube IGRA by sending 3 blood specimens from each participant to 3 different laboratories noted to have extensive experience and proficiency with IGRA testing and interpretation.91 Across all 3 laboratories, 7.7% of participants had discordant results (none had indeterminate results); κ values of pairwise laboratory sample comparisons ranged from 0.87 to 0.93.91 One study (n = 130) assessed the reliability of IGRA results by processing 2 blood samples from each study participant (using the same laboratory and same type of test interpretation); 5.8% of participants had discordant results for the QuantiFERON TB Gold In-Tube IGRA, and 6.5% had discordant results for T-SPOT.TB.89 Additional reliability results are provided in the eResults in the Supplement.
Key Question 3. Does treatment of LTBI with CDC-recommended pharmacotherapy improve quality of life or reduce progression to active TB, TB transmission, or disease-specific or overall mortality?
Study characteristics of trials evaluating the benefits of treatment are reported in Table 2. Three RCTs that evaluated the benefits of treatment for LTBI were included; 1 compared isoniazid with placebo (n = 27 830)97; 1 compared rifampin with isoniazid (n = 847)95; and 1 compared rifapentine plus isoniazid with isoniazid alone (n = 6886).96 No studies reported benefits related to quality of life or TB transmission.
The International Union Against Tuberculosis (IUAT) trial randomized 27 830 adults with fibrotic pulmonary lesions and a 6-mm or greater Mantoux TST induration, but without active TB or previous anti-TB treatment, to 4 groups: placebo or isoniazid (300 mg daily) for 12 weeks, 24 weeks (currently a CDC-approved regimen), or 52 weeks.97 The median age was 50 years, and 53% were men. After 5 years, 1.4% of the placebo group and 0.5% of the 24-week treatment group developed active TB, for a relative risk of 0.35 (95% CI, 0.24-0.52; number needed to treat, 112). Individuals with larger fibrotic lesions had a greater risk of developing active TB; the incidence of active TB in the placebo group was approximately half as great among individuals with lesions less than 2 cm2 (11.6 per 1000) as among individuals with larger lesions (21.3 per 1000). There were no deaths attributable to TB in any of the isoniazid groups; 3 individuals died of TB in the placebo group. One open-label trial randomized 847 participants to 4 months of rifampin or 9 months of isoniazid to compare adverse events and treatment completion.95 It reported zero deaths from TB in either group, zero deaths (due to any cause) in the rifampin group, and 1 death in the isoniazid group.
The PREVENT TB study was an open-label, noninferiority RCT that randomized 7731 individuals to directly observed once-weekly rifapentine plus isoniazid for 3 months or to daily self-administered isoniazid for 9 months.96 Most participants (89%) were from the United States or Canada and were high-risk individuals with a positive TST result. Most (71%) had a close contact with a patient with active TB within 2 years; 25% were included solely because of conversion to skin-test positivity. Risk factors for TB included a history of incarceration (5.1%), injection-drug use (3.7%), and homelessness (27.8%). Data were obtained from the CDC for the subset of participants most directly relevant for this review: the 6886 adults (18 years or older) who were HIV negative and TST or IGRA positive. The median age for this subset was 37 years; 54.2% were men, and 57% were white. For this subset, active TB developed in 5 individuals in the combination-therapy group and 10 individuals in the isoniazid-only group over 33 months of follow-up. The combination therapy was found to be noninferior to isoniazid-only treatment. Overall mortality was similar for the 2 groups (30 participants vs 34 participants, respectively; P = .42).
Four RCTs identified as comparing isoniazid with placebo did not meet all eligibility criteria (mainly because of duration of treatment or dose as described in the Methods) but were used in sensitivity analyses (eTable 13 in the Supplement).15- 18 Sensitivity analyses using data from the 24- and 52-week groups from the IUAT trial and from these 4 additional RCTs found a relative risk (RR) of 0.31 (95% CI, 0.24-0.41; 36 823 participants) and no statistical heterogeneity in effects between studies (I2 = 0.0%) (eTable 14 and eFigure 4 in the Supplement).
Key Question 4. Are there harms associated with screening for LTBI? Do these harms differ by screening method or strategy? Do these harms differ by population?
Key Question 5. Are there harms associated with treatment for LTBI with CDC-recommended pharmacotherapy?
Study characteristics of trials evaluating the harms of treatment are reported in Table 2. Five RCTs were included.94- 98 One compared isoniazid with placebo (n = 27 830)97; 3 compared rifampin with isoniazid (n = 1327)94,95,98; and 1 compared rifapentine plus isoniazid with isoniazid alone (n = 6886).96
The IUAT trial (described above) reported the RRs for developing hepatitis (undefined by study authors) associated with isoniazid compared with placebo as 3.45 (95% CI, 1.49-7.99) for 12 weeks of treatment, 4.59 (95% CI, 2.03-10.39) for 24 weeks (number needed to harm [NNH], 279), and 6.21 (95% CI, 2.79-13.79) for 52 weeks. Mortality rates from hepatitis were 0.03% for the 12-week isoniazid treatment group, 0.0% for the 24-week treatment group, and 0.01% for the 52-week treatment group (zero deaths from hepatitis among placebo-treated patients). The mortality rate from hepatitis was 0.14 per 1000 persons receiving isoniazid (RR, 2.35 [95% CI, 0.12-45.46]; NNH, 6947). Sensitivity analyses for isoniazid compared with placebo for hepatitis using data from the IUAT trial (3 treatment groups combined) and 3 additional RCTs15,19,20 that did not meet all eligibility criteria (eTables 13 and 15 in the Supplement) found an RR of 5.04 (95% CI, 2.50-10.15 [4 studies, 35 161 participants]) and no statistical heterogeneity among studies (I2 = 0.0%; P = .63).
In the IUAT trial, discontinuation because of adverse events was reported for 345 patients (1.8%) receiving isoniazid compared with 84 patients (1.2%) receiving placebo (RR, 1.50 [95% CI, 1.18-1.89]; NNH, 167). The most common reason was gastrointestinal distress (1.2% receiving isoniazid vs 0.9% placebo; RR, 1.33 [95% CI, 1.01-1.75]).
Three studies provided evidence on harms of rifampin as compared with isoniazid. One open-label RCT conducted in Canada (n = 116) compared 4 months of rifampin with 9 months of isoniazid.94 A later study by the same authors (described above) randomized 847 participants to the same 2 treatments.95 Participants in both studies were 18 years or older with documented LTBI. The third trial randomized inmates (n = 365) in the San Francisco City and County Jail with LTBI at jail entry to 9 months of isoniazid or 4 months of rifampin.98
Rates of hepatotoxicity in these 3 RCTs among individuals receiving isoniazid were 5.2%,94 3.7%,95 and 11.4%,98 respectively. Rates among rifampin-treated patients were lower (0.0%, 0.7%, and 4.4%, respectively). Pooled estimates from these 3 RCTs found a greater risk of hepatotoxicity for patients treated with isoniazid than for those treated with rifampin (RR, 3.29 [95% CI, 1.72-6.28] [3 studies, 1327 participants]) (eFigure 5 in the Supplement). All studies reported zero deaths from hepatotoxicity. Rates of discontinuations because of adverse events were 13.8% (isoniazid) and 3.4% (rifampin)94; 5.6% (isoniazid) and 3.8% (rifampin)95; and 0.0% (isoniazid) and 1.1% (rifampin).98 The pooled estimate found no statistically significant difference between treatments (RR, 1.61 [95% CI, 0.57-4.57] [3 studies; n = 1327]). Similar rates of gastrointestinal adverse events were reported among the 3 studies; various other harms were reported, but no significant differences between isoniazid and rifampin were identified.
The PREVENT TB trial (described above) reported rates of grade 3 hepatotoxicity of 4.9% in the rifapentine plus isoniazid group and 5.5% in the isoniazid-only group; corresponding rates of grade 4 hepatotoxicity were 1.0% and 1.1%, respectively.96 The RR for grade 3 or 4 hepatotoxicity was 0.90 (95% CI, 0.75-1.08). Mortality from hepatotoxicity was reported in 1.0% of patients receiving isoniazid and 0.8% of patients receiving rifapentine plus isoniazid (RR, 0.83 [95% CI, 0.51-1.35]). Rates of discontinuation because of adverse events were 5.2% in the rifapentine plus isoniazid group and 4.1% in the isoniazid-only group. The RR of treatment discontinuation because of adverse events for rifapentine plus isoniazid vs isoniazid only was 1.28 (95% CI, 1.03-1.59). Possible hypersensitivity was reported in 0.5% of patients receiving isoniazid and 4.1% of patients receiving rifapentine plus isoniazid. The relative risk of possible hypersensitivity for rifapentine plus isoniazid vs isoniazid only was 8.04 (95% CI, 4.88-13.26).
Table 3 summarizes the evidence reviewed to inform an updated USPSTF recommendation on screening for LTBI within primary care settings. For the populations and settings evaluated, currently available screening tests were moderately sensitive and, in countries with low TB burden , highly specific. Treatment with current CDC-recommended pharmacotherapy regimens was effective at reducing the progression to active TB, but treatment was associated with an increased risk for hepatotoxicity.
Quiz Ref IDThe applicability of the evidence on accuracy and reliability of screening tests to primary care practice settings and populations is uncertain for several reasons. The lack of a direct test for LTBI requires test accuracy studies to be performed in specific, nonprimary care–related populations (ie, active, confirmed TB for sensitivity; healthy populations with low TB risk for specificity). Estimates for specificity were lower in studies conducted with populations from countries with intermediate TB burden, specifically Turkey and South Korea. This could be the result of unintentional inclusion of participants with unknown past TB exposure, inclusion of BCG-vaccinated participants, or other factors that affect the administration or interpretation of tests in these countries. The studies of screening tests in this review did not consistently report comorbidities of the study population tested, and although studies from populations with more than 25% HIV-infected individuals were excluded, patients with active TB often have underlying comorbidities related to immunosuppression. The extent to which sensitivity of tests is blunted by this underlying immunosuppression is not known and may result in lower estimates for sensitivity than would be found in populations with latent infection. Conversely, the presence of active TB disease may result in more host sensitization, so this population may overestimate the true sensitivity of the tests for latent infection. Although 7 studies for KQ2 may have included 15-, 16-, and 17-year-olds,26,34,35,42,67,70,77 the scope of this review did not include children and adolescents, and so findings should not be generalized to this population.
The evidence on effectiveness of treatment for LTBI comes primarily from the IUAT trial. It enrolled participants with pulmonary fibrotic lesions, a group thought to be at the highest risk for progression to active TB. It also found that individuals with smaller lesions progressed to active TB at lower rates than those with larger lesions. Thus, estimates of treatment effectiveness may represent the upper bounds of effectiveness, and effectiveness may be lower in other populations. The evidence on harms suggests an RR of 4.59 for hepatotoxicity with 6 months of isoniazid compared with placebo and an RR of 3.29 compared with rifampin. Deaths because of hepatotoxicity were rare across all studies, so estimates were imprecise. In the IUAT study, all 3 participants who died of hepatitis had continued to take isoniazid after liver abnormalities were recognized.97 The rate of treatment discontinuation because of adverse events was modestly increased for isoniazid compared with placebo based on a single study but was no different between isoniazid and rifampin based on a pooled estimate from a 3-study body of evidence that was somewhat inconsistent and imprecise.
Quiz Ref IDIsoniazid was established as an effective treatment of LTBI several decades ago, and CDC treatment recommendations have evolved based on studies comparing shorter durations and alternative regimens against the standard isoniazid regimen to reduce harms, improve adherence, or both, rather than to assess efficacy. Given that treatment of LTBI has been the standard of care for decades, contemporary data for estimating efficacy or effectiveness among untreated populations are not available. Furthermore, over time the prevalence of active TB has declined, yet the prevalence of resistant strains among those infected has increased. Thus, the applicability of treatment evidence from before the current era is unclear. In addition, proponents for screening suggest benefits on outcomes related to TB transmission and through case-finding of active TB that occurs during screening. However, no studies meeting eligibility criteria that reported these outcomes were identified.
Quiz Ref IDThis review had several limitations. A substantial amount of statistical heterogeneity was identified in some of the pooled estimates of test accuracy; however, this heterogeneity is unlikely to be clinically relevant and can be explained by the number of included studies with large sample sizes and precise estimates, a phenomenon that has been described as producing elevated I2 estimates.99,100 The review excluded treatments not recommended by the CDC and also excluded several populations at highest risk of TB (eg, individuals with HIV), as the scope of the review was limited to generally healthy adults in primary care settings. Although the scope of the review was narrow, the findings are consistent with those from several other reviews of test characteristics and treatment that included broader populations and settings.101- 105
No studies evaluated the benefits and harms of screening compared with no screening. Both the TST and IGRAs are moderately sensitive and highly specific within countries with low TB burden. Treatment reduced the risk of active TB among the populations included in this review. Isoniazid is associated with higher rates of hepatotoxicity than placebo or rifampin.
Corresponding Author: Leila C. Kahwati, MD, MPH, RTI International, 3040 E Cornwallis Rd, Research Triangle Park, NC 27709 (firstname.lastname@example.org).
Author Contributions: Dr Kahwati had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kahwati, Feltner, Halpern, Jonas.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Kahwati, Halpern, Boland, Jonas.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Kahwati, Halpern, Amick, Jonas.
Obtained funding: Feltner, Woodell, Jonas.
Administrative, technical, or material support: Feltner, Woodell, Boland, Amick, Weber.
Study supervision: Kahwati, Feltner, Halpern, Jonas.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This research was co-funded by the Agency for Healthcare Research and Quality (AHRQ) and Centers for Disease Control and Prevention (CDC) under a contract to support the US Preventive Services Task Force (USPSTF) (Agency for Healthcare Research and Quality contract HHSA-290-2012-00015i; Task Order 4).
Role of the Funders/Sponsors: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight; reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings.
Additional Contributions: The authors gratefully acknowledge the following individuals for their contributions to this project, including AHRQ staff (Tina Fan, MD, and Tracy Wolff, MD), CDC Staff (Philip LoBue, MD, and Christine Ho, MD), Kaiser Permanente Research Affiliates EPC Staff (Evelyn Whitlock, MD), RTI International/University of North Carolina EPC Staff (Meera Viswanathan, PhD, Russell Harris, MD, Molly Howard, PharmD, Makda Majerette, BA, Roberta C. Wines, MPH, Christiane Voisin, MSLS, Rachael Posey, MSLS, Janice Handler, BA, Jennifer Drolet, MA, and Loraine Monroe). The authors also acknowledge the contributions of members of the US Preventive Services Task Force. No specific compensation was provided to any contributors listed here.
Additional Information: A draft version of the full evidence report underwent external peer review from 4 content experts (John Bernardo, MD, Boston University School of Medicine, Dick Menzies, MD, McGill University, Neil Schluger, MD, Columbia University Medical Center), 1 methodologic expert (Steven Teutsch, MD, Robert Wood Johnson Foundation Health and Society Scholar and independent consultant), and 4 federal partner reviewers, all from the CDC. Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.
Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.