Population Screening and Treatment of LTBI in TB Control in the US
| Margarita Elsa Villarino MD MPH | |
| Division of TB Elimination, CDC | |
| April 14, 2004 |
TB Prevention and Control in the United States
| The fundamental strategies include: | ||
| Early detection and treatment of patients who have active TB disease | ||
| Therapy for persons with latent TB infection to prevent the development of TB | ||
| Prevention of institutional transmission of M. tb | ||
| BCG vaccination is not recommended as a routine strategy | ||
Therapy for Latent Tuberculosis Infection
| Rationale | ||
| Reduce individual risk for developing active disease | ||
| Shrink pool of infected persons at risk for tuberculosis | ||
| Latent tuberculosis infection (LTBI) | |
| Treatment of LTBI (TLTBI) | |
| Targeted testing (TTTLTBI) | |
| “Decision to test is a decision to treat.” |
Reported TB Cases per
100,000 Population
United States, 1953 – 2000
Factors Affecting the Impact of TTTLTBI
| Tuberculin skin testing: the diagnosis | |
| Prediction of progression to disease | |
| Completion of therapy and programmatic costs | |
| Efficacy of treatment | |
| Safety of treatment |
The Tuberculin Skin Test (TST)
| Some 2-12 wks after infection with M. tb, there is a delayed-type hypersensitivity (DTH) reaction at the site of tuberculin injection | |
| DTH reactions begin 5-6 hrs after injection and reach a maximum at 48-72 hrs | |
| Since the 1930s, TST has been used to screen persons or populations for LTBI | |
| Yield of testing | ||
| higher rate gives higher yield | ||
| Predictive value of a positive result | ||
| higher rate gives better predictive value | ||
Positive Predictive Value
of a Tuberculin Test
Am J Respir Crit Care Med; 2000, Vol 161, p 1389
| “Infections with NTM are responsible for the majority of 5-14 mm PPD reactions among US-born health care workers...” | ||
Tuberculosis Screening in Private Physicians' Offices, Pennsylvania, 1996
| “Only 8/59 (14%) physicians followed published guidelines for placement and reading of tuberculin tests.” | |
| whole-blood IFN g release assay for the detection of M. tuberculosis infection |
| in vitro | ||
| multiple antigen mixes | ||
| no boosting | ||
| 1 patient visit | ||
| minimal inter-reader variability | ||
| results in 1 day | ||
| stimulate w/i 12 hrs | ||
| in vivo | ||
| single antigen mix (PPD) | ||
| boosting | ||
| 2 patient visits | ||
| inter-reader variability | ||
| results in 2 - 3 days | ||
| read in 48 - 72 hrs | ||
Learning
Objective
(QuantiFERON)
| Name prospective new blood tests that could detect latent infection as well as a skin test can? | ||
| QuantiFERON®-TB (QFT) is approved for specific indications. Research is underway for robust tests with broader applications. | ||
Factors Affecting the Impact TTTLTBI
| Tuberculin skin testing | |
| Prediction of progression to disease | |
| Completion of therapy and programmatic costs | |
| Efficacy of treatment | |
| Safety of treatment |
| Markers for risk: | |||
| recent infection | |||
| contacts | |||
| converters | |||
| underlying medical conditions: HIV infection | |||
Risk of TB Disease by Time of M. tb Infection
| Among 1,472 persons enrolled in the placebo arm of 2 trials of the efficacy of LTBI (Ferebee SH. Adv Tuberc Res. 1970) | ||
| 19 developed TB in 1st yr of follow-up (FU) | ||
| 7 developed TB in subsequent 7 yrs of FU | ||
| Difference in case rate 12.9 vs 1.6 per 1,000 person-yrs | ||
| Among 2,550 British children enrolled in the unvaccinated arm of TB vaccine study (Sutherland I. TSRU Prog Rep. 1978) | ||
| 121 (5%) developed TB in 15 yrs of FU | ||
| Of these, 54% cases during 1st yr, 82% within 2 yrs | ||
Factors Affecting the Impact of TTTLTBI
| Tuberculin skin testing | |
| Prediction of progression to disease | |
| Completion of therapy and programmatic costs | |
| Efficacy of treatment | |
| Safety of treatment |
Issues Associated With Completion of TLTBI
| Programs and systems | |
| Duration of regimen | |
| >21,000 admissions (1 yr.) | |
| 75% of inmates tested | |
| 68% of tests read | |
| 07.3% reactor rate | |
| 12.3% start rate | |
| 48% completion rate (81 inmates; 2-mo regimen) |
A Tuberculin Screening and Isoniazid Preventive Therapy Program in an Inner-city Population
| 7,246 participants, various community settings | |
| 4,701 (65%) tests read | |
| 809 (17%) reactors | |
| 409 eligible for treatment | |
| 84 completed treatment |
Optimal Duration of INH Therapy for the TLTBI, MMWR 2000;49(No.6)
| The duration of INH therapy should be >6 months to provide maximum protection. | |
| Therapy for 9 months appears to be sufficient, with little or no value of longer treatment. |
Effect of the Duration of INH Therapy on the Prevention of Active TB
| TB Case Rates Reduction in TB | |
| Placebo INH (10 yr. follow-up) | |
| Patients taking >80% of medication for: | |
| 10-12 mo 24.9 7.9 68.3 | |
| 0 - 9 mo 18.6 15.6 16.1 | |
| Patients taking medication >10 months compliant for: | |
| 60%-79% 26.2 11.2 57.3 | |
| 40%-59% 19.0 9.1 52.1 | |
| Ferebee, SH. Adv Tub Res 1970;17:28-106 |
How Much Isoniazid Is Needed for the Prevention of Tuberculosis?
| Longer duration of therapy corresponded to lower TB rates among those who took 0-9 mo | |
| No extra increase in protection among those who took >9 mo |
Percentage of Infected
Contacts
Age 15 - 34
Completing Treatment for LTBI
Isoniazid Preventive
Therapy
HIV Infection - TST Positive
Short-Course
Regimens
HIV Infection - TST Positive
Problems Associated with TLTBI
| Low adherence with INH therapy, mostly associated with long duration | ||
| Potential better adherence with shorter (2RZ) regs | ||
| Effectiveness of 2RZ has not been studied in | ||
| HIV-seronegative persons (decreased tolerability?) | ||
| children | ||
| High pill burden, drug toxicity, drug interactions with 2RZ | ||
| DOT necessary for intermittent regimens | ||
USPHS Study 26: Highly intermittent short-course treatment of LTBI
| Patients with LTBI at high risk for developing active disease will receive INH for 9 months OR once weekly INH/rifapentine for 12 doses (3INH/RPT) | |
| Main study outcome: rate of development of active tuberculosis | |
| Almost ~3,000 enrolled to date, sample size = 8,000 total or 4,000 per arm |
Factors Affecting the Impact of TTTLTBI
| Tuberculin skin testing | |
| Prediction of progression to disease | |
| Completion of therapy and programmatic costs | |
| Efficacy of treatment | |
| Safety of treatment |
Toxicity of Isoniazid in Persons Without HIV Infection
| Hepatitis 10.3/1000 persons | ||
| Death due to hepatitis 0.6/1000 persons | ||
| Age-related hepatotoxicity | ||
| £ 35 years 0.6-1.3/100 persons | ||
| > 35 years 2.0-3.1/100 persons | ||
| Risk factors | ||
| Active liver disease, Alcohol | ||
| Mortality risk associated with pregnancy, Hispanic ethnicity | ||
Reports of Severe Liver
Injury Associated
with RZ Treatment of LTBI
October 2000 – May 23, 2002
| 40 *cases (17 jurisdictions) | ||
| 32 hospitalized | ||
| 8 fatal | ||
| 33 investigated | ||
| 96 other reports of liver injury | ||
| * A case is defined as a person who was hospitalized or died due to | ||
| liver injury associated with RZ. | ||
Essential TB Infection Control Activities
| Screening. Measures to identify persons with active TB disease or LTBI | |
| Containment. Measures used to prevent transmission | |
| Assessment. Collection and analysis of data to monitor whether the S&C activities are being implemented |