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Latent Tuberculosis Infection (LTBI) 101

Janice Louie, MD, MPHMedical Director

San Francisco Tuberculosis Prevention and Control Program

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§ Background§ Screening (Who to Test)§Testing§ LTBI Treatment

Outline

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TB Epidemiology-U.S. (2017)

• US: 9,105 active TB cases* (2.8 per 100,000 population)

• California is a hotspot (5.3 per 100,000)

• San Francisco is super hot (13.1 per 100,000)

*Centers for Disease Control and Prevention TB Data and Statistics: https://w w w.cdc.gov/tb/statistics/default.htm

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San Francisco TB Cases: 2018

• Incidence rate of 13.1 per 100,000 (n=118)• Non-US Born: 86%• Most common countries of origin outside

of the US: China, Philippines, Vietnam• Median age: 64 years (range 3-95)• 49% were ≥65 years of age• The median age of TB cases in San

Francisco is increasing.• Most of these cases are preventable!

50.352.751.356.4

52.454.550.1

57.258.1 59 59.6 6064

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2006

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Age

(Yea

rs)

TB Case Age Trend Over Time

M ed ia n Age

2018 TB Cases by Country of Origin

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Health disparity in TB: API San Franciscans

The TB case-rate in Asian-Americans is 10.8X that in Non-Hispanic White populations

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~2.4 million Californians with latent TB infection-most are unaware and untreated

1.8M

20% 12%0.0

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2.0

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LTBI preva lence Aware of LTBI Treat ed f or LTBI

Mill

ions

of p

erso

ns

U.S. -bornForeign-born

NHANES 2011-2012 applied to California population 6

Estimated 65,111 San Franciscans with LTBI

(2017, CDPH TBCB Report)

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TB Disease vs. (Latent) Tuberculosis Infection (LTBI)

Active TB disease Latent TB infection

Cough, fever, weight loss, night sweats

No symptoms

Abnormal chest x-ray Normal chest x-ray

Infectious Not infectious

May progress to active TB disease

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Natural History of TB

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Latent TB (LTBI)(Dormant or “sleeping”)

Active TB disease

Exposure to infectious

TB

Rapidly developactive TB disease (~1-5%)

- Children <5 years- Im m unocom prom ised/HIV

- Recent converters

years

Not infected

5-10% over lifetime, depending on risk factors

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• Background• Screening (Who To Test)• Testing• LTBI Treatment

Outline

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Risk of false positives is high in a low incidence population

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86% of TB cases in SF are non-US born. Countries of origin for most cases outside of US include: China, Philippines and Vietnam.

HIV patients have exceptionally high rate of reactivation (7-10% per year); screen annually

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Routine testing of persons without risk factors is not recommended and may result in unnecessary evaluation and treatment because of false positive results

Note: Age not considered in this assessment, however younger adults have more years of expected life. Some clinicians may choose to prioritize younger non-US born persons

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Watch out! Patients with abnormal CXR and report that says “lesions consistent with old TB, no evidence of active TB”

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• Risk of developing active TB is up to 19-fold higher

• TST or IGRA may be negative• Check sputa and await culture

results before starting LTBI treatment

• Data still unclear on what are best regimenso At SFDPH we use INH+ RIF x

4 months or INH x 9 months

Radiographic lesions “consistent with inactive TB”

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LTBI with abnormal chest X-ray: 3 casesA

B

C

• Non- US born• Asymptomatic• QFT+• CXR report: “BUL nodules, calcified,

consistent with old granulomatous disease. No active disease.”

What do you do?

Check sputa!Sputa preliminary results: • Smear neg x 3, geneXp neg x 1• Await cultures (8 weeks)

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Culture resultsA

B

C

Å Yes, Active TB, pan-sensitive

Å No, TB 4 (old granulomatous disease, LTBI treatment with INH and rifampin)

Å Yes, Active TB, pan-sensitive

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Pathophysiology of TB lesions: a dynamic state

A radiographic interpretation of “old” TB on chest X-ray does NOT rule out active disease

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Risk Factors for Developing Active TB

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• Children <5 years at high risk of disseminated TB/TB meningitis

• Active TB in children is usually pauci-bacillary:- Asymptomatic or atypical

symptoms- CXR abnormalities non-

specific: look for infiltrate in lower lobes, mediastinal lymphadenopathy

- Sputum typically non-diagnostic, need gastric aspirates x 3 (geneXp often not available)

- Exposure history important- Infants and children <5 yrs

are “sentinels of transmission”

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§ Background§ Screening (Who to Test)§Testing§ LTBI Treatment

Outline

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Tuberculin Skin Testing

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> 5 mm of induration > 10 mm of induration*

Considered positive in: • Persons with HIV or immunosuppression • Recent contacts to an active case of

pulmonary or laryngeal TB • Persons with fibrotic changes on chest X-ray

consistent with old TB

Considered positive in all other persons recommended for TB screening

California TST interpretation guidelines

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History of BCG vaccination

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ESAT-6, CFP-10, and proprietary CD8 antigens (absent from all BCG strains and from most nontuberculous mycobacteria with the exception of M. kansasii, M. szulgai, and M. marinum)

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Repeat testing provided valid result (positive or negative) in 68% (Banach Int Jl TB Lung Dis 2011)

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73% false positive rate

12% false positive rate

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§ Background§ Screening (Who to Test)§Testing§ LTBI Treatment

Outline

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LTBI Treatment OptionsNormal CXR• Rifampin x 4 months• INH + rifapentine x 3 months• INH x 6 months• INH x 9 months (gold standard)- immunocompromised/HIV

TB-4 (Radiographic evidence of old TB disease)• INH + Rifampin x 4 months*

*Jasmer et al. Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis. Am J Respir Crit Care Med 2000 Nov;162(5):1648-52.

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First Line: RifampinMulti-center Phase 3 RCT: N= 3443

Rifampin x 4 months vs INH x 9 months

Study sites: Australia, Canada, Benin, Brazil, Ghana, Guinea, Indonesia, Korea, Saudi Arabia

Findings:

• Rifampin x 4 months was non-inferior to INH x 9 months for the prevention of active TB at 28 months of follow-up

• Higher rate of treatment completion

• Lower rate of adverse events and hepatotoxicity

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First Line: 3-HP by Directly Observed Therapy

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Multi-center RCT (n=8053)

3HP DOT x 12 weeks vs INH x 9 months

Study Sites: U.S., Canada, Brazil and Spain

• 3HP was non-inferior to INH x 9 months for the prevention of active TB at 33 months of follow-up

• Higher rate of treatment completion

• Lower rate of hepatotoxicity

Prevent TB Study

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Self Administered-3HP• Recommended by CDC June 2018*• Based on study of 1000+ adults in Denver, median age 36 years• SFDPH protocol:

Inclusion criteria: o All adults, who upon mutual assessment by MD and nursing, can be complianto Children <18 years who are able to swallow pills (without crushing) and can be monitored by

a parentExclusion criteria: o Any patient who requires DOPT

o Any adult where noncompliance is a concerno Children who need crushed pills or liquid formulationso Children (including adolescents and teenagers) where parents do not agree or are unable to

monitor compliance

*M M W R Weekly / June 29, 2018 / 67(25);723–726

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“52 weeks of INH prevented the most tuberculosis, but 24 weeks prevented the most tuberculosis per case of hepatitis caused.”

Second line- Isoniazid x 6 months(Use when rifamycin is not tolerated or contra-indicated)

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*But increased hepatoxicity as duration of INH increases

Second line- Isoniazid x 9 monthsRecommended for immunocompromised/HIV

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Isoniazid Adverse Events• Hepatitis

• Uncommon in age <20 years• Increased risk with older age: ~2% in ages 50-64 years• Increased risk with ETOH abuse or chronic liver disease

• Asymptomatic transaminitis (20%)• Peripheral neuropathy (<0.2%); supplement with B6 50 mg• Rash• Mild CNS effects• Note drug interactions: increase Dilantin, carbamazepine and

Antabuse levels

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Monthly Monitoring• Adherence• Symptoms:

o Fatigue, anorexia, nausea/vomiting, abdominal paino Icterus, jaundice, dark urineo Rash, itchinesso Peripheral numbness

• LFTS:o History of liver disease or ETOH useo HIVo Pregnancy/post-partum (<3 months)o Other hepatotoxic meds (e.g. statins)o Age> 50

ATS/CDC LTBI Guidelines 2000

Hold medications if:• Symptomatic and LFTS >3X ULN• Asymptomatic and LFTS >5X ULN

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Dosing recommendations in children vary:https://www.cdc.gov/tb/topic/treatment/ltbi.htm

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Take-Home MessagesTargeted Testing takes into account differing risks in populations. Do test:

• Foreign-born, especially those with medical risk factors for progression to active TB• Immunocompromised• Contacts• Converters• Residents of congregate settings• Abnormal CXR concerning for old or active TB

Diagnosis• IGRA is more specific; preferred in non-US born• TST is cheaper, reasonable to use in US born (but beware misinterpretation)

Treatment Options: Short courses are now the standard of care• Rifampin x 4 months• 3-HP x 3 months• INH x 6 months (9 months if immunocompromised)• INH x 9 or RIF/INH x 4 months if CXR suggests old TB (rule out active TB first)

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SFDPH TB Prevention and Control Program Resources

Physician/RN questions• Phone: 628 206-8524• E-consult• E-mail: janice.louie@sfdph.org or Rocio.agraz-lara@sfdph.org

Felix Crespin, Surveillance• Questions about possible active case or hospitalization discharge

approvalo628 206-3398

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Questions?

Questions?

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