Tuberculosis: An update for Primary care physicians

Tuberculosis: An Update for Primary Care Physicians

Todd Pollack, M.D. Deputy Medical Director, HAIVN Clinical Instructor in Medicine, Harvard Medical School Beth Israel Deaconess Medical Center

Outline

 Epidemiology of tuberculosis  Diagnosis and treatment of latent

tuberculosis infection (LTBI)

 Diagnosis of pulmonary tuberculosis,

including new diagnostics

 Overview of tuberculosis treatment

Global Burden of TB, 2010

Estimated number of cases Estimated number of deaths

All forms of TB 8.8 million (range: 8.5–9.2 million) 1.1 million (range: 0.9–1.2 million)

HIV-associated TB

Global tuberculosis control: WHO report 2011.

1.1 million (13%) (Range: 1.0-1.2 million) 350,000 (range: 320,000-390,000)

TB cases, by region

Global tuberculosis control: WHO report 2011.

Majority of cases in 2010 occurred in Asia (59%) 4

Estimated TB Incidence Rates, 2010

Vietnam ranks 12 / 22 countries with the highest burden of TB

Global tuberculosis control: WHO report 2011.

TB Epidemiology in Vietnam, 2010

2010 Country Data  Estimated new cases:

Multi-drug resistant TB:  2.7% of new TB

180,000

cases

 Estimated TB deaths:

 19% of re-treatment

29,000

cases

 Case detection rate:

54% (43-71)

Global tuberculosis control: WHO report 2011

Latent TB Infection (LTBI)

 In most individuals, TB infection is contained

initially by host defenses, and infection remains latent.

 In Vietnam, an estimated 50-60% of the

population has latent TB infection*

 Identification and treatment of LTBI can reduce the risk of development of disease by as much as 90 percent

*Source: Lien LT, et al. (2009) Prevalence and Risk Factors for Tuberculosis Infection among Hospital Workers in Hanoi, Viet Nam. PLoS ONE 4(8): e6798

Diagnosis of LTBI

Advantages

Tuberculin skin test (TST)

• Inexpensive • Historical “gold

standard”

• Requires a single

Disadvantages • Requires follow-up visit for reading • Reading is prone to subjective exam • False positives with recent BCG vaccine, non-TB mycobacteria

patient visit

Interferon gamma release assay (IGRA)*

• Limited data • Expensive • Errors in collecting and transporting blood can decrease accuracy

• Results available within 24 hours • BCG vaccination does not cause false positive

8 * WHO does not recommend the use of IGRAs in low and middle income countries.

Case Scenario

Duc is a 30 year-old man who is found to have latent TB infection (LTBI) during an employment health exam. He has no known contact with an active TB case. He is healthy with no medical problems. His employer also requires an HIV antibody test and his result is pending.

Question #1

What is his approximate risk for developing active TB if he is HIV negative? and what is his risk if he is HIV positive? a) Risk is same for both: 10% over lifetime b) HIV (-): 10% over lifetime; HIV (+): 10%

per year

c) HIV (-): 10% per year; HIV (+): 10% over

lifetime

Progression to TB Disease (1) TB and HIV People who are infected with both M. tuberculosis and HIV are much more likely to develop TB disease

TB infection and NO risk factors TB infection and HIV infection (pre-Highly Active Antiretroviral Treatment [HAART])

Risk is about 7% to 10% PER YEAR, a very high risk over a lifetime

Source: CDC Self-Study Modules on Tuberculosis, 2010

Risk is about 5% in the first 2 years after infection and about 10% over a lifetime

Progression to TB Disease (2)

Some conditions increase probability of LTBI progressing to TB disease

• Injection drug use • Underweight or malnourished

• HIV infection • Recent TB infection • History of prior, untreated TB or fibrotic lesions on chest x-ray

• Silicosis • Diabetes mellitus • Chronic renal failure or on

hemodialysis

• Solid organ transplantation • Prolonged therapy with corticosteroids or other immunosuppressants • Carcinoma of head or neck • Gastrectomy or jejunoilial

bypass

Source: CDC Self-Study Modules on Tuberculosis, 2010

Evaluation of Persons with Positive TST or IGRA

Person has a positive test for TB infection

TB disease ruled out

Consider for LTBI treatment

Person accepts and is able to receive treatment of LTBI

If person refuses or is unable to receive treatment for LTBI, follow-up TST or IGRA and serial chest radiographs are unnecessary

Develop a plan of treatment with patient to ensure adherence

Educate patient about the signs and symptoms of TB disease

Source: CDC Self-Study Modules on TB, 2010

Question #2

Assuming his HIV antibody test is negative, what is a preferred option for treatment of LTBI is this patient? a) Rifampin daily for 4 months Isoniazid daily for 9 months

b) c) Rifampin plus pyrazinamide daily for 2

months Isoniazid plus rifapentine weekly for 3 months

Treatment Regimens for LTBI

Drug(s)

Duration

Interval

Minimum Doses

Isoniazid 9 months Daily 270

Twice weekly* 76

6 months Daily 180

Twice weekly* 52

3 months Once weekly* 12

Isoniazid & Rifapentine 

* Use Directly Observed Therapy (DOT)

# Option equal to 9-month INH regimen in certain groups (healthy patients, ≥ 12 years old, at higher risk for developing TB)

Rifampin 4 months Daily 120

15 Source: Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection, MMWR, 2011

Case Scenario

After discussion with his physician, Duc elects not to take treatment for latent TB infection. One year later, he presents to the clinic with 2 weeks of fever, cough, and night sweats.

Question #3

What diagnostic tests should be ordered, if available, to evaluate for pulmonary TB? a) Chest x-ray and sputum smear for AFB b) Chest x-ray, sputum smear for AFB and

molecular testing (nucleic acid amplification) c) Chest x-ray, sputum smear for AFB, sputum

culture for AFB, and molecular testing

d) Chest x-ray, sputum smear for AFB, sputum culture for AFB, molecular testing, and drug susceptibility testing (if culture positive)

Diagnosis of Pulmonary TB

History and Exam

Chest Radiograph

Sputum AFB smear and culture

Nucleic Acid Amplification (NAA)

TB Chest Radiograph

Distinguishing features: 1) Predilection for upper lobes  Apical and posterior

segments 2) Tendency for cavitation

Radiographic Manifestations of Tuberculosis: A Primer for Clinicians, 2nd Edition, June 2006

Diagnosis of Pulmonary TB Sputum AFB Smear and Culture

 Sputum AFB smear

• Most rapid and inexpensive TB diagnostic tool • Obtain 3 sputum specimens • Sputum can be collected spontaneously or by

induction  AFB Culture

• Higher sensitivity than microscopy

 Smear: 45-80%; Culture: 80-98%

• Allows for drug susceptibility testing and species

identification

• Better for monitoring treatment response

Diagnosis of Pulmonary TB Nucleic Acid Amplification (NAA)

 Amplification of a specific target RNA or DNA sequence

that can be detected via a nucleic acid probe

 Provides rapid results (24-48 hours)  High sensitivity and specificity in respiratory specimens

Sensitivity

Specificity

AFB Smear +

95%

98%

AFB Smear -

75-88%

95%

 Does not replace need for AFB smear and culture

• Culture is required for drug susceptibility testing • NAA can detect nucleic acid from dead and live organisms so

not useful for monitoring treatment response

Source: Updated Guidelines for the Use of Nucleic Acid Amplification Tests in the Diagnosis of Tuberculosis, JAMA. 2009;301(10):1014-1016.

New TB Diagnostics: GeneXpert test (1)

 Automated nucleic acid amplification test

 Simultaneously

identifies M.TB and rifampin resistance  Rapid results (< 2

hours)

 17 machines

donated to Vietnam

Source: Rapid Molecular Detection of Tuberculosis and Rifampin Resistance, NEJM 2010; 363:1005

GeneXpert Test (2)

HIV (+) individuals suspected of having TB

Individuals at risk of MDR-TB

Primary considerations

• Diagnosed with TB • Suspected of having TB

HIV (-) individuals not at risk of MDR-TB with either:

Secondary considerations

• Abnormal CXR • Sputum smear (-) but still suspected of having TB

Individuals accessing health centre

Xpert MTB/RIF

TB, Rif resistance

TB, no Rif resistance

No TB detected

- MDR-TB regimen

- Appropriate further clinical management

- Drug susceptibility testing

- Treatment regimen based on patient history

Adapted from: Rapid implementation of the Xpert MTB/RIF diagnostic test, WHO 2011

Diagnosis of Pulmonary TB Interpretation of Test Results Action

Interpretation NAA

+ Diagnosis AFB smear +

+ Presumptive diagnosis

established

Start treatment Await culture results for drug susceptibility testing Repeat NAA to confirm result Consider starting TB therapy while awaiting culture results

- +

False negative NAA or Nontuberculous mycobacteria Repeat NAA to confirm result Use clinical judgment while awaiting culture results

- -

TB cannot be definitely excluded Use clinical judgment while 24 awaiting culture results

Case Scenario

Duc is diagnosed with pulmonary TB based on his clinical presentation and a positive sputum AFB smear. Culture and drug susceptibility testing is not available.

Question #4

What is the best treatment regimen for this patient? a) 2RHZE, 4RH b) 2RHZE, 6HE c) 2SRHZE, 1RHZE, 3HRE d) 2RHE, 6HE

NOTE: Rifampin (R), Isoniazid (H), Ethambutol (E), Pyrazinamide (Z), Streptomycin (S)

Basics of TB Treatment

 Principles of treatment

• Use a safe, effective combination of drugs for

the shortest time possible

• Use multiple drugs • Never add single drug to failing regimen • Ensure adherence to therapy (DOT)

Basics of TB Treatment Initial Phase

 TB must be treated with at least two drugs

to which the organism is susceptible. • Susceptibility is not known initially • Assume resistance until proven susceptible • Modify the regimen after results are known  Begin with 4 drugs (in areas where the rate of INH monoresistance is > 4%)

Basics of TB Treatment Continuation Phase

 Most patients are treated with a 4 month

continuation phase consisting of INH and RIF • RH leads to less treatment failure and relapse

compared to HE*

 Total duration of treatment for pulmonary TB

is 6 months

 Longer treatment is indicated for patients with bone and joint disease (6-9 nine months) and CNS disease (12 months)

*Source: Results at 30 months of a randomized trial of two 8-month regimens for the treatment of tuberculosis. IJTLD 15(6):741–745

Vietnam National TB Treatment Guidelines

Intensive Phase Indications

Continuation Phase

I S(H)ERZ x 2 months HE x 6 months

or RH* x 4 months

New TB cases *RH used only with DOT

HRE x 3 months Treatment failure,

recurrent or severe TB

II SRHZE x 2 months, then RHZE x 1 month

Source: Vietnam TB Treatment Guidelines. Ministry of Health, 2009.

III HRZE x 2 months HR x 4 months Pediatric TB cases

Key Points

 Vietnam has one of the highest burden of TB

cases in the world

 HIV infection significantly increases the risk

of progression from latent to active TB

 NAA testing, when added to sputum smear and culture, allows for rapid diagnosis of pulmonary TB

 Treatment should follow drug susceptibility testing, if available, and national treatment guidelines

Tuberculosis: An update for Primary care physicians - Todd Pollack, M.D

Outline of Tuberculosis - An update for Primary care physicians: Epidemiology of tuberculosis; diagnosis and treatment of latent tuberculosis infection (LTBI); diagnosis of pulmonary tuberculosis, including new diagnostics; Overview of tuberculosis treatment.