Tuberculin skin testing and treatment of latent TB

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Tuberculin skin testing and treatment of latent TB
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Outline

• Terminology of TB
• Importance of TB among HIV infected persons
• Issues in tuberculin skin-testing placement,
  reading, interpretation, evaluation of a positive
  test
• Issues in treatment of latent TB infection dose
  of INH, side effects and their management,
  duration, adherence issues

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Tuberculosis
1.
2.
3.
4.
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Terminology of TB

• Tuberculin skin test (TST), PPD skin test
• Latent TB infection (LTBI), inactive TB, dormant
  TB
• Treatment of latent TB infection,TB preventive
  therapy, TB prophylaxis
• Active TB - TB disease
• Treatment of active TB

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Why is Tuberculosis Important in Persons with HIV
Infection?

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Why is tuberculosis important?

• Most common opportunistic infection among
  HIV-infected patients in Africa, SE Asia
• Leading cause of AIDS-related deaths worldwide

One-third of all AIDS-related deaths are due to TB
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Global distribution of tuberculosis
Dye et. al. JAMA 1999 282 677
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Case 1

• 26 year old woman enrolled in MTCT-Plus
• 8 weeks after delivery
• Mother CD4 cell count 420 cells/mm3
• 2 year old HIV positive
• Infant HIV tests pending
• Mother has no symptoms and physical exam is
  normal

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Case 1 Questions

• Would a tuberculin skin test (TST) be done as
  part of the initial evaluation at your site?
• If yes, would your site provide INH as treatment
  of latent TB infection if the skin test was
  positive?

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Latent Tuberculosis Infection

• Common Concerns about Screening and Treatment

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Common Concerns

• National TB control program does not recommend
  TST, treatment of latent TB
• Use of routine BCG during infancy makes skin
  testing inaccurate
• Treatment of latent infection wont make a
  significant difference where TB is so common
• Using INH for treatment of latent TB will
  increase rates of INH resistance

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What are your national TB Control Programme
Guidelines?

• For tuberculin skin testing among HIV infected
  persons?
• For the use of INH treatment of latent TB?

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Effect of TB exposure on TST results in a BCG
vaccinated population

• Setting - village in Ghana, country with
  universal BCG just after birth (96 coverage
  rate)
• Study - tuberculin skin testing of two kinds of
  households
• 1) household with recently-diagnosed case of
  active pulmonary TB
• 2) neighboring households without active TB

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TST results and TB exposure in area using BCG
vaccination - results in infants/children
Am J Respir Crit Care Med 2003 168 448-455
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Conclusions Use of TST where BCG vaccination is
common

• In a setting of universal BCG
• Positive TST is strongly associated with TB
  exposure
• TST reaction is not associated with presence of
  BCG scar
• True for children and adults
• Interpret TST the same whether BCG has been given
  or not
• HIV-positive or recent contact 5 mm
• HIV-negative, not recent contact 10 mm

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TST identifies persons at high risk of active TB
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Isoniazid (INH) reduces active TB rate by 60
among patients with positive TST ( 5 mm)

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Adverse events in studies of INH treatment of
latent TB - Uganda
Severe 0 0
DC meds 0.2 0.6
Group Placebo INH
Mild 5 10
Moderate 0 0.7
Conclusion - side effects were more common
with INH, but most were mild
N Engl J Med 1997337801-8
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Types of adverse events from INH for latent TB -
Zambia
Adverse event leading to drug discontinuation He
patitis Rash GI symptoms Others
Placebo (n 360) 0 0 1 (0.3) 2 (0.6)
INH (n 360) 3 (0.8) 1 (0.3) 5 (1.4) 3
(0.8)
AIDS 1998122447-57
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Efficacy of INH among HIV-positive, TST-negative
persons in Africa
AIDS 199711875-82, AIDS 1998122447-57, N Engl
J Med 1997337801-8
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Risk of INH resistance after INH treatment for
LTBI data among HIV-positive patients
Placebo INH-resis / total 0 / 21 1 / 24 0 / 15 1
/ 5 0 / 5 2 / 70 (2.9)
INH treatment INH-resis / total 2 / 17 5 / 20 0
/ 4 0 / 3 0 / 3 7 / 47 (14.9)
Trial site Kenya Uganda Haiti Zambia U.S. Total
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INH for LTBI and INH-resistance data from
placebo-controlled trials in the era prior to HIV
INH-susceptible, n INH-resistant, n ()
INH 43 2 (4.4)
Placebo 64 2 (3.0)
Bull Wld Hlth Org 196635509-26
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Effect of INH resistance on outcomes of treatment
for active TB
Died 2 2 2
Failure 2 4 11
Default/ transfer 11 12 13
Success 85 82 73
Drug-susceptible IHN-resistant
(any) RIF-resistant (any)
JAMA 20002832537-45
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Common concerns about screening for and treating
latent TB - responses

• MTCT-Plus programs may be able to help bring
  about change in guidelines
• TST results correlate with TB exposure even when
  BCG is used
• TST positive patients are at greatly increased
  risk of active TB
• Treatment of latent infection effective in
  decreasing risk of active TB, but only among
  TST-positive patients
• INH-resistance may be more common in those who
  receive INH for latent TB, but treatment can
  still be effective

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Diagnosis of Latent TB Infection

• The Tuberculin Skin Test

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Case 1 - continued

• TSTs placed and read 3 days later
• Woman 10 mm
• 2 year old son 6 mm
• Questions
• Are these tests positive?
• What should be done now?

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Diagnosis of latent TB with the TST

• The issues
• Applying the tuberculin skin test
• Reading the test
• Interpreting the test including in children
• Management of positive TST

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Applying the tuberculin skin test
Courtesy of Dr. Marc Steben
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Applying the tuberculin skin test
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Applying the tuberculin skin test
Courtesy of Dr. Marc Steben
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Reading the tuberculin skin test

• Read 2-3 days after placing the test
• Feel for induration
• Color change without induration is not included
  in the measurement
• Use a ruler or calipers
• Have someone else check if unsure
• Always document the exact size (mm) not just
  positive or negative

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Reading the tuberculin skin test
Courtesy of Dr. Marc Steben
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Reading the tuberculin skin test
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Yield of TST among patients with HIV infection -
Uganda

• Patients diagnosed with HIV at voluntary
  counseling and test site
• 1524 offered TST, 1344 (88) accepted
• Of 1344 TSTs placed, 1094 (81) were read
• 579 (53) of TSTs read were positive ( 5 mm
  induration)
• 33 (5.7) of the 579 with positive TST had active
  TB

AIDS 19959267-73
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Possible ways to increase adherence with return
for TST reading

• Stress importance of TST reading
• Schedule return for reading TST results with
  another medical appointment or support group
  meeting
• Incentive small amount of money or coupon
• Help with transportation
• Schedule TST reading for the day of a home visit
  - have an outreach worker trained to read TST
  results

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Positive Tuberculin Skin TestsEvaluation and
Management
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Evaluation of a patient with positive TST

• Evaluate for active TB
• Re-check symptoms and exam cough, fever, weight
  loss, enlarged lymph nodes, dyspnea
• Chest X-ray, if possible
• 33 / 579 (5.7) of TST-positive patients had TB
  in Uganda

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Management of patient with positive TST

• If no signs of active TB
• Check for contraindications to INH prior
  intolerance, symptoms of hepatitis (nausea,
  jaundice)
• Assess readiness for INH treatment
• Discuss importance of adherence with INH and with
  clinic visits for monitoring
• Offer INH treatment of latent infection to
  positive (5mm) TST
• Adults INH 300 mg daily plus MTCT Plus
  multivitamin daily x 6 months

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Use of Isoniazid to prevent TB in pregnant women

• Some evidence that INH-related hepatitis may be
  more severe during pregnancy
• Risk of progression to active TB is significant
• Recommendation offer INH preventive therapy to
  HIV-positive pregnant women with positive TST
• Monitor carefully for signs of hepatitis

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Use of Isoniazid to prevent TB in infants/
children

• INH dose
• 20 mg/kg per day, maximum of 300 mg
• Giving INH to children who cannot swallow pills
• Crush tablets, give with food
• Dont give with food with high sugar content
• Side effects of INH are rare in children

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Adherence to INH treatment of latent TB
Country Uganda Uganda Tanzania
Completed 6 months and compliance 80 62
(332 / 520) 76 (72 / 98) 55 (16 / 29)
Conclusion prolonged therapy of any kind is
an adherence challenge
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Side effects of INH

• Common
• Mild upset stomach
• Mild skin rash
• Mild decrease in energy level
• Uncommon, but serious
• Drug-induced hepatitis
• Seizures (very rare with standard dose of INH)
• Peripheral neuropathy (very rare if MTCT-Plus
  multivitamin is given)

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Suggested monitoring during INH treatment of
latent TB

• Ask about symptoms of TB
• Educate on the importance of evaluation in the
  clinic for nausea, poor appetite, dark urine, or
  jaundice
• Dispense no more than one months supply of INH
• Ask patients about symptoms of hepatitis at each
  visit
• If symptomatic, stop INH and obtain SGOT

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Case 1 (continued)

• TST interpretation
• Mother 10 mm positive TST
• 2 year old son 6 mm positive TST
• No signs or symptoms of TB
• Both have normal CXRs
• Management INH for 6 months

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Summary

• TB is the most common complication of HIV in
  Africa
• Tuberculin skin test identifies persons at high
  risk of TB
• Prior history of BCG should not change TST
  interpretation
• INH preventive therapy decreases the risk of
  active TB by 60
• TST recommended as part of initial and ongoing
  evaluation in MTCT-Plus

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Effect of ART on Prevention of TB

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Effect of ARV on incidence of active TB, by
baseline CD4 cell count
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Summary of the effect of antiretroviral therapy
on rates of active TB

• In multiple studies done in a variety of
  settings, use of antiretroviral therapy decreases
  the rate of active TB in the population
• The effect of antiretroviral therapy is greatest
  in areas with high rates of TB and among patients
  with lower CD4 cell counts
• Decreasing the risk of active TB is an important
  benefit of antiretroviral therapy

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MTCT-Plus recommends

• For patients without history of active TB
  disease
• TST at enrollment
• Annual TST thereafter
• Treatment with isoniazid for all patients with
  positive TST in whom active TB disease has been
  excluded