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Tuberculin skin testing and
treatment of latent TB
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
The MTCT-Plus Initiative 2
Tuberculosis
1. 2.
3. 4.
The MTCT-Plus Initiative 3
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
The MTCT-Plus Initiative 4
Why is Tuberculosis Important in
Persons with HIV Infection?
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
The MTCT-Plus Initiative 6
Global distribution of tuberculosis
Dye et. al. JAMA 1999; 282: 677
The MTCT-Plus Initiative 7
Case #1
26 year old woman enrolled in MTCT-Plus
8 weeks after delivery
– Mother: CD4 cell count = 420 cells/mm 3
– 2 year old: HIV positive
– Infant: HIV tests pending
• Mother has no symptoms and physical
exam is normal
The MTCT-Plus Initiative 8
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?
The MTCT-Plus Initiative 9
Latent Tuberculosis Infection:
Common Concerns about Screening
and Treatment
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 won’t make
a significant difference where TB is so
common”
• “Using INH for treatment of latent TB will
increase rates of INH resistance”
The MTCT-Plus Initiative 11
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?
The MTCT-Plus Initiative 12
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
The MTCT-Plus Initiative 13
TST results and TB exposure in area using
BCG vaccination - results in infants/children
Am J Respir Crit Care Med 2003; 168: 448-455
The MTCT-Plus Initiative 14
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
The MTCT-Plus Initiative 15
TST identifies persons at
high risk of active TB
The MTCT-Plus Initiative 16
Isoniazid (INH) reduces active TB rate by 60%
among patients with positive TST (> 5 mm)
The MTCT-Plus Initiative 17
Adverse events in studies of INH
treatment of latent TB - Uganda
Group Mild Moderate Severe DC meds
Placebo 5% 0 0 0.2%
INH 10% 0.7% 0 0.6%
Conclusion - side effects were more common with
INH, but most were mild
N Engl J Med 1997;337:801-8
The MTCT-Plus Initiative 18
Types of adverse events from INH for
latent TB - Zambia
Adverse event leading Placebo INH
to drug discontinuation (n = 360) (n = 360)
Hepatitis 0 3 (0.8%)
Rash 0 1 (0.3%)
GI symptoms 1 (0.3%) 5 (1.4%)
Others 2 (0.6%) 3 (0.8%)
AIDS 1998;12:2447-57
The MTCT-Plus Initiative 19
Efficacy of INH among HIV-positive, TST-
negative persons in Africa
AIDS 1997;11:875-82, AIDS 1998;12:2447-57, N Engl J Med 1997;337:801-8
The MTCT-Plus Initiative 20
Risk of INH resistance after INH treatment
for LTBI – data among HIV-positive patients
Trial site INH treatment Placebo
INH-resis / total INH-resis / total
Kenya 2 / 17 0 / 21
Uganda 5 / 20 1 / 24
Haiti 0/4 0 / 15
Zambia 0/3 1/5
U.S. 0/3 0/5
Total 7 / 47 (14.9%) 2 / 70 (2.9%)
The MTCT-Plus Initiative 21
INH for LTBI and INH-resistance – data from
placebo-controlled trials in the era prior to HIV
INH Placebo
INH-susceptible, n 43 64
INH-resistant, n (%) 2 (4.4%) 2 (3.0%)
Bull Wld Hlth Org 1966;35:509-26
The MTCT-Plus Initiative 22
Effect of INH resistance on outcomes of
treatment for active TB
Failure Died Default/ Success
transfer
Drug-susceptible 2% 2% 11% 85%
IHN-resistant (any) 4% 2% 12% 82%
RIF-resistant (any) 11% 2% 13% 73%
JAMA 2000;283:2537-45
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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
The MTCT-Plus Initiative 24
Diagnosis of Latent TB Infection
The Tuberculin Skin Test
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?
The MTCT-Plus Initiative 26
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
The MTCT-Plus Initiative 27
Applying the tuberculin skin test
Courtesy of Dr. Marc Steben
The MTCT-Plus Initiative 28
Applying the tuberculin skin test
The MTCT-Plus Initiative 29
Applying the tuberculin skin test
Courtesy of Dr. Marc Steben
The MTCT-Plus Initiative 30
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”
The MTCT-Plus Initiative 31
Reading the tuberculin skin test
Courtesy of Dr. Marc Steben
The MTCT-Plus Initiative 32
Reading the tuberculin skin test
The MTCT-Plus Initiative 33
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 1995;9:267-73
The MTCT-Plus Initiative 34
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
The MTCT-Plus Initiative 35
Positive Tuberculin Skin Tests:
Evaluation and Management
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
The MTCT-Plus Initiative 37
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
The MTCT-Plus Initiative 38
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
The MTCT-Plus Initiative 39
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
– Don’t give with food with high sugar content
• Side effects of INH are rare in children
The MTCT-Plus Initiative 40
Adherence to INH treatment of latent TB
Country Completed 6 months and
compliance > 80%
Uganda 62% (332 / 520)
Uganda 76% (72 / 98)
Tanzania 55% (16 / 29)
Conclusion – prolonged therapy of any kind
is an adherence challenge
The MTCT-Plus Initiative 41
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)
The MTCT-Plus Initiative 42
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 month’s supply
of INH
• Ask patients about symptoms of hepatitis at
each visit
• If symptomatic, stop INH and obtain SGOT
The MTCT-Plus Initiative 43
The MTCT-Plus Initiative 44
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
The MTCT-Plus Initiative 45
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
The MTCT-Plus Initiative 46
Effect of ART on Prevention of TB
Effect of ARV on incidence of active TB,
by baseline CD4 cell count
The MTCT-Plus Initiative 48
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
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