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TUBERCULOSIS
IN SPECIAL
SITUATIONSDR VIPUL
ASSISTANT PROFESSORTB & RESPIRATORY MEDICINE
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SPECIAL SITUATIONS
PREGNANCY AND LACTATION
DIABETES MELLITUS
ELDERLY LIVER DISEASE
HIV/AIDS
CHILDREN MDR AND XDR TB
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Treatment During Pregnancy
Risk to mother and fetus is far greater fromuntreated TB than from the drugs used to treatTB
Increased risk of spontaneous abortionIncrease in perinatal mortality
Small for gestational age births
Increased maternal morbidity
Congenital TB
Increased risk of perinatal and early post-nataltransmission
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Isoniazid (INH), rifampicin and ethambutol areknown to be safe for administration during
pregnancy There is insufficient data on the teratogenic
effect of PZA
Pregnant and postpartum women are atincreased risk of INH induced hepatitis
Supplement with pyridoxine 50mg/day
Monitor for signs of hepatotoxicity duringpregnancy and immediate post-partum
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SM induced ototoxicity has been reported
irrespective of period of gestation. Therefore
SM should not be used during pregnancy.
WHO recommends standard chemotherapy
under DOTS for pregnant patients.
Duration of ATT need not be modified.
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MDR TB IN PREGNANCY
Almost all second line drugs are teratogenic.
Pregnancy is best avoided.
If required treatment should be postponed tillsecond trimester.
The decision should be based on analysis of
relative risks and benefits.
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Breastfeeding
Most of the TBmedications are secretedinto breast milk but notin significant
concentrations (usually 5 times if asymptomatic
INH, PZA and RIF can all cause hepatotoxicity
Hepatitis from INH is age related, from PZA is dose related,
and RIF is unpredictable and less common
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GRADING
Grade I: ALT 51-125 IU/L
Grade II: ALT 126-250 IU/L
Grade III: ALT 251-500 IU/L Grade IV: ALT > 500 IU/L
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TB Treatment and Hepatitis
If3x normal with symptoms or >5x normalwithout symptoms:
stop all anti-TB medications and evaluate patient
refer patient to doctor for clinical evaluation
try to rule out other causes of acute liver disease
if severely ill, may start 3 non-hepatotoxic drugs
after AST
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REINTRODUCTION OF DRUGS
When AST levels reach less than 2 times normal,reintroduction should be tried.
Restart RIF first followed by INH and PZA
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TB and HIV infection
the cursed duet
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Immunopathogenesis
Kaufmann et al, Nature Medicine 2005
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HIV TB pandemic
TB is the leading opportunistic infection in
HIV infected patients
Often the first indicator of immune deficiency (AIDSdefining Illness)
World wide 40 million HIV infected of whom15million are co infected with TB
Tuberculosis accelerates the progression of HIVinfection and HIV increases the likelihood of active TBdisease
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Immunopathogenesis of TB-HIV
HIV infection is associated to:
Decreased chemotaxis
Defective granuloma formation and maintenance
Impaired antigen processing and presentation
Loss of CD4+ T cells
Selective clonal deletion ofM. tuberculosis-specific CD4+ T
cells Loss of IFN-g+/IL-2+ CD4+T cell precedes the loss of IFN-
g+ /TNF-a+ CD4+ T cells
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Opportunistic diseases in the course
of HIV-infection
CD4+
(cells/L)
800-
600-
400-
200-
0-
0 2 4 6 8 10
50-
Seroconversion:
Acute retroviral syndrome
MACCMV
Pneumococcal pneumonia
Candida vaginitis
ITP
Years after infection
Oral Candida-infection
Kaposi sarcoma
Lymphoma
Dementia
Oral haircell-leukoplacia
CachexiaToxoplasmosis
PCP
HSV
Candida esophagitis
Cryptococcosis
TB
P l l
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Pulmonary vs extra-pulmonary
TB: HIV+ vs HIV-
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TB diagnosis in HIV+ persons
Microbiology
Radiology
TST
IGRA
http://www.chestjournal.org/cgi/content/full/121/3/774/F17/30/2019 TB in special situations
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Microbiological diagnosis
Microscopy, AAFB sputum staining: 1 day
Culture: liquid medium (2-8 weeks), solid medium (8-18weeks)
Identification: analysis of positive cultures by molecularbiology assays (2-4 weeks)
Drug- sensitive assays:
to INH and RFP: 2-4 weeksto other drugs: 6-8 weeks
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Microbiological diagnosis
Microscopy, smear AAFB sputum: sensitivity isaround 45% in HIV+ compared to 60% of HIV-patients (Hirao et al, 2007)
Probably due to the reduction of cavitationwhich results in a lower number of bacilliexpectorated
R di l i l f f HIV+
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Radiological features of HIV+
patients
cavitary TB
CD4+ 510 (23%)
TB Pleuritis
CD4+ 34 (8%)
miliary TB
CD4+ 194 (18%)
Lange et al, Pneumologie 2004
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Radiological tools
Pulmonary TB:
Chest xRay: 14% of those with culture-positive TBhave a normal chest xRay
CT-scan: mediastinal and hilarlymph nodes
HRCT (1 mm slices): interstitial lesions tree and bud appearance
Extra-pulmonary TB:
Radio-nuclide scans/MRI (bone, CNS)CT-scan
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TST
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Positive TST
M. tuberculosis
Active TB diseaseLatent TB infection
(past exposure to M.tuberculosis)
Latent TB infection(recent exposure to M.
tuberculosis)
NTMExposure to environmental
mycobacteria
BCG-vaccination
BCG-vaccination
Tuberculin skin test (TST)
TST does not distinguish
among all these different clinical situations
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Tuberculin skin testing
Tuberculin reactivity four fold less in HIV infection
Reactivity declines with increasing immunesuppression
early HIV 40-70 % advanced HIV 10-30%
Annual tuberculin testing for HIV infection to
detect latent infection
Tuberculin anergy assoc. with risk of active TB iscontroversial
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T cell-based assays
Interferon Gamma Release Assay (IGRA)
New generation of diagnostic tests for TB that
measure in vitro the interferon- release fromactivated T-cells in response to TB specific RD1antigens (ESAT6, CFP10,+/-TB7.7)
Commercially available IGRAs
QuantiFERON-TB Gold (QF-TB-2G), in Tube (QF-TB-3G) T-SPOT.TB (TSPOT)
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Treatment of TB/HIV complicated by
Optimal regimen for treatment of co-infection not defined
Optimal timing of HAART unclear
Drug-drug interactions
Large pill burden
Variable drug absorption
Risk of further AIDS-defining illnesses if HAART is deferred
during TB treatment Paradoxical reactions
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ART drug Classes
Nucleoside reverse transcriptase inhibitors(NRTI)
Non nucleoside reverse transcriptase
inhibitors (NNRTI)
Protease inhibitors (PI) Fusion inhibitors
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NRTIS
Zidovudine
Lamivudine
Stavudine
Zalcitabine
Didanosine
Abacavir
Tenofovir
Emtricitabine
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Protease Inhibitors
Indinavir
Ritonavir
Nelfinavir
Saquinavir
Amprenavir
Lopinavir
Atazanavir
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NNRTIs Nevirapine
Delavirdine
Efavirenz
FUSION INHIBITORS
Enfuviritide
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Combinations never used
AZT+ Stavudine - antagonistic
Ddi+ Stavudine
Stavudine+Zalcitabine
Zalcitabine+ Ddi additive toxicity
Atazanavit+Indinavir
Emtricitabine +lamivudine ~ resistance profile Efavirenz based regime in pregnancy
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Drug interactions
Use of Rifampicin with PI / NNRTI based
ART is contraindicated.
NRTI are not metabolized by hepatic cytochrome P450 enzyme system hence they can safely be used withRifampicin based ATT
Other first line ATT (SHEZ) no interactions with ARTand can be used safely : SHEZ x 2 months followed bySHZx7months
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Rifabutin :less potent inducer and can be used in
place of Rifampicin in ATT with PI
NNTRI based ART ( equivalent bactericidal
action, clinical cure rates )
Ritonavir retards Rifabutin metabolism(levels 35 fold) toxic reactionsuveitis,
neutropenia , arthralgia occur. combination
is contraindicated
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ART+ ATT Recommendations
CD4 count 350cells/mm3
Treat TB. Monitor CD4 counts. Defer ART.
A i i l h
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Antiretroviral therapyfor HIV infection in adults
and adolescents2010 revision
HIV/TB co infection Irrespective of CD4 cell counts, patients co
infected with HIV and TB should be started
on ART as soon as possible after starting TBtreatment
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THANK YOU