Transcript Tuberculosis in the Setting of HIV Infection

Tuberculosis in the Setting of HIV
Infection
Zelalem Temesgen, M.D.
Tuberculosis Clinical Intensive
Sept 9-11,2013
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Disclosures
• Unrestricted educational grants
• Gilead, Janssen, ViiV, Merck, CDC
• Research grants
• Gilead, Pfizer, NIH
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Learning Objectives
• Describe the epidemiology of TB/HIV co-infection
• Describe the impact of HIV on the natural history of
TB
• Describe current guidelines for the diagnosis and
treatment of LTBI in the setting of HIV infection
• Explain treatment and management strategies for
TB patients with HIV.
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Epidemiology
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Tuberculosis: 2011 Global Burden of
Disease
• 12 million prevalent cases • 1.4 million people died
(10-13 million)
from TB in 2011
• 1 million deaths among
• 8.7 million incident cases
HIV-negative
(8.3-9 million)
individuals
• 125 cases per 100 000
• 430 000 among people
population
who were HIV-positive.
• Asia (59%)
• Africa (26%)
• Eastern Mediterranean
Region (7.7%)
• Europe (4.3%)
• Americas (3%)
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Tuberculosis: High-Burden Countries
• Afghanistan
• Myanmar
• Bangladesh
• Nigeria
• Brazil
• Pakistan
• Cambodia
• Philippines
• China
• Russian Federation
• DR Congo
• South Africa
• Ethiopia
• Thailand
• India
• Uganda
• Indonesia
• UR Tanzania
• Kenya
• Viet Nam
• Mozambique
• Zimbabwe
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United States: Reported TB Cases
United States, 1982–2012
30,000
2012 Data
9,951 Cases
Rate
3.2/100,000
No. of Cases
25,000
20,000
15,000
10,000
5,000
0
Year
Data are updated as of 2/22/13 and are provisional
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Reported new tuberculosis cases, by county —
United States, 2010–2012
DC
Reported a new TB case
Did not report a new TB case
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Rate* of TB Cases by Race/Ethnicity — United States, 2012
2012
2012
2012
Race
Race
Rate
Hispanic
Asian
Black
White
Race
Rate
Rate
5.2
Hispanic
5.2
19.8
Asian
19.8
5.7
Black
5.7
0.8
White
0.8
7.3x
6.6x
Hispanic
5.2
Asian
19.8
Black
5.7
White
0.8
25.0x
* Per 100,000 population
Data are updated as of 2/22/13 and are provisional.
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©2010
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TB
HIV/TB
HIV
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TB and HIV Coinfection
• Of the 8.7 million incident cases in 2011, 1.1
million (13%) were among people living with
HIV
• In Africa, 39% of TB cases were estimated to be
coinfected
• Africa accounted for 79% of TB cases among
people living with HIV worldwide
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Estimated HIV Coinfection in Persons
with HIV Test Results, United States, 1993–2012
30
% Coinfection
25
20
15
10
5
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Aged 25-44
All Ages
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Natural History
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HIV Immune Deficiency
• Loss of specific antibody
responses
• Reduced lymphocyte function decreased
• Increased immune
• Delayed hypersensitivity
activation
• Diminished T cell repertoire
response to recall antigens
• Phagocytosis
• Chemotaxis
• Intracellular killing
• Natural killer cell-mediated
killing
• disruption of
immunoregulatory
cytokine expression and
production
• Decreased IL-2, γ
interferon, and IL-12
• Increased IL-1, IL-6, TNFα
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Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, 483-490 (2011) doi:10.1038/nature09657
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Tuberculous infection progressed to active disease within 106
days of acquiring the infection in 37 percent (11 of 30) of HIVinfected patients.
Tuberculosis did not develop in any of 28 staff members with
exposures, although there were 6 with documented tuberculin
conversions and 8 others had positive tuberculin reactions of
unknown duration.
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7 of 18 (39%) HIV-infected inpatients developed
active tuberculosis within 60 days of diagnosis of the
index case
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Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, 483-490 (2011) doi:10.1038/nature09657
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• Forty-nine HIV-seropositive subjects and 62 HIVseronegative subjects had a positive TST
response.
• Active tuberculosis developed in eight of the HIVseropositive subjects (4 percent) and none of the
seronegative subjects during the study period
(P<0.002).
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HIV Epidemic State and Estimated Relative Risk of Developing Tuberculosis (TB) in
HIVInfected Persons in Comparison with HIV-Uninfected Persons (Incidence Rate Ratio).
Getahun H et al. Clin Infect Dis. 2010;50:S201-S207
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Diagnosis of LTBI in HIV-Infected
Individuals
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Am J Respir Crit Care Med Vol 175. pp 737–742, 2007
•
•
•
•
294 HIV-infected subjects
TST vs. QFT
89.3% concordance between QFT and TST
only 28% subjects with positive test results by
either TST or QFT had positive test results by
both modalities.
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• 2348 household contacts of sputum smear positive
TB cases followed over 24 months
• Twenty six contacts diagnosed with definite TB
• TST sensitivity 56%
• ELISPOT 52%
• 71% were positive by one or other test
• Those negative on either or both tests had the
lowest rate of progression
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J Acquir Immune Defic Syndr 2011;56:230–238
• 37 studies with 5736 HIV-infected individuals
• Are IGRAs better than TST at predicting which HIV-infected
individuals are at highest risk of progression to active TB?
• Are IGRAs more sensitive than TST for diagnosis of MTB
infection in HIV-infected individuals with advanced
immunosuppression?
• Insufficient evidence to conclude that either test is superior to
the other.
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• Testing for LTBI at the time of HIV diagnosis should be
routine regardless of epidemiologic risk factors
• Annual testing for LTBI only in those with ongoing exposure
• If negative screen for LTBI while CD4 count is low, repeat
testing post cART once CD4 is above 200.
• Both TST and FDA-approved IGRAs are appropriate for TB
screening in HIV-infected individuals
• Routine use of both TST and IGRAs to screen for LTBI is
not recommended
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Natural History of M. tuberculosis infection.
A Koul et al. Nature 469, 483-490 (2011) doi:10.1038/nature09657
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• 23,517 culture-positive, pulmonary tuberculosis
patients from the California tuberculosis case
registry from 1993 to 2007 who completed antituberculosis therapy.
• 148 (0.63%) had a late recurrence.
• Human immunodeficiency virus infection
(adjusted hazard ratio, 1.81; p = 0.0149
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The Journal of Infectious Diseases 2010;
201:704–711
• Retrospective cohort study of South African gold miners, men with known dates
of seroconversion to HIV (from 1991 to 1997) and HIV-negative men were
followed up to 2004.
• 342 HIV-positive and 321 HIV-negative men who had had1 previous episode of
tuberculosis,
• Rates of tuberculosis recurrence:
• HIV-positive 19.7 cases per 100 person-years at risk (95% confidence
interval [CI], 16.4–23.7)
• 7.7 cases per 100 PYAR (95% CI, 6.1–9.8)
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Diagnosis of Active Tuberculosis in the
Setting of HIV
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TB in the Setting of HIV: Clinical
Presentation
• In general, similar to that seen in HIV-uninfected
patients
• However, differential diagnosis broader
• HIV itself
• Other opportunistic infections
• Extrapulmonary
• HIV main risk factor
• 35-80% vs. 15-50%
• Bones and joints, lymph nodes, the pleura,
peritoneum, CNS
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Laboratory Diagnosis of Active TB
• Sputum smear
• HIV-infected patients are more likely to have smearnegative pulmonary TB
• Range 31 – 81%
• CXR
• Individuals with advanced HIV are likely to have
atypical presentations
• Lower lobe locations
• Less cavities
• Consolidation
• Intrathoracic LAD
• May appear normal
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Treatment of Tuberculosis
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Treatment of LTBI
Drugs
Duration
Interval
Minimum doses
Isoniazid
9 months
Daily
270
Twice weekly*
76
Daily
180
Twice weekly
52
Isoniazid
6 months
Isoniazid and
Rifapentine
3 months
Once weekly
12
Rifampin
4 months
Daily
120
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Studies of the Effect of Human Immunodeficiency Virus (HIV) Coinfection on the Outcome of
Tuberculosis Treatment.
Swaminathan S et al. Clin Infect Dis. 2010;50:1377-1386
© 2010 by the Infectious Diseases Society of America
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• Treatment of TB in HIV-infected individuals is the same as for those
who are HIV uninfected
• Treatment of TB in HIV-infected individuals should include an initial 4drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol
• DOT is recommended for all patients with suspected HIV-related TB
• Daily therapy (5–7 days per week) given as DOT is recommended
during the intensive phase
• Daily (5–7 days per week) or thrice-weekly dosing is recommended
during the continuation phase
• Once- or twice-weekly dosing during the continuation phase assoc.
with treatment failure/relapse with acquired rifamycin resistance
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TB and HIV coinfection: Treatment
Issues
• Drug-drug interactions
• Overlapping drug toxicities
• Pill Burden
• Immune-reconstitution inflammatory syndrome (IRIS)
• Sequencing with antiretroviral therapy
• Highly intermittent Dosing
• TB treatment outcome in HIV
• ART treatment effect on TB incidence
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TB/HIV Treatment Issues: Drug Interactions
• Rifamycins induce hepatic cytochrome P450 (CYP3A4)
enzymes, accelerating metabolism of:
• Protease inhibitors (PIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), etc.
• Rifampicin >> Rifabutin
• For patients receiving PIs or NNRTIs, substitute rifabutin
for rifampin, if available
• Alternative non-rifamycin regimens less optimal, longer
duration of therapy
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NNRTIs and Rifampicin
Rifampicin decreases blood levels of
NVP and EFV
NNRTI
Effect of Rifampicin
Nevirapine
 37–58%
Efavirenz
 22%
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PIs and Rifamycins
Rifampicin decreases blood levels of all PIs
Protease Inhibitor
Effect of Rifampicin
Saquinavir
 by 84%
Ritonavir
 by 35%
Indinavir
 by 89%
Nelfinavir
 by 82%
Amprenavir
 by 81%
Lopinavir/ritonavir
 by 75%
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Rifamycins and Intermittent Therapy
• Evidence for development of acquired
rifamycin resistance with intermittent
therapy
• Intermittent therapy not recommended
during initial phase of TB treatment in
patients with HIV infection
• No twice-weekly continuation phase
with advanced immune suppression
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Overlapping Side Effects
Side Effect
Skin rash*
Nausea,
vomiting
TB Drug
PZA, RIF, INH
PZA, RIF, INH
ARV
 Nevirapine
 Efavirenz
 Abacavir
 Zidovudine
 Ritonavir
 Amprenavir
 Indinavir
* May also see rash with cotrimoxazole
Burman et al, Am J Respir Crit Care Med 2001
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Overlapping Side Effects
Side Effect
Hepatitis
Leukopenia,
anemia
TB Drug
ARV
 Nevirapine
 Protease
inhibitors
PZA, RIF, INH
 IRIS
(with chronic
hepatitis)
RIF
 Zidovudine
Burman et al, Am J Respir Crit Care Med 2001
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TB/HIV: Barriers to Adherence
• Dual social stigma
• Higher pill burden
• Greater number of potential drug side effects
• Additional illness (opportunistic infections)
• Difficult medical access, drug-supply
interruptions
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IRIS
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Clinical worsening in the setting of an
adequate response to ART
• “Paradoxical” worsening of previously
known treated (completed or ongoing)
opportunistic pathogen
• “Unmasking” of subclinical opportunistic
pathogen
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Incidence of Tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS) in Human
Immunodeficiency Virus (HIV)–Tuberculosis Coinfection.
Swaminathan S et al. Clin Infect Dis. 2010;50:1377-1386
© 2010 by the Infectious Diseases Society of America
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IRIS
• Risk factors
• Disseminated TB
• Shorter delay between onset of TB and ART
drugs
• Low baseline CD4, higher baseline viral load
• Greater CD4 or viral load response to ART
• Timing of onset
• Usually within first 6 weeks of ART (often 2–3
weeks, but can be months after ART started)
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IRIS
Clinical presentation:
• Fever
• Nodal enlargement
• Worsening pulmonary
infiltrates (with or without
respiratory symptoms)
• Local worsening in
extrapulmonary sites
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IRIS Differential Diagnosis
• TB treatment failure
• Drug-resistant TB
• ART failure
• Other opportunistic (or non-opportunistic)
infections
• Lymphoma, Kaposi’s sarcoma
• Hypersensitivity drug reactions
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IRIS Management
• Continue TB treatment
• Continue ART
• Exclude TB treatment failure
• Adherence
• Drug resistance
• Exclude additional/new diagnosis
• Consider NSAIDS, steroids
• Drainage of lesions
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Studies of the Timing of Antiretroviral Therapy (ART) in Human Immunodeficiency Virus
(HIV)–Infected Patients with Tuberculosis Undergoing Antituberculosis Therapy.
Swaminathan S et al. Clin Infect Dis. 2010;50:1377-1386
© 2010 by the Infectious Diseases Society of America
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When to Start Antiretrovirals
HIV-infected TB patients not yet on ART
CD4
Start ART
<50
Within 2 weeks of TB Rx
>50 and TB
severe
Within 2 - 4 weeks of TB Rx
>50 but TB not
severe
Can defer ART beyond 2 - 4
weeks but should start within 812 weeks
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Antiretroviral Therapy (ART) Significantly
Reduces TB Incidence
Decrease in TB
incidence after
starting ART in
resource-limited,
high-burden area
Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685
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Tuberculosis/HIV Coinfection: Summary
• Substantial global disease burden, individually
and as coinfection
• Bidirectional impact on natural history
• Difficulties in diagnosis and treatment
• TB, even in the setting of HIV, is curable
• ART has tremendous impact on TB incidence in
the population
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