case-based discussions tb hiv...candida esophagitis cryptococcosis tbc in absence of art trends in...
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Case-based discussionsTB HIV
Dr. Delia GolettiNational Institute for Infectious Diseases L. Spallanzani, ItalySingapore, September 26-28, 2019
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Conflict of interestIn the last year I have been a consultant or I presented talks for:
Diasorin, Janssen, Qiagen, Quidel
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy in HIV-LTBI
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TB-HIV in 2017
TB: 10 millionTB-HIV: 0.9 million1.7 million deaths370,000 deaths estimated to be
attributable to HIV–TB coinfection.
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy in HIV-LTBI
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Immunopathogenesis of TB-HIVHIV infection is associated to:
Reduction of apoptosis in M. tuberculosis–infected macrophagesLower ability of alveolar macrophages to acidify M. tuberculosis–infected phagosomesImpaired ability of neutrophils to control M. tuberculosis growthImpaired antigen processing and presentation of M. tuberculosisLoss of CD4+ T cellsSelective clonal deletion of M. tuberculosis-specific CD4+ T cellsLoss of IFN-γ+/IL-2+ CD4+ T cell precedes the loss of IFN-γ+ /TNF-α+ CD4+ T cells
Impairment of the degranulation and proliferation of CD8 T cells in response to M. tuberculosis
Innate immunity
Adaptiveimmunity
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Cell-mediated immune response to M. tuberculosis is crucial for granuloma integrity and control of bacillary replication
Esmail at al, Annual Review of Immunology, 2018
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Progression toward active tuberculosis in HIV-uninfected and HIV-infected persons
Esmail at al, Annual Review of Immunology, 2018
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy in HIV-LTBI
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In the absence of ART, is TB occurrence associated to a particular stage of HIV disease? Yes, it occurs only at late stages of immune suppression
Yes, it occurs only at the early stages of HIV disease
No, it can occur during the all course of the HIV disease
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Opportunisticdiseases in thecourse of HIV-infection
CD4+
(cells/µL)
800-
600-
400-
200-
0-0 2 4 6 8 10
50-
Seroconversion:
Acute retroviral syndrome
MAC
CMV
Pneumococcal pneumonia
Candida vaginitis
ITP
Years after infection
Oral Candida-infection
Kaposi sarcoma
Lymphoma
Dementia
Oral hairy leukoplakia
Cachexia
Toxoplasmosis
PCP
HSV
Candida esophagitis
CryptococcosisTBC
In absence of ART
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Trends in incidence rates of TB according to duration of HIV seroconversion in the pre- ART era and time since initiation of ART
Before ART initiation After ART initiation
Lodi et al and Girardi, Thorax, 2014
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TB risk is increasedin HIV+ patientsand depends on CD4 cell counts at the time of ART initiation
Lodi at al and Girardi, Thorax, 2014
Lodi at al, Torax, 2014
CD4 cell counts at ART initiation
CD4: <50 µl CD4: 50-199 µl
CD4: >350 µlCD4: 350-499 µl
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Does ART reduce HIV-associatedTB incidence to background rates?yes
no
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TB rates during long-term ART remained substantially greater than rates in the local HIV-uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/mL
Gupta et al, PloS One 2012
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ART does not reduce HIV-associatedTB incidence to background rates
Tuberculosis incidence by months on ART in thenational HIV cohort in England, Wales, and Northern Ireland
Tuberculosis incidence in national HIV cohort comparedwith that in background HIV-negative population in 2009
Gupta et al, Lancet 2015
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Impact of HIV infection on TB localization: pulmonary vs extra-pulmonary TB
HIV-ununfected
infected
Sharma and T Kadhiravan, IJMR 2005
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Is lung cavitation common in HIV-TB?yes
no
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Pulmonary TB characteristics in HIV-infected patients
HIV-infected patients with culture-confirmed pulmonary TB
Chamie at al, Int J Tuberc Lung Dis. 2010
AFB negative sputum Cavitation
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IRIS
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TB immune reconstitution inflammatory syndrome (IRIS)TB-IRIS can occur in approximately 18% of HIV–TB coinfected people upon ART initiation. Transient worsening or appearance of new symptoms, signs or radiographic manifestations of TB after initiation of ART. Risk factors:High HIV loadLow CD4+ T cell count (below 100/µl) ART initiation soon after TB diagnosis
To exclude:Drug resistance No adherence to therapyConcurrent pathologies; i.e. lymphoma
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Pathogenesis of IRIS and immune responses
Dysregulated recovery of specific immune response (to ESAT-6, α-crystallins 1 and 2, and PPD) resulting in granulomatous and necrotizing inflammation directed at mycobacterial antigens released by dead or dying organismsPro- and anti-inflammatory cytokines and chemokines of both innate and adaptive origins are involved. IL-6 has been described as a major pathological indicator of TB-IRIS. Increased serum concentrations of IL-6 before ART are associated with development of TB-IRIS (Narendran, Plos One 2013) and early mortality (Ravimohan, Lancet ID, 2015). Microarray profiling revealed that TLR signaling and inflammasome activation are critical in mediating TB-IRIS pathogenesis (Lai, Nat Com 2015)
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Paradoxical TB-associated IRIS and ART-associated TB
Meintjes et al, Lancet 2008
ParadoxicalIRIS
ART-associated TB(unmasking TB-associated IRIS)
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IRIS: organs’ involvementRespiratory system◦ Expansion of pulmonary infiltrates
Lymph nodes◦ nodes enlargement
Abdominal organs:◦ Abdominal nodes enlargement◦ Liver funtion derangement (cholestatic attern)
Central nervous system◦ tuberculosis-meningitis-associated IRIS (TBMIRIS)
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy
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TB diagnosis in HIV-infected persons
Microbiology
Radiology
TST
IGRA
Experimental tests
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Technologies for TB diagnosis
Pai et al, Microb Spectrum, 2016
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Comparison of XpertMTB/RIF with Other Nucleic AcidTechnologies for Diagnosing Pulmonary Tuberculosis in a High HIV Prevalence Setting: A Prospective Study
Scott et al, PloS One, 2011
HIV+
HIV-
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Diagnostic accuracy of Xpert MTB/RIF forTB detection in different regions with differentendemic burden
Li et al, PloS One 2017
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Impact of XpertMTB/RIF specifically among HIV co-infected individuals
Scott et al, CurrentOpinion in HIV/AIDS, 2017
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Imaging toolsPulmonary TB: ◦ Chest xRay: 14% of HIV-infected subjects with culture-positive TB have a
normal chest xRay◦ CT-scan: lymph nodes, mediastin
◦ HRCT (1 mm slices): interstitial lesions
◦ 2-deoxy-2-[18F]fluoro-d-glucose positron emission and computed tomography (PET–CT): activity of the lesions (research purposes)
Extra-pulmonary TB:◦ NMR (es: bone, CNS)◦ CT-scan◦ US
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Radiological features of HIV+ patients
cavitary TB
580 CD4+ (26%)
miliary TB
152 CD4+ (15%)
From dr Schininà, INMI
Pleural effusion TB
105 CD4+ (11%)
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TB-HIV: lung involvement
From dr Schininà, INMI
Bronchogenic spreadIRIS
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From dr Schininà, INMI
TB lesions in the column in an HIV-TB coinfected patient
T2 STIRT1 T1+mdcSpondylodiscitislesions in L3, L5
Caseum
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Central nervous system TB in HIV-TB coinfected patients
Caseum granuloma
TB abscessus
From dr Schininà, INMI
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LTBI
x
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Does TST is an accurate test for LTBI in HIV-infected patients?yes
no
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The probability of being TST+ is correlated with CD4+ T cell counts
Elzi et al, CID 2007
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Risk assessment of tuberculosis in immunocompromised patients. A TBNET Study
Indeterminate results Positive results
Sester et al, AJRCCM 2014
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IGRA should be used for LTBI diagnosis in HIV-infected subjects (BHIVA 2017)
British HIV Association guidelines for the management of TB/HIV co-infection in adults 2017
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IGRA and/or TST should be used for LTBI diagnosis in HIV-infected subjects (ERS/ECDC statement)
ERS/ECDC Statement: European Union standards for tuberculosis care, 2017
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Accuracy of TB-immune tests in published studies
Test Sensitivity for active TB
Specificity for active TB
Proportions
TST 65 75
QFT-IT 80 79
T-SPOT.TB 8159
Sester et Sotgiu et al, ERJ 2010Santin et al, PloS One 2012
Sensitivity:QFT: 61%T SPOT-TB: 65%
Specificity:QFT: 63%T SPOT-TB: 70%
HIV-uninfected HIV-infected
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QuantiFERON Plus accuracy in HIV-infected subjects in Zambia
Telisinghe at al, IJTLD 2017
CD4 counts correlation
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy in HIV-LTBI
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British HIV Association guidelines for the management of TB/HIV co-infection in adults 2017
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British HIV Association guidelines for the management of TB/HIV co-infection in adults 2017
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Length of TB treatment in HIV co-infected patients with drug susceptible pulmonary TB
In patients with drug-susceptible pulmonary TB who are living with HIV and receiving antiretroviral therapy during TB treatment, a 6-month standard treatment regimen is recommended over an extended treatment for 8 months or more (Conditional recommendation/very low certainty in the evidence).
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Improved survival and cure rates with concurrent treatment for MDR-TB/HIV co-infection in South Africa
Brust, CID, 2018
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ART increases CD4-specific Mtb response in LTBI subjects, no in active TB patients
Chiacchio et al, Immunol Letters, 2018
T. Chiacchio
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IRIS
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Therapy for IRISPrednisone is the only drug that has been evaluated by a randomized, double-blind, placebo-controlled trial. Patients with paradoxical TB-IRIS who received prednisone for four weeks had more rapid symptom improvement, reduced need for hospitalization or therapeutic procedures, and better quality of life compared to the placebo arm.
Recently steroids to prevent TB-IRIS, in high-risk patients (moderate dose of prednisone at the time of ART initiation) led to a 30% reduced risk of developing TB-IRIS compared to those receiving placebo
Other nonsteroid inflammatory drugs have shown to be useful.
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Agenda TB-HIV in the world
Immunopathogenesis
Clinical course of the disease
TB diagnosis
TB therapy and TB-HIV therapy
TB preventive therapy in HIV-LTBI
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Is any short regimen for preventive therapyrecently proposed for the HIV-infectedpatients?yes
no
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One Month of Rifapentine plus Isoniazid to Prevent HIV-RelatedTuberculosis
Swindells et al, NEJM, 2019
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One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis
Swindells et al, NEJM, 2019
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Recommended drugs for LTBI treatment
Latent tuberculosis infection report, WHO, 2018Migliori et al, ERJ, 2017
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Adults, adolescents living with HIVAdults and adolescents living with HIV, with unknown or a positive tuberculin skin test (TST) and are unlikely to have active TB should receive preventive treatment of TB as part of a comprehensive package of HIV care.
Treatment should be given to these individuals irrespective of the degree of immunosuppression and also to those on antiretroviral treatment (ART), those who have previously been treated for TB and pregnant women. (Strong recommendation, high-quality evidence. Existing recommendation)
Latent tuberculosis infection report, WHO, 2018
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Gaps in the implementation of preventivetreatment for PLHIV
Global TB report, WHO, 2018
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Preventive therapy coverage in HIV-infected patients
Preventive therapy started in 36% of the elegible
HIV-infected subjects in the59 countries that reported it
Global TB report, WHO, 2018
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Conclusions
HIV-epidemiology: high burden
Immunopathogenesis: still difficult to completely understand
Clinical diagnosis: different features in HIV. Think about!
Diagnosis: difficult. Several steps are involved for both active TB and LTBI
Therapy: TB treatment and ART are needed. IRIS: be careful!
IPT in HIV-infected: extremely important
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Thank you!
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Thank you INMI
Enrico Girardi
Fabrizio Palmieri
Andrea Antinori
Vincenzo Schininà
Giuseppe Ippolito
Translational Research Unit
Teresa Chiacchio
Gilda Cuzzi
Linda Petrone
Elisa Petruccioli
Valentina Vanini
Tonino Alonzi