south africa july 2016 - report international · south africa july 2016 valeria rolla, afranio...
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South Africa
July 2016
Valeria Rolla, Afranio Kritski, Bruno Andrade,
Marcelo Cordeiro, Betina Durovni,
Solange Calvacante, Jose Roberto Lapa e Silva, Catherine McGowan, Timothy
Sterling
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Protocol
900 adults with culture-positive pulmonary TB
Cohort A
Drug-susceptible or drug-resistant
Followed for response to therapy, TB recurrence
2,700 close contacts of the TB patients in Cohort A
Cohort B
TST or QuantiFERON positive or negative
Followed for development of TB
Duration of follow-up: 24 months
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Specimen Collection
TB Patients
Baseline, 2 months, end of therapy, TB recurrence
Close Contacts
Baseline, end of therapy (if any, or at 6 months), TB
disease
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Biorepository
Study sites
Sites and Specimen flow
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Rio sites and Specimen flow
Duque de Caxias
Fiocruz - INI
Rocinha
UFRJ
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Laboratory Quality ControlCurrent Status
Mycobacteriology labs (SMILE)
Evaluations: twice a year
All Labs approved:
Fiocruz: approved since August 2013
Salvador: approved since March 2015
Manaus: approved since March 2015
+UFRJ: developing new lab (space, equipment, personnel)
Repeat SMILE visit to all labs in October 2016
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Laboratory Quality ControlCurrent Status
Immunology labs (Duke for PBMCs, Qiagen for QuantiFERON)
Evaluations: every quarter
Rio de Janeiro
Fiocruz: approved since June 2015
UFRJ: approved since June 2015
Salvador: approved since March 2016 (new lab)
Manaus: approved since December 2015
Specimen processing, flow, storage: SOPs finalized at allsites
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Data/Specimen Quality
Shipping of specimens:
From Rio de Janeiro’s study sites to the immunology and
microbiology labs at Fiocruz and UFRJ
From labs to the Biorepository:
Temperature control, time to receive samples and storage
Protocol / data collection / specimen monitoring:
Case Report Forms (CRFs)
Label system
REDCap system to collect data from study participants, and track
specimen transportation from the study sites to local labs, then to
Biorepository
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Biorepository
Biorepository: Salvador, Bahia
Fundação José Silveira: Instituto Bahiano de Reabilitação
All equipment installed, personnel trained
Freezers, N2 containers, computer/inventory system, back-up generators
Monitoring systems in place
FreezerPro system working very well
Institutional infrastructure, SOPs in place
Started from a brand new location and now will be expanded
More than 12,500 samples!
Load: Freezers (7,5%), N tank (9%)
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Biorepository
Biorepository Expansion:
- Fundação José Silveira investment
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Biorepository
Distribution (+12,500):
Plasma: 4,099 vials
PBMCs: 931 vials
Whole blood: 972 vials
Urine: 4,131 vials
Sputum: 810 vials
TB isolates: 436 vials
QuantiFERON: 1,200 vials (400 each)
Paxgene tubes: 343 tubes
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Receiving area
Inventory/Management system - office
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Budget Received:
$1.5M from NIH
$1.0M from Brazilian Ministry of Health
$500K received in 2016
Extra costs not originally planned:
Equipment for labs, lab QC programs, extra personnel and
suplies for immunology labs, IATA training, etc.
Special labels (long duration)
FreezerPro
Specimen transportation
BSC and HEPA filters for Biorepository
Generators, alarms...
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EnrollmentStatus as of July 8 2016
Protocol approved at all study sites; CONEP approval notrequired
All 5 sites enrolling:
Cohort A: 184 TB cases
20% treatment completed
10% MDR
12% Diabetes
Cohort B: 162 close contacts
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EnrollmentStatus as of July 8 2016
Rio de Janeiro:
INI-Fiocruz – 89 participants (started JUN 2015)
Rocinha – 62 participants (started SEP 2015)
Duque de Caxias – 121 participants (started SEP 2015)
Salvador – 23 participants (started JUN 2016)
Manaus – 51 participants (started JAN 2016)
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Overall Areas of Scientific FocusTranslational studies
M. tuberculosis transmission and infection
Biomarkers to identify patients at risk for:
Progression from M. tuberculosis infection to TB disease
Poor response to TB treatment
Risk factors for TB recurrence (relapse, reinfection)
Role of mixed M. tuberculosis infection
Epidemiologic studies
MDR-TB and XDR-TB
TB/HIV
TB and other co-morbid conditions: diabetes, alcohol,
tobacco, etc.
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Scientific projects affiliated with RePORT
Biomarker discovery for tuberculosis infection and disease
Co-funded by CNPq (Brazil) and NIH (U.S.)
Social determinants of TB and HIV in Brazil (Rocinha)
Funded by Vanderbilt University
Pharmacogenomic predictors of treatment toxicity, failure, and relapse in HIV-related tuberculosis
R01 funding pending
Mixed M. tuberculosis infection and whole genome sequencing (Rio)
Afranio Kritski, Sebastien Gagneux. Submitted to FAPERJ
Mechanisms of emergence of drug resistance in MDR-TB
Bob Horsburgh (RePORT-India + Brazil) R01 to be resubmitted September 2016
Other areas of interest:
Biomarkers of TB infection/disease
TB/Diabetes
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Gene ontologies differentially expressed in TST +
household contacts compared to active TB cases
Gene Ontologies %1Zinc Regulation 6,1
2Interferon Regulation 14,3
3Chemokines 2,0
4Cytokines 16,3
5Receptors & intracellular receptors 20,4
6Complement 6,1
7Neuronal precursors 6,1
8Grow Factors 4,1
9Mithocondrial Regulators 4,1
10Retinoic Acids 2,0
11Intracelluar mediators 18,4
Biomarker discovery for TB infection and
disease - CNPq and NIH: Preliminary Data
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Metabolism profile for anti-TB drugs and
efavirenz in HIV/AIDS patients in Rio de
Janeiro
Samples from a randomized clinical trial to treat TB-HIV
patients with EFV 600 or 800mg and TB drugs in fixed-
dose combination
Study drug metabolism and ancestry markers in Rio de
Janeiro’s TB-HIV patients
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53%45%
2%
Acetylation profile based only on theknown functional genotypes
Intermediate
Slow
Fast
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Perfil de acetilação na população brasileira. Osgráficos mostram a distribuição dos status deacetilação nas 5 macrorregiões do Brasil. Os valoresestão expressos em percentagem.
Acetylation profile according to region of Brazil
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Viral load <1000 and>1000 Fisher's exact test
NAT2
1 - 1 (1.8) 0 (0)
2 - 29 (51.8) 8 (66.7) 0.609
3 - 26 (46.4) 4 (33.3)
CYP2E1
1 - 69 (95.8) 12 (92.3)
2 - 3 (4.2) 1 (7.7) 0.492
CYP2B6
1 - 33 (46.5) 3 (25) 0.023
2 - 36 (50.7) 6 (50)
3 - 2 (2.8) 3 (25)
GSTM1
1 - 27 (37.5) 4 (30.8) 0.761
2 - 45 (62.5) 9 (69.2)
DOSE EFV 600 or 800mg
600mg - 36 (50) 5 (38.5) 0.642
800mg – 36 (50) 8 (61)
Adverse reactions during therapy
G1 and 2 - 35 (48.6) 10 (76.9) 0.114
G3 and 4 - 37 (51.4) 3 (23.1)
SNPs profile of TB-HIV patients treated with
efavirenz based regimen 600X800mg
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SNP profile of TB-HIV patients treated with efavirenz
based regimen 600X800mgAdverse reactions to EFV (G1 and2XG3and4) Fisher's exact test
NAT2
1 - 0 (0) 1 (1.7)
2 - 8 (72.7) 30 (51.7) 0.431
3 - 3 (27.3) 27 (46.6)
CYP2E1
1 - 13 (92.9) 69 (95.8)
2 - 1 (7.1) 3 (4.2) 0.516
CYP2B6
1 - 7 (53.8) 30 (42.3) 0.54
2 - 5 (38.5) 37 (52.1)
3 - 1 (7.7) 4 (5.6)
GSTM1
1 - 7 (50) 24 (33.3 0.377
2 - 7 (50) 48 (66.7)
DOSE EFV 600 or 800mg
600mg - 3 (21.4) 39 (54.2) 0.051
800mg 11 (78.6) 33 (45.8)
Age
Mean 36.8 (9.6) 39.5 (10.2) 0.114
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AFR EUR NAMSample Size
AFR 0.996 0.002 0.002 105
EUR 0.002 0.993 0.005 158
NAM 0.002 0.023 0.976 64
TB HIV 0.361 0.473 0.166 96
Genetic ancestry at the individual level using
autosomal ancestry informative marker (AIM)-indels
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Recent published data reflecting RePORT-Brazil’s
other research interests related to TB
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Conclusions
Outstanding progress has been made:
Protocol implementation
Laboratory infrastructure
Establishment of Biorepository
Participant enrollment
Focus over the next 6-12 months:
Continue enrollment and retention
Increase funding through grants and other sources