Tuberculosis
Back with Vengeance
and
Refined Approach Towards Management
DR. RAJESH N.SOLANKI
MD, FNCCP,MICS
PROFESSOR & HEAD
DEPARTMENT OF PULMONARY MEDICINE,
B.J.MEDICAL COLLEGE & CIVIL HOSPITAL,
AHMEDABAD.
NODAL OFFICER-STATE DOTS PLUS COMMITTEE, GUJARAT
MEMBER, NATIONAL EXPERT COMMITTEE OF DIAGNOSIS AND
MANAGEMENT OF TB UNDER RNTCP GOVERNMENT OF INDIA
TB in Ancient Age
• There have been references to this ancient
disease in the VEDAS and it was called
RAJAYAKSHMA (meaning wasting disease).
• Hippocrates called the disease PTHISIS a
greek word which meant “to consume” “to
spit” and “to waste away”.
• The word tuberculosis is a derivative of the
latin word “tubercula” which means a small
lump.
TB in Ancient Age
• Oliver holmes referred to the disease as "white plague"
• “lung cough” & “lung fever” has been used in ancient
Chinese literature.
• Evidence of TB lesions of bone have been found in ancient
mummies dating back to 3400 B.C.
• Middle ages, records of healing touch of monarchs was
being used to treat “scrofula”
• By around 1629, death certificates in London specified the
disease as “consumption” a leading cause of death.
• By this time the contagious nature of TB was strongly
believed. Though, there were people who contested this
opinion.
Discovery of Mycobacteria
Mycobacterium tuberculosis is a pathogenic bacterial
species in the family Mycobacteriaceae
and the causative agent of most cases of tuberculosis.
First discovered in 1882 by Robert Koch,
M. tuberculosis has an unusual, waxy coating on its cell
surface (primarily due to the presence of mycolic acid),
which makes the cells impervious to Gram staining
The Ziehl-Neelsen stain, or acid-fast stain, is used instead.
TB Management Early 19th Century
Pre-antibiotic era: before 1940s (e.g., cod liver oils, bed rest, fresh air)
Era of conventional chemotherapy
Dr P V Benjamin
FATHER OF ANTI-TB MOVEMENT IN INDIA
TB Chemotherapy : The Effective TB Control
• Drugs used to treat TB:
(a) Front-line Drugs:
isoniazid (INH)
rifampicin (RMP),
pyrazinamide (PZA),
streptomycin,
ethambutol.
1952
1946
Isoniazid
PAS
1944
Streptomycin
(b) Second-line Drugs: PAS, kanamycin, cycloserine,
ethionamide, thiacetazone, ciprofloxacin/ofloxacin,
rifapentine, amikacin, viomycin, capreomycin.
1963
Rifampicin
Drug action on TB bacillary population
INH
RIF
RIF
Extra-cellular
rapidly
multiplying 108
SM
EMB
PAS
Dormant No drugs
Extra-cellular
slowly
multiplying <105
PZA
Intra- and extracellular, acidic
environment
<105
Intensive Phase
•
•
•
•
•
Aims for a rapid killing of bacilli
A state of non-infectiousness within 2/52
Quick relief of symptoms
Smear negativity by 2/12
Prevent development of drug resistance
 multi-drug regimens and DOT
Continuation Phase
• Aims to eliminate remaining bacilli
• Killing of “persisters” prevents relapses
• Multi-drug regimens and DOT necessary
(unless R not used) even though risk of
emergence of drug resistance is less as
fewer bacilli remain
Tuberculosis Management
•
•
•
•
•
•
•
•
Standard/Conventional Chemotherapy
Supervised Chemotherapy
Short course Chemotherapy
RNTCP based on DOTS
Directly Observed Treatment Short course
Stop TB Strategy
DOTS Plus strategy and ISTC
STCI
The slow road to microscopy diagnosis of TB
 “The starting-point in the fight against all contagious diseases is the obligation to report
because without this most cases of the disease remain unknown.” Nobel lecture by Robert Koch,
1905
 A new POC TB Diagnostic tool could save up to 400,000 lives per year. Nature
Estimated number of MDR-TB Cases, 2013
More tha 50% of all cases are in Russian
3 countries
Federation
41,000
(15% of global MDR burden)
China
54,000
India
3.5 % new cases
21 % previously
treated cases
* among notified TB cases
(20% of global MDR burden)
62,000
(22% of global MDR burden)
Countries that had reported at least one
XDR-TB case - 2013
92 countries
9 % MDR TB cases have XDR TB
17 %MDR-TB cases with additional resistance to fluoroquinolones
Is MDR-TB a real threat in India?
State
Proportion of MDR
amongst new TB cases
Proportion of MDR
amongst re-treatment TB
cases
Gujarat
2.4%
17.4%
Maharashtra
2.7%
14%
Andhra Pradesh
1.8%
11.8%
National DRS – (7 sites) co-ord. by AIIMS, patients of Medical colleges, DTC & PHC
7 sites
(unpublished)
7.8%
29.8%
Community survey of TB prevalence- MDR out of TB
Gujarat
7.8%
17.1%
>30% of Tuberculosis cases amongst the contacts of MDR TB are found
to be MDR-TB
Primary transmission ?
Is XDR TB a real threat in India?
High XDR / pre-XDR levels out of XDR suspects undergoing
Second-line Drug Susceptibility Testing at NRLs
Source: National TB Institute, Bangalore
The case of Mumbai and the
“TDR-TB outbreak” – Jan 2012
March 2012 - WHO convened 40 experts meet
• Such cases pose a formidable challenge to clinicians
and public health authorities
• No reliable definition beyond XDR-TB
• Improvements in the accuracy of drug susceptibility
testing to certain drugs
• Release of innovative new drugs will, however,
change this position in future.
• India turned this crisis into opportunities for
improvements in Mumbai and country wide
Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis. 2012 Feb 15;54(4):579–81.
Cumulative data up to June 2014
MDRTB Suspects tested
MDRTB Put on Rx
XDR TB Put on Treatment
447670
53883
1021
122 DR-TB centres and
50 linked DR-TB centres (district level)
DIAGNOSIS OF TB: Drug Resistance
TB
MONO & POLY
RR TB
DR TB
MDR TB
MDR TB Plus
XDR TB
XDR TB Plus
NTM ??
Role of the Laboratory
• Ideally all TB cases should
need C & DST
• Genotyping or Phenotyping
• Quality Assurance Lab.
• Clinically Correlation is
Mandatory
• No Trial ATT
• Treatment Adherence
• Problems with NTM/Atypical
Mycobacteria
MTB
Diagnostic Aspects:
Drug Resistance TB
PHENOTYPING
SOLID (L J MEDIUM)
LIQUID (MGIT 960)
•
•
•
•
VIABLE BACILLI
BSL II & III
LABOURIOUS PROCESS
TIME CONSUMING
GENOTYPING/ MOLECULAR
LPA
CBNAAT (GENEXPERT)
•
•
•
•
RAPID TEST
DNA BASED
BSL – I FACILITY
95 % CONCORDANSE
MTB DRplus: Line probe assay
• Based on PCR line probes
• Identifies M.Tb and detects
Rif & INH resistance
in a day
Integrated automated NAAT: Cepheid
Xpert MTB/RIF Assay
Major advantages in workflow
 fully automated with 1-step external
sample preparation
 time-to-result 2 h (walk away test)
 throughput: up to 4 tests / module
 no bio-safety cabinet
 closed system (no contamination
risk)
Performance
 specific for MTB
 sensitivity similar to solid culture
 detection of rif-resistance via rpoB
gene
cartridge
MTB
Management of Tuberculosis
Grouping of Anti TB Agents
Grouping
Drugs
Group 1:
First-line oral anti-TB
agents
Isoniazid (H); Rifampicin (R); Ethambutol (E);
Pirazinamide (Z)
Group 2:
Injectable anti-TB agents
Streptomycin (S); Kanamycin (Km); Amikacin
(Am); Capreomycin (Cm); Viomycin (Vm).
Group 3:
Flouroquinolones
Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin
(Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)
Group 4:
Oral second-line anti-TB
agents
Ethionamide (Eto); Prothionamide (Pto);
Cycloserine (Cs); Terizadone (Trd);
para-aminosalycilic acid (PAS);
Group 5:
Agents with Unclear role
in Treatment of DR TB
Clofazimine(cfz); Clarithromycin(Clr)
Amoxacillin/Clavulanate(amx/clv);
Thioacetazone(Thz); High Dose INH;
Imipenem/Cilastatin(Ipm/Cln); Linezolide(lzd);
RNTCP Category IV Regimen
RNTCP is using a Standardised Treatment Regimen (STR) for the treatment of
MDR-TB cases under the programme.
REGIMEN:
- 6 (9) Km Lvx Eto Cs Z E /
- 18 Lvx Eto Cs E
• All drugs to be given daily under direct observation with Inj KM.
• On Sundays, Inj KM is omitted and oral drugs are given un-observed
• Na PAS is a reserve drug to be used instead on any one drug
In patients care (DR TB Center)
• Airborne Infection control Measures
• Individual rooms
• Well-spaced wards
DR-TB – Ambulatory Care
• After completion of in patient Care, patient has to
receive Ambulatory daily DOT services
• Hence need to create DR-TB DOT provider
network for MDR-TB patients
• Follow-up smear and culture examinations at
months 3, 4, 5, 6, 7, 9, 12, 15, 18, 21, and 24
• Outcome will be based on culture results
• Treatment outcome report submitted 31-33 months
after patients in the respective cohort registered for
treatment
Treatment outcomes of patients diagnosed
with MDR-TB, 2007-11 cohorts
Among MDR cases starting treatment in 2010,
the 75% treatment success threshold was achieved
by 34 of the 107 countries
RNTCP Category V Regimen
RNTCP is using a Standardised Treatment Regimen
(STR) for the treatment of XDR-TB cases under the
programme by daily DOT.
REGIMEN:
6 (12) Cm Mfx PAS, High Dose H, Cfz, Lzd,Amx-Clv./
18 Mfx PAS, High Dose H, Cfz, Lzd,Amx-Clv
Clr. & TZN are substitute drugs for any one drug
in case of intolerance or ADRs
Regimen for XDR TB
Moxifloxacin (Mfx)
High dose INH (High dose-H)
Clofazimine (Cfz)
Linezolid (Lzd)
Amoxyclav(Amx/Clv)
Pyridoxine
Inj. Capreomycin (Cm)
PAS
Type-A
Type-B
Treatment outcome of XDR-TB, Global
Total 1,269 XDR TB patients from 40 countries for whom outcomes were reported in 2013.
Palliative Care
MDR TB: Cure rate 40%, Death: 26%, Failure 10%, Default 24%*
Treatment causes frequent and severe side effects
Palliative care for M/XDR TB
• Should begin at the time of the diagnosis
• Is not limited to
– Patients who do not respond to active treatment
– Patients who no longer qualify for active treatment
• Includes but is not limited to «end of life care»
Complications and Sequelae
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Advanced lung diseases
Dyspnea, cachexia
Chronic obstructive lung diseases
Unhealed cavities in lungs
Recurrent hemoptysis
Bronchiectasis with recurrent infections
Partial or complete lung collapse
Thoracic empyema….etc.
Psychosocial issues: Patients and Families
•
•
•
•
•
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Anxiety, depression and Suicidal ideation
Fear of dying
Stigma, discrimination and social isolation
Adverse drug reactions
Adherence issues
Lack of support - social, financial,
psychological
• Loss of employment affecting livelihood
• Alcohol abuse
• Co-morbid conditions
Psychosocial support
Counsel patient & family
Meditation, Tranquilizers
Patient peer groups
Become a Provider
Vocational
Rehabilitation
Vocational Training
Skill development
Microfinancing
Physiotherapy
Pulmonary
Rehabilitation
Nutrition
Appropriate Diet,
Maintenance of BMI within
normal limits
Breathing Exercises
Yoga, recreation
Engage in light works
Surgical intervention
Decortication
Lobectomy
PC Window
RNTCP Challenges
• Diagnosis reliant on age old low sensitivity tools and
case finding strategies
• Multi drug resistance
– HIV/AIDS infection and other comorbid conditions
• Barriers to DOTS
– Practical challenges in rural conditions
– patients cultural beliefs
– human rights
• Insufficient infrastructure
– Lack of motivated personnel
• No regulation over private providers
• Need for stronger national policy
• Funding gaps
REFINED APPROACH
Newer Diagnostics
• CXR (Digital; Computer Aided Detection
for TB)
Newer Diagnostics
• Sputum smear microscopy (LED FM)
• Automated staining tool and slide processors
(RAL STAINER)
• Automated slide reader
(TBDx system)
• Automated slide reader
Newer Diagnostics
• Fluorescence in situ
hybridization (FISH)
• Liquid culture plateforms
(MGIT 960, BacT/Alert 3D 120,
VersaTREK 528)
Case finding strategy
• Proactive case finding approach
 Widespread awareness with community
engagement in identifying presumptive TB case and
referring them to diagnostic centres
 Community mobilization with support of local selfgovernment
 Active TB case finding among high risk groups
• Urban slum, PLHIV, DM, malnutrition, high risk health care
settings, patient contacts, migrants
Management of TB: First Line therapy
-
Intensive Phase:
3 HERZ ( Extension of 1 month if
require)
Continuous Phase: 6 HER
RIETT Panel (Redefining Indian Expertise based
Tuberculosis Treatment 2006)
-
Initial phase : Two months of HERZ &
Continuation phase consist of three HER at least four months.
The duration of continuation phase may be extended by three to
six months in special situations like Bone & Joint TB, Spinal TB
with neurological involvement and neuro-tuberculosis.
(Standard of TB Care in India WHO 2014)
Management of TB: First Line therapy
All patients should be given daily regimen under direct
observation.
However, the country programme may consider daily
or intermittent regimen for treatment of TB
depending on the available resources
and operational considerations as both are effective
provided all doses are directly observed
All paediatric TB patients and HIV associated TB
patients should be given daily regimen under direct
observation.
(Standard of TB Care in India WHO 2014)
Management of Tuberculosis
• Patients with mono-resistant TB and patients
with poly-resistant TB other than MDR-TB.
• Mono-resistance refers to resistance to a
single first-line drug, (without Rifampicin)
• Poly-resistance refers to resistance to two or
more first-line drugs. (without Rifampicin)
Suggested regimen for Mono & Poly Drug
Resistance TB (WHO 2008)
Pattern of
Suggested
drug resistant regimen
Minimum
duration
(months)
For extensive disease
H ( S)
RZE
6-9
FQ strengthen regimen
HZ
REFQ
9-12
Longer duration of
treatment
HE
RZFQ
9-12
Longer duration of
treatment
HEZ ( S)
RFQ+oral 18
SLD+inj for
2-3 months
Longer duration (6
months) of injectables
DRUG RESISTANCE PATTERN
Monodrug resistant TB
 INH Resistance- By LPA
 S, H, E or Z monoresistance by Liquid
Culture
Basic regimen- 5 drugs
Inj SLD + FQ + Rifampicin+ 2 out of the
remaining three first line drugs to
which the patient is sensitive (from
H,E & Z) to make a total of 5 effective
drugs given DAILY
Polydrug resistant TB
Basic regimenInj SLD + FQ + Rifampicin + any 2
FLD (from H,E,Z). If 2 FLDs cannot
be used, select from WHO Group 4
drugs -Ethionamide, Cycloserine or
PAS to make a total of 5 given
DAILY
The regimens for every DR TB Patient will be decided by the DR TB
Centre committee and the patient will be sent back to the DTO for
further management
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
To have a National Guidelines for
DST guided Treatment Regimen
for MDR TB and XDR TB
Rifampicin Resistance/MDR TB
STARTS REGIMEN FOR MDR TB STRKM/E/Z/ETO/CS/LFX/H
LC DST results of E,Z,KM, AM, CM,LFX, MFX received after 6-8
weeks
ADDL RESISTANCE PATTERN
FLDS ONLY
FLUOROQUI
NOLONES
SL
INJECTABLES
MIXED FLDS
AND SLDS
Further modification on the regimen to be decided by DR-TB centre
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
MDR TB (With or without Additional Resistance)
Additional Drug
Resistance
Treatment
Recommendation
Additional
recommendation
None
Regimen for STR of
MDR,
continue STR
Ethambutol
Ethambutol to be
removed
Less reliability of
Ethambutol sensitivity
Pyrazinamide
Omit Pyrazinamide in
STR
Good Reliability of PZA by
LC
Levofloxacin or
Moxifloxacin
Resistance to
both Levofloxacin
or Moxifloxacin
Use FQ to which patient
is sensitive
Replace FQ in regimen
with PAS + Clofa + LNZ
in IP and continue in
CP
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
MDR TB (With or without Additional Resistance)
Additional Drug
Resistance
Treatment Recommendation
Resistance to any Use one Injectable as per
S.L. INJECTABLE DST & in following order:
(AM,KM,CM)
1.Kanamycin
Additional
recommendation
Kanamycin
vs.Amikacin to be
decided by CTD later
2.Amikacin
3.Caperomycin
All SL injectables
Replace Injectable with PAS
+ Clofa + LNZ in IP and
continue in CP also
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
MDR with mixed pattern of resistance
Resistance
Pattern
Treatment Recommendation Additional
recommendation &
Justification
Mixed
resistance
pattern any
FLD/Inj SLD/FQ
/ Ethionamide,
PAS, LZ, CF
Basic regimen : Cat IV regimen &
modify based on resistance pattern:
(including XDRTB)
USE ANY INJECTABLE and FQ as
per recommendation discussed earlier
CONSIDER OTHER ORAL DRUGS
as per DST pattern and in
following Sequence of preference :PYRAZINAMIDE (if sensitive),
ETHAMBUTOL, ETHIONAMIDE,
CYCLOSERINE, PAS,
CLOFAZIMINE,LINEZOLID,
COAMOXYCLAV, HIGH DOSE INH &
CLARITHROMYCIN
if Injectable SLD &
FQ are included:
Minimum 6 Drugs in
IP and 4 Drugs in CP
if Injectable SLD
and /or FQ are not
included:
Minimum 8-9 drugs
are to be given in IP
and 7-8 drugs in CP
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
Special Considerations
• Extension of services to Pediatric group and
EPTB
• All MDR & XDR TB Patients: evaluate for
surgery
• Management of terminally ill patients without any
appropriate regimen available
• Salvage Regimen for XDR-TB Plus, newer
drugs
• Infection control measures
• Management of contacts of MDR/XDR TB
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for
Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
Need for Newer Molecules
There is an urgent need to improve treatment
either enhancing the application of existing agents
or introducing new drugs.
Potential new agents should
reduce treatment duration,
have an acceptable tolerability profile,
active against MDR/XDR TB,
useful in HIV-infected patients with TB, and be
active against latent TB
Challenge in TB drug development
• In phase II clinical trials, culture conversion after 2 months of treatment surrogate marker for relapse rate,
value of surrogate marker is controversial,
Several other surrogate markers are under evaluation
• The phase of clinical testing of new anti-TB drugs
time-consuming,
“gold standard” to assess efficacy of anti-TB regimens in phase III
clinical trials, relapse rate 2 years after completing treatment.
•
Large sample sizes needed in phase III clinical trials
to compare the effective standard regimen to a new regimen,
even in trials that use a non inferiority design.
Contributes to length TB drug development process
• Scarcity of trial sites with sufficient research capacity.
• Trials should be performed in countries where the TB burden is highest,
Global TB Drug Pipeline
Discovery1
Preclinical Development
Lead Optimization
Diarylquinoline
DprE Inhibitors
GyrB inhibitors
InhA Inhibitors
LeuRS Inhibitors
MGyrX1 inhibitors
Mycobacterial Gyrase
Inhibitors
Pyrazinamide Analogs
Riminophenazines
Ruthenium (II) complexes
Spectinamides
Translocase-1 Inhibitors
Preclinical
Development
CPZEN-45
DC-159a
Q201
SQ609
SQ641
Clinical Development
GLP
Tox.
Phase I
BTZ043
TBA-354
4 Repurposed
Drugs
6 New Drugs
3 New Classes
Phase II
Phase III
AZD5847
Bedaquiline (TMC-207)
Linezolid
Novel Regimens2
PA-824
Rifapentine
SQ-109
Sutezolid (PNU-100480)
Delamanid (OPC-67683)
Gatifloxacin
Moxifloxacin
Rifapentine
Drugs currently in the regulatory
review process
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone
1 Ongoing
projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.
2
Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,
moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The second
clinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitive
and multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and
clofazimine in combinations and is scheduled to begin September 2012.
www.newtbdrugs.org
Updated: June 18, 2013
Global TB Vaccine Pipeline
Phase I
Phase II
AdAg85A
VPM 1002
McMaster, CanSino
Max Planck, VPM,
TBVI, Serum Institute
MTBVAC
TBVI, Zaragoza, Biofabri
ID93+GLA-SE
Infectious Disease
Research Institute (IDRI),
Aeras
Crucell Ad35/MVA85A
Crucell, Oxford, Aeras
Phase IIb
MVA85A/
AERAS-485
Phase III
M. Vaccae
Anhui Longcom
Oxford, Aeras,
EDCTP
H1+IC31
SSI, TBVI, EDCTP,
Intercell
M72+AS01
GSK, Aeras
RUTI
Archivel Farma, S.L.
H56/AERAS-456
+IC31
SSI, Aeras, Intercell
Prime
Boost
Post-infection
Immunotherapy
June 2013
H4/AERAS-404
+IC31
SSI, sanofi-pasteur,
Aeras, Intercell
Crucell
Ad35/AERAS-402
Crucell, Aeras
TB Vaccine Types
Viral-vectored: MVA85A, AERAS-402, AdAg85A
Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56, ID93
rBCG: VPM 1002
Killed WC or Extract: Mw, RUTI
Awards & Honours
Dr.M.M.Prabhakar, MS, CHA, receiving the
Dr. M.M.Prabhakar, MS, CHA, receiving the "BEST MULTI
"BEST
MEDICAL
SPECIALTY HOSPITAL" HealthCare Excellence Awards
COLLEGE (METRO)" the India HealthCare
2014 from Hon’ble Dr.T.Rajaiyah, Deputy CM & Minister
Awards 2013 from Mr. Montek Singh
for Medical and Health, Telangana State, Hyderabad on
Ahluwalia,
Planning
22 -06- 2014 Hyderabad. Jointly presented by IMA, The
Commission on 23rd December 2013 at
Indus Foundation, Government of Andhra Pradesh and
New Delhi presented by ICICI Lombard
The Federation of Andhra Pradesh Chambers of
Health Insurance and CNBC TV18
Commerce and Industry (FAPCCI).
HOSPITAL
Deputy
WITH
Chairman
62
FICCI Healthcare Excellence Award-2014
63
Civil Hospital Ahmedabad receives the "Skoch Order of Merit Award" for Blood
Bank Data Management system under "Minimum Government Maximum
Governance" at India Habitat Centre, New Delhi on 20th September, 2014
64
THANK YOU