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RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT
Qais Abdulmajeed Haddad
Consultant ID & IC
Security Forces Hospital Program
Riyadh - Saudi Arabia
RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT
History
Epidemiology
Latent Tuberculosis
Diagnosis
Therapy
Vaccine
Infection Control
Future Trends
1.5 m/year = 4110/day
Pulmoary Tuberculosis
TB Pleural effusion
Tuberculous meningitis
CNS Tuberculoma
Milliary tuberculosis
Renal & urogenital tuberculosis
Bone & joint tuberculosis
GIT tuberculosis
TB Peritonitis
Ileocecal TB
Colonic TB
Hepatic TB
TB retinitis
Extrapulmoary Tuberculosis
Tuberculosis History
Neolithic skeleton (stone age)
Spinal TB Pre-Columbian skeleton
Early Egyptian remains
After 1850 Laennec Pulmonary & Extrapulmonary
tuberculosis is one disease
1865 F. Villemin Tuberculosis transmitted to guinea pig by injecting diseased tissue
1882 Koch AFB & its pathogenicity
1840 1920 1860 1900 1940 1960 1980 2000 1880
1993: TB cases decline due to
increased funding and enhanced TB
control efforts
Mid-1970s: Most TB
sanatoriums in U.S.
closed
1884:
First TB
sanatorium
established
in U.S.
1865:
Jean-Antoine
Villemin
proved TB is
contagious
1943:
Streptomycin
(SM) a drug used
to treat TB is
discovered
1882:
Robert Koch discovers
M. tuberculosis
Mid-1980s:
Unexpected rise in
TB cases
1943-1952:
Two more drugs are
discovered to treat
TB: INH and PAS
TB History Timeline
Rifampicin introduced 1967
M. tuberculosis causes most TB cases in the world
Mycobacteria that cause TB:
M. tuberculosis
M. bovis
M. africanum
M. microti
M. canetti
Mycobacteria that do not cause TB (NTM)
e.g., M. avium complex, M. chelonae
Types of Mycobacteria
TB TRANSMISSION
Dots in air represent droplet nuclei containing
M. tuberculosis
Probability that TB will be transmitted depends on:
Infectiousness of person with TB disease
Environment in which exposure occurred
Length of exposure
Virulence (strength) of the tubercle bacilli
The best way to stop transmission is to:
Isolate infectious persons
Provide effective treatment to infectious persons as
soon as possible
TB Transmission
WHO Global TB Report 2014
Incidence: 9 million (2013)
95% occurs in low- and middle-income countries
Alarming increase in the number of patients with MDR-TB and XDR-TB has been noted (East Europe & Africa)
Globally, 45% drop in mortality between 1990 & 2012
Mortality: 1.5 million / year
0.5 million are children
HIV co-infection with TB:
360,000 deaths / year
13% of total active TB infections
RR-TB (Rifampicin Resistant)
MDR-TB (INH+Rifampicin Resistant)
Latent Tuberculosis
LTBI VS. TB DISEASE
Latent TB Infection (LTBI) TB Disease (in the lungs)
Inactive, contained tubercle
bacilli in the body
Active, multiplying tubercle
bacilli in the body
TST or blood test usually
positive
TST or blood test usually
positive
Chest x-ray usually normal Chest x-ray usually
abnormal
Sputum smears and cultures
negative
Sputum smears and cultures
may be positive
No symptoms Symptoms such as cough,
fever, weight loss
Not infectious Often infectious before Rx
Not a case of TB A case of TB
PPD VS IGRA
Latent TB infection (LTBI) diagnosis remained to
be dependent on PPD (Mantoux test) which
was first described by Robert Koch in 1890
PPD needs two patient visits and liable for
observer error in reading
Interferon-Gamma Release Assays (IGRAs) are
whole-blood tests that can aid in diagnosing LTBI
with one patient visit
QFT-TB Gold T-Spot Initial Process Process whole blood
within 16 hours
Process peripheral
blood mononuclear
cells (PBMCs) within 8
hours, or if T-Cell
Xtend® is used, within
30 hours
M. Tuberculosis Antigen
Single mixture of
synthetic peptides
representing ESAT-6,
CFP-10 & TB7.7.
Separate mixtures of
synthetic peptides
representing ESAT-6 &
CFP-10
Measurement IFN-g concentration Number of IFN-g
producing cells (spots)
Possible Results Positive, negative,
indeterminate
Positive, negative,
indeterminate,
borderline
Isoniazid
only
Isoniazid + Rifapentine P Value
Rates of Treatment
completion
69% 82% <0.001
Drug Discontinuation 3.7% 4.9% 0.009
Doses 270 12
Isoniazid VS Isoniazid + Rifapentine
1148 patients had a median age of 30 years
and a median CD4 cell count of 484/ml
This was an open-label, randomized trial of LTBI in HIV
patients (PPD 5mm or more)
Divided in 4 blocks 2:2:2:1
rifapentine (900 mg) plus isoniazid (900 mg) once
weekly for 12 weeks
Rifampin (600 mg) plus isoniazid (900 mg) twice weekly
for 12 weeks
Isoniazid (300 mg) daily for duration of the study (≤6 yrs)
Control regimen of isoniazid (300 mg) daily for 6 months
Conclusions
The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment completion rate
Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid
A Trial of Mass Isoniazid Preventive Therapy
for Tuberculosis Control
In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid for 9 months
If active tuberculosis was diagnosed, they were referred for treatment
Conclusions: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold miners, despite the successful use of isoniazid in preventing tuberculosis during treatment
Laboratory Diagnosis of Tuberculosis
AFB smear by ZN stain and culture remain the
gold standard in diagnosis
Detecting AFB by fluorochrome stain using
fluorescence microscopy
The smear may be stained by auramine-O dye. In this method
the TB bacilli are stained yellow against dark background &
easily visualized using florescent microscope
Advantages:
- More sensitive
- Rapid
Disadvantages:
- Hazards of dye toxicity
- more expensive
- must be confirmed by Z-N stain
Cultures on L J media
Lowenstein –Jensen medium is an egg based media with
addition of salts, 5 % glycerol, Malachite green & penicillin
Advantages: - Specificity about 99 %
- More sensitive (need lower no. of bacilli 10-100 / ml)
- Can differentiate between TB complex & NTM using biochemical reactions
- Sensitivity tests for antituberculous drugs
( St, INH, Rif., E)
Disadvantages: Slowly growing ( up to 8 weeks )
Rapid Radiometric Culture System
BACTEC
specimens are cultured in a liquid medium (Middle
brook7H9 broth base ) containing C14 – labelled palmitic
acid & PANTA antibiotic mixture
Growing mycobacteria utilize the acid, releasing
radioactive CO2 which is measured as growth index (GI)
in the BACTEC instrument
The daily increase in GI output is directly proportional to
the rate & amount of growth in the medium
Microscopic-Observation Drug-Susceptibility
Assay for the Diagnosis of TB
A single MODS culture of a sputum sample offers
more rapid and sensitive detection of
tuberculosis and multidrug-resistant tuberculosis
than the existing gold-standard methods used
Moore DA et al, N Engl J Med 2006;355:1539-50.
Nucleic Acid Amplification (NAP) Test
A new molecular diagnostic test called Xpert MTB/RIF
assay detects M. tuberculosis complex within 2 hours,
with an assay sensitivity that is much higher than that of
smear microscopy
.
Treatment of Tuberculosis
TB Drug Resistance
Mono-resistance
MDR-TB: Resistance to isoniazid and rifampicin
XDR-TB: Resistance to at least isoniazid and rifampicin, and
to any fluoroquinolone, and to any of the 3
2nd line injectables (amikacin, capreomycin & kanamycin)
CDC, Mortal Wkly Rep 2006; 55: 301-5
FLD: Resistance to all first-line anti-TB drugs
SLD: Resistance to second-line anti-TB drugs
TDR: cohort of 15 patients in Iran was reported which
were resistant to all anti-TB drugs tested
Velayati AA et al, Chest 2009; 136: 420-5)
Major Problems in Treatment OF TB
MDR-TB
Paradoxical expansion of TB lesions (brain)
Chronic Liver Disease Raised ALT
Raised bilirubin
Chronic Renal Disease Mild renal impairment
ESRD
Group Anti-TB Drugs Anti-TB Drugs
Group 1: First line Oral
agents Isoniazid, Rifampicin, Pyrazinamide, ethambutol, Rifabutin, Rifapentin
Group 2: Injectable agents Kanamycin, Amikacin, Capreomycin, Streptomycin
Group 3: Fluoroquinolones Levofloxacin, Moxifloxacin, Ofloxacin
Group 4: Oral
Bacteriostatic Second Line
Agents
Para–aminosalicylic acid, Cycloserine, Terizidone, Ethionamide, Prothionamide,
viomycin
Group 5: Agents with an
unclear role in the Rx of
drug resistant TB
Clofazimine, Linezolid,
Amoxicillin/clavulanate, Thioacetazone,
Imipenem/cilastatin, high dose Isoniazid, Clarithromycin
CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY
REGIMENS
Study Regimen PATIENTS ASSESSED
Comp.
N
Failures
N (%)
Relapses
N (%)
1st BTA 1975 2S(E)HR/7HR 99 0 0
2ND BTA 1982 2EHR/7HR 136 0 2 (1.5)
1ST French 1981 2EHR/7HR 85 0 2 (2.4)
2nd French 1974 3E(S)HR/6HR 52 0 2 (3.8)
Arkansas 1984 1HR/8H2R2 751 21 (2.8) 15 (2.1)
San Francisco 88 2HRE/7HR 200 3 (1.5) 4 (2)
9 MONTHS DURATION REGIMENS
CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY
REGIMENS FOR TUBERCULOSIS
6 MONTHS’ DURATION REGIMENS
PATIENTS ASSESSED
Study Regimen Comp.
N
Failures
N (%)
Relapses
N (%)
East Africa BMRC
1983
2HRSZ/4HR (Z) 80 0 1 (1.3)
Singapore BMRC
1985
2(H)HR(S)Z/HR 319 1 (.3) 3 (1)
Singapore BMRC 2HRSZ/4HR(Z) 158 0 3 (1.9)
1986
2nd BTA 1982 2HRS(E)Z/4HR 257 0 4 (1.6)
Poland 1984 2HRSZ/4HR 84 0 0
Algeria 1984 4EHRZ/2HR 131 0 4 (3)
Hongkong/BMRC 6HRZ(S) (E)3 626 0 9 (1.4)
1987
Germany 1982 6HRSZ 95 2 (2.1) 0
BACTERIOLOGIC RELAPSE RATES IN SMEAR-POSITIVE & CULTURE
POSITIVE DISEASE: HIGHLY EFFECTIVE SIX-MONTH REGIMENS WITH ISONIAZID & RIFAMPIN
Study Regimen mo Follow-up mo Patients
Assessed
Bacteriologic
Relapses (%)
US Public
Health Service
study 20
HR 30 220 (9)
Second East
African-BMRC
study
HR 30 164 (7)
East African-
BMRC study
2 SHR/HRZ
2SHRZ/HR
24
24
40
40
0
1 (2)
18 160 4 (2)
Singapore-
BMRC study
2 SHRZ/HRZ
2 SHRZ/HR
24
24
80
80
0
2 (2)
Second BTA study
2 SHRZ/HR 24 125 1 (1)
USPHS TUBERCULOSIS SHORT COURSE (1990)
THERAPY TRIAL 21, RANDOMIZED, MULTI-CNTRE TRIAL
Myco. tuberculosis, positive sputum culture
All susceptible
617 pts. HRZ (2) / HR (4)
445 pts. HR (9)
6 months 9 months
Sputum conversion (16 wks) 95% 90%
Non-compliance 7.7 6.4
Relapse (22 months) 305 2.8
Completed therapy 61 51
TREATMENT ALTERNATIVES WITH SUSPECTED
INITIAL DRUG RESISTANCE
Continuing Regimens
Beginning
Regimens
INH ( R ) OR
INH ( R ) and
SM (R)
SM ( R )
(1) HRE (2) RE (10) HR (7)
(2) HRZS (2) RE (10) HR (7)
(3) HRZE (2) RE (10) HR (7)
SHORT COURSE FOR EXTRAPULMONARY
TUBERCULOSIS
350 pts 402 sites
Pleural (119), Disseminated (51), GU (51)
Lymphatic (56), Bone/joints (26), Vertebral (21)
Abdominal (21), Meningeal (18), Pericardial (12)
Laryngeal (13), Misc (14)
HR (1) daily/ H (300mg), R (600mg)
HR (8) TW H (900mg), R (600mg)
Mortality 5/297 = 1.7%
Treatment failure 6/297 = 2.0%
Late relapse 2/297 = 0.7%
Ann Int. Med 1986 ASIM DUTT
Four-Month Moxifloxacin or Gatifloxacin
Based Regimens for Drug-Sensitive TB
Gillespie S et al, NEJM 2014
Merle CS et al, NEJM 2014
Fouad M, Ann Pharmacother 2011
Conde MB et al, Lancet 2009
Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown
THE IMPACT OF DOT ON EPIDEMIOLOGY
The WHO-recommended Stop TB Strategy provides
the framework for treating and caring for those who
are sick and controlling the epidemic of drug-susceptible and drug-resistant disease
The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national
programs designed to control disease by means of
early diagnosis with the use of bacteriologic testing,
standardized treatment with supervision and patient support, and provision and management of the
drugs used in treatment
Where might ―new‖ anti-TB drugs
come from
Repurposing of existing drugs used for other infections:
Fluoroquinolnes, linezolid, clofazimine
Improved use of existing TB drugs:
Rifamycins
Development of new chemical entities:
Bedaquiline (TMC207) (Diaryquinoline)
Delamanid (OPC67683) and Petomanid (Nitroimidazole)
Sutezolid and AZD5847 (Oxazolidinone)
SQ109 (Ethylene diamine)
FDA NEWS RELEASE
For Immediate Release: Dec. 31, 2012
Media Inquiries: Sandy Walsh, 301-796-4669, [email protected]
Consumer Inquiries: 888-INFO-FDA
On Dec. 28, the U.S. Food and Drug Administration approved Sirturo
(bedaquiline) as part of combination therapy to treat adults with multi-drug
resistant pulmonary tuberculosis (TB) when other alternatives are not
available.
BEDAQUILINE
Bedaquiline fumarate is an oral diarylquinoline; it was
approved by the United States Food and Drug Administration (FDA) in 2012 for treatment of multidrug-
resistant tuberculosis (MDR-TB)
Provisional Centers for Disease Control and Prevention
(CDC) guidelines have been issued for both approved
and unapproved uses
The World Health Organization (WHO) has also
published recommendations on the use of bedaquiline
BEDAQUILINE
Toxicity — The FDA issued a black box warning to alert healthcare practitioners regarding an increased rate of death due to QT prolongation has been observed among patients treated with bedaquiline compared with patients treated with placebo (11.4 percent versus 2.5 percent, respectively).
Bedaquiline may also result in increases in liver function tests
Delamanid (OPC-67683)
Delamanid (OPC-67683), a new agent derived from the nitro-dihydro-
imidazooxazole class of compounds
Inhibits mycolic acid synthesis,
Has shown potent in vitro and in vivo activity
Against both drug-susceptible and drug-resistant
Administered at doses of 200 and 300 mg daily resulted in a decrease in the
sputum M. tuberculosis burden that was similar to that of the potent
antituberculosis drug rifampicin in previous studies of early bactericidal activity
TB Recurrences: Relapse vs Reinfection
In a population‐based study in northern Malawi, tuberculosis patients diagnosed from 1996‐2010 were actively followed after the end of treatment
Whole genome sequencing with approximately 100X coverage was carried out on all available cultures
IS6110 Restriction Fragment Length Polymorphism (RFLP) was available on cultures up to 2008
a single nucleotide polymorphism (SNP) difference of:
≤10 SNPs was used to define relapse
>100 SNPs for reinfection
Guerra‐Assunção1 JA et al, J Infect Dis 2014
TB Recurrences: Relapse vs Reinfection
Of 1471 patients 139 had laboratory-confirmed recurrences:
55 had relapse
20 had reinfection
64 type of recurrence was unclassified
Almost all relapses occurred in the first 2 years
HIV infection was associated with reinfection but not relapse
Relapses were associated with:
Isoniazid resistance
Treatment before 2007
Lineage-3 strains
Guerra‐Assunção1 JA et al, J Infect Dis 2014
TB Vaccine - BCG
The protection conferred by the BCG vaccine is significantly greater when the vaccine is administered to neonates or school children and for miliary or meningeal TB
Protection against pulmonary TB, which accounts for the majority of TB mortality and morbidity worldwide, is age dependent
In children,protection against pulmonary TB can reach up to 80% [5]; however,
only 50% of adults are protected, and some studies have reported no real preventive effects
Previous exposure to environmental mycobacteria appears to be an important limiting factor for the BCG vaccine
Subjects with latent TB infection are less protected and the vaccine’ efficacy has been shown
N. Principi; Tuberculosis 2014 (in press)
N. Principi; Tuberculosis 2014 (in press)
TB Infection Control
Negative pressure room
Wear N95 mask
Hand Hygiene
Limit patient movement
(put mask if patient moved to radiology, surgery, etc …)
Investigate family contacts and close contacts
No need for special hospital or sanatorium
WHO Ambitious Target
Reducing TB incidence to 10 per 105 by year 2035
Aim at eliminating TB as a public health problem
by 2050 (reducing TB incidence to 1 per 105)