Post on 30-Oct-2019
MDR – TB
Jaime C. Montoya MD, MSc
Definitions of MDRTB and XDRTB
Historical background of the problem
Global and Philippine Data on MDRTB
Risk Factors
Diagnosis
Treatment
Research Gaps
Guidelines for the programmatic management of drug-resistant tuberculosis, WHO, 2006, 2008, 2011 update
Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015, WHO Progress Report 2011
Management of MDRTB: A Field Guide, WHO and Partners in Health, 2009
Multidrug-resistant tuberculosis (MDRTB) indicators, WHO, 2010
Discussions and recommendations apply only to MDR-TB
Findings may not be generalizeable to all populations in settings with high or low prevalences of drug resistance or different levels of resources
Problems, however, in resource poor settings considered
Results represent best available evidence to date for recommendations
Multidrug resistant tuberculosis (MDRTB)
- TB caused by strains of Mycobacterium tuberculosis that are resistant to at least isoniazid and rifampicin
Extensively drug resistant tuberculosis (XDRTB)
- MDRTB plus resistance to a fluoroquinolone and at least one second line injectable agent: amikacin, kanamycin and/or capreomycin
In 2006, first reports of XDR-TB (Extensively Drug Resistant TB)
Within the same year, cases of TB resistant to all first line and second line drugs reported in Italy (Extremely Drug Resistant TB or XXDRTB?)
In 2009, cohort of 15 patients in Iran resistant to all anti-TB drugs reported (Totally Drug Resistant TB or TDRTB?)
In 2009, the Beijing Call for Action and the passage of World Health Assembly Resolution 62.15 signaled a major step forward in coordinated planning for the treatment and control of MDRTB and commitment to achieve universal access to diagnosis and treatment by 2015
• Mainstream PMDT to NTP – With implementing guidelines for PMDT
implementation – DOH AO 2008-0018 “Guidelines for the Implementation of PMDT”
– With the development of 2010–2016 Philippine Plan of Action to Control TB (PhilPACT) The vision is a TB-free Philippines. - # 5 strategy:Address MDR-5. TB, TB/HIV, and needs of vulnerable populations
– Training for different health staff involved in the management of DR/MDR cases (TOT, TC/STC/
TS, Volunteers)
In the Philippines……
Stop TB department of WHO convened technical consultation in Geneva March 2012 back to back with expert group meeting
Objectives included overview of current information on XDRTB with additional drug resistance and feasibility and implications of new definitions
A new definition or category beyond XDRTB not recommended given technical difficulties of DST
Insufficient evidence for linking DST results to treatment outcomes of patients
Lack of standardised DST methods for several anti-TB drugs including investigational drugs
DST for drugs used to define MDR and XDRTB are standardised, accurate and reproducible
All injectables and fluoroquinolones should routinely be tested in specimens from confirmed MDRTB to screen for XDRTB
DST for all other drugs remains problematic for technical reasons
Countries not advised to invest resources for developing capacity for DST of new drugs
Need for research to develop standardized DST methods
Estimated % of New TB cases with MDR – TB
Estimated % of Retreatment TB cases with MDR – TB
Global 3.4 20
Western Pacific Region (WPR)
4.9 23
High MDR – TB Burden Countries
3.8 21
Philippines 4.0 21
Estimated Proportion of TB Cases that Have MDR - TB
Global tuberculosis control: WHO report 2011
As of January 2012, a total of:
12 regions are engaged in PMDT
18 PMDT treatment centers (12 public and 6 private facilities)
13 PMDT Satellite treatment centers (12 public facilities and 1 private facility)
Total of 2, 303 patients currently ongoing Category IV Treatment
2003 2008 2009 2010 2011
NCR Reg. 7 Reg. 10 CAR CARAGA
Reg. 11 Reg. 6
Reg. 1 Reg. 9
Reg. 5 Reg. 12
Reg. 4A 1) NCR
2) Reg. 7
7) Reg. 4A
6) Reg. 5
9) Reg. 6
11) Reg. 12
10) Reg. 9
3) Reg. 10
4) Reg. 11
5) Reg. 1
8) CAR
15) CARAGA
• Regions to be engaged in 2012 – 2013: • Reg. 2 • Reg. 3 • Reg. 4B • Reg. 8 • ARMM
Region Treatment Center Satellite Treatment Center NCR KASAKA – QI
LCP – PHDU DJNRMH PTSI – Tayuman San Lazaro Hospital
Lagrosa HC Gat Andres MMH Tondo foreshore Moonwalk Super Batasan Grace Park Lacson HC
7 Eversley Child’s Vicente Sotto MC 1 ITRMC Region 1 MC
4A DLSHSI and Batangas Reg. Hosp
Cainta PPMD, Gumaca and Laguna
5 SMMGHHSC BMC 10 German Doctors ISI PPMD 11 SPMC DRH 6 WVMC and DPOTMH Roxas CHO 9 ZCMC Dr. Jose Rizal Mem Hosp
12 Koronadal CHO CAR BGHMC
CARAGA CARAGA Reg. Hosp. OVERALL 18 TCs 13 (4 incomingSTC)
PMDT Indicators 2009 2010 2011 TOTAL
No. of lab confirmed MDR-TB cases detected
Target 1535 2490 3083 7108
Actual
No. of MDR-TB cases enrolled for treatment among those detected
Target 844 1494 1,002 4342
Actual 538 566 2516* 3620
(83.4%)
Interim Outcome
Target 70% 70% 70% 70%
Actual 73% 74%
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
New patients 7 15 86 56 22 99 191 134 313 514 538 566 2516
Cumulative 7 22 108 164 186 285 476 610 923 1437 1975 2541 5057
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
New patients Cumulative
Patient enrolment under Category IV treatment from 1999 to 2011
• An additional 6,981 MDR – TB cases is targeted to be treated under Category IV teatment from 2012 to 2014 • A total of about 15,000 MDR – TB cases is targeted to be treated by 2016 (PhilPACT)
Start of RCC
Cure rate = 48.5%
Success rate = 64%
Cure rate = 38.31%
Success rate = 53.64%
Medium Risk
Migrant worker
Health worker with new TB
Treatment after relapse or default
High Risk
Household contact of known MDRTB patient with new TB
Probable treatment failure
History of treatment with second-line drugs
Mediated exclusively by chromosomal mutations
Affect either the drug itself or bacterial enzymes that activate prodrugs
Well identified in INH and Rifampicin
Local studies being done using spoligotyping and VNTR to identify the common mutations in Philippine isolates
Rapid diagnostic tests
- tests providing diagnosis within two days
of specimen testing
- include test using molecular techniques
(line probe assay and Xpert MDR/RIF)
Rapid DST of isoniazid and rifampicin or rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB subject (very low quality of evidence)
Best strategy for averting deaths and preventing acquired MDR-TB
Most cost-effective strategy for any patient group or setting, even at very low levels of resistance among TB patients
For previously untreated patients, DST at start of treatment was a better strategy than waiting to test only those patients who remained sputum smear-positive later in the course of their first line treatment
High value placed on prevention of death , transmission of MDR-TB as a result of delayed diagnosis and lowered costs to TB control program
Sputum smear microscopy and culture rather than sputum smear microscopy alone recommended for the monitoring of patients with MDR-TB during treatment (very low quality of evidence)
Limit of detection:
smear 10,000 bacilli/ml
culture 10 – 100 bacilli/ml
Concomitant use of sputum smear and culture helps identify patients whose bacteriology remains positive or reverts to positive following initial conversion to negative –
“fall and rise phenomenon”
In the treatment of patients with MDR-TB:
A fluoroquinolone (FQ) should be used (SR)
A later gen FQ rather than earlier gen FQ should be used (SR)
Ethionamide (or prothionamide) should be used (SR)
In the treatment of patients with MDR-TB:
Four second-line anti-TB drugs likely to be effective (including a parenteral agent) as well as PZA should be included in the intensive phase (CR)
Should include at least PZA, a FQ, a parenteral agent, ethionamide (or prothionamide) and either cycloserine or PAS if cycloserine cannot be used (CR)
Recommendations based on three major systematic reviews
Meta-analysis included 32 studies with more than 900 treatment episodes
No superior second line parenteral agent
However, due to lower cost, kanamycin preferred
Use of streptomycin not recommended
Ciprofloxacin, even if with some anti-TB activity should not be used
Cure rates among bacteriostatic drugs:
Ethionamide>cycloserine>PAS
For Group 5 drugs, no significant association with cure due to confounders so not included in recommended standard MDR-TB regimen
In the treatment of patients with MDR-TB:
Intensive phase of at least 8 months duration is recommended (CR)
A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (CR)
In the treatment of patients with MDR-TB:
Intensive phase of at least 8 months duration is recommended (CR)
A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (CR)
Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based principally on hospitalization (CR)
Benefit of reduced transmission can only be expected if proper infection control measures are in place
Persistent or new weight loss
Persistent or new TB symptoms (fever, cough)
Persistently positive sputum smears or culture
Smear or culture positive after being negative for sometime
Lack of high quality evidence from RCT for optimizing treatment regimens in patients with MDR-TB including the best combination of drugs and treatment duration
Lack of evidence for the best drug regimens for treating patients with MDRTB, with XDR-TB and others
Very limited information about treatment of pediatric MDR-TB
Identification of most effective chemoprophylaxis for contacts of MDR-TB cases
Therapy for symptomatic relief from adverse reactions linked to second-line anti-TB drugs
Dr. Rosalyn Vianzon, NTP, DOH
Dr. Celine Garfin, NTP, DOH
Dr. Vivian Lofranco, Lung Center and NTP, DOH
Dr. Charles Yu, DLSU
Dr. Toro Mori, Research Institute of TB, Japan
Dr. Yoshiro Murase, Research Institute of TB, Japan
Dr. Akihiro Ohkado, Research Institute of TB, Japan
So here we are…quite frankly and free
So tell Pasteur and Koch
and whoever they may be
That they have not seen the last
of my comrades and me