GUIDELINES ON PROGRAMMATIC
MANAGEMENT OF DRUG RESISTANT
TUBERCULOSIS IN ETHIOPIA
Second Edition
December 2013
Addis Ababa
...
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GUIDELINES ON PROGRAMMATIC
MANAGEMENT OF DRUG RESISTANT
TUBERCULOSIS IN ETHIOPIA
Second Edition
December 2013
Addis Ababa
2
ACKNOWLEDGMENTS
The development of these guidelines is an expression of the commitment by the
FMOH and its development p...
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TABLE OF CONTENTS
ACKNOWLEDGMENTS..........................................................................................
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6.5. DEFINITIONS OF DR-TB TREATMENT OUTCOMES...............................................................................
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13.9 SUBSTANCE DEPENDENCE..................................................................................................
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20.8. PROGRAM MONITORING...................................................................................................
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ACRONYMS
ADR Adverse drug reaction
AFB Acid-fast bacilli
AIDS Acquired Immuno Deficiency Syndrome
ART Anti-retroviral th...
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FOREWORD
Ethiopia is a high TB, TB/HIV and MDR TB Burden country. The FMOH is
implementing a comprehensive TBL and TB/HI...
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1. INTRODUCTION TO THE GUIDELINE
The national TB control program has released the first PMDT guideline in 2009 and
has b...
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acceptable and nonjudgmental terms are inserted as and “presumptive TB” instead
of “TB suspect” and “lost to follow up”...
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2. BASIC CONCEPTS AND NATIONAL CONTROL FRAMEWORK
2.1 Basics of Drug Resistance in Tuberculosis
Resistance to anti-tuber...
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2.2 Definitions of drug resistance in tuberculosis
Drug resistance among New TB patients: refers to resistance in patie...
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Table: Causes of inadequate Anti- tuberculosis treatment
Health-care provider/
program related factors
Drug related fac...
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i. Early detection and high quality treatment of drug-susceptible TB.
ii. Early detection and high quality treatment of...
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success rate of 75% or more for patients with MDR-TB was achieved in 34 of 107
countries.
Global Plan to Stop TB 2011–2...
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National DR-TB Implementation frame work:
1. Sustained political commitment
Addressing the factors leading to the emerg...
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3. MDR-TB Programmatic Design, Coordination and Management
3.1 MDR-TB Program Design
National Tuberculosis program in E...
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Treatment follow up centers (TFC): are health facilities with TB DOTS clinic where
clinically stable patients continue ...
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arrange weekly evaluation of the patient till stabilization and move to next
phase. or
Patient can stay at TIC level ti...
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TFC are responsible for daily DOT supervision and routine screening of
adverse events. Patient must be referred back to...
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Health Facility MDR-TB panel team
Every Treatment initiating center needs to establish a medical/clinical panel team
to...
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Health facility serving as Ambulatory TIC: All Hospitals and high volume Health
centers must initiate treatment with SD...
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Clinical Mentoring support in PMDT: refers to regular site-level technical support
by DR- TB clinical team from TIC to ...
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Lab professionals Basic AFB and Three-days lab Bio-safety precautions
Pharmacy technicians Three-days IPLS for TB drugs...
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4. CASE FINDING STRATEGIES
4.1 Introduction
This chapter emphasizes on the national case finding strategy for high risk...
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Note that, the risk stratification not only helps for prioritization for DST screening
but also for subsequent clinical...
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4.3 Case finding strategies for XDR-TB
All strains of confirmed MDR-TB cases should routinely undergo second-line
DST i...
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4.5 Specimen collection, packing and transportation techniques and
procedures
Considering the problem of accessibility ...
ALGORITHM 1: TB AND DR TB DIAGNOS
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Presumptive TB: cough longer than 2 weeks, or
breath; chest pain, weight loss, fever o...
ALGORITHM 2: DIAGNOSIS OF DR
As shown above, the diagnosis of RR, MDR
facility level using Xpert or at reference laborator...
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If the LPA result shows resistant to R and H, or R only, patient must be treated with
SLDs, while LPA results of INH re...
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4.8 DR-TB Patient referral and linkage to MDR TB treatment centers
All confirmed DR-TB cases have to be linked to the d...
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5. LABORATORY ASPECTS OF DR-TB IN ETHIOPIA
The roles of the laboratory are critical in the diagnosis and follow up of D...
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specimens should be scrupulously followed. Ultraviolet light is useful for surface de-
contamination and may be applied...
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results. Usually, an external quality assurance program with a supranational TB
reference laboratory consists of:
• An ...
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organisms nor differentiate between drug-susceptible and drug-resistant M.
tuberculosis bacteria or between different s...
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time especially for DR TB treatment follow up even though contamination rates
may be very high.
5.4.3 Drug susceptibili...
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examination. It is fully automated for sample processing, DNA extraction and
amplification, making it possible for mole...
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In Ethiopian context, Gene Xpert MTB/RIF is the preferred method considering the
suitability for use at health facility...
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technical and administrative guidance of the national level reference laboratory
found at apex of the pyramid at the na...
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6. DR-TB PATIENT CLASSIFICATION AND DEFINITION OF TERMS
Standardized definitions, classification, registration and repo...
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6.1.2 Classification of DR TB based on Laboratory Confirmation:
• Laboratory confirmed DR-TB: refers to those cases wit...
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Classification is determined by history of treatment at the time of collection of
the sample that was used to confirm M...
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2. The collection date of the sample on which the laboratory examination was
performed was less than 30 days before, or...
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Treatment
outcome
Definition
Cured Treatment completed according to national
recommendation without evidence of failure...
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7. MANAGEMENT OF CONTACTS OF DR-TB PATIENTS
Household members or other close contact with a person who has infectious T...
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investigation generally focuses on a defined group of potentially exposed people in
which other (secondary) cases may b...
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Contact investigation starts with the education of the MDR-TB patient. Patients
should be educated about the infectious...
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ii. A chest X-ray should be done even if extrapulmonary TB is suspected,
since the contact may have unsuspected pulmona...
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7.3.4 Management of Asymptomatic contact cases
As the risk for developing active TB after exposure with infectious case...
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7.4 Chemoprophylaxis of contacts of MDR-TB index cases
Currently there is no enough evidence to recommend the use of ch...
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
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GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
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GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
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GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
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GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014
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GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014

Ethiopia is a high TB, TB/HIV and MDR TB Burden country. The FMOH is implementing a comprehensive TBL and TB/HIV control program and has achieved a lot in the past decade and is on track to achieve the MDG targets regarding TB and HIV. The increasing emergence of drug-resistant strains of TB is due to treatment defaulters and other challenges ranging from delays in initiating treatment, inadequate bed capacity, poor infection control in health facilities, and new infections. The following policy guidelines are intended for use by health care professionals involved in the complex and difficult task of MDR- and XDR-TB patients in Ethiopia. The guidelines focus on the clinical management, referral mechanisms and models of care. However, psychosocial support to ensure comprehensive management of the patients, strategies for infection prevention and control, and health services for health care workers (HCWs) are covered. Management of DR-TB is an evolving strategy, and needs to be adapted through evidence-based information. These guidelines contain recommendations based on the most recent and available scientific evidence and expert opinions. Comments and suggestions from those working in the field are essential to ensure a dynamic process, aimed at optimal control of DR-TB in Ethiopia.
Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA; 2014

  • 1. GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA Second Edition December 2013 Addis Ababa FEDERAL DEMOCRATIC REPUBLIC OF ETHIOPIA MINISTRY OF HEALTH
  • 2. 1 GUIDELINES ON PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN ETHIOPIA Second Edition December 2013 Addis Ababa
  • 3. 2 ACKNOWLEDGMENTS The development of these guidelines is an expression of the commitment by the FMOH and its development partners for delivering high quality DR TB detection, treatment and care and prevention services. The ministry of health would like to acknowledge the following experts for their contribution and commitment in the development of this guideline. Name Organization Name Organization Biruck Kebede FMOH Dr Mulugeta Tsegaye ALERT Hospital Dr Blen Ayele FMOH Dr Desalegn Nigatu Bahir Dar University Dr Anteneh Kassa FMOH/PHSP Dr Solomon Tamiru ICAP Dr Wubaye Walelgne TBCARE I/KNCV Abubeker Hussien CHAI Dr Andargachew Kumsa FMOH/ICAP Mekides Gebeyew CHAI Addisalem Yilma FMOH/WHO Dr Tadesse Anteneh HEALTB/MSH Lelisa Fekadu FMOH Dr Yohannes Molla HEALTB/MSH Birru Shigut FMOH Dr Belaineh Girma HEAL TB/MSH Kasech Sintayehu FMOH Abraham Ashenafi GHC Solomon Hassen FMOH Dr Meseret Tamirat Oromia RHB Etsegenet FMOH Dr Dawit Assefa TBCARE I/KNCV Endale Mengesha FMOH Dr Getachew Wondimagegn TBCARE I/KNCV Abebaw Kebede EHNRI/NRL Dr Yared Kebede Haile USAID Dr Endale Berta FMOH/WHO Dr Endalkachew Melese USAID Dr Daniel Meressa St. Peter Hospital/GHC Dr Yared Tedla St. Peter Hospital Dr Ermias Diro Gondar University Dr Nebiyu Mesfin Gondar University Dr Fikreselam Desalegn Mekele referral Hospital International Consultants Dr Agnes Gebhard from KNCV TB Foundation, Dr Rocio….from GHC and Dr Ernesto from WHO MDR TB Unit have reviewed the draft document and forwarded valuable comments. _____________________________________ State Minister (Program), Ministry of Health
  • 4. 3 TABLE OF CONTENTS ACKNOWLEDGMENTS.................................................................................................................................2 TABLE OF CONTENTS ..................................................................................................................................3 ACRONYMS......................................................................................................................................................7 FOREWORD .....................................................................................................................................................8 1. INTRODUCTION TO THE GUIDELINE....................................................................................................9 2. BASIC CONCEPTS AND NATIONAL CONTROL FRAMEWORK ....................................................11 2.1 BASICS OF DRUG RESISTANCE IN TUBERCULOSIS....................................................................................................11 2.2 DEFINITIONS OF DRUG RESISTANCE IN TUBERCULOSIS..............................................................................................12 2.3 CAUSES OF DRUG-RESISTANCE IN TUBERCULOSIS MANAGEMENT...............................................................................12 2.4 PREVENTION OF DEVELOPMENT OF DR TB...........................................................................................................13 2.5 EPIDEMIOLOGY OF DRUG RESISTANT TUBERCULOSIS ..............................................................................................14 2.6 NATIONAL DR-TB CONTROL FRAMEWORK ..........................................................................................................15 3. MDR-TB PROGRAMMATIC DESIGN, COORDINATION AND MANAGEMENT...........................17 3.1 MDR-TB PROGRAM DESIGN ............................................................................................................................17 3.2 MDR-TB TREATMENT CENTERS .........................................................................................................................17 3.3 PHASES OF TREATMENT IN TREATMENT DELIVERY...................................................................................................18 3.4 MANAGEMENT TEAMS/COMMITTEES AT DIFFERENT LEVELS....................................................................................20 3.5 COMMUNICATION AND SUPPORT MECHANISM BETWEEN TREATMENT CENTERS..........................................................21 3.6 HUMAN RESOURCE REQUIREMENT AND CAPACITY DEVELOPMENT .............................................................................23 3.7 SERVICE INITIATION REQUIREMENTS AND PREPARATION ..........................................................................................24 4. CASE FINDING STRATEGIES .......................................................................................................25 4.1 INTRODUCTION ............................................................................................................................................25 4.2 CASE-FINDING STRATEGIES FOR DR-TB...............................................................................................................25 4.3 CASE FINDING STRATEGIES FOR XDR-TB..............................................................................................................27 4.4 IDENTIFICATION AND REFERRAL OF PRESUMPTIVE DR-TB PATIENTS ..........................................................................27 4.5 SPECIMEN COLLECTION, PACKING AND TRANSPORTATION TECHNIQUES AND PROCEDURES..............................................28 4.6 MDR-TB DIAGNOSTIC ALGORITHM IN ETHIOPIA...................................................................................................28 4.7 COMMUNICATION OF RESULTS FROM CULTURE AND DST LABORATORY.....................................................................31 4.8 DR-TB PATIENT REFERRAL AND LINKAGE TO MDR TB TREATMENT CENTERS ..............................................................32 5. LABORATORY ASPECTS OF DR-TB IN ETHIOPIA .........................................................................33 5.1 LABORATORY INFRASTRUCTURE FOR CULTURE AND DST SERVICES.............................................................................33 5.2 INFECTION CONTROL AND BIO-SAFETY IN CULTURE AND DST LABORATORY................................................................33 5.3 QUALITY CONTROL AND ASSURANCE...................................................................................................................33 5.4 MYCOBACTERIAL LABORATORY SERVICES FOR DRUG RESISTANT-TB ...........................................................................35 5.5 DST SERVICE IN ETHIOPIA.................................................................................................................................38 5.6 ORGANIZATION AND ROLE & RESPONSIBILITIES TB LABORATORY SYSTEM ..................................................................39 6. DR-TB PATIENT CLASSIFICATION AND DEFINITION OF TERMS...............................................41 6.1 DEFINITIONS OF DRUG-RESISTANT TB ...............................................................................................................41 6.2 REGISTRATION GROUP BASED ON HISTORY OF ANTI-TB TREATMENT ..........................................................................42 6.3 DEFINITIONS OF SPUTUM AND CULTURE CONVERSION AND REVERSION.......................................................................43 6.4. INTERIM INDICATORS FOR MDR-TB PROGRAM MONITORING .................................................................................44
  • 5. 4 6.5. DEFINITIONS OF DR-TB TREATMENT OUTCOMES.................................................................................................44 7. MANAGEMENT OF CONTACTS OF DR-TB PATIENTS ..................................................................46 7.1 DEFINITIONS OF TERMS...................................................................................................................................46 7.2 REASONS FOR HOUSEHOLD CONTACTS SCREENING.................................................................................................47 7.3 IDENTIFICATION AND MANAGEMENT OF CONTACTS OF DR-TB CASES .......................................................................47 7.4 CHEMOPROPHYLAXIS OF CONTACTS OF MDR-TB INDEX CASES.................................................................................51 8. TREATMENT OF DRUG RESISTANT TUBERCULOSIS..................................................................52 8.1 GROUPS OF ANTI-TB DRUGS.............................................................................................................................52 8.2 CROSS RESISTANCE AMONG FIRST LINE AND SECOND LINE DRUGS..........................................................................54 8.3 DESIGNING MDR-TB TREATMENT REGIMEN ..................................................................................................... 55 8.4 DR TB TREATMENT STRATEGIES......................................................................................................................57 8.5 PHASES AND DURATION OF TREATMENT MDR TB..............................................................................................59 8.6 STANDARD CODE FOR TB TREATMENT REGIMENS...............................................................................................60 8.7 EXTRAPULMONARY DR-TB.............................................................................................................................61 8.8 ADJUVANT THERAPIES IN DR TB......................................................................................................................63 8.9 TREATMENT OF XDRTB .................................................................................................................................66 8.10 MANAGEMENT OF FLUOROQUINOLONE OR SECOND LINE INJECTABLE RESISTANCE (PRE-XDR TB). ........................69 8.11 MANAGEMENT OF MONO- AND POLY-DRUG RESISTANT TB CASES....................................................................69 9. EVALUATION AND MONITORING OF PATIENTS ON TREATMENT......................................71 9.1 PRE-TREATMENT EVALUATION AND SCREENING.................................................................................................71 9.2 TREATMENT MONITORING AND FOLLOW UP..................................................................................................... 72 9.3. POST-TREATMENT MONITORING ....................................................................................................................76 10. ADHERENCE SUPPORT AND DIRECTLY OBSERVED TREATMENT ..........................................77 10.1 ADHERENCE SUPPORT ..................................................................................................................................77 10.2 DIRECTLY OBSERVED TREATMENT..................................................................................................................80 10.3 DOT PROCEDURES ......................................................................................................................................81 10.4 PSYCHOSOCIAL AND ECONOMIC SUPPORT..........................................................................................................83 10.5 SUPPORT GROUPS........................................................................................................................................85 11. MANAGEMENT OF DR TB TREATMENT INTERRUPTIONS AND LOST TO FOLLOW OF UP ......86 11.1 MANAGEMENT OF TREATMENT INTERRUPTIONS ..................................................................................................86 11.2 MANAGEMENT OF PATIENTS WHO RETURN AFTER LOST TO FOLLOW UP (LTFU) ........................................................87 12. MANAGEMENT OF MDR-TB TREATMENT FAILURE ...................................................................89 12.1 ASSESSMENT OF PATIENTS AT RISK FOR FAILURE...................................................................................................89 12.2 MANAGEMENT OF DR TB TREATMENT FAILURE ..................................................................................................90 13. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS IN SPECIAL SITUATIONS..........................92 13.1 PREGNANCY................................................................................................................................................92 13.2 BREASTFEEDING ..........................................................................................................................................94 13.3 FAMILY PLANNING .......................................................................................................................................94 13.4 DIABETES MELLITUS.....................................................................................................................................95 13.5 RENAL INSUFFICIENCY ..................................................................................................................................96 13.6 LIVER DISORDERS ........................................................................................................................................99 13.7 SEIZURE DISORDERS...................................................................................................................................100 13.8 PSYCHIATRIC DISORDERS ............................................................................................................................100
  • 6. 5 13.9 SUBSTANCE DEPENDENCE...........................................................................................................................101 13.10 DRUG RESISTANT TB AND HIV..................................................................................................................102 14. DRUG-RESISTANT TB IN CHILDREN..............................................................................................107 14.1 INTRODUCTION...........................................................................................................................................107 14.2 DR TB CASE FINDING IN CHILDREN ................................................................................................................107 14.3 DIAGNOSIS OF MDR-TB IN CHILDREN.............................................................................................................108 14.4 TREATMENT OF MDR-TB IN CHILDREN...........................................................................................................109 14.5 TREATMENT FAILURE IN CHILDREN..................................................................................................................110 15. MANAGEMENT OF ADVERSE DRUG REACTIONS ..................................................................111 15.1 SCREENING FOR ADVERSE EFFECTS .................................................................................................................111 15.2 GENERAL CONSIDERATIONS ...........................................................................................................................111 15.3 SPECIFIC MANAGEMENT OF ADVERSE DRUG REACTIONS (ADRS).........................................................................114 16. PALLIATIVE CARE IN DRUG RESISTANT TB...................................................................................128 16.1 DEFINITIONS AND PRINCIPLES OF PALLIATIVE CARE IN DR TB ...............................................................................128 16.2 TERMINAL ILLNESS AND END OF LIFE CARE........................................................................................................129 16.3 MANAGEMENT OF COMPLICATIONS OF MDR-TB..............................................................................................131 17. INFECTION CONTROL IN THE CONTEXT OF DRUG RESISTANT-TB ...................................135 17.1 SET OF TB INFECTION CONTROL MEASURES FOR HEALTH FACILITIES......................................................................135 17.2 MINIMUM PACKAGE OF TB INFECTION CONTROL INTERVENTIONS FOR DR TB TREATMENT FACILITIES..........................145 17.3 INFECTION CONTROL IN THE COMMUNITY AND HOME LEVEL.................................................................................146 17.4 INFECTION CONTROL DURING PATIENT TRANSPORT ...........................................................................................147 17.5 CARE OF THE HEALTH CARE WORKER ...............................................................................................................148 18. LEGISLATIVE FRAMEWORK AND PUBLIC HEALTH ETHICS IN DR TB.................................149 18.1 GUIDANCE ON ETHICS OF TUBERCULOSIS PREVENTION, CARE AND CONTROL.........................................................149 18.2 PATIENT MANAGEMENT RELATED CHALLENGES IN M/XDR TB............................................................................151 19. MANAGEMENT OF SECOND-LINE ANTI-TB DRUGS AND OTHER COMMODITIES ...........152 19.1 SELECTION QUANTIFICATION AND PLACING SECOND-LINE DRUGS ORDER ...............................................................152 19.2 PROCUREMENT...........................................................................................................................................152 19.3 REGISTRATION AND IMPORTATION..................................................................................................................153 19.4 QUALITY ASSURANCE AND QUALITY CONTROL AND SHELF LIFE.............................................................................153 19.5 DISTRIBUTION TO TREATMENT CENTERS...........................................................................................................153 19.6 INVENTORY CONTROL ..................................................................................................................................154 19.7 RATIONAL USE............................................................................................................................................155 19.8 DISTRIBUTION OF ANCILLARY MEDICINE AND CONSUMABLES................................................................................155 19.9 PHARMACOVIGILANCE..................................................................................................................................155 20. MONITORING AND EVALUATION OF DR-TB PROGRAM ............................................................156 20.1 INTRODUCTION...........................................................................................................................................156 20.2. RECORDING AND REPORTING FORMATS AND REGISTERS ....................................................................................156 20.3. DESCRIPTION OF DR-TB RECORDING AND REPORTING TOOLS ............................................................................157 20.4. KEY INDICATORS IN PMDT ..........................................................................................................................160 20.5. RECORDING AND REPORTING IN PMDT .........................................................................................................161 20.6. DATA MANAGEMENT AND INFORMATION DISSEMINATION..................................................................................162 20.7. SUPPORTIVE SUPERVISION ...........................................................................................................................162
  • 7. 6 20.8. PROGRAM MONITORING.............................................................................................................................162 20.9 PROGRAM EVALUATION..............................................................................................................................163 REFERENCES..............................................................................................................................................164 ANNEXES...................................................................................................................................................166 ANNEX 1: DOSING OF ANTI-TB DRUGS BY WEIGHT CLASS IN ADULTS AND ADOLESCENTS...................................................166 ANNEX 2. PEDIATRIC DOSING OF SECOND-LINE MEDICATIONS ..................................................................................167 ANNEX 3. SPECIMEN FOR ANALYSIS OF PRESUMPTIVE TB IN CHILDREN ......................................................................168 ANNEX 4: MINIMUM PACKAGE OF TB IC INTERVENTIONS AT HEALTH FACILITY LEVEL.......................................................169 ANNEX 5: SIMPLIFIED TB IC PLAN FOR HEALTH CARE FACILITY.....................................................................................170 ANNEX 6: MDR TB PATIENT SOCIOECONOMIC AND HOME ASSESSMENT TOOL...............................................................171 ANNEX 7: STEPWISE INTRODUCTION NEW TB DRUGS FOR USE IN DRTB PATIENTS...........................................................172 ANNEX 8: SAMPLE TRANSPORTATION SOP..............................................................................................................173
  • 8. 7 ACRONYMS ADR Adverse drug reaction AFB Acid-fast bacilli AIDS Acquired Immuno Deficiency Syndrome ART Anti-retroviral therapy BCG Bacille-Calmette-Guérin CBC Complete blood count COC Combined oral contraceptives CPT Cotrimoxazole Preventive Therapy CXR Chest X-ray DOT Directly observed treatment DOTS Direct observed Therapy short-course DR-TB Drug-resistant tuberculosis DST Drug susceptibility testing FBS Fasting blood sugar FIND Foundation for Innovative New Diagnostics FLD First line anti-TB drugs GDF Global drug facility GFATM The Global Fund to fight AIDS, Tuberculosis and Malaria HCG Human Chorionic Gonadotropin HCW Health care worker HEW Health Extension worker HIV Human immunodeficiency virus IUCD Intra-uterine contraceptive device LED Light-emitting diode LFT Liver function test LPA Line probe assay MDR-TB Multidrug-resistant tuberculosis NGO Nongovernmental organization NSAIDs Non-steroidal anti-inflammatory drugs NTP National tuberculosis control programme OI Opportunistic infections PMDT Programmatic management of drug resistant Tuberculosis PPM Public–private mix RFT Renal function test RHB Regional health bureau RR-TB Rifampicin-resistant tuberculosis SLD Second line anti-TB drugs TFC Treatment follow up center TIC Treatment initiating center TSH Thyroid stimulating hormone TB Tuberculosis TBL Tuberculosis leprosy WHO World health organization XDR-TB Extensively drug-resistant TB Xpert MTB/RIF Xpert Mycobacterium Tuberculosis/ Rifampicin test ZN Stain Ziehl Neelsen otherwise called AFB stain
  • 9. 8 FOREWORD Ethiopia is a high TB, TB/HIV and MDR TB Burden country. The FMOH is implementing a comprehensive TBL and TB/HIV control program and has achieved a lot in the past decade and is on track to achieve the MDG targets regarding TB and HIV. The increasing emergence of drug-resistant strains of TB is due to treatment defaulters and other challenges ranging from delays in initiating treatment, inadequate bed capacity, poor infection control in health facilities, and new infections. The following policy guidelines are intended for use by health care professionals involved in the complex and difficult task of MDR- and XDR-TB patients in Ethiopia. The guidelines focus on the clinical management, referral mechanisms and models of care. However, psychosocial support to ensure comprehensive management of the patients, strategies for infection prevention and control, and health services for health care workers (HCWs) are covered. Management of DR-TB is an evolving strategy, and needs to be adapted through evidence-based information. These guidelines contain recommendations based on the most recent and available scientific evidence and expert opinions. Comments and suggestions from those working in the field are essential to ensure a dynamic process, aimed at optimal control of DR-TB in Ethiopia.
  • 10. 9 1. INTRODUCTION TO THE GUIDELINE The national TB control program has released the first PMDT guideline in 2009 and has been implementing the DR-TB program since then. The first edition of the guideline is revised in order to incorporate scientific updates and best practices on PMDT both from in country and abroad. Since the publication of the first edition of the PMDT guideline in 2009 several new developments occurred in the diagnosis and management of DR TB globally. Some of the key changes include evidence based policy update on PMDT, expanded role of rapid diagnostics in DST for LPA and Xpert MTB/RIF Tests, updates on definitions and reporting framework for tuberculosis, new drugs like bedaquiline, new guidance on contact investigation, new guidance on ethics of TB control, role of rapid tests in SLD DST. The second edition of the guideline has tried to incorporate all the new developments internationally and tries to build upon the successes of PMDT implementation nationally. Summary of the key changes made in the second edition of the guideline Section two presents the basic principles of DR TB causation. It also summarizes the DR TB control frame work of Ethiopia. Section three presents the program design, coordination and management aspects of DR-TB in Ethiopia. It describes the shift made in the treatment model from hospitalized to outpatient Ambulatory model of care as it benefits decentralization of the service and reduce burden on the patients. Elaboration is made on the role of treatment centers in the provision of care, treatment and support to the patient during the course of treatment. Communication and referral mechanism has to be strong between treatment centers through CAM and Mentoring. In the case finding strategy and laboratory aspects of DR-TB section, this edition emphasized on the need for systematic identification of presumptive DR-TB cases and use of WHO approved rapid DST techniques like LPA and Xpert MTB/RIF. Separate DR-TB diagnostic algorithms are introduced to be used at HF and reference laboratory level. Further elaboration is provided on how to use the sample transportation system to access culture and DST services and annexed Standard operating procedure for proper sample collection and transport. Section on the DR-TB case definition and registration is updated based on the new WHO definitions and reporting framework, 2013. New changes on Rifampicin resistant TB (RR-TB) cases to be enumerated and reported separately, case definition based on WHO newly approved confirmatory results like Xpert MTB/RIF and revised definition for cure and treatment failure are incorporated. In addition, ethically
  • 11. 10 acceptable and nonjudgmental terms are inserted as and “presumptive TB” instead of “TB suspect” and “lost to follow up” for “Defaulter”. Section seven to nine deals with the treatment aspects of DR-TB. It presents the treatment principles in designing effective regimen to treat DR-TB Tuberculosis and describes Cm-Lfx-Pto-Cs-Z as the preferred Standardized regimen in Ethiopia.in Ethiopia. Kanamycin is alternate drug for Capreomycin in the regimen. Prothionamide is a prodrug for Ethionamide is preferred in the regimen for its better tolerance though either of them can be used interchangeably based on the availability. The treatment duration is also redefined as minimum of 8 months or four month after culture conversion, and total duration of 20 months or 18 months after culture conversion. In the management of pre-XDR and XDR cases, the use of newly WHO approved drugs can be used if there are no adequate drugs to construct likely effective regimen. The wide range and frequent occurrence of Adverse drugs reactions to Second line TB drugs complicates the case management of DR-TB patients and at large the success of the program. This section gives due emphasis to assist health professionals to develop the necessary knowledge and skill to systematically screen patient for ADRS and identify early and treat promptly. Patient preparation and monitoring section presents how to prepare, monitor and support patient receiving DR-TB treatment and place Direct observed therapy throughout treatment. Besides, justifies why psychosocial support is part and parcel of treatment packages and advice on the package and modalities of support to the eligible population.
  • 12. 11 2. BASIC CONCEPTS AND NATIONAL CONTROL FRAMEWORK 2.1 Basics of Drug Resistance in Tuberculosis Resistance to anti-tuberculosis drugs is a natural phenomenon occurring in all wild- type populations of M. tuberculosis by spontaneous chromosomal mutations. Within wild-type M. tuberculosis populations, small populations of mutants are found to be resistant to anti-tuberculosis drugs. For instance, in a given wild-type population 3.5 x 10-6 are resistant to INH and 1.2 x 10-8 are resistant to Rifampicin. As resistance to the various drugs is not linked genetically, for a bacillus to be resistance to more than one TB drug is even rarer phenomena: 3.5 x 10-6 X 1.2 x 10-8 = 4.2 x 10-14 are resistant to the combination of INH and RIF. Hence, the chance for wild-type resistant mutants to cause clinically significant TB with either mono- or poly- resistant forms in an untreated M. tuberculosis population is extremely rare as it would require very large number of mutant bacilli. Rather, the selection of naturally occurring drug-resistant mutants by inadequate TB treatment is mainly responsible for the population of M. tuberculosis bacteria to become increasingly drug-resistant. As the drug-susceptible organisms are killed during sub-optimal treatment, the drug-resistant mutants gradually become an increasing proportion of the disease burden, and results in emergence of drug resistant form of TB. The chance for having single chromosomal mutation to cause resistance to two or more anti-TB drugs is an extremely rare event. Hence, Poly- or multi-drug-resistant TB is caused by sequential mutations in different genes. Susceptible TB bacilli develop resistance first to one drug (-acquired resistance) and subsequently to another drug by amplification of resistance. This evolution involves multiple cycles of “fall and rise” phenomena where susceptible strains will be killed leaving the resistant strains to multiply and predominate the bacillary population. Despite the fact that HIV epidemic ‘speeds up’ the emergence of drug resistance in communities by shortening the natural history of TB, resulting in a higher proportion of individuals to develop TB disease, there is no evidence of an association of drug resistance with HIV infection per se.
  • 13. 12 2.2 Definitions of drug resistance in tuberculosis Drug resistance among New TB patients: refers to resistance in patients who have no history of treatment for tuberculosis for a period longer than one month. Drug resistance among previously treated TB patients: refers to resistance in patients who have been treated for TB for a period lasting more than one month. 2.3 Causes of drug-resistance in Tuberculosis management Causes associated with the emergence of drug resistance in an individual could be either microbial, clinical and programmatic. However, common causes are essentially man-made errors following an inadequate or poorly administered treatment regimen that allows a drug-resistant strain to become the dominant strain in a patient infected with TB. Table 1.1summarizes the common causes of inadequate treatment although DR-TB can then spread from one person to another. These potential causes of inadequate treatment can be broadly categorized in to:- • Health care factors: provider, program related factors • Drug related factors • Patient related factor
  • 14. 13 Table: Causes of inadequate Anti- tuberculosis treatment Health-care provider/ program related factors Drug related factors Patient- related factors • Inappropriate guidelines • Non-compliance with guidelines • Absence of guidelines • Poor training • Poor supervision • No monitoring of treatment provision • Poorly organized or funded TB control program • Inadequate regimens • Lack of DST • Poor access to health care • Poor quality medicines • Unavailability of certain drugs due to stock-outs of delivery disruptions • Poor storage conditions • Wrong doses or combinations (manufacture related) • Poor regulation of medicines • Poor adherence/default • Lack of information • Lack of money • If Treatment not given for free • Lack of transportation money or support • Drug adverse effects/interaction, • Mal-absorption • HIV • Diabetes mellitus • Malnutrition • Psychiatric condition • Substance/alcohol dependence • Social barriers 2.4 Prevention of development of DR TB Environments conducive for TB transmission in general, including crowding, poor ventilation, and poor infection control practices in health facilities and other places where transmission occur, also contribute to transmission of MDR-TB. Similar to drug-susceptible TB, DR-TB only progresses to active disease in a minority of those infected, and DR-TB infection can remain latent for long periods of time. A poorly functioning immune system increases the risk of progression, and therefore all factors that can impair the immune system (e.g. HIV, under-nutrition, diabetes, silicosis, smoking, alcohol abuse, a wide range of systemic diseases and treatments with immunosuppressant) are risk factors for DR-TB disease in a person initially infected with a DR-TB strain. Evidences show that poor standardized TB treatment and transmission of resistant strains as major causes for development of Drug resistant TB in the community. There are four standard ways to prevent DR-TB:
  • 15. 14 i. Early detection and high quality treatment of drug-susceptible TB. ii. Early detection and high quality treatment of DR-TB. For people with DR-TB, early diagnosis, proper treatment and patient support are key elements to decrease transmission and amplification of resistance. iii. Health system strengthening and regulation: integration of services, strengthen lab capacity, strengthen TB Infection Control and Drug regulation (Quality and availability of both 1st and 2nd line medicines need to be assured, such that regulation of registration, import and manufacturing of TB drugs is addressed). iv. Addressing underlying risk factors and social determinants: Poverty, Vulnerable groups (Refugees, Prison), HIV, Diabetes, Malnutrition, Substance abuse (alcohol, Cigarette) Cognizant of this, national TB control program (NTP) has decentralized TB control activities in the community through the health extension program, with primary aim of improving case finding, adherence support and treatment success. The national TB program through integrated management of both drug susceptible and resistant forms of Tuberculosis will focus on early identification of TB cases, administration effective treatment, and strengthening of infection prevention practices to prevent and control the threat of all forms of TB, including DR TB. 2.5 Epidemiology of Drug Resistant Tuberculosis Globally in 2012, there were an estimated 450 000 (range: 300 000‒600 000) new cases of MDR-TB. Data from drug resistance surveys and continuous surveillance among notified TB cases suggest that 3.6% (95% CI: 2.1–5.1%) of newly diagnosed TB cases and 20% (95%CI: 13.3–27.2%) of those previously treated cases are estimated to have MDR-TB. A total of 94 000 TB patients eligible for MDR-TB treatment were detected in 2012. At least one case of extensively drug-resistant TB (XDR-TB) had been reported by 92 countries by the end of 2012. Nonetheless, on average, 9.6% of MDR-TB cases are estimated to have XDR-TB. Globally, only 48% of MDR-TB patients in the 2010 cohort of detected cases were successfully treated, reflecting high mortality rates and loss to follow-up. A treatment
  • 16. 15 success rate of 75% or more for patients with MDR-TB was achieved in 34 of 107 countries. Global Plan to Stop TB 2011–2015 sets targets to screen 20% of all new bacteriologically-positive TB cases and all previously treated cases with DST for at least rifampicin and isoniazid, and Planned to perform SLDs DST for all patients with MDR-TB. However, in 2012, only 5% of new and 9% of previously treated cases was tested for MDR-TB. In Ethiopia, FLD DST was performed for 469(<1%) new and 180(4%) retreatment TB cases, respectively, in 2012 to confirm 284 MDRTB; 30 among new and 102 among previously treated cases. The 2003-2005 drug resistance TB survey result showed, 1.6% of new cases and 11.8 % of retreatment cases in Ethiopia to be resistant to at least isoniazid and rifampicin. The global TB Report 2013, has estimated 2,010(1,200-3,000) MDRTB cases to occur among all notified TB cases in 2012, comprising of 1600 (830–2 700) among new and 480 (230–870) among retreated TB cases. 2.6 National DR-TB Control Framework For the provision of comprehensive and quality diagnostic and treatment services for MDR-TB, implementation of the STOP TB STRATEGY must be adapted to the context of DR-TB control framework. It addresses TB/HIV and MDR-TB, health system strengthening, engagement community and all care providers and operational researches in addition to DOTS. Each component of the extended DR-TB strategy, shown below, contributes for the success of the program. Each of these components involves more complex and costly operations than those for controlling drug sensitive TB. However addressing multidrug-resistant TB will strengthen the existing TB control program.
  • 17. 16 National DR-TB Implementation frame work: 1. Sustained political commitment Addressing the factors leading to the emergence of MDR-TB Long-term investment of staff and resources Coordination of efforts between communities, local governments and international agencies A well-functioning DOTS program 2. Appropriate case-finding strategy including quality-assured culture and drug susceptibility testing (DST) Rational triage of patients into DST and the DR-TB control programme Relationship with supranational TB reference laboratory 3. Appropriate treatment strategies that use second-line drugs under proper case management conditions Rational treatment design DOT Monitoring and management of adverse effects Properly trained human resources Active pharmacovigilance in the introduction of new drugs or novel regimens 4. Uninterrupted supply of quality-assured second-line anti-tuberculosis drugs 5. Recording and reporting system designed for drug resistance-TB control programs
  • 18. 17 3. MDR-TB Programmatic Design, Coordination and Management 3.1 MDR-TB Program Design National Tuberculosis program in Ethiopia has shifted the hospitalized model of care for DR-TB case Management, mentioned in the first edition of PMDT guideline, to Clinic –based Ambulatory model of care as it is more feasible for decentralized implementation of the program in the local context and would be convenient for patient follow up. Clinic-based Ambulatory Model of care: is designed to deliver the treatment course on outpatient basis so long as the patient is fit to be followed as ambulatory. The place of temporary inpatient care is reserved mainly for patients who develop severe adverse events during the course of treatment. However, patients either with serious medical or social reason may be admitted with the decision of the panel team. 3.2 MDR-TB treatment centers In treatment of DR-TB patients in Ethiopia, health facilities could serve as either treatment initiating centers (TIC) or treatment follow up centers (TFC) or both. These two levels of treatment centers have complementary roles in order for the program to function efficiently and deliver comprehensive DR-TB care, treatment and support. Treatment initiating centers (TIC): are health facilities selected by the TB program to provide patient care and treatment services right from time of DR-TB diagnosis and throughout the course of treatment with SLDs. The clinical panel of team in these centers is authorized to initiate treatment, perform all scheduled clinical evaluation and lab monitoring tests, manage difficult cases and those with serious complications and/or ADR and decide on the need of regimen modification when indicated. Responsibilities of Treatment Initiation center (TIC) • Designate space for inpatient and outpatient MDRTB treatment service • Involve in case finding process of DR-TB • handle all Patient preparation and initiation of treatment with SLDs • Admit difficult cases and those with serious complications
  • 19. 18 Treatment follow up centers (TFC): are health facilities with TB DOTS clinic where clinically stable patients continue to receive DOT for SLDs and perform routine screening of adverse events and management with the aim to decentralize the delivery of treatment services closer to the patient residence. Responsibilities of Treatment follow up center (TFC) • manage all patients referred/transferred from treatment initiation center • Involve in case finding process of DR-TB • Routine screening of adverse events, supervise DOT and administer injection 3.3 Phases of treatment in treatment delivery The national TB program designed the DR TB treatment to be delivered in three phases whereby the respective treatment centers have specific tasks and responsibilities at each phase in order to implement the standard patient care packages defined by the national guidelines. Phases of MDR-TB treatment delivery: Phase I: Intensive phase: stabilization Phase II: Intensive phase: out patient Phase III: Continuation Phase Phase I: Intensive phase: stabilization In this phase, all efforts are directed to ensure that patients are both clinically stable and adherent to SLDs; hence, the role of clinical team at TICs is more intensive to provide the necessary clinical, adherence and social support arrangements to enables the patient to be fit enough to be followed at TFC level. In this phase, TIC is responsible for patient preparation, regimen selection and treatment initiation & monitoring. However, daily Supervision of DOT and administration of injection could be made either at TIC or TFC level considering the patient clinical and social condition, arrangement with TFC or need for adherence. Patient can start treatment at TFC level if the panel team decides to link the patient to TFC right from the start for daily DOT and administration of injection. TIC must handle patient preparation and treatment initiation and
  • 20. 19 arrange weekly evaluation of the patient till stabilization and move to next phase. or Patient can stay at TIC level till the panel team decides to transfer to next phase and link the patient to TFC to continue with phase II. Criteria for transferring patients to next phase include: o Clinical condition and satisfactory treatment adherence of the patient, o Having satisfactory follow-up plan with the patient, and o Arrangement with TFC and the TB program officer. Indication for in-patient care of MDRTB patients: Temporary in-patient management of DRTB patients are indicated for: Patients who are not able to ambulate for medical or social reason Poorly controlled or complicated co-morbidities (diabetes, Liver failure, renal insufficiency, psychiatric illness, cardiac problems and substance dependency) Patients from congregate settings (prisoners, refuges and homeless shelters) Patient who developed serious ADR or other concomitant illness XDR suspect/case or contact of presumed or known XDRTB case Adherence problems or with failing MDR regimens* All confirmed or presumptive XDR-TB cases* N.B: Pregnant women and children do not need to be hospitalized if clinically stable. *Such patients should only be admitted in TB isolation rooms with limited contact with other patients with strict IP precautions to avoid increased risk of transmission of resistant strains within the health facility level. Phase II - Intensive phase out-patient In phase II, the clinical management of the patient is similar to stabilization phase, but now the patient has stable clinical condition, satisfactory adherence to treatment and can be followed at TFC level, while TICs continue to perform the scheduled monthly clinical and lab assessment of treatment.
  • 21. 20 TFC are responsible for daily DOT supervision and routine screening of adverse events. Patient must be referred back to TIC if they develop severe adverse events or serious medical condition requiring admission or expert evaluation. Phase III – Continuation Phase The continuation phase of treatment is provided under directed supervision of either HCWs at TFC, HEWs at Health post or by family DOT provider, under close supportive supervision by the treatment follow up center. Supervision of treatment at home level must consider: • Linkage with the responsible HEWs at HP to support treatment • Patients clinical condition • Availability and Capacity family DOT provider • Demonstrated successful adherence to oral and injectable TB medicines National Tuberculosis program in Ethiopia has shifted the hospitalized model of care for MDR-TB case Management, mentioned in the first edition of PMDT guideline, to Clinic –based Ambulatory model of care as it is more feasible for decentralized implementation of the program in the local context and would be convenient for patient follow up. 3.4 Management Teams/Committees at Different Levels For Successful implementation of MDRTB program and service up from the national program down to the health facilities where patient are receiving MDRTB care and treatment; there need to be technical coordinating teams at national, regional and site-level assuming appropriate role and responsibilities as follows: MDR-TB TWGs at national and regional levels: Under the national and regional TB technical working groups, there has to be MDRTB subgroups to oversee, monitor and assist the successful PMDT implementation at respective level. The team should be composed of all relevant stakeholders at the respective level.
  • 22. 21 Health Facility MDR-TB panel team Every Treatment initiating center needs to establish a medical/clinical panel team to assist smooth implementation of the program and provide appropriate patient care at service delivery points. The team is expected to meet every month to review patients’ profiles and decide on major action and document their final decision on the appropriate box on patients’ treatment card. Team composition: Clinicians from MDR-TB center, nurses, pharmacist, laboratory technologist, chief Clinical officer, social workers, local health office (-regional, zonal &/or Woreda) TBL officers, and technical advisors from partners. Responsibilities of the team include: • Evaluation of clinical and social profile of each patient who is about start treatment • Decision on mode of treatment initiation for individual patient • MDR TB treatment based on clinical criteria for selected patients. • To construct individual treatment regimen when needed • Arrangement of social support for eligible patients • To decide on end of intensive phase and continue with continuation phase • To define patient’s interim and final treatment outcome • To decide patient’s transfer to respective TFC • To assist TFCs, together with the program, to practice standard of care. 3.5 Communication and Support Mechanism between Treatment Centers In MDRTB program implementation, treatment centers, DST laboratories and programmatic stake holders need to be organized and have clear mechanisms for regular communication in order to deliver standardized level of care for the patients. 3.5.1 Organization of DR-TB treatment centers The implementation of comprehensive MDRTB care and treatment services requires the combined efforts of health facilities at different levels within the existing heath care system. The integrated service at the hospital, health centers, culture & DST labs and lower community level care needs to be defined so that no component of the comprehensive care neither missed out nor duplicated.
  • 23. 22 Health facility serving as Ambulatory TIC: All Hospitals and high volume Health centers must initiate treatment with SDLs and provide follow up services for stable and uncomplicated cases. Health facility serving as referral level TIC: Hospitals with dedicated MDRTB wards with isolations rooms should act as referral medical centers in addition to the services designated to be provided by Ambulatory TIC. Health facility serving as TFC: All DOT clinics must serve as TFC center whereby screening of all TB cases for possible Drug resistance, MDRTB follow up treatment and care services is to be provided. 3.5.2 Communication and support mechanism In order to provide the comprehensive and Quality DR TB care and treatment services, centers with different and complementary roles needs to have strong referral communication and support mechanisms. As a result, NTP has arranged 8-10 TFCs under one TIC as a catchment unit so that there will be Catchment area meetings and clinical mentoring support among centers within the same unit. Besides, centers with small number of patients may be supported by supportive supervision and review meetings organized by the TB control program. Catchment Area Meeting in PMDT: refers to meetings conducted between Treatment centers within same catchment to improve quality of care in the comprehensive DR-TB case management. The meeting shall be held bimonthly till the program matures, and then linked to the quarterly review meetings. The purpose of the meetings includes: • To strengthen the referral and communication system between TIC, TFC, DST lab, Health offices & various actors in the program • To improve the case management and clinical decisions skills of HCWs at TFCs • To foster the spirits of team work to improve quality of care and patient satisfaction • To deal on areas of improvements identified during the mentoring support visits Catchment area team members includes HCWs and administrators from Treatment centers, TB officers from local zonal and Woreda offices and representatives of partners supporting TB program.
  • 24. 23 Clinical Mentoring support in PMDT: refers to regular site-level technical support by DR- TB clinical team from TIC to HCWs at TFC levels in order to improve the clinical case management skill of staffs and hence quality of patient care at TFC levels. It is recommended to be conducted every month for the first Six month, then every two months for the next six months, and then linked to programmatic support through supportive supervision. The purpose of conducting mentoring support includes: • To transfer skill on case management of DR-TB at TFC level • To ensure practice of DOT and monitoring of side effects • To support staffs to conduct contact screening and manage • To assist TFCs to maintain good infection control standards • To ensure all Recording and reporting forms are kept updated • To arrange transferring of patients and their SLDs to TFC upon discharge Clinical Mentoring team comprises of Health workers from TIC who are directly involved in case management of DR TB patients, and/or TB/HIV experts from Regional/ zonal/ wereda/ partners who is experienced on PMDT. Note that, in areas where logistic arrangement to conduct catchment area meetings and clinical mentoring by hospital staffs from TIC are limited, TB program officer from the respective RHB/Zonal or woreda health offices and partners should provide the necessary technical and programmatic support for HCWs at TFCs through supportive supervision to maintain the quality of patient care. 3.6 Human resource requirement and capacity development For comprehensive implementation of DR-TB service package at treatment centers and respective TB program management units, the following capacity development are recommended for program managers, health care workers, supportive staffs and hospital administrators. Professional category Training package MD and Health officer or BSC nurse Five-days Modular PMDT training package for GHWs, or Advanced clinical TB training for clinicians
  • 25. 24 Lab professionals Basic AFB and Three-days lab Bio-safety precautions Pharmacy technicians Three-days IPLS for TB drugs TB officers at various levels Five-days TBL and DRTB training for program managers General hospital supportive staffs, in particular at referral levels One day Sensitization on Airborne infection control measures 3.7 Service initiation requirements and preparation • Orientation to the hospital administration and respective Health office • Site identification and preparation for DR TB service delivery • Identify requirement based on the package for the designated service • Designate rooms with minimum TB IC measures • Ensure the necessary furnishers and equipment for the designated rooms • Arrangement for Lab networking and sample transportation for culture and DST • Ensure availability of recommended lab monitoring tests at the facility • Provide TB IC material, RR tools, and provider support tools • Ensure the presence of ancillary drugs in the center • Trained health professionals and program managers in the respective centers • Establishment MDR-TB panel team at TIC • Sensitization forum for service initiation at treatment centers • Decide on mechanism for mentoring support and catchment area meeting
  • 26. 25 4. CASE FINDING STRATEGIES 4.1 Introduction This chapter emphasizes on the national case finding strategy for high risk groups for development of DR TB in Ethiopian context. The national Diagnostic algorithms for DR-TB using DST techniques at health facility and reference laboratory levels are also described with recommended procedure for sample collection, referral and result delivery system. 4.2 Case-finding Strategies for DR-TB The main aim of DR-TB case finding strategy in the TB program is to diagnose cases early, initiate them on effective treatment and interrupt the chain of disease transmission in the community. Countries are increasingly moving toward a "universal DST" strategy, testing all patients with active TB disease for drug resistance at the start of therapy. However there is limited resources to perform culture and drug susceptibility testing (DST) for all TB patients and the prevalence of M(X) DR-TB in new patients is very low , and so performing culture and DST for every patient is not cost- effective. DST should therefore be used selectively for patients at risk for MDR-TB based on a careful history. Patients with medium to high risk for DR TB will be triaged for more efficient use of DST. In Ethiopia DST will prioritize all TB patients who were previously treated with FLDs for one or more months, and those presumed or confirmed TB cases who are either close contact with confirmed/presumed M(X) DR TB cases or working/living in settings where exposure to DR-TB is likely to be high. These settings may include health facilities, prisons, refugees and other congregated settings which favor transmission of TB in the community. Table 4.1 shows presumptive MDR-TB cases categorized by the level of risk for development of DR-TB as high risk (may reach 60-80%) or moderate risk (usually 20-30%).
  • 27. 26 Note that, the risk stratification not only helps for prioritization for DST screening but also for subsequent clinical management. Table 4.1 Presumptive MDR TB cases in Ethiopia. Risk for DR- TB Risk group Action High - Failure of the re-treatment TB regimen - Symptomatic close contacts of confirmed/presumed DR-TB cases - Sputum smear positive at 3rd month of TB re-treatment - Failure of New TB regimen - Relapse after second or subsequent course of TB treatment Perform Rapid DST If not clinically stable, consider SLD treatment by the MDR-TB panel team decision Medium - Relapse , - Return after loss to follow up of TB treatment - Any previously treated patients presenting with presumptive or confirmed TB - Sputum smear positive at 3rd month of treatment of New TB case - presumptive or confirmed TB in patients from congregated settings (prison, homeless shelters, refugee camps) - presumptive or confirmed TB in Health care workers Perform Rapid DST Treat with First-Line anti- TB regimen till DST result is available
  • 28. 27 4.3 Case finding strategies for XDR-TB All strains of confirmed MDR-TB cases should routinely undergo second-line DST in order to determine susceptibility for the newly constructed TB regimen. However, considering the local epidemiology and resource limitation, the place of second line DST in Ethiopia is prioritized for the following patients/ conditions: • Symptomatic contacts of known XDR-TB patients • Lack of culture conversion by end of the fourth months of the standardized regimen • Bacteriological reversion in the continuation phase after conversion to negative among MDR-TB cases on SLDs • Evidence of MDR-TB treatment failures • MDR TB patients who returned after being lost to follow up • Confirmed MDR TB cases among health care workers and supportive staffs working in MDR TB settings, • Confirmed MDR TB cases from congregate settings (prisons, homeless shelters and refugee camps) where cases of XDR TB had been reported. As the national capacity for second line anti-TB drugs (SLDs) DST improves, routine SLDs DST should be performed for all confirmed MDR TB cases. 4.4 Identification and Referral of presumptive DR-TB patients All health care facilities involved in the diagnosis and treatment of tuberculosis shall actively participate in the identification, prioritization, and confirmation of Drug resistant TB among presumptive cases using nationally recommended diagnostic algorithms. On-site screening and diagnosis can be performed using Gene X-pert test. However, patients’ sample may need to be collected and transported to the nearest testing site for DST based on the laboratory networking arrangements from the TB control program. Collection and transportation of samples to testing sites must follow national Standard procedure for biological transport (Refer to national procedure for sample collection guideline, 2013).
  • 29. 28 4.5 Specimen collection, packing and transportation techniques and procedures Considering the problem of accessibility for culture and DST services for all TB DOTS and MDRTB clinics, the national TB program is implementing sample referral and transportation system to minimize risk of infection transmission and reduce indirect cost to patients during transportation. Hence, samples of the presumed MDRTB cases is collected, packed and transported by Courier system to DST labs for processing. (SOP for sample collection and referral Annex 1). HCWs at Health facility level, Woreda and Zonal TB officers need to: • Understand the lab network system and identify designated DST testing sites • Communicate with the sample transport system and the schedule • Instruct the clients how to produce and collect quality sample • Collect samples, pack and store using triple packing system • Store biological samples at recommended temperature using safety precaution • Organize with the program and facilitate courier system • Collect the result according to the TAT and manage the patient accordingly • Link confirmed DR-TB patients to treatment centers 4.6 MDR-TB diagnostic Algorithm in Ethiopia. Considering the applicability, access & appropriateness of DR-TB diagnostic methods and lead time to diagnosis, the national program has developed DST Algorithms to diagnose DRTB at Health facility and Reference lab levels in Ethiopia. Hence, Xpert test is preferred DST method at health facility level, while Line probe Assay(LPA) is preferred diagnostic test for reference laboratory.
  • 30. ALGORITHM 1: TB AND DR TB DIAGNOS 1 Presumptive TB: cough longer than 2 weeks, or breath; chest pain, weight loss, fever or night sweats 2 Assess risk: History of previous cases; Third month follow up smear remains positive congregated settings (prison, refugee, homeless shelters) 3 Presumptive DR TB is defined based on National PMDT Guideline 4 EPTB diagnosis: CSF, LN aspirate, P diagnosis of TB by XPERT MTB/RIF 5 Investigate for Smear Negative TB CXR) DR TB DIAGNOSIS AT HEALTH FACILITY LEVEL cough longer than 2 weeks, or any cough plus any one of hemoptysis, , weight loss, fever or night sweats. of previous TB treatment; TB cases among contacts of known/presumed DR TB cases; Third month follow up smear remains positive; TB cases among HCW or residents in congregated settings (prison, refugee, homeless shelters) defined based on National PMDT Guidelines. CSF, LN aspirate, Pus, Pleural biopsy or fluid samples are recommended for XPERT MTB/RIF test. Investigate for Smear Negative TB as per National TBL Guideline (Repeat sputum, antibiotic trial, 29 AT HEALTH FACILITY LEVEL hemoptysis, shortness of ts of known/presumed DR TB ; TB cases among HCW or residents in are recommended for as per National TBL Guideline (Repeat sputum, antibiotic trial,
  • 31. ALGORITHM 2: DIAGNOSIS OF DR As shown above, the diagnosis of RR, MDR facility level using Xpert or at reference laboratory mainly using LPA though conventional DST could also be used. Hence, Samples from presumptive DR should be processed with DST techniques (Xpert, LPA, or conventional DST) to confirm or rule out the diagnosis of DRTB. At reference laboratory, direct smear microscopy must be done from samples to decide whether to directly perform LPA, in case of positive smear results, o LPA indirectly if MTB grows on culture after negative smear result. DIAGNOSIS OF DR-TB AT REFERENCE LABORATORY As shown above, the diagnosis of RR, MDR-TB cases can be made either at Health facility level using Xpert or at reference laboratory mainly using LPA though conventional DST could also be used. Hence, Samples from presumptive DR with DST techniques (Xpert, LPA, or conventional DST) to confirm or rule out the diagnosis of DRTB. At reference laboratory, direct smear microscopy must be done from samples to decide whether to directly perform LPA, in case of positive smear results, o LPA indirectly if MTB grows on culture after negative smear result. 30 TB cases can be made either at Health facility level using Xpert or at reference laboratory mainly using LPA though conventional DST could also be used. Hence, Samples from presumptive DR-TB case with DST techniques (Xpert, LPA, or conventional DST) to At reference laboratory, direct smear microscopy must be done from samples to decide whether to directly perform LPA, in case of positive smear results, or Do the
  • 32. 31 If the LPA result shows resistant to R and H, or R only, patient must be treated with SLDs, while LPA results of INH resistant but susceptible to Rifampicin and results with susceptible results for R and H, should be treatment with FLD using registration system for Drug susceptible TB. Invalid results from LPA should be reprocessed at the laboratory level as smear negative sample. At Health facility level, where Xpert is used, Samples from the presumptive DR TB case, Presumptive TB in HIV infected individuals, presumptive TB in children and presumptive EPTB cases are subjected to Xpert test directly. Those cases with rifampicin resistance should be treated with SLDs using DRTB registration and reporting system, while those cases with Rifampicin susceptible results are managed with FLD using Drug susceptible TB registration and reporting system. Second line Drug Susceptibility Testing should be done for all confirmed RR/MDR-TB patients. However, due to resource constraints, eligibility for SLDs DST may be prioritized based on the risk and capacity to perform the test. 4.7 Communication of Results from Culture and DST Laboratory All attempts must be made to communicate the culture and DST results to the provider or the Woreda TB officer as soon as available so that treatment decision for the patient to receive effective TB treatment can be made promptly. The laboratory, together with the Tb program, has to arrange reliable and fast mechanism to return results to the provider. SMS printer machines, SMS messages, emails, or postal system can be applied to minimize the turnaround time of results and expedite the treatment decision.
  • 33. 32 4.8 DR-TB Patient referral and linkage to MDR TB treatment centers All confirmed DR-TB cases have to be linked to the designated treatment initiating center (TIC) without delay once the DST results is received from the diagnostic center. HCWs must provide the following key information for the patient and his/her caregiver: • Interpretation of the laboratory results and next action to be taken • Need for clinical evaluation of household and close contacts of the confirmed case • Infection control measures at home and community to be followed for • Basic information on the nature of the disease • Treatment modality and duration of treatment • Treatment sites and mechanism of follow up of treatment • Expected follow up visits including necessary laboratory monitoring examinations.
  • 34. 33 5. LABORATORY ASPECTS OF DR-TB IN ETHIOPIA The roles of the laboratory are critical in the diagnosis and follow up of Drug- resistant TB (DR-TB). Definitive diagnosis of Drug-resistant TB requires that Mycobacterium tuberculosis be isolated and drug susceptibility results be completed and results conveyed to the clinician. Prompt turnaround time of laboratory results is of paramount importance for rapid diagnosis and appropriate treatment of drug-resistant TB; hence, uses of rapid molecular tests are preferred to expedite the diagnosis of MDRTB in Ethiopia. 5.1 Laboratory infrastructure for culture and DST services The complex nature of performing tests using Culture and DST techniques restricts programs from routine use for diagnosis of MTB and drug resistance in the field at peripheral laboratories. In the past decade, however, the increasing demand for information on drug resistant pattern of the bacilli from TB patients has increased concerns on the infrastructure quality and safety precaution required to improve access to the service. Performing the Xpert MTB/RIF assay, however, is relatively simple and involves minimal specimen manipulation. Therefore, the laboratory infrastructure required for Xpert implementation are establishing uninterrupted electric power supply (or UPS with minimum capacity of 2 hours and/or a Generator with fuel supply), closed room with temperature no higher than 30o C and Air Conditioning system in hot areas and adequate storage room for cartridges at temperatures no higher than 28o C. 5.2 Infection Control and Bio-safety in TB Culture and DST Laboratory Transmission of TB – including drug-resistant forms– is a recognized risk for laboratory workers. Regularly maintained and properly functioning Class II B biological safety cabinet and installment of a negative pressure room are an indispensable piece of laboratory equipment for the performance of culture and DST of specimens from presumptive or confirmed MDR-TB patients. The biological safety cabinet Class II B serves for personnel as well as product protection. Personal protective equipment (PPE) designed to protect from inhalation of airborne bacilli should always be used while processing specimen. Instructions on safe handling of
  • 35. 34 specimens should be scrupulously followed. Ultraviolet light is useful for surface de- contamination and may be applied to radiate the work area when it is not in use. Training in laboratory procedures and strict adherence to safety measures should be accompanied by a simple surveillance program whereby the health status of laboratory staff is monitored regularly. Laboratory workers who choose to disclose their HIV-positive status should be offered safer work responsibilities and should be excused from working with MDR-TB specimens. Pregnant women should be reassigned until after childbirth. Technological advances has made DST techniques to be performed with lower level of biosafety requirement using Xpert MTB/RIF technique, which can be performed at BSC I level similar to direct microscopic examination for AFB. 5.3 Quality Control and Assurance A comprehensive quality control/quality assurance program is developed in each TB laboratory to ensure the accuracy, reliability and reproducibility of the results obtained and to ensure bio-safety. Quality control/quality assurance procedures should be performed regularly as an integral part of laboratory operations. The procedures for internal quality control must be performed during each test round to verify that the test is working correctly. The external quality control comprises procedures that are carried out by an external organization to test that the results are correct. Quality assurance is control for the entire process of testing, covering all stages from collection of sputum until the result is reported back to the treatment facility. A manual of standard operating procedures (SOPs) should be available for each of the laboratory operations. Standard operating procedures must be based on precisely how the procedure is carried out in the particular laboratory and incorporate any minor modifications that may have been made when compared with a standard protocol. The manual should also describe a protocol for regular maintenance checks and repairs of equipment. The network of supranational TB reference laboratories provides quality assurance service to ensure the quality of laboratory services and regular validation of DST
  • 36. 35 results. Usually, an external quality assurance program with a supranational TB reference laboratory consists of: • An initial assessment visit by the laboratory • Proficiency testing with a panel of coded isolates, and • Periodic rechecking of isolates obtained within the program. The national reference laboratory, in turns, provides QA services to culture and DST laboratories found in the regions and reference centers through: • Site preparation, • Pre-launching validation of DST service • Regular site level supervision, and • Periodic re-checking of isolates obtained within the lab. 5.3.1 Annual Calibration of GeneXpert Machine Calibration of GeneXpert machine is needed because frequency of use and time might alter performance. It verifies that the system performs within a set of specifications and ensures reading at correct wavelength and temperature ramping are sufficient. The annual calibration must be performed every 2000 tests or every 12 months, whichever occurs first. 5.4 Mycobacterial laboratory services for drug resistant-TB Definitive diagnosis of DR-TB requires that Mycobacterium tubercu1osis bacteria be detected and resistance to anti-TB drugs determined. This can be done by iso1ating the bacteria by cu1ture, identifying it as M. tubercu1osis, and conducting drug-susceptibi1ity testing (DST) on so1id or 1iquid media or by using WHO-endorsed mo1ecu1ar tests to detect mutations associated with resistance. 5.4.1 Smear Microscopy (ZN/FM): Direct smear microscopy is the cornerstone test for the diagnosis of drug-susceptible pulmonary TB. It is particularly important as the technique is simple, inexpensive and detects those cases of pulmonary tuberculosis (irrespective of the DR status) that are infectious. Microscopy for acid-fast bacilli (AFB) cannot distinguish viable from non-viable
  • 37. 36 organisms nor differentiate between drug-susceptible and drug-resistant M. tuberculosis bacteria or between different species of Mycobacterium. Therefore, the main uses of direct sputum microscopy for drug-resistant TB are limited to monitoring of treatment response, along with culture and to assess infectiousness of patients. 5.4.2 Culture: Mycobacterium culture test provides a definitive diagnosis of TB. However, growth detection and identification of M. tuberculosis complex may take several weeks. The slow growth of mycobacterial strains (a common characteristic noted in many MDR-TB strains) further lengthens the time to identification and susceptibility testing. Mycobacteria also require a special culture media: Solid culture media: is culture media (Löwenstien-Jensen) which has several advantages including ease of preparation, low cost, and low contamination rate. Agar-based culture media (Middlebrook 7H10, 7H11) has similar advantages but more expensive. Solid media culture result may take several weeks, 21-42 days, for growth. Solid culture media is the gold standard for diagnosis of MTB. Colonies of M. tuberculosis growing on media Liquid culture: is a specially enriched broth-based culture method (BACTEC 460, MGIT 960) which reduces the time for MTB growth to 5-10 days. Liquid culture technique is currently limited to few laboratories in country due to high cost of installation and maintenance but it has the advantage of fast turnaround
  • 38. 37 time especially for DR TB treatment follow up even though contamination rates may be very high. 5.4.3 Drug susceptibility testing (DST): Drug Susceptibility testing (DST) is required to make a definitive diagnosis of M(X)DR-TB. DST can be done either by: Phenotypic: MTB culture and DST performed by mixing specific concentrations of TB drugs with the culture medium and comparing the rates of growth of the TB culture, also called convention DST. It is considered the gold standard technique to test susceptibility to various drugs used to treat Tuberculosis. However, the technique can only be performed on MTB that has grown on culture media. The result of Phenotypic DST, in addition, is most reliable for INH and Rifampicin; but not for other first line drugs (- STM, E & Z) and many second line TB drugs. Molecular techniques for DST: Molecular methods for DST are based on detection of specific mutations associated with drug resistance. Most genotypic methods involve two steps: first, a nucleic amplification method such as polymerase chain reaction (PCR) is used to amplify sections of the M. tuberculosis genome known to be altered in resistant strains. In the second step, amplification products are assessed for mutations correlated with resistance. i) Line Probe Assay (LPA): is a rapid and accurate test to identify cases with DR-TB and can be done either directly from smear positive sputum sample or from culture isolates if sputum smear is negative. If a patient with TB is smear positive, the sputum contains enough bacilli to perform line probe assay directly on the sputum and MDR-TB can be proved on the two days’ time. If the sputum is smear negative, growth of bacilli should be demonstrated on culture first (preferably on liquid medium) and then, LPA can be performed on the isolates to check for sensitivity for H and R. ii) Xpert MTB/RIF test: is the rapid test used for detection of MTB and Rifampicin resistance directly from the sputum without need for prior smear
  • 39. 38 examination. It is fully automated for sample processing, DNA extraction and amplification, making it possible for molecular testing to be performed at service delivery points with less level of expertise. Its bio-safety requirement is similar to smear microscopy. However, it does not inform susceptibility to INH. 5.4.4 Second line Drug Susceptibility Testing DST for second line drugs is done through conventional phenotypic DST for the injectable drugs (kanamycin/amikacin and capreomycin) and fluoroquinolones at reference laboratories. LPA is starting to incorporate resistance mutations for second-line anti-TB drugs. The assay shows moderate sensitivity for the detection of fluoroquinolone and second- line injectable resistance, with high specificity. It has the potential to be used as a rule-in test for XDR-TB. But LPA negative for second-line drug resistance does not rule out resistance. Hence, second line LPA cannot be used as a replacement test for conventional phenotypic drug susceptibility testing (DST) and cannot be used to define XDR TB for surveillance. It cannot be used to guide the choice of individual second line drugs to be included in M/XDR TB regimens. In general the results of any Second line DST should be carefully interpreted by experienced clinician taking into account treatment history besides the susceptibility patterns reported by the laboratory. Selected XDR TB suspects will be tested for Second line DST initially until full capacity is developed in country. However, all confirmed MDR TB strains should tested for second line drug resistance. 5.5 DST service in Ethiopia Different WHO-approved DST techniques are recommended to be used for screening of drug resistant strains from samples of Presumptive DR-TB cases. The preferred techniques must provide information on the susceptibility patterns of, preferably all FLDs, at least to Rifampicin. However, the choice of the DST technique in field depends on the simplicity and applicability of the procedure, infection control precaution level and result turn-around time.
  • 40. 39 In Ethiopian context, Gene Xpert MTB/RIF is the preferred method considering the suitability for use at health facility level, the rapid turnover time of results, and minimal need for expertise & infection control precautions. However, Line probe Assays and conventional DST techniques will continue to be used at reference laboratory (see table 5.1). Table 5.1 Options for first line DST in Ethiopian context DST techniques Turn-around time DST results Recommendation MTB detection DST GeneXpert MTB/RIF Assay 2hrs 2hrs R only Preferred for use at Health facility level with minimal Bio- safety requirements and less experienced professionals Line probe Assay (LPA) - 48hrs (direct, smear +ve), 21-42 days (indirect, smear -ve) R and H Preferred for use at reference laboratories, and when information on INH susceptibility is required *. Liquid culture Technique (MGIT system) 8days (smear +ve) 16days (smear –ve) 4 weeks R, H, E, and S Preferred for use at reference laboratories, and when information on full DST pattern is required π . Solid culture medium (LJ standard medium) 16days (smear +ve) 29 days (smear –ve) 6 weeks R,H,E, and S Preferred for use at reference laboratories as gold standard, and when information on full DST pattern is required π . * Second line DST can be done by LPA but cannot accurately rule out resistance. π Solid or liquid culture techniques can be used to do second line DST. Adapted from PIH. 2013. The PIH Guide to the Medical Management of Multidrug-resistant Tuberculosis 2nd Edition.pp13. 5.6 Organization and Role & Responsibilities TB Laboratory system The laboratory network has a pyramidal structure with three inter-linked levels. At the bottom of the pyramid are the peripheral laboratories located in health facilities providing TB diagnostic services for presumptive/confirmed TB and DR-TB cases. At the middle are the regional reference laboratories located mainly at regional administrative level assuming the role of reference laboratories but under the
  • 41. 40 technical and administrative guidance of the national level reference laboratory found at apex of the pyramid at the national level. Table 5.2 Different functions and responsibilities TB laboratories at the three different levels of laboratory services system: National TB reference laboratory Regional TB reference laboratories Health facility TB laboratories • Organize, coordinate and manage the overall national TB lab system including culture and DST services • Update and standardize national laboratory guidelines, training manuals and SOPs • Forecast, quantify and procure TB culture lab reagents and consumables to the designated regional laboratory • Perform national anti- tuberculosis drug resistance surveillance • Organize and deliver the necessary training for laboratory professionals • Provide Quality Assurance services for microscopy, culture and DST performed national level • Organize and manage the sputum sample transport system at national level • Perform TB culture and DST tests for FLD and SLDs • Perform TB sputum culture and DST tests for FLD and SLDs • Provides training for laboratory personnel from Health facilities • Arrange, organize and manage the sputum sample transport system from the networked Health facilities • Monitor the Quality of sputum sample collection and packing system in each respective catchment Health facilities • Participate in national QA tests from the national reference laboratory • Support to and supervision of peripheral- level staff with respect to microscopy • Quality improvement and proficiency testing of microscopy at peripheral laboratories • All the functions of Health facility TB laboratory • Perform Gene Xpert MTB/RIF test • Perform smear microscopy using direct microscopy or florescent microscope • Prepare reagent for florescent microscope • Perform internal quality assurance service and participate in EQA • Collect, pack and transport biological samples as per SOP • Keep activity records and regularly report • Cleaning and maintenance of equipment
  • 42. 41 6. DR-TB PATIENT CLASSIFICATION AND DEFINITION OF TERMS Standardized definitions, classification, registration and reporting systems have been developed by the World Health Organization to facilitate uniform communication of concepts related to drug resistant TB. Ethiopia has adopted these case definitions and reporting framework. It is an extension of the Drug susceptible TB information system and is integrated into the national HMIS system. The categorization, definitions and registration procedures will facilitate: • standardized patient registration and case notification • assignment to appropriate treatment regimens • case evaluation according to disease site, bacteriology and history of treatment • Cohort analysis of registered DR-TB patients and their treatment outcomes. 6.1 Definitions of Drug-Resistant TB 6.1.1 Classification based on drug resistance: a) Mono-drug resistance: resistance to one first-line anti-TB drug only. b) Poly-drug resistance: resistance to more than one first-line anti-TB drug (other than both isoniazid and rifampicin). c) Multi-drug resistance: resistance to at least both isoniazid and rifampicin. d) Extensive-drug resistance: resistance to any fluoroquinolones and to at least one of three second-line injectable drugs (capreomycin, kanamycin and Amikacin), in addition to multidrug resistance. e) Rifampicin resistance(RR-TB): resistance to rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin, whether mono-drug resistance, multi-drug resistance, poly-drug resistance or extensive drug resistance. Any patient who falls into one of the above listed types of drug-resistance is considered a DR-TB patient. But emphasis is on RR-TB and MDR TB when it is referred in this document.
  • 43. 42 6.1.2 Classification of DR TB based on Laboratory Confirmation: • Laboratory confirmed DR-TB: refers to those cases with documented laboratory DST (phenotypic or molecular) results for DR-TB or Rifampicin Resistant TB. This could include any of the forms described in section 6.1.1 above. • Clinically diagnosed DR-TB: refers to those cases with no documented DST results but the clinical panel team decided to treat the patient empirically with a course of treatment including SLD based on clinical criteria alone. It includes cases diagnosed on the basis of X-ray abnormalities or suggestive histology and extra-pulmonary cases without laboratory. When culture and DST results are available these cases will be reclassified as bacteriologically confirmed. 6.1.3 Site of DR-TB disease a) Pulmonary DR TB: DR-Tuberculosis involving the lung parenchyma. b) Extrapulmonary TB: DR-Tuberculosis involving organs other than the lungs. 6.2 Registration group based on history of anti-TB treatment All RR/MDRTB patients must be registered according to the history of anti-TB treatment. Patients should be classified in two ways: Classification according to history of previous drug use: Used mainly to assign the appropriate treatment regimen. Registration groups are: o New: A patient who has received no or less than one month of anti- tuberculosis treatment. o Previously treated with First line drugs: a patient who has received first line anti-tuberculosis treatment for four weeks or more. o Previously treated with Second line drugs: a patient who has received second-line anti-tuberculosis treatment for four weeks or more. Classification according to the history of their previous treatment:
  • 44. 43 Classification is determined by history of treatment at the time of collection of the sample that was used to confirm MDR-TB. Previous history refers to outcome of the latest TB treatment of the patient. Registration groups are: • New: A patient who has received no or less than one month of anti- tuberculosis treatment. • Relapse: A patient who was previously treated for TB and whose most recent treatment outcome was “cured” or “treatment completed”, and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy, Xpert MTB/RIF, or culture. • Treatment after being lost to follow-up: A patient after taking treatment for more than one month who returns to treatment, bacteriologically positive by sputum smear microscopy, Xpert MTB/RIF, or culture, following interruption of treatment for two or more consecutive months. • Treatment after failure of New TB regimen: A patient who has received new regimen for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment. • Treatment after failure of Retreatment regimen: A patient who has received retreatment regimen for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment. • Transfer in: A patient who has been transferred from another TIC to continue MDR-TB treatment. • Other: refers to any DR-TB patient who does not fit into any of the above categories. 6.3 Definitions of sputum and culture conversion and reversion In order for a patient to be considered bacteriologically positive at the start of second-line treatment, the following criteria must be met: 1. At least one pre-treatment specimen was positive for smear, Xpert MTB/RIF or culture
  • 45. 44 2. The collection date of the sample on which the laboratory examination was performed was less than 30 days before, or 7 days after, initiation of second-line treatment At least one sputum sample for smear and culture should always be taken at initiation of MDRTB treatment (the result of this will be labeled as month zero in the treatment card and MDR TB register). Examinations are required at the start of treatment firstly to confirm the diagnosis of TB and determine the infectiousness. Sputum smear positive forms are the most infectious. Both sputum smear and sputum culture testing should be used to monitor patients throughout therapy. The monitoring of sputum culture is important for decisions on changes in treatment. Sputum conversion: is defined as two sets of consecutive negative smears and cultures, from samples collected at least 30 days apart. The date of collection for the first sample is considered as the date of conversion. Reversion (to positive): culture is considered to have reverted to positive when, after an initial conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive. For the purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation phase. 6.4. Definitions of DR-TB Treatment Outcomes All DR-TB patients who are registered to receive treatment with SLDs should be assigned one of the following treatment outcomes upon completion or interruption of treatment by the national program recommendation or with the decision of panel team:
  • 46. 45 Treatment outcome Definition Cured Treatment completed according to national recommendation without evidence of failure and three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment completed Treatment completed according to national recommendation without evidence of failure but no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase. Treatment failed Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: - lack of conversion by the end of the intensive phase, or - bacteriological reversion in the continuation phase after conversion to negative after intensive phase, or - evidence of additional acquired resistance to fluoroquinolones or second line injectable drugs, or - Adverse drug reactions Lost To Follow Up (LFTU) A patient whose treatment was interrupted for two consecutive months or more. Died A patient who dies for any reason during the course of treatment. Not evaluated A patient for whom no treatment outcome is assigned either due to being transferred out to other facility or still on treatment.
  • 47. 46 7. MANAGEMENT OF CONTACTS OF DR-TB PATIENTS Household members or other close contact with a person who has infectious TB are themselves found to have previously undiagnosed, active TB. Besides, various studies indicate that if close contacts of index cases with DR-TB develop active TB, 60-80% of them may have drug-resistant form of the disease. Based on data collected from systematic review, WHO in 2012 reported a pooled average of 3.5–5.5% of household members or other close contact with a person who has infectious TB to have previously undiagnosed active TB. This is 5 to 10 times higher compared to the general population. 7.1 Definitions of terms Index case (index patient): is generally the case identified initially, although she or he may not be the source case. It could be a person of any age in a specific household or other comparable setting in which others may have been exposed. An index case is the case around which a contact investigation is centered. Exposure may be intense or casual, easily identified or obscure. Close exposure, such as sharing a living or working space, is generally easily identified and quantified, whereas casual exposure, such as on public transport or in social situations, may be unidentifiable. Household contact: a person who shared the same enclosed living space for one or more nights or for frequent or extended periods during the day with the index case during the 3 months before commencement of the current treatment episode. Close contact: A person who is not in the household but shared an enclosed space, such as a social gathering place, workplace or facility, for extended periods during the day with the index case during the 3 months before commencement of the current treatment episode. Out-of-household exposure is as likely to result in transmission as household exposure in many situations. Contact investigation is defined as a systematic process intended to identify previously undiagnosed cases of TB among the contacts of an index case. The
  • 48. 47 investigation generally focuses on a defined group of potentially exposed people in which other (secondary) cases may be found. 7.2 Reasons for Household contacts screening The prevalence of active MDR-TB in household contacts of MDR-TB patients is very high: • Household contacts are likely to be infected because they are in close contact with infectious patients for prolonged periods of time. • Household contacts are likely to develop active TB because they have recently been infected, and active TB is more likely soon after infection. • Household contacts of MDR-TB patients have usually been exposed for months or years, longer than household contacts of drug-susceptible TB patients. • The prevalence of active MDR-TB in household contacts of MDR-TB patients is likely to be higher than that of household contacts of drug-susceptible index cases, and that of XDR-TB higher still. Advantages of contact investigation • Early treatment of MDR-TB is cheaper and more effective compared to MDR- TB that is detected late. • Contacts of MDR-TB patients can be treated immediately with an MDR-TB regimen and prevented from starting an ineffective regimen. • Contact investigation of MDR-TB prevents the transmission of this strain to others inside or outside of the home. • Contact investigation is an excellent opportunity to educate family members about the risk of TB, MDR-TB, and other co-morbidities such as HIV. 7.3 Identification and Management of Contacts of DR-TB Cases 7.3.1. Who should do the contact investigation? Contact investigation should be integrated into routine programmatic management of MDR-TB.
  • 49. 48 Contact investigation starts with the education of the MDR-TB patient. Patients should be educated about the infectiousness of their disease and the high risk of transmission to contacts who share the same living space. • The clinical team (TIC and TFC team) that is responsible for the MDR-TB patient should initiate contact investigation by listing all family members at patient enrollment. The Clinical team will also be responsible for any diagnostic workup needed by the patient's close contacts. • The TIC, TFC and the HEW should interview close contacts as soon as possible after MDR-TB treatment starts, since contacts are most likely to develop active TB soon after becoming infected. • The clinical team is best suited to make sure that close contacts of the MDR- TB patient do not receive empiric treatment for drug-susceptible TB. • The HEWs that provides DOT of the MDR-TB regimen is best situated to do a home visit and the contact investigation, and make sure that household contacts with symptoms are investigated promptly and correctly. 7.3.2 Clinical evaluation and Investigation of contacts of M/X DR- TB 1. Routine screening of all household contacts should include: o Asking about cough, fever, weight loss, and other symptoms of TB. o Detailed medical history for additional risk factors o Physical examination o Ask about HIV status of household contacts or do HIV counseling and testing 2. A household contact with any symptoms suggestive of active TB should receive all of the following: a. Evaluation by a physician, including history and physical examination. b. Chest X-ray to look for signs of active TB (e.g., infiltrates, cavities) or inactive TB (e.g., scarring, granulomas). i. The chest X-ray should be kept on file by the clinical team to compare with subsequent X-rays if the contact continues to have symptoms or develops new symptoms in the future.
  • 50. 49 ii. A chest X-ray should be done even if extrapulmonary TB is suspected, since the contact may have unsuspected pulmonary TB at the same time. c. Bacteriological investigations of sputum or other samples: i. Xpert MTB/RIF is the recommended initial diagnostic test because it provides diagnosis of TB and MDR-TB rapidly. ii. Culture and DST may be sent if Xpert MTB/RIF is negative and suspicion of active TB or MDR-TB remains high. 7.3.3 Management of Symptomatic Contacts a) Household contacts of MDR-TB patients with active PTB should almost always be treated with an MDR-TB regimen 1. Household contacts of MDR-TB patients who develop active PTB almost always have MDR-TB themselves, even if the pattern of resistance is not always exactly the same. Young children are even more likely than other close contacts to be infected in the home with an MDR-TB strain. 2. If rapid molecular DST is not available, household contacts with active PTB should be empirically treated with the same regimen as the index patient if culture-based DST is expected to take several months. If the DST eventually shows that the contact was infected outside the home by a pan-susceptible strain, the contact can be switched to a regimen of first-line drugs. b) Household contacts of MDR-TB patients with extra-pulmonary TB 1. Extrapulmonary TB is often culture-negative and DST will not be available. These contacts should be started on an MDR-TB regimen based on the DST of the index patient. 2. Every effort should be made to culture aspirates of pleural, peritoneal, or cerebrospinal fluid, depending on the site, but there is no need to wait for laboratory confirmation of MDR-TB. c) Household contacts of MDR-TB patients with culture-negative TB • If cultures are negative or contaminated, close contacts should be continued on the empiric regimen based on the DST of the index patient for the full duration of treatment.
  • 51. 50 7.3.4 Management of Asymptomatic contact cases As the risk for developing active TB after exposure with infectious case is increased, all contacts with no active TB at time of evaluation should continue to receive careful clinical follow-up quarterly for a period of at least two years. If clinical TB is suspected, full clinical evaluation, as mentioned above is recommended. All contacts and index cases should be educated/ informed about: • Reason for increased risk of being contact • Clinical manifestations that could indicate TB • The risk period after exposure of the index case • The need for prompt evaluation, if any of these indicators develops • The higher risk of developing TB in children and PLHIV • Infection prevention measures at household level and other risky settings • The need to have regular quarterly clinical follow-up screening • If contact is HIV positive, he/she should be evaluated promptly, keeping in mind an increased likelihood for extra-pulmonary TB, manifested by local and systemic, rather than pulmonary, symptoms. PLHIV may be less likely to have cough as the predominant symptom and should be fully evaluated if they have systemic symptoms such as fever, night sweats and weight loss. • If the contact is under 5 years of age, especial focus should be given to promptly diagnosis as they are highly vulnerable to develop TB and may have more severe forms of the disease. Remark: Document contact tracing activities on the space provided on DR-TB treatment card
  • 52. 51 7.4 Chemoprophylaxis of contacts of MDR-TB index cases Currently there is no enough evidence to recommend the use of chemoprophylaxis for close contacts of M/XDR TB who developed latent infection. Therefore the national guideline does not recommend the use of chemoprophylaxis for contacts of DR TB cases. Close contacts of DR-TB patients, instead, should receive careful clinical follow-up quarterly for a period of at least two years. If clinical TB is suspected at any time, full clinical evaluation, as mentioned above is recommended.

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