PHILIPPINE CLINICAL PRACTICE

GUIDELINES
FOR THE DIAGNOSIS AND TREATMENT
OF ADULT TUBERCULOSIS:
2021 UPDATE

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 TABLE OF CONTENTS
List of Tables ……………………………………………………………………………………………..………... 3

List of Figures …………………………………………………………………………………………….……….. 4

Participating Professional Societies and Agencies ……………………………………………….. 5

Composition of CPG TB Task Force………………………………………………………………………. 6

Composition of Consensus Panel ……………………………………………………………………..…. 8

Commonly Used Abbreviations …………………………………………………………………………… 10

Executive Summary ……………………………………………………………………………………………. 11

Introduction ……………………………………………………………………………………………………….. 21

Methodology………………………………………………………………………………………………………. 23

Quick Guide On How To Interpret The Evidence……………………………………… 29

Statements of Updated Recommendations and Evidence ………………………………….. 36

Screening for Tuberculosis ……………………………………………........................... 37
Updates on Diagnosis of Tuberculosis …………………………………………………….. 45
Updates on Treatment of Tuberculosis …………………………………………………… 75
Updates on Management of Suspected or Confirmed MDR Tuberculosis… 79
Updates of Diagnosis and Management of Latent Tuberculosis ………………. 89
Updates on Infection Control for Tuberculosis ………………………………………… 103
Updates on Management of TB-HIV Coinfection …………………………………….. 117
Mandatory Notification for Tuberculosis in the Philippines …………………….. 127
Annexes Affiliations, Declaration of Conflicts of Interest
A Steering Committee …………………………………………………………………………….. 136
B Technical Committee …………………………………………………………………………… 137
C Consensus Panel ………………………………………………………………………………….. 140
D External Reviewers …………………………………………………………………………….. 142

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LIST OF TABLES

Table 1. Summary of Recommendations of 2020 Update of TB CPGs ……………………………. 11

Table 2. Comparison of 2016 Statement with the New 2020 Recommendations ……………….... 15
Table 3. List of Questions Identified by the Steering Committee to be Urgent & Relevant…… 24
Table 4. Basis for Assessing the Quality of the Evidence using GRADE Approach…………………… 26
Table 5. Interpreting likelihood ratios (LRs)…………………………………………………………………………… 30
Table 6. Ways of Expressing Effectiveness……………………………………………………………………………… 31
Table 7. Interpreting 95% Confidence Intervals (CIs)……………………………………………………………… 32
Table 8. Quality of evidence in GRADE…………………………………………………………………………………… 35
Table Q1.1. Diagnostic accuracy of CXR and other TB screening methods……………………………… 38
Table Q1.2. Crude median and weighted mean NNS for different screening algorithms……….. 38
Table Q1.3. NNS Using CXR versus No CXR among Risk Groups…………………………………………….. 39
Table Q1.4. NNS of risk groups………………………………………………………………………………………………. 39
Table Q1.5. Risk factors for TB cases compared to non-cases, 2016 NTPS, Philippines …………. 40
Table Q2.1. Pooled sensitivity and specificity of chest radiograph as a screening tool for PTB.. 43
Table Q2.2 Distribution of negative symptoms and CXR central reading among microbiologically
confirmed survey cases, NTPS 2016, Philippines…………………………………………. 44
Table Q3.1. Comparison of Diagnostic Accuracy Estimates Between Xpert® MTB/RIF & DSSM.. 45
Table Q4.1 Reference standards used by Shete ………………………………………………………………….. 49
Table Q4.2. Accuracy of TB-LAMP and the Xpert® MTB/RIF assay*………………………………………… 49
Table Q4.3 Accuracy of TB-LAMP compared to Xpert® MTB/RIF Reference Standard 1………... 51
Table Q4.4. Accuracy of TB-LAMP compared to Xpert® MTB/RIF Reference Standard 2………... 52
Table Q4.5. Accuracy of TB-LAMP compared to Xpert® MTB/RIF Reference Standard 3……. 53
Table Q5.1 Summary of studies on Xpert® MTB/Rif to detect rifampicin resistance…………… 55
Table Q5.2. GradePro Summary of Findings for Xpert® MTB/RIF and DST……………………. 57
Table Q6.1. Test characteristics using histopathology as reference standard………………….. 59
Table Q6.2 (a-c) Summary of Findings on the Diagnostic Performance of Xpert MTB/RIF …… 61
Table Q7.1 Summary of Evidence on Treatment for PTB………………………………………….. 67
Table Q7.2 Summary of Evidence on Empiric Treatment vs No Treatment for HIV patients….. 68
Table Q8.1 Pooled sensitivity and specificity of Xpert MTB/Rif and Xpert Ultra as
diagnostic tool for PTB……………………………………………………………… 69
Table Q10.1 Summary of Evidence on Moxifloxacin + recommended regimen compared to
recommended regimen for newly diagnosed TB………………………………… 77
Table Q10.2 Summary of evidence of Fluoroquinolones in Newly Diagnosed TB………………. 78
Table Q11.1 NTP 6th MOP Treatment Regimens for Drug-Susceptible and Drug-Resistant TB . 81
Table Q11.2 Studies describing Outcomes of TB Retreatment Regimen……………………….. 83
Table Q11.3 Treatment outcomes among Monoresistant, polyresistant and Combined
Resistance Patients treated with Category 1 or Category II regimens………… 84
Table Q12.1 Summary of Evidence on Shortened Regimen compared to Long Duration for
Multiple-Drug Resistant TB………………………………………………………….. 88
Table Q13.1. Characteristics of Included Studies…………………………………………………… 90
Table Q13.2. Side-by-Side Comparison of Sensitivity and Specificity of Index Tests…………… 92
Table Q13.3 Summary of Certainty of Evidence: IGRA Or TST for Latent Tuberculosis………… 95
Table Q14.1 Treatment Recommendations of the 6th MOP for LTBI……………………………….. 96
Table Q14.2. Efficacy in terms of prevention of TB vs. no treatment……………………………….. 98
Table Q14.3. Efficacy in terms of treatment completion vs. placebo 12 months………………….. 98
Table Q14.4. Hepatotoxicity vs. no treatment…………………………………………………………. 99
Table Q14.5 Rates of hepatotoxicity in nonrandomized studies ……………………………………. 99
Table Q14.6.Summary of Certainty of Evidence for Treatment of LTBI……………………………. 101
Table Q15.1 Respiratory hygiene to reduce TB transmission to HCWs…………………………… 109
Table Q15.2 Respiratory hygiene to reduce TB transmission to others……………………………. 109
Table Q15.3 Prompt initiation of effective treatment of TB patients to reduce transmission ……. 110

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Table Q15.4 Prompt initiation of effective treatment of TB patients to reduce transmission……. 110
Table Q15.5 Triage of people with TB signs to reduce to reduce transmission to HCWs………. 111
Table Q15.6 Triage of people with TB signs to reduce to reduce transmission to others……….. 112
Table Q15.7 Respiratory isolation of people with TB signs to reduce transmission to HCWs….. 112
Table Q15.8 Respiratory isolation of people with TB signs to reduce transmission to others….. 114
Table Q15.9 Use of Germicidal Ultraviolet irradiation to reduce transmission of TB to HCWs…. 114
Table Q15.10 Use of Germicidal Ultraviolet irradiation to reduce transmission of TB to others… 115
Table Q15.11 Use of particulate respirators to reduce TB transmission to HCWs……………….. 115
Table Q15.12 Use of particulate respirators to reduce TB transmission to others……………….. 116
Table Q16.1 Summary of Results for Rifampicin Containing Regimens………………………….. 118
Table Q16.2 Summary of certainty of Evidence re TB-HIV coinfection…………………………… 120
Table Q17.1. Summary of Results……………………………………………………………………. 122
Table 17.2 Summary of Certainty of Evidence for TB-HIV………………………………………… 124
Table 17.3 Summary of Certainty of Evidence for TB-HIV………………………………………… 125

LIST OF FIGURES

Figure 1. Admissible evidence for evaluation of a screening program…………………………… 29

Figure 2. Indirect (A) and direct (B) trials of the effectiveness of screening……………………… 30
Figure 3. Using Bayes nomogram for estimating post-test probability………………………….… 31
Figure 4.How to interpret forest plots…………………………………………………………….….. 33
Figure Q7.1 Empiric treatment vs. no treatment in smear-negative patients……………………. 65
Figure Q7.2 Empiric treatment vs. No Treatment Among HIV patients…………………………. 65
Figure Q8.1. Algorithm for the Interpretation of Xpert MTB/Rif Ultra Results……………………. 70
Figure Q13.1. Forest Plot of Sensitivity and Specificity of IGRAs ……………………………….. 91
Figure Q13.2. Forest Plot of Sensitivity and Specificity of Tuberculin Skin Test….. ………….... 91
Figure Q16.1 Total adverse events (The treatment groups with varying doses of pretomanid
were grouped together as non-rifampicin containing)………………………….. 119
Figure Q16.2 Total adverse events (The treatment groups with varying doses of pretomanid
were separated and compared to HRZE)………………………………………… 119
Figure Q17.1 Effects of boosted doses compared to nonboosted doses of LPV/r on
virologic failure………………………………………………………………………. 126
Figure Q17.2 Effects of boosted doses compared to standard doses of LPV/r on virologic failure. 126
Figure Q17.3 Adverse events experienced by patients on boosted doses compared to
nonboosted doses of LPV/r………………………………………………………… 126
Figure Q17.4 Adverse events experienced by patients on boosted doses compared to
standard doses of LPV/r……………………………………………………………. 126
Figure 5 How to Register on ITIS Lite……………………………………………………………….. 130
Figure 6 First Page of AO 2020-0057……………………………………………………………….. 131

LIST OF BOXES
Box 1: Standard criteria for grading of evidence ………………………………………………….. 34
Box 2: Contact Details for Assistance on Mandatory TB Notification …………………… 129

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 PARTICIPATING
PROFESSIONAL SOCIETIES AND AGENCIES
MAIN PROPONENT SOCIETIES
Philippine Coalitions against Tuberculosis (PhilCAT)
Philippine Society for Microbiology and Infectious Diseases (PSMID)
Philippine College of Chest Physicians (PCCP)

PARTICIPATING SOCIETIES AND AGENCIES

American College of Chest Physicians (ACCP) – Philippine Delegation
Association of Philippine Medical Colleges Foundation Inc (APMC)
Culion Foundation
Samahan ng Lusog Baga (TB Patients’ Group)
Philippine Academy of Family Physicians (PAFP)
Philippine College of Occupational Medicine (PCOM)
Philippine College of Radiology (PCR)
Philippine College of Physicians (PCP)
Philippine Hospital Association (PHA)
Philippine Medical Association (PMA)
Philippine Neurological Association (PNA)
Philippine Tuberculosis Society Inc (PTSI)
TB Heals (TB Patients’ Group)

IMPLEMENTING AGENCY
University of the Philippines National Institutes of Health
Institute of Clinical Epidemiology ((UP NIH ICE)
In collaboration with
Department of Health – Health Policy and Development Bureau (HPDB)
and Disease Prevention and Control Bureau (DPCB)

FUNDING AGENCY: DOH-AHEAD Program through PCHRD

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CLINICAL PRACTICE GUIDELINE FOR TUBERCULOSIS
TASK FORCE 2021
STEERING COMMITTEE
Over-all Chair Regina P. Berba, MD (PhilCAT, PSMID)
Co-Chairs Marissa M. Alejandria, MD (PSMID)
Vincent M. Balanag, MD (PhilCAT, PCCP)
Jubert P. Benedicto, MD (PhilCAT, PCCP
Lalaine L. Mortera, MD (PhilCAT, PCCP)

TECHNICAL WORKING COMMITTEES (TWC)

Technical Coordinator: Evelyn Salido, MD (UP NIH ICE)

COMMITTEE ON SYSTEMATIC SCREENING

Chair Mario M. Panaligan, MD (PSMID)
Evidence Reviewers Rowena Genuino, MD (UP NIH ICE)
Adelaine J. Lopez, MD (UP NIH ICE)
Monica Pia Reyes-Montecillo, MD (UP NIH ICE)

COMMITTEE ON DIAGNOSIS
Chair Janice Campos-Caoili, MD (PSMID)
Evidence Reviewers Marc Evans Abat, MD (UP NIH ICE)
Aldrich Ivan Lois Burog, MD (UP NIH ICE)
Gina Antonina Eubanas, MD (UP NIH ICE)
Bryan Albert Lim, MD (UP NIH ICE)
Kathryn Roa, MD (UP NIH ICE)
Gelza Mae Zabat, MD (UP NIH ICE)

COMMITTEE ON TREATMENT
Chair Jemelyn U. Garcia, MD (PSMID)
Evidence Reviewers Ian Theodore Cabaluna, MD (UP NIH ICE)
Gina Antonina Eubanas, MD (UP NIH ICE)
Karen Marie R. Gregorio, MD (UP NIH ICE)
Mark Evans Abat, MD (UP NIH ICE)
Stephanie Carol Tan-Lim, MD (UP NIH ICE)

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 COMMITTEE ON DRUG-RESISTANT TB and HIV
Chair Ma. Tarcela S. Gler, MD (PSMID)
Evidence Reviewer Ian Theodore Cabaluna, MD (UP NIH ICE)

COMMITTEE ON LATENT TB
Chair Jubert P. Benedicto, MD (PCCP)
Members Mitzi Marie M. Chua (PSMID)
Deborah Ignacia David-Ona, MD (PCP)
Marietto L. Partosa, Jr., MD, (PCCP)
Ma. Kriselda Karlene G. Tan, MD (PCCP)
Ralph Elvi M. Villalobos, MD (PCCP)
Evidence Reviewer Lia Palileo Villanueva, MD (PCP)

COMMITTEE ON INFECTION PREVENTION AND CONTROL

Chair Evalyn A. Roxas, MD (PSMID, PHICS)
Evidence Reviewers Kingbherly L. Li, MD (PSMID)
Marissa J. Nepomuceno, MD (PSMID)
Issa Rufina S. Tang, MD (PSMID)

EXTERNAL REVIEWERS AND RESOURCE EXPERTS

Camilo Roa (PhilCAT)
Mary Ann Lansang (University of the Philippines)
Rajendra Prasad Hubraj Yadav (WHO Philippines)
Tauhidul Islam (WPRO)

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 CONSENSUS PANEL

Voting Members
*Alternate voting member

American College of Chest Physicians (ACCP) – Philippine Delegation

Aileen David-Wang, MD

Association of Philippine Medical Colleges Foundation Inc (APMC)

Endymion Ervin Tan, MD (APMC)

Culion Foundation
Eugene Caccam

Department of Health
Anna Marie Celina Garfin, MD (DOH)
Ronald Allan Fabella, MD (DOH)*
Flora Marin, MD (DOH)

Philippine Academy of Family Physicians (PAFP)

Naomi Ruth Saludar, MD
Luz Revita, MD *
Paul Ygusguiza MD*

Philippine Coalition against Tuberculosis (PhilCAT)

Freddie Peleo, MD
Amelia Sarmiento *

Philippine College of Occupational Medicine (PCOM)

Arnold Tabun, Jr, MD

Philippine College of Radiology (PCR)

Katleya Manlapaz, MD

Philippine College of Physicians (PCP)

Ma. Encarnita Limpin, MD
Imelda Mateo, MD*

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 Philippine College of Chest Physicians (PCCP)
Jose Hesron Morfe, MD
Augusto Sablan, MD*
Julie Christie Visperas, MD*

Philippine Hospital Association (PHA)

Edgardo Salud, MD

Philippine Medical Association (PMA)

Rogelio Dazo, MD

Philippine Neurological Association (PNA)

Rene B. Punsalan, MD

Philippine Society for Microbiology and Infectious Diseases (PSMID)

Karl Evans R. Henson, MD
Arthur Dessi Roman, MD*

Philippine Tuberculosis Society Inc (PTSI)

Elizabeth Cadena, MD

Samahan ng Lusog Baga

Eden Mariano

TB Heals
Loraine Anne Obana (TB Heals)

Non-voting members

World Health Organization- Philippines

Rajendra Prasad Hubraj Yadav, MD (WHO-Philippines)

WHO-Regional Office for the Western Pacific

Tauhid Islam, MD

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 COMMONLY USED ABBREVIATIONS

C - Ciprofloxacin
CPG - Clinical Practice Guidelines
CXR - Chest x-ray
DOH - Department of Health
DOT - Directly Observed Therapy
DSSM - Direct Sputum Smear Microscopy
DRTB - Drug Resistant Tuberculosis
DST - Drug Susceptibility Testing
E - Ethambutol
EPTB - Extrapulmonary tuberculosis
HIV - Human Immunodeficiency Virus
H/INH - Isoniazid
IGRA - Interferon Gamma Release Assay
LAMP - Loop-mediated isothermal amplification
Lo - Levofloxacin
MDRTB - Multi-Drug Resistant Tuberculosis
M - Moxifloxacin
MTB/RIF - Mycobacterium tuberculosis/Rifampicin
NTP-MOP - National Tuberculosis Program Manual of Procedures
a. - Ofloxacin
Pa - Pretomanid
PI - Protease inhibitor
PTB - Pulmonary Tuberculosis
R/RIF - Rifampicin
RR - Rifampicin Resistance
RR-TB - Rifampicin Resistant Tuberculosis
RFP/P - Rifapentine
NNS - Number needed to screen
NTPS - National TB Prevalence Survey
S/STM - Streptomycin
TB - Tuberculosis
TB – MAC - Tuberculosis Medical Advisory Committee
TST - Tuberculin Skin Test
WHO - World Health Organization
Z - Pyrazinamide

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 EXECUTIVE SUMMARY

Following the 2018 Manual for CPG Development [7] by the DOH as the main guide for
updating the 2016 CPG for Tuberculosis, the results of over three years of search and
review of evidence, consultations, consensus gathering, feedback from stakeholders, the
2021 TB CPG Task Force presents Table 1 below to summarize the key findings of
the 2021 Updates of the Clinical Practice Guidelines for the Diagnosis, Management
and Prevention of TB in Adults in the Philippines. Listed are the statements and
strength of recommendations and the quality of evidence behind them.

Table 1. Summary of Recommendations of 2021 Update of TB CPGs

Recommendations Strength of Quality of
Recommendation Evidence
1. Among asymptomatic adults with risk factors for Strong Moderate
pulmonary tuberculosis, screening via chest x-ray has
a 93.8% sensitivity and is recommended to identify
individuals warranting further bacteriologic work-up.

2. Among asymptomatic adults without risk factors for Strong Moderate

pulmonary tuberculosis, there is NO evidence
demonstrating the accuracy of chest x-ray. However,
because of the high prevalence of TB locally and
considering that ~10% of bacteriologically confirmed
TB had neither risk factors or symptoms, a chest x-
ray is recommended as a screening tool for identifying
individuals warranting further bacteriologic work-up.

3. Xpert® is a more accurate test (Sn 0.74-1.00; Sp Strong High

0.82-0.99; LR+ 21.8, LR- 0.04) compared to DSSM
(Sn 0.26-0.86; Sp 0.84-0.98; LR+ 10.8, LR- 0.49) and
is recommended as the initial diagnostic test of choice
for pulmonary TB.

4. TB LAMP is as accurate as GeneXpert® in the Weak Very low

diagnosis of pulmonary TB (Sn = 0.78 (95% CI 0.81-
0.83); Sp = 0.98 (95% CI 0.96-0.93); LR+ = 58.2, LR-
= 0.24). Due to its ability to detect rifampicin
resistance, GeneXpert® is still the recommended
diagnostic test of choice. In areas where Xpert is
unavailable and the risk of resistance is low, TB LAMP
may be used.

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5. Sputum culture with drug susceptibility testing is Strong Moderate
recommended to detect resistance to other anti-TB
drugs, when Xpert MTB/RIF shows rifampicin
resistance.

6. Among adults clinically diagnosed with Strong Low

extrapulmonary TB (EPTB) based on
radiologic/imaging findings, bacteriologic workup (i.e.
GeneXpert® and TB culture) in addition to
histopathology are recommended for the diagnosis.

7. There is no evidence for or against recommending Weak Very low

empiric treatment among patients with negative
bacteriologic tests but with clinical signs and
symptoms of TB. Empiric treatment may be
recommended for HIV-positive patients.

8. Among patients with PTB, Xpert Ultra may be used Strong High
in lieu of Xpert MTB/RIF as the initial test in adults with
presumptive PTB.

9. Among patients with presumptive EPTB, Xpert Strong Low

MTB/RIF Ultra is non-inferior to and replaces Xpert®
MTB/RIF in establishing diagnosis of EPTB.

10a. Among adults newly diagnosed to have Strong High

rifampicin-susceptible pulmonary tuberculosis,
2HRZE/4HR is still the recommended treatment
regimen.

10b. The inclusion of fluoroquinolone is not Strong High

recommended.

11a. In patients who require TB retreatment with Good practice N/A

confirmed rifampicin susceptibility by rapid drug statement
susceptibility testing, the Category II regimen should
no longer be prescribed. (WHO 2017 Good practice
statement)

11b. On the basis of the availability of rapid drug Good practice N/A
susceptibility testing for rifampicin, the standard first- statement
line treatment regimen of 2HRZE/4HR is
recommended. Revisions in the drug regimen should
be made based on the results of full drug susceptibility
testing. If rifampicin resistance is present, referral to a
facility for the evaluation of drug-resistant TB is
recommended.

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12a. A shortened regimen of moxifloxacin, Conditional Moderate
clofazimine, ethambutol and pyrazinamide in 40
weeks supplemented by kanamycin, isoniazid and
protionamide in the first 16 weeks among MDR/RR
pulmonary tuberculosis may be recommended.

12b An all-oral bedaquiline-containing regimen of 9–12 Conditional Very low

months duration is recommended in eligible patients with
confirmed MDR/RR-TB who have not been exposed to
treatment with second-line TB medicines used in this
regimen for more than 1 month, and in whom resistance to
fluoroquinolones has been excluded.

13. Among non-HIV adult household/close contacts of Conditional Very low

patients with active TB (regardless of bacteriologic
status), either a tuberculin skin test or an interferon-
gamma release assay (IGRA) may be used to screen
for latent tuberculosis infection (LTBI).

14a. Among non-HIV adults diagnosed to have LTBI, Strong Moderate

isoniazid given once daily for 6 months is
recommended for the treatment of LTBI among non-
HIV adult patients.

14b. Rifampicin given once daily for 4 months or Conditional Low to

rifampicin + isoniazid given once daily for 3 to 4 moderate
months may be considered as alternative treatments
for LTBI.

14c. Directly observed therapy with Rifapentine + Conditional Low

Isoniazid for 12 doses weekly may also be
considered.

15a.1. Triage of people with TB signs and symptoms, Conditional Very low
or with TB disease is recommended to reduce M.
tuberculosis transmission to healthcare workers
(including community health workers), persons
attending healthcare facilities or other persons in
settings with a high risk of transmission.

15a.2. Separation or isolation of people with Conditional Very low

presumed or documented infectious TB is
recommended to reduce M. tuberculosis transmission
to healthcare workers or other persons attending
healthcare facilities.

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15a.3. Prompt initiation of effective TB treatment of Strong Very low
people with TB disease is recommended to reduce M.
tuberculosis transmission to healthcare workers,
persons attending health care facilities or other
persons in settings with a high risk of transmission.

15a.4. Respiratory hygiene (including cough Strong Low

etiquette) in people with presumed or confirmed TB is
recommended to reduce M. tuberculosis transmission
to healthcare workers, persons attending healthcare
facilities or other persons in settings with a high risk
of transmission.

15b.1. Upper-room germicidal ultraviolet (GUV) Conditional Moderate

systems are recommended to reduce M. tuberculosis
transmission to healthcare workers, persons
attending health care facilities, or other persons in
settings with a high risk of transmission.

15b.2. Ventilation systems (including natural, mixed- Conditional Very low

mode, mechanical ventilation and recirculated air
through high-efficiency particulate air [HEPA] filters)
are recommended to reduce M. tuberculosis
transmission to healthcare workers, persons
attending healthcare facilities or other persons in
settings with a high risk of transmission.

15c.1. Particulate respirators, within the framework of Conditional Very low

a respiratory protection program, are recommended
to reduce M. tuberculosis transmission to healthcare
workers, persons attending healthcare facilities or
other persons in settings with a high risk of
transmission.

16. Among patients with TB-HIV co-infection, Weak Very low

rifampicin-containing regimens are comparable to
non-rifampicin based regimens in terms of
effectiveness and safety.

17. Among HIV patients with TB co-infection who are Weak Very low
on rifampicin-based regimens, caution should be
exercised when increasing the dose of
lopinavir/ritonavir. Increasing the dose may increase
the risk of adverse events without reducing virologic
failure.

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 Table 2. Comparison of 2016 Statement with the New 2021 Recommendations

2016 Statement 2021 Recommendation

QUESTIONS ON SCREENING
Q1. Among adults with no Together with a good Among asymptomatic adults with
symptoms but with risk factors , clinical history, a good risk factors for pulmonary
how accurate is screening by quality chest xray film is tuberculosis, screening via chest x-
chest x-ray in identifying needed to initially guide ray has a 93.8% sensitivity and is
individuals warranting further the clinician in the recommended to identify
bacteriologic work-up? identification of individuals warranting further
presumptive PTB for bacteriologic work-up.
Q2. Among adults with no further bacteriologic Among asymptomatic adults
symptoms and no risk factors, confirmation. without risk factors for pulmonary
how accurate is screening by tuberculosis, there is NO evidence
chest demonstrating the accuracy of
x-ray in identifying individuals chest x-ray. However, because of
warranting further bacteriologic the high prevalence of TB locally
work-up? and considering that ~10% of
bacteriologically confirmed TB had
neither risk factors or symptoms, a
chest x-ray is recommended as a
screening tool for identifying
individuals warranting further
bacteriologic work-up.
QUESTIONS ON DIAGNOSIS
Q3. Among adults with Initial diagnostic test Xpert® is a more accurate test (Sn
presumptive pulmonary TB (PTB), among presumptive TB 0.74-1.00; Sp 0.82-0.99; LR+ 21.8,
how accurate is pooled sensitivity of 89% LR- 0.04) compared to DSSM (Sn
Sputum Xpert MTB/Rif compared and specificity of 99% 0.26-0.86; Sp 0.84-0.98; LR+ 10.8,
to sputum DSSM in establishing LR- 0.49) and is recommended as
diagnosis of Pulmonary TB? the initial diagnostic test of choice
for pulmonary TB.
Q4. Among adults with No mention TB LAMP is as accurate as
presumptive PTB, how accurate is GeneXpert® in the diagnosis of
Sputum TB LAMP pulmonary TB (Sn = 0.78 (95% CI
compared to Xpert MTB/Rif in 0.81-0.83); Sp = 0.98 (95% CI 0.96-
establishing initial diagnosis of 0.93); LR+ = 58.2, LR- = 0.24). Due to
Pulmonary TB? When is the its ability to detect rifampicin
sputum TB LAMP a preferred test resistance, GeneXpert® is still the
over Xpert MTBRif? diagnostic test of choice. In areas
where Xpert is unavailable and the
risk of resistance is low, TB LAMP
may be used.

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Q5. Among adults with TB culture remains the gold Sputum culture with drug
presumptive pulmonary TB (PTB), standard for TB Diagnosis. susceptibility testing is
should sputum TB culture with If available, sputum TB recommended to detect resistance
drug susceptibility testing (DST) 16tandar can be requested to other anti-TB drugs, when Xpert
be done with Xpert MTB/Rif? in the diagnostic workup of MTB/RIF shows rifampicin
TB specifically in ruling out resistance.
NTM
Q6. Among adults clinically Similar to PTB, diagnostic Among adults clinically diagnosed
diagnosed with EPTB based on bacteriologic confirmation with EPTB based on radiologic/
imaging studies, should further of EPTB includes direct imaging findings, bacteriologic
bacteriologic workup be done microscopy, TB culture and workup (i.e. GeneXpert® and TB
versus histopathology alone to Xpert MTB/Rif. culture) in addition to
establish diagnosis of EPTB? histopathology are recommended
for the diagnosis.
Q7. Among adults whose No mention There is no evidence for or against
bacteriologic workup for active recommending empiric treatment
TB disease is negative, how among patients with negative
effective bacteriologic tests but with clinical
is empiric treatment based on signs and symptoms of TB. Empiric
physician’s clinical judgement in treatment may be recommended
achieving treatment for HIV-positive patients.
success and reducing relapse and
mortality?

Q8. Among adults with No mention Among patients with PTB, Xpert
presumptive pulmonary TB (PTB), Ultra may be used in lieu of Xpert
how accurate is Sputum Xpert MTB/RIF as the initial test in adults
MTB/Rif compared to sputum with presumptive PTB.
Xpert Ultra in establishing
diagnosis of Pulmonary TB?

Q9. Among adults with No mention 9. Among patients with

presumptive extrapulmonary TB presumptive EPTB, Xpert MTB/RIF
(EPTB), how accurate is Xpert Ultra is non-inferior to and replaces
MTB/Rif compared to Xpert Ultra Xpert® MTB/RIF in establishing
in establishing diagnosis of diagnosis of EPTB.
extrapulmonary TB?

QUESTIONS ON TREATMENT OF TB
Q10. Among adults newly 2HRZE/4HR (Category 1) 10a. Among adults newly diagnosed
diagnosed to have rifampicin- for PTB and EPTB except to have rifampicin-susceptible PTB,
susceptible PTB, is standard maninges, bones or joints. 2HRZE/4HR is still the
2HRZE/4HR still the recommended treatment regimen.
recommended treatment
regimen to optimize treatment
success/ completion and reduce

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risk for treatment failure, relapse, 10b. The inclusion of
and mortality compared to HRZE fluoroquinolone is not
plus fluoroquinolone? recommended.

Q11. Among adults who need All retreatment cases 11a. In patients who require TB
retreatment for tuberculosis with should be immediately be retreatment with confirmed
known susceptibility to referred to the nearest rifampicin susceptibility by rapid
rifampicin, is the standard Xpert MTB/Rif facility for drug susceptibility testing, the
2HRZE/4HR the recommended rifampicin susceptibility Category II regimen should no
regimen to optimize treatment testing. longer be prescribed. (WHO 2017
success/ completion and reduce Category II regimen Good practice statement)
risk for treatment failure, relapse (2HRZES/HRZE/5HRE) 11b. On the basis of the availability
and mortality compared to should only be given of rapid drug susceptibility testing
2HRZES/1HRZE/5HRE or among confirmed for rifampicin, the standard first-
immediate referral to PMDT? Rifamipicin sensitive line treatment regimen of
retreatment cases or in 2HRZE/4HR is recommended.
circumstances where Xpert Revisions in the drug regimen
MTB/Rig services cannot should be made based on the
be performed results of full drug susceptibility
testing. If rifampicin resistance is
present, referral to a facility for the
evaluation of drug-resistant TB is
recommended.

Q12. Among persons with multi- All DR-TB patients should 12a. A shortened regimen of
drug resistant or rifampicin be managed under moxifloxacin, clofazimine,
resistant-TB, is the standard programmatic setting. ethambutol and pyrazinamide in 40
shortened regimen as effective as Management of DR TB weeks supplemented by
WHO conventional multi-drug or involves the use of second kanamycin, isoniazid and
rifampicin-resistant line drugs that are more protionamide in the first 16 weeks
regimens? expensive, less effective among MDR/RR pulmonary
and more toxic for at least tuberculosis may be recommended.
18 months. Management 12b An all-oral bedaquiline-
outside the proper containing regimen of 9–12 months
framework will only lead to duration is recommended in eligible
further drug resistance. patients with confirmed MDR/RR-
TB who have not been exposed to
treatment with second-line TB
medicines used in this regimen for
more than 1 month, and in whom
resistance to fluoroquinolones has
been excluded.

17
QUESTIONS ON DIAGNOSIS AND MANAGEMENT OF LATENT TB
Q13. Should non-HIV adult Tuberculin skin test (TST) is Among non-HIV adult
household/close contacts of the preferred screening household/close contacts of
active TB cases (regardless of test for LTBI in resource patients with active TB (regardless
bacteriologic status) with no limited setting like the of bacteriologic status), either a
Philippines. tuberculin skin test or an
active disease undergo the
interferon-gamma release assay
interferon gamma release
(IGRA) may be used to screen for
assay (IGRA) or tuberculin skin latent tuberculosis infection (LTBI).
test (TST) to identify latent TB?
Is IGRA more accurate than
standard TST?
Q14. Will treatment of latent Isoniazid 300mg daily for 6 14a.Among non-HIV adults
TB infection (LTBI) of non-HIV months under supervised diagnosed to have LTBI, isoniazid
adults diagnosed to have LTBI, treatment is the given once daily for 6 months is
using any of 9H, 6H, 3-4HR, 4R recommended regimen for recommended for the treatment of
LTBI. LTBI among non-HIV adult patients.
or 12 doses weekly INH-
14b. Rifampicin given once daily for
Rifapentine vs no treatment
4 months or rifampicin + isoniazid
be effective in reducing the given once daily for 3 to 4 months
risk for conversion of latent TB may be considered as alternative
to active TB? treatments for LTBI.
14c. Directly observed therapy with
Rifapentine + Isoniazid for 12 doses
weekly may also be considered.

QUESTIONS ON PREVENTION AND INFECTION CONTROL FOR TB

Q15. Among high risk or Isolation is recommended 15a.1. Triage of people with TB signs
special settings, what are the for the ff cases: and symptoms, or with TB disease is
Bacteriologically recommended.
recommended measures to
confirmed PTB not tarted 15a.2. Separation or isolation of
prevent transmission of TB?
or are in early stages of TB people with presumed or
treatment documented infectious TB
Presumptive DRTB or 15.a.3 Prompt Initiation of TB
known MDR/XDR TB Treatment
Documented HIV/ADIS 15.a.4 Respiratory hygiene
cases or those with strong 15.b.1 Upper-room germicidal
clinical evidence for ultraviolet (GUV) systems are
HIV/AIDS recommended
15b.2. Ventilation systems
(including natural, mixed-mode,
mechanical ventilation and
recirculated air through high-

18
 efficiency particulate air [HEPA]
filters) are recommended.
15c.1. Particulate respirators are
recommended.

QUESTIONS ON TB-HIV COINFECTION

Q16. Among patients with TB- No mention 16. Among patients with TB-HIV co-
HIV co-infection, how effective infection, rifampicin-containing
and safe are rifampicin- regimens are comparable to non-
containing rifampicin based regimens in terms
of effectiveness and safety.
regimens in terms of clinical
cure and adverse reactions
compared to non-rifampicin
based regimens?
Q17. Among patients with TB- No mention 17. Among HIV patients with TB co-
HIV co-infection who are on infection who are on rifampicin-
second line ART (lopinavir- based regimens, caution should be
ritonavir) and rifampicin-based exercised when increasing the dose
of lopinavir/ritonavir. Increasing
regimen, should the dose of
the dose may increase the risk of
ART (lopinavir-ritonavir) be
adverse events without reducing
boosted or not to reduce virologic failure.
clinical failure and adverse
events?

REFERENCES:

1. Bloom BR, Atun R, Cohen T, Dye C, Fraser H, Gomez GB, Knight G, et, al, Chapter
11: Tuberculosis. In: Major Infectious Diseases. 3rd edition. Holmes KK, Bertozzi S,
Bloom BR, Jha P, editors. Washington (DC): The International Bank for
Reconstruction and Development / The World Bank; 2017 Nov.
2. World Health Organization. Global Tuberculosis Report 2018. Geneva: World Health
Organization.
3. Lansang MA and the NTPS Writing Team. National Tuberculosis Prevalence Survey
2016 Philippines. Department of Health – Disease Prevention and Control Bureau.
https:// ntp.doh.gov.ph/ downloads/publications/NTPS2016.pdf
4. World Health Organization. Tuberculosis: The End TB Strategy. 2015
https://www.who.int/tb/strategy/end-tb/en/
5. Subbaraman R, Nathavitharana RR, Satyanarayana S, Pai M, Thomas BE, Chadha
VK, et al. (2016)The Tuberculosis Cascade of Care in India’s Public Sector: A
Systematic Review and Meta-analysis. PloSMed 13(10):e1002149
doi:10.1371/journal.pmed.1002149

19
6. Task Force: Clinical Practice Guidelines for the Diagnosis, Treatment, Prevention
and Control of Tuberculosis in Adult Filipinos: 2016 Update (CPGTB2016).
Philippine Coalition Against Tuberculosis (PhilCAT), Philippine Society for
Microbiology and Infectious Diseases (PSMID), Philippine College of Chest
Physicians (PCCP). Available online. https://www.pcp.org.ph/
documents/PSBIM/2017/ CPG%20TB%202016%20E-copy.pdf Accessed March 13,
2021
7. 2018 Manual for Clinical Practice Guideline Development
8. Schunemann H, Brozek J, Oxman A, editors. GRADE Handbook for Grading Quality
of Evidence and Strength of Recommendations. The GRADE Working Group.
Available at http://ims.cochrane.org/revman/gradepro.

20
 INTRODUCTION

Tuberculosis (TB) continues to be the leading cause of death from an infectious disease
globally.[1] In the 2019 Global TB report [2], the Philippines now ranks 4th among high
TB-burden countries with an incidence rate of 554 per 100, 000 population. The recent
2016 National TB Prevalence Survey (NTPS) also reported alarmingly high TB
prevalence rates at 434 per 100,000 (95% C.I. 350–518) and 1,159 per 100,000 (95%
C.I. 1,016–1,301), respectively, for smear positive and bacteriologically confirmed TB
among those age ≥15 years old.[3]

In 2014, the World Health Organization (WHO) declared the urgent need to unite and
accelerate efforts to end TB in the next 20 years.[4] This new global strategy envisions a
world free of TB with zero deaths, zero disease and zero suffering due to TB by the year
2035. To achieve these ambitious goals, the End TB Strategy calls on all countries to
embody specific principles, actions and strategies. The End TB Strategy has three pillars
which highlight the following: (1) patient-centered care for all people with TB; (2) the use
of bold policies and supportive systems; and (3) innovations and research. To
successfully implement the End TB Strategy, the cascade of care (also called the
continuum of care) model will be adapted by countries to assure and evaluate patient
retention across sequential stages of TB care. [5] The supportive systems in the pillars
should be able to navigate patients seamlessly through the screening, diagnosis,
treatment, prevention and control of TB, whether in public or private healthcare.
Additionally, the Department of Health (DOH) has plans to transform the healthcare
delivery system to follow the Universal Health Care (UHC) model by January 2020. It is
in this context that the 2021 Clinical Practice Guidelines (CPG) TB Update was
developed.

Objectives of the 2021 TB CPG Update

This TB CPG has the following objectives:

1) To update the 2016 Philippine Clinical Practice Guidelines on TB in Adults with recent
medical evidence (2015 -2020) in light of new developments at the global level and
contextualized to the national setting;
2) To guide clinicians and other TB personnel regarding the current standards of care
related to the screening, diagnosis, treatment and prevention of TB among both
immunocompetent and high-risk adult clinical groups in the Philippines;
3) To harmonize with and complement the most recent NTP-MOP on TB.
4) To reduce practice variability among public and private health practitioners and
improve detection, treatment and other clinical outcomes in adult patients diagnosed
with tuberculosis.

21
Scope and Target Population of Update: New Evidence since the 2016

This document is intended to update the 2016 Philippine Clinical Practice Guidelines
on the Diagnosis, Treatment and Prevention of TB [6]. Therefore, reference to the 2016
CPG is still advised for issues which are stable, well-grounded on strong evidence and
continues to be current acceptable practice. On the other hand, the new 2021 CPG TB
Update addresses identified issues where previous unresolved questions or
controversies were present and now reports new findings which form the basis for new
recommendations affecting current practices on TB care.

Additionally this 2021 update realigns the Philippine CPG with the End TB strategy’s
successful continuum of care, as well as DOH’s National TB Program (NTP) 6th Manual
of Procedures (MOP) which was released in 2020. It thus reduces the differences in
processes between the previous CPG and the current MOP.

The 2021 Update is also intended to prepare TB health providers with guidance aligned
to the Republic Act. No. 11223, also known as the Universal Health Care (UHC) Act,

Being an update, publications which were included in the previous 2006 and 2016
versions of the Philippine CPG were not reiterated anymore. Thus the evidence reviewed
in this document are from publications and other materials which have been released
from 2015 to 2019.

This 2021 Update covers only the Management, Diagnosis and Treatment of the adult
population in the country. Best practices among both immunocompetent and
immunocompromised individuals in the adult population are discussed.

Intended Users of this Update:

This document is intended for practicing clinicians and other healthcare professionals
involved in the holistic care of adult patients with presumptive or confirmed TB. These
include physicians of all specialties, nurses, medical technologists and other paramedical
staff caring for TB patients, as well as other health practitioners indirectly involved in TB
care such as program managers, hospital administrators, educators, policy makers,
diagnostic and therapeutic product developers and similar professionals. This update
was written for use in both private and public health systems. Details of the available
evidence have been painstakingly included here for greater understanding of medical and
paramedical students, trainees and other practitioners of modern medicine.

Developments and Challenges Encountered during the COVID-19

Pandemic

While most of the preliminary work on the evidence review and consensus were
completed pre-pandemic, the occurrence of the COVID-19 in 2020 led to the major delay
in the public consultations and presentations to stakeholders, necessary steps in CPG
development.

22
 METHODOLOGY

The process outlined in the 2018 Manual for CPG Development [7] by the DOH was
followed including preparation and prioritization of key clinical questions, appraisal and
synthesis of evidence, development of recommendations, external review and revision,
and dissemination.

Following the international standards and the DOH Manual for CPG Development [1],
this 2021 TB CPG Update was operationalized in four phases: 1) preparation and
prioritization, 2) CPG generation, 3) CPG appraisal, and 4) implementation.

I. Preparation, Prioritization and Organization of the Process

Steering Committee. In the preparation and prioritization phase, the Steering Committee
for the TB CPG Update was convened on the second quarter of 2019. It was composed
of five members, all of whom were clinicians and a past or present president of any of
the main proponent professional societies (PhilCAT, PSMID, PCCP) and/or were lead
chairpersons in the previous versions of the 2006 and 2016 TB CPGs. The Steering
Committee was tasked to oversee the 2021 guideline development process. It set the
CPG objectives, scope, target audience, and clinical questions. In consultation with their
respective professional societies and other relevant groups, the committee identified and
prioritized key clinical questions in a meeting held on November 19, 2019. They listed the
burning key issues to be included in the TB CPG update. They also identified and formed
the working groups who would be involved in creating the evidence base and finalizing
the recommendations for each clinical question.

II. Evidence Generation and Synthesis

Technical Working Group. Immediately after, the Technical Working Group (TWG) was
formed consisting of six committees working on 1) screening; 2) diagnosis; 3) treatment;
4) prevention and control of TB; 5) drug resistant TB; and 6) latent TB.

Each committee commissioned evidence review experts (ERE) who searched,

appraised, and synthesized relevant published or unpublished local and/or foreign
medical studies from 2015 to 2019.

Formulation of Clinical Questions. The Steering Committee formulated the guideline

questions structured in PICO format (population, intervention, comparator - control, and
outcome). A complete list of the guideline questions in PICO format is presented in Table
3 below.

23
Table 3. List of Questions Identified by the Steering Committee to be Urgent and Relevant
to the current practice of Tuberculosis Care.

QUESTIONS ON SCREENING
1. Among adults with no symptoms but with risk factors , how accurate is screening by
chest x-ray in identifying individuals warranting further bacteriologic work-up?
2. Among adults with no symptoms and no risk factors, how accurate is screening by chest
x-ray in identifying individuals warranting further bacteriologic work-up?

QUESTIONS OF TB DIAGNOSIS
Q3. Among adults with presumptive pulmonary TB (PTB), how accurate is Sputum Xpert
MTB/Rif compared to sputum DSSM in establishing diagnosis of Pulmonary TB?
Q4. Among adults with presumptive pulmonary TB (PTB), how accurate is Sputum TB LAMP
compared to Xpert MTB/Rif in establishing initial diagnosis of Pulmonary TB? When is the
sputum TB LAMP a preferred test over Xpert MTB/ Rif?
Q5. Among adults with presumptive pulmonary TB (PTB), should sputum TB culture with drug
susceptibility testing (DST) be done with Xpert MTB/Rif?
Q6. Among adults clinically diagnosed with extrapulmonary TB (EPTB) based on imaging
studies, should further bacteriologic workup be done versus histopathology alone to
establish diagnosis of EPTB?
Q7. Among adults whose bacteriologic workup for active TB disease is negative, how
effective is empiric treatment based on physician’s clinical judgement in achieving treatment
success and reducing relapse and mortality?
Q8. Among adults with presumptive pulmonary TB (PTB), how accurate is Sputum Xpert
MTB/Rif compared to sputum Xpert Ultra in establishing diagnosis of Pulmonary TB?
Q9. Among adults with presumptive extrapulmonary TB (EPTB), how accurate is Xpert
MTB/Rif compared to Xpert Ultra in establishing diagnosis of extrapulmonary TB?

QUESTIONS ON TREATMENT OF TB
Q10. Among adults newly diagnosed to have rifampicin-susceptible PTB, is standard
2HRZE/4HR still the recommended treatment regimen to optimize treatment success/
completion and reduce risk for treatment failure, relapse, and mortality compared
to HRZE plus fluoroquinolone?
Q11. Among adults who need retreatment for tuberculosis with known susceptibility to
rifampicin, is the standard 2HRZE/4HR the recommended regimen to optimize treatment
success/ completion and reduce risk for treatment failure, relapse and mortality compared
to 2HRZES/1HRZE/5HRE or immediate referral to PMDT?
Q12. Among persons with multi-drug resistant or rifampicin resistant-TB, is the standard
shortened regimen as effective as WHO conventional multi-drug or rifampicin-resistant
regimens?

24
 DIAGNOSIS AND MANAGEMENT OF LATENT TB
Q13. Should non-HIV adult household/close contacts of active TB cases (regardless of
bacteriologic status) with no active disease undergo the interferon gamma release assay
(IGRA) or tuberculin skin test (TST) to identify latent TB? Is IGRA more accurate than
standard TST?
Q14. Will treatment of latent TB infection (LTBI) of non-HIV adults diagnosed to have LTBI,
using any of 9H, 6H, 3-4HR, 4R or 12 doses weekly INH-Rifapentine vs no treatment be
effective in reducing the risk for conversion of latent TB to active TB?

PREVENTION AND INFECTION CONTROL FOR TB

Q15. Among high risk or special settings, what are the recommended measures to prevent
transmission of TB?

TB-HIV COINFECTION
Q16. Among patients with TB-HIV co-infection, how effective and safe are rifampicin-
containing regimens in terms of clinical cure and adverse reactions compared to non-
rifampicin based regimens?
Q17. Among patients with TB-HIV co-infection who are on second line ART (lopinavir-
ritonavir) and rifampicin-based regimen, should the dose of ART (lopinavir-ritonavir) be
boosted or not to reduce clinical failure and adverse events?

Search Strategy, Evidence Selection and Data Synthesis. The EREs for each of the
six committees started to search the evidence based on their specific assigned questions.
An independent literature searches were systematically performed by the designated
ERE for each guideline question. Electronic search was conducted in at least two
databases such as Cochrane Database, MEDLINE via PubMed, HERDIN, and clinical
trial registries up to November 2019. Other databases such as CENTRAL and Google
Scholar were searched when needed. Relevant local databases and websites of medical
societies were also utilized in the search. Keywords were based on PICO (MeSH and free
text) set for each question. In general the search terms "tuberculosis”, “TB”, “Kochs
Disease”, “Koch's Disease”, “Koch Disease”, “Mycobacterium tuberculosis infection”
combined with pertinent keywords based on the question listed in Table 3. Related
articles were also examined. Unpublished data were also sourced, especially from local
researches. Assistance from librarians, clinical epidemiologists, and statisticians was
sought.

The criteria for inclusion of evidence into the data synthesis include the following:
directness, methodological validity, results, and applicability of each article. RevMan,
STATA, and GRADEPro were used for the quantitative synthesis of important clinical
outcomes for each question. The Quality of Evidence was assessed using the GRADE
approach. (2)

25
Creation of the Evidence Summaries The EREs assessed the quality of evidence as high,
moderate, low or very low based on methodologic quality of the studies, directness of the
evidence, heterogeneity of the study results, precision of the estimates of effect of critical
outcomes and publication bias according to the Grades of Recommendation, Assessment,
Development and Evaluation (GRADE) approach seen in Table 4 .[8] When relevant, existing
CPGs were appraised and adapted. Together with the committee members, they summarized the
evidence, and drafted the initial recommendations.

The evidence summaries were then prepared for presentation to the consensus panel
members to finalize the recommendations.

Table 4. Basis for Assessing the Quality of the Evidence using GRADE Approach
Certainty of Evidence Interpretation

High We are very confident that the true effect lies close to that
of the estimate of the effect

Moderate We are moderately confident in the effect estimate: The

true effect is likely to be close to the estimate of the effect,
but there is a possibility that it is substantially different

Low Our confidence in the effect estimate is limited: The true

effect may be substantially different from the estimate of
the effect

Very Low We have very little confidence in the effect estimate: The
true effect is likely to be substantially different from the
estimate of effect

Factors that lower quality of the evidence are:

● Risk of bias
● Important inconsistency of results
● Some uncertainty about directness
● High probability of reporting bias
● Sparse data/Imprecision
● Publication bias

Additional factors that may increase quality are:

● All plausible residual confounding, if present, would reduce the observed
effect.
● Evidence of a dose-response gradient
● Large effect

26
III. Development of Evidence-based Recommendations by Consensus

Creation of the CPG Consensus Panel. Simultaneously, the Consensus Panel was also
formed. The Steering Committee convened the Consensus Panel (CP), considering
possible conflicts of interests of each panel member. To ensure fairness and
transparency, the composition was guided by the DOH manual (1). The key stakeholders
included policymakers, patient advocates, and physicians. Thus, the 2021 CPG
Consensus Panel was composed of representatives invited from relevant professional
societies, academic institutions, agencies, and patient groups (Samahan ng Lusog Baga
and TB Heals). Each stakeholder group had at least one key representative and backup
member to anticipate possible unforeseen absences. The conflicts of interest of the panel
members were declared and assessed by the Steering Committee.

The consensus panel representatives were tasked to review the evidence summaries and
develop recommendations during the en banc meeting. In the meeting, they prioritized
critical and important outcomes; discussed necessary considerations revolving around
the recommendations and voted on each recommendation and its strength.

Formulation of the Recommendations. Draft recommendations were formulated based

on the quality of evidence, trade-offs between benefit and harm, cost-effectiveness,
applicability, feasibility, equity, resources and uncertainty due to research gaps.
.
The strength of each recommendation (i.e. strong or weak) was determined by the panel
considering all the factors mentioned above. Strong recommendation means that the
panel is “confident that the desirable effects of adherence to a recommendation outweigh
the undesirable effects” while weak recommendation means that the “desirable effects of
adherence to a recommendation probably outweigh the undesirable effect but is not
confident.” (4)

En Banc Meeting for Consensus Development. On December 7, 2019, the evidence

summaries with draft recommendations were presented to the multidisciplinary
Consensus Panel, which also included representatives of TB patients (Samahan ng
Lusog Baga and TB Heals). This was held at the Function Room of the Mezzanine of
Tropicana Suites, LM Guerrero, Malate, Manila. After the evidence was presented by the
technical working teams for each of the clinical guideline questions, each of the panelists,
including the TB patients, were encouraged to raise their queries, feedback, concerns
and other issues. The panelists deliberated on the direction and strength of the
recommendations based on the balance between desirable and undesirable effects,
quality of evidence, patients’ values and preferences, cost and access to tests or
interventions, and potential implications to patients, clinicians, and policy makers, as
outlined in the GRADE approach. They then voted for or against each of the draft
recommendations and rated the strength of the recommendations as strong, weak or
conditional. To reach consensus, statements should have received at least 70% votes
from the consensus panel members. Major or minor reservations were addressed through
discussion.

27
The recommendation for each question and its strength was determined through voting.
A consensus decision was reached if 75% of all CP members agreed. (2) If consensus
was not reached in the first voting, questions, and discussions were encouraged. Two
further rounds of voting on an issue were conducted. Evidence-based draft
recommendations were also revised based on input arrived at by consensus in the en
banc discussions.

Managing Conflicts of Interest. The Steering Committee (SC) facilitated the whole CPG
formulation process, but their members had no direct participation in assessing and
synthesizing the evidence, generating the evidence summaries and evidence-based draft
recommendations of the Evidence Review Experts, and voting on final recommendations
during the en banc consensus panel review. They invited the relevant organization to
nominate individuals who can become part of the consensus panel.

Each nominee was required to fill out and sign a declaration of interest form and submit
their curriculum vitae. The SC a screened the nominees for any possible conflict of
interest that may bias their decisions. Those with significant potential COI based on the
decision of the COI Committee were not allowed to vote during the en banc meeting but
fully participated in the panel discussions. See Annex E.

External Review. The second draft which was the product of the consensus meeting was
routed for external review by four independent external reviewers who were also present
during the consensus panel meeting. Each reviewed the draft guidelines on the content,
clarity, acceptability, applicability and feasibility of the recommendations. Their feedback
was taken into consideration by the steering committee prior to finalizing the CPG

The draft was finalized by the steering committee for presentation to stakeholders and
future users in medical conferences. The final recommendations are summarized in
Table 1. The finalized draft was presented in public for a for further feedback. It was first
presented in full during the 2020 PSMID Annual Convention, and subsequently in the
2021 Philippine College of Physicians Annual Convention, both of which targeted the
expected end-users of the guidelines. Comments and questions were encouraged and
considered in the finalization of the draft.

Up to this point in the CPG development, the CPG team has worked independently of the
funding body (DOH)..

Submission to the Department of Health for Approval. The final recommendations

were first submitted in April 2023 and then re-submitted on November 2023 to answer
comments of reviewers.

Guideline Dissemination. The updated guidelines are being disseminated to all training
institutions for implementation. As soon as approved, electronic version will be uploaded
in the websites of PSMID, PhilCAT and PCCP. Printed copies of the guidelines will also
be distributed to medical societies as well as for posting online for wider coverage.

28
Guideline Monitoring and Updating. A standard presentation portfolio has been
created for easy access and easier dissemination. Its use will be monitored by
committees within the PhilCAT, the PSMID and training institutions under the PCP.
Percent compliance to the 2021 TB CPG will be monitored through health facilities with
training residency and fellowship programs. Programs found to have 70% compliance or
lower will undergo re-orientation by any of main professional societies. On the other hand,
the compliance to the mandatory notification can be monitored using the ITIS.

Because of the dynamic and vigorous TB research taking place, there is always new
information which needs to be appraised and shared The next update of the TB CPGs is
set to begin starting 2024. The Steering Committee has started the discussion about how
the CPG could be updated in a more efficient manner. The template of the COVID-19
Living Guidelines where the evidence is reviewed almost as soon as it becomes available,
and recommendations are made accordingly appears to address the concerns about
timeliness and relevance of CPGs. Thus, the approach to maintain the TB CPG as a
Living Guideline is preferred and likely to be pursued in the next several years.

Sponsorship and Funding. The development of this guideline was funded by the
Philippine Department of Health (DOH). Supplementary budget for printing has been
approved by the PBSP.

REFERENCES
1. DOH, PHIC. Manual for Clinical Practice Guideline Development 2018.
2. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE,
Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the
quality of evidence. J Clin Epidemiol. 2011 Apr;64(4):401-6. Doi:
10.1016/j.jclinepi.2010.07.015. Epub 2011 Jan 5. PMID: 21208779.
3. Schunemann H, Wiercioch W, Brozek J, Etxeandia-Ikobaltzeta I, Mustafa R, Manja
V. GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de
novo development of trustworthy recommendations: GRADE-ADOLOPMENT. J Clin
Epidemiol. 2017;81:101-10.
4. Guyatt, G. H., Oxman, A. D., Kunz, R., Falck-Ytter, Y., Vist, G. E., Liberati, A.,
Schünemann, H. J., & GRADE Working Group (2008). Going from evidence to
recommendations. BMJ (Clinical research ed.), 336(7652), 1049–1051.
https://doi.org/10.1136/bmj.39493.646875.

29
 Quick Guide to Users of this Update
On How To Interpret The Evidence

A. Interpreting Evidence on Screening Program

Note: This quick guide on how to read evidence on diagnostic tests will be helpful for
Questions 1 and 2.

The criteria for evaluating screening programs are:

1. The burden of illness must be high.

2. The tests must be accurate.
3. Early treatment must be more effective than late treatment.
4. Diagnostic tests and early treatment must be safe.
5. The cost of the screening strategy must be commensurate to the potential
benefit.

Figure 1. Admissible evidence for evaluation of a screening program3

3
Adapted from Dans Al, Dans LF and Silvestre MA. Painless Evidence – Based Medicine. 2nd edition. 2016.

CPG Adult TB - 12/1/23 3:12 PM

30
Figure 2. Indirect (A) and direct (B) trials of the effectiveness of screening1

B. Interpreting Evidence on Diagnosis

Note: This quick guide on how to read and interpret evidence on diagnostic tests will be
helpful for Questions 3 to 9.

There are four conventional ways of determining how accurate a test is. These measures
are adequate when comparing results of two tests using a 2 x 2 table.

• Sensitivity (sn) refers to the proportion of persons with disease who correctly have a
positive test.
• Specificity (sp) refers to the proportion of persons with no disease who correctly have
a negative test.
• Positive predictive value (PPV) is the proportion of persons with a positive test who
correctly turn out to have disease
• Negative predictive value (NPV) is the proportion of persons with a negative test
who correctly turn out to have no disease

Table 5. Interpreting likelihood ratios (LRs)

Likelihood Likelihood of Grade of likelihood
ratio disease
LR<3.0 (close to 1.0) – weakly positive
LRs > 1.0 INCREASE LR=3.0-10.0 – moderately positive
LR10.0 is strongly positive
LR >0.3 (close to 1.0) – weakly negative
LRs < 1.0 DECREASE LR=0.3-0.1 – moderately negative
LR<0.1 strongly negative

CPG Adult TB - 12/1/23 3:12 PM

31
However, if we need to evaluate a test with multi-level results, we need a “2 x n” table
and compute for likelihood ratio (LR). LR is a measure of how much the likelihood of the
disease changes given a test result.

STEP 2. Determine the likelihood ratio of

the test result from the studies reviewed.
Plot this on the middle vertical axis.

STEP 1.
Estimate the
pre-test
probability
from the
clinical history,
physical STEP 3.
examination of Connect the
the patient, two points in
survey results Step 1 and 2
or from the and extend the
hospital’s line to the
surveillance. rightmost
Plot this on vertical axis.
the left-most The point of
vertical axis. intersection is
the probability
of disease after
the test.

Figure 3. Using Bayes nomogram for estimating post-test probability

C. Interpreting Evidence on Therapy

Table 6. Ways of expressing effectiveness

Summary of result within each Comparison of results between
Outcome
group two groups
Dichotomous (e.g. lived or Proportion (e.g. deaths per 100 Relative risk reduction, absolute risk
died, BP controlled or not) patients) reduction (ARR), relative risk (RR)
(see Table 4)
Rate (e.g. deaths per 100 Hazard ratio = rate in treatment / rate
patients) in control
Continuous (e.g. blood Mean (e.g. mean blood pressure) Mean difference = mean in control –
pressure in mmHg, quality mean in treatment group
of life on a scale of 0 to 1)

Instructions: When researchers express the effect of treatment using the relative risk
reduction, absolute risk reduction, or relative risk, they often provide a range of

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32
possibilities rather than a single estimate. This range of possibilities is called a ‘95%
Confidence Interval (95% CI)’ to mean ‘we are 95% sure that the true effect of a drug lies
in this range’. Table 4 below shows examples of the usefulness of interpreting 95% Cis.

Table 7. Interpreting 95% Confidence Intervals (Cis)

Interpreting 95% Confidence Intervals (Cis)
Measure of
Superior Inferior
effectiveness and Inconclusive Equivalent
(treatment surely (treatment surely
interpretation of (more studies (treatments
better than worse than
estimates needed) ¶ are equal) ¶
control) control)
95% CI
Both ends of 95% Both ends of 95% 95% CI wide;
Relative risk (RR)§ narrow;
CI <1.0 CI >1.0 straddles 1.0
= Rt / Rc straddles 1.0
<1.0 Treatment beneficial Example: Example:
Example: Example:
=1.0 Treatment no effect RR = 1 RR = 1
RR = 0.7 RR = 2.4
>1.0 Treatment harmful [95% CI: 0.2, [95% CI: 0.9,
[95% CI: 0.6, 0.8] [95% CI: 1.8, 3.2]
5.3] 1.1]
Absolute Risk 95% CI 95% CI
Reduction Both ends of 95% Both ends of 95% straddles 0%; straddles 0%;
(ARR) CI >0% CI <0% either end is either end is
= Rc – Rt (usually in %) far from 0% close to 0%
>0% Treatment beneficial Example: Example: Example:
Example:
=0% Treatment no effect ARR = -3% ARR = 1% ARR =0.2%
ARR = 2%
<0% Treatment harmful [95% CI: -7%, - [95% CI: - [95% CI: -
[95% CI: 1%, 3%]
1%] 20%, 32%] 0.1%, 0.5%]
¶ In both inconclusive and equivalent results, the 95% CI interval straddles the point of no effect (ARR = 0% or RR = 1.0). One end
reflects the worst possible harm, while the other end reflects the best possible benefit. The only difference is that, in equivalence,
either end is close to “no effect” (i.e. any benefit is ignorable, and any harm is ignorable too). Consider the ends of the 95% CI to make
sure there is agreement that the benefits and harms are ignorable.

§ Rc is the rate of the outcomes in the Control group; Rt is the rate of the outcome in the Treatment group

Note: The interpretations in this table only hold if the dichotomous events are expressed
as adverse rather than desirable events, e.g. death rather than survival, treatment failure
rather that cure, or disease rather than disease-free. When dichotomous outcomes are
expressed as desirable events, the interpretation of benefit and harm is reversed.

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 Instructions: The balloons below label the most important parts of the forest plot. Go
through these labels and familiarize yourself with the anatomy of the graph and
understand what the forest plot can signify.

Figure 4. How to interpret forest plots

GRADE APPROACH IN ASSESSING THE LEVEL OF QUALITY OF EVIDENCE

(GRADE: Grading of Recommendations Assessment, Development and Evaluation;

modified from WHO Handbook in Guideline Development, 2014)

These quality ratings apply to the body of evidence assessed for the research question,
not to individual studies. Evidence based on randomized controlled trials is initially given
a high-quality rating, while evidence from observational studies is given a low-quality
rating. The level is then adjusted according to the following criteria.

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Box 1. Standard criteria for grading of evidence4
Domain Grade Characteristic
STUDY DESIGN 0 All randomized controlled trials
-1 All observational studies
0 Most of the pooled effect provided by studies, with low risk of bias (“A”)
-1 Most of the pooled effect provided by studies with moderate (“B”) or high
(“C”) risk of bias. Studies with high risk of bias weighs <40%
-2 Most of the pooled effect provided by studies with moderate (“B”) or high
(“C”) risk of bias. Studies with high risk of bias weighs ≥40%
Note:
STUDY DESIGN Low risk of bias (no limitations or minor limitations) – “A”
LIMITATIONS
Moderate risk of bias (serious limitations or potentially very serious limitations
including unclear concealment of allocation or serious limitations, excluding
limitations on randomization or concealment of allocation) – “B”

High risk of bias (limitations for randomization, concealment of allocation, including

small blocked randomization (<10) or other very serious, crucial methodological
limitations) – “C”
INCONSISTENCY 0 No severe heterogeneity (I2< 60% or X2<0.05)
-1 Severe, non-explained, heterogeneity (I2 ≥60% or X2<0.05)

If heterogeneity could be caused by publication bias or imprecision due to

small studies, downgrade only for publication bias or imprecision (i.e. the
same weakness should not be downgraded twice)
INDIRECTNESS 0 No indirectness
-1 Presence of indirect comparison, population, intervention, comparator, or
outcome
0 The confidence interval is precise according to the figure below.
IMPRECISION The total cumulative study population is not very small (i.e. sample size is
more than 300 participants) and the total number of events is more than
30.

-1 One of the above-mentioned conditions is not fulfilled.

-2 The two above-mentioned are not fulfilled.
Note: If the total number of events is less than 30 and the total cumulative sample
size is appropriately large (e.g. above 3000 patients, consider not downgrading
the evidence). If there are no events in both control and control groups, the quality
of evidence in the specific outcome should be regarded as very low.
PUBLICATION 0 No evident asymmetry in the funnel plot or less than five studies to be
BIAS plotted.
-1 Evident asymmetry in funnel plot with at least five studies

2. Dans Al, Dans LF and Silvestre MA. Painless Evidence – Based Medicine. 2nd edition. 2016.

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 Table 8. Quality of evidence in GRADE

Quality Level Definition

We are very confident that the true effect lies
High
close to that of the estimate of the effect.
We are moderately confident in the effect
estimate: the true effect is likely to be close to
Moderate
the estimate of the effect, but there is a
possibility that it is substantially different.
Our confidence in the effect estimate is
Low limited: the true effect may be substantially
different from the estimate of effect.
We have very little confidence in the effect
estimate: the true effect is likely to be
Very Low
substantially different from the estimate of
effect.

REFERENCES:

1. Dans Al, Dans LF and Silvestre MA. Trade-off between benefit and harm is
crucial in screening recommendations. J Clin Epidem. 2010

2. Dans Al, Dans LF and Silvestre MA. Painless Evidence – Based Medicine. 2nd
edition. 2016.

3. Schϋnemann H, Brozek J, Oxman A, editors. GRADE handbook for grading

quality of evidence and strength of recommendations. The GRADE Working
Group. Available at: http://ims.cochrane.org/revman/gradepro. (This document is
contained within the “Help” section of the GRADE profiler software version
v.3.2.2.)

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 RESULTS:
UPDATED RECOMMENDATIONS
For Tuberculosis in Adults
2021

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 UPDATES ON SCREENING FOR TUBERCULOSIS
Q1: AMONG ADULTS WITH NO SYMPTOMS BUT WITH RISK FACTORS OF
TUBERCULOSIS5, HOW ACCURATE IS SCREENING BY CHEST X-RAY IN
IDENTIFYING INDIVIDUALS WARRANTING FURTHER BACTERIOLOGIC WORK-
UP?

RECOMMENDATION

Among asymptomatic adults with risk factors for pulmonary tuberculosis (PTB), the chest
x-ray (CXR) is an accurate screening tool with a 93.8 % sensitivity and is recommended
to identify individuals warranting further bacteriologic work-up. (Strong
recommendation, moderate-quality evidence)

REMARKS

Despite the absence of clinical studies directly addressing the question, the consensus
panel still recommends using CXR as a screening test among asymptomatic adults due
to its high sensitivity. This current recommendation is also consistent with existing
guidelines and reports from the WHO regarding TB screening. The 6th MOP recommends
annual CXR among those consulting in health facilities, including targeted workplaces,
communities, and congregate settings. Steps must be taken to make good quality CXR
more accessible in health facilities across the country.
Voting: 15/15 Agree

SUMMARY OF EVIDENCE

There were no studies that directly assessed the accuracy of CXR compared to other
diagnostic methods (e.g. culture, Xpert® MTB/RIF, LAMP, LPA) for screening
asymptomatic patients with risk factors.

A TB prevalence survey in Kenya (HIV-prevalence, 14.9%) showed that the presence of

any abnormality on CXR had a sensitivity of 94% (95% CI 88–98; 92% in HIV-infected
and 100% in HIV-uninfected) and a specificity of 73% (95% CI 68-77; not specified as to
HIV status).[1] However, the study did not stratify patients into symptomatic and
asymptomatic patients. Table Q1.1 summarizes the diagnostic performance of different
screening methods employed in this study, including CXR.

5 Risk factors include: healthcare workers, contacts of TB patients, those ever treated for TB (i.e., with history of previous TB
treatment), people living with HIV (PLWHIV), elderly (>60 years old), diabetics, smokers, urban and rural poor, all those with
immunosuppressive medical conditions, congregate settings.

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 Table Q1.1. Diagnostic accuracy of CXR and other TB screening methods6

Another systematic review investigated the number needed to screen (NNS) to detect a
case of active TB among different risk groups.[2] Of the many combinations of
components of a screening algorithm (Table Q1.2), the presence of CXR in the algorithm
consistently resulted in a lower NNS. NNS was lower when CXR was used as the primary
screening tool (NNS = 27) or as a component of the screen (NNS = 37). In contrast, higher
NNS values were found in strategies that used symptom screening alone (NNS = 142) or
did not use CXR imaging (NNS = 73). Furthermore, this review [2] also showed that using
CXR versus not using CXR yielded lower NNS among HIV/AIDS (8 vs. 54), household
contacts (17 vs. 54), and homeless subjects (67-70 vs. 455) (Table Q1.3).

Table Q1.2. Crude median and weighted mean NNS for different screening algorithms*

Low & moderate Moderate & high

Screening algorithm Overall
incidence incidence
70 (22-282) 112 (39-573) 27 (9-106)
CXR in primary screen
148 (2-11,019) 127 (3-11,019) 204 (2-3,189)
143 (34-1,112) 302 (54-61,729) 73 (24-285)
No CXR in primary screen
212 (3-30,865) 343 (3-30,865) 188 (3-6,355)
94 (27-415) 145 (45-1,202) 37 (12-144)
CXR in primary or secondary
149 (2-11,019) 203 (2-2,189) 180 (2-30,865)
Symptom screen only as 156 (42-773) 713 (57-30,030) 142 (40-601)
primary screen 319 (3-30,865) 713 (15-30,865) 308 (3-6,355)
*Adapted from Shapiro et al. (2013). CXR = chest x-ray

6
Source: p.6, Table 4, 1. van’t Hoog AH, Meme HK, Laserson KF, Agaya JA, Muchiri BG, Githui WA, et al. Screening strategies for
tuberculosis prevalence surveys: the value of chest radiography and symptoms. PLoS One. 2012;7(7):1–9.

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Note: Numbers given in table are crude median NNS (IQR) (top row) and weighted mean NNS and (range
of NNS) (bottom row) from the studies included in each category. ND=not defined

Table Q1.3. NNS Using CXR versus No CXR among Risk Groups*

NNS (95% CI)

Risk factors Incidence of TB Purpose of screen
With CXR Without CXR
HIV/AIDS medium and high
8 54
incidence
Household medium and high primary or secondary
17 (2-155) 54 (5-568)
contacts incidence screen
Drug users 54 (5-108)
Homeless primary screen among 67 (33-1,778)
455 (22-590)
other screening tools 70 (33-1,778)
*Adapted from Shapiro et al. (2013) data

The NNS presented may provide guidance in setting priorities in the local context,
especially in settings where resources are limited, and TB incidence is high. Prioritizing
the screening of risk groups with low NNSs may be useful for patients in the HIV clinic,
elderly, household contacts of patients with TB, and drug users (Table Q1.4).

Table Q1.4. NNS of risk groups*

Risk group NNS range

HIV-infected (including VCT attendees 10-37
Elderly/nursing homes, etc. 7-45
Household contacts 17-25
Drug users 20
Persons with diabetes 35
Miners 36
Pregnant women and GYN clinic attendees 36-39
Community-wide screening (high-incidence) 100
*Adapted from Shapiro et al. (2013) data

The 2016 NTPS showed that the proportion of TB cases among individuals with diabetes
mellitus was higher (8%) compared to non-cases (4%) (P<0.001). [3] There were also
more cases of TB identified among those with a history of smoking (67%) compared to
non-cases (39%) (P<0.001) (Table Q1.5). However, they did not perform subgroup
analysis for these risk groups to determine the accuracy of using CXR in asymptomatic
individuals. The survey concluded that risk groups should be targeted, and further studies
on cost-effectiveness of CXR screening among these high-risk groups is recommended.

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 Table Q1.5. Risk factors for TB cases compared to non-cases, 2016 NTPS,
Philippines

Survey TB cases Non-cases Total participants

Characteristics n = 466 n = 46,223 N = 46,689
No. %a No. %a No. %a
Diabetes mellitus
Yes 38 8.2 1,828 4.0 1,866 4.0
No 428 91.8 44,395 96.0 44,823 96.0
Smoking
Yes 313 67.2 18,222 39.4 18,535 39.7
No 153 32.8 27,975 60.5 28,128 60.2
Don’t know 0 0.0 26 0.1 26 0.1
Total 466 100.0 46,223 100.0 46,689 100.0
a
Column percentage

Chest radiography is a good screening tool for PTB because of its high sensitivity (87 to
98%).[4] Due to its low specificity (46% to 89%), however, CXR screening should be
followed by a rapid, highly sensitive and specific test to confirm TB diagnosis.

Based on the WHO TB operational guide, systematic screening for TB needs to properly
target high-risk groups and consider epidemiological, social and health-systems
contexts.[5] The profile of the risk group can influence the choice of algorithm since
accuracy of certain tools is affected by underlying biological factors associated with
certain risk factors (e.g. CXR, Xpert® MTB/RIF, and sputum-smear microscopy have
lower sensitivity among people living with HIV).[4]

The WHO End TB Strategy includes systematic screening for active TB in high-risk
groups highlighting the need for early TB diagnosis. WHO strongly recommends
systematic screening for active TB among household contacts and other contacts of
people with TB (NNS 17, 89 studies), people living with HIV (NNS 10, 74 studies), and
people exposed to silica (NNS 36, 8 studies). Systematic screening for active TB should
be considered in people in prisons and other penitentiary institutions, in people with an
untreated fibrotic CXR lesion, in geographically defined subpopulations with extremely
high levels of undetected TB, in a highly endemic country (e.g.,100 per 100,000
population or higher), and in subpopulations with very poor access to health care. [6]

REFERENCES:
1. Van’t Hoog AH, Meme HK, Laserson KF, Agaya JA, Muchiri BG, Githui WA, et al.
Screening strategies for tuberculosis prevalence surveys: the value of chest
radiography and symptoms. PloS One. 2012;7(7):1–9.

2. Shapiro AE, Chakravorty R, Akande T, Lonnroth K, Golub JE. A systematic

review of the number needed to screen to detect a case of active tuberculosis in
different risk groups [Internet]. 2013. Available from:
https://www.who.int/tb/Review3NNS_case_active_TB_riskgroups.pdf

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41
3. Department of Health. National Tuberculosis Prevalence Survey 2016 Philippines
[Internet]. Manila; 2018. Available from:
http://www.ntp.doh.gov.ph/downloads/publications/Philippines_2016 National TB
Prevalence Survey_March2018.pdf

4. World Health Organization. Chest radiography in tuberculosis detection: Summary

of WHO recommendations and guidance on programmatic approaches [Internet].
2016. Available from:
https://apps.who.int/iris/bitstream/handle/10665/252424/9789241511506-
eng.pdf?sequence=1

5. World Health Organization. Systematic screening for active tuberculosis: an

operational guide [Internet]. 2015. Available from:
https://apps.who.int/iris/bitstream/handle/10665/181164/9789241549172_eng.pdf
?sequence=1

6. World Health Organization. Systematic screening for active tuberculosis:

principles and recommendations [Internet]. 2013. Available from:
https://apps.who.int/iris/bitstream/handle/10665/84971/9789241548601_eng.pdf?
sequence=1

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Q2: AMONG ADULTS WITH NO SYMPTOMS AND NO RISK FACTORS, HOW
ACCURATE IS TB SCREENING BY CHEST X-RAY IN IDENTIFYING INDIVIDUALS
WARRANTING FURTHER BACTERIOLOGIC WORK-UP?

RECOMMENDATION

There is no evidence that demonstrates the accuracy of the CXR (98.2% Sn, 71.4% Sp,
+LR 3.44, -LR 0.03) as a screening tool among asymptomatic adults without TB risk
factors. However, because of the high prevalence of TB locally and considering that
based on the NTPS ~10% of bacteriologically confirmed TB (n=466) had no risk factors
and no symptoms (n=121), CXR is recommended as a screening tool for identifying
individuals warranting further bacteriologic work-up. (Strong recommendation,
moderate-quality evidence)

REMARKS

The panel made this recommendation to improve case detection and provide guidance
for TB screening in health facilities and in the workplace since TB incidence in the country
is high. [1,2] Currently, WHO has no strong recommendation regarding the use of CXR
for asymptomatic individuals without risk factors in the general population, but advocates
screening people living in highly endemic areas (i.e. > 1% TB prevalence). Early detection
of TB to reduce the severity of illness and to minimize spread of infection is a pillar of the
“End TB” strategy of the WHO. The 6th MOP recommends CXR as the primary screening
tool for active case finding in congregate settings, targeted communities and workplaces.

Concerns about access, cost, film quality for analog type x-ray, unnecessary exposure to
radiation (although negligible), turn-around times and standardized reading need to be
addressed to implement this.
Voting: 14/14 agree (1 person left at the time of the voting)

SUMMARY OF EVIDENCE

Review of published literature from 2015 to 2019 using the search terms “tuberculosis,
pulmonary”[Mesh], screening, adult, chest radiography, chest x-ray, symptom, and
asymptomatic” yielded 17 articles. Without the 5-year restriction, an additional 37 articles
published before the year 2015 were retrieved. Pooled estimates in studies cited by WHO
[3] and another systematic review [4] showed that CXR had a higher sensitivity for
detecting PTB in the general population compared to symptom screening (Table Q2.1).

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 Table Q2.1. Pooled sensitivity and specificity of chest radiograph as a
screening tool for pulmonary TB in the general population

Population HIV
Quality of Sensitivity Specificity
prevalence/region Reference test
evidence % (95% CI) % (95% CI)
(No. of participants)
Sputum culture or 97.8
CXR, any Combined 75.4
sputum-smear Moderate (95.1 –
abnormality 72,065 (72.0 – 78.8)
microscopy, or both 100.0)
(3 studies)

CXR, TB- Sputum culture or 86.8

Combined 89.4
related sputum-smear Low (79.2 –
163,646 (86.7 – 92.0)
abnormality microscopy, or both 94.5)
(5 studies)

However, these studies were not designed to evaluate the diagnostic accuracy of CXR
as a screening tool specifically among asymptomatic individuals not belonging to high-
risk groups. Only indirect evidence regarding the possible use of CXR in this population
may be derived from some studies. For example, in one prevalence survey conducted in
Cape Town, South Africa, 9 of 780 asymptomatic individuals were bacteriologically
positive for TB, with 6 of 9 patients showing TB-related abnormalities on CXR [5]. Another
prevalence survey in Western Kenya reported 48 (1.2%) TB cases among 3,852
asymptomatic participants, with no TB cases seen among the 15,893 asymptomatic
participants with normal CXR results. [6] In a cross-sectional study in Vietnam, case yield
was higher for screening by CXR (90.5%) compared to symptom screening by interview
(37.9%).[7] Lastly, a retrospective study in Vaud Canton, Switzerland, compared the
bacteriological and clinical presentation of the actively screened TB cases by CXR with
other patients detected by passive screening. [8] More asymptomatic patients were found
among actively screened patients (49.3%; 95% CI 37.4-61.2) compared to passively
screened patients (17.6%; 95% CI 10.3-24.9). Among patients with culture confirmed
PTB, 42.2% (95% CI 27.2-57.2) of actively screened patients had no symptoms
compared to 13% (95% CI 5.31-20.7) of passively screened patients.[8]

Data from the 2016 NTPS showed that among the survey cases with CXR findings
suggestive of TB (Table Q2.2), majority (67.5%, 276/409) were negative by symptom
screening. Only 133 (28.5%) of the survey cases were positive for both symptoms and
CXR.[1]

Of the 437 available CXRs, 409 (93.6%) were interpreted as suggestive of TB. Chest x-
ray screening alone identified 98.2% (430/438) cases compared to 32.2% (150/466)
identified by symptom screening alone; screening for TB cases using symptoms alone
would have missed one- to two-thirds of bacteriologically confirmed PTB cases. [1]

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 Table Q2.2. Distribution of negative symptoms and CXR central reading among
microbiologically confirmed survey cases, NTPS 2016, Philippines.
Smear-positive survey cases Bacteriologically confirmed
CXR (central
Screening symptoms (N = 173) survey cases (N = 466)
reading)
Number % Number %
Positivea Positive 79 45.7 133 28.5
Positivea Negative 2 1.2 6 1.3
Negative but with other symptomsb Positive 56 32.4 168 36.0
Negative but with other symptomsb Negative 2 1.2 17 3.6
Negative Positive 21 12.1 108 23.2
Negative Negative 1 0.6 5 1.1
a
Positive for screening symptoms of cough for at least two weeks at the time of the interview and/or blood in sputum (hemoptysis) in the past month
b
Negative but with other symptoms i.e. fever, weight loss, night sweats

REFERENCES:
1. Department of Health. National Tuberculosis Prevalence Survey 2016 Philippines
[Internet]. Manila; 2018. Available from:
http://www.ntp.doh.gov.ph/downloads/publications/Philippines_2016 National TB
Prevalence Survey_March2018.pdf

2. World Health Organization. Global tuberculosis report 2019 [Internet]. 2019. Available
from: https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-
eng.pdf?ua=1

3. World Health Organization. Systematic screening for active tuberculosis: an operational

guide [Internet]. 2015. Available from:
https://apps.who.int/iris/bitstream/handle/10665/181164/9789241549172_eng.pdf?seque
nce=1

4. van’t Hoog A, Langendam M, Mitchell E, Cobelens F, Sinclair D, Leeflang MMG, et al. A

systematic review of the sensitivity and specificity of symptom- and chest-radiography
screening for active pulmonary tuberculosis in HIV-negative persons and persons with
unknown HIV status. [Internet]. 2013. Available from:
https://www.who.int/tb/Review2Accuracyofscreeningtests.pdf

5. Boon S Den, White NW, Lill SWP Van, Borgdorff MW, Verver S, Lombard CJ, et al. An
evaluation of symptom and chest radiographic screening in tuberculosis prevalence
surveys. Int J Tuberc Lung Dis. 2006;10(8):876–82.

6. Van’t Hoog AH, Meme HK, Laserson KF, Agaya JA, Muchiri BG, Githui WA, et al.
Screening strategies for tuberculosis prevalence surveys: the value of chest radiography
and symptoms. PloS One. 2012;7(7):1–9.

7. Hoa NB, Cobelens FGJ, Sy DN, Nhung N V, Borgdorff MW, Tiemersma EW. Yield of
interview screening and chest X-ray abnormalities in a tuberculosis prevalence survey.
Int J Tuberc Lung Dis. 2012;16(September 2011):762–7.

8. Monney M, Zellweger J-P. Active and passive screening for tuberculosis in Vaud
Canton, Switzerland. Swiss Med Wkly. 2005;135:469–74.

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 UPDATES ON DIAGNOSIS OF TUBERCULOSIS
Q3: AMONG ADULTS WITH PRESUMPTIVE PULMONARY TB (PTB), HOW
ACCURATE IS SPUTUM XPERT® MTB/RIF COMPARED TO SPUTUM DSSM IN
ESTABLISHING THE DIAGNOSIS OF PTB?

RECOMMENDATION

Xpert® MTB/RIF is a more accurate test (Sn 0.74-1.00; Sp 0.82-0.99; LR+ 21.8, LR- 0.04)
compared to direct sputum smear microscopy (DSSM) (Sn 0.26-0.86; Sp 0.84-0.98; LR+
10.8, LR- 0.49) and is recommended as the initial diagnostic test of choice for PTB.
(Strong recommendation, high-quality evidence)

REMARKS AND CONSENSUS ISSUES

The consensus panel recommends the use of Xpert® MTB/RIF as the initial diagnostic
test for the diagnosis of PTB. Unlike DSSM, Xpert® MTB/Rif is a more sensitive test
and has the added benefit of determining rifampicin resistance (RR). Xpert® MTB/RIF
testing is a useful tool for early diagnosis of TB and multi-drug resistant TB (MDRTB).

Voting: 15/15 agree

SUMMARY OF EVIDENCE

Xpert® MTB/RIF is an automated, cartridge-based nucleic acid amplification test for TB.
It detects M. tuberculosis as well as the mutation that confers RR. The assay provides
results directly from specimens in less than 2 hours.

Search terms included ("GeneXpert") OR ("Nucleic Acid Amplification

Techniques"[Mesh]) AND (("Tuberculosis"[Mesh]) OR "tuberculosis")
Based on 4 high-quality studies [1-4] comparing the sensitivities and specificities of
Xpert® MTB/RIF and DSSM, with TB culture as a reference standard, the following
parameters were derived (Table Q3.1):

Table Q3.1. Comparison of Diagnostic Accuracy Estimates Between

Xpert® MTB/RIF and DSSM

Diagnostic Performance
Xpert® MTB/RIF DSSM
Measures
Sensitivity
Range 0.74-1.00 0.26-0.86
Pooled/Summary (CI 95%) 0.96 (0.69-1.00) 0.54 (0.29-0.77)
Specificity
Range 0.82-0.99 0.84-0.98
Pooled/Summary (CI 95%) 0.96 (0.84-0.99) 0.95 (0.89-0.98)
Likelihood Ratios
LR+ (CI 95%) 21.8 (5.2-91.6) 10.8 (7.6-15.4)
LR- (CI 95%) 0.04 (0.00-0.42) 0.49 (0.29-0.83)

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Xpert® MTB/RIF had a better sensitivity, with a pooled estimate of 96%, compared to
DSSM at 54%. This means that Xpert® MTB/RIF identifies more true positive cases and
less false positive cases of PTB compared to DSSM. Both Xpert® MTB/RIF and DSSM
had comparable specificities and had similar yields for true negative cases.

The likelihood of PTB increases 21.8 times with a positive Xpert® MTB/RIF result
compared to DSSM, with a likelihood of 10.8 times with a positive result. In contrast, a
negative Xpert® MTB/RIF decreases the likelihood of PTB by 0.04 times, as compared
to a negative sputum smear, which decreases the likelihood by 0.49.

Favorable qualities of the Xpert® platform include automaticity of the process, consistent
quality, and the diagnostic utility to simultaneously detect RR. DSSM can still be used for
TB diagnosis in resource-limited settings with no access to Xpert ® MTB/RIF testing.
Recognized limitations of DSSM include requirements for higher specimen volume (5-
10mL) compared to Xpert ® MTB/RIF (1mL) and laboratory expertise to minimize
technique-related concerns including smear preparation and interpretation. The NTP
MOP 6th ed. States that the use of Xpert MTB/RIF assay is the primary diagnostic test for
TB in the Philippines replacing DSSM, and that smear-positive specimens by DSSM will
require further Xpert® MTB/Rif testing for rapid determination of RR.

The WHO included Xpert® MTB/RIF in its policy framework for implementing TB
diagnostics in 2015, citing its advantages over sputum microscopy [6]. Access to Xpert®
MTB/RIF and cost are factors to be considered in the utilization of this test. In the past
few years, the Philippine DOH has embarked on the rollout of rapid TB testing utilizing
the Xpert® MTB/RIF to detect TB and drug resistant TB. From just 84 Xpert® machines
in 2014, there are now 488 Xpert® machines distributed in various government TB
treatment centers. The rollout is further augmented by optimized specimen transport
process to address access to free Xpert® MTB/RIF testing.

To address the concerns regarding Xpert® MTB/RIF testing access in private healthcare
institutions, a national platform to access concessional pricing through consortium has
been established to offer reduced and uniform pricing to patients.

REFERENCES:

1. Lee H, Kee S, Shin J, Kwon Y, Chun S, Shin H, et al. Xpert MTB/RIF assay as a
substitute for smear microscopy in an intermediate burden setting. Am J Respir
Crit Care Med. 2019;199(6):784–94.

2. Orina GM, Adoka S, Amolo AS, Orindi OT. Comparative study of smear
microscopy, Gene Xpert and culture and sensitivity assays in detection of
Mycobacterium tuberculosis on sputum samples among tuberculosis suspected
cases in Nyamira County Referral Hospital. Mycobact Dis. 2017;7(3).

3. Pinyopornpanish K, Chaiwarith R, Pantip C, Keawvichit R, Wongworapat K,

Khamnoi P, et al. Comparison of Xpert MTB / RIF assay and the conventional

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47
 sputum microscopy in detecting Mycobacterium tuberculosis in Northern
Thailand. Tuberc Res Treat. 2015;1–6.

4. Taddese BD, Desalegn DM, Misganaw AS, Kitila KT, Hailu K, Bika AT.
Diagnostic performance of Xpert MTB / RIF assay versus Ziehl-Neelsen method
for the diagnosis of pulmonary tuberculosis in Addis Ababa, Ethiopia. Open
Microbiol J. 2018;12:390–6.

5. National Tuberculosis Control Program (NTP, 2020). Manual of Procedures 6th

Edition. Available from:
http://ntp.doh.gov.ph/downloads/publications/guidelines/NTP_MOP_6th_Edition.p
df

6. World Health Organization. Implementing tuberculosis diagnostics: policy

framework [Internet]. 2015. Available from:
https://apps.who.int/iris/bitstream/handle/10665/162712/9789241508612_eng.pdf
?sequence=1

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Q4: AMONG ADULTS WITH PRESUMPTIVE PULMONARY TB (PTB), HOW
ACCURATE IS SPUTUM TB LAMP COMPARED TO XPERT® MTB/RIF IN
ESTABLISHING THE INITIAL DIAGNOSIS OF PTB? WHEN IS SPUTUM TB LAMP
PREFERRED OVER XPERT® MTB/RIF?

RECOMMENDATION
TB LAMP is as accurate as GeneXpert® in the diagnosis of PTB (Sn = 0.78 (95% CI 0.81-
0.83); Sp = 0.98 (95% CI 0.96-0.93); LR+ = 58.2, LR- = 0.24). Due to its ability to detect
RR, GeneXpert® is still the recommended diagnostic test of choice. In areas where
GeneXpert® is unavailable and the risk of resistance is low, TB LAMP may be used.
(Weak recommendation, Very low-quality evidence)

REMARKS AND CONSENSUS ISSUES

The inability of TB-LAMP to detect RR, as well as its limited availability in the country
were identified by the panel as key issues. TB LAMP has recently been made available
in the Philippines for TB testing in a few government and private laboratories. The NTP
MOP 6th ed. Policy statement on TB LAMP is for this test to be used as an alternative
diagnostic test if Xpert® MTB/RIF is inaccessible [1]. Unlike Xpert® MTB/RIF, TB LAMP
cannot detect RR. As such, for patients with positive TB-LAMP results, follow-up testing
using rapid molecular tests that detect RR should still be done. This limitation may
contribute to delays in treatment initiation for individuals who tested positive and are
suspected to have resistance.
Voting: 15/15 agree

SUMMARY OF EVIDENCE
PubMed was used for the search with the search terms " TB LAMP" or
"tuberculosis LAMP", "Xpert" or "Genexpert" or "Cepheid", "Pulmonary TB" or "PTB" or
"pulmonary tuberculosis."
Loop-mediated isothermal amplification (LAMP) is a manual molecular assay that
amplifies DNA independent of room temperature. A commercial assay that employs the
LAMP technique to detect tuberculosis, TB-LAMP has logistical advantages compared to
Xpert® MTB/RIF. It does not require air conditioning, has less need for infrastructure, and
less maintenance costs. The results of TB-LAMP can be read by the naked eye or under
ultraviolet light after 15 to 60 minutes. TB-LAMP can process 14 samples in 1-1.5 hours,
up to 70 samples per day, compared to 16 tests per working day for Xpert® MTB/RIF.
These properties make TB-LAMP a viable option for barangay health centers to replace
DSSM. However, unlike Xpert® MTB/RIF, TB-LAMP cannot detect RR.

A 2019 meta-analysis and systematic review which included 13 studies (n=5,099)

explored the diagnostic accuracy of TB-LAMP in the diagnosis of PTB. [2] Six studies
performed Xpert® MTB/RIF and TB-LAMP on the same participants (n = 2,837) but used
different reference standards (Table Q4.1). Of 2,837 participants eligible for inclusion in
the analysis, 1,075 (38%) qualified for Standard 1 status across four studies; 1,809 (64%)
qualified for Standard 2 across 6 studies, and 2,772 (98%) qualified for Standard 3 across
eight studies.

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 Table Q4.1. Reference standards used by Shete (2019) [2]

STANDARD WITH TB NO TB
1 No positive and at least 2
negative cultures performed on 2
different sputum samples
at least 1 positive culture
2 confirmed to be MTB by No positive and at least 2
speciation testing negative cultures performed on
at least 1 sputum sample
3
No positive and at least 1
negative culture

Table Q4.2 shows the pooled sensitivities and specificities of Xpert® MTB/RIF and TB-
LAMP across the three reference standards in this review. The pooled sensitivity of TB-
LAMP was lower than that of Xpert® MTB/RIF. The specificities of all three tests were
similar. In head-to-head comparisons, TB-LAMP appeared to be less sensitive than the
Xpert® MTB/RIF, but the difference in sensitivity was not statistically significant. The
evidence profile for this PICO question is reported in Appendix Q4 (Table Q4.3, Table
Q4.4, and Table Q4.5). These results were similar to the findings of a recent meta-
analysis conducted in China.[3]

Table Q4.2. Accuracy of TB-LAMP and the Xpert® MTB/RIF assay*

Reference standarda Pooled sensitivityb Pooled specificityb

TB-LAMP
Standard 1 78.0 (66.6 – 86.4) 98.9 (97.4 – 99.6)
Standard 2 74.1 (64.1 – 82.2) 98.8 (96.8 – 99.6)
Standard 3 75.8 (63.2 – 85.0) 98.2 (96.0 – 99.2)
Xpert® MTB/RIF
Standard 1 81.1 (70.6 – 88.5) 98.2 (95.9 – 99.2)
Standard 2 80.4 (73.4 – 85.9) 97.4 (94.9 – 98.7)
Standard 3 84.0 (75.6 – 90.0) 97.2 (94.4 – 98.6)
* Source: Shete PB, Farr K, Strnad L, Gray CM, Cattamanchi A. Diagnostic accuracy of TB-LAMP for
pulmonary tuberculosis: a systematic review and meta-analysis. BMC Infect Dis. 2019;19(268):1–11.
a
Data were restricted to study participants for whom there were valid results for both TB-LAMP and
the Xpert® MTB/RIF assay and cases in which testing was performed on non-frozen specimens
b
Values are percentages (95% confidence intervals).

Several limitations were identified in this review. First, there was a lack of a consistent
reference standard which could have resulted in misclassification of patients depending
on what standard was used. Second, conflicts of interest could not be ruled out as most
of the studies were conducted by national government organizations sponsored by the
manufacturers of the test. Third, these studies were conducted in areas where individuals
underwent extensive training. Lastly, the results may have been confounded by
operational issues or by the inclusion of patients with HIV.

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Even in the absence of these methodological issues, TB-LAMP still exhibits the major
disadvantage of not being able to detect RR. Thus, its use is limited for screening and it
cannot replace Xpert® MTB/RIF especially in an area with high TB endemicity and rising
MDR-TB cases.

A 2016 policy guidance from WHO described an unpublished cost-effectiveness study

comparing Xpert® MTB/RIF and TB-LAMP conducted in Malawi and Vietnam. [4]
Findings from this study showed that TB-LAMP was potentially more cost-effective than
smear microscopy in areas where setting up a laboratory containing Xpert® MTB/RIF
poses logistic challenges.

The weighted average per-test cost of TB-LAMP and Xpert® MTB/RIF ranged from US$
13.78 to 16.22 and US$ 19.17 to 28.34 respectively, when they were used as routine
diagnostic tests at all peripheral-level laboratories in both countries. [3] The first-year
expenditure required for implementation at peripheral laboratories with a medium
workload (10–15 sputum smear microscopy tests per day) in Vietnam was US$ 26,917
for TB-LAMP and US$ 43,325 for the Xpert® MTB/RIF assay.

In the cost–effectiveness analyses, TB-LAMP improved case-detection rates and was

cost–effective when compared with WHO’s willingness-to-pay threshold levels. As a test
performed at peripheral laboratories, TB-LAMP is generally a cheaper and more
affordable alternative molecular test to the Xpert® MTB/RIF assay. The findings of the
cost–effectiveness analysis also demonstrated that TB-LAMP is potentially a cost–
effective alternative to DSSM in settings where the Xpert® MTB/RIF assay cannot be
implemented due to its infrastructure requirements (e.g. continuous power supply).
However, given the inability of TB-LAMP to detect RR-TB and its suboptimal sensitivity
for detecting TB among persons living with HIV, policymakers must cautiously evaluate
the operational feasibility and cost considerations prior to introducing this technology in
their countries.

A local cost-effectiveness study is recommended.

REFERENCES:

1. National Tuberculosis Control Program (NTP, 2020). Manual of Procedures 6th Edition. Available
from: http://ntp.doh.gov.ph/downloads/publications/guidelines/NTP_MOP_6th_Edition.pdf

2. Shete PB, Farr K, Strnad L, Gray CM, Cattamanchi A. Diagnostic accuracy of TB-LAMP for
pulmonary tuberculosis: a systematic review & meta-analysis. BMC Infect Dis. 2019;19(268):1–11.

3. Deng S, Sun Y, Xia H, Liu Z, Gao L, Yang J, et al. Accuracy of commercial molecular diagnostics
for the detection of pulmonary tuberculosis in China: a systematic review. Sci Rep [Internet].
2019;9(4553):1–11. Available from: http://dx.doi.org/10.1038/s41598-019-41074-8

4. World Health Organization. The use of loop-mediated isothermal amplification (TB-LAMP) for the
diagnosis of pulmonary tuberculosis: policy guidance [Internet]. 2016. Available from:
https://apps.who.int/iris/bitstream/handle/10665/249154/9789241511186-eng.pdf?sequence=1

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 APPENDIX Q4

GRADE Evidence Profiles

Table Q4.3. Accuracy of TB-LAMP compared to Xpert® MTB/RIF

MTB/RIF in establishing initial diagnosis of PTB among adults with presumptive PTB (Reference Standard 1)

Explanations:
a. Failure to perform mycobacterial culture on at least two sputum samples, failure to use liquid culture or because liquid culture contamination rates were outside the acceptable range of 5-12%
b. Significant heterogeneity I2: 61 – 78%; P <0.03

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Table Q4.4. Accuracy of TB-LAMP compared to Xpert® MTB/RIF in establishing initial diagnosis of PTB among adults with presumptive
PTB (Reference Standard 2)

Explanations:
a. Failure to perform mycobacterial culture on at least two sputum samples, failure to use liquid culture or because liquid culture contamination rates were outside the acceptable range of 5-12%
b. Significant heterogeneity I2: 61 – 78%; P <0.03

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Table Q4.5. Accuracy of TB-LAMP compared to Xpert® MTB/RIF in establishing initial diagnosis of PTB among adults with presumptive
PTB (Reference Standard 3)

Explanations:
a. Failure to perform mycobacterial culture on at least two sputum samples, failure to use liquid culture or because liquid culture contamination rates were outside the acceptable range of 5-12%
b. Significant heterogeneity I2: 61 – 78%; P <0.03

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Q5: AMONG ADULTS WITH PRESUMPTIVE PTB, SHOULD SPUTUM TB CULTURE
WITH DRUG SUSCEPTIBILITY TESTING (DST) BE DONE WITH XPERT® MTB/RIF?

RECOMMENDATION

a. Sputum culture with DST is recommended to detect resistance to other anti-TB

drugs, when Xpert® MTB/RIF shows RR. (Strong recommendation, moderate-
quality evidence)

b. There is no evidence for or against concurrent testing with Xpert® MTB/RIF and
sputum culture with DST in patients with presumptive PTB.

REMARKS AND CONSENSUS ISSUES

The second recommendation regarding concurrent testing was made as Xpert® MTB/RIF
and TB culture are usually ordered at the same time in healthcare settings where both
tests may be available. The TB MOP 6th ed. States that patients with Xpert® MTB/RIF
results showing RR and who are considered high risk for DRTB, should submit two
sputum samples for the following: 1) rapid molecular testing using line probe assay for
determination of first-line and second-line drug resistance and 2) TB culture with
phenotypic DST for first-line and second-line anti-TB drugs. [1]
Voting: 14/14 agree

SUMMARY OF EVIDENCE

There were no studies that directly compared the use of Xpert® MTB/RIF alone with
Xpert® MTB/RIF and sputum culture with DST at the operational level (i.e in service
provision to patients). All studies encountered to date determined the accuracy of Xpert®
MTB/RIF in detecting TB using sputum culture as the standard reference. The evidence
profile for this PICO question is reported in Appendix Q5 (Table Q5.2). Other studies
investigated the ability of Xpert® MTB/RIF to detect RR. [2-4,6,7] This is particularly
important especially in areas like the Philippines where the incidence of TB is ≥20/100
000 and DRTB is ≥2%.[5]

The 2016 NTPS involving 61,466 individuals aged ≥15 years showed that 1,159
individuals per 100,000 (95% CI 1,016-1,301) were bacteriologically positive for PTB.
Under field conditions, Xpert® MTB/RIF detected 1.7 times more M. tuberculosis cases
than sputum culture. [5]

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 Table Q5.1 Summary of studies on Xpert® MTB/Rif to detect rifampicin
resistance.
STUDY REFERENCE SENSITIVITY SPECIFICITY
STUDY POPULATION
DESIGN STANDARD % (95%CI) % (95% CI)
Meta-analysis
with 95 studies
Culture-based Drug
combined, 48 8020 participants,
Horne, 2018 Susceptibility 96 98
of which respiratory
(USA) Testing/ (95.0-96.9) (97.6-98.3)
addressed specimens
MTBDRplus
Xpert® MTB/Rif
RR detection
256 smear-negative
Lin Fan, 2018 Prospective 100 100
suspected TB cases DST
(China) Cohort (95.8-100) (29.2-100)
(ages 11-89)
1625 sputum
Feliciano, samples (out of 2241 Phenotypic DST 94.68 97.8
Retrospective
2019 (Brazil) various respiratory and/or WGS (90.4-97.4) (97.0-98.6)
specimen collected)
85 culture-positive
PTB patients, 37 100
Pandey, 2017 Cross-sectional Drug Susceptibiity 98.57
newly diagnosed and (78.2-100)
(Nepal) study testing (92.3-99.9)
48 previously treated
(ages 13-82)

In the same survey, RR was detected in 29 of the 397 Xpert® MTB-positive specimens.
Of these, 3 were susceptible by DST and 10 were concordant with Xpert® MTB/RIF.
Rifampicin resistance rate by DST was 5.7% (13/397), of which 9 were both rifampicin
(RIF) + isoniazid (INH) resistant. 17 of the 81 previously treated for TB were positive for
RR by Xpert®. Hence, previous TB treatment was significantly associated with RR by
Xpert®MTB/RIF (OR 8.2; 95% CI 3.8-18).

WHO recommended that DST should still be performed to detect resistance to anti-TB
agents other than RIF and INH and to monitor progress of treatment.[8] Similar
recommendations were echoed by the NTPS report. [5]

REFERENCES:

1. National Tuberculosis Control Program (NTP, 2020). Manual of Procedures 6th Edition. Available
from: http://ntp.doh.gov.ph/downloads/publications/guidelines/NTP_MOP_6th_Edition.pdf

2. Feliciano CS, José L, Menon B, Maria L, Anselmo P, Dippenaar A, et al. Xpert MTB / RIF
performance to diagnose tuberculosis and rifampicin resistance in a reference centre in southern
Brazil. ERJ Open Res. 2019;5(00043–2019).

3. Fan L, Li D, Zhang S, Yao L, Hao X, Gu J, et al. Parallel tests using culture, Xpert MTB/RIF, and
SAT-TB in sputum plus bronchial alveolar lavage fluid significantly increase diagnostic
performance of smear-negative pulmonary tuberculosis. Front Microbiol. 2018;9(June):1–7.

4. Horne, David J, Mikashmi K, Zifodya JS, Schiller I, Dendukuri N, Tollefson D, Schumacker SG,
Ochodo EA, Pai M, Steingart KR. Xpert MTB/Rif and Xpert MTB/Rif Ultra for 56tandardi
tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2019 Jun
7;6:CD009593. Doi: 10.1002/14651858.CD009593.pub4.

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5. Department of Health. National Tuberculosis Prevalence Survey 2016 Philippines [Internet].
Manila; 2018. Available from: http://www.ntp.doh.gov.ph/downloads/publications/Philippines_2016
National TB Prevalence Survey_March2018.pdf

6. Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of drug-
resistant tuberculosis: an official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit
Care Med. 2019;200(10):e93–142.

7. Pandey_P, Pant_ND, Rijal_KR, Shrestha_B, Kattel_S, Banjara_MR, et al. Diagnostic accuracy of

GeneXpert MTB/RIF assay in comparison to conventional drug susceptibility testing method for the
diagnosis of multidrug-resistant tuberculosis. PloS One 2017;12(1):e0169798.
8. World Health Organization. Policy guidance on Drug-Susceptibility Testing (DST) of second-line
anti-tuberculosis drugs. WHO/HTM/TB/2008.392. Geneva: World Health Organization, 2008

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 APPENDIX Q5

Table Q5.2. Grade Pro Summary of Findings for Xpert® MTB/RIF and DST.

a
The majority of the studies were observational.
b
There was comparison between DST and Xpert® but DST is the standard reference and hence there was no study that directly addressed the query.
c
The prevalence rates of 2%, and 21% were based on the local prevalence of newly diagnosed and previously diagnosed cases of RR.
d
The 22% was the prevalence derived from the pooled data of the 51 studies.

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Q6: AMONG ADULTS CLINICALLY DIAGNOSED WITH EXTRAPULMONARY TB
(EPTB) BASED ON IMAGING STUDIES, SHOULD FURTHER BACTERIOLOGIC
WORKUP BE DONE VERSUS HISTOPATHOLOGY ALONE TO ESTABLISH
DIAGNOSIS OF EPTB?

RECOMMENDATION

Among adults clinically diagnosed with extrapulmonary TB (EPTB) based on

radiologic/imaging findings, bacteriologic workup (i.e.Xpert® MTB/RIF and TB culture) in
addition to histopathology are recommended for the diagnosis. (Strong
recommendation, low-quality evidence)

REMARKS

Despite the low certainty of evidence, the guideline panel decided to strongly recommend
performing bacteriologic workup (at least using Xpert® MTB/RIF) to reduce the variability
in practice observed among clinicians. In the 2016 version of this guideline, Xpert®
MTB/RIF was already recommended as the preferred initial diagnostic test for
bacteriologic confirmation of EPTB. The NTP MOP 6th ed. Also states as policy that for
patients suspected to have EPTB, body fluid or biopsy samples that are appropriate for
Xpert® MTB/RIF testing shall be obtained for bacteriologic confirmation. Healthcare
workers should be aware of the requirements for collection, storage and processing of
extrapulmary specimens for bacteriologic confirmation. [1]
Voting: 15/15 agree

SUMMARY OF EVIDENCE

Despite a systematic search of major databases, no studies were found directly

evaluating the effect of additional bacteriological evaluation on TB detection for adult
patients diagnosed with EPTB on the basis of strong clinical evidence and radiologic
findings.

However, the search yielded a single-center prospective study from Pakistan that
evaluated TB diagnosis based on microbiological and histopathological findings among
patients suspected clinically to have tuberculous lymphadenitis (TBLA). [2] Results of this
study showed that among 297 included patients, 89.6% had histopathology suggestive of
TB and there was microbiologic evidence of TB in 32.6% by Xpert® MTB/RIF, 26.6% by
TB culture, and 12.5% by AFB smear positivity. The histopathology findings among those
with positive microbiologic evidence of TB ranged from acute suppurative or necrotizing
inflammation to chronic granulomatous inflammation, caseation necrosis, or reactive
lymphoid hyperplasia.

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 Table Q6.1. Test characteristics using histopathology as
reference standard

Sensitivity Specificity
Test LR+ LR- AUC,% (95% CI)*
% %
AFB smear 12.7 93.4 1.92 0.93 51.5 (43.2-59.8)
AFB culture 30.7 90.2 3.13 0.77 60.7 (53.1-68.3)
GeneXpert® 33.2 85.0 2.21 0.79 59.5 (51.7-67.4)
*AUC-area under the curve, measures overall diagnostic accuracy

The accuracy of Xpert® MTB/RIF was also determined compared to culture positivity for
Mycobacterium tuberculosis (MTB). The sensitivity, specificity, positive and negative
likelihood ratio of Xpert® MTB/RIF were as follows: 65.7%, 80.4%, 3.35, and 0.43,
respectively. The overall diagnostic accuracy using area under the curve (AUC) was
51.5% (43.2-59.8).

A recently published systematic review and meta-analysis determined the accuracy of

Xpert® MTB/RIF compared with culture in people with presumptive EPTB. [2] Across the
different types of specimens, pooled Xpert® MTB/RIF sensitivity varied from 31% in
pleural tissue to 97% in bone or joint fluid, and more than 80% in urine, bone, or joint fluid
and tissue samples. Pooled Xpert® MTB/RIF specificity had less variation: 82% for bone
or joint tissue to ≥ 98% in cerebrospinal fluid, pleural fluid, urine and peritoneal fluid.

Xpert® MTB/RIF pooled sensitivity and specificity (95% credible interval) compared to
culture in cerebrospinal fluid were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%),
respectively (29 studies, 3774 specimens; moderate level of evidence). The positive and
negative likelihood ratios were 35.55 and 0.29, respectively. (Appendix Q6, Table Q6.2a)

Xpert® MTB/RIF pooled sensitivity and specificity (95% credible interval) compared to
culture in pleural fluid were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%),
respectively (27 studies, 4006 specimens; low level of evidence). The positive and
negative likelihood ratios were 63.62 and 0.49, respectively. (Appendix Q6, Table Q6.2b)

Xpert® MTB/RIF pooled sensitivity and specificity (95% credible interval) compared to
culture in urine were 82.7% (69.6% to 91.1%) and 98.7% (94.8% to 99.7%), respectively
(13 studies, 1199 specimens; moderate level of evidence). The positive and negative
likelihood ratios were 63.63 and 0.18, respectively. (Appendix Q6, Table Q6.2c)

Recommendations from Other Clinical Practice Guidelines

• As per the WHO, the basis of EPTB diagnosis should be one of the following: one
culture-positive specimen, or positive histology, or strong clinical evidence
consistent with active EPTB.

• EPTB presentation often varies with an extremely wide spectrum of signs and
symptoms dependent on the organs affected, aggressiveness of disease and host

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 immune response. [3] Also, EPTB is often pauci-bacillary, and the sites of infection
are difficult to access for specimen collection for diagnostic work-up (i.e.,
microscopy, histology, culture or molecular tests). [3] Currently, there is no
available and reliable single rule-out test (i.e., test with minimal or absent false-
negative results) in the diagnosis of EPTB. Thus, the diagnosis of EPTB is often
made in the context of integrating several non-specific findings from different forms
of investigations. [3]

REFERENCES:

1. National Tuberculosis Control Program (NTP, 2020). Manual of Procedures 6th Edition. Available
from: http://ntp.doh.gov.ph/downloads/publications/guidelines/NTP_MOP_6th_Edition.pdf

2. Sarfaraz, S., Iftikhar, S., Memon, Y., Zahir, N., Hereker, F. F., & Salahuddin, N. (2018).
Histopathological and microbiological findings and diagnostic performance of GeneXpert in
clinically suspected Tuberculous lymphadenitis. International Journal of Infectious Diseases.
Doi:10.1016/j.ijid.2018.08.020

3. Kohli, M., Schiller, I., Dendukuri, N., Ryan, H., Dheda, K., Denkinger, C. M., Steingart, K. R. (2017).
Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance. Cochrane
Database of Systematic Reviews. Doi:10.1002/14651858.cd012768

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Table Q6.2 (a-c) Summary of Findings on the Diagnostic Performance of Xpert MTB/RIF

Table Q6.2a Summary of Findings on the Diagnostic Performance of Xpert MTB/RIF in CSF

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Table Q6.2b Summary of Findings on the Diagnostic Performance of Xpert MTB/RIF in Pleural Fluid

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Table Q6.2c Summary of Findings on the Diagnostic Performance of Xpert MTB/RIF in Urine

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Q7: AMONG ADULTS WHOSE BACTERIOLOGIC WORKUP FOR ACTIVE TB
DISEASE IS NEGATIVE, HOW EFFECTIVE IS EMPIRIC TREATMENT BASED ON A
PHYSICIAN’S CLINICAL JUDGEMENT IN ACHIEVING TREATMENT SUCCESS
AND REDUCING RELAPSE AND MORTALITY?

RECOMMENDATION

There is no evidence for or against recommending empiric anti-TB treatment based on

a physician’s clinical judgment among patients with negative bacteriologic tests, but with
clinical signs and symptoms of TB. However, empiric treatment may be considered for
HIV-positive patients. (Weak recommendation, very low-quality evidence)

REMARKS

Physicians treat patients with anti-TB medications based solely on clinical diagnosis with
no bacteriologic evidence of TB. However, there is limited information regarding the
outcome of patients who are empirically treated for TB. Due to the paucity of studies
addressing this question, as well as the low quality of the evidence available, the guideline
panel is unable to make any recommendations for this specific clinical scenario. The
panel recognizes that there is a knowledge gap that should be addressed by future
research conducted on this specific population. Further studies should include a
description of patient characteristics (e.g., symptomatic, non-responsive to antibiotics) to
facilitate valid comparisons with participants in other studies.

In the NTP MOP 6th ed., TB suspects with negative bacteriologic tests are evaluated by
the health facility physician who shall decide on the diagnosis based on best clinical
judgment, and if needed, initiate treatment with anti-TB medications. The patient can be
also referred to the TB Medical Advisory Committee (TB MAC). [1] The panel, however,
recommends empiric TB treatment among HIV-positive patients whose bacteriologic
workup for TB is negative. This was based on one observational study among severely ill
HIV patients with smear negative PTB. The study showed that patients who were
empirically treated with anti-TB medications based on clinical decision had better 8 week
mortality outcomes after starting treatment, compared to no treatment.
Voting: 15/15 agree

SUMMARY OF EVIDENCE

Based on one cohort study with a low risk of bias, smear negative PTB suspect patients
who were not given treatment had a better mortality outcome at 6 months after the 1st
consultation, compared to those who were given empiric TB treatment (Figure Q7.1). This
was observed for both HIV-positive and HIV-negative subgroups. [1]

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65
 Figure Q7.1 Empiric treatment vs. no treatment in smear-negative patients

Figure Q7.2 Empiric treatment vs. No Treatment Among HIV patients

Based on a single observational study with a low risk of bias, empiric treatment based on
clinical decision of smear-negative, severely-ill HIV patients had better mortality outcome
at 8 weeks versus those were not given treatment (Figure Q7.2).[3] Severely ill was
described as a subgroup of HIV patients with 3 danger signs like fever (axillary
temperature >39°C), tachycardia (pulse>120 beats per minute), or tachypnea (respiratory
rate >30 breaths per minute). For HIV patients without warning signs, there was no
difference in outcomes between empiric treatment or no treatment (Table Q7.2, Appendix
Q7).

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REFERENCES:
1. National Tuberculosis Control Program (NTP, 2020). Manual of Procedures 6th Edition. Available
from: http://ntp.doh.gov.ph/downloads/publications/guidelines/NTP_MOP_6th_Edition.pdf

2. Huerga H, Ferlazzo G, Wanjala S, Bastard M, Bevilacqua P, Ardizzoni E, et al. Mortality in the first
six months among HIV-positive and HIV-negative patients empirically treated for tuberculosis. BMC
Infect Dis. 2019;19(132):1–11.

3. Katagira W, Walter ND, Boon S Den, Kalema N, Ayakaka I, Vittinghoff E, et al. Empiric TB treatment
of severely ill patients with HIV and presumed pulmonary TB improves survival. J Acquir Immune
Defic Syndr. 2016;72(3):297–303.

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67
 APPENDIX Q7

Table Q7.1 Summary of Evidence on Treatment versus no Treatment for PTB

Author(s): M. Abat
Question: No treatment compared to treatment of bacteriologically confirmed PTB for PTB in bacteriologically negative patients
Setting: Western Kenya
Bibliography: Huerga H, Ferlazzo G, Wanjala S, Bastard M, Bevilacqua P, Ardizzoni E, et al. Mortality in the first six months among HIV-positive and HIV-negative patients empirically treated for tuberculosis. BMC Infect Dis. 2019;19(132):1–11.

Certainty assessment № of patients Effect

treatment of Certainty Importance

№ of Study Relative Absolute
Risk of bias Inconsistency Indirectness Imprecision Other considerations No treatment bacteriologically
studies design (95% CI) (95% CI)
confirmed PTB

Mortality at 6 months after 1st consultation

1 observational not serious not serious serious a serious b none 9/261 (3.4%) 16/184 (8.7%) RR 0.45 48 fewer per
studies (0.17 to 1.17) 1,000 ⨁◯◯◯
(from 72 VERY LOW
fewer to 15
more)

Mortality at 6 months after 1st consultation – HIV negative

1 observational not serious not serious not serious very serious b,c none 3/112 (2.7%) 1/49 (2.0%) RR 1.31 6 more per
studies (0.14 to 12.31) 1,000 ⨁◯◯◯
(from 18 VERY LOW
fewer to 231
more)

Mortality at 6 months after 1st consultation – HIV positive

1 observational not serious not serious serious d not serious none 6/149 (4.0%) 15/135 (11.1%) RR 0.36 71 fewer per
studies (0.14 to 0.91) 1,000 ⨁◯◯◯
(from 96 VERY LOW
fewer to 10
fewer)

CI: Confidence interval; RR: Risk ratio

Explanations
a. mix of HIV and non-HIV patients
b. CI straddles unity
c. wide CI
d. HIV patients

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Table Q7.2 Summary of Evidence on Empiric Treatment versus No Treatment for HIV patients
Author(s): M. Abat
Question: Empiric treatment compared to no treatment in severely ill HIV patients for PTB in bacteriologically negative patients
Setting: Kampala, Uganda
Bibliography: Katagira W, Walter ND, Boon S Den, Kalema N, Ayakaka I, Vittinghoff E, et al. Empiric TB treatment of severely ill patients with HIV and presumed pulmonary TB improves survival. J Acquir Immune Defic Syndr. 2016;72(3):297–303.
Certainty assessment № of patients Effect

no treatment in Certainty Importance

№ of Study Empiric Relative Absolute
Risk of bias Inconsistency Indirectness Imprecision Other considerations severely ill HIV
studies design treatment (95% CI) (95% CI)
patients

Mortality at 8 weeks after starting treatment

1 observational not serious not serious serious a not serious none 27/126 (21.4%) 159/505 (31.5%) RR 0.66 107 fewer
studies (0.46 to 0.94) per 1,000 ⨁◯◯◯
(from 170 VERY LOW
fewer to 19
fewer)

Mortality at 8 weeks after starting treatment – with danger signs

1 observational not serious not serious serious a not serious none 16/74 (21.6%) 97/248 (39.1%) RR 0.55 176 fewer
studies (0.35 to 0.88) per 1,000 ⨁◯◯◯
(from 254 VERY LOW
fewer to 47
fewer)

Mortality at 8 weeks after starting treatment – without danger signs

1 observational not serious not serious serious a serious b none 11/52 (21.2%) 62/257 (24.1%) RR 0.88 29 fewer per
studies (0.50 to 1.55) 1,000 ⨁◯◯◯
(from 121 VERY LOW
fewer to 133
more)

CI: Confidence interval; RR: Risk ratio

Explanations
a. HIV patients
b. straddles unity

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Q8: AMONG ADULTS WITH PRESUMPTIVE PULMONARY TB (PTB), HOW
ACCURATE IS SPUTUM XPERT® MTB/RIF COMPARED TO SPUTUM XPERT
ULTRA IN ESTABLISHING DIAGNOSIS OF PULMONARY TB?

Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for
PTB. Recognizing the minimal trade off with Xpert Ultra, it is non-inferior to, and may be
used in lieu of Xpert MTB/Rif as the initial test in adults with presumptive PTB. (Strong
Recommendation, high quality evidence)

REMARKS

Xpert MTB/Rif Ultra is currently provided in selected private hospitals and laboratories,
and soon in government facilities. DOH has recently released guidance for the
interpretation for Xpert MTB/Rif Ultra.

SUMMARY OF EVIDENCE

Xpert Ultra sensitivity was slightly higher at 88%, (CI 85% to 91%) compared to Xpert
MTB/RIF at 85% (CI 82% to 88%); however, Xpert Ultra specificity was slightly lower at
96% (CI 94% to 97%) versus Xpert MTB/RIF at 98% (CI 97% to 98%) [1].

Table Q8.1 Pooled sensitivity and specificity of Xpert MTB/Rif and Xpert Ultra as
diagnostic tool for PTB

Test Number of Quality of Sensitivity Specificity

participants evidence
(studies)
Xpert MTB/Rif 10, 409 (70 High 85% (82 to 88)
studies)
26,828 (70 High 98% (97 to 98)
studies)
Xpert Ultra 462 (1 study) Moderate 88% (85 to 91)
977 (1 study) Moderate 96% (94 to 97)

Studies included in the analysis for Xpert MTB/Rif had median tuberculosis prevalence of
26% and are applicable to settings with higher tuberculosis prevalence such as the
Philippines.

Xpert Ultra was developed to improve Xpert MTB/Rif sensitivity especially among smear-
negative and HIV-associated TB. One study reported that the limit of detection using
Xpert MTB/Rif of 112.6 CFU/ml increased to 15.6 CFU/ml using Xpert Ultra [2]. It is
worth noting that Xpert Ultra added a new result category, “trace call”, corresponding to
the lowest MTB burden detection [3].

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A WHO Technical Experts Group agreed that Xpert Ultra was non-inferior to Xpert
MTB/Rif assay for the detection of rifampicin resistance. It also recognized that it has
higher sensitivity than Xpert MTB/Rif particularly in smear-negative culture-positive
specimens and in specimens from HIV-infected patients. However, this increase in
sensitivity results in a slightly lower specificity in a higher TB burden setting as Xpert Ultra
also detects non-replicating or non-viable bacilli present particularly in patients with recent
history of TB.

In the 2020 WHO Consolidated guidelines for diagnostics, repeat testing with Xpert Ultra
for patients with “trace call” result was not conditionally recommended since evidence
was insufficient at that time.

Special mention was given regarding the use of Xpert Ultra in adults with signs and
symptoms of PTB, with a prior history of TB and an end of treatment within the last 5
years – the lower threshold for bacillary detection by Xpert Ultra might be associated with
a high false-positive rate. As such, this was only given a conditional recommendation due
to the low certainty for test accuracy in these clinical scenarios [4].

Algorithm for the Interpretation of Xpert MTB/Rif Ultra Results

Adapted from GLI Planning for country transition to Xpert MTB/RIF Ultra Cartridges (2017)
downloadable at http://www.stoptb.org/wg/gli/assets/documents/GLI_ultra.pdf

Presumptive TB patients1
pulmonary or extrapulmonary

Collect one (1) specimen and perform Ultra assay

• MTB detected, RIF resistance detected (RR) MTB detected trace

Repeat Ultra assay2 using fresh specimen
• MTB detected, RIF resistance not detected (T) (TT)
• MTB detected, RIF resistance indeterminate (TI)
• MTB not detected (N)
• No result, error, or invalid result (I)
Results immediately and readily Likely delay in obtaining results or difficult access to Ultra repeat
available test (especially in severe disease, EPTB, and young children)3

Follow NTP MOP interpretation

similar to Xpert MTB/RIF
Assess treatment history and risk of having drug resistance;
assign treatment regimen IMMEDIATELY based on assessment

If treatment initiation can wait3,

MTB detected trace MTB not detected
• MTB detected, RIF resistance detected (RR) e.g. non-severe disease,
(TT) (N)
• MTB detected, RIF resistance not detected (T) wait for repeat test result
• MTB detected, RIF resistance indeterminate (TI)
• No result, error, or invalid result (I)

Refer to R-TB MAC for possible initiation of Refer to R-TB MAC6 for possible initiation of
Modify initial
DRTB treatment regimen if presumptive DRTB4 DRTB treatment regimen if presumptive DRTB
treatment regimen
OR OR accordingly once
repeat Ultra result
Treat with first-line treatment regimen Treat with first-line treatment regimen
is available7
if presumptive DSTB5 if presumptive DSTB

Figure Q8.1. Algorithm for the Interpretation of Xpert MTB/Rif Ultra Results

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71
REFERENCES:

1. Horne_DJ, Kohli_M, Zifodya_JS, Schiller_I, Dendukuri_N, Tollefson_D, Schumacher_SG, Ochodo_EA,

Pai_M, Steingart_KR.Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin
resistance in adults. Cochrane Database of Systematic Reviews 2019, Issue 6. Art. No.: CD009593.
DOI: 10.1002/14651858.CD009593.pub4.

2. Chakravorty_S, Simmons_AM, Rowneki_M, Parmar_H, Cao_Y,Ryan_J, et al. The new Xpert MTB/RIF
Ultra: improving detection of Mycobacterium tuberculosis and resistance to rifampin in an assay suitable
for point-of-care testing. Molecular Biology 2017;8(4):e00812-17. [DOI: 10.1128/mBio.00812-17]

3. World Health Organization. WHO meeting report of a technical expert consultation: non-inferiority
analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. WHO/HTM/TB/2017.04.Geneva: WHO 2017.

4. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid
diagnostics for tuberculosis detection. Geneva: World Health Organization; 2020.

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72
Q9: AMONG ADULTS WITH PRESUMPTIVE EXTRAPULMONARY TB (EPTB), HOW
ACCURATE IS XPERT® MTB/RIF COMPARED TO XPERT® ULTRA IN
ESTABLISHING DIAGNOSIS OF EXTRAPULMONARY TB?

RECOMMENDATION

In general, among patients with presumptive EPTB, Xpert MTB/RIF Ultra is non-inferior
to, and may replace Xpert MTB/RIF in establishing diagnosis of EPTB. (Strong
recommendation, low quality of evidence)

TB meningitis
Strong recommendation, low certainty of evidence for test accuracy for Xpert Ultra.

TB lymphadenitis (both lymph node biopsy and lymph node aspirate)

Conditional recommendation, low certainty of evidence for Xpert Ultra

EPTB – Others
For other specimens such as pleural fluid, peritoneal fluid, pericardial synovial fluid, and
urine, conditional recommendation, insufficient evidence for Xpert Ultra.

SUMMARY OF EVIDENCE

Due to challenges encountered in obtaining extrapulmonary specimens and technical

limitations of conventional bacteriological diagnosis, a mix of both microbiologic and
composite reference standards are used in literature for extrapulmonary TB. A recently
published Cochrane review in 2021 included studies until January 2020 [1], evaluating
Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and
rifampicin resistance in adults.
Sensitivity varied across specimens while for most specimens, specificity remained high.

In 2017, WHO commissioned a non-inferiority analysis [2] of Xpert Ultra compared with
Xpert MTB/Rif. Based on the results of this study, WHO recommended that use of Xpert
MTB/Rif be applied to Xpert Ultra as well. This was reiterated in the updated consolidated
guidelines of 2020 [3].

TB meningitis (CSF)

Six studies [1-6] were included with n= 475. The pooled sensitivity for Xpert Ultra was
89.4% (95% CI, 79.1-95.6) and pooled specificity was 91.2% (83.2-95.7). There was low
certainty of evidence, and it was downgraded for imprecision.
For Xpert MTB/Rif, 30 studies in one review [1] were included with 3395 subjects. Pooled
sensitivity was 71.1% (95% CI, 62.8-79.1) and pooled specificity was 96.9% (95% CI,
95.4-98) with moderate certainty of evidence. This was also downgraded for imprecision.

Overall, for CSF samples, Xpert Ultra had higher sensitivity but lower specificity
compared to Xpert MTB/Rif.

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73
Pleural fluid

For Xpert Ultra, four studies [6-9] were included with 398 subjects. The pooled sensitivity
was 75% (95% CI, 58-86.4) and pooled specificity was 87% (95% CI, 63.1-97.9) with very
low certainty of evidence. This was downgraded for indirectness, inconsistency and
imprecision.

For Xpert MTB/Rif, 25 studies were included in one review [1], with a total of 3065
subjects. The pooled sensitivity was 49.5% (95% CI, 39.8-59.9) and pooled specificity
was 98.9% (95% CI, 97.6-99.7) with moderate certainty of evidence. Downgraded for
indirectness, inconsistency and imprecision.

There were no studies that directly compared Xpert Ultra vs. Xpert MTB/Rif using
pleural fluid samples.

Lymph node aspirate

Against composite reference standard

For Xpert ultra, only 1 study [10] was included with 73 subjects. Sensitivity was 70% (95%
CI, 51-85) and specificity was 96.4 (95% CI, 91.3-98.6) with very low certainty of
evidence. This was downgraded for indirectness and imprecision.

For Xpert MTB/Rif, four studies [1, 11-14] were included with 670 subjects. Pooled
sensitivity was 81.6% (95% CI, 61.9-93.3) and pooled specificity was 96.4 (85% CI,
91.3-98.6) with low certainty of evidence. This was downgraded for risk of bias and
indirectness.

For other EPTB specimens, there were sparse subjects and trials.

The higher sensitivity of Xpert Ultra is due to its low TB detection limit and is found in
specimens with low numbers of bacilli, especially in smear-negative, culture-positive
specimens. However, because of this, the Ultra may be more prone to detecting small
numbers of non-replicating or non-viable bacilli present. This may give rise to false
positive results in TB detection. Rifampicin resistance detection is not similarly affected.

The Perez-Risco study [7] used different types of specimens: sterile fluids, nonsterile
fluids, lymph nodes, abscess aspirates, and tissues. The highest sensitivity was obtained
in samples of lymph nodes (94.1%), and nonsterile fluids (93.7%), followed by tissue
specimens (86.6%), stool material (80%), abscess aspirates (64.7%) and sterile fluids
(60.5%)

More studies on Xpert Ultra with standardized sampling collection will be helpful to inform
future practice.

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74
Recommendations from other CPGs:

In 2020 the WHO recommended the use in all settings of Xpert® MTB/RIF Ultra as a
replacement for the Xpert® MTB/RIF cartridge.

REFERENCES:

1. Kohli M, Schiller I, Dendukuri N, Yao M, Dheda K, Denkinger CM, Schumacher SG, Steingart KR.
Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin
resistance in adults. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.:
CD012768. DOI: 10.1002/14651858.CD012768.pub3.

2. Dorman SE, Schumacher SG, Alland D, Nabeta P, Armstrong DT, King B, et al. Xpert MTB/RIF
Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective
multicentre diagnostic accuracy study. Lancet Infectious Diseases 2018;18(1):76-84.

3. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3: diagnosis –

rapid diagnostics for tuberculosis detection. Licence: CC BY-NC-SA 3.0 IGO.
Who.int/publications/i/item/who-consolidated-guidelines on-tuberculosis-module-3-diagnosis---
rapid-diagnostics-for tuberculosis-detection 2020.

4. Zhang M, Xue M, and He J. Diagnostic accuracy of the new Xprt MTB/RIF Ultra for tuberculous
disease: a preliminary systematic review and meta analysis. Int J of Infect Dis 2020; 90: 35-45.

5. Chin JH, Musubire AK, Morgan N, Pellinen J, Grossman S, et al. Xpert MTB/RIF Ultra for detection
of Mycobacterium tuberculosis in cerebrospinal fluid. J Clin Microbiol 2019; 57 e00249-19.

6. Bahr NC, Nuwagira E, Evans, EE, Cresswell FV, Bystrom PV, et al. Diagnostic accuracy of Xpert
MTB/RIF Ultra for tuberculosis meningitis in HIV-infected adults: a prospective cohort study. Lancet
Infect Dis 2018; 18:68-75.

7. Perez-Risco D, Rodriguez-Temporal D, Valledor-Sanchez I, and Alcaide F. Evaluation of the Xpert

MTB/RIF Ultra Assay for Direct Detection of Mycobacterium tuberculosis Complex in Smear-
negative extrapulmonary samples. J Clin Microbiol 2018; 56:e00659-18.

8. Sun Q, Wang S, Dong W, Huo F and Ma Y, et al. Diagnostic value of Xpert MTB/RIF Ultra for
osteoarticular tuberculosis. J Infect 2019; 79(2): 153-158.

9. Wu X, Tan G, Gao R, Yao L, Bi D, et al. Assessment of the Xpert MTB/RIF Ultra Assay on rapid
diagnosis of extrapulmonary tuberculosis. Int J Infect Dis 2019; 81: 91-96.

10. Meldau R, Randall P, Pooran A, Limberis J, and Makambwa E, et al. Same-day tools, including
Xpert Ultra and IRISA-TB, for rapid diagnosis of pleural tuberculosis: a prospective observational
study. J Clin Microbiol 2019. 57: e00614-19.

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75
 UPDATE ON TREATMENT OF TUBERCULOSIS

Q10: AMONG ADULTS NEWLY DIAGNOSED WITH RIFAMPICIN-SUSCEPTIBLE

PTB, IS STANDARD 2HRZE/4HR STILL THE RECOMMENDED TREATMENT
REGIMEN TO OPTIMIZE TREATMENT SUCCESS/COMPLETION AND REDUCE
THE RISK OF TREATMENT FAILURE, RELAPSE, AND MORTALITY COMPARED
TO HRZE PLUS FLUOROQUINOLONE?

RECOMMENDATION

a. Among adults newly diagnosed with rifampicin susceptible PTB, 2HRZE/4HR is

still the recommended treatment regimen. (Strong recommendation, high-
quality evidence)

b. The inclusion of fluoroquinolone as part of the primary regimen for rifampicin

susceptible PTB is not recommended. (Strong recommendation, high-quality
evidence)

REMARKS

A member of the guideline panel suggested adding the phrase “as long as subject to
close bacteriological monitoring” to recommendation 10a due to the observed increase in
INH resistance among patients (estimated at 10-15%). Relapse rates have also increased
sharply, matching INH resistance. Monitoring sputum samples (i.e. sputum at 5 months)
was also suggested. Neither the substitution nor addition of fluoroquinolone to the primary
regimen were recommended as they do not offer any additional benefit. Voting: 14/15
agree, 1/15 abstain

SUMMARY OF EVIDENCE

Search strategy used the PubMed and search terms: ("smear negative") OR
("bacteriologically negative") OR ("sputum negative") OR ("sputum smear negative") OR
(smear negative) OR (sputum negative) OR (bacteriologically negative)) AND
("Tuberculosis"[Mesh])) AND (("empiric treatment") OR ("decision to treat") OR (empiric
treatment) OR (decision to treat))

Based on high level of evidence [1,2], fluoroquinolone-containing regimens did not show
superiority over standard 2HRZE/4HR on the following outcomes – treatment failure,
serious adverse events and all-cause death. However, compared with HRZE alone,
moxifloxacin-containing regimens significantly increased sputum conversion for patients
with newly diagnosed PTB.

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A network meta-analysis of 12 randomized controlled trials involving 6,465 newly
diagnosed, sputum positive adult patients was reviewed. [1] The regimens compared
were HRZE, RZE+Moxifloxacin (MRZE), HRZ+Moxifloxacin (HRZM), HRZ+Gatifloxacin
(HRZG), HRZ+Ofloxacin (HRZO), HR+Ciprofloxacin (HRC), HRZE+Moxifloxacin
(HRZEM), and HRZE+Levofloxacin (HRZELo). All studies included reported sputum
conversion by the eighth week using Löwenstein-Jensen solid culture method. HRZEM
(OR 4.96; 95% CI 2.83-8.67), MRZE (OR 1.48; 95% CI 1.19-1.84) and HRZM (OR 1.32;
95% CI 1.08-1.62) had higher sputum conversion rates than the HRZE regimen. HRZM
(OR 1.29; 95% CI 1.04-1.59) and MRZE (OR 1.27; 95% CI 1.07-1.50) regimens also had
higher conversion rates than HRZE using the liquid medium. In contrast, HRC (OR 0.39;
95% CI 0.19-0.77) and HRZO (OR 0.47; 95% CI 0.24-0.92) had lower conversion rates
compared to HRZE.

The meta-analysis did not show significant differences in treatment failure for MRZE (OR
0.72; 95% CI 0.04-14.58), HRZM (OR 0.46; 95% CI 0.06-3.30) and HRZG (OR 0.27; 95%
CI 0.02-3.88). The difference in all-cause mortality by the end of treatment and during the
intensive phase was likewise not statistically significant. The most common adverse
events noted were gastrointestinal, neurological, skin and appendages, cutaneous and
urinary system disorders, but no statistical differences were found among them by the
end of treatment and during the two-month intensive phase: MRZE (OR 0.87, 95% CI
0.60–1.25) and HRZM (OR 0.83, 95% CI 0.55–1.26).[1]

Another meta-analysis including 9 studies examined the effectiveness and safety of

moxifloxacin in addition to the recommended regimen for the treatment of TB. [2] The
results showed that adding moxifloxacin during the first 2 months of drug treatment for
TB increased sputum conversion compared to the recommended regimen alone (OR
1.895; 95% CI 1.355-2.651, p = 0.000). Moreover, the moxifloxacin-containing regimen
reduced TB relapse after treatment (OR 0.516; 95% CI 0.342-0.920, p = 0.022),
suggesting that the introduction of moxifloxacin into the recommended regimen reduced
TB relapse after treatment. No significant difference was noted in terms of adverse events
(OR 1.001; 95% CI 0.855-1.172, p = 0.989).

Appendix Q10 shows the summary of findings table for the results discussed above.

REFERENCES:

1. Li D, Wang T, Shen S, et al. Effects of fluroquinolones in newly diagnosed, sputum-positive

tuberculosis therapy: A systematic review and network meta-analysis. PloS One. 2015;10(12):1-
14. Doi:10.1371/journal.pone.0145066

2. Xu P, Chen H, Xu J, et al. Moxifloxacin is an effective and safe candidate agent for tuberculosis
treatment: a meta-analysis. Int J Infect Dis. 2017;60:35-41. Doi:10.1016/j.ijid.2017.05.003

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 APPENDIX Q10

Table Q10.1 Summary of Certainty of Evidence on Moxifloxacin + recommended regimen compared to recommended regimen for
newly diagnosed TB
Authors: Tan, Carol
Question: Moxifloxacin + recommended regimen compared to recommended regimen for newly diagnosed TB
Setting:
Bibliography: Xu P, Chen H, Xu J, et al. Moxifloxacin is an effective and safe candidate agent for tuberculosis treatment: a meta-analysis. Int J Infect Dis. 2017;60:35-41. Doi:10.1016/j.ijid.2017.05.003
1.
Certainty assessment No. of patients Effect
Moxifloxacin Certaint Importanc
No. of Other Relativ Absolut
Risk of Inconsistenc Indirectnes Imprecisio + Recommende y e
studie Study design consideration e (95% e (95%
bias y s n recommende d regimen
s s CI) CI)
d regimen
Sputum conversion (assessed with: 2 or more consecutive negative sputum cultures detected at the endpoint of treatment)
2 fewer
OR per
not 1.90 1,000
not ⨁⨁⨁⨁ CRITICA
9 78tandardiz trials seriou not serious not serious none (1.35 (from 3
serious HIGH L
s to fewer
2.65) to 1
fewer)
Recurrence of TB (follow up: mean 12 months; assessed with: recurrence during 1 year after treatment was collected)
1 fewer
OR per
not 0.56 1,000
not ⨁⨁⨁⨁
3 78tandardiz trials seriou not serious not serious none (0.34 (from 1
serious HIGH
s to fewer
0.92) to 0
fewer)

CI: Confidence interval; RR: Risk ratio

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Table Q10.2 Summary of evidence of Fluoroquinolones in Newly Diagnosed TB.

Bibliography: Li D, Wang T, Shen S, et al. Effects of fluroquinolones in newly diagnosed, sputum-positive tuberculosis therapy: A systematic review and network meta-analysis. PloS One.
2015;10(12):1-14. Doi:10.1371/journal.pone.0145066

No. of participants Certainty of the evidence

Outcomes Impact
(studies) (GRADE)

HRZEM (OR 4.96; 95% CI 2.83-8.67)

HRZELo (OR 1.85; 95% CI 0.71-4.79)
Week-8 Sputum Negativity MRZE (OR 1.50; 95% CI 1.21-1.86)
Assessed with: Löwenstein-Jensen solid culture method HRZM (OR 1.37; 95% CI 1.13-1.66) (7 RCTs)
⨁⨁⨁⨁
Follow up: range 2 months to 30 months HRC (OR 0.39; 95% CI 0.19-0.77) HIGH
HRZO (OR 0.47; 95% CI 0.24-0.92)
HRZG (OR 1.23; 95% CI 0.97-1.57)
HRZM (OR 1.29; 95% CI 1.04-1.59)
Week 8 Sputum Negativity MRZE (OR 1.27; 95% CI 1.05-1.53)
(4 RCTs)
⨁⨁⨁⨁
Assessed with: Liquid medium HRZG (OR 1.43; 95% CI 0.69-2.95) HIGH
HRZO (OR 0.84; 95% CI 0.39-1.78)
Secondary outcome: Treatment failure by the end of treatment MRZE (OR 0.72; 95% CI 0.04-14.58)
Assessed with: defined as continued or recurrent positive sputum cultures (culture HRZM (OR 0.46; 95% CI 0.06-3.30) (3 RCTs)
⨁⨁⨁⨁
confirmed) and evaluated by the end of treatment HRZG (OR 0.27; 95% CI 0.02-3.88) HIGH
Secondary outcome: Serious adverse events by the end of treatment
MRZE (OR 0.65; 95% CI 0.30-1.44)
Assessed with: grade 3 and higher adverse events including death according to the
HRZM (OR 1.15; 95% CI 0.60-2.19) (3 RCTs)
⨁⨁⨁⨁
modified version of criteria from National Institute of Allergy and Infectious Diseases, HIGH
HRZG (OR 0.91; 95% CI 0.22-3.80)
Division of AIDS
HRZM (OR 0.38; 95%: CI 0.08-1.84)
Secondary outcome: Serious adverse events during intensive phase
HRZO (OR 0.39; 95% CI 0.09-1.58)
Assessed with: grade 3 and higher adverse events including death according to the
HRZELo (OR 0.53; 95% CI 0.14-1.91) (5 RCTs)
⨁⨁⨁⨁
modified version of criteria from National Institute of Allergy and Infectious Diseases, HIGH
MRZE (OR 0.75; 95% CI 0.45-1.25)
Division of AIDS
HRZG (OR 1.42; 95% CI 0.59-3.44)
HRZG (OR 0.32; 95% CI 0.02-4.36)
Death from all cause by the end of treatment HRZM (OR 1.01; 95% CI 0.34-3.04) (3 RCTs)
⨁⨁⨁⨁
MRZE (OR 1.19; 95% CI 0.24-6.05) HIGH
HRZO (OR 0.19; 95% CI 0.01-4.03)
HRZELo (OR 0.58; 95% CI 0.07-4.53)
Death from all cause during intensive phase HRZM (OR 0.61; 95% CI 0.03-13.15) (5 RCTs)
⨁⨁⨁⨁
MRZE (OR 0.80; 95% CI 0.35-132.49) HIGH
HRZG (OR 0.98; 95% CI 0.10-9.50)
New outcome (0 studies) -
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: network odds ratio

GRADE Working Group grades of evidence

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

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 UPDATE ON SUSPECTED OR CONFIRMED MDR TUBERCULOSIS

Q11: AMONG ADULTS WHO NEED RETREATMENT FOR TUBERCULOSIS WITH

KNOWN SUSCEPTIBILITY TO RIFAMPICIN BY XPERT® TESTING, IS THE
STANDARD 2HRZE/4HR THE RECOMMENDED REGIMEN TO OPTIMIZE
TREATMENT SUCCESS/ COMPLETION AND REDUCE RISK FOR TREATMENT
FAILURE, RELAPSE AND MORTALITY COMPARED TO 2HRZES/1HRZE/5HRE OR
IMMEDIATE REFERRAL TO PROGRAMMATIC MANAGEMENT OF DRUG-
RESISTANT TB (PMDT)?

RECOMMENDATION

b. In patients who require TB retreatment with confirmed rifampicin susceptibility by

rapid DST, the Category II regimen should no longer be prescribed. (WHO 2017
Good practice statement)

c. On the basis of the availability of rapid DST to RIF, the standard first-line
treatment regimen (2HRZE/4HR) is recommended. Revisions in the drug
regimen should be made based on the results of the full DST. If RR is present,
referral to a facility specialized in the care of drug-resistant TB should be made.
(Good practice statement)

d. This statement supersedes the previous 2016 CPG recommendation on

Category II treatment regimen for retreatment cases.

REMARKS

We provide an update to the recommendation in the 2016 version of this guideline

regarding the preferred treatment regimen for re-treatment cases. Rapid DST for drugs
other than RIF should be done to inform the choice of the treatment regimen. However,
rapid DST may not always be available in health facilities. In such cases, physicians are
suggested to start Category I empiric treatment regimen while awaiting results of a rapid
and/or full DST.
Voting: 15/15 agree, 2 rounds

SUMMARY OF EVIDENCE

There were no RCTs comparing HRZE vs. HRZES or immediate referral to PMDT for
retreatment cases. The 2017 WHO Guidelines for treatment of DST and patient care [1]
was adapted to answer this clinical question. The guideline was appraised using the
AGREE tool and obtained an overall quality rating of 6/7.

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The good practice statement from the 2017 WHO Guidelines was based on a systematic
review of 20 studies on clinical outcomes of the WHO Category II empiric treatment
regimen. The median treatment success rate was 68%, which was below the WHO target
of 85%. The use of streptomycin (STM) further increased adverse events (e.g. ototoxicity,
nephrotoxicity). The addition of a single drug to a previously ineffective regimen (e.g.,
HRZE) also did not improve treatment success rate. A GRADE recommendation could
not be formulated based on evidence; thus, the WHO guideline development group
(GDG) drafted a good practice statement instead.

The results of a More recent systematic review by Cohen et al.[2] support the WHO
recommendation above. This review evaluated the clinical outcomes of a TB retreatment
regimen for both microbiologically confirmed and unconfirmed cases. There were 39
studies, which were mostly (33/39) retrospective cohorts. Majority were performed in Asia
(predominantly in India) and Africa. Significant heterogeneity was noted between studies
(I2 =0.95), which precluded calculation of a pooled estimate. Treatment success rates
ranged from 27% to 92%. Only 2/39 (5%) studies met the WHO target of 85% treatment
success. The treatment success rate was <75% in 29 (74%) studies, and <50% in 4
studies (Appendix Q11.1). The low rates of treatment success in the majority of the
studies do not favor the Category II regimen.

In 2005, Saravia et al did a comparative retrospective cohort of Category I failures in

Lima, Peru. [3] Patients received either one of two regimens: Strategy A was a Category
II regimen; if that regimen failed, an 18-month standardized regimen including second-
line drugs was used. Strategy B was a pilot protocol that included DST and empiric
treatment regimen (ETR) for MDR-TB. If DST results showed resistance to only INH and
RIF, the ETR was continued unchanged. If DST results showed resistance to other drugs,
the patient received an individualized treatment regimen (ITR) tailored to the susceptibility
profile of the infecting strain. Strategy B was 3x more likely than Strategy A to cure
patients (79% vs. 38%; RR 2.9; 95% CI 1.7-5.1). Strategy B was 5x more likely to cure
patients than the Category II regimen alone (79% vs. 15%; RR 5.2; 95%CI 3.0-9.2).

In the Philippine setting, a retrospective cohort analysis of PTB patients from two data
sets from the National Drug Resistance Survey and the PMDT was done by Lew et al. [4]
This analysis looked at outcomes of Category I and II regimens in mono- and poly-
resistant tuberculosis cases in the Philippines and linked drug resistance patterns with
treatment outcomes. Among 138 Category II patients, 92 were INH-resistant (66.7%), 9
were either EMB- or STM-resistant, and 37 were poly-resistant. The Category II regimen
produced poor outcomes: 59.4% (95% CI 49.2-68.9) treatment success in mono-resistant
and 40.5% (95% CI 25.2-57.8) treatment success in poly-resistant cases (Appendix
Q11.2).

Recommendations from the 6th MOP:

The DOH-NTP 6th MOP recommends the following regimens for drug-susceptible and
drug-resistant PTB or EPTB (Table 11.1). A TB MAC shall be established per region to
provide clinical expertise and guidance on the diagnosis of clinically diagnosed DRTB

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and management of difficult DSTB and DRTB cases. All regions have been trained on all
oral MDRTB regimens and are currently transitioning to programmatic implementation in
treatment centers, satellite treatment centers, and health centers implementing i-DOTS
(integrated delivery of TB services) for both DS and DRTB using patient-centered care.

Table Q11.1 NTP 6th MOP Treatment Regimens for Drug-Susceptible and Drug-
Resistant TB

Regimen Name Regimen

Regimen 1: New or Retreatment 2HRZE/4HR

PTB or EPTB (except CNS, bones, joints) with MTB/Rif sensitive

or intermediate results on Xpert; smear-positive; TB LAMP
positive; or clinically diagnosed (MTB not detected, or
bacteriologic testing not done)

Regimen 2: New or Retreatment 2HRZE/10HR

EPTB of CNS, bones, joints with MTB/Rif sensitive or

intermediate results on Xpert; smear-positive; TB LAMP
positive; or clinically diagnosed (MTB not detected, or
bacteriologic testing not done)

Regimen 3: Standard Short All Oral Regimen (SSOR) 4-6 months of Lfx-Bdq(6)-Cfz-Pto-
Z-E-Hhd; 5 months of Lfx-Cfz-Z-E

Regimen 4: Standard Long All Oral Regimen for FQ Susceptible 6 months of Lfx-Bdq-Lzd-Cfz
(SLOR FQ-S) 12-14 months of Lfx-Lzd-Cfz
Regimen 5: Standard Long All Oral Regimen for FQ Resistant 6 months of Bdq-Lzd-Cfz-Cs-Dlm;
(SLOR FQ-R) 12-14 months of Lzd-Cfz-Cs

Individualized Treatment Regimen (ITR) Construct to have at least 4-

5 likely effective drugs
LEGEND: Amikacin (Am), Bedaquiline (Bdq), Clofazimine (Cfz), Cycloserine (Cs), Delamanid (Dlm), Ethambutol I, Imipenem-
cilastatin (Imp-cln), Isoniazid (H), Isoniazid high dose (Hhd)Levofloxacin (Lfx), Linezolid (Lzd), Meropenem (Mpm), Moxifloxacin
(Mfx), p-aminosalicylic acid (PAS), Prothionamide (Pto), Pyrazinamide (Z), RifampicI(R), Streptomycin (S),

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REFERENCES

1. Geneva: World Health Organization; 2017. Guidelines for Treatment of Drug-Susceptible

Tuberculosis and Patient Care 2017 Update. Vol 1. 2017th ed. Geneva: World Health
Organization; 2017. doi:10.1586/17476348.1.1.85

2. Cohen DB, Meghji J, Squire SB. A systematic review of clinical outcomes on the WHO Category II
retreatment regimen for tuberculosis. Int J Tuberc Lung Dis. 2018;22(10):1127-1134.
doi:10.5588/ijtld.17.0705

3. Saravia JC, Appleton SC, Rich ML, Sarria M, Bayona J, Becerra MC. Retreatment management
strategies when first-line tuberculosis therapy fails. Int J Tuberc Lung Dis. 2005;9(4):421-429.

4. Lew WJ, Harrington K, Garfin C, Islam T, Hiatt T, Nishikiori N. Outcomes of Category I and II regimens
in mono-and polyresistant tuberculosis cases in the Philippines. Int J Tuberc Lung Dis.
2016;20(2):170-176. doi:10.5588/ijtld.15.0292

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 APPENDICES Q11.1 [2]
Table Q11.2 Studies describing Outcomes of TB Retreatment Regimen

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 Appendix Q11.2 [4]

Table Q11.3 Treatment outcomes among Monoresistant, polyresistant and Combined

Resistance Patients treated with Category 1 or Category II regimens

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Q12: AMONG PERSONS WITH MULTI-DRUG RESISTANT (MDR TB) OR RIFAMPICIN
RESISTANT-TB (RR TB), IS THE STANDARD SHORTENED TREATMENT REGIMEN
AS EFFECTIVE AS THE WHO CONVENTIONAL MULTI-DRUG, OR RR REGIMENS?

DRAFT RECOMMENDATION

A shortened regimen of moxifloxacin, clofazimine, ethambutol and pyrazinamide in 40

weeks supplemented by kanamycin, isoniazid and prothionamide in the first 16 weeks
among MDR or RR TB may be recommended (Conditional recommendation,
moderate-quality evidence) Oral bedaquiline-containing regimen of 9–12 months
duration is recommended in eligible patients with confirmed MDR/RR-TB who have not
been exposed to treatment with second-line TB medicines used in this regimen for more
than 1 month, and in whom resistance to fluoroquinolones has been excluded.
(Conditional recommendation, very low certainty in the evidence)

REMARKS

The guideline panel decided to wait for the results of other ongoing trials before making
any recommendation. There are now newer studies showing adverse effects for certain
drugs (e.g. kanamycin, capreomycin).

The Panel recommends that all patients with RR TB or MDR TB be referred to the nearest
MDRTB clinic for initiation of appropriate MDR TB regimen. (Best practice statement)

If the clinician so desires, he/she can present the patient’s case to the National or
Regional TB MAC whenever applicable during their regular meetings. (Best practice
statement)

Please refer to Annex X for the complete directory and process of referral to the Regional
TB MAC in the country.

SUMMARY OF EVIDENCE

After a systematic search of two databases (e.g., MEDLINE and ClinicalTrial.gov), only
one randomized clinical trial was found comparing the efficacy of a shortened regimen
compared to the standard long regimen among MDR TB patients.[1] The STREAM
(Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR TB) trial
was an open-label, randomized, multi-center international parallel non-inferiority trial
involving 424 adults with RR PTB. The trial evaluated the effectiveness of a 40-week
regimen over an 80-week regimen as prescribed by the 2011 WHO guideline. The short
regimen included moxifloxacin (high dose), clofazimine, ethambutol, and pyrazinamide
administered over a 40-week period, supplemented by kanamycin (injectable), isoniazid,

CPG Adult TB - 12/1/23 3:12 PM

86
and prothionamide in the first 16 weeks, while the long regimen was the WHO-approved
MDR TB regimen. [1]

Results showed that a short regimen of 9-11 months did not significantly differ from a long
duration regiment of 20-24 months in terms of the following out–mes -- favorable status
(RR 1.01; 95% CI 0.91-1.13), mortality (RR 1.31; 95% CI 0.62-2.74), and serious adverse
events (RR 0.85; 95% CI 0.65-1.10). Favorable status was defined as negative cultures
for M. tuberculosis at 132 weeks, with no intervening positive culture or previous
unfavorable response. An unfavorable outcome was defined by the initiation of two or
more drug therapies that were not included in the assigned regimen, treatment extension
beyond the permitted duration, death from any cause, a positive culture from one of the
two most recent specimens, or no visit at 76 weeks or later. The study, however, excluded
patients with previous exposure to fluoroquinolones and second-line agents, known
resistance to fluoroquinolones, and pregnant and breastfeeding individuals.

Khan et al. assessed the effectiveness and safety of shortened MDR TB regimens using
individual patient data and aggregate meta-analysis.[2] They included five prospective
observational studies (3 published, 2 unpublished) which included 796 MDR TB patients.
Out of 796 patients, 669 were successfully treated with a pooled success rate of 83%
(95% CI 71.9-90.3). However, 4 out of 5 of the studies did not include the patients who
had previous exposure to second-line agents.

The updated WHO 2020 consolidated guidelines on MDR TB recommends that a shorter
all-oral bedaquiline-containing regimen of 9–12 months duration is recommended in
eligible patients with confirmed MDR/RR-TB who have not been exposed to treatment
with second-line TB medicines used in this regimen for more than 1 month, and in whom
resistance to fluoroquinolones has been excluded. [3] The WHO also does not
recommend giving the short-course treatment to children as well as pregnant and
breastfeeding women as these patients were not included in the STREAM trial.

The American Thoracic Society guideline has not made a recommendation either for or
against the standardized shorter-course regimen compared with the longer individualized
regimens, but instead recommends trials using regimens that include the novel oral
agents and exclude the injectables. [4]

Since the publication of this first clinical trial on MDR TB, the WHO MDR TB guideline
has changed to recommending an all-oral regimen based on observational studies.
Several clinical trials on all oral regimens are underway.

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REFERENCES:

1. Nunn A et al. A shorter regimen for rifampin-resistant tuberculosis. New England Journal of
Medicine. 2019;381(11):e22.
2. Ahmad Khan F, Salim M, du Cros P, Casas E, Khamraev A, Sikhondze W et al. Effectiveness
and safe88tandardizedrdised shorter regimens for multidrug-resistant tuberculosis:
individual patient data and aggregate data meta-analyses. European Respiratory Journal.
2017;50(1):1700061.
3. WHO consolidated guidelines on tuberculosis. Module 4: trea–ment - drug-resistant
tuberculosis treatment. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA
3.0 IGO.
4. Nahid P, Mase S, Migliori G, Sotgiu G, Bothamley G, Brozek J et al. Treatment of Drug-Resistant
Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. American Journal of
Respiratory and Critical Care Medicine. 2019;200(10):e93-e142.

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Table Q12.1 Summary of Evidence on Shortened Regimen compared to Long Duration for Multiple-Drug Resistant TB
Author(s): Ian Theodore Cabaluna
Question: Shortened Regimen compared to Long Duration for Multiple-Drug Resistant TB
Setting: Ethiopia, Mongolia, South Africa and Vietnam
Bibliography: Nunn A et al. A Shorter Regimen for Rifampin-Resistant Tuberculosis. New England Journal of Medicine. 2019;381(11):e22.
Certainty assessment № of patients Effect

Risk Certainty Importance

№ of Study Other Shortened Long Relative Absolute
of Inconsistency Indirectness Imprecision
studies design considerations Regimen Duration (95% CI) (95% CI)
bias

Favorable status (defined as cultures negative for M. tuberculosis at 132 weeks, with no intervening positive culture or previous unfavorable response which include by
initiation of two or more drug therapies that were not included in the assigned regimen, treatment extension beyond the permitted duration, death from any cause, a
positive culture from one of the two most recent specimens, or no visit at 76 weeks or later
8 more per
RR 1.01
1
randomised not
not serious not serious not serious none
99/124 193/245
(0.91 to
1,000 ⨁⨁⨁⨁
trial serious (79.8%) (78.8%) (from 71 fewer to HIGH
1.13)
102 more)
Time to an unfavorable outcome (follow up: 132)
253 HR 1.06 -- per 1,000
participants (0.65 to –rom -- to --)
1
randomised not
not serious not serious serious a none
1.72) ⨁⨁⨁◯
trial serious [Time to an -- per 1,000 MODERATE
- 0.0% unfavorable –rom -- to --)
outcome]
All-cause mortality (follow up: 132 weeks)
20 more per
RR 1.31
1
randomised not
not serious not serious serious a none
24/282 9/141
(0.62 to
1,000 ⨁⨁⨁◯
trial serious (8.5%) (6.4%) (from 24 fewer to MODERATE
2.74)
111 more)
Time to death (follow up: 132 weeks)
HR 1.38 -- per 1,000
(0.64 to –rom -- to --)
1
randomised not
not serious not serious serious a
none 2.96)
⨁⨁⨁◯
trial serious -- per 1,000 MODERATE
- 0.0% [Time to
death] –rom -- to --)

Serious Adverse Event (follow up: 132 weeks)

46 fewer per
RR 0.85
1
randomised not
not serious not serious serious a
none
91/282 53/141
(0.65 to
1,000 ⨁⨁⨁◯
trials serious (32.3%) (37.6%) (from 112 fewer MODERATE
1.10)
to 29 more)
CI: Confidence interval; RR: Risk ratio; HR: Hazard Ratio
Explanations
a. Wide confidence interval

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 UPDATES ON MANAGEMENT OF LATENT TUBERCULOSIS

Q13: SHOULD NON-HIV ADULT HOUSEHOLD/CLOSE CONTACTS OF ACTIVE TB

CASES (REGARDLESS OF BACTERIOLOGIC STATUS) WITH NO ACTIVE DISEASE
UNDERGO THE INTERFERON GAMMA RELEASE ASSAY (IGRA) OR TUBERCULIN
SKIN TEST (TST) TO IDENTIFY LATENT TB INFECTION (LTBI)? IS IGRA MORE
ACCURATE THAN STANDARD TST?

RECOMMENDATION

a. Children aged ≥ 5 years, adolescents and adults who are household contacts
of people with bacteriologically confirmed PTB who are found not to have active
TB by an appropriate clinical evaluation or according to national guidelines may
be given TB preventive treatment. (Conditional recommendation, low
certainty in the estimates of effect)

b. Either a tuberculin skin test (TST) or an interferon-gamma release assay

(IGRA) may be used to screen for latent tuberculosis infection (LTBI) among non-
HIV close contacts of patients with active TB. Cost, availability, and the need for
other resources have to be considered when deciding which test to use. (Weak
recommendation, very low-quality evidence).

REMARKS

In the 2016 version of this CPG, IGRA was recommended prior to the treatment of LTBI
among those starting biological agents. Other risk groups who could potentially benefit
from IGRA could not be answered in this question.
Voting: 14/14 agree

The 6th NTP MOP recommends that TST or IGRA shall not be required prior to initiation
of preventive treatment in the following eligible individuals: (a) Persons living with HIV
(PLHIV); (b) Children less than 5 years old who are household contacts of
bacteriologically confirmed PTB; and (c) Individuals aged 5 years and older who are
household contacts of bacteriologically confirmed PTB with other TB risk factors.

SUMMARY OF EVIDENCE

We reviewed the literature for evidence on the utility of IGRA and TST in predicting
progression to active TB among non-HIV close contacts of active TB cases.

We searched MEDLINE since inception, with no language restrictions, for articles on

diagnostic accuracy/predictive utility using the following search terms: “latent
tuberculosis”[MESH]; “tuberculin test”[MESH] OR “tuberculin skin test” OR Mantoux test;

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“interferon-gamma release tests”[MESH] OR “QuantiFERON-TB” OR “T.SPOT.” We
identified, retrieved, and reviewed several relevant systematic reviews [1-4], then
manually searched their reference lists for relevant studies. We also reviewed the
evidence profile of the latest WHO guidelines on LTBI. [5]

Based on very low-quality evidence, IGRA and TST can accurately identify non-HIV close
contacts of active TB cases that may progress to active TB.

Several prospective cohort studies assessed the accuracy of IGRAs and TST in
identifying non-HIV close contacts of active TB cases that may progress to active TB
within 2 years and would therefore be candidates for chemoprophylaxis. Most of the
studies were done in low-burden, high to middle-income countries, and included adult
and pediatric close household contacts of identified active TB patients or immigrants from
high-burden countries (Table Q13.1). Index tests included IGRAs (QuantiFERON Gold
TB, T-SPOT.TB, ELISPOT, and ESAT-6), and TST with different cutoff values (5mm,
10mm, 15mm). In all the studies, progression to active TB was considered the marker of
LTBI. Determination of active TB varied across studies, with some requiring confirmation
by culture, and others utilizing clinical criteria that included radiographic and
histopathologic evidence of TB and treatment response as determined by a physician.

Table Q13.1. Characteristics of Included Studies

Study Country Study Population Index Tests

Abubakar 2018 UK contacts or migrants from high burden QFT, T-SPOT.TB, TST
Diel 2008 Germany immunocompetent close contacts QFT, TST
Harstad 2010 Norway recent migrants, asylum seekers QFT, TST
Kik 2010 Netherlands immigrants who are close contacts QFT, T-SPOT.TB, TST
Yoshiyama 2010 Japan household or work contacts QFT
Yoshiyama 2015 Japan household or work contacts QFT
Sharma 2017 India close household contacts QFT, TST
Hill 2008 Gambia household contacts ELISPOT
Doherty 2002 Ethiopia household contacts in-house ELISA

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 Figure Q13.1. Forest Plot of Sensitivity and Specificity of IGRAs

Figure Q13.2. Forest Plot of Sensitivity and Specificity of Tuberculin Skin Test

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Tuberculin Skin Test (TST)

A total of 6 studies [6-11] investigated the accuracy of TST in predicting progression to

active TB among patients with LTBI: 3 for TST > 5mm, 4 for TST > 10mm, and 3 for TST
> 15mm. Sensitivity ranged from 0.33 (95% CI 0.07-0.70) to 1.00 (95% CI 0.54-1.00),
while specificity ranged from 0.15 (95% CI 0.12-0.20) to 0.85 (95% CI 0.83-0.88). The
sensitivity and the specificity estimates for each study are shown in Table Q13.2. Due to
the significant variability across studies, estimates of sensitivity and specificity were not
pooled.

Comparison of IGRA and TST

There are significant overlaps in the confidence intervals of the sensitivity of IGRA and
TST in all of the studies. Some studies showed a better specificity for IGRA compared to
TST, but the differences were marginal. [6-7,10] There was no substantive advantage of
one test over the other in terms of identifying patients with LTBI who would progress to
active TB. Hence, other considerations such as cost and availability may determine the
choice of screening test LTBI for non-HIV close contacts of patients with active TB.

Table Q13.2. Side-by-Side Comparison of Sensitivity and Specificity of Index Tests

IGRA TST
Study Index Test
Sn/Sp (95% CI) Sn/Sp (95% CI)
Sn 0.61 (0.49 to 0.72) 0.83 (0.73, 0.91)
QFT 5mm
Sp 0.78 (0.77 to 0.79) 0.54 (0.53, 0.55)
Sn 0.68 (0.56 to 0.78) 0.75 (0.64 to 0.84)
Abubakar 2018 10 mm
Sp 0.81 (0.80 to 0.82) 0.67 (0.66 to 0.68)
T-SPOT
Sn 0.68 (0.56 to 0.78)
15 mm
Sp 0.77 (0.83 to 0.88)
Sn 0.94 (0.52 to 1.00) 0.83 (0.36 to 1.00)
Diel 2008 QFT 5 mm
Sp 0.71 (0.68 to 0.75) 0.62 (0.58 to 0.66)
Sn 0.89 (0.52 to 1.00) 1.00 (0.54 to 1.00)
5 mm
Sp 0.71 (0.68 to 0.75) 0.65 (0.55 to 0.75)
Harstad 2010 QFT
Sn 0.33 (0.07 to 0.70)
15 mm
Sp 0.85 (0.83 to 0.88)
Sn 0.52 (0.30 to 0.74) 0.56 (0.35 to 0.76)
Hill 2008 ELISA 10 mm
Sp 0.63 (0.60 to 0.65) 0.62 (0.60 to 0.64)
Sn 0.63 (0.24 to 0.91) 0.90 (0.55 to 1.00)
QFT 10 mm
Sp 0.46 (0.40 to 0.51) 0.15 (0.12 to 0.20)
Kik 2010
Sn 0.75 (0.35 to 0.97) 0.88 (0.47 to 1.00)
T-SPOT 15 mm
Sp 0.40 (0.34 to 0.46) 0.44 (0.38 to 0.49)
Sn 0.75 (0.63 to 0.84) 0.55 (0.43 to 0.67)
Sharma 2017 QFT 10 mm
Sp 0.39 (0.37 to 0.42) 0.52 (0.49 to 0.55)

Recommendations of Other Guidelines:

• Philippine TB Guidelines 2016 [15]: TST is the preferred screening test for LTBI
in a resource-limited setting like the Philippines. (Strong recommendation, low
quality evidence)

2018 WHO LTBI Guidelines [5]: Either TST or IGRA can be used to test for
LTBI. (Strong recommendation, very low quality evidence)

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 • 2020 WHO Consolidated Guidelines On Tuberculosis: Tuberculosis Preventive
Treatment [16]: Either a TST or IGRA can be used to test for LTBI. (Strong
recommendation, very low certainty in the estimates of effect)

REFERENCES:

1. Auguste P, Madan J, Tsertsvadze A, Court R, McCarthy N, Sutcliffe P, et al. Identifying latent

tuberculosis in high-risk populations: systematic review and meta-analysis of test accuracy. Int J
Tuberc Lung Dis. 2019 Nov 1;23(11):1178-1190. doi: 10.5588/ijtld.18.0743.

2. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K,
Wilkinson RJ, Pai M.Predictive value of interferon-γ release assays for incident active tuberculosis:
a systematic review and meta-analysis. Lancet Infect Dis. 2012 Jan;12(1):45-55. doi:
10.1016/S1473-3099(11)70210-9. Epub 2011 Aug 16.

3. Greenaway C, Pareek M, Abou Chakra CN, Walji M, Makarenko I,Alabdulkarim B, et al. The
effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the
EU/EEA: a systematic review. Euro Surveill. 2018 Apr;23(14). doi: 10.2807/1560
7917.ES.2018.23.14.17-00543.

4. Diel R, Goletti D, Ferrara G, Bothamley G, Cirillo D, Kampmann B, et al. Interferon-γ release assays
for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-
analysis. Eur Respir J. 2011 Jan;37(1):88-99. doi: 10.1183/09031936.00115110. Epub 2010 Oct
28.

5. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management.
Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.

6. Abubakar I, Drobniewsky F, Southern J, Sitch AJ, Jackson C, Lipman M, et al. Prognostic value of
interferon- γ release assays and tuberculin skin test in predicting the development of active
tuberculosis (UK PREDICT TB): a prospective cohort study. Lancet Infect Dis 2018;18:1077-87.
doi: 10.1016/s1473-3099(18)30355-4.

7. Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, and Nienhaus A. Predictive value of a

whole blood IFN-gamma assay for the development of active tuberculosis disease after recent
infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med 2008;177:1164-1170.

8. Harstad, I., Heldal, E., Steinshamn, S. L., Garåsen, H., Winje, B. A., & Jacobsen, G. W. Screening
and treatment of latent tuberculosis in a cohort of asylum seekers in Norway. Scandinavian Journal
of Public Health, 2009;38(3), 275–282. doi:10.1177/1403494809353823.

9. Hill PC, Jackson-Sillah DJ, Fox A, Brookes RH, de Jong BC, et al. Incidence of tuberculosis and
the predictive value of ELISPOT and Mantoux tests in Gambian case contacts. PLoS ONE
2008;3(1): e1379. doi:10.1371/journal.pone.0001379.

10. Kik SV, Franken WPJ, Mensen M, Cobelens FGJ, Kamphorst M, Arend SM, et al. Predictive value
for progression to tuberculosis by IGRA and TST in immigrant contacts. Eur Respir J 2010; 35:
1346–1353 DOI: 10.1183/09031936.00098509.

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11. Sharma SK, Vashishtha R, Chauhan LS, Sreenivas V, Seth D. Comparison of TST and IGRA in
Diagnosis of Latent Tuberculosis Infection in a High TB-Burden Setting. PLoS ONE 2017;12(1):
e0169539. doi:10.1371/journal.pone.0169539.

12. Yoshiyama T, Harada N, Higuchi K, Sekiya Y, Uchimura K. Use of the QuantiFERON-TBGold test
for screening tuberculosis contacts and predicting active disease. Int J Tuberc Lung Dis
2010;14(7):819-827.

®
13. Yoshiyama T, Harada N, Higuchi K, Saitou M, Kato S. Use of the QuantiFERON -TB Gold in Tube
test for screening TB contacts and predictive value for active TB. Infectious Diseases 2015;47:8,
542-549. doi: 10.3109/23744235.2015.1026935.

14. Doherty TM, Abebech D, Olobo J, Wolday D, Britton S, Eguale T, et al. Immune responses to the
Mycobacterium tuberculosis-Specific Antigen ESAT-6 signal subclinical infection among contacts
of tuberculosis patients. Journal of Clinical Microbiology, Feb. 2002;40(2):704-706. doi:
10.1128/JCM.40.2.704-706.2002.

15. Task Force: Clinical Practice Guidelines for the Diagnosis, Treatment, Prevention and Control of
Tuberculosis in Adult Filipinos: 2016 Update (CPGTB2016). Philippine Coalition Against
Tuberculosis (PhilCAT), Philippine Society for Microbiology and Infectious Diseases (PSMID),
Philippine College of Chest Physicians (PCCP).
16. WHO consolidated guidelines on tuberculosis: tuberculosis preventive treatment. Geneva: World
Health Organization; 2020.

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 APPENDIX Q13

Table Q13.3 Summary of Certainty of Evidence: Interferon Gamma Release Assay (IGRA) Or Tuberculin
Skin Test (TST) for Latent Tuberculosis
Factors that may decrease certainty of evidence Test
№ of studies
Study design accuracy
(№ of patients)
Risk of bias Indirectness Inconsistency Imprecision Publication bias CoE

Observational
11 studies study
13,323 patients (Prospective
serious a serious b serious c not serious none d ⨁◯◯◯
cohort) VERY LOW

a. Not all confounders controlled for; Lack of independence between index test and confirmatory test (i.e. confirmation of incident
active TB); Some studies used clinical criteria rather than microbiologic confirmation for diagnosis of TB
b. Some studies included children; some studies included both immigrants from high burden settings, not just those who are close
contacts of persons with active TB
c. Study settings varied according to disease burden
d. There are ongoing longitudinal studies, specifically for IGRAs.

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Q14: WILL TREATMENT OF LATENT TB INFECTION (LTBI) OF NON-HIV ADULTS
DIAGNOSED TO HAVE LTBI, USING ANY OF 9H, 6H, 3-4HR, 4R OR 12 DOSES
WEEKLY INH-RIFAPENTINE (RFP) VS. NO TREATMENT BE SAFE AND
EFFECTIVE IN REDUCING THE RISK OF CONVERSION OF LTBI TO ACTIVE TB?

RECOMMENDATIONS

a. Among non-HIV adults diagnosed to have LTBI, INH given once daily for 6
months is recommended for the treatment of latent TB infection among non-HIV
adult patients. (Strong recommendation, moderate quality of evidence)

b. RIF given once daily for 4 months or RIF+INH given once daily for 3 to 4 months
may be considered as alternative treatments for latent TB infection.
(Conditional recommendation, low to moderate quality of evidence)

c. Directly observed therapy with RFP + INH 12 doses weekly may also be
considered. (Conditional recommendation, low quality of evidence)

REMARKS

Outcomes were expanded to include safety and not just the conversion of LTBI to active
TB. It is important to note that these recommendations are based on the available
evidence regarding hepatotoxicity, completion rates, and efficacy—drug resistance was
not included.
Voting: 14/14 agree

The 6th MOP recommends the following treatment regimens for LTBI:

Table Q14.1 Treatment Recommendations of the 6th MOP for LTBI

TB Preventive Indications
Treatment Regimen
(TPT)
6H (Isoniazid daily) Currently available under the program
3HP (Isoniazid, Weekly dosing for 3 months
Rifapentine weekly) Contraindicated in pregnant and <2 years old
3HR (Isoniazid, Preferred for children if 3HP not available
Rifampicin daily)
4R (Rifampicin daily) Preferred for adults if 3HP not available

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SUMMARY OF EVIDENCE

We searched MEDLINE since inception, with no language restrictions, for articles on the
effectiveness and safety of treatments for LTBI using the following search terms: “Latent
Tuberculosis”[MESH] OR “latent tuberculosis”; “Isoniazid”[MESH] OR isoniazid;
“Rifampin”[MESH] OR (“rifapentine”[Supplementary concept] OR rifapentine) OR
“rifamycins”[MESH]; randomized controlled trial [pt], meta analysis [pt]. To identify
additional articles for safety, we added (“Hepatitis”[MESH] OR “Chemical and Drug
Induced Liver Injury”[MESH]) to our search. We retrieved relevant meta-analyses and
systematic reviews and checked their reference lists for other potentially relevant articles.
We also reviewed the evidence tables and references of the 2018 WHO guidelines on
LTBI. [1]

Efficacy
Based on low to moderate quality of evidence, INH monotherapy given for 6 months, RIF
monotherapy given for 4 months, combination INH + RIF given for 3 to 4 months, and
combination INH and RFP 12 doses given weekly are effective in preventing active TB
among non-HIV patients with LTBI when compared with placebo.

In a meta-analysis of 11 randomized controlled trials including 73,375 participants, INH

given for 6 months, or 12 months reduced the risk of progression to active TB by 60%
(RR 0.40; 95% CI 0.31;0.52) over two years or longer when compared to placebo. [2] Two
studies including 14,145 participants showed that INH given for 6 months is effective (RR
0.44; 95% CI 0.27;0.73) in preventing active TB. [2] This is consistent with the findings of
two network meta-analyses that assessed the comparative effectiveness of treatments
for LTBI [3, 4].

No studies directly compared the other treatment regimens with placebo or no treatment.
Indirect comparisons of the different LTBI treatments with placebo were reported in two
network meta-analyses. [3, 4] Zenner et al. [4] included a total of 61 randomized controlled
trials, while Pease et al. [3] included 30 trials in which patients had confirmed LTBI and
reported rate ratios to account for differences in follow-up across studies. In addition,
Pease et al. [3] also compared completion rates across the different LTBI treatments.
Despite these differences, findings on efficacy were consistent between the 2 network
meta-analyses.

The overall quality of the included studies in both network meta-analyses was rated low
to moderate. Risk of bias was rated down due to unclear allocation concealment and
blinding in most trials. Both meta-analyses also included studies on children, patients with
HIV, and countries with both low and high TB burden.

Table Q14.1 shows the odds ratios of the different treatments for LTBI compared to no
treatment. [4] INH monotherapy, RIF monotherapy or in combination with INH, and
INH/RFP combination therapy were shown to be effective in preventing active TB. The
data suggest that RIF or RFP-containing treatments may be more effective than INH

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monotherapy, but strong conclusions cannot be made because the confidence intervals
across all treatments overlapped significantly.

Table Q14.2. Efficacy in terms of prevention of TB vs. no treatment

(Zenner et al., 2017)

Total number of Prevention of active TB

Treatment
participants OR (95% CrI)
INH 6 months 18,084 0.40 (0.26 to 0.60)
INH 9 months 6,350 0.46 (0.22 to 0.95)
INH/RPT 12 doses weekly 4,726 0.36 (0.18 to 0.73)
INH/RIF 3 to 4 months 1,833 0.33 (0.20 to 0.54)
RIF 4 months 1,068 0.25 (0.11 to 0.57)
Note: INH, isoniazid; RPT, rifapentine; RIF, rifampicin; CrI, credible intervals

Pease et al. [3] also compared treatment completion, defined as 80% to 100% medication
consumption, across the different LTBI treatments (Figure 1). [3] The results showed that
a 3- to 4-month course of treatment was 3 to 4 times more likely to be completed than a
12-month course of placebo (Table Q14.2).

Table Q14.3. Efficacy in terms of treatment completion vs. placebo 12 months

(Pease et al., 2017)

Treatment completion
Treatment Total # of Participants
OR (95% CrI)
INH 6 months 8,837 1.49 (0.73 to 2.89)
INH 9 months 4,323 1.64 (0.57 to 4.45)
INH/RMP 3 to 4 months 1,103 3.14 (1.43 to 6.77)
INH/RPT 12 doses weekly 4,520 3.58 (1.40 to 8.83)
RIF 3 to 4 months 476 3.95 (1.15 to 13.72)
Note: INH, isoniazid; RPT, rifapentine; RIF, rifampicin; CrI, credible intervals

Safety

Based on moderate quality of evidence, preventive treatment with INH increases the risk
for hepatotoxicity compared to placebo. The risk for hepatotoxicity was lower for RIF
monotherapy compared to INH monotherapy. There is limited data on the safety of the
other treatment regimens compared to placebo.

One large study including 10,874 participants from Eastern Europe showed that the risk
for hepatotoxicity in patients receiving INH was 5.5 times higher than those receiving
placebo (RR 5.54; 95% CI 2.56;12.00). [2] However, absolute event rates were low—only
7 out of 6,990 participants (0.1%) who received INH and 77 out of 3,884 participants
(2.0%) who received placebo reported hepatotoxicity.

A meta-analysis of 5 randomized controlled trials including 1,774 adults and children

showed a lower risk for hepatotoxicity, defined as significant elevations in liver

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99
transaminase levels, among patients who received RIF monotherapy compared to INH
monotherapy (RR 0.15; 95% CI 0.07;0.35, I2 16%). [5] However, there was no significant
difference in the rates of hepatotoxicity between combination RIF and INH and INH alone
(RR 0.88; 95% CI 0.43;1.81). [5]

Table Q14.3 shows the odds ratios for hepatotoxicity of the different LTBI treatment
regimens. [4] The data suggest that the risk for hepatotoxicity is lower in RIF only, RIF/INH
combination, and RFP/INH combination therapies compared to INH monotherapy. This is
consistent with the findings of a systematic review on adverse events of LTBI treatment
by Pease et al. [6], which reported median rates for hepatotoxicity to be below 7.0% for
all treatment regimens (Table Q14.4). However, these results should be interpreted with
caution because of significant between-study variability and limited overall reporting of
adverse events. It should also be noted that RFP/INH combination therapy was
administered through DOT in all the studies that included this treatment regimen.

Table Q14.4. Hepatotoxicity vs. no treatment (Zenner et al., 2017)

Total number of Hepatotoxicity
Treatment
participants OR (95% CrI)
RMP 4 months 1,068 0.14 (0.02 to 0.81)
INH/RPT 12 doses weekly 4,726 0.52 (0.13 to 2.15)
INH/RIF 3 to 4 months 1,833 0.72 (0.21 to 2.37)
INH 6 months 18,084 1.10 (0.40 to 3.17)
INH 9 months 6,350 1.70 (0.35 to 8.05)
Note: INH, isoniazid; RPT, rifapentine; RIF, rifampicin; CrI, credible intervals

Table Q14.5. Rates of hepatotoxicity in nonrandomized studies

(Pease et al., 2018)
Total number of Hepatotoxicity
Treatment
participants Median % (min-max)
RMP 4 months 2,346 0.01% (0 to 2.0%)
INH/RPT 12 doses weekly 2,826 1.1% (0 to 3.9%)
INH/RIF 3 to 4 months 1,000 5.1% (1.0 to 20%)
INH 9 months 8,432 3.1% (0 to 9.0%)
INH 6 months 1,817 6.3% (0 to 13.3%)
Note: INH, isoniazid; RPT, rifapentine; RIF, rifampicin; CrI, credible intervals

Recommendations from other guidelines:

Philippine TB Guidelines 2016

• INH 300 mg daily for 6 months under supervised treatment is the recommended
regimen for LTBI (Strong recommendation, moderate quality of evidence)

• Pyridoxine at a dose of 25 mg/day is recommended to prevent peripheral

neuropathy. (Strong recommendation, low quality of evidence)

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CPG Adult TB - 12/1/23 3:12 PM
2018 WHO Guidelines:

• INH monotherapy for 6 months is recommended for treatment of LTBI in both

adults and children in countries with high and low TB incidence. (Strong
recommendation, high-quality evidence. Existing recommendation)

• RFP and INH weekly for 3 months may be offered as an alternative to 6 months
of isoniazid monotherapy as preventive treatment for both adults and children in
countries with a high TB incidence. (Conditional recommendation, moderate-
quality evidence. New recommendation)

REFERENCES

1. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management.
Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.

2. Smieja M, Marchetti C, Cook D, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected
persons. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001363. doi:
10.2002/14651858.CD001363.

3. Pease C, Hutton B, Yazdi F, Wolfe D, Hamel C, Quach P, et al. Efficacy and completion rates of
rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis
infection: a systematic review with network meta-analyses. BMC Infectious Diseases 2017;17:265.
doi: 10.1186/s12879-017-2377-x.

4. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of latent
tuberculosis infection: an updated network meta-analysis. Annals of Internal Medicine 2017 Aug
15;167(4):248-255. doi: 10.7326/M17-0609. Epub 2017 Aug 1.

5. Sharma SK, Sharma A, Kadhiravan T, Tharyan P. Rifamycins (rifampicin, rifabutin and rifapentin)
compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB.
Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.:CD007545. doi:
10.1002/14651858.CD007545.pub2.

6. Pease C, Hutton B, Yazdi F, Wolfe D, Hamel C, Barbeau P, et al. A systematic review of adverse
events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection.
Pharmacoepidemiol Drug Saf. 2018 Jun;27(6)557-566. doi: 10.1002/pds.4423. Epub 2018 Mar 23.

101
CPG Adult TB - 12/1/23 3:12 PM
 APPENDIX Q14
Table 14.6.Summary of Certainty of Evidence for Treatment of LTBI

Authors: Palileo, L.
Question: INH compared to no treatment or placebo for latent tuberculosis infection among non-HIV
Setting:
Bibliography: Smieja M, Marchetti C, Cook D, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001363.
doi: 10.2002/14651858.CD001363.

Certainty assessment Summary of findings

Study event rates (%) Anticipated absolute effects

№ of
Overall Relative Risk with
participants Risk Publication With no
Inconsistency Indirectness Imprecision certainty of effect no
(studies) of bias bias treatment Risk difference
evidence With INH (95% CI) treatment
Follow-up or with INH
or
placebo
placebo

Active TB

73375 not not serious serious a not serious none ⨁⨁⨁◯ 557/33113 239/40262 RR 0.40 17 per 10 fewer per 1,000
(11 RCTs) serious MODERATE (1.7%) (0.6%) (0.31 to 1,000 (from 12 fewer to 8
0.52) fewer)

Extrapulmonary TB

44636 not not serious serious a not serious none ⨁⨁⨁◯ 28/22257 9/22379 RR 0.34 1 per 1 fewer per 1,000
(4 RCTs) serious MODERATE (0.1%) (0.0%) (0.16 to 1,000 (from 1 fewer to 0
0.71) fewer)

TB Deaths

25714 not not serious serious a serious b none ⨁⨁◯◯ 10/9396 3/16318 RR 0.29 1 per 1 fewer per 1,000
(2 RCTs) serious LOW (0.1%) (0.0%) (0.07 to 1,000 (from 1 fewer to 0
1.18) fewer)

Safety: Hepatitis

10874 not not serious serious c not serious none ⨁⨁⨁◯ 7/6990 77/3884 RR 5.54 1 per 5 more per 1,000
(1 RCT) serious MODERATE (0.1%) (2.0%) (2.56 to 1,000 (from 2 more to 11
12.00) more)
CI: Confidence interval; RR: Risk ratio
a. Studies mostly in low burden settings
b. Wide confidence interval
c. Studies done in European countries—there might be important differences in risk for INH toxicity between study population and Filipinos given physiologic differences in
metabolising INH.

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GRADE TABLE

Certainty assessment
Certainty
№ of Risk of Other
Study design Inconsistency Indirectness Imprecision
studies bias considerations

61 randomized trials serious not serious serious b not serious none ⨁⨁◯◯
a
LOW

30 randomized trials serious not serious serious b not serious none ⨁⨁◯◯
a
LOW

61 randomized trials serious not serious serious b serious c none ⨁◯◯◯

a
VERY
LOW

78 observational studies serious not serious serious b serious c none ⨁◯◯◯

d
and randomized trials VERY
LOW

a. Unclear risk of bias for allocation concealment and blinding for many studies
b. Studies included both adult and pediatric populations, HIV and non-HIV patients, and high and low burden countries.
c. Small number of events, wide confidence intervals
d. limited control of confounders, ascertainment bias

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 UPDATE ON INFECTION CONTROL OF TUBERCULOSIS

Q15: AMONG HIGH RISK OR SPECIAL SETTINGS, WHAT ARE THE

RECOMMENDED MEASURES TO PREVENT TRANSMISSION OF TB?

RECOMMENDATIONS

Administrative Controls

• Recommendation 1: Triage of people with TB signs and symptoms, or with TB

disease, is recommended to reduce M. tuberculosis transmission to health workers
(including community health workers), persons attending health care facilities or
other persons in settings with a high risk of transmission. (Conditional
recommendation based on very low certainty in the estimates of effects)

• Recommendation 2: Respiratory separation / isolation of people with presumed

or demonstrated infectious TB is recommended to reduce M. tuberculosis
transmission to health workers or other persons attending health care facilities.
(Conditional recommendation based on very low certainty in the estimates
of effects)

• Recommendation 3: Prompt initiation of effective TB treatment of people with TB

disease is recommended to reduce M. tuberculosis transmission to health workers,
persons attending health care facilities or other persons in settings with a high risk
of transmission. (Strong recommendation based on very low certainty in the
estimates of effects)

• Recommendation 4: Respiratory hygiene (including cough etiquette) in people

with presumed or confirmed TB is recommended to reduce M. tuberculosis
transmission to health workers, persons attending health care facilities or other
persons in settings with a high risk of transmission. (Strong recommendation
based on low certainty in the estimates of effects)

Environmental Controls

• Recommendation 5: Upper-room germicidal ultraviolet (GUV) systems are

recommended to reduce M. tuberculosis transmission to health workers, persons
attending health care facilities or other persons in settings with a high risk of
transmission. (Conditional recommendation based on moderate certainty in
the estimates of effects)

• Recommendation 6: Ventilation systems (including natural, mixed-mode,

mechanical ventilation and recirculated air through high-efficiency particulate air
[HEPA] filters) are recommended to reduce M. tuberculosis transmission to health
workers, persons attending health care facilities or other persons in settings with

104
 a high risk of transmission (Conditional recommendation based on very low
certainty in the estimates of effects)

Respiratory Protection

• Recommendation 7: Particulate respirators, within the framework of a respiratory

protection program, are recommended to reduce M. tuberculosis transmission to
health workers, persons attending health care facilities or other persons in settings
with a high risk of transmission. (Conditional recommendation based on very
low certainty in the estimates of effects)

REMARKS

The panel unanimously voted to adapt the recommendations from the 2019 WHO
guidelines on tuberculosis infection prevention and control. N95 masks may be
recommended considering the high TB burden in the Philippines, but cost and treatment
setting must be considered. Voting: 13/13 agree

SUMMARY OF EVIDENCE

Search terms used were "guidelines" AND "tuberculosis" AND "infection" and
"prevention" AND "control. This yielded four (4) results, which included two (2) guidelines;
one published by the WHO in 2019 and one (1) from Center for Disease Control and
Prevention (CDC) in 2005. [1,2]. We performed a critical group appraisal of the two
guidelines using the Appraisal of Guidelines Research and Evaluation (AGREE) II
instrument. Overall assessment of the WHO and CDC guidelines using the AGREE II
instrument yielded scores of 83% and 50%, respectively

Currency survey since the end of search date of the WHO guidelines in 2018 did not yield
any pertinent additional studies.

The 2005 CDC guideline for preventing transmission of tuberculosis in health-care

settings has identified the following characteristics of patients with TB disease that
increases the risk for infectiousness:

• presence of cough;
• cavitation on chest radiograph;
• positive acid-fast bacilli (AFB) sputum smear result;
• respiratory tract disease with involvement of the larynx (substantially infectious);
• respiratory tract disease with involvement of the lung or pleura (exclusively pleural
involvement is less infectious);
• failure to cover the mouth and nose when coughing;
• incorrect, lack of, or short duration of anti-tuberculosis treatment; and

105
 • undergoing cough-inducing or aerosol-generating procedures (e.g., bronchoscopy,
sputum induction, and administration of aerosolized medications)

In addition, they also listed the probability of increased risk for transmission of M.
tuberculosis as a result of various environmental factors, such as:

• exposure to TB in small, enclosed spaces.

• inadequate local or general ventilation that results in insufficient dilution or removal
of infectious droplet nuclei.
• recirculation of air containing infectious droplet nuclei.
• inadequate cleaning and disinfection of medical equipment.
• improper procedures for handling specimens.

Both the updated 2019 WHO guideline on tuberculosis infection prevention and control
and the 2005 CDC guideline for preventing tuberculosis in healthcare settings have
enumerated measures to prevent transmission of TB that involves administrative control,
environmental control, and respiratory protection.

The 2019 WHO guidelines include respiratory hygiene (including cough etiquette) in
people with presumed or confirmed TB to reduce M. tuberculosis transmission to health
workers, persons attending health care facilities, or other persons in settings with a high
risk of transmission. The 2019 WHO guidelines do not present interventions directed to
household settings, given that there was no directly applicable evidence that fulfilled the
inclusion criteria for this systematic evaluation of data. However, some considerations
pertinent to households are mentioned, where applicable (i.e. respiratory hygiene and
respiratory protection) under implementation considerations (Table 1, WHO 2019 Annex
4, PICO 2).

Zayas et al. evaluated the effect of cough etiquette on the chain of transmission of
infectious respiratory diseases. [3] Participants in this study performed a voluntary cough
while covering their mouth and nose with their hands, sleeve/arm, tissue, or while wearing
a surgical mask. Droplets released were quantitatively characterized to assess how
effective the maneuvers were in controlling the cough aerosol jet. The study showed that
cough etiquette maneuvers did not fully interrupt the chain of transmission of infectious
respiratory diseases.

Recommendations from the 2019 WHO guidelines include prompt initiation of effective
TB treatment of people with TB disease to reduce M. tuberculosis transmission to health
workers, persons attending health care facilities, or other persons in settings with a high
risk of transmission. Evidence continues to mount showing that delays in initiation of
effective TB treatment increase the probability of forward transmission of the disease
(Table 2, WHO 2019 Annex 4, PICO 1). [4,5]

The recommendations given in the 2019 WHO guidelines on TB-specific interventions

are components of a comprehensive hierarchy of controls, which in turn is a component

106
of the overall framework of infection prevention and control (IPC) practices and depends
on the adoption of a multimodal strategy. Thus, the adoption of several elements needs
to be integrated.

Looking at the effect of triage on the incidence of LTBI and TB disease among health
workers, a systematic search yielded 15 observational studies from secondary and
tertiary health care facilities, of which 73% were carried out in low TB burden settings.
[6] A total of six studies [7,8,9,10,11,12] measuring the effect of triage on the incidence
of LTBI alone among health workers in all settings were included in the analysis (Table
3, WHO 2019 Annex 4, PICO 1).

Estimates of reduction of TB incidence in high TB burden settings, calculated from crude

pooled data, seemed to indicate very slight or no reduction in TB incidence (crude
incidence rate ratio [IRR]: 0.98) among health workers after the implementation of triage
within a set of composite IPC measures (WHO 2019, Annex 3). These studies seemed
to indicate that there is a 12.6% absolute risk reduction (crude estimate combining data
from two studies) in the number of active TB disease cases in persons attending health
care settings with the use of triage (in combination with other IPC measures) compared
to similar populations in settings where triage was not implemented.

In an additional study reporting on the use of isolation (an infection control audit at 121
primary health care facilities in South Africa), the authors reported slightly increased odds
of developing smear-positive TB (unadjusted odds ratio [OR]: 1.09; 95% confidence
interval [CI] 0.99–1.19) in health workers for a unit increase in the administrative audit
tool score, where a higher score equates to better administrative control measures. [13]
However, the 2019 WHO guideline review showed that isolation of TB patients seemed
to have an inconspicuous effect or no effect on the risk of active TB disease among health
workers, as indicated earlier (Table 4, WHO 2019 Annex 4, PICO 2).

Multiple studies suggest that the decline in healthcare-associated transmission observed

in specific institutions is associated with rigorous implementation of infection IPC
measures. [1]
Primary environmental controls consist of controlling the source of infection by using local
exhaust ventilation (e.g., hoods, tents, or booths) and diluting and removing contaminated
air by using general ventilation. Secondary environmental controls consist of controlling
the airflow to prevent contamination of air in areas adjacent to the source (AII rooms) and
cleaning the air by using high efficiency particulate air (HEPA) filtration or UVGI.

A systematic review assessing the effectiveness of GUV systems yielded a total of five
included studies [9,14,15,16,17], of which three evaluated IPC interventions involving
health workers [9,14,15] (Table 5, WHO 2019, PICO 3). A meta-analysis could not be
performed, owing to differences in outcome measurement and heterogeneity among the
interventions.

107
Use of respiratory protection can further reduce the risk of exposure of HCWs to infectious
droplet nuclei that have been expelled into the air by a patient with infectious TB disease.
A systematic review assessing the effectiveness of respiratory protection in reducing the
risk of M. tuberculosis transmission yielded a total of nine studies
[7,9,10,11,14,15,18,19,20] (Table 6, WHO 2019, annex 4 PICO). The systematic search
also identified four studies [9,11,14,20] in which respirators were used as part of a
broader respiratory protection program. No included studies focused on the
implementation of respiratory protection programs in non-health care congregate
settings. The included studies provided heterogeneous results on the effect of such
programs to protect health workers from acquiring TB infection or developing TB disease.
The reduction in TST conversion ranged from a 4.3% absolute reduction (with the
introduction of particulate respirators and fit-testing as part of a respiratory protection
program) to a 14.8% reduction.

REFERENCES:

1. WHO guidelines on tuberculosis infection prevention and control, 2019 update, Geneva: World
Health Organization; 2019

2. Centers for Disease Control and Prevention. Guidelines for Preventing the Transmission of
Mycobacterium tuberculosis in Health-Care Settings, 2005. MMWR 2005;54(No. RR-17)

3. Zayas G, Chiang MC, Wong E, et al. Effectiveness of cough etiquette maneuvers in disrupting the
chain of transmission of infectious respiratory diseases. BMC Public Health. 2013;13:811.
Published 2013 Sep 8. doi:10.1186/1471-2458-13-811

4. Harris TG, Meissner JS, Proops D. Delay in diagnosis leading to nosocomial transmission of
tuberculosis at a New York City health care facility. Am J Infect Control. 2013;41(2):155–60

5. Cheng S, Chen W, Yang Y, Chu P, Liu X, Zhao M et al. Effect of diagnostic and treatment delay
on the risk of tuberculosis transmission in Shenzhen, China: an Observational Cohort Study, 1993–
2010. PLoS One. 2013;8(6):e67516

6. Fielding K, Harris R, Karat A, Falconer J, Moore D. Systematic review for evidence of administrative
infection control interventions to reduce tuberculosis (TB) transmission and three related
background questions (PROSPERO 2018 CRD42018085226). National Institute for Health
Research; 2018

7. Roth VR, Garrett DO,Laserson KF,Starling CE,Kritski AL,Medeiros EAS,Binkin N,Jarvis WR. A
multicenter evaluation of tuberculin skin test positivity and conversion among health care workers
in Brazilian hospitals.. Int J Tuberc Lung Dis; 2005.

8. Wenger PN, Otten J,Breeden A,Orfas D,Beck-Sague CM,Jarvis WR. Control of nosocomial
transmission of multidrug-resistant Mycobacterium tuberculosis among healthcare workers and
HIV-infected patients. Lancet; 1995.

9. Welbel SF, French AL,Bush P,DeGuzman D,Weinstein RA. Protecting health care workers from
tuberculosis: a 10-year experience. Am J Infect Control; 2009.

10. Blumberg HM, Watkins DL,Berschling JD,Antle A,Moore P,White N,Hunter M,Green B,Ray
SM,McGowan Jr. J E. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med;
1995.

108
11. Bangsberg DR, Crowley K,Moss A,Dobkin JF,McGregor C,Neu HC. Reduction in tuberculin skin-
test conversions among medical house staff associated with improved tuberculosis infection control
practices. Infect Control Hosp Epidemiol; 1997.

12. Holzman, RS. A comprehensive control program reduces transmission of tuberculosis to hospital
staff. Clin Infect Dis; 1995.

13. Claassens MM, Van Schalkwyk C, Du Toit E, Roest E, Lombard CJ, Enarson DA et al. Tuberculosis
in healthcare workers and infection control measures at primary healthcare facilities in South Africa.
PLoS One. 2013;8(10):e76272

14. Yanai H, Limpakarnjanarat K, Uthaivoravit W, Mastro T, Mori T, Tappero J. Risk of Mycobacterium

tuberculosis infection and disease among health care workers, Chiang Rai, Thailand. Int J Tuberc
Lung Dis. 2003;7(1):36–45

15. Fella P, Rivera P, Hale M, Squires K, Sepkowitz K. Dramatic decrease in tuberculin skin test
conversion rate among employees at a hospital in New York City. Am J Infect Control.
1995;23(6):352–6

16. Mphaphlele M, Dharmadhikari AS,Jensen PA,Rudnick SN,van Reenen TH,Pagano MA,Leuschner

W,Sears TA,Milonova SP,van der Walt M,Stoltz AC,Weyer K,Nardell EA. Institutional Tuberculosis
Transmission Controlled Trial of Upper Room Ultraviolet Air Disinfection: A Basis for New Dosing
Guidelines. Am J Respir Crit Care Med; 2015.

17. Escombe AR, Moore DAJ,Gilman RH,Navicopa M,Ticona E,Mitchell B,Noakes C,Martinez
C,Sheen P,Ramirez R,Quino W,Gonzalez A,Friedland JS,Evans CA. Upper-Room Ultraviolet Light
and Negative Air Ionization to Prevent Tuberculosis Transmission. Plos Medicine; 2009.

18. Maloney SA, Pearson ML,Gordon MT,Del Castillo R,Boyle JF, Jarvis WR. Efficacy of control
measures in preventing nosocomial transmission of multidrug-resistant tuberculosis to patients and
health care workers. Ann Intern Med; 1995.

19. Baussano I, Bugiani M,Carosso A,Mairano D,Barocelli AP,Tagna M,Cascio V,Piccioni P,Arossa W.
Risk of tuberculin conversion among healthcare workers and the adoption of preventive measures.
Occup Environ Med; 2007.

20. da Costa P, Trajman A ,Mello FC,Goudinho S,Silva MA,Garret D,Ruffino-Netto A,Kritski AL.
Administrative measures for preventing Mycobacterium tuberculosis infection among healthcare
workers in a teaching hospital in Rio de Janeiro, Brazil. J Hosp Infect; 2009.

109
 APPENDIX Q15
GRADE Profiles

Table Q15.1 Respiratory hygiene to reduce TB transmission to HCWs (WHO 2019 Annex 4, PICO 2)

Table Q15.2 Respiratory hygiene to reduce TB transmission to other persons (WHO 2019 Annex 4, PICO 2)

110
Table Q15.3 Prompt initiation of effective treatment of TB patients to reduce transmission (WHO 2019 Annex 4, PICO 1)

Table Q15.4 Prompt initiation of effective treatment of TB patients to reduce transmission (WHO 2019 Annex 4, PICO 1)

111
Table Q15.5 Triage of people with TB signs to reduce to reduce transmission (WHO 2019 Annex 4, PICO 1)

112
 Table Q15.6 Triage of people with TB signs to reduce to reduce transmission (WHO 2019 Annex 4, PICO 1)

Table Q15.7 Respiratory isolation of people with TB signs to reduce to reduce transmission (WHO 2019 Annex 4, PICO 1)

113
114
 Table Q15.8 Respiratory isolation of people with TB signs to reduce transmission (WHO 2019 Annex 4, PICO 1)

Table Q15.9 Use of Germicidal Ultraviolet irradiation to reduce transmission of TB among healthcare workers (WHO 2019 Annex 4,
PICO 3)

115
Table Q15.10 Use of Germicidal Ultraviolet irradiation to reduce transmission of TB to others (WHO 2019 Annex 4, PICO 3)

Table Q15.11 Use of particulate respirators to reduce TB transmission (WHO 2019, Annex 4 PICO 4)

116
Table Q15.12 se of particulate respirators to reduce TB transmission (WHO 2019, Annex 4 PICO 4)

117
 UPDATE ON MANAGEMENT OF TB-HIV COINFECTION

Q16: AMONG PATIENTS WITH TB-HIV CO-INFECTION, HOW EFFECTIVE AND

SAFE ARE RIFAMPICIN-CONTAINING REGIMENS IN TERMS OF CLINICAL CURE
AND ADVERSE REACTIONS COMPARED TO NON-RIFAMPICIN BASED
REGIMENS?

RECOMMENDATION

Among patients with TB-HIV co-infection, RIF-containing regimens are comparable to

non-RIF based regimens in terms of effectiveness and safety. (Weak
recommendation, very low-quality evidence)

REMARKS

Anti-retroviral treatments for HIV patients need to be specified as these drugs may
have potential interactions with RIF. Voting: 15/15 agree

SUMMARY OF EVIDENCE

Search terms for this question included Free text: tuberculosis, HIV, human
immunodeficiency virus, AIDS, acquired immunodeficiency syndrome, rifampicin,
rifampin and Mesh terms: Tuberculosis, HIV, Acquired Immunodeficiency Syndrome,
Rifampin.

Based on very low level of evidence, there is no significant difference between RIF-
containing regimens and non-RIF containing regimens in terms of effectiveness and
safety.

There were 2 RCTs comparing RIF-containing regimens and non-RIF-based regimens.

A randomized controlled trial in 2015 included 207 treatment-naive smear-positive adult
patients with PTB, 40 of whom had HIV co-infection. [1] Of the 207, 181 were DS-TB,
and 26 were MDR TB. Patients with HIV were eligible if their CD4 count was greater
than 200 cells per μl and they had no AIDS-defining illness besides TB. Drug susceptible
patients were randomized to receive 8 weeks of MPa100Z (moxifloxacin, 100 mg
pretomanid, pyrazinamide), MPa200Z, or HRZE. Patients with MDR TB were not
randomized because they were not eligible for HRZE therapy. Subgroup analysis for
patients with TB-HIV co-infection was not done.

Overall results showed that MPa200Z had significantly greater bactericidal activity than
HRZE in terms of decreasing the colony forming unit (CFU) counts of TB. There was no
significant difference in the time to culture positivity and adverse events among the
treatment groups. The most common adverse events were hyperuricemia in 59 patients
(29%), nausea in 37 patients (18%) and vomiting in 25 patients (12%).

118
Another randomized controlled trial in 2010 included 69 treatment-naive, drug-sensitive,
sputum smear-positive, adult patients with PTB, 10 of whom had HIV co-infection.[2]
Individuals with HIV infection under antiretroviral treatment or with a CD4 cell count of
≤300 x 106/liter were excluded, as were those with bacilli resistant to RIF. Patients were
randomized to receive pretomanid monotherapy at 200 mg, 600 mg, 1000 mg, 1200 mg
or standard treatment HRZE. Subgroup analysis for patients with TB-HIV co-infection
was not done.

Overall results showed no significant difference in bactericidal activity among the

treatment groups, as measured by the CFU counts and time to culture positivity. Higher
number of adverse events was observed in patients given higher Pa doses. There were
2 serious adverse events (hemoptysis), 1 from the Pa200 group and 1 from the HRZE
group.

Pooling of data for the bactericidal activity of non-RIF containing drugs could not be
done due to differences in reporting of results (e.g., mean daily change in CFU in 1
study, actual CFU counts at the end of the time period in another study). Based on
qualitative evaluation, pretomanid monotherapy and MPa100Z have comparable
bactericidal activity to RIF-containing regimens as measured by CFU counts of TB and
time to culture positivity. MPa200Z had significantly greater bactericidal activity
compared to RIF containing regimens as measured by CFU counts.

In terms of adverse events, the summary of results are shown in Table Q16.1.

Table Q16.1. Summary of Results for Rifampicin Containing Regimens*

Measure of treatment
Outcome 95% CI Interpretation Basis
effect
Total adverse events RR = 0.93 0.81-1.06 Not significant 2 RCTs
*Please refer to appendix to view forest plots of combined studies.

Data pooled from both RCTs show no significant difference in adverse events between
RIF containing and non-RIF containing regimens.

Given these findings, both RIF-containing regimens and non-RIF containing regimens
may be considered for the treatment of patients with TB-HIV co-infection.

REFERENCES:

1. Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, et al. Efficiency and
safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the
first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in
patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015;385:1738-
1747.

2. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal
activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrobial
Agents and Chemotherapy. 2010;54(8):3402-3407.

119
 APPENDIX Q16

Figure Q16.1 Total adverse events (The treatment groups with varying doses of pretomanid were grouped together as
non-rifampicin containing)

Figure Q16.2 Total adverse events (The treatment groups with varying doses of pretomanid were
separated and compared to HRZE)

120
 Author(s): Tan-Lim, CC

Date: 22 November 2019

Question: Among patients with TB-HIV co-infection, how effective and safe are rifampicin-containing regimens in terms of
clinical cure and adverse reactions compared to non-rifampicin based regimens?

Setting: Dawson 2015 – South Africa and Tanzania; Diacon 2010 – South Africa
Bibliography:
1. Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, et al. Efficiency and safety of the combination of moxifloxacin,
pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in
patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015;385:1738-1747.
2. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal activity and
pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrobial Agents and Chemotherapy.
2010;54(8):3402-3407.

Table Q16.2 Summary of certainty of Evidence re TB-HIV coinfection

Summary of Findings
Quality Assessment

Over-all
Quality OR/RR or MD Importance
Study
Participants Risk of Bias Inconsistency Indirectness Imprecision Reporting
Outcomes Design
Bias
Not pooled
276 (50 with
Clinical
2 RCTs TB-HIV co- Seriousa Not serious Very seriousb Not serious
Not ⨁◯◯◯ due to
Critical
cure serious Very Low inadequate
infection)
data

276 (50 with RR = 0.93

Adverse
2 RCTs TB-HIV co-
Very
Not serious Seriousd Not serious
Not ⨁◯◯◯ (95% CI 0.81, Critical
events seriousc serious Very Low
infection) 1.06)

a
Serious risk of bias due to differences in baseline characteristics of treatment groups. Although blinding was not done, outcome
was assessed using microbiologic techniques
b
Very serious indirectness due to inclusion in both RCTs of HIV-positive and HIV-negative patients, and use of surrogate
outcome (CFU counts) in place of clinical outcome (cure)
c
Very serious risk of bias due to differences in baseline characteristics of treatment groups and lack of blinding which would
affect reporting and detection of adverse events
d
Serious indirectness due to inclusion in both RCTs of HIV-positive and HIV-negative patient

121
Q17: AMONG PATIENTS WITH HIV ON LOPINAVIR-RITONAVIR (LPV/r) AND ARE
RECEIVING RIFAMPICIN-BASED REGIMENS FOR TB CO-INFECTION, SHOULD
THE DOSE OF ART (LOPINAVIR-RITONAVIR) BE INCREASED (BOOSTED OR
DOUBLED) TO REDUCE VIROLOGIC FAILURE AND ADVERSE EVENTS?

RECOMMENDATION

Among patients with TB-HIV co-infection who are on RIF-based regimens, caution
should be exercised when increasing the dose of LPV/r. Increasing the dose may
increase the risk of adverse events without reducing virologic failure. (Weak
recommendation, very low-quality evidence)

REMARKS

Current evidence suggests that increasing the dose offers no clear benefit but increases
the possibility of harm. The panel also suggests to replace clinical failure with virologic
failure as one of the outcomes, because RIF, when used with protease inhibitors (PIs),
substantially decreases the levels of PIs. Issues regarding the applicability of the
boosted doses used in the cited studies were raised. It is not also possible to determine
which among boosted vs. double dose produces better outcomes from the studies
reviewed.

Voting: 1st round – 6/15 agree, 3/15 abstain, 6/15 disagree; 2nd round – 8/15
agree, 3/15 abstain, 4/15 disagree; 3rd round – 13/15 agree, 2 abstain

SUMMARY OF EVIDENCE

Medline, Cochrane Library and Trip Database were used to search using Free
text: “tuberculosis”, “HIV, human” “immunodeficiency virus, AIDS, acquired
immunodeficiency syndrome, ritonavir, lopinavir” Meshterms used were: Tuberculosis,
HIV, Acquired Immunodeficiency Syndrome, Lopinavir, Ritonavir

Based on very low level of evidence, LPV/r should not be given as a boosted dose
among patients with TB-HIV co-infection on RIF-based TB regimens due to significantly
increased risk of adverse events with no significant difference in clinical failure.

There are 4 cohort studies[1-4] that evaluated the effect of boosted doses of
lopinavir/ritonavir (LPV/r) among patients given concurrent RIF for treatment of TB. The
prospective study [2] and one of the retrospective studies [1] compared boosted dose
LPV/r (400mg/400mg BID) to double dose LPV/r (800mg/200mg BID). The other 2
retrospective cohort studies [3,4] compared boosted dose to standard dose LPV/r

122
(400mg/100mg BID). All cohort studies reported virologic failure and adverse events
necessitating treatment modification as outcomes.

One retrospective cohort study [1] used a historical cohort as the control group.
However, numerical data on the outcome of this historical cohort was not provided.
Thus, the results of this study could not be pooled into the meta-analysis. This study
compared boosted dose to double dose LPV/r. There was virologic failure in 3 out of 25
patients given double dose LPV/r. The authors reported that these results are similar to
the overall rate of second line treatment failure observed among patients requiring
second-line antiretroviral therapy in their setting. In terms of safety, 3 out of 25 patients
(12%) given double dose LPV/r experienced adverse events necessitating treatment
discontinuation. The historical control group given boosted dose LPV/r had significantly
higher adverse events (47%, p value = 0.024),

There were also 2 pharmacokinetic studies on the effect of LPV/r when given as
boosted dose among patients with TB-HIV coinfection and treated with RIF based
regimens. [5,6] These studies had no control group; hence, results could also not be
pooled into the meta-analysis. The 2014 study [6] reported that 3 out of 5 patients had
detectable viral load at the end of the study, while the 2019 study [5] reported that 1 out
of 11 had <1.0 decrease in viral load at the end of the study. The earlier study [6] had 3
dropouts due to adverse events noted after LPV/r initiation. The more recent one [5[ had
no dropouts due to adverse events, but 1 out of 11 patients developed a severe adverse
event (marked elevation of transaminases).

The summary of results is shown in Table Q17.1.

Table Q17.1. Summary of Results

Outcome Measure of 95% CI Interpretation Basis

Treatment
Effect
Virologic failure: Boosted dose vs. non- OR = 0.76 0.23, 2.51 Not significant 3 cohort
boosted dose studies
(Fig Q17.1)
Virologic failure: Boosted dose vs. OR = 0.60 0.13, 2.8 Not significant 2 cohort
standard dose studies
(Fig Q17.2)
Adverse events necessitating treatment OR = 7.05 1.86, Significant 3 cohort
modification: 26.63 studies
Boosted dose vs. non-boosted dose
(Fig Q17.3)
Adverse events necessitating treatment OR = 6.38 1.47, Significant 2 cohort
modification: 27.70 studies
Boosted dose vs. standard dose
(Fig Q17.4)
*Please refer to appendix to view forest plots of combined studies

123
Data pooled from the 3 cohort studies [2-4] show that there is no significant difference
in virologic failure between boosted doses of LPV/r and non-boosted doses (standard
or double dose) of LPV/r. Subgroup analysis on boosted dose compared to standard
dose of LPV/r similarly shows no significant difference in virologic failure, based on 2
cohort studies [3,4].

In terms of adverse events, boosted doses of LPV/r is associated with significantly

higher risk of adverse events compared to non-boosted doses of LPV/r, based on 3
cohort studies [2-4]. Based on subgroup analysis of 2 cohort studies [3,4] on boosted
dose compared to standard dose of LPV/r, there is a significant increase in adverse
events among those given boosted doses compared to those given standard doses of
LPV/r. The most common reported adverse events reported were elevation in
transaminase levels.

Given these findings, LPV/r should not be given as boosted dose among patients with
TB-HIV co-infection taking RIF-based TB regimens. There is no significant difference in
virologic failure, but there is a significantly higher risk of adverse events.

REFERENCES:

1. Sunpath H, Winternheimer P, Cohen S, Tennant I, Chelin N, Gandhi RT, et al. Double-dose

lopinavir-ritonavir in combination with rifampicin- based anti-tuberculosis treatment in
South Africa. Int J Tuberc Lung Dis. 2014;18(6):689-693.
2. Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H. The Safety, Effectiveness
and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-
Based Antitubercular Therapy. PLoS One. 2012;7(3):e32173.
3. L’homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, et al. Clinical
experience with the combined use of lopinavir/ritonavir and rifampicin. AIDS.
2009;23(7):863-865.
4. Murphy RA, Marconi VC, Gandhi RT, Kuritzkes DR, Sunpath H. Coadministration of
Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South
Africa. PLoS One. 2012;7(9):e44793.
5. Boulanger C, Rolla V, Al-Shaer MH, Peloquin C. Evaluation of Super-Boosted
Lopinavir/Ritonavir in combination with Rifampin in HIV-1-infected Patients with
Tuberculosis. Int J Antimicrob Agents. 2019;S0924-8579(19)30301-2.
6. Schmaltz CS, Costa MM, Cattani VB, Pinto DP, Liporage J, Benjamin A, et al. Pharmacological
Interaction of Lopinavir/Ritonavir 800/200 mg BID and Rifampicin in Subjects Presenting
Tuberculosis with Contraindication for an Efavirenz containing Antiretroviral Regimen. J AIDS
Clin Res. 2014;5:10.

124
 APPENDIX Q17

Author(s): Tan-Lim, CC Date: 23 November 2019

Question: Among patients with TB-HIV co-infection who are on second line ART (lopinavir-ritonavir) and rifampicin-
based regimen, should the dose of ART (lopinavir-ritonavir) be boosted or not to reduce clinical failure and adverse
events?
Setting: South Africa
Bibliography:
1. Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H. The Safety, Effectiveness and
Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin- Based Antitubercular
Therapy. PLoS One. 2012;7(3):e32173.
2. L’homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, et al. Clinical experience with the
combined use of lopinavir/ritonavir and rifampicin. AIDS. 2009;23(7):863-865.
3. Murphy RA, Marconi VC, Gandhi RT, Kuritzkes DR, Sunpath H. Coadministration of Lopinavir/Ritonavir and
Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa. PLoS One. 2012;7(9):e44793.
Table 17.2 Summary of Certainty of Evidence for TB-HIV

Summary of Findings
Quality Assessment

Over-all
Study Risk of Quality OR/RR or Importance
Participants Inconsistency Indirectness Imprecision Reporting MD
Outcomes Design Bias Bias

3 OR = 0.76
Clinical Not ⨁◯◯◯
Cohort 81 Seriousa Not serious Seriousb Seriousc (95% CI Critical
failure serious Very Low
studies 0.23, 2.51)
OR = 7.05
3
Adverse Not ⨁◯◯◯ (95% CI
Cohort 81 Seriousa Not serious Not serious Not serious Critical
events serious Very Low 1.86,
studies
26.63)

a
Serious risk of bias because cohort studies did not match the 2 groups for all variables associated with the
outcome and did not do statistical adjustment
b
Serious indirectness due to reporting of outcome as virologic failure instead of clinical failure
c
Serious imprecision due to wide confidence intervals

125
 APPENDIX Q17
Author(s): Tan-Lim, CC Date: 23 November 2019
Question: Among patients with TB-HIV co-infection who are on second line ART (lopinavir-ritonavir) and rifampicin-
based regimen, should the dose of ART (lopinavir-ritonavir) be boosted or not to reduce clinical failure and adverse
events?
Setting: South Africa
Bibliography:
1. Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H. The Safety, Effectiveness and
Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin- Based Antitubercular
Therapy. PLoS One. 2012;7(3):e32173.
2. L’homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, et al. Clinical experience with the
combined use of lopinavir/ritonavir and rifampicin. AIDS. 2009;23(7):863-865.
3. Murphy RA, Marconi VC, Gandhi RT, Kuritzkes DR, Sunpath H. Coadministration of Lopinavir/Ritonavir and
Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa. PLoS One. 2012;7(9):e44793.
Table Q17.3 Summary of Certainty of Evidence for TB-HIV

Summary of Findings
Quality Assessment

Over-all
Quality OR/RR or MD Importance
Study Risk of Reporting
Outcomes Participants Inconsistency Indirectness Imprecision
Design Bias Bias

3 OR = 0.76
Clinical Not ⨁◯◯◯
Cohort 81 Seriousa Not serious Seriousb Seriousc (95% CI Critical
failure serious Very Low
studies 0.23, 2.51)
OR = 7.05
3
Adverse a Not ⨁◯◯◯ (95% CI
Cohort 81 Serious Not serious Not serious Not serious Critical
events serious Very Low 1.86,
studies
26.63)

a
Serious risk of bias because cohort studies did not match the 2 groups for all variables
associated with the outcome and did not do statistical adjustment
b
Serious indirectness due to reporting of outcome as virologic failure instead of clinical failure
c
Serious imprecision due to wide confidence intervals

126
Figure Q17.1 Effects of boosted doses compared to nonboosted doses of LPV/r on virologic failure

Figure Q17.2 Effects of boosted doses compared to standard doses of LPV/r on virologic failure

Figure Q17.3 Adverse events experienced by patients on boosted doses compared to nonboosted doses
of LPV/r

Figure Q17.4 Adverse events experienced by patients on boosted doses compared to standard doses of
LPV/r

127
 SPECIAL UPDATE ON MANDATORY TB NOTIFICATION

A. FREQUENTLY ASKED QUESTIONS ON MANDATORY TB NOTIFICATION

What is mandatory TB notification?

Mandatory TB notification is a process of requiring all health care providers and

facilities, both public and private, providing part or all TB services such as
diagnosis, treatment and prevention, to report to the DOH every person with TB
using format and processes designed for this purpose.
What is the legal basis for the mandatory TB notification?
Republic Act (RA) 10767 (Section 12) mandates that “all public & private health
centers, hospitals and facilities observe the national protocol on TB management
and notify DOH of all TB cases as prescribed under the Manual of Procedures of
the National TB Program.” Its Implementing Rules and Regulations (IRR) Section
8.1 requires that current TB notification system be revised to cover all service
providers, not only those that are considered part of an established TB service
delivery network, to ensure that all persons diagnosed and treated are reported,
including its outcome, according to the requirements of the MOP.
Why do we need to notify TB cases?
TB is a notifiable disease and a major public health problem. This will bolster case
finding, help ensure high quality TB management in both public and private sectors
and assess progress towards TB disease elimination goals. This is an important
component of an improved surveillance system.
What is required to notify?
The physician or healthcare provider or medical facility needs to register manually
using the TB Service Provider Information Sheet for doctors or health facilities or
electronically through URL itis.doh.gov.ph/register.
How does one notify a patient with TB?
Once registered, physicians notify patients diagnosed or initiated treatment with
TB, following case definitions prescribed in the 6th MOP. Notification can be done
(1) manually by filling out the TB Case Notification Form; (2) through the ITIS Lite
website by visiting URL itis.doh.gov.ph/mandatorynotification; or (3) via the
ITIS Lite mobile notification app (android or IOS). The app requires a smartphone
or tablet that runs IOS or Android operating systems, reliable internet connection
at least 1 mbps to install the app and to sync encoded cases.

128
Notification is done by (1) direct encoding in ITIS or ITIS Lite by the physician; (2)
collected by a trained hospital point person, (3) referred to a TB Clinic for
notification, or (4) encoded by a TB Notification Officer assigned to the physician.
When do I need to notify?
Notification shall be done at 3 time points: (1) upon diagnosis, whether treatment
is initiated or not, referred to another provider for treatment, or even when patient
refused treatment; (2) upon initiation of treatment; and (3) once treatment
outcomes is known. Double notification will be filtered by the system.
Reporting is done at the end of each month. Zero reporting is also required if no
TB cases are seen for the month.
Is patient consent required in mandatory TB notification?
Patient consent is not required in mandatory TB notification, but the patient needs
to be informed about the physician’s responsibility and purpose to notify as
mandated by law, following procedures consistent with the Data Privacy Act of
2012. This aims to protect the right to information privacy while ensuring free flow
of mandated information through fair, secure and lawful data collection and
processes.
How are patient data utilized?
The designated TB Notification Officer by the NTP Coordinator will review and
analyze ITIS-generated reports. All Rural Health Units and Health Centers and their
designated TB Notification Officers at the municipality, city, provincial and regional
levels shall be responsible in the collection, consolidation and analysis of TB
notification reports.
Why is it taking too long to proceed during my first login in ITIS Lite?
During the first login, the app is syncing all previous TB notification cases encoded
in the web. This is to ensure that the same data will be available to you whether
using mobile or web version. A slow internet connection is also a factor.
Is the mobile app secure to store patient information?
The application is designed to handle personal sensitive information such as
patient demographics. Some of the security features of ITIS Lite are: (1) app logs
out a user every 15 minutes of inactivity; (2) app requires username and password
every session; (3). Local database on mobile device is encrypted; and (4) DOH can
blacklist a device for malicious activities.
Can I use more than one ITIS Lite account on my mobile device?
No. If you have installed the app on your mobile device and have already logged
in, the app automatically downloads data from the DOH to your mobile device. As

129
of the moment, it will not be possible for another ITIS Lite user to use your device
to notify.
Why does my TB Notification turn from orange to white color in ITIS Lite?
When one notifies a case to DOH, the initial orange color signifies that data entered
have been saved on the mobile device. It turns to white if saved data have been
successfully submitted and received by DOH, which automatically happens
whenever a reliable internet connection is available.

For immediate technical assistance related to mandatory TB notification:

For Assistance on Mandatory TB Notification

Landline: (02) 8651-7800 local 1941
Mobile: (0949) 993-3489 SMART;
(0917) 815-0469 GLOBE
Email: integtbis@gmail.com

Box 2: Contact Details for Technical Assistance related to Mandatory TB

Notification

130
B: STEP BY STEP PROCESS TO REGISTER AS A PHYSICIAN NOTIFIER

Figure 5. How to Register on ITIS Lite

131
C: ADMINISTRATIVE ORDER 2020-0057 ON MANDATORY TB NOTIFICATION

Figure 6. First Page of the AO 2020-0057

132
D: PROCESS OF REFERRAL TO THE TB MEDICAL ADVISORY COMMITTEE
(TB-MAC)

Who can be referred to the TB-MAC?

Difficult or challenging cases of TB that cannot be resolved or decided upon at the
health facility or individual physician level can be referred to the Regional TB
Medical Advisory Committee (R-TBMAC). The patient being referred should be
notified in ITIS/ITIS Lite before referral.

Who can refer to the Regional TB-MAC?

Any physician or facility can refer their patients to the R-TBMAC. Referring
physician may be requested to either respond to queries by email or present to the
committee via online meeting platform. Recommendations will be provided within
24-48 hours or elevated to the national TB MAC with recommendations within 24-
48 hours.

How to refer to the Regional TB-MAC?

Referral can be via email, e-TBMAC website or mobile app. An active ITIS or ITIS
Lite Account is required when using the web or mobile app. The following
information need to be provided:
• TB Treatment Enrolment and Case Management form sent by email or
recorded in ITIS/ITIS Lite if using web or mobile app.
• Medical abstract with pertinent diagnostic work-up results

The eTBMAC platform can be accessed through the web

(https://etbmac.doh.gov.ph) or mobile app (for iOS and android) and log-in using
ITIS/ITIS Lite credentials. Referring doctor will choose “Health Care Worker” option
to access the landing page that displays the enrollment, case management, and
treatment outcome modules. Select the module consistent with reason for referral.

To refer a case, click the “Create new” button and provide all relevant information
about the patient being referred. TB case number is not required for the enrolment
module where case being referred are pending registration, except for case
management and treatment outcome modules. Upload relevant imaging (jpeg, png
or pdf file) and provide additional remarks on the appropriate sections. Once all
information is provided, click the “Create new enrollment” button if for enrollment
or “Create new case” if for case management and treatment outcome. The status
of referral can be viewed by clicking the specific module and reviewing the tabs
under each module. For more information, check the link
https://youtube.com/channel/UCmgUwrmSIo6iZuu_iUU2QCQ/videos.

133
Please refer to the directory of national and regional TB MAC

AREA EMAIL
National ntbmacph@gmail.com
CAR ntpleprosy.idccar@gmail.com
Ilocos Region r1tbmac@gmail.com
Cagayan Valley cvrtbmac2@gmail.com
Central Luzon ro3tbmac@gmail.com
NCR-North - Caloocan, Malabon, Navotas, tbmacncrnorth@gmail.com
Valenzuela, Pasig, Taguig, Marikina,
Quezon City, Pateros
NCR-South - Manila, San Juan, tbmacsouthncr@gmail.com
Mandaluyong, Pasay, Las Pinas,
Muntinlupa, Paranaque, Makati
CaLaBaRZon pmdt4a@gmail.com
MiMaRoPa mimaropa.tbmac@gmail.com
Bicol bicoltbmac@gmail.com
Western Visayas tbmacwesternvisayas@gmail.com
Central Visayas tbmacregion7@gmail.com
Eastern Visayas region8tbmac@gmail.com
Zamboanga Peninsula r9tbmac@gmail.com
Northern Mindanao tbmacregionx@gmail.com
Davao rtbmac11@gmail.com
SOCCSKSARGEN rtbmac.xii@gmail.com
CARAGA caragatbmac.13@gmail.com
BARMM BARMMtbmac@yahoo.com

134
 ANNEXES
(Each member of the CPG team was required to
complete his/her own
Declarations of Conflicts of Interest)

135
 ANNEX A
SUMMARY OF AFFILIATIONS, EXPERTISE and CONFLICTS OF INTEREST OF
STEERING COMMITTEE

NAME EXPERTISE Affiliations COI DISPOSITION

declared
REGINA P. BERBA Infectious PhilCAT Past Allowed
MD Diseases PSMID National
Clinical UP PGH Chair
Epidemiology The Medical City PhilCAT

MARISSA M. Infectious PSMID Board Allowed

ALEJANDRIA, MD Diseases UP PGH Member of
Clinical The Medical City PSMID
Epidemiology

VINCENT M. Pulmonary PhilCAT Medical Allowed

BALANAG, MD Medicine PCCP Director of
Clinical Lung Center of the Lung
Epidemiology Philippines Center
Philippines
Pulmonary PhilCAT Past Allowed
JUBERT P. National
Medicine PCCP
BENEDICTO, MD Chair
UP PGH
Lung Center of the PhilCAT
Philippines

Pulmonary PhilCAT Past Allowed

LALAINE L. Medicine PCCP National
MORTERA, MD Chair
PhilCAT

136
 ANNEX B
SUMMARY OF AFFILIATIONS, EXPERTISE and CONFLICTS OF INTEREST OF
TECHNICAL WORKING GROUP

NAME EXPERTISE Affiliation COI DISPOSITION

Declared
EVELYN SALIDO MD Interrnal UP NIH None Allowed
Medicine
Rheumatology
Clinical
Epidemiology

MARIO M. Infectious PSMID None Allowed

PANALIGAN, MD Diseases
Clinical
Epidemiology

ROWENA GENUINO, Dermatology UP PGH None Allowed

MD Clinical Makati Medical
Epidemiology Center
Manila Doctors
Hospital
ADELAINE J. LOPEZ, Infectious PSMID None Allowed
MD DIseases

Infectious PSMID None Allowed

DIseases PCP
Westlake MC
Unihealth
MONICA PIA REYES- Southwoods Hosp
MONTECILLO, MD TMC South Luzon
Qualimed
Hospital Sta Rosa
Calamba MC
Univ of Perpetual
Help MC- Binan
JANICE CAMPOS- Infectious PSMID Board Allowed
CAOILI, MD Diseases PhilCAT Member of
Makati Medical PhilCAT
Center and
PSMID
MARC EVANS ABAT, Internal PCP None Allowed
MD Medicine
Geriatrics

ALDRICH IVAN LOIS Clinical None Allowed

BUROG, MD Epidemiology

137
GINA ANTONINA None Allowed
EUBANAS, MD

BRYAN ALBERT LIM, Infectious PSMID None Allowed

MD DIseases

KATHRYN ROA, MD Infectious PSMID None Allowed

Diseases

GELZA MAE ZABAT, Infectious PSMID None Allowed

MD Diseases PMA PCP
St. Luke's MC
UERMMMC
Philippine Heart
Center;
EAMC
Commonwealth
Hosp & MC
JEMELYN U. Infectious PSMID None Allowed
GARCIA, MD Diseases RITM

IAN THEODORE UP NIH None Allowed

CABALUNA, MD

GINA ANTONINA Dermatologist Philippine Allowed

EUBANAS, MD Clinical Dermatology
Epidemiologist Society

KAREN MARIE R. Infectious PSMID None Allowed

GREGORIO, MD Diseases

MARC EVANS ABAT, Internal PCP None Allowed

MD Medicine Phil College of
Geriatrics Geriatic Medicine
Medicine UP PGH
The Medical City
Manila Doctors
Hospital
Cardinal Santos
MC
STEPHANIE CAROL None Allowed
TAN-LIM, MD

MA. TARCELA S. Infectious PSMID PI in study Allowed

GLER, MD Diseases Makati Medical TB Reach
Center

138
JUBERT P. Pulmonary PCCP Past Allowed
BENEDICTO, MD Medicine PhilCAT PhilCAT
UP PGH National
Lung Center Phil Chair

MITZIE MARIE M. Infectious PSMID None Allowed

CHUA Diseases

DEBORAH IGNACIA Hypertension PCP None Allowed

DAVID-ONA, MD Medicine St Lukes Medical
Center
MARIETTO L. Pulmonary PCCP None Allowed
PARTOSA, JR., MD Medicine

MA. KRISELDA Pulmonary PCCP None Allowed

KARLENE G. TAN, Medicine UP PGH
MD

RALPH ELVI M. Pulmonary PCCP None Allowed

VILLALOBOS, MD Medicine UP PGH

LIA PALILEO Adult Medicine PCP None Allowed

VILLANUEVA, MD UP PGH

EVALYN A. ROXAS, Infectious PSMID Past Allowed

MD Diseases PHICS President
UP PGH PHICS
UP CPH
Ospital ng College
Maynila Secretary
Manila Med UP CPH
KINGBHERLY L. LI, Infectious PSMID Board Allowed
MD Diseases PCP member
PHICS PHICS
Chinese General
Hosp and MC

MARISSA J. Infectious PSMID None Allowed

NEPOMUCENO, MD Diseases PCP
Manila Med- Med

ISSA RUFINA S. Infectious PSMID None Allowed

TANG, MD Diseases PCP
Phil Orthopedic
Center
LCP

139
 Pasig COVID-19
Referral Ctr
NKTI
De Los Santos
Medical Ctr
HOWELL H. BAYONA Speech St Lukes None Allowed
MD language Medical Center
(technical Writer) pathologist Global City
Philippine
Society of
Speech
Pathology

140
 ANNEX C
SUMMARY OF DECLARATION OF CONFLICTS OF INTERESTS OF
CONSENSUS PANEL MEMBERS

NAME REPRESENTATIVE DECLARATION OF DISPOSITION BY

CONFLICT OF INTEREST STEERING
COMMITTEE
Elizabeth V. Cadena Philippine Investment Allowed
Tuberculosis PI in research
Society
Rogelio V. Dazo JR Philippine Medical None to declare Allowed
Association
Allan Fabella DOH Adviser to National TB Allowed
Prevalence Survey
Ann Marie Garfin DOH (National TB National TB Program Allowed
Program) manager
Karl Evans Henson Philippine Society None to declare Allowed
of Microbiology
and Infectious
Diseases
Arthur Dessi Roman Philippine Society Board member PSMID Allowed
of Microbiology Medical Specialist of
and Infectious Research Institute of
Disease Tropical Medicine
Maria Encarnita Philippine College Consulting for Pascual Allowed
Limpin of Physicians Pharma for Acetimax
Secretary of the
Philippine College of
Physicians
Executive director on
Action on Smoking and
Health, Philippines
Imelda Mateo Philippine College Regent of Philippine Allowed
of Physicians College of Physicians

Treasure of Philippine
College of Chest
Physician

Vice-president on Action
on Smoking and Health,
Philippines

141
Raquel Evangelista- Philippine None to declare Allowed
Lopez Association of
Family Physicians

Paul Leandrey Philippine None to declare Allowed

Ygusguiza Association of
Family Physicians

Loraine Anne Obana TB Heals None to declare Allowed

Augusto Sablan Jr. Philippine College None to declare Allowed

of Chest
Physicians

Julie Christie Philippine College None to declare Allowed

Visperas of Chest
Physicians

Amelia Sarmiento Philippine Executive Director, Allowed

Coalition Against PhilCAT
TB (PhilCAT)

Aileen David-Wang CHEST Philippines None to declare Allowed

142
 ANNEX D
SUMMARY OF DECLARATION OF CONFLICTS OF INTERESTS OF
EXTERNAL REVIEWERS

NAME AFFILIATION DECLARATION OF DISPOSITION

CONFLICT oF
INTEREST
CAMILO ROA MD PhilCAT NONE Allowed
PCCP

MARY ANN LANSANG MD University of the NONE Allowed

Philippines
RAJENDRA PRASAD WHO NONE Allowed
HUBRAJ YADAV MD

TAUHIDUL ISLAM MD WPRO NONE Allowed

143
144