Crossroads in TB Management - thoracicsocietythai.org

เช่ียวชาญศาสตร์สรรพ์ ยดึม่ันคุณธรรม ชีน้ าสังคม

Crossroads in TB Management

Nitipatana Chierakul

Division of Respiratory Disease and Tuberculosis,

Department of Medicine,

Siriraj Medical School

11:00-11:30 AM, November 23rd, 2018

เช่ียวชาญศาสตร์สรรพ์ ยดึม่ันคุณธรรม ชีน้ าสังคมWHO 2018 Thailand Population 69 Million


Thailand Population 69 Million WHO 2018



Encounter with asymptomatic abnormal CXR

Pulmonary TB disease monitoring

Handle of anti-TB drug-induced liver injury DILI


Cavitary TB at Superior Segment of Right Lower Lobe


False Smear-negative Pulmonary TB

• A 65-year-old man with DM,

30 pack-years current

smoker, presented with low-

graded fever and scanty

hemoptysis

• Treatment for smear-

negative, one month later,

stroke-mimic occurs,

CT-scan reveals bleeding

multiple brain metastases


Low-dose CT for Minimal Pulmonary TB

• A 22-year-old nurse developed anterior

uveitis, CXR was reported to be normal,

but tuberculin skin test is 15 mm

• Opthalmologist consults for TB

consideration while treated with

prednisolone


What should we do when

encounter smear-negative pulmonary TB

Start anti-TB drugs if CXR reveal new cavity, adenopathy, or miliary pattern

Bronchoscopy CT scan if no suggestive CXR pattern and harbour risk of TB or lung cancer

Otherwise, follow-up clinical symptoms and radiological findings every 3 months for 2 years

Also take risk for transmission and side effect of anti-TB drugs into consideration


Inappropriate Use of Indirect Diagnostic Tools

• A 43-year-old man developed

severe back pain for 1 month

• Progressive paraparesis after

treatment with anti-TB drugs for 8

weeks, surgical tissue reveals

metastatic hepatoma


WHO Policy Statement 2011


• A 45-year-old man

HCW, previously

healthy, developed

smear-positive PTB

• After 2-month

intensive phase

treatment, symptoms

were markedly

improved

D0

AFB 3+

D56

AFB 1+


Can Serial Qualitative PCR Monitoring Predict

Outcome of PTB Treatment?Chierakul N, et al. Respirology 2001; 6:305-9.

53 patients with PTB, non-HIV, drug-sensitive,

23 female , 4 DM, 31 had cavity, 14 had extensive disease

8 weeks 16 weeks 24 weeks

Culture + 15 - -

Smear + 41 11 -

PCR + 53 21 7 Among 4 with persistent PCR after complete treatment, 1 had slow

smear and culture conversion and do relapse 6 months later

Presence of cavity and extensive disease can determine smear

persistence at 8 weeks (RR 3.23 and 2.11, p 0.04 and 0.03) but not for

culture conversion


Positive Smears After Intensive Phase

Poorly supervised and non-adherence to the regimen

Poor quality of anti-TB drugs Doses of anti-TB drugs are below the

recommended range Extensive cavitation and heavy initial bacillary

load Non-viable bacilli Co-morbid conditions interfere either with

adherence or with response Drug-resistant M. tuberculosis


Prompt Empiric Treatment for MDR-TB

desire • A 55-year-old man has

had smear-positive

pulmonary TB (AFB 3+)

• After complete 2 months

of HRZE his clinical

symptoms and CXR were

not improved, AFB 2+

• Xpert MTB/RIF was

positive, empiric MDR-TB

regimen was prescribed,

subsequent DST reveals

H and R resistant isolates


M0: S +

M2: S -

PDST M0

GDST(+PDST)

Close follow-upRepeat GDST as dictated

Repeat smear at M5Repeat CXR at M6

Responder

MDR-TB regimensAdjust after PDST

Other GDST or

Repeat same GDSTConsultation

Y

Y

Y

Y

N

N

-N

-

Algorithm for Pulmonary TB Disease Monitoring

Adjust accordingly

-N

GDST: genotypic DST (Xpert MTB/RIF, Hain LPA test)

PDST; phenotypic or conventional DST


M0: S -

M2: S -

PDST M0

GDST(+PDST)

Close follow-upRepeat GDST as dictated

Repeat smear at M5Repeat CXR at M6

Responder

MDR-TB regimensAdjust after PDST

Other GDST or

Repeat same GDSTConsultation

Y

Y

Y

Y

N

N

-N

-

Algorithm for Pulmonary TB Disease Monitoring

Adjust accordingly

-N

GDST: genotypic DST (Xpert MTB/RIF, Hain LPA test)

PDST; phenotypic or conventional DST


WHO Policy Statement 2013

• Xpert MTB/RIF should be used

rather than microscopy,

culture and DST as the initial

diagnostic test in MDR-TB

suspects or HIV-associated TB

• May be used in all adults

suspected of having PTB and

EPTB

• May be used as a follow-on

test if no risk of MDR-TB or

HIV-associated TB, especially

when further testing of S- is

necessary


WHO’s Policy Recommendation 2016

Line probe Assay (FL-LPA)• For persons with S+ or a cultured

isolate of MTB complex (MTBC),

LPAs may be used as the initial

test instead of phenotypic

culture-based DST to detect R

and H resistance

(conditional recommendation,

moderate certainty)

• Not recommended for the direct

testing of S-

• Conventional culture-based DST

must also be performed

• Negative H-resistance must be

interpreted along with clinical

probability

Hain Test


WHO’s Policy Recommendation 2016

Second-line Line probe Assay (SL-LPA)

• May be used as the initial test, instead of phenotypic

culture-based DST, to detect resistance to FQs and

second-line injectable drugs (SLID)

• Can be used both directly (initial specimen) or

indirectly (cultured specimen) both for PTB (regardless

of smear status) and EPTB

• Phenotypic DST is still be necessary to confirm

resistance to other drugs, and for evaluation those with

negative SL-LPA with high clinical suspicious for

resistance to FQs and SLID

• Moxifloxacin and gatifloxacin can be used according to

phenotypic DST even they are resisted from SL-LPA


WHO Guideline 2016

Group of Drugs for rifampicin-resistant-TB and MDR-TB Treatment


WHO Guideline 2016

Summary of Changes of 2016 from 2011 Drug-resistant TB Guidelines

• Rapid DST is recommended over conventional testing or no testing at

the time of diagnosis of TB

• Consider shorter MDR-TB regimen (9-12 m) in those

Have not been treated with second-line drugs AND

Exclude resistance to fluoroquinolones and second-line injectable

agents

• ≥ 5 effective drugs during intensive phase: pyrazinamide + 1 from

group A, 1 from group B, ≥ 2 from group C (use 1 from group D2 and

others from group D3 to make 5 drugs if it is not possible as mention

earlier)

• Further strengthened with high-dose isoniazid and/or ethambutol

• Rifampicin-resistant-TB (RR-TB) with isoniazid-sensitive should be

treated with shorter MDR-TB regimen or with conventional MDR-TB

with additional isoniazid

• Clofazimine and linezolid are put in group C

• Clarithromycin and other macrolides are abandoned

• Elective partial lung resection may be used alongside a recommended

MDR-TB regimen


WHO Guideline 2016

EXCLUSION CRITERIA


WHO 2018: Revised Drug for MDR-TB

3 categories and ranked based on effectiveness

and safety

Group A (prioritized): Levofloxacin (Lfx) /

moxifloxacin (Mfx), Bedaquiline (Bdq), Linezolid (Lzd)

Group B (added next) : Clofazimine (Cfz), Cycloserine

(Cs)

Group C (adjuncted): Ethambutol, Delamanid (Dlm),

Pyrazinamide, Imipenem-cilastatin (Ipm-Cln), Meropenem

(Mpm), Amikacin (streptomycin), Ethionamide, PAS

• No longer recommended kanamycin and capreomycin due to

increased risk of treatment failure and relapse

• Amoxicillin-clavulanic acid is only to be used to accompany the

carbapenems


WHO 2018: Rapid Communication for MDR-TB

• Longer regimen (18-20 m) is the preferred

option for most patients

• Kanamycin and capreomycin are no longer

recommended

• Bedaquiline, linezolid, and clofazimine are

rising in importance

• Ethionamide, prothionamide, amikacin, and

streptomycin becoming less important

• Inclusion of drugs is decided upon a balance

of benefits to harms and guided by DST


WHO 2018: Rapid Communication for MDR-TB

• Shorter MDR-TB regimen may still be used but its

role is now impacted by additional requirements

for DST and close monitoring of patients’

response

• Kanamycin is systematically replaced by amikacin

• More emphasis is placed upon DST, active TB

drug safety monitoring and management (aDSM),

monitoring for treatment response, and support to

all patients to complete therapy

• No changes are made to a patient’s regimen

unless a better alternative is available



• Safety and effectiveness of Bdq beyond 6 months was

insufficient

• Optimal duration of Lzd is not established (at least 6 months)

• Position Dlm will be re-assessed

• Evidence on concurrent use of Bdq and Dlm was insufficient

for review.

• Z is only counted as an effective agent when DST results

confirm susceptibility

• Am and S are only to be considered if DST results confirm

susceptibility and high-quality audiology monitoring for

hearing loss can be ensured

• S is to be considered only if Am cannot be used and if DST

results confirm susceptibility (S resistance is not detectable

with SL-LPA and phenotypic DST is required)



• Eligible patients, treatment success was similar

between shorter and longer MDR-TB regimens

• Shorter regimens showed lower risk of treatment

interruption, however were associated with higher

risk of treatment failure and relapse, especially when

resistance to key medicines in the shorter regimen

was present or when longer regimens included one or

more of the New Group A medicines

• Evidence is lacking for the performance of shorter

regimens modified from the standardized form

recommended in 2016 (e.g. Bdl or Bzd replacing the

injectable agent or Lfx replacing Mfx)



• Personalize regimen from innovations in diagnostics

and growing scientific understanding of the molecular

basis for drug resistance and the pharmacokinetics

and pharmacodynamics of TB medicines

• Key issues

• Effective and fully oral treatment

• Ensure drug resistance is excluded (Fqs and

injectables)

• Close monitoring of safety and response

• Low threshold for switching non-responder or

those with drug intolerance to alternative medicines

and/or new regimens based on the regrouping of

agents


WHO 2017: Isoniazid-resistant TB (Hr-TB)

In patients with confirmed R-susceptible and H-resistant TB, treatment with R, Z, E, and levofloxacin is recommended for a duration of 6 months (6 RZELfx) (Conditional recommendation, very low certainty)

In patients with confirmed R-susceptible and H-resistant TB, it is NOT recommended to add S or other injectable agents to the treatment regimen (Conditional recommendation, very low certainty)

Lfx must be last for 6 months, if not, 6 RZE is an alternative


Favorable Minimal Residual Lesion

(fibrosis in less than one lobe)


Non-favorable Moderate Residual Lesion

(fibrosis and tuberculoma confined in 2 lobes)


Non-favorable Profuse Residual Lesion

(bilateral destroyed lungs)


Attribute Favorable Non OR (95% CI) P-value

Sex Male 23 34 0.64 (0.3-1.3) 0.21

Female 35 33

Age > 40 y 24 49 0.26 (0.1-0.6) < 0.001

< 40 y 34 18

HIV + 4 0 NA

- 20 30

Cavity + 10 27 0.31 (0.1-0.7) 0.005

- 48 40

Extensive lesion + 12 37 0.22 (0.1-0.5) < 0.001

- 45 30

Drug resistance + 7 10 0.78 (0.3-2.2) 0.64

- 51 57


Anti-TB

Drug-induced Liver Injury (DILI)

• A 33-year-old man developed miliary

TB and CNS tuberculoma

• After 2-week treatment with HRZE

he had nausea and vomiting, LFT:

TB/DB 1.6/0.7, AST/ALT 65/70 (<40),

ALP 260 (<115)

• Continue current medications with

adding antiemetic drugs

• One week later, he develops full-

blown hepatitis, failure for RMP

challenging


Anti-TB Drug-induced Liver Injury (DILI)

Risk Factors

Advanced age

Alcoholism

Previous significant liver abnormalities

HBV, HCV, and HIV infection

Malnutrition

Concomitant potential hepatotoxic drugs:

antiepileptics, methotrexate


Antituberculosis-DILI

Inform the patients before prescription

Avoid alcohol and hepatotoxic agents

Baseline LFTs for those harbour risks

• Normal or near normal: repeat if symptomatic or every 2-4 weeks during the first 8 weeks

• Abnormal: close observe, repeat if symptomatic or 1-2/week during the first 2 weeks and then every 2 weeks during the intensive phase

Always aware for confounding viral hepatitis


Antituberculosis-DILI

Elevation of ALT > 3 times with symptoms or 5 times without, ¾ occurs in first 2 months

Weigh between disease severity and degree of liver impairment, consider discontinue or replace less hepatotoxic agents (ethambutol, quinolones, aminoglycosides)

Drug challenging with low-dose or full-dose (R H Z) every 3-7 days after ALT < 2 times, rechecking if symptoms recur, the last drug added should be stopped

Up to ¾ of those with no pre-existing liver abnormality can resume HRZE

Rechallenge with Z may be hazardous in those with prolonged or severe hepatotoxicity.

Alternative regimens: 6RZE, 2SHRE/6HR, 2HRE/7HR, 2 HZE/10HE, 2SHE/16 HE

Close follow-up in case suspected of TB hepatitis


Comparison 2HRZE/4HR vs 2HRE/7HR

Attribute 2HRZE/4HR 2HRE/7HR

Compliance Average Decreased complete rate

Efficacy Highest Decreased cure rate

Adverse reactions Average Less

DILI Average Less


Thailand Renown

for Tuberculosis

True success is not in the learning,

but in its application to the benefit of mankind

Crossroads in TB Management - thoracicsocietythai.org

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