RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT

Qais Abdulmajeed Haddad

Consultant ID & IC

Security Forces Hospital Program

Riyadh - Saudi Arabia

RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT

History

Epidemiology

Latent Tuberculosis

Diagnosis

Therapy

Vaccine

Infection Control

Future Trends

1.5 m/year = 4110/day

Pulmoary Tuberculosis

TB Pleural effusion

Tuberculous meningitis

CNS Tuberculoma

Milliary tuberculosis

Renal & urogenital tuberculosis

Bone & joint tuberculosis

GIT tuberculosis

TB Peritonitis

Ileocecal TB

Colonic TB

Hepatic TB

TB retinitis

Extrapulmoary Tuberculosis

Tuberculosis History

Neolithic skeleton (stone age)

Spinal TB Pre-Columbian skeleton

Early Egyptian remains

After 1850 Laennec Pulmonary & Extrapulmonary

tuberculosis is one disease

1865 F. Villemin Tuberculosis transmitted to guinea pig by injecting diseased tissue

1882 Koch AFB & its pathogenicity

1840 1920 1860 1900 1940 1960 1980 2000 1880

1993: TB cases decline due to

increased funding and enhanced TB

control efforts

Mid-1970s: Most TB

sanatoriums in U.S.

closed

1884:

First TB

sanatorium

established

in U.S.

1865:

Jean-Antoine

Villemin

proved TB is

contagious

1943:

Streptomycin

(SM) a drug used

to treat TB is

discovered

1882:

Robert Koch discovers

M. tuberculosis

Mid-1980s:

Unexpected rise in

TB cases

1943-1952:

Two more drugs are

discovered to treat

TB: INH and PAS

TB History Timeline

Rifampicin introduced 1967

M. tuberculosis causes most TB cases in the world

Mycobacteria that cause TB:

M. tuberculosis

M. bovis

M. africanum

M. microti

M. canetti

Mycobacteria that do not cause TB (NTM)

e.g., M. avium complex, M. chelonae

Types of Mycobacteria

TB TRANSMISSION

Dots in air represent droplet nuclei containing

M. tuberculosis

Probability that TB will be transmitted depends on:

Infectiousness of person with TB disease

Environment in which exposure occurred

Length of exposure

Virulence (strength) of the tubercle bacilli

The best way to stop transmission is to:

Isolate infectious persons

Provide effective treatment to infectious persons as

soon as possible

TB Transmission

WHO Global TB Report 2014

Incidence: 9 million (2013)

95% occurs in low- and middle-income countries

Alarming increase in the number of patients with MDR-TB and XDR-TB has been noted (East Europe & Africa)

Globally, 45% drop in mortality between 1990 & 2012

Mortality: 1.5 million / year

0.5 million are children

HIV co-infection with TB:

360,000 deaths / year

13% of total active TB infections

RR-TB (Rifampicin Resistant)

MDR-TB (INH+Rifampicin Resistant)

Latent Tuberculosis

LTBI VS. TB DISEASE

Latent TB Infection (LTBI) TB Disease (in the lungs)

Inactive, contained tubercle

bacilli in the body

Active, multiplying tubercle

bacilli in the body

TST or blood test usually

positive

TST or blood test usually

positive

Chest x-ray usually normal Chest x-ray usually

abnormal

Sputum smears and cultures

negative

Sputum smears and cultures

may be positive

No symptoms Symptoms such as cough,

fever, weight loss

Not infectious Often infectious before Rx

Not a case of TB A case of TB

PPD VS IGRA

Latent TB infection (LTBI) diagnosis remained to

be dependent on PPD (Mantoux test) which

was first described by Robert Koch in 1890

PPD needs two patient visits and liable for

observer error in reading

Interferon-Gamma Release Assays (IGRAs) are

whole-blood tests that can aid in diagnosing LTBI

with one patient visit

QFT-TB Gold T-Spot Initial Process Process whole blood

within 16 hours

Process peripheral

blood mononuclear

cells (PBMCs) within 8

hours, or if T-Cell

Xtend® is used, within

30 hours

M. Tuberculosis Antigen

Single mixture of

synthetic peptides

representing ESAT-6,

CFP-10 & TB7.7.

Separate mixtures of

synthetic peptides

representing ESAT-6 &

CFP-10

Measurement IFN-g concentration Number of IFN-g

producing cells (spots)

Possible Results Positive, negative,

indeterminate

Positive, negative,

indeterminate,

borderline

Isoniazid

only

Isoniazid + Rifapentine P Value

Rates of Treatment

completion

69% 82% <0.001

Drug Discontinuation 3.7% 4.9% 0.009

Doses 270 12

Isoniazid VS Isoniazid + Rifapentine

1148 patients had a median age of 30 years

and a median CD4 cell count of 484/ml

This was an open-label, randomized trial of LTBI in HIV

patients (PPD 5mm or more)

Divided in 4 blocks 2:2:2:1

rifapentine (900 mg) plus isoniazid (900 mg) once

weekly for 12 weeks

Rifampin (600 mg) plus isoniazid (900 mg) twice weekly

for 12 weeks

Isoniazid (300 mg) daily for duration of the study (≤6 yrs)

Control regimen of isoniazid (300 mg) daily for 6 months

Conclusions

The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment completion rate

Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid

A Trial of Mass Isoniazid Preventive Therapy

for Tuberculosis Control

In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid for 9 months

If active tuberculosis was diagnosed, they were referred for treatment

Conclusions: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold miners, despite the successful use of isoniazid in preventing tuberculosis during treatment

Laboratory Diagnosis of Tuberculosis

AFB smear by ZN stain and culture remain the

gold standard in diagnosis

Detecting AFB by fluorochrome stain using

fluorescence microscopy

The smear may be stained by auramine-O dye. In this method

the TB bacilli are stained yellow against dark background &

easily visualized using florescent microscope

Advantages:

- More sensitive

- Rapid

Disadvantages:

- Hazards of dye toxicity

- more expensive

- must be confirmed by Z-N stain

Cultures on L J media

Lowenstein –Jensen medium is an egg based media with

addition of salts, 5 % glycerol, Malachite green & penicillin

Advantages: - Specificity about 99 %

- More sensitive (need lower no. of bacilli 10-100 / ml)

- Can differentiate between TB complex & NTM using biochemical reactions

- Sensitivity tests for antituberculous drugs

( St, INH, Rif., E)

Disadvantages: Slowly growing ( up to 8 weeks )

Rapid Radiometric Culture System

BACTEC

specimens are cultured in a liquid medium (Middle

brook7H9 broth base ) containing C14 – labelled palmitic

acid & PANTA antibiotic mixture

Growing mycobacteria utilize the acid, releasing

radioactive CO2 which is measured as growth index (GI)

in the BACTEC instrument

The daily increase in GI output is directly proportional to

the rate & amount of growth in the medium

Microscopic-Observation Drug-Susceptibility

Assay for the Diagnosis of TB

A single MODS culture of a sputum sample offers

more rapid and sensitive detection of

tuberculosis and multidrug-resistant tuberculosis

than the existing gold-standard methods used

Moore DA et al, N Engl J Med 2006;355:1539-50.

Nucleic Acid Amplification (NAP) Test

A new molecular diagnostic test called Xpert MTB/RIF

assay detects M. tuberculosis complex within 2 hours,

with an assay sensitivity that is much higher than that of

smear microscopy

.

Treatment of Tuberculosis

TB Drug Resistance

Mono-resistance

MDR-TB: Resistance to isoniazid and rifampicin

XDR-TB: Resistance to at least isoniazid and rifampicin, and

to any fluoroquinolone, and to any of the 3

2nd line injectables (amikacin, capreomycin & kanamycin)

CDC, Mortal Wkly Rep 2006; 55: 301-5

FLD: Resistance to all first-line anti-TB drugs

SLD: Resistance to second-line anti-TB drugs

TDR: cohort of 15 patients in Iran was reported which

were resistant to all anti-TB drugs tested

Velayati AA et al, Chest 2009; 136: 420-5)

Major Problems in Treatment OF TB

MDR-TB

Paradoxical expansion of TB lesions (brain)

Chronic Liver Disease Raised ALT

Raised bilirubin

Chronic Renal Disease Mild renal impairment

ESRD

Group Anti-TB Drugs Anti-TB Drugs

Group 1: First line Oral

agents Isoniazid, Rifampicin, Pyrazinamide, ethambutol, Rifabutin, Rifapentin

Group 2: Injectable agents Kanamycin, Amikacin, Capreomycin, Streptomycin

Group 3: Fluoroquinolones Levofloxacin, Moxifloxacin, Ofloxacin

Group 4: Oral

Bacteriostatic Second Line

Agents

Para–aminosalicylic acid, Cycloserine, Terizidone, Ethionamide, Prothionamide,

viomycin

Group 5: Agents with an

unclear role in the Rx of

drug resistant TB

Clofazimine, Linezolid,

Amoxicillin/clavulanate, Thioacetazone,

Imipenem/cilastatin, high dose Isoniazid, Clarithromycin

CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY

REGIMENS

Study Regimen PATIENTS ASSESSED

Comp.

N

Failures

N (%)

Relapses

N (%)

1st BTA 1975 2S(E)HR/7HR 99 0 0

2ND BTA 1982 2EHR/7HR 136 0 2 (1.5)

1ST French 1981 2EHR/7HR 85 0 2 (2.4)

2nd French 1974 3E(S)HR/6HR 52 0 2 (3.8)

Arkansas 1984 1HR/8H2R2 751 21 (2.8) 15 (2.1)

San Francisco 88 2HRE/7HR 200 3 (1.5) 4 (2)

9 MONTHS DURATION REGIMENS

CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY

REGIMENS FOR TUBERCULOSIS

6 MONTHS’ DURATION REGIMENS

PATIENTS ASSESSED

Study Regimen Comp.

N

Failures

N (%)

Relapses

N (%)

East Africa BMRC

1983

2HRSZ/4HR (Z) 80 0 1 (1.3)

Singapore BMRC

1985

2(H)HR(S)Z/HR 319 1 (.3) 3 (1)

Singapore BMRC 2HRSZ/4HR(Z) 158 0 3 (1.9)

1986

2nd BTA 1982 2HRS(E)Z/4HR 257 0 4 (1.6)

Poland 1984 2HRSZ/4HR 84 0 0

Algeria 1984 4EHRZ/2HR 131 0 4 (3)

Hongkong/BMRC 6HRZ(S) (E)3 626 0 9 (1.4)

1987

Germany 1982 6HRSZ 95 2 (2.1) 0

BACTERIOLOGIC RELAPSE RATES IN SMEAR-POSITIVE & CULTURE

POSITIVE DISEASE: HIGHLY EFFECTIVE SIX-MONTH REGIMENS WITH ISONIAZID & RIFAMPIN

Study Regimen mo Follow-up mo Patients

Assessed

Bacteriologic

Relapses (%)

US Public

Health Service

study 20

HR 30 220 (9)

Second East

African-BMRC

study

HR 30 164 (7)

East African-

BMRC study

2 SHR/HRZ

2SHRZ/HR

24

24

40

40

0

1 (2)

18 160 4 (2)

Singapore-

BMRC study

2 SHRZ/HRZ

2 SHRZ/HR

24

24

80

80

0

2 (2)

Second BTA study

2 SHRZ/HR 24 125 1 (1)

USPHS TUBERCULOSIS SHORT COURSE (1990)

THERAPY TRIAL 21, RANDOMIZED, MULTI-CNTRE TRIAL

Myco. tuberculosis, positive sputum culture

All susceptible

617 pts. HRZ (2) / HR (4)

445 pts. HR (9)

6 months 9 months

Sputum conversion (16 wks) 95% 90%

Non-compliance 7.7 6.4

Relapse (22 months) 305 2.8

Completed therapy 61 51

TREATMENT ALTERNATIVES WITH SUSPECTED

INITIAL DRUG RESISTANCE

Continuing Regimens

Beginning

Regimens

INH ( R ) OR

INH ( R ) and

SM (R)

SM ( R )

(1) HRE (2) RE (10) HR (7)

(2) HRZS (2) RE (10) HR (7)

(3) HRZE (2) RE (10) HR (7)

SHORT COURSE FOR EXTRAPULMONARY

TUBERCULOSIS

350 pts 402 sites

Pleural (119), Disseminated (51), GU (51)

Lymphatic (56), Bone/joints (26), Vertebral (21)

Abdominal (21), Meningeal (18), Pericardial (12)

Laryngeal (13), Misc (14)

HR (1) daily/ H (300mg), R (600mg)

HR (8) TW H (900mg), R (600mg)

Mortality 5/297 = 1.7%

Treatment failure 6/297 = 2.0%

Late relapse 2/297 = 0.7%

Ann Int. Med 1986 ASIM DUTT

Four-Month Moxifloxacin or Gatifloxacin

Based Regimens for Drug-Sensitive TB

Gillespie S et al, NEJM 2014

Merle CS et al, NEJM 2014

Fouad M, Ann Pharmacother 2011

Conde MB et al, Lancet 2009

Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown

THE IMPACT OF DOT ON EPIDEMIOLOGY

The WHO-recommended Stop TB Strategy provides

the framework for treating and caring for those who

are sick and controlling the epidemic of drug-susceptible and drug-resistant disease

The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national

programs designed to control disease by means of

early diagnosis with the use of bacteriologic testing,

standardized treatment with supervision and patient support, and provision and management of the

drugs used in treatment

Where might ―new‖ anti-TB drugs

come from

Repurposing of existing drugs used for other infections:

Fluoroquinolnes, linezolid, clofazimine

Improved use of existing TB drugs:

Rifamycins

Development of new chemical entities:

Bedaquiline (TMC207) (Diaryquinoline)

Delamanid (OPC67683) and Petomanid (Nitroimidazole)

Sutezolid and AZD5847 (Oxazolidinone)

SQ109 (Ethylene diamine)

FDA NEWS RELEASE

For Immediate Release: Dec. 31, 2012

Media Inquiries: Sandy Walsh, 301-796-4669, sandy.walsh@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

On Dec. 28, the U.S. Food and Drug Administration approved Sirturo

(bedaquiline) as part of combination therapy to treat adults with multi-drug

resistant pulmonary tuberculosis (TB) when other alternatives are not

available.

BEDAQUILINE

Bedaquiline fumarate is an oral diarylquinoline; it was

approved by the United States Food and Drug Administration (FDA) in 2012 for treatment of multidrug-

resistant tuberculosis (MDR-TB)

Provisional Centers for Disease Control and Prevention

(CDC) guidelines have been issued for both approved

and unapproved uses

The World Health Organization (WHO) has also

published recommendations on the use of bedaquiline

BEDAQUILINE

Toxicity — The FDA issued a black box warning to alert healthcare practitioners regarding an increased rate of death due to QT prolongation has been observed among patients treated with bedaquiline compared with patients treated with placebo (11.4 percent versus 2.5 percent, respectively).

Bedaquiline may also result in increases in liver function tests

Delamanid (OPC-67683)

Delamanid (OPC-67683), a new agent derived from the nitro-dihydro-

imidazooxazole class of compounds

Inhibits mycolic acid synthesis,

Has shown potent in vitro and in vivo activity

Against both drug-susceptible and drug-resistant

Administered at doses of 200 and 300 mg daily resulted in a decrease in the

sputum M. tuberculosis burden that was similar to that of the potent

antituberculosis drug rifampicin in previous studies of early bactericidal activity

TB Recurrences: Relapse vs Reinfection

In a population‐based study in northern Malawi, tuberculosis patients diagnosed from 1996‐2010 were actively followed after the end of treatment

Whole genome sequencing with approximately 100X coverage was carried out on all available cultures

IS6110 Restriction Fragment Length Polymorphism (RFLP) was available on cultures up to 2008

a single nucleotide polymorphism (SNP) difference of:

≤10 SNPs was used to define relapse

>100 SNPs for reinfection

Guerra‐Assunção1 JA et al, J Infect Dis 2014

TB Recurrences: Relapse vs Reinfection

Of 1471 patients 139 had laboratory-confirmed recurrences:

55 had relapse

20 had reinfection

64 type of recurrence was unclassified

Almost all relapses occurred in the first 2 years

HIV infection was associated with reinfection but not relapse

Relapses were associated with:

Isoniazid resistance

Treatment before 2007

Lineage-3 strains

Guerra‐Assunção1 JA et al, J Infect Dis 2014

TB Vaccine - BCG

The protection conferred by the BCG vaccine is significantly greater when the vaccine is administered to neonates or school children and for miliary or meningeal TB

Protection against pulmonary TB, which accounts for the majority of TB mortality and morbidity worldwide, is age dependent

In children,protection against pulmonary TB can reach up to 80% [5]; however,

only 50% of adults are protected, and some studies have reported no real preventive effects

Previous exposure to environmental mycobacteria appears to be an important limiting factor for the BCG vaccine

Subjects with latent TB infection are less protected and the vaccine’ efficacy has been shown

N. Principi; Tuberculosis 2014 (in press)

N. Principi; Tuberculosis 2014 (in press)

TB Infection Control

Negative pressure room

Wear N95 mask

Hand Hygiene

Limit patient movement

(put mask if patient moved to radiology, surgery, etc …)

Investigate family contacts and close contacts

No need for special hospital or sanatorium

WHO Ambitious Target

Reducing TB incidence to 10 per 105 by year 2035

Aim at eliminating TB as a public health problem

by 2050 (reducing TB incidence to 1 per 105)