Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013

Recent Advances in Multidrug-Resistant TB

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Faculty and Disclosure Information

Richard E. Chaisson, MDProfessor of Medicine, Epidemiology and International Health Johns Hopkins UniversityDirector, Johns Hopkins Center for AIDS Research and Center for Tuberculosis ResearchBaltimore, Maryland

Richard E. Chaisson, MD, has disclosed that his spouse has ownership interest in Merck.

Maunank Shah, MD, has no significant financial relationships to disclose.

Maunank Shah, MDAssistant ProfessorDepartment of Infectious DiseaseJohns Hopkins UniversityMedical DirectorTuberculosis ProgramBaltimore City Health DepartmentBaltimore, Maryland

Epidemiology of MDR-TB


Tuberculosis Drug Resistance: Definitions

Acquired drug resistance

– Selection of resistant mutants by inadequate treatment

Primary drug resistance

– Disease caused by an organism that was resistant when infection was acquired

Multidrug-resistant TB

– Resistance to at least isoniazid and rifampin (and other rifamycins)

Extensively drug–resistant TB

– MDR-TB plus resistance to fluoroquinolones and an injectable agent (amikacin, kanamycin, capreomycin)


Drug-Resistant TB: MDR and XDR

Drug-resistant TB first arises from improper treatment

– Wrong selection of drugs by doctors or poor adherence to treatment by patients results in selection of naturally occurring mutants with innate resistance

Patients with acquired drug-resistant TB can spread infection to others, causing primary resistance in their contacts

In many countries, transmission of drug-resistant TB is now more common than acquired resistance[1]

The key prevention strategies for drug-resistant TB are:

– Avoid creating new cases by treating TB properly and thoroughly

– Prevent transmission of infection through early and proper diagnosis and infection control

1. WHO. 2013. Surveillance of drug resistance in tuberculosis.


MDR-TB: Epidemiology

In 2012, an estimated 450,000 new cases of MDR-TB emerged globally[1]

Among all new cases of TB, 3.6% are estimated to have MDR-TB[1]

An estimated 20% of persons with previously treated TB have MDR-TB[1,2]

More than one half of the new MDR-TB cases occur in China, India, and the Russian Federation[1]

Mortality in MDR-TB patients usually exceeds 10%[3]

In 2012, MDR-TB caused an estimated 170,000 deaths[1]

1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12. 3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.


MDR-TB Among New TB Cases, 1994-2012

WHO. 2013. Surveillance of drug resistance in tuberculosis.


MDR-TB Among Previously Treated TB Cases, 1994-2013

WHO. 2013. Surveillance of drug resistance in tuberculosis.

Diagnosis of MDR-TB


Diagnosis of MDR-TB

Gold-standard test: Culture of patient specimen (sputum) to assess inhibition of M tuberculosis growth in the presence of antibiotics (phenotypic assay)

Solid-media assays: Result may not be available for 3-6 wks

Automated liquid culture systems: Faster and more sensitive than solid-media cultures; results available in 1-2 wks

Rapid molecular tests can identify genotypic resistance in 1-2 days

– Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time PCR

– Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and rifampin

1-2 days 1-2 wks 3-6 wks 4-12 wks

Average Turnaround Time for Diagnostic Tests


WHO Recommendations: Diagnosis of MDR-TB Xpert MTB/RIF should be used as the initial diagnostic test in

individuals suspected of MDR-TB[1]

However, Xpert MTB/RIF does not eliminate need for conventional microscopy, culture, and DST to monitor treatment progress and to detect resistance to drugs other than rifampin [1]

1. WHO. Xpert MTB/RIF system policy statement 2011. 2. Aurum Institute. Managing TB in a new era of diagnostics. 2012.

Xpert Result[2]

Xpert Positive,Rifampin

Susceptible

Xpert Positive, Rifampin Resistant

Xpert Positive, Rifampin

Unsuccessful

Xpert Negative Xpert Unsuccessful

Interpretation Drug-sensitive TB Presumed MDR-TB Presumed drug-sensitive TB

TB unlikely but further investigation

necessary

No diagnosis

Actions Treat for drug-sensitive TB;

collect sputum for microscopy and culture with DST

Treat with regimen for MDR-TB; collect

sputum for TB culture/DST

Treat for drug-sensitive TB;

collect sputum for microscopy and culture with DST

Collect sputum for TB microscopy and

culture to exclude TB

Collect sputum for TB

microscopy and culture to

exclude TB


Performance of Xpert MTB/RIF vs Other Diagnostic Modalities

Boehme C, et al. Lancet. 2011;377:1495-1505.

Proportion of TB Cases and Resistance Results by Each Method in Culture-Positive Patients

Liquid cultureMTB/RIF testSolid cultureMicroscopy

TB

Ca

ses

De

tect

ed (

%)

100

90

80

70

60

50

40

30

20

10

01000 20 40 60 80

Days to Detection

100%

90%

89%

67%

Line-probe assayMTB/RIF testPhenotypic drug-susceptibility testing

0 20 40 60 80 100 120 140Days to Detection

100%

94%

RIF

Res

ista

nce

Det

ecte

d (

%)

100

90

80

70

60

50

40

30

20

10

0


Time to DST Results Halved With MDR Line Probe Assay in South Africa

Time Period Median Time, Days (IQR) P Value

Before LPA After LPA

1 Sputum collection to lab receipt of sample

1 (0-1) 0 (0-1) < .001

2 Lab receipt to DST testing 27 (21-34) 19 (12-31) < .001

Smear positive 26 (21-43) 13 (9-16) < .001

Smear negative 29 (22-43) 29 (22-42) .497

3 DST testing 9 (2-14) 0 (0-1) < .001

Total Sputum collection to DST results available

52 (41-77) 26 (11-52) .008

Sputum collection

Lab receiptof sputum

DST started DST results reported

1 2 3

Hanrahan CF, et al. PLoS One. 2012;7:e49898.


Time to MDR Treatment Before and After Line-Probe Assay in South AfricaFrom initial patient sputum sample to date of appropriate MDR therapy

Mos to MDR Treatment

80 2 4 6

1.00

0.75

0.50

0.25

0Cu

mu

lati

ve P

rop

ort

ion

on

M

DR

Tre

atm

ent

After LPABefore LPA (study data)Before LPA (undetected MDR modeled)

Hanrahan CF, et al. PLoS One. 2012;7:e49898.


Resistance at Start of Second-line TB Therapy

Drug Resistance, n (%)

First-line drugs Ethambutol 826 (64.6) Streptomycin 881 (69.0) 4 first-line drugs* 625 (49.0)

Second-line drugs

Any second-line drug 559 (43.7) At least 1 fluoroquinolone 165 (12.9)

Second-line Injectable drugs

Kanamycin 237 (18.5) Amikacin 205 (16.0) Capreomycin 152 (12.0) At least 1 255 (20.0) All 134 (10.5)

Other oral second-line drug

Ethionamide 249 (19.5) Aminosalicylic acid 137 (10.7) At least 1 346 (27.1)

XDR-TB 86 (6.7)

PETTS Study: Prevalence of Drug Resistance in 1278 Pts With MDR-TB 1278 pts enrolled in several

countries at start of second-line TB treatment, 2005-2008

DST done centrally at CDC

High levels of resistance to second-line drugs detected

– 43.7% with resistance to ≥ 1 second-line drug

– 20% with resistance to ≥ 1 injectable second-line drug

– 12.9% with resistance to ≥ 1 fluoroquinolone

– 6.7% with XDR-TB

Dalton T, et al. Lancet. 2012;380:1406-1417. *Isoniazid, rifampin, ethambutol, streptomycin.

Principles of MDR-TB Treatment


MDR-TB General Principles

An individualized approach should be undertaken

– Guided by drug susceptibility testing when available

– Assessment of comorbidities that may affect therapy should be undertaken before therapy

Never add a single drug to a failing regimen

Use at least 3-5 previously unused drugs to which an isolate has in vitro susceptibility

Supervise treatment to ensure adherence

Continue treatment for at least 18-24 mos after culture conversion

WHO. Guidelines for programmatic management of drug-resistant TB. 2011.Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.


Drugs for MDR-TB

Group 1: First-line oral drugsEthambutol Pyrazinamide High-dose isoniazid

Group 2: Fluoroquinolones

LevofloxacinMoxifloxacin GatifloxacinOfloxacin

Group 3: Injectable drugs

Kanamycin Amikacin CapreomycinStreptomycin

Group 4: Oral bacteriostatic second-line drugs

Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid

Group 5: Drugs of unclear efficacy

Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanateThioridazine*Other newer drugs

Adapted from: Chang KC, et al. Respirology. 2013;18:8-21.*Newer drugs will be discussed later in the educational activity.


Building a Treatment Regimen for MDR-TB

Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians. Chang KC, et al. Respirology. 2013;18:8-21.

Step 1: Include any first-line drugs to which the isolate is susceptible

Injectables

Kanamycin Amikacin Capreomycin Streptomycin

Step 2: Add a fluoroquinolone

Fluoroquinolone

LevofloxacinMoxifloxacin Gatifloxacin

First-line Drugs

Ethambutol Pyrazinamide

Step 3: Include an injectable agent

Oral Second-line Drugs

Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid

Third-line Drugs

Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanateThioridazineOther new drugs

Step 4: Include second-line drugs until you have 4-6 drugs to which the isolate is susceptible

Consider third-line drugs if there are not 4-6 drugs to which the isolate is susceptible


Treatment Regimens for MDR-TB

Resistance Pattern Regimen Comments

INH and RIF Strept PZA + EMB + FQN + injectable (for ≥ 6 mos) + second-line agent if

extensive disease

Treat 18-24 mos following conversion

INH, RIF + (PZA or EMB)

(PZA or EMB) + FQN + 2 second-line agents + injectable agent (for

first 6 mos)

Treat 18-24 mos following conversion;

consider additional agents, high-dose INH

INH, RIF, PZA, EMB FQN + 3 second-line agents + injectable drug for first 6-12 mos

Treat 18-24 mos following conversion

INH, RIF, PZA, EMB, FQN

Injectable + 3 second-line agents + third-line agents

Treat 24 mos following conversion;consider high-dose INH,

Surgery

INH, RIF, PZA, EMB,injectables

FQN + all available second-line agents; consider any third-line

agents if susceptible

Treat 24 mos following conversion;consider surgery

Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.


“Bangladesh” Regimen: Experimental Short-Course Treatment for MDR-TB

Controlled trial under way to confirm the efficacy of this regimen

van Deun A, et al. Am J Respir Crit Care Med. 2010;182:684-692.

*Resistance likely for many MDR patients.

Phase Drugs

4-mo intensive phase High-dose INH*Prothionamide*KanamycinGatifloxacinEthambutol*Pyrazinamide*Clofazimine

5-mo continuation phase Gatifloxacin Ethambutol*Pyrazinamide*Clofazimine


Potency and Tolerability of Existing TB Drugs

Dorman SE, et al. Nat Med. 2007;13:295-298.

Increasing potency, reliability, reproducibility of susceptibility testing

Decreasing tolerability

Fir

st-l

ine

Dru

gs

Sec

on

d-l

ine

Dru

gs

RifampinIsoniazidPyrazinamideEthambutol

Fluoroquinolones(moxifloxacin, gatifloxacin,levofloxacin)

Injectable agentsAminoglycosides (streptomycin,amikacin, kanamycin)Polypeptides (capreomycin)

Oral bacteriostatic agents(ethionamide, protionamide, cycloserine/terizidone, p-aminosalicylic acid, thiacetazone)

Agents with unclear efficacy (clofazimine, amoxicillin-clavulanate, clarithromycin, linezolid)


Adverse Effects of MDR-TB Drugs

Drug Toxicities and Adverse Effects

Ethambutol Visual acuity, color vision

Pyrazinamide Hepatotoxicity

Isoniazid Neurologic effects, hepatotoxicity

Injectables Vestibular, renal toxicity, hearing loss

Fluoroquinolones GI, CNS, cardiac toxicities, tendinopathy

Cycloserine/terizidone CNS toxicity, behavioral changes

Ethionamide GI toxicity, hypothyroidism

PAS GI toxicity, hypothyroidism, osteoarticular pain.

Clofazimine Changes in skin and ocular pigmentation, GI effects

Linezolid Thrombocytopenia, neutropenia, neuropathy, metallic taste

Aurum Institute. Managing TB in a new era of diagnostics. 2012.

Newer Drugs for MDR-TBPrevention Strategies


Bedaquiline

Oral diarylquinoline

Target: ATP synthase

– Activity specific to mycobacteria

Bactericidal activity comparable to RIF-INH-PZA in mice

Sterilizing activity comparable to rifampin in mice

Synergy with PZA

No cross-resistance with other antimycobacterial drugs (INH, RIF, EMB, PZA, streptomycin, amikacin, or moxifloxacin)

Andreas K, et al. Science. 2005;307:223-227. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.

Br

N O

(S)

HO(R) N


C208: Phase II Trial of Bedaquiline for MDR-TB Stage I study: 47 pts with newly

diagnosed pulmonary MDR-TB randomized to bedaquiline or placebo in combination with 5-drug second-line TB regimen

– BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 6 wks

BL resistance: pyrazinamide, 65%; ethambutol, 59%; kanamycin, 8%; ofloxacin, 8%; ethionamide, 8%

BDQ reduced time to culture conversion (HR: 11.8; 95% CI: 2.3-61.3; P = .003)

Incidence of AEs similar between arms

– Nausea more frequent in BDQ vs placebo: 26% vs 4% (P = .04).Diacon AH, et al. N Engl J Med. 2009;360:2397.

0

0.2

0.4

0.6

0.8

1.0

0 7 42 C

ult

ure

-Po

siti

ve P

atie

nts

(%

)14 21 28 35 49 56

Placebo (n = 24)Bedaquiline (n = 23)

Days

52%

91%


C208: Phase II Trial of Bedaquiline for MDR-TB Stage II study: 15 sites in Brazil,

India, Latvia, Peru, Philippines, Russia, South Africa, Thailand

Pts randomized to receive BDQ (n = 67) vs placebo (n = 66) for 24 wks with 5-drug BR

– BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 22 wks

After Wk 24, both groups continued the 5-drug BR to total of 96 wks

Culture conversion at Wk 24 significantly higher with bedaquiline vs placebo

Cure rate also significantly higher

WHO. The use of BDQ in treatment of MDR-TB—interim policy guidance. 2013.

Outcome BDQ Placebo P Value

Median time to sputum conversion, days (95% CI)

83(56-97)

125(98-168)

< .0001

Pts with culture conversion, %Wk 24Wk 72Wk 120

78.871.262.1

57.656.143.9

.008

.069

.035

Proportion cured, %

57.6 31.8 .003


FDA Bedaquiline Indication

Approved by FDA in 2012 as part of combination therapy in adults with pulmonary MDR-TB

– Should be used only when an effective treatment regimen cannot otherwise be provided[1]

Recommended dose: 400 mg PO QD for 2 wks, then 200 mg PO TIW, for a total duration of 24 wks

First drug with novel mechanism approved by FDA for TB since 1971

Bedaquiline [package insert].


CDC Provisional Guidance on Bedaquiline

BDQ may be used as a component of TB therapy when an effective treatment regimen cannot otherwise be provided

– Administer by DOT for 24 wks with food in adults with laboratory-confirmed pulmonary MDR-TB

– Use on case-by-case basis in children, HIV-positive pts, pregnant women, pts with extrapulmonary MDR-TB, and pts with comorbid conditions on concomitant medications

– Use on case-by-case basis for durations > 24 wks

CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.


WHO Interim Guidance on Use of Bedaquiline BDQ may be added to a WHO-recommended regimen in

adult MDR-TB patients under following conditions:

– When an effective treatment regimen containing 4 second-line drugs in addition to PZA, according to WHO recommendations, cannot be designed

– When there is documented resistance to any fluoroquinolone in addition to MDR

– Recommended for adults older than 18 yrs of age under carefully monitored conditions

WHO. Bedaquiline for MDR-TB. 2013.


Bedaquiline Safety Concerns

Black box warning: increase in all-cause mortality and prolongation of QT interval—monitor EKGs[1]

– 30 deaths occurred in the clinical trial program in patients receiving BDQ vs 6 on placebo[2]

BDQ should be used with caution with other drugs that can cause QT interval prolongation and EKGs should be monitored more often[1]

– Includes clofazimine and fluoroquinolones

BDQ should not be used with rifampin or rifapentine, which are strong inducers of CYP3A4[1]

1. Bedaquiline [package insert]. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.


Bedaquiline Monitoring

All patients should be monitored wkly for adverse effects

EKGs should be monitored at baseline and at least 2, 12, and 24 wks after starting treatment

Serum potassium, calcium, and magnesium should be measured at baseline and whenever clinically indicated, especially if QT interval prolongation is detected

All patients started should be included in a registry for ongoing monitoring

Additional notes:

– Bedaquiline should never be used as a single drug

– Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before other drugs in regimen

– Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations

– Bioavailability is significantly affected by food

CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.


Delamanid (OPC-67683)

Nitro-dihydro-imidazooxazole

Derivative of metronidazole

Inhibits mycolic acid synthesis

Potent preclinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of TB

Skripconoka V, et al. Eur Respir J. 2013;41:1393-1400.

N

O

O

FF

FOOO

ON+

N

N


Delamanid: Phase II Trial vs Placebo

Multinational trial of pts with pulmonary MDR-TB

Pts randomized to 2 mos of

– Delamanid 100 mg (n = 161)

– Delamanid 200 mg (n = 160)

– Placebo (n = 160)

– Each with WHO BR

Primary endpoint: sputum culture conversion at 2 mos

Delamanid significantly increased rate of sputum conversion vs placebo after 2 mos of treatment

QT prolongation reported significantly more frequently with delamanid

All other AEs mild to moderate and similar among groups

Gler MT, et al. N Engl J Med. 2012;366:2151-2163.

Pat

ien

ts (

%)

41.929.6

45.4

100

80

60

40

20

0Delamanid

200 mgDelamanid

100 mgPlacebo

57/136 37/12564/141

P = .04

P = .008

n/N =

Mycobacterial Growth Indicator Tube Culture Conversion at Day 57


EMEA Delamanid Recommendation

In November 2013, the European Committee for Medicinal Products for Human Use recommended granting a conditional marketing authorization for delamanid for the treatment of MDR-TB

Recommended indication:

– Use as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability

EMEA. Marketing authorization for delamanid. November 2013.


Linezolid

Oxazolidinone, approved to treatdrug-resistant, Gram-positive bacteria

Good activity against MDR-TB in vitro and in animal studies

Use in TB often limited due to long-term toxicities (bone marrow suppression, neuropathy)

However, retrospective chart review (2003-2007) of 30 pts (29 with pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as part of a regimen for MDR-TB concluded[1]:

– Culture conversion occurred in all pulmonary cases at median of 7 wks

– AEs occurred in only 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea

– Only 3 patients stopped linezolid treatment because of AEs

1. Schecter GF, et al. Clin Infect Dis. 2010;50:49-55.

F

ON

N

O

O O

NH


Linezolid 600 mg QD immediately*

Linezolid 600 mg QDdelayed by 2 mos*

Pts with sputum-culture–positive XDR-

TB (no response to any TB drugs in previous 6 mos)

(N = 41)

Smear conversion or 4 mos

*All pts remained on background regimen of drugs they were taking before study entry.Second randomization continued at least 18 mos after smear conversion or after 4 mos on first regimen.

Linezolid 600 mg QD

22 mos

Linezolid 300 mg QD

Lee M, et al. N Engl J Med 2012;367:1508-1518.

Phase II Trial of Linezolid in Patients With XDR-TB Phase II trial in South Korea

Primary endpoint: time to sputum-culture conversion on solid medium (data censored 4 mos after study entry)

Linezolid 600 mg QD

Linezolid 300 mg QD


Phase II Trial of Linezolid in Patients With XDR-TB Culture conversion at 4 mos:

– 79% (15/19) in immediate arm vs 35% (7/20) in delayed arm (P = .001)

87% (34/39) with negative sputum culture within 6 mos

31 pts (82%) with clinically significant AEs related to LZD

– 3 pts d/c therapy

Pts on LZD 300 mg on second randomization had fewer AEs

13 pts completed therapy without relapse

4 pts acquired LZD resistanceLee M, et al. N Engl J Med. 2012;367:1508-1518.

1.0

0.8

0.6

0.4

0.2

00 30 60 90 120 150 180

Days Since Start of LZDC

um

ula

tive

Pro

bab

ility

o

f C

on

vers

ion

Conversion Probability According to Time on Treatment


Sutezolid (PNU-100480)

Oxazolidinone, related to linezolid

MOA: protein synthesis inhibition[1]

Like LZD, has a high barrier to resistance

More potent than LZD in mice, whole blood culture

Efficacy in mice similar to isoniazid and/or rifampin and may be synergistic with other first-line drugs

May be safer than LZD

SN

F

O

N OOH

NH

CH3

1. Alffenaar JW, et al. Antimicrob Agents Chemother. 2011;55:1287-1289.


Early Bactericidal Activity of Sutezolid in HIV+/- Pts With Drug-Susceptible TB Significant log CFU reductions with

both sutezolid regimens during the 14-day treatment period

– 600 mg BID: -0.09 log/day (90% CI: -0.06 to -0.11)

– 1200 mg QD: -0.07 log/day (90% CI: -0.04 to -0.09)

– Trend toward superior response with BID dosing

Both dosing schedules generally safe and relatively well tolerated

– 7/50 sutezolid-treated pts experienced ALT increases to 2-3 x ULN, which were asymptomatic and resolved spontaneously

Wallis RS, et al. AIDS 2012. Abstract THLBB02. Graphic used with permission.

0

-1

-2

-3

140 2 4 6 8 10 12

Day

Ch

ang

e in

lo

g C

FU

1200 QD600 BIDHREZ


PA-824

PA-824: nitroimidazole-oxazine

– Active in vitro and in mouse models

Cross-resistant with delamanid

High protein binding may render PA-824 less accessible in cavities of pulmonary TB

May be useful in combination regimens; synergistic with other drugs

F

F F

O

O

O

O

ONN+


Novel Drug Combinations With PA-824 Show Promise in Mouse Models PA-824 with moxifloxacin and

pyrazinamide cures TB more rapidly than the first-line regimen in mice[1]

Bedaquiline + PA-824 + sutezolid may provide a novel 3-drug backbone for a universally active short-course regimen[2]

Regimen (Duration)

Mice Cured, % (n/N)

4 Mos 5 Mos 6 Mos

RIF-INH-PZA (2 mos) + RIF-INH (4 mos)

50(10/20)

100 (20/20)

100 (20/20)

RIF-MXF-PZA (2 mos) + RIF-MXF (3 mos)

95 (19/20)

100 (20/20)

100 (20/20)

Pa-MXF-PZA (2 mos) + Pa-MXF (4 mos)

100 (20/20)

100 (20/20)

100 (20/20)

RegimenRelapse, % (n/N) After Tx for

2 Mos 3 Mos 4 Mos

RIF + PZA + INH

ND100

(15/15)64

(9/14)

BDQ + SUT + CFZ + Pa

93 (14/15)

13 (2/15)

7 (1/15)

BDQ + SUT + CFZ

87 (13/15)

27 (4/15)

7(1/14)

BDQ + SUT + Pa

100(15/15)

43(6/14)

0(0/15)

BDQ + CFZ + Pa

100(15/15)

60(9/15)

33(5/15)

SUT + CFZ + Pa

100(15/15)

100(15/15)

100(15/15)

1. Nuermberger EL, et al. Antimicrob Agents Chemother. 2008;52:1522-1524. 2. Williams K, et al. Antimicrob Agents Chemother. 2012;56:3114-3120.


HIV-negative or HIV-positive pts* with

newly diagnosed pulmonary smear and culture-positive drug-

sensitive TB(N = 83)

Day 14

Early Bactericidal Activity of Novel Combinations of TB Drugs Phase II trial in TB-infected pts

Diacon AH, et al. Lancet. 2012;380:986-993.

Bedaquiline + Pyrazinamide (n = 15)

Bedaquiline + PA-824 (n = 15)

PA-824 + Pyrazinamide (n = 15)

Rifampin/Isoniazid/Ethambutol/Pyrazinamide (n = 8)

Bedaquiline(n = 15)

PA-824 + Pyrazinamide + Moxifloxacin (n = 15)

*6 HIV-positive subjects.


Early Bactericidal Activity of Novel TB Regimens

0.5

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.00 142 4 6 8 10 12

Day

Lo

g C

FU

Ch

ang

e F

rom

Bas

elin

e

BedaquilineBedaquiline + PZABedaquiline + PA-824

RHEZPA-824 + PZAPA-824 + PZA + moxifloxacin

Diacon AH, et al. Lancet. 2012;380:986-993.

Standard-of-care regimen

Novel PA-824/ PZA/moxifloxacin regimen


Prevention of MDR-TB

Prevention of MDR-TB involves adequate, proper treatment of initial disease to prevent selection of resistance

– Prompt diagnosis with adequate TB treatment under DOT

– Rapid identification of MDR-TB and use of appropriate second-line regimens

– Avoid further evolution of resistance

– Airborne infection control

– Preventive treatment of TB/HIV coinfection with optimal use of ART

Management strategies for established cases mainly rely on specific alternative treatment regimens complemented with surgery in carefully selected cases


Preventive Therapy in Contacts of Pts With MDR-TB in Micronesia 232 contacts of 5 pts with 2 different MDR-TB strains

105 with positive TST received preventive therapy

Strain A: resistant to isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin

– Contacts offered fluoroquinolone alone or in combination with ethionamide

Strain B: resistant to isoniazid, rifampin, and ethionamide

– Contacts offered fluoroquinolone with ethambutol

No cases of MDR-TB developed in those treated

– 28 untreated contacts developed MDR-TB

ECDC. Management of contacts of MDR TB and XDR TB patients. 2012.


Conclusions

Current approaches to MDR-TB therapy are long, with much toxicity

Bedaquiline is the first drug with a novel mechanism of action to be approved by FDA for MDR-TB since 1971

Delamanid recently approved by European Medicines Agency

– Both agents indicated only when an effective regimen cannot otherwise be provided

Multiple new drugs are in the pipeline

Successful eradication of MDR-TB will require new drug regimens with novel drug combinations

Go Online for More CCO Educational Content on Multidrug-

Resistant TB!Interactive Virtual Presentation featuring streaming narration of these slides by expert faculty Richard E. Chaisson, MD, and Maunank Shah, MD

clinicaloptions.com/hiv

http://www.clinicaloptions.com/hiv

Date post:	17-Aug-2015
Category:	Health & Medicine
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Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013

Health & Medicine