Constance A. Benson, MD, director of the UC San Diego AntiViral Research Center, presents "New Drugs and Novel Approaches to Treatment Shortening for Drug-Susceptible and Drug-Resistant TB" for AIDS Clinical Rounds at UC San Diego

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2. Slide 1
New Drugs and Novel Approaches to
Treatment Shortening for DrugSusceptible and Drug-Resistant TB
Constance A. Benson, M.D.
Professor of Medicine
Division of Infectious Diseases
University of California, San Diego

3. WHO Report 2013
Global Tuberculosis Control
Worldwide, 8.6 million new
incident cases of TB in 2012;
1.3 million TB deaths
~1.1 million (13%)
HIV-TB cases;
320,000 HIV-TB deaths
in 2012

4. Global Trends in Estimated Rates of TB
Incidence, Prevalence & Mortality-2012

5. Case Presentation
• 28 y.o. W presents with a 3 week h/o fevers,
night sweats, non-productive cough, dyspnea, 15
lb weight loss, cervical lymphadenopthy
– Visited a cousin 2 months earlier who had fever and
cough at the time of the visit
• Past medical history:
– Brief h/o IDU 10 yrs ago; smoker 1 ppd x 8 yrs; no
other underlying illnesses
• SHX: Born in northern Mexico; employed as a clerical
worker; heterosexual, divorced, 2 children ages 8 and 6

6. Case Presentation
• On exam she is a WNWD woman, ill-appearing
– T 39oC, P 106, tachypneic, bronchial breath sounds
right and left upper lung fields, no murmurs or rubs,
palpable but non-tender anterior cervical LNs
• HIV antibody positive by rapid test (subsequently
confirmed by EIA and WB)
• A sputum sample was obtained
– AFB smear negative
– Pneumocystis DFA negative
– Gram’s stain  PMNs, no organisms seen
• Cultures pending

7. Case Presentation
• CD4+ T cell count 113
cells/µL
• Plasma HIV-1 RNA level
167,800 copies/ml
• Hgb 9.0 gm/dL, WBC
16,800 with normal diff
• O2 sat RA 88%
• Liver chemistry tests
normal
• CXR diffuse interstitial
infiltrates; reticulonodular
pattern

8. Case Presentation
• Hospitalized in respiratory isolation
• Started on rifampin, isoniazid, pyrazinamide,
and ethambutol (RHZE) and trimethoprimsulfamethoxazole for possible TB and possible
Pneumocystis pneumonia
• Bronchoscopy with BAL  friable
endobronchial mucosa; secretions AFB smear
and MTD positive for MTB; DFA positive for
Pneumocystis

9. Case Presentation
• Stable on RHZE and trimethoprimsulfamethoxazole x 2 weeks with clinical
improvement
• Based on low CD4 count she is started on
efavirenz, tenofovir, and emtricitabine with
good initial response
• During a clinic visit 2 months after starting TB
treatment she reported
– Recurrent fevers, night sweats, and had worsening
infiltrates and hilar lymphadenopathy on CXR

10. Reported TB Cases
United States, 1982–2012*
30,000
9,945 new TB cases in
2012; 3.2/100,000
(San Diego 234 new TB
cases; 7.4/100,000)
No. of Cases
25,000
20,000
15,000
10,000
5,000
Foreign born (63%) in 2012;
Mexico, Philippines, India,
Vietnam, China, Guatemala, Haiti
account for 61% of total
0
Year
*Updated as of June 10, 2013.

11. TB Case Rates,* United States, 2012
D.C.
< 3.2 (2012 national average)
>3.2
*Cases per 100,000.

12. Estimated HIV Coinfection in Persons
Reported with TB, United States, 1993 – 2012*
70
% Coinfection
60
50
40
30
20
10
0
Aged 25-44
All Ages
*Updated as of June 10, 2013
Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group

13. WHO Global Tuberculosis Report 2013
Drug Resistance
Globally, 3.6% of new
and 20.2% of
previously treated
cases were MDR-TB
An estimated 9.6% of
MDR-TB cases have
XDR-TB; reported from
92 countries

14. No. of Cases
Primary MDR TB,
United States, 1993 – 2012*
500
Percentage
3
400
2
300
200
1
100
0
0
No. of Cases
Percentage
*Updated as of June 10, 2013.
Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at
least isoniazid and rifampin.

15. XDR TB Case Count Defined on Initial DST*
by Year, 1993 – 2012**
12
Case Count
10
8
6
4
2
0
Year of Diagnosis
* Drug susceptibility test
** Updated as of June 10, 2013.
Note: Extensively drug-resistant TB (XDR TB) is defined as resistance to isoniazid and rifampin, plus resistance
to any fluoroquinolone and at least one of three injectable second-line anti-TB drugs

16. Current Antituberculous Drugs
First-Line Drugs
• Isoniazid (INH)
• Rifamycins
– Rifampin (RIF)
– Rifabutin (RBT)
– Rifapentine
(RPT)*
• Pyrazinamide (PZA)
• Ethambutol (EMB)
Second-Line Drugs
• Streptomycin (injectable)
• Amikacin, kanamycin (injectable)
• Capreomycin (injectable)
• Levofloxacin, moxifloxacin
(fluoroquinolones)
• Cycloserine
• p-Aminosalicylic acid (PAS)
• Ethionamide
• Linezolid
• Bedaquiline, delamanid†

17. Initial Treatment of Drug Susceptible
Tuberculosis
• Intensive phase
– INH, RIF, PZA, EMB daily x 2 months (56 doses)
– Twice or thrice per week dosing schedules for DOT*
• Continuation phase
– INH, RIF daily x 4 months (126 doses)
– Twice or thrice per week dosing schedules for DOT*
• Extend duration….
– 9 months for severe cavitary or extrapulmonary
disease
– 9-12 months for CNS, bone/joint disease
*Not recommended for HIV-infected patients

18. Management of MDR-TB and XDR-TB
• Drug susceptibility for second line agents
• Primary (need treatment history from index case if possible)
– INH/RIF/PZA/EMB + fluoroquinolone + 2 additional
drugs empirically until DST results are known
• Acquired (need previous treatment history if possible)
– Start with at least 4 new drugs not previously used
– Modify based on DST results to provide at least 4
active drugs
• Treatment for 18-24 months

19. Treatment Outcomes for MDR-TB
• Overall cure rate for ~34,000 MDR-TB globally
~40-60%; highest for the Americas and
Eastern Mediterranean regions in 2010
• Subset of 795 with XDR-TB, success rate 20%
overall and 44% died

20. Why Do We Need New TB Drugs?
• Drug Resistant TB
• Challenges of current therapy
– Prolonged duration/multiple drugs
• Compromises adherence, treatment completion
• Tolerability, toxicities and drug interactions
– Cost
• Costs associated with DOT, adverse events, consequences of
interrupted or incomplete therapy (MDR and XDR TB)
• Public health “costs”  transmission
• More effective, better tolerated, more convenient
regimens of shorter duration could improve this
landscape

21. New Drugs and Classes in the
Pipeline for TB Treatment
• Bedaquiline (TMC-207): diarylquinoline; inhibits
mycobacterial ATP synthase
• Delamanid (OPC-67683) and PA-824:
nitroimidazoles; inhibit mycolic acid synthesis
• Sutezolid (PNU-100480), linezolid, AZD-5847:
oxazolidinones; inhibit protein synthesis
• SQ-109: ethambutol analogue; blocks cell wall
synthesis, prevents efflux of companion drugs from
macrophages
• Long acting rifamycins (rifapentine and others)

22. Slide 21
Bedaquiline for Treatment of MultidrugResistant TB
 Phase 2b RCT in 47
patients with newly
diagnosed MDR-TB
randomized to TMC-207 vs
placebo + 5-drug regimens
 AEs potentially associated
with TMC207

Nausea, arthralgia, H/A,
hyperuricemia, vomiting
Week 8 interim analysis
1.0
Proporion Culture-Positive Patients
 TMC207 (Bedaquiline) is a
diarylquinoline
91.3%
0.8
P = .003
0.6
TMC207
0.4
52.5%
Placebo
0.2
0.0
Diacon AH, et al. NEJM 2009; 360:2397-405
0
7
14 21 28
35 42 49 56 63
Days

23. Bedaquiline for Treatment of MDRTB:
24-72 Week Followup Results
• Only one pt receiving
bedaquiline acquired
drug resistance to
companion drugs vs. 4
receiving placebo

24. Bedaquiline for MDR-TB
• FDA-approved for “combination anti-TB therapy for
adults > 18 y.o. with a diagnosis of pulmonary MDR-TB
when an effective regimen cannot otherwise be
provided”
• Dose: 400 mg daily x 2 weeks, then 200 mg 3x/wk for 22
weeks (with food)
– Metabolized by CYP450 to M2 metabolite (~5 fold less
active against MTB), so not recommended for use with
rifamycins; terminal half-life 5.5 months
• Black box warning – unexplained increase in all-cause
mortality (30/380 [7.9%] vs. 6/205 [2.9%]) and prolongation of
QTc interval

25. CDC Guidance on the Use of
Bedaquiline
• May be used for 24 weeks (with at least 3 other drugs but
avoid rifamycins) in adults with laboratory-confirmed MDRTB when an effective treatment regimen cannot otherwise
be provided
• May be used on a case-by-case basis in children, HIV-infected
persons, pregnant women or those with comorbid conditions
“on concomitant medications” when…
• May be used on a case-by-case basis for longer than 24
weeks when…
• DOT, monitor AEs weekly and sputum culture monthly,
baseline ECG repeated at 2, 12, and 24 wks
MMWR October 2013

26. Simulations of standard and alternative dosing regimens of BDQ evaluated as weekly
exposures (AUC0–168) and maximum concentrations (Cmax) at week 24 of treatment
(representative for a large proportion of the treatment period).
A=standard; B=standard + EFV; C=200 mg/d + EFV; D=400 mg 3x/wk + EFV
Svensson E M et al. Antimicrob. Agents Chemother.
2013;57:2780-2787

27. Delamanid for Treatment of MDR-TB
• Nitro-dihydro-imidazooxazole
– Inhibits mycolic acid synthesis
• 481 pts with MDR
pulmonary TB randomized
to 100 mg BID vs. 200 mg
BID vs. placebo + OBT
• 10 endpoint: Sputum culture
conversion in liquid medium
at 2 mos
• AEs similar in all arms
except QTc prolongation
with delamanid
Gler MT, et al. NEJM 2012

28. Linezolid for Treatment of XDR-TB
• 41 pts with sputum
culture-confirmed
XDR-TB
• Randomized to
immediate vs. delayed
(2 mos) linezolid + OBT
• After 4 mos or sputum
culture conversion
randomized to
continue 300 mg vs.
600 mg linezolid x 18
mos
• Higher rate of culture
conversion immediate
arm; 87% culture
conversion at 6 mos
after adding linezolid
Lee M, et al. NEJM 2012

29. Mean lung log10 CFU counts (±SD) after 1 and 2 months of treatment in experiment 2.
Tasneen R et al. Antimicrob. Agents Chemother.
2011;55:5485-5492

30. Pa-824 Activity
• Nitroimidazo-oxazine
• RCT dose ranging and
EBA in DS pulmonary
TB
– 4 different dose arms
vs RHZE x 14 days
• 10 endpoint mean rate
of decline in sputum
log CFU/ml
• All doses well
tolerated with no AEs
Diacon AH, et al. AAC 2012

31. 14 Day EBA of
Novel Anti-TB Drugs
• TB Rx-naïve pulmonary TB
randomized to:
–
–
–
–
–
–
Bedaquiline (TMC207)
Bedaquiline/PZA
Bedaquiline/Pa-824
Pa-824/PZA
Pa-824/PZA/Moxi
RHZE (standard control)
• PZA increased EBA of
TMC207 and PA-824
• TMC207 and PZA with
other novel drugs may
shorten treatment
Diacon AH, et al. Lancet 2012

32. Oxazolidinones with Other Novel TB
Drugs
• AZD-5847 welltolerated over 14 d
in healthy volunteers
• 21d of sutezolid
(PNU-100480)
combined with its
metabolite PNU1603 and rifampin
reduced MTB
CFU/ml in sputum
and prevented
resistance in vitro
Reele S, et al. ICAAC 2011. Abstract A1-1735; Louie A, et al. ICAAC 2011. Abstract A11737; Wallis R, et al. PLoS One 2012

33. Other Novel TB Drugs
• SQ-109 – ethambutol analogue
– 10 times more active in preclinical studies than
EMB (Nikonenko BV, et al. Antimicrob Agents Chemother 2007;
51:1563-5).
– Dual mechanism of action – blocks cell wall
synthesis and prevents the efflux of companion
drugs from macrophages
– Synergistic with isoniazid, rifampin, and
bedaquiline and has activity against EMB-resistant
strains in vitro (Chen P, et al. J Antimicrob Chemother 2006;
58:332-7).

34. Challenges in New TB Drug
Development
• No “surrogate marker” of treatment response
• Difficulty evaluating individual contribution of
each drug in multidrug regimens
– Prolonged development timelines of single drug
substitution vs. replacing all drugs
• Drug resistance mechanisms not well
characterized
• Drug interactions complex
• The special case of HIV co-infection
– Higher bacillary burden; effect of immunodeficiency
on treatment response; drug interactions with ARVs

35. What About Treatment
Shortening?

36. RIFAQUIN: High Dose Rifapentine +
Moxifloxacin for Shortening TB Treatment
• Randomized controlled multicenter trial (N=876)
– AFB smear positive TB
– 26% HIV-infected but none on ART during trial
Intensive 2 mos
EMRZ
N=275
Continuation 4 mos
6 mos
Moxifloxacin 500 mg
BIW + Rifapentine
900 mg BIW
EMRZ
N=277
Moxifloxacin 500 mg QW +
Rifapentine 1200 mg QW
EHRZ
N=275
Isoniazid +
Rifampicin QD
Follow-up 18 mos
post-randomization
Jindani A, et al., Abstr. 147LB, 20th CROI, 2013

37. RIFAQUIN: High Dose Rifapentine +
Moxifloxacin for Shortening TB Treatment
120
100
80
60
40
20
0
Unfavorable
Favorable
• 4 month regimen
inferior to control
• Similar outcomes
when moxifloxacin
substituted for INH
• All regimens safe and
well-tolerated
• No difference in
outcomes by HIV
status
Jindani A, et al., Abstr. 147LB, 20th CROI, 2013

38. Treatment-Shortening Trials for
Drug-Susceptible TB
• OFLOTUB (data analysis underway)
– Phase 3 RCT of RHZE standard course vs.
– 2 mos RHZ + gatifloxacin then 2 mos RH +
gatifloxacin
• REMox (completion 2Q 2014)
– Phase 3 RCT of RHZE standard course vs.
– 2 mos RHZ + moxifloxacin then 2 mos RH +
moxifloxacin (replacing ethambutol)
– 2 mos RMZE then 2 mos RM (replacing INH)

39. Treatment Shortening Studies for
MDR-TB: “Bangladesh Regimen”
• Observational study from 1997-2007 of 427 previously
untreated MDR-TB pts sequentially assigned to one of
six standardized regimens
– Subsequent cohorts treated with regimens adapted from
the most successful regimens used in previous cohorts
• Most effective regimen: 9 mos of gatifloxacin,
clofazimine, EMB, PZA throughout + initial 4 mos of high
dose INH, prothionamide, kanamycin
– Relapse-free cure rate 87%
– 33 deaths; 41 “defaulted”
– Generally tolerated; GI upset most common AE
Van Duen A, et al. Am J Resp Crit Care Med 2010

40. Treatment Shortening Studies for
MDR-TB: ACTG A5319
• 240 participants with culture-confirmed MDR-TB with or
without HIV co-infection
• RCT 1:1:1:1 to four arms stratified by HIV and EFV-based
ART
– BDQ + Pa824 + Sutezolid (1200 mg/d) + PZA
– BDQ + Pa824 + Sutezolid (600 mg BID) + PZA
– BDQ + Pa824 + Linezolid + PZA
– Local SOC (optimized by DST) for MDR-TB
• Primary endpoints: Safety/tolerability; culture
conversion rates to determine which regimens to move
to Stage 2 (potential treatment shortening)

41. Case Presentation
• Additional history:
– Cousin in Mexico ill with fever, cough; had been
treated for TB twice in the past
• Streptomycin and moxifloxacin added to RHZE
pending DST results which subsequently
demonstrated INH and RIF resistance
• Treated with PZA, EMB, moxi, STM x 18 months
– Six months later CD4 count had increased to ~400;
viral load undetectable on ART
• Household contacts were tested; not infected
with TB or HIV

42. Questions?