AIDS CLINICAL ROUNDS
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinic...
Slide 1

New Drugs and Novel Approaches to
Treatment Shortening for DrugSusceptible and Drug-Resistant TB
Constance A. Ben...
WHO Report 2013
Global Tuberculosis Control
Worldwide, 8.6 million new
incident cases of TB in 2012;
1.3 million TB deaths...
Global Trends in Estimated Rates of TB
Incidence, Prevalence & Mortality-2012
Case Presentation
• 28 y.o. W presents with a 3 week h/o fevers,
night sweats, non-productive cough, dyspnea, 15
lb weight...
Case Presentation
• On exam she is a WNWD woman, ill-appearing
– T 39oC, P 106, tachypneic, bronchial breath sounds
right ...
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 ...
Case Presentation
• Hospitalized in respiratory isolation
• Started on rifampin, isoniazid, pyrazinamide,
and ethambutol (...
Case Presentation
• Stable on RHZE and trimethoprimsulfamethoxazole x 2 weeks with clinical
improvement
• Based on low CD4...
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...
TB Case Rates,* United States, 2012

D.C.

< 3.2 (2012 national average)
>3.2
*Cases per 100,000.
Estimated HIV Coinfection in Persons
Reported with TB, United States, 1993 – 2012*
70

% Coinfection

60
50
40
30
20
10
0
...
WHO Global Tuberculosis Report 2013
Drug Resistance
Globally, 3.6% of new
and 20.2% of
previously treated
cases were MDR-T...
No. of Cases

Primary MDR TB,
United States, 1993 – 2012*

500

Percentage

3

400
2

300
200

1

100
0

0
No. of Cases

P...
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 su...
Current Antituberculous Drugs
First-Line Drugs
• Isoniazid (INH)
• Rifamycins
– Rifampin (RIF)
– Rifabutin (RBT)
– Rifapen...
Initial Treatment of Drug Susceptible
Tuberculosis
• Intensive phase

– INH, RIF, PZA, EMB daily x 2 months (56 doses)
– T...
Management of MDR-TB and XDR-TB
• Drug susceptibility for second line agents
• Primary (need treatment history from index ...
Treatment Outcomes for MDR-TB
• Overall cure rate for ~34,000 MDR-TB globally
~40-60%; highest for the Americas and
Easter...
Why Do We Need New TB Drugs?
• Drug Resistant TB
• Challenges of current therapy
– Prolonged duration/multiple drugs
• Com...
New Drugs and Classes in the
Pipeline for TB Treatment
• Bedaquiline (TMC-207): diarylquinoline; inhibits
mycobacterial AT...
Slide 21

Bedaquiline for Treatment of MultidrugResistant TB

 Phase 2b RCT in 47
patients with newly
diagnosed MDR-TB
ra...
Bedaquiline for Treatment of MDRTB:
24-72 Week Followup Results
• Only one pt receiving
bedaquiline acquired
drug resistan...
Bedaquiline for MDR-TB
• FDA-approved for “combination anti-TB therapy for
adults > 18 y.o. with a diagnosis of pulmonary ...
CDC Guidance on the Use of
Bedaquiline
• May be used for 24 weeks (with at least 3 other drugs but
avoid rifamycins) in ad...
Simulations of standard and alternative dosing regimens of BDQ evaluated as weekly
exposures (AUC0–168) and maximum concen...
Delamanid for Treatment of MDR-TB
• Nitro-dihydro-imidazooxazole
– Inhibits mycolic acid synthesis

• 481 pts with MDR
pul...
Linezolid for Treatment of XDR-TB
• 41 pts with sputum
culture-confirmed
XDR-TB
• Randomized to
immediate vs. delayed
(2 m...
Mean lung log10 CFU counts (±SD) after 1 and 2 months of treatment in experiment 2.

Tasneen R et al. Antimicrob. Agents C...
Pa-824 Activity
• Nitroimidazo-oxazine
• RCT dose ranging and
EBA in DS pulmonary
TB
– 4 different dose arms
vs RHZE x 14 ...
14 Day EBA of
Novel Anti-TB Drugs
• TB Rx-naïve pulmonary TB
randomized to:
–
–
–
–
–
–

Bedaquiline (TMC207)
Bedaquiline/...
Oxazolidinones with Other Novel TB
Drugs

• AZD-5847 welltolerated over 14 d
in healthy volunteers
• 21d of sutezolid
(PNU...
Other Novel TB Drugs
• SQ-109 – ethambutol analogue
– 10 times more active in preclinical studies than
EMB (Nikonenko BV, ...
Challenges in New TB Drug
Development
• No “surrogate marker” of treatment response
• Difficulty evaluating individual con...
What About Treatment
Shortening?
RIFAQUIN: High Dose Rifapentine +
Moxifloxacin for Shortening TB Treatment
• Randomized controlled multicenter trial (N=87...
RIFAQUIN: High Dose Rifapentine +
Moxifloxacin for Shortening TB Treatment
120
100
80
60
40
20
0

Unfavorable
Favorable

•...
Treatment-Shortening Trials for
Drug-Susceptible TB
• OFLOTUB (data analysis underway)
– Phase 3 RCT of RHZE standard cour...
Treatment Shortening Studies for
MDR-TB: “Bangladesh Regimen”
• Observational study from 1997-2007 of 427 previously
untre...
Treatment Shortening Studies for
MDR-TB: ACTG A5319
• 240 participants with culture-confirmed MDR-TB with or
without HIV c...
Case Presentation
• Additional history:
– Cousin in Mexico ill with fever, cough; had been
treated for TB twice in the pas...
Questions?
Upcoming SlideShare
Loading in …5
×

New Drugs and Novel Approaches to Treatment Shortening for Drug-Susceptible and Drug-Resistant TB

2,108 views

Published on

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

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,108
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
75
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

New Drugs and Novel Approaches to Treatment Shortening for Drug-Susceptible and Drug-Resistant TB

  1. 1. AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
  2. 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. 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. 4. Global Trends in Estimated Rates of TB Incidence, Prevalence & Mortality-2012
  5. 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. 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. 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. 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. 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. 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. 11. TB Case Rates,* United States, 2012 D.C. < 3.2 (2012 national average) >3.2 *Cases per 100,000.
  12. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 35. What About Treatment Shortening?
  36. 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. 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. 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. 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. 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. 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. 42. Questions?

×