new drugs and novel approaches to treatment shortening for drug-susceptible and drug-resistant tb
DESCRIPTION
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 DiegoTRANSCRIPT
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.
AIDS CLINICAL ROUNDS
Slide 1
New Drugs and Novel Approaches to Treatment Shortening for Drug-
Susceptible and Drug-Resistant TB
Constance A. Benson, M.D. Professor of Medicine
Division of Infectious Diseases University of California, San Diego
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
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 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
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
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
Case Presentation • Hospitalized in respiratory isolation
• Started on rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) and trimethoprim-sulfamethoxazole 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
Case Presentation
• Stable on RHZE and trimethoprim-sulfamethoxazole 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
Reported TB Cases United States, 1982–2012*
*Updated as of June 10, 2013.
0
5,000
10,000
15,000
20,000
25,000
30,000
No.
of C
ases
Year
Foreign born (63%) in 2012; Mexico, Philippines, India, Vietnam, China, Guatemala, Haiti account for 61% of total
9,945 new TB cases in 2012; 3.2/100,000 (San Diego 234 new TB cases; 7.4/100,000)
TB Case Rates,* United States, 2012
*Cases per 100,000.
< 3.2 (2012 national average)
>3.2
D.C.
Estimated HIV Coinfection in Persons Reported with TB, United States, 1993 – 2012*
*Updated as of June 10, 2013
Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group
% C
oin
fect
ion
0
10
20
30
40
50
60
70
Aged 25-44 All Ages
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
Primary MDR TB, United States, 1993 – 2012*
*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.
No. of Cases Percentage
0
1
2
3
0
100
200
300
400
500
No. of Cases Percentage
XDR TB Case Count Defined on Initial DST* by Year, 1993 – 2012**
* 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
Cas
e C
ou
nt
Year of Diagnosis
0
2
4
6
8
10
12
• Isoniazid (INH) • Rifamycins
– Rifampin (RIF) – Rifabutin (RBT) – Rifapentine
(RPT)* • Pyrazinamide (PZA) • Ethambutol (EMB)
First-Line Drugs Second-Line Drugs
Current Antituberculous Drugs
• Streptomycin (injectable) • Amikacin, kanamycin (injectable) • Capreomycin (injectable) • Levofloxacin, moxifloxacin
(fluoroquinolones) • Cycloserine • p-Aminosalicylic acid (PAS) • Ethionamide • Linezolid • Bedaquiline, delamanid†
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
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
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
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
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)
Slide 21
Bedaquiline for Treatment of Multidrug-Resistant TB
TMC207 (Bedaquiline) is a diarylquinoline
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
Diacon AH, et al. NEJM 2009; 360:2397-405
0.0
0.2
0.4
0.6
0.8
1.0
0 7 42
Prop
orio
n Cul
ture
-Pos
itive
Pat
ient
s
14 21 28 35 49 56 63
TMC207
Placebo
Days
52.5%
91.3%
P = .003
Week 8 interim analysis
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
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
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 MDR-TB 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
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).
Svensson E M et al. Antimicrob. Agents Chemother. 2013;57:2780-2787
A=standard; B=standard + EFV; C=200 mg/d + EFV; D=400 mg 3x/wk + EFV
Delamanid for Treatment of MDR-TB • Nitro-dihydro-imidazo-
oxazole – 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
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
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
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
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
Oxazolidinones with Other Novel TB Drugs
• AZD-5847 well-tolerated over 14 d in healthy volunteers
• 21d of sutezolid (PNU-100480) combined with its metabolite PNU-1603 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 A1-1737; Wallis R, et al. PLoS One 2012
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).
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
What About Treatment Shortening?
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
Jindani A, et al., Abstr. 147LB, 20th CROI, 2013
EMRZ N=275
EMRZ N=277
EHRZ N=275
Moxifloxacin 500 mg BIW + Rifapentine
900 mg BIW Moxifloxacin 500 mg QW + Rifapentine 1200 mg QW
Isoniazid + Rifampicin QD
Intensive 2 mos Continuation 4 mos 6 mos
Follow-up 18 mos post-randomization
0
20
40
60
80
100
120
UnfavorableFavorable
• 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
RIFAQUIN: High Dose Rifapentine + Moxifloxacin for Shortening TB Treatment
Jindani A, et al., Abstr. 147LB, 20th CROI, 2013
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)
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
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)
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
Questions?