“Hot” Issues in Tuberculosis: Treatment of Latent TB...
Transcript of “Hot” Issues in Tuberculosis: Treatment of Latent TB...
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Slide 1
“Hot” Issues in Tuberculosis: Treatment of Latent TB Infection and
New TB Drugs
Constance A. Benson, M.D. Professor of Medicine
Division of Infectious Diseases University of California, San Diego
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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
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Global Trends in Estimated Rates of TB Incidence, Prevalence & Mortality-2012
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Slide #4
HIV Treatment as TB Prevention • CIPRA HT001: Starting
ART between 200-350 vs. < 200 reduced TB by 50%
• HPTN 052: Early ART in HIV+ patient with CD4 ≥ 350 led to a 47% reduction in risk of TB
Severe P, et al. NEJM 2010, Grinstein B, et al. 6th IAS MOAX0105, 2011
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The Impact of ART on TB Incidence
UNAIDS Report on the Global AIDS Epidemic; 2010
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Risk of Developing Active TB • Latent TB Infection (LTBI)
– Any positive test for LTBI (TST or IGRA) in a person with no clinical, laboratory or radiographic evidence of active TB
• Risk of active TB in immunocompetent adults: – 12.9 per 1,000 person-years (~10% lifetime risk)
• Risk in HIV-infected individuals: – After index exposure: 30-40% within 6 months – Risk of reactivation TB in persons with LTBI
• 35-162 per 1,000 person-years (3%-16% per year)
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Treatment of Latent TB Infection in HIV Infected Persons
• Review of 12 RCTs of TB preventive therapy in HIV (N=8,578; any anti-TB drugs vs placebo)
– 32% ↓ in incidence of active TB (RR 0.68; 95% CI 0.54-0.85); 62% ↓ for TST+ pts (RR 0.38; 95% CI 0.25-0.57)
– Reduced mortality: • INH alone vs. placebo in TST+ (RR 0.74, 95% CI 0.55-1.00)
• INH+RIF vs. placebo regardless of TST (RR 0.69, 95% CI 0.50-0.95)
– Efficacy similar for all regimens; effect wanes over time
Akolo C, et al. The Cochrane Collaboration; 2010
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Continuous IPT More Effective in TST+ HIV-Infected Patients
• Botusa Trial – Botswana – 6 mos INH for all then
randomized to 30 mos continued INH vs placebo
– 34 (3.4%) incident TB in controls vs 20 (2.0%) on continued INH (1.26 vs. 0.72 per year; HR 0.57% [95% CI 0.33-0.99])
– HR 0.26 for TST+ – TB incidence ↓ by 50% in
those on ART – TB incidence ↑ within 200d
after stopping INH
Samandari T, et al. Lancet 2011
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Neither Continuous INH nor 3-mos Rifamycin + INH Superior to 6-mos IPT
Martinson NA, et al. NEJM 2011
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Slide #10
Mass screening and 9 months IPT had no significant effect on TB control in SA gold
miners • Cluster randomized trial among 78,744 miners with 7
control and 8 intervention clusters (Churchyard GJ, et al. NEJM 2014)
– Outcome influenced by post-treatment reinfection; ongoing
risk due to HIV, silicosis, other factors; failure to rapidly find and treat active TB or to clear LTBI
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WHO Guidelines for TB Prevention in Resource-Limited Settings
• HIV-infected adults and adolescents should be screened for TB; those without current cough, fever, weight loss or night sweats should be offered IPT
• Those with unknown or +TST and unlikely to have TB should receive 6 months of IPT irrespective of degree of immunosuppression, including those on ART, with previous TB Rx, or pregnancy (strong recommendation; high quality of evidence) – OR 36 months of IPT (conditional recommendations;
moderate quality of evidence)
WHO, 2010
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Rifapentine + INH for 3 mos as Effective as 9 mos INH with Higher Completion Rates
Randomized, open-label study: – Once weekly rifapentine +
INH x 12 weeks (DOT) – Daily INH x 9 months (self-
administered)
Sterling TR, et al. NEJM 2011
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A5259/Study 26: 3 Month Regimen of INH+RPT is Safe and Effective in HIV-Infected Pts
9H MITT (N=193)
3P MITT (N=206)
9H PP (N=123)
3P PP (N=183)
# TB Cases 6 2 2 1
TB rate/100 pt-yrs 1.25 0.39 0.63 0.21
Cumulative TB rate 3.50 1.01 1.81 0.56
Δ Cumulative TB rate by arm -2.49 (upper 95% CI 0.60) -1.25 (upper 95% CI 1.47)
• Phase 3, open-label, RCT • HIV-infected pts > 2 y.o. • TST + or close contact TB • Randomized to:
• 9 mos INH (SA) • 3 mos INH/RPT (DOT)
Treatment completion 89% 3HP vs 64% 9H
Sterling T, et al. Abstr. 817; 21st CROI 2014
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ACTG A5279 • Prospective, multicenter, randomized trial • Study design
– N=3,000 HIV-infected patients • +TST/+IGRA or reside in high endemic area
– Randomized 1:1 to daily RPT (10 mg/kg) + INH 300 mg x 4 weeks or daily INH 300 mg x 9 months
– EFV ART allowed – Followed for 3 years after last patient enrolled
• Primary Endpoint = Time to first diagnosis of TB – Secondary Endpoints: Safety, tolerability, survival,
adherence, MTB resistance, EFV and NVP PK
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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
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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
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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
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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 extended spectrum fluoroquinolones
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Bedaquiline for Treatment of MDR-TB: 24-72 Week Follow-up Results
• C208 (N=66 in each arm mITT) median time to culture conversion in liquid medium 83d for Bedaquiline + OBT vs 125d for placebo + OBT
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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” – May be used on a case-by-case basis in children, HIV-infected
persons, pregnant women or those with comorbid conditions “on concomitant medications”
• Dose: 400 mg daily x 2 weeks, then 200 mg 3x/wk for 22 weeks (with food); terminal half-life 5.5 months – Metabolized by CYP450 to M2/M3 metabolite (~5-fold less active
against MTB), so not recommended for use with rifamycins
• Black box warning – unexplained increase in all-cause mortality (30/380 [7.9%] vs. 6/205 [2.9%]) and prolongation of QTc interval; monitor ECG at baseline, 2, 12, 24 weeks
MMWR October 2013
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WHO Interim Recommendations for Use of Bedaquiline
• Bedaquiline may be added to a WHO-recommended regimen in adults with pulmonary MDR-TB when an “effective regimen of 4 second-line drugs plus PZA cannot be designed.” – Documented evidence of fluoroquinolone resistance
– Should be used with caution in patients with HIV and/or other co-morbid conditions, alcohol or substance use
– Baseline testing and monitoring for QT prolongation; clinical monitoring and management of comorbidities; adverse drug reaction reporting and pharmacovigilance
– Assessment and monitoring for BDQ resistance, resistance to other anti-TB drugs
WHO Interim Policy Guidance, 2013
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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
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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 end point: 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
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14 Day EBA of Novel Anti-TB Drugs • TB Rx-naïve pulmonary TB
randomized to: – Bedaquiline (TMC-207) – Bedaquiline/PZA – Bedaquiline/PA-824 – PA-824/PZA – PA-824/PZA/Moxi – RHZE (standard control)
• PZA increased EBA of TMC-207 and PA-824
• TMC-207 and PZA with other novel drugs may shorten treatment Diacon AH, et al. Lancet 2012
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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
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What About Treatment Shortening?
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RIFAQUIN: High-Dose Rifapentine + Moxifloxacin for Shortening TB Treatment • Randomized controlled
multicenter trial (N=876) – F/U 18 mos post-
randomization
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
4-month regimen inferior to control; no difference by HIV status
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Treatment-Shortening Trials for Drug-Susceptible TB
• OFLOTUB (final data analysis underway)
– Phase 3 RCT of standard RHZE vs. 4 month regimen of RHZ + gatifloxacin x 2 mos then RH + gatifloxacin x 2 mos
– “Failed to show that 4-mos gatifloxacin regimen was non-inferior to 6-mos control”
• REMox (completion 2Q 2014)
– Phase 3 RCT of standard RHZE vs. – 4 month regimen of RHZ + moxifloxacin x 2 mos then RH
+ moxi x 2 mos vs. – 4 month regimen of RZE + moxi x 2 mos then R + moxi x 2
mos
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Summary • TB incidence, prevalence and mortality declining
globally; those with HIV infection remain at increased risk but benefit from early ART
• 6-month and 36-month IPT and alternative short course regimens effective; uptake remains low in RLS – Durability of protection of concern, especially in high TB
endemic areas • Ongoing need for new TB drugs, especially for MDR
and XDR TB – Bedaquiline available but must be used with caution,
careful monitoring – New drugs and drug classes in clinical trials with the
promise of treatment shortening not yet realized