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“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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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

The Impact of ART on TB Incidence

UNAIDS Report on the Global AIDS Epidemic; 2010

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)

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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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

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

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

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