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
WHO Report 2013 Global Tuberculosis Control Slide 2 of 46 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
Slide 3 of 46 Global Trends in Estimated Rates of TB Incidence, Prevalence & Mortality-2012
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
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
Slide 8 of 46 Continuous IPT More Effective in TST+ 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 HIV-Infected Patients
Slide 9 of 46 Neither Continuous INH nor 3-mos Rifamycin + INH Superior to 6-mos IPT Martinson NA, et al. NEJM 2011
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
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
Slide 12 of 46 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 (selfadministered) Sterling TR, et al. NEJM 2011
Slide #13 A5259/Study 26: 3 Month Regimen of INH+RPT is Safe and Effective in HIV-Infected Pts 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) Sterling T, et al. Abstr. 817; 21 st CROI 2014 9H MITT (N=193) Treatment completion 89% 3HP vs 64% 9H 3P MITT (N=206) 9H PP (N=123) # TB Cases 6 2 2 1 3P PP (N=183) 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)
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
Slide 15 of 46 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
Slide 16 of 46 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
Slide 17 of 46 Why Do We Need New TB Drugs? Drug-Resistant TB Challenges of current therapy Prolonged duration/multiple drugs Cost Compromises adherence, treatment completion Tolerability, toxicities and drug interactions 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
Slide 18 of 46 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
Slide 19 of 46 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
Slide 20 of 42 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
Slide 21 of 42 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
Slide 22 of 46 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
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 1 0 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 Slide 23 of 46
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 Slide 24 of 46 Diacon AH, et al. Lancet 2012
Slide 25 of 46 Oxazolidinones With Other Novel TB AZD-5847 welltolerated 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 Drugs 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
Slide 26 of 46 What About Treatment Shortening?
Slide 27 of 46 RIFAQUIN: High-Dose Rifapentine + Moxifloxacin for Shortening TB Treatment Randomized controlled multicenter trial (N=876) F/U 18 mos postrandomization Intensive 2 mos Continuation 4 mos 6 mos 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 120 100 80 60 40 20 0 Control 4-mo regimen 6-mo regimen Unfavo rable Favora ble 4-month regimen inferior to control; no difference by HIV status Jindani A, et al., Abstr. 147LB, 20 th CROI, 2013
Slide 28 of 42 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